Bilious vomiting in infants is recognized as a sign of potential surgical pathology, and these infants often require retrieval from the peripheral hospital to a surgical center for specialist investigation. We set out to show the frequency of surgical pathology, time-critical pathology, and cardiorespiratory deterioration during retrieval among infants with bilious vomiting. In addition, we aimed to show whether there is an association between the need for cardiorespiratory support at the time of referral and time-critical pathology or cardiorespiratory deterioration during the retrieval. We completed a retrospective observational study of 104 infants younger than 44 weeks' corrected gestational age retrieved for bilious vomiting or aspirates over a 103-month period identified from the electronic retrieval record database of an Australian retrieval service. Of the infants included in the study, 21 (20.19%) had a surgical pathology, 6 (5.77%) had a time-critical pathology, and 10 (9.62%) experienced a cardiorespiratory deterioration during the retrieval. Infants receiving cardiorespiratory support at the time of referral were more likely to have a time-critical pathology (risk difference [RD], 24.45%; 95% confidence interval [CI], 3.23-60.07; risk ratio [RR], 6.93; 95% CI, 1.52-31.5) and more likely to experience a cardiorespiratory deterioration (RD, 50.95%; 95% CI, 18.17-78.19; RR, 9.24; 95% CI, 3.38-25.27). Our findings can help the retrieval service plan their response to referrals for infants with bilious vomiting. Awareness of the frequency of time-critical pathology and of deterioration during retrieval and the increased risk of both among those requiring cardiorespiratory support at the time of referral could inform the timing of response and team composition.
Despite recent advances in medical informatics, extracting tumor information from pathology reports remains a challenge in modern cancer registry and surveillance workflows. These documents often have an unstructured format, complex medical content, and a considerably lengthy context, creating significant challenges for automated phenotypic information extraction. Although some recent language models such as BERT, GatorTron, and GPT-4 have demonstrated efficacy in medical applications, they are either constrained by sequence length limitations or cloud-based computing that violates the handling of protected health information. We introduce two oncology pathology-optimized transformer models OncoPT, based on Longformer and BigBird architectures and trained on real-world pathology reports. OncoPT efficiently processes reports up to 4,096 tokens, making it suitable for hospitals' onsite deployment with limited resources. We apply OncoPT to a common malignancy (exemplified by breast cancer) and a rare malignancy (exemplified by gastric cancer), across five key tumor phenotypes: Subsite, Histology, Grade, Stage, and Laterality. The results demonstrate that OncoPT achieves state-of-the-art weighted F-1 on a private pathology dataset and surpasses commercial chatbots (ChatGPT 4o and o1) on the public CORAL dataset (up to 30% improvement). These findings highlight the robustness of OncoPT models with the added benefit of preserving the privacy of patient health information.
Core needle biopsy is the gold standard procedure for sampling tissues for pathology-based diagnostics. However, it produces significant tissue damage and may lead to undue pain and risk of complications such as infections. Alternatives such as fine needle aspiration and liquid biopsy have not yet achieved the same widespread utility owing to the limited abundance of cells and relevant biomarkers in extracted samples. Here we introduce a shock-scattering micro-histotripsy-aided fine needle aspiration technology which uses cavitation to liquefy nano-liter to micro-liter volumes to produce tissue homogenates with both intact and lysed cells. It permits not only conventional cytopathology with high success but sufficient high-quality tissue homogenates to enable reliable ancillary testing such as genetic biomarker profiling and even whole genome sequencing with improved quality compared to formalin-fixed samples. Our approach represents an advance in tissue diagnostics with orders of magnitude less damage than core-needle biopsy procedures.
