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Aims Periacetabular osteotomy (PAO) is performed in young, opioid-naive patients and is associated with postoperative pain. Optimizing perioperative analgesia while limiting opioid exposure remains a priority. This study evaluated postoperative pain trajectories, hospital length of stay (LOS), and opioid-prescribing patterns associated with an institutional transition from epidural-based to periarticular injection (PAI)-based analgesia after PAO. Secondary aims were to assess the influence of preoperative opioid exposure and compare outcomes between ropivacaine-based and bupivacaine PAI formulations. Methods The study included 724 patients who underwent PAO between January 2010 and December 2022 at a single academic institution, with epidural use replaced by PAI in 2016. Patients were stratified by postoperative analgesia strategy: epidural catheter (n = 333) or PAI (n = 391). Outcomes included daily postoperative pain scores, LOS, discharge opioid prescriptions (morphine milligram equivalents (MMEs)), total opioid exposure, and 30-day refill rates. Statistical comparisons were performed using chi-squared, Fisher’s exact, and Kruskal–Wallis tests. Results Baseline characteristics were similar between groups. Epidural analgesia was associated with lower pain scores during the first 48 hours (last pain postoperative day 0 to 1: mean 2.9 (SD 2.0) vs 4.7 (SD 2.1); p < 0.001), whereas the PAI group had a shorter LOS (mean 2.2 days (SD 1.0) vs 3.4 days (SD 0.9); p < 0.001) and higher pain scores at discharge (mean 4.8 (SD 1.9) vs 4.0 (SD 1.9); p < 0.001). Median discharge opioid prescriptions (313 (IQR 225 to 388) vs 825 (IQR 600 to 1,000) MMEs) and total 30-day opioid exposure (360 (IQR 275 to 575) vs 900 (IQR 638 to 1,100) MMEs) were lower in the PAI group (both p < 0.001), while refill rates were higher (34.0% vs 19.2%; p < 0.001). Within the PAI cohort, ropivacaine-based and bupivacaine injections showed similar pain trajectories and refill rates. Conclusion Epidural analgesia provided superior early postoperative pain control, whereas PAI-based pathways enabled earlier discharge and lower overall opioid prescribing but with higher refill rates. These findings highlight trade-offs in contemporary perioperative pathways and support individualized analgesic strategies after PAO. Cite this article: Bone Jt Open 2026;7(11):1410–1418.

ABSTRACT Persistent gaps in anatomical knowledge among incoming residents have raised concerns about clinical preparedness, especially in surgical and interventional disciplines. Conventional anatomy instruction and limited cadaveric exposure and learning opportunities in medical curricula have prompted calls for innovative, clinically focused anatomical curricular integration in clinical training. This article describes the development, implementation, and impact of a tailored Year 4 Clinical Anatomy Elective in the Department of Clinical Anatomy at Mayo Clinic, designed to reinforce competency in clinically relevant anatomical understanding and support learners' perceived preparedness during transitions to residency. A 4‐week elective was designed for fourth‐year medical students interested in pursuing a specific residency program. The course was personalized for students' clinical interests and incorporated fresh tissue dissection, simulation, procedural skills training, and imaging using an immersive learning platform. The elective was structured within the experiential learning model using a guided, self‐directed format within a multicapability laboratory and instructional environment, grounded in constructivist theory. A 5‐year review of elective records and informal thematic analysis of student feedback were conducted. Most participants pursued surgically related specialties, with orthopedic surgery being the most common. Exploratory thematic analysis identified six core themes: Professional Identity Formation, Educational Benefits, Learning Challenges, Connection to Clinical Practice, Patient Care Implications, and Future Preparation and Transferability. These students perceived gains in areas aligned with ACGME milestones: increased confidence, greater preparedness for residency, and improvement in their ability to apply anatomical knowledge in clinical settings. This perception may be indicative of lifelong learning and early educator identity formation. A specialty‐specific, clinically integrated anatomy elective may support learners' perceived preparedness for residency, reinforce clinically relevant anatomical understanding, and support the development of educational and professional competencies. Such targeted interventions may help address perceived gaps in anatomical preparedness during the transition to residency and contribute to postgraduate training within a competency‐based medical education framework.

CD4 + effector T helper 1 (T H 1) cells drive inflammatory bowel disease (IBD). Here, we investigated how integrated signaling, metabolic, and epigenetic programs sustain their pathogenic persistence. We found that enforcing mitochondrial pyruvate metabolism with methyl pyruvate (MePyr) suppressed T H 1 cell effector function and induced the acquisition of a regulatory-like phenotype. MePyr suppressed the activity of glycogen synthase kinase 3β (GSK3β), promoting a metabolic shift from glycolysis toward oxidative phosphorylation (OXPHOS) and limiting the accumulation of intracellular acetyl-CoA. This metabolic reprogramming decreased histone H3 acetylation at genes encoding inflammatory cytokines, thereby decreasing T H 1 cell–associated gene expression. Restoration of inflammatory cytokine production by acetate supplementation or histone deacetylase inhibition established acetyl-CoA–dependent histone acetylation as a mechanistic link between metabolic flux and effector function. Conversely, the cytokine interleukin-21 enhanced T H 1 cell effector activity by promoting a GSK3β-dependent shift from OXPHOS to glycolysis. Single-cell transcriptomic analysis of Crohn’s disease tissue revealed enrichment of glycolytic gene programs in nonregulatory CD4 + T cells. Consistent with these findings, pharmacologic inhibition of GSK3β attenuated disease severity in a T cell–transfer mouse model of colitis. Together, these findings identify a GSK3β-dependent metabolic-epigenetic axis that sustains T H 1 cell pathogenicity and highlight GSK3β as a potential therapeutic target for IBD.

