The Ohio State University Wexner Medical Center

Extracellular vesicles (EVs) are a heterogeneous population of lipid bilayer-enclosed particles secreted by nearly all cell types into the extracellular milieu. Once considered cellular debris, EVs are now recognized as biologically active entities capable of transferring proteins, lipids, and nucleic acids to recipient cells, thereby modulating their function and contributing to intercellular communication. EVs play pivotal roles in immune regulation, signal transduction, and antigen presentation. EV molecular cargo reflects the physiological or pathological state of the parent cell, offering potential as diagnostic and prognostic biomarkers in a range of diseases, including cancer, neurodegeneration, and cardiovascular disorders. Traditionally, EVs have been classified into exosomes, microvesicles, and apoptotic bodies based on their size and biogenesis. Recent discoveries have expanded this taxonomy to include novel subtypes with distinct biophysical and molecular characteristics. This review focuses on EVs, with an emphasis on their biogenesis, mechanisms of ionic balance and homeostasis, and the presence and function of ion channels and transporters. We also highlight current methodologies for detecting functional ion channels within exosomes, underscoring their emerging significance in cellular physiology and disease pathogenesis.

Left ventricular (LV) dysfunction is a potential cardioembolic source of ischemic stroke, but its role in recurrent stroke risk and treatment response remains unclear. We explore whether LV injury associates with the risk of recurrent stroke and modifies the association between anticoagulation and stroke recurrence using real-world data. We performed a multicenter, retrospective study of Cardiac Abnormalities in Stroke Prevention and Recurrence cohort across 27 US sites. Patients with LV ejection fraction ≥20% were included. LV injury, defined as LV ejection fraction 20% to 40% and wall motion abnormality, was the primary exposure and treatment effect modifier. The treatment of interest was anticoagulant versus antiplatelet therapy. The composite outcome included recurrent stroke, major bleeding, or death. Outcomes were evaluated using unadjusted and inverse probability weighting adjusted Cox proportional hazards models, with treatment effect modification tested by LV injury status. Among 2685 patients enrolled, 2328 with complete data were analyzed (median age, 65 years; 49.8% female; median follow-up, 1.6 years). LV injury was present in 310 patients (13.3%). Overall, 535 events occurred: 258 recurrent ischemic strokes, 28 hemorrhagic strokes, 67 major hemorrhages, and 256 deaths. LV injury was associated with a higher unadjusted risk of the primary outcome (hazard ratio [HR], 1.51 [95% CI, 1.21-1.87]), though nonsignificant after inverse probability weighting adjustment (adjusted HR, 1.29 [95% CI, 0.97-1.70]). In the LV injury subgroup, anticoagulation versus antiplatelet therapy was associated with a lower risk of the primary outcome (adjusted HR, 0.24 [95% CI, 0.10-0.59]), relative to the non-LV injury subgroup (adjusted HR, 1.28 [95% CI, 0.83-1.95]; p[LV-interaction], 0.001). Similar interactions were seen for EF 20% to 40% (versus >40%; adjusted HR, 0.19 [95% CI, 0.04-0.86]; p[LV-interaction], 0.001) and wall motion abnormality (versus no wall motion abnormality; adjusted HR, 0.33 [95% CI, 0.15-0.73]). After cryptogenic stroke, anticoagulation in those with LV injury was associated with lower rates of recurrent stroke, major bleeding, and death. These findings warrant confirmation in a dedicated randomized controlled trial. URL: https://www.clinicaltrials.gov; Unique identifier: NCT06398366.