Dirofilaria repens is a mosquito-borne filarial nematode that causes subcutaneous dirofilariasis in dogs and is closely related to Dirofilaria immitis. Infection with D. immitis can lead to immune-mediated glomerulonephritis characterized by immune complex deposition along the glomerular basement membrane, resulting in proteinuria and renal dysfunction. Reported histopathological changes include membranous glomerulonephritis with potential chronic progression to chronic interstitial nephritis, glomerulosclerosis, and amyloidosis. Despite the close relationship between these two Dirofilaria species, renal clinicopathological changes associated with D. repens infection have been only rarely investigated, and renal ultrastructural and immunofluorescence findings have not been described in naturally infected dogs. The objective of this study was to collect clinicopathological data and evaluate kidneys from dogs naturally infected with D. repens for structural abnormalities using light microscopy (LM), immunofluorescence (IF), and transmission electron microscopy (TEM). Seventy-two shelter dogs from the university neutering program were screened for D. repens infection. Six infected dogs were identified, and renal biopsies were obtained during neutering. Serum urea, creatinine, and SDMA concentrations were measured, and comprehensive urinalysis was performed, including urinary protein-to-creatinine and albumin-to-creatinine ratios. None of the dogs had increased serum creatinine or SDMA; two of six dogs had mildly increased urea. Mean urine specific gravity was 1.029 ± 0.011, and urine sediment was unremarkable in all dogs. Two dogs were borderline proteinuric and one was proteinuric; the mean urine protein-to-creatinine ratio was 0.29 ± 0.15. Microalbuminuria was detected in one case (median: 0.001). Histopathology predominantly demonstrated podocyte injury with variable podocyte foot process effacement, without evidence supporting an immune complex-mediated glomerulopathy. Two dogs had mild focal and segmental glomerulosclerosis (FSGS). IF was available for two dogs and did not support immune complex-mediated disease, in agreement with TEM findings. In this cohort, dogs naturally infected with D. repens showed predominantly mild renal lesions characterized mainly by podocyte injury and, less frequently, focal segmental glomerulosclerosis. These findings differ from the immune-complex-dominant renal pathology commonly described in D. immitis infection and highlight the value of ultrastructural and immunofluorescence assessment for characterizing renal changes associated with D. repens infection.
Placental histopathology provides important insights into maternal and fetal health, yet the organ's spatial heterogeneity poses significant challenges for objective and reproducible histological analysis. Systematic assessment of cellular and structural composition across placental slides remains limited by the scale and subjectivity of manual evaluation. Quantitative approaches are therefore needed to characterise placental responses to injury beyond visually apparent lesions. We applied the Histology Analysis Pipeline.PY (HAPPY), a biologically inspired hierarchical deep learning framework for quantitative single-cell-resolution analysis of Haematoxylin and Eosin (H&E) slides, to 130 placental parenchyma slides from 62 singleton full-term live births. The dataset included healthy normal controls and four common placental lesion types: infarction, perivillous fibrin, avascular villi, and intervillous thrombosis. Cell-type and tissue-structure compositions were quantified, and slide-level deviation from a healthy reference was assessed using compositional data analysis. Placental slides with lesions exhibited significant cellular composition differences compared with healthy controls, including increased extravillous trophoblast and leukocyte densities and decreased Hofbauer cell densities. These cellular changes were accompanied by tissue-level alterations, particularly increased fibrin deposition and changes in villous structure. Compositional deviation increased with infarction size but not with other lesion types. Notably, compositional differences were also detected in slides without an apparent lesion from placentas with lesion(s) elsewhere, indicating organ-wide responses extending beyond focal pathology. Quantitative deep phenotyping reveals widespread cellular and structural changes associated with placental lesions, including effects not evident on routine histological assessment. These findings demonstrate the potential of AI-based digital histology to complement conventional placental pathology in research and clinical settings.
Wild isolates of Toxoplasma gondii may exhibit different virulence characteristics and host adaptability compared with those of laboratory strains. In this study, we isolated a novel rodent-derived T. gondii strain, denoted TgRodGz1, and evaluated its pathogenic features. TgRodGz1 was isolated from T. gondii-positive wild rodents in Guangdong Province and compared with the RH and Me49 strains in C57BL/6 mice. Virulence and intestinal injury were evaluated by survival analysis, brain cyst quantification, histopathology, tight junction assessment and qPCR. Gut microbiota and metabolic alterations were analyzed by metagenomic sequencing and LC-MS/MS-based metabolomics. Compared with theT. gondii laboratory strains RH and Me49, TgRodGz1 was associated with more pronounced intestinal injury, including villus atrophy, barrier disruption and downregulation of tight junction proteins and increased gut permeability and inflammation. Metagenomic analysis revealed significant intestinal flora dysbiosis, with a marked reduction in beneficial bacteria and expansion of pathogenic bacteria. Metabolomic analysis revealed suppression of arachidonic acid (ARA) metabolism during TgRodGz1 infection. Supplementation with ARA did not directly inhibit parasite growth but significantly alleviated intestinal lesions, reduced brain cyst burden and attenuated inflammatory responses, including microglial activation. These findings suggest that TgRodGz1 represents a distinct T. gondii genotype associated with pronounced intestinal pathology and suggest that ARA supplementation may alleviate intestinal and neuroinflammatory changes associated with T. gondii infection.