Abstract Neuroanatomy remains a core competency in neurosurgical training, particularly in skull base education, where learners must integrate three‐dimensional spatial understanding, radiologic correlation, and stepwise procedural knowledge. Cadaveric dissection remains foundational, but adjunctive digital tools may strengthen repeated visualization and anatomical review. We describe the educational rationale and implementation of integrating stereoscopic teaching, a stepwise digital application, photogrammetry, and virtual reality within an established neurosurgical skull base curriculum. Within the Mayo Clinic cranial base course embedded in a broader longitudinal curriculum, four postgraduate year 4 neurosurgery residents participated in transcranial and endoscopic cadaveric dissections supported by stereoscopic lectures, workstation‐based tablet guidance, and immersive review using photogrammetry, virtual reality, and computed tomography/magnetic resonance imaging correlation. The integrated design aligned these modalities with course objectives in anatomical landmark recognition, operative corridor planning, radiologic‐anatomic translation, and stepwise procedural rehearsal. The educational contribution of this model lies in the intentional integration of digital adjuncts around cadaveric dissection rather than in a single technology alone. This multimodal sequence may support spatial understanding, procedural preparation, and competency‐oriented skull base training while extending review beyond the laboratory. Current evaluation is best interpreted as preliminary program evaluation rather than definitive learner‐outcome evidence. This model may offer a transferable approach for programs seeking to complement cadaveric education with emerging digital tools and provides a basis for future prospective evaluations using multiple low‐stakes assessment data points across the broader curriculum.

Abstract The apolipoprotein E ε4 ( APOE4 ) allele is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD), yet the mechanistic underpinnings by which it alters human microglial function remain poorly understood. Here, we utilize CRISPR/Cas9-engineered isogenic human induced pluripotent stem cell-derived microglia-like cells (iMGs) expressing APOE3 or APOE4 to systematically interrogate genotype-dependent effects on microglial proteomes and their secreted extracellular vesicles (EVs) under basal and fibrillar amyloid-β (fAβ)-challenged conditions. Quantitative proteomics revealed that APOE4 iMGs exhibit downregulated RNA processing, impaired phagocytosis, and exacerbated pro-inflammatory signaling, particularly upon fAβ exposure. Functionally, APOE4 iMGs demonstrated increased NF-κB activation, enhanced neuronal apoptosis and tau pathology in 2D and 3D co-culture systems. Interestingly, APOE4 iMGs released greater amount of EVs enriched in proteasomal components over APOE3 iMG. Integrated proteomic analyses further highlighted APOE4 -specific selective packaging of EV cargo linked to neuron-glia communication, inflammatory signaling, and proteostasis dysregulation, suggesting a potent, non-cell-autonomous mechanism driving neuronal damage. Consistently, these APOE4 iMGEVs were preferentially internalized by neurons, leading to disrupted neuronal proteostasis, impaired neuronal firing, and increased tau phosphorylation, particularly under pathological stress. Notably, pharmacologic inhibition of NF-κB in APOE4 iMGs reduced EV cargo-loading of proteasomal molecules and mitigated iMGEV-driven neuronal dysfunction and tau pathology. These findings establish a mechanistic link between APOE4 , dysregulated microglial homeostasis, and microglial EV-mediated propagation of proteostatic dysfunction and neurodegeneration, advancing our understanding of how APOE4 contributes to AD pathogenesis.

The intestinal epithelium is exposed to diverse combinations of microbiota-derived compounds; however, the mechanisms by which the host integrates these signals remain poorly defined. Studying two highly abundant microbial metabolites, we identified the purine metabolite hypoxanthine as an effector metabolite that directly drives signaling and the short-chain fatty acid butyrate as a regulatory metabolite that conditions host responsiveness. Specifically, hypoxanthine activates the adenosine A1 receptor–TRPC4 axis in enterochromaffin (EC) cells, triggering calcium influx and serotonin release resulting in accelerated gastrointestinal transit locally and increased platelet activation systemically. In contrast, butyrate epigenetically upregulates specific G protein–coupled receptors and ion channels to enhance response to hypoxanthine and the neurotransmitters norepinephrine and dopamine. These findings define a cooperative signaling framework and highlight the role of EC cells as a distinct epithelial signaling hub that senses and integrates microbial metabolite signals to drive physiological responses. Our findings provide a mechanistic foundation for therapeutic strategies that leverage combinatorial microbial signaling.

