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Blinded, bias-controlled multi-rater evaluation of human-versus-AI brain metastasis segmentation using a hybrid foundation-model framework.

Han Y et al. · Jul 1, 2026

Background Accurate segmentation of brain metastases (BM) is essential for diagnosis, stereotactic radiosurgery planning, and longitudinal assessment. However, manual contouring is time-intensive, limiting clinical scalability, and exhibits substantial inter-observer variability. This variability complicates objective assessment of automated segmentation methods and challenges interpretation of model performance. Purpose To address these limitations, we developed TUM-SAM, a hybrid foundation-model framework for fully automated BM segmentation, and introduced a bias-controlled, blinded multi-rater evaluation paradigm to determine whether AI-based BM segmentation has reached expert-level performance and whether AI-generated contours are preferred by human experts under unbiased assessment. Methods TUM-SAM integrates nnU-Net-based lesion detection with a tumor-adapted Med-SAM segmentation model to enable prompt-free, fully automated segmentation. Training used 301 patients (2548 lesions), and external evaluation used an independent cohort of 105 patients (397 lesions). Segmentation accuracy was benchmarked against DeepMedic and nnU-Net using Dice similarity coefficient (DSC) and 95th-percentile Hausdorff distance (HD95). Two physicians contoured all external cases, and a third physician contoured a 20-patient subset for a blinded, tumor-level, multi-rater preference study. Pairwise contour preferences were analyzed using a Bradley-Terry probabilistic model to obtain bias-adjusted estimates of relative contour quality while accounting for rater-specific tendencies and case difficulty. Results In the external cohort, TUM-SAM achieved a lesion-wise detection sensitivity of 0.94 and outperformed DeepMedic and nnU-Net across all tumor sizes, with a mean DSC of 0.84 and HD95 of 1.9 mm (nnU-Net/DeepMedic: DSC   3.3 mm). Across voxel-wise evaluation, TUM-SAM's geometric performance fell within the range of inter-observer variability among physicians and was sensitive to reference construction. In contrast, in the blinded rater study, experts preferred TUM-SAM-generated contours over individual physician contours in 81-87% of raw comparisons; Bradley-Terry analysis yielded conservative, bias-corrected win probabilities of 55-56%, indicating consistent preference after adjustment for rater and case difficulty. Conclusion Using a bias-controlled, blinded multi-rater evaluation framework, TUM-SAM demonstrates brain metastasis segmentation quality that is consistently preferred by expert physicians, highlighting the limitations of agreement-based voxel-wise metrics under inter-observer variability. These findings underscore the dependence of conventional evaluation on reference definition and support preference-based assessment as a complementary approach for evaluating AI segmentation quality in BM MRI.

Medicine

Nebivolol Protects the Thoracic and Abdominal Aorta and Their Perivascular Adipose Tissue From the Differential Detrimental Effects of Obesity.

Dourado TMH et al. · Jul 1, 2026

The effects of obesity on the vasculature and perivascular adipose tissue (PVAT) function vary according to the vascular territory. Nebivolol is a third-generation β-blocker that exerts vasculoprotective effects in obesity. The thoracic and abdominal aorta show different responses under physiological conditions, and their PVATs have a distinctive composition and secretory profile. We hypothesized that obesity would affect thoracic and abdominal aortic responsiveness, as well as their PVAT function, differently and that nebivolol would restore obesity-induced vascular and PVAT changes. To test this hypothesis, male Wistar Hannover rats were fed a hypercaloric diet for 14 weeks. Nebivolol (10 mg/kg/day) was administered via gavage during the last 4 weeks. Obesity increased superoxide (O 2 • - ) generation within the thoracic PVAT, but this response did not result in a loss of its anticontractile effect. Vascular hypercontractility was detected in thoracic aortas, which was mediated by the overproduction of NADPH oxidase-derived O 2 • - and reduced nitric oxide (NO) bioavailability. Conversely, obesity induced a pro-contractile phenotype in the PVAT of the abdominal aorta. This response occurred in an endothelium-dependent manner, was ameliorated by tiron, and was accompanied by increased O 2 • - levels. In all cases, nebivolol reversed the effects of obesity. In summary, obesity differentially affects the thoracic and abdominal aorta and their respective PVATs. Nebivolol exerts vasculoprotective effects through antioxidant mechanisms, leading to a reversal of obesity-induced vascular hypercontractility in both aortic segments. The beneficial effects of nebivolol described here could help mitigate cardiovascular complications associated with obesity. Obesity induces PVAT dysfunction. Extending this knowledge, we demonstrated that obesity differentially affects the thoracic and abdominal aorta along with their associated PVATs. This widespread impairment of PVAT function can drive various adverse vascular consequences, including arterial hypertension and aneurysm formation. Critically, peri-aortic PVAT is of particular clinical relevance due to its association with metabolic risk factors and vascular calcification. Nebivolol exerts vasculoprotective effects via antioxidant mechanisms within PVAT, ultimately reversing obesity-induced vascular hypercontractility in both aortic segments. Thus, investigating pharmacological agents that restore PVAT function, as demonstrated here with nebivolol, represents a promising therapeutic strategy to mitigate obesity-related cardiovascular complications.