Tuberculosis (TB) remains a major global health threat, underscoring the need for vaccines that surpass BCG efficacy. We developed QTAP-R, a novel mRNA-lipid nanoparticle (LNP) vaccine encoding Ag85B, Hsp70, and ESAT-6, to enhance immunity against Mycobacterium tuberculosis. QTAP efficiently encapsulated and delivered mRNA with high transfection efficiency and low cytotoxicity. In C57BL/6 mice, QTAP-R induced strong antigen-specific IgG and T-cell responses, including elevated CD4⁺ and CD8⁺ activation and increased polyfunctional cytokines (IFN-γ, TNF-α, IL-2, IL-17A). When combined with BCG (BCG + QTAP-R), the vaccine elicited enhanced immune memory, reduced bacterial burden in lungs and spleen, and minimized lung pathology following M. tuberculosis challenge. Subcutaneous QTAP-R (QTAP-SQ) provided partial protection under high-dose challenge, outperforming intranasal delivery. Transcriptomic profiling revealed upregulation of inflammatory cytokines (IL-1, IL-6, IL-12) and chemokines (CCL3, CCL4, CXCL9, CXCL10), indicating enhanced immune recruitment and activation. CD4⁺ T-cell depletion abolished protection, confirming their critical role in QTAP-R-mediated immunity. Overall, QTAP-R demonstrates potent immunogenicity and synergistic efficacy with BCG, positioning it as a promising mRNA-based TB vaccine candidate.
Photothermal therapy (PTT) holds transformative potential for precision cancer treatment, yet clinical translation remains constrained by the scarcity of molecularly defined, biocompatible, and efficiently NIR-absorbing photothermal agents (PTAs). Here we report a rational donor-acceptor-donor (D-A-D) framework that delivers ultrasmall organic PTAs with record photothermal conversion efficiencies (49.8%) and intrinsic immunogenic cell death (ICD) activity. The design exploits 6,7-diphenyl-[1,2,5]thiadiazolo[3,4-g]quinoxaline as a π-extended, multi-nitrogenated acceptor core flanked by trifluoromethyl groups to deepen the LUMO, while methoxylated triphenylamine donors intensify intramolecular charge-transfer and suppress radiative decay. Nanoprecipitation furnishes monodisperse nanoparticles that exhibit intense NIR-II absorption, exceptional photostability across five hyperthermic cycles, and lysosome-directed uptake. In vitro, single-dose FTPA NPs plus 808-nm laser irradiation trigger mitochondrial depolarization, G0/G1 arrest, and apoptosis in > 70% of 4T1 cells while releasing abundant ATP and surface calreticulin-canonical ICD signals. A prophylactic vaccination model corroborates these molecular cues: mice primed with FTPA-NP-treated tumor cells reject contralateral challenge, achieving > 90% long-term survival, expansion of cytotoxic CD8+ T cells (≈ 70% activation), and suppression of Tregs (≈ 3%). No systemic toxicity or off-target pathology is observed. This study establishes a chemically tunable, metal-free PTA platform that synergizes thermal ablation with systemic anti-tumor immunity, providing a versatile scaffold for next-generation precision immuno-photothermal medicine.
Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, affecting nearly 0.3% of the global population. Its pathology is primarily linked to dopaminergic neuronal loss in the substantia nigra, leading to hallmark motor impairments such as tremor, rigidity, and bradykinesia. A defining molecular feature of PD is the aberrant aggregation of α-synuclein, alongside dysregulation of proteins such as MAO-B, COMT, and LRRK2, which collectively contribute to disease progression. Within the current research, these proteins were designated as docking targets to explore the enzyme-modulating activity and the therapeutic promise of steroidal alkaloid candidates from the genus Fritillaria, a taxon long recognized in traditional medicine for its neuroprotective properties. Docking analyses revealed that among 70 compounds analysed, compound 65 exhibited strong MAO-B inhibitory activity (binding energy - 11 kcal/mol), compound 5 demonstrated pronounced COMT inhibition (- 9 kcal/mol), and compound 42 emerged as a promising dual-acting agent capable of targeting both enzymes. Favorable physicochemical attributes, including optimal lipophilicity, low polar surface area, and blood-brain barrier permeability, further support their suitability. These findings identify preliminary computational leads that warrant further experimental validation for potential future development.