Abstract Glioblastoma (GBM) remains the most lethal primary brain cancer due to its remarkable metabolic plasticity and therapeutic resistance. Here, we identify cholesterol dependency as a therapeutically exploitable vulnerability in GBM using two FDA-approved drugs: the H1 histamine antagonist clemastine and the retinoid X receptor agonist bexarotene. Combined treatment induces potent synergistic anti-tumor activity across patient-derived glioma models, suppressing proliferation, stemness, and survival at sub-IC50 concentrations. Mechanistically, this therapy disrupts cholesterol biosynthesis, transport, and homeostasis, triggering endoplasmic reticulum stress and activation of the unfolded protein response, ultimately leading to autophagy and apoptotic cell death. Orthotopic patient-derived glioma models recapitulate these mechanisms in vivo, where local intracranial administration significantly reduces tumor progression and prolongs survival using fourfold lower doses than systemic intraperitoneal delivery. Single-cell RNA sequencing revealed activation of regeneration and plasticity programs, accompanied by immune microenvironment remodeling and enhanced inflammatory signaling. Importantly, syngeneic models preserved immune cell composition, supporting future integration with immunotherapeutic strategies. Together, these findings establish cholesterol dysregulation–induced metabolic collapse as a promising therapeutic approach for GBM.

Aims Extensor mechanism disruption is a major complication following total knee arthroplasty, with treatment often consisting of extensor mechanism reconstruction utilizing monofilament polypropylene mesh (Marlex mesh, C. R. Bard, Inc). Infection following this procedure is devastating, often resulting in revision surgery and mesh removal, with permanent limb dysfunction. This study evaluated the in vitro ability of vancomycin-loaded polypropylene mesh to inhibit growth of isolates of three Staphylococcus species from patients with periprosthetic joint infection. Methods The mesh was prepared in two configurations – single-layer and eight-layer – and soaked for ten minutes in either sterile water (control) or vancomycin solution (50 mg/ml), after which the mesh was placed on tryptic soy agar plates inoculated with staphylococci and incubated at 37°C for 18 to 24 hours. Zones of inhibition were measured daily over seven days, with mesh transferred to freshly inoculated plates daily. Testing was performed in triplicate, with experiments repeated three times for each bacterial isolate. A total of 30 clinical isolates were tested (five methicillin-susceptible Staphylococcus epidermidis , five methicillin-resistant S. epidermidis , ten methicillin-resistant Staphylococcus aureus , and ten Staphylococcus lugdunensis ). Results Across all species, the eight-layer vancomycin-loaded mesh produced statistically significantly larger median zones of inhibition than the single-layer mesh. The antibacterial activity of the eight-layer mesh persisted through to day 7, while the single-layer mesh showed reduced activity by days 4 to 5. Conclusion Compared with single-layer vancomycin-loaded mesh, multilayer vancomycin-loaded mesh, which mimics clinical application, provides enhanced and sustained antibacterial activity in vitro. Cite this article: Bone Joint Res 2026;15(8):998–1004.

BACKGROUND The authors aimed to evaluate the feasibility/safety of stereo-electroencephalography (SEEG) and SEEG-guided radiofrequency thermocoagulation (RFTC) in patients with drug-resistant epilepsy previously implanted with neuromodulation devices, using a retrospective cohort design evaluating patients treated at the Mayo Clinic Florida Epilepsy Center. OBSERVATIONS Nine patients (mean age 36.3 ± 10.9 years, 33% female) with prior implantation of neuromodulation devices were included. A vagus nerve stimulator was present in 8 of 9 patients, and 4 patients had undergone previous intracranial neuromodulation. Five patients underwent SEEG-RFTC. The mean SEEG monitoring duration was 6.5 ± 2.9 days. No intraoperative or procedural complications occurred, including hardware-related issues. No permanent or significant neurological/cognitive deficits occurred. One patient experienced transient postoperative neurological symptoms attributed to perilesional edema. Seizure reduction ranged from 50% to 75% following SEEG-RFTC. LESSONS SEEG and SEEG-RFTC are feasible in patients who have implanted neuromodulation devices, including intracranial implants. These procedures may be performed without interference with existing hardware and provide meaningful seizure reduction in highly refractory populations. Further studies with larger cohorts and longer follow-up are needed to better define efficacy and patient selection. https://thejns.org/doi/10.3171/CASE26376

Objective: To determine whether sleep apnea–specific hypoxic burden (SASHB) is associated with self-reported hypertension beyond conventional obstructive sleep apnea metrics in rail workers. Methods: Cross-sectional study of 84 Argentine rail workers undergoing home sleep apnea testing. Associations between SASHB and hypertension were evaluated using adjusted logistic regression. Drowsy driving was examined as an unadjusted exploratory secondary outcome. Results: Higher SASHB was independently associated with hypertension in the fully adjusted model (OR per SD 2.42; 95% CI 1.24–5.29; p=0.015). Higher SASHB was also associated with more severe self-reported drowsy driving in unadjusted exploratory ordinal analyses (OR per SD 1.78; 95% CI 1.09–3.28; p=0.035). Conclusions: SASHB may provide complementary information beyond conventional OSA metrics for cardiovascular risk assessment in occupational populations.