Medicine

Pulse‑level characterization of low monitor unit deliveries on a modern linear accelerator using a plastic scintillation detector.

White AJ et al. · Jul 1, 2026

Background Variability in low monitor unit (MU) deliveries has been previously documented, but the underlying pulse‑level behavior has not been fully described due to the integrating nature of most conventional detectors. A plastic scintillation detector (PSD) enables direct visualization of MU microstructure by isolating individual linac pulses. Purpose To use a high temporal resolution PSD to characterize pulse‑level MU substructure on a modern linac and quantify how variation in integral pulse magnitude and pulse count influence the reproducibility of low MU and fractional MU deliveries. Methods A Blue Physics Model 11 PSD was used to measure response from individual linac pulses of a Varian TrueBeam operating at energies of 6 MV, 6 MV FFF, 10 MV, and 10 MV FFF. Initial measurements benchmarked reproducibility in pulse count and dose per pulse by delivering 100 MU at a constant dose rate of 400 MU/min. Subsequent measurements focused on low MU cases, delivering 1-3 MU at dose rates of 5-2400 MU/min. Results The dose per pulse is variable during a single pulse train with a measured coefficient of variation (COV) of up to 13.3%. However, the average dose per pulse across multiple deliveries is stable ( Conclusions Time-resolved analysis shows that dose per pulse fluctuations and the limited number of pulses comprising low MU FFF deliveries lead to measurable variability in delivered MU. These findings characterize the pulsed MU substructure on a modern linac, in which each MU is composed of a finite number of discrete radiation pulses, and quantify the achievable precision of fractional MU delivery, which is fundamentally limited by the dose per pulse (∼0.1 MU for TrueBeam FFF beams).

Agricultural and Biological Sciences

Expansion of the Phenotypic and Genotypic Spectrum of MED13L-Associated Neurodevelopmental Disorder: A Case Report and Literature Review.

Wang Z et al. · Jul 1, 2026

Background Pathogenic variants in MED13L, including copy-number changes and sequence variants, cause MED13L syndrome. This rare neurodevelopmental disorder is characterized by global developmental delay, intellectual disability (ID), distinctive facial dysmorphism, hypotonia, and variable congenital heart defects. The phenotypic heterogeneity of MED13L syndrome underscores the significance of genotype-phenotype correlation analysis for improving clinical diagnosis and precise phenotypic characterization of affected individuals. Methods Venous blood samples anticoagulated with EDTA were collected from the patient and family members, followed by whole-exome sequencing analysis and subsequent validation using fluorescent quantitative PCR. Concurrently, a systematic search of the PubMed database was performed to summarize previously reported cases harboring MED13L copy number Variations (CNVs). Results Whole-exome sequencing revealed a de novo heterozygous single-copy duplication of a ~19-kb region within the MED13L gene (exons 8-16) in the proband. The patient presents phenotypic features consistent with MED13L syndrome and represents the first reported case exhibiting cleft lip. A literature review indicates that vision impairment, developmental delay, and congenital heart disease are widely observed phenotypes, while other less frequent manifestations vary between patients with duplications and deletions. Conclusion This study, integrating a case report and a literature review, provides important reference evidence for the clinical genetic counseling of MED13L syndrome.

Biochemistry, Genetics and Molecular Biology

Fix or freeze? Spectral differences arising from tissue preparation in chemical imaging.

Zheng T et al. · Jun 29, 2026

Spectrochemical imaging has emerged as a powerful, label-free modality for visualizing the biochemical composition of tissues based on intrinsic vibrational signatures. Specifically, mid-infrared spectrochemical imaging (MIRSI) is becoming essential for fundamental biomedical research studying disease mechanisms, identifying biomarkers, and guiding drug development. However, the sensitivity of MIRSI to sample preparation protocols and its impact on spectral data interpretation remain poorly characterized. Here, we systematically compared spectral data collected from rat kidney and liver tissues prepared using standard fresh frozen (FF) and formalin-fixed, paraffin-embedded (FFPE) tissue processing methods using quantum cascade laser (QCL)-based MIRSI. We applied frequently used spectral data processing techniques, including uniform manifold approximation and projection (UMAP), correlation matrices, and second-derivative spectral analysis to characterize preparation-induced differences. FF samples preserved a broader range of biochemical signals, retaining the innate chemical composition of tissues, while FFPE tissues showed reduced spectral diversity and absorption signal intensity. Moreover, we observed a consistent spectral band at 1026 cm -1 primarily in FFPE samples, likely arising from fixation-induced chemical modifications and/or structural rearrangements. Our findings demonstrate that tissue preparation substantially alters chemical and morphological information captured by MIRSI, necessitating careful consideration of processing protocols in workflows involving chemical imaging and Artificial Intelligence (AI)-based spectral analysis.

Biochemistry, Genetics and Molecular Biology

Pharmacovigilance Signal Detection and Mutually Exclusive Driver Mutations of the PI3K/AKT Pathway in Breast Cancer Treated With Capivasertib.