This study investigates the identification of Benign Prostatic Hyperplasia (BPH) through a deep learning-based analysis of RGB prostate histopathological images. Adaptive Contrast Limited Adaptive Histogram Equalization (CLAHE) is selectively applied to the L-channel in the LAB color space to enhance tissue visibility while preserving chromatic fidelity. At the architectural level, Convolutional Neural Networks (CNNs) are integrated with Bidirectional Long Short-Term Memory (BiLSTM) layers, enhanced further through spatial and temporal attention mechanisms. This hybrid design facilitates both localized pattern recognition and the modeling of long-range contextual dependencies across tissue regions. To mitigate class imbalance and prevent overfitting, the training regime incorporates two key strategies: an adaptive focal loss function and a comprehensive image augmentation protocol. The proposed model achieved an AUC of 0.7220 on the validation set and an AUC of 0.73 on the test set. While the precision for normal tissue classification remained high, the recall for BPH detection highlighted the need for improvement in sensitivity. The proposed CNN-BiLSTM-Attention architecture demonstrates potential as a diagnostic aid in digital pathology, offering interpretable insights and forming a foundation for enhancing histological classification systems. Future work will focus on improving recall performance for BPH detection and expanding the architecture to support multi-class prostate disease grading frameworks. This study utilizes an RGB histopathological dataset consisting of 176 prostate images, each appropriately annotated. The model demonstrates moderate classification performance and a moderate true-positive rate for detecting Normal samples. The model, however, has a low sensitivity in the detection of the cases of BPH as indicated by the relatively low recall values.
To compare the effectiveness of injected low- and high-molecular-weight hyaluronic acid (HA-LMW, HA-HMW) vs corticosteroids (CCS), placebo- or physical therapy (PT), on pain at rest (Prest), at night (Pnight), and during activity (Pact), range of motion (ROM), functional status (FS), and quality of life (QoL) in patients with chronic Sp, at 3 (3mo) and 6 months (6mo) follow-up. A systematic literature search was conducted through October 2024 across MEDLINE, Embase, and Cochrane CENTRAL. Fourteen studies were included: 12 randomized controlled trials and 2 prospective cohort studies that compared at least two of the treatments of interest in adults with chronic shoulder pain (Sp). Two reviewers independently extracted data related to the outcomes. A frequentist network meta-analysis with mean differences (MD) and standardized mean differences (SMD) was performed; p<0.05 was statistically significant. PT reduced Prest compared to HA-HMW (MD = -3.02, p<0.01 at 3mo; MD = -2.08, p<0.01 at 6mo) and HA-LMW (MD = -1.95, p<0.01 at 6mo) in tendinopathy. PT showed greater reduction than both HA formulations in Pnight and Pact at 6mo in tendinopathy. No differences were observed between HA-HMW and HA-LMW for pain outcomes considering shoulder different diseases. HA improved adduction and internal rotation at 3mo considering shoulder different disease; PT was superior for flexion and external rotation at 6mo in tendinopathy. Stratified by pathology, HA-HMW showed moderate efficacy in adhesive capsulitis. HA-HMW improved FS compared to HA-LMW at 3mo. CCS improved abduction in shoulder disease due to different causes. PT provides greater pain control for Sptendinopathy, particularly for Prest, Pnight, and Pact at both 3mo and 6mo. HA may contribute to improved QoL and specific ROM parameters. Further high-quality studies are required to consolidate these findings.
Population-based organized prostate-specific antigen (PSA) screening is implemented in 80% of Japanese municipalities; however, Shiga Prefecture remains a unique exception without such a systematic program. This study characterized the longitudinal clinical features and treatment patterns in this opportunistic testing environment using data from 1716 patients diagnosed via prostate biopsy in 2012, 2017, and 2022. While median PSA levels remained stable (10.40-11.43 ng/mL), median age at diagnosis increased from 72 to 74 years. Over the decade, the incidence of International Society of Urological Pathology Grade Group 1 and cT1c stages decreased significantly (p < 0.001), with nearly 90% of cases being cT2 or higher in 2022. Risk classification showed a decrease in low-risk cases and a rise in high-risk cases. Regarding treatment, radical prostatectomy rates remained stable at approximately 25%, whereas the overall use of active surveillance (AS) increased from 1 to 9%. Notably, among low-risk patients, AS adoption rose markedly from 2.3% in 2012 to 68% in 2022. While clinical practices have evolved to successfully minimize unnecessary invasive intervention, these findings suggest that clinical progress alone cannot fully compensate for the lack of organized efforts to improve early detection.
Although contemporary models of obsessive-compulsive disorder (OCD) have primarily emphasized fear, recent accounts suggest that abnormal disgust learning may also contribute to OCD pathology, particularly in contamination-related OCD (C-OCD). The present study examined the neural correlates of disgust learning in individuals with elevated contamination-related obsessive-compulsive symptoms. Event-related potentials (ERPs) were recorded while 28 participants high in contamination-related obsessive-compulsive symptoms (HC) and 30 participants low in such symptoms (LC) completed disgust acquisition and extinction tasks. Behavioral measures included unconditioned stimulus (US) expectancy and conditioned stimulus (CS) disgust ratings, alongside electrophysiological indices of conditioned disgust. During acquisition, the HC group showed higher US expectancy for the CS+ than the LC group. At the neural level, both groups showed larger P3 amplitudes to the CS+ than to the CS-, indicating enhanced attentional significance. However, the HC group exhibited smaller overall P3 amplitudes than the LC group, which may reflect greater avoidance during disgust learning. During extinction, US expectancy differences between the CS+ and CS- remained evident in both groups, whereas P3 differences were no longer observed, suggesting a dissociation between self-reported and neural responses. Overall, these findings indicate that individuals with elevated contamination fear show enhanced disgust acquisition and altered neural processing during disgust learning, which may help clarify how maladaptive disgust responses are formed and maintained in contamination-related OCD.
The adnexal region in females presents complex imaging due to the menstrual cycle. Accurate diagnosis is crucial for effective tumor treatment. This study aims to assess the clinical utility of abnormal adnexal uptake on 68Ga-FAPI PET/CT for early and precise lesion characterization. This study retrospectively analyzed all female patients with abnormal adnexal uptake on 68Ga-FAPI PET/CT at our institution from November 2021 to June 2024. Semiquantitative analysis of PET/CT imaging parameters was performed, combined with serum tumor markers and immunohistochemical markers. Pathological findings or imaging follow-up ≥ 6 months served as the gold standard for evaluating the diagnostic performance of 68Ga-FAPI PET/CT. The study included 121 female patients with a mean age of 53.8 ± 12.2 years (18-80 years). A total of 184 adnexal lesions with abnormal uptake were identified. Pathology/follow-up confirmed 82.6% as malignancies, comprising 84 primary and 16 metastatic cases. Additionally, 2 borderline tumors and 19 benign lesions were detected. The positive predictive value was 83.5%. SUVmax differed significantly among primary malignant, metastatic, and benign lesions (12.52 ± 5.41 vs. 9.78 ± 3.39 vs. 5.52 ± 4.17). In the subset of patients with available pathological specimens, SUVmax showed weak to moderate positive correlations with Ki-67 (r = 0.361, p < 0.001) and p53 (r = 0.419, p < 0.001). Notably, the mean SUVmax in the Ki67 > 20% group was significantly higher than in the Ki67 ≤ 20% group (p < 0.001). ROC analysis showed an AUC of 0.85 of SUVmax alone for diagnosing malignant adnexal lesions, increasing to 0.89 when combined with tumor markers. 68Ga-FAPI PET/CT demonstrates high diagnostic performance for ovarian lesions. Among pathologically confirmed cases, SUVmax correlates with proliferative activity and malignant potential, supporting its role in diagnostic optimization.
The substantial antigenic diversity of Influenza A virus (IAV) presents significant challenges to the development of broadly protective vaccines for swine. Moreover, pigs vaccinated with whole-inactivated virus or hemagglutinin (HA) subunit vaccines may experience more severe lung consolidation than non-vaccinated pigs when exposed to antigenically mismatched IAV strains, a phenomenon known as vaccine-associated enhanced respiratory disease (VAERD). We recently developed a lipid nanoparticle-encapsulated DNA (LNP-DNA) vaccine encoding the HA of IAV, which elicited robust immune responses following a single immunization and protected pigs against homologous IAV challenges. In this study, we compared the immunogenicity and protective efficacy between the HA protein-based vaccine and the HA DNA-based vaccine against an antigenically mismatched IAV strain in pigs. Neither vaccine induced cross-reactive hemagglutination inhibition (HI) antibodies nor prevented viral shedding in nasal secretions following heterologous challenge. However, while the HA protein-based vaccine exacerbated lung lesions compared to non-vaccinated controls, the HA DNA-based vaccine prevented the development of gross lung pathology. Transcriptomic analyses revealed distinct gene expression profiles between the two vaccine groups. These findings suggest that the LNP-DNA vaccine platform may offer a safer and more effective strategy for developing vaccines against IAV in swine.