Luo Z et al. · Jun 25, 2026

Background and objective This study is aimed at comprehensively evaluating the real-world safety profile and underlying molecular mechanisms of the AKT inhibitor capivasertib by integrating pharmacovigilance data, computational biology, and multiomics analyses. Methods Adverse event (AE) reports from the FAERS database were analyzed using disproportionality algorithms (ROR, PRR, BCPNN, EBGM) to detect significant safety signals. To elucidate potential toxicological mechanisms, we employed network toxicology and molecular docking, further validated by 100 ns molecular dynamics (MD) simulations. Additionally, bulk genomic cohorts (e.g., TCGA, METABRIC) and single-cell RNA sequencing (scRNA-seq) datasets were utilized to assess mutation patterns and delineate key targets within the tumor microenvironment (TME). Results Analysis of 22,143 AE reports yielded 133 significant safety signals, predominantly involving metabolism (e.g., hyperglycemia), the gastrointestinal system (e.g., nausea, stomatitis), and dermatological conditions (e.g., rash). Pathway enrichment highlighted the PI3K-AKT, HIF-1, and EGFR signaling networks. Integrative analyses identified critical toxicity-related modulators, notably AKT1, IGF1, PTEN, TP53, and GSK3B. Crucially, MD simulations robustly confirmed the thermodynamic stability of the capivasertib-GSK3B complex. Genomic profiling revealed pronounced mutual exclusivity among PIK3CA, AKT1, and PTEN alterations. Furthermore, scRNA-seq analysis demonstrated that GSK3B overexpression defines a highly aggressive, proliferative malignant subpopulation that profoundly reshapes intercellular communication with stromal fibroblasts. Conclusion By seamlessly bridging real-world pharmacovigilance with advanced structural biology and single-cell transcriptomics, this study delineates the comprehensive safety landscape of capivasertib. Our findings provide crucial clinical alerts for AE monitoring and offer deep mechanistic insights to optimize personalized therapeutic management in breast cancer.

Medicine

Severe Pediatric Snakebite With Coagulopathy and Compartment Syndrome: Conservative Management With Plasma Exchange.

Al Muqbel ZM et al. · Jun 25, 2026

Snakebite envenomation is a global public health concern, and hemotoxic bites can lead to severe coagulopathy, microangiopathic hemolytic anemia, and compartment syndrome. We describe a previously healthy 6-year-old boy who presented with progressive left lower limb swelling, discoloration, and bleeding from intravenous cannula sites following a snakebite sustained in rural Pakistan, consistent with severe hemotoxic envenomation. Despite antivenom and transfusion support, he developed persistent venom-induced consumption coagulopathy with hypofibrinogenemia, markedly prolonged clotting times, thrombocytopenia, and features of microangiopathic hemolytic anemia. Severe limb swelling raised concern for compartment syndrome; however, fasciotomy was deferred due to the high risk of bleeding in the setting of uncontrolled coagulopathy. Transferred to Bahrain, he underwent five sessions of therapeutic plasma exchange, initiated due to ongoing clinical and laboratory deterioration, resulting in stabilization of hematologic parameters, resolution of limb swelling, and preservation of limb function. This case highlights the role of plasma exchange in children unresponsive to conventional therapy and demonstrates that conservative management of suspected compartment syndrome may be feasible when surgical intervention carries significant risk, underscoring the importance of early recognition and multidisciplinary care in complex pediatric envenomation.

Biochemistry, Genetics and Molecular Biology

Lymphatic Embolization for Lymphatic Leakage After Pelvic Lymph Node Dissection: Case Report.

Oshima R et al. · Jun 25, 2026

Introduction Radical cystectomy with pelvic lymph node dissection for muscle-invasive bladder cancer may be complicated by postoperative lymphatic leakage when high-output drainage persists despite conservative management. We describe treatment of diffuse lymphoascites after pelvic lymph node dissection using upstream lymphatic embolization. Case presentation A man in his 70s developed lymphatic leakage with drainage > 1000 mL/day after radical cystectomy and pelvic lymph node dissection. Lymphoscintigraphy showed bilateral iliac leakage with diffuse intraperitoneal spread, making local sclerotherapy unsuitable. Intranodal lymphangiography via bilateral inguinal nodes identified iliac lymphatic duct leaks. Upstream embolization with a N-butyl cyanoacrylate-ethiodized oil mixture through multiple inguinal nodes rapidly reduced drainage, allowing drain removal by day 4 and discharge by day 10 without persistent lymphedema. Conclusion Upstream lymphatic embolization is a minimally invasive option for refractory high-output lymphatic leakage after pelvic lymph node dissection.

Medicine

RETRACTED: Ferlazzo et al. A Flavonoid-Rich Extract from Bergamot Juice, Alone or in Association with Curcumin and Resveratrol, Shows Protective Effects in a Murine Model of Cadmium-Induced Testicular Injury. Pharmaceuticals 2021, 14, 386.

Ferlazzo N et al. · Jun 25, 2026

The journal retracts the article titled, "A Flavonoid-Rich Extract from Bergamot Juice, Alone or in Association with Curcumin and Resveratrol, Shows Protective Effects in a Murine Model of Cadmium-Induced Testicular Injury" [...].

Environmental Science