Duchenne muscular dystrophy (DMD) is a severe X-linked disorder marked by progressive muscle degeneration and regeneration, inflammation and fibrosis. Cellular senescence has emerged as a potential driver of chronic muscle damage, yet its temporal dynamics and therapeutic relevance remain unclear. We analyzed senescent cell burden in skeletal and cardiac muscles of the DBA/2-mdx mouse model, which closely mimics features of human DMD. The senolytic combination of dasatinib and quercetin (D + Q) was administered during early or late disease phases to evaluate the impact of senescent cell clearance. Skeletal muscle strength was measured by grip strength and ex vivo force assays, while cardiac function was assessed by echocardiography. Fibrosis and senescence markers were quantified histologically, and transcriptional changes associated with senolysis were identified using bulk RNA sequencing (RNA-seq). In skeletal muscle, senescent cells appear and peak during early stages of disease progression (3-5 months), coinciding with high degeneration and regeneration activity, and then decline with age as fibrosis increases. In contrast, in the heart, senescent cells emerge at late stages of disease progression (around 12 months), correlating with heart fibrogenesis. Notably, senolytic intervention in the DBA/2-mdx mice promotes a regenerative and antifibrotic gene signature in both tissues. However, the timing of senolytic therapy determines its efficacy: early treatment with D + Q reduces senescent cell burden, decreases fibrosis, and improves fiber size and contractile performance in skeletal muscle, while later treatment reduces cardiac senescence and fibrosis but does not improve skeletal muscle pathology. Cellular senescence is a dynamic and targetable feature in DMD, with tissue- and age-specific patterns. It represents a potential modifiable therapeutic target, and temporally optimized senolytic strategies could serve as effective adjuncts to current and emerging DMD treatments.
High-altitude hypobaric hypoxia induces inflammation and oxidative stress, yet the role of myeloperoxidase (MPO) in this pathology remains incompletely understood. This study aimed to investigate whether MPO mediates injury to the liverspleen axis under hypoxic conditions. Using a 3day murine hypoxia model, we unexpectedly found that MPO deficiency exacerbated, rather than mitigated, damage to the liverspleen axis. Compared with hypoxic wildtype mice, MPO-/- mice displayed aggravated histopathological injury, accompanied by excessive phagocyte recruitment and elevated expression of key chemokines (KC, MCP1, MIP2) and proinflammatory mediators (TNFα, IL1β, IL17A). At the molecular level, MPO absence increased splenic protein expression of NFκB, NLRP3, and iNOS, while dysregulating the antioxidant response via the NRF2/HO1 pathway. These results reveal a novel protective role for MPO during hypoxic stress, where it functions to moderate the innate immune response and limit collateral tissue damage in the liverspleen axis. The study provides new insights into the complex immunomodulatory functions of MPO and suggests its activity is essential for maintaining immune homeostasis during acute hypoxia.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlapping pathology. Mutations in CCNF, encoding the E3 ubiquitin ligase, Cyclin F, can cause ALS, FTD, or both, even within the same family. Most prior studies of CCNFS621G have relied on overexpression systems, potentially confounding outcomes through disruption of endogenous Cyclin F. Here, we generated the first knock-in mouse model of endogenous CcnfS621G using CRISPR/Cas9. Heterozygous and homozygous CcnfS621G mice showed no motor decline or neuronal loss after 18 months, however immunohistochemistry revealed increased hippocampal astrocyte ramification, with sex-, age, and subfield-dependent effects. These data indicate that endogenous CcnfS621G may prime early astrocyte alterations in the absence of overt neurodegeneration. Similar astrocyte morphological changes were observed in canonically affected regions of sporadic ALS and FTD-ALS patients post mortem, as well as in CCNFS621G iPSC-derived astrocytes following inflammatory stimulation. Proteomics on Ccnf mice identified early dysregulation of pathways related to translation, mitochondrial function, cytoskeletal remodelling, synaptic transmission and neuroinflammation. Correspondingly, CCNFS621G iPSC-derived astrocytes displayed impaired mitochondrial membrane potential and altered network morphology under both basal and inflammatory stimuli. As altered neuronal excitability is a hallmark of ALS, we examined astrocyte-driven changes to neuronal excitability. CCNFS621G iPSC-derived motor neurons cultured alone were hyperexcitable, firing more action potentials than isogenic controls. Remarkably, co-culture with CCNFS621G astrocytes, but not isogenic control astrocytes, abolished repetitive firing, increased the proportion of neurons unable to generate action potentials, and reduced voltage-gated sodium currents in CCNFS621G and isogenic control neurons. Together, these findings identify astrocyte alterations as an early feature of CCNFS621G-mediated disease, in the absence of neuronal loss. Moreover, the combination of astrocytic mitochondrial dysfunction and the ability of CCNFS621G astrocytes to suppress repetitive neuronal firing suggests a critical astrocyte-driven non-cell autonomous mechanism that may contribute to an oligogenic role for CCNF in ALS/FTD pathogenesis.
Coccidioidomycosis is a fungal infection endemic to the southwestern United States, particularly Arizona. Fine needle aspiration biopsy (FNAB) is established as effective in diagnosing infectious diseases. However, existing literature evaluating FNAB of thoracic coccidiomycosis remains limited. We present a large single institution series of thoracic coccidioidomycosis cases diagnosed through FNAB. The Mayo Clinic Arizona Pathology database was searched for all FNAB cases with a diagnosis of coccidioidomycosis from January 1, 2013, to December 31, 2025. Electronic medical records were reviewed to tabulate demographics, clinical history, serology, and radiologic findings. All key cytologic, histologic, and special stained slides were reviewed. One-hundred and one FNAB samples were obtained from 100 patients: 37 cases combined endobronchial ultrasound-guided transbronchial needle aspirate (EBUS-TBNA) and robotic-assisted bronchoscopy (RAB), 31 cases RAB, 20 cases EBUS-TBNA, 12 cases percutaneous computed tomography-guided, 1 case endoscopic ultrasound-guided. Coccidioides organisms were identified during rapid on-site evaluation in 34 cases, saving 18 patients from unnecessary procedures. Coccidioides organisms were identified in 94.1% (95/104) of cytology slides and in 67.1% and 66.7% of tissue biopsies and cell blocks, respectively. For the 6 cases without Coccidioides organisms on cytology slides, concurrent tissue biopsies or cell blocks with or without Grocott's methenamine silver stains helped confirm the diagnosis. Of the 41 patients with a malignancy history, one had both Coccidioides and malignancy in the same specimen. FNAB is accurate at diagnosing thoracic coccidioidomycosis when combined with EBUS-TBNA and RAB. Rapid on-site evaluation is critical during interventional procedures and can eliminate the need for unnecessary procedures.
Adult intussusception is an uncommon clinical condition, representing a rare cause of intestinal obstruction. Unlike the pediatric form, most adult cases are secondary to an identifiable pathological lead point. Idiopathic intussusception, particularly involving the small bowel, is exceedingly rare and poses diagnostic and therapeutic challenges. We report the case of a 42-year-old woman with no prior abdominal surgery who presented with a three-day history of abdominal pain, vomiting, and cessation of stool and flatus. Physical examination revealed mild abdominal distension without peritoneal signs. Abdominal computed tomography demonstrated a jejuno-jejunal intussusception with the classic "target" configuration and no detectable underlying lesion. The patient underwent an exploratory laparotomy, which confirmed a jejuno-jejunal intussusception without any pathological lead point. Gentle manual reduction was performed, and no resection was required. The postoperative course was uneventful, and the patient was discharged on postoperative day three. Adult idiopathic intussusception is rare, accounting for a small minority of adult intussusception cases. CT imaging is the cornerstone of diagnosis, enabling visualization of characteristic features and assessment of complications. Surgical exploration remains the standard of care, with management tailored to intraoperative findings. Reduction without resection is justified when the bowel is viable, and no underlying pathology is evident. Idiopathic small bowel intussusception in adults is a diagnostic rarity that should be considered in cases of unexplained bowel obstruction. Early diagnosis and tailored surgical management can ensure favorable outcomes while avoiding unnecessary bowel resection.