Head and neck squamous cell carcinoma (HNSCC) presents with higher incidence and poorer prognosis in males compared to females, yet the mechanisms underlying this sex disparity remains unclear. We investigated whether sex-specific immune responses contribute to differential tumor control using syngeneic and oral carcinogen-induced HNSCC mouse models., Female mice exhibited significantly reduced tumor burden, delayed progression and decreased metastatic potential compared to males. Immune profiling revealed a more robust antitumor immune landscape in females, characterized by heightened effector T cell activation, increased production of pro-inflammatory cytokines (IFN-γ, TNF-α), reduced expression of T cell exhaustion markers (PD-1, TIGIT), and a lower frequency of immunosuppressive myeloid-derived suppressor cells. Importantly, CD8+ T cell depletion in females abrogated the resistance to HNSCC in females, establishing CD8+ T cells as key mediators of sex-dependent antitumor immunity. Collectively, these findings demonstrate that enhanced effector T cell function coupled with reduced immunosuppression underlies improved tumor control in females and underscores the importance of integrating sex as a biological variable in immuno-oncology.

Intravenous and intracardiac leiomyomatosis (IVL/ICL) are rare benign smooth-muscle tumors that can extend from pelvic veins into the right heart, often mimicking thrombus or malignancy. A 51-year-old woman with uterine fibroids was referred for evaluation of a right atrial mass initially suspected to be thrombus. Multimodality imaging, including echocardiography, computed tomography, magnetic resonance imaging, positron emission tomography, venography, and intravascular ultrasound, identified a highly vascular intraluminal mass extending from the right gonadal vein through the inferior vena cava into the right atrium, consistent with IVL/ICL. She underwent single-stage en bloc resection, and pathology confirmed a benign leiomyoma. This case highlights the pivotal role of multimodality imaging in early diagnosis and multidisciplinary surgical planning, preventing treatment delay and improving outcomes. Multimodality imaging is essential for early and accurate diagnosis of IVL/ICL and for guiding safe, complete resection.

The use of spinal cord stimulation (SCS) for managing severe refractory chronic pain has expanded considerably due to positive statistical evidence regarding its use; however, the statistical robustness of the underlying randomized controlled trials (RCTs) requires further scrutiny. One such tool that can be used for this purpose is the fragility index, which quantifies how many individual outcome events must be altered for an outcome to lose statistical significance. Thus the index can be used quantitatively to assess the stability and robustness of an RCT's conclusions, with higher values indicating increased trial stability. This study assesses the fragility of pain outcomes across RCTs investigating SCS for chronic pain to better understand the quality and robustness of evidence. A systematic search was conducted for RCTs assessing SCS for any chronic pain indication. The primary outcome was an evaluation of the trial-specific fragility index for the prespecified pain primary outcomes of RCTs. Secondary outcomes included an evaluation of fragility for (1) specified indications for SCS therapy, (2) reported pain outcomes appearing in three or more RCTs, (3) the presence/absence of a conflict of interest, and (4) comparisons of SCS to conservative management or different SCS waveform modalities. A total of 30 RCTs were included. The median (interquartile range [IQR]) fragility index across the primary outcome of all trials was 5.45 (3.00 to 11.45). There was no statistical difference between the (1) types of outcomes (dichotomous vs. continuous; P = 0.710), (2) primary versus secondary pain outcomes ( P = 0.771), or (3) presence versus absence of trial conflict of interest ( P = 0.753). Indications with a median (IQR) fragility score greater than three included persistent spinal pain syndrome type 2 with a score of 8.00 (2.80 to 12.60), painful diabetic neuropathy with a score of 6.00 (3.00 to 11.80), complex regional pain syndrome with a score of 7.20 (4.62 to 81.50), mixed etiologies with a score of 9.00 (3.00 to 38.00), and other etiologies with a score of 3.00 (1.00 to 8.55). This study suggests that the majority of RCTs investigating primary pain outcomes after SCS therapy are robust with relatively high fragility scores. Reporting the fragility of outcomes in trials can provide a more comprehensive assessment of trial robustness and can further aid clinicians in interpreting trial results and making informed treatment decisions.

Background:In most clinical specialties, including plastic surgery, saying “no” to unnecessary, ill-timed, or simply frivolous referrals is discouraged and never taught. Carried forward into practice, this inability leads to overwhelming workloads, chaotic schedules, loss of professional autonomy, and exhaustion—well-known triggers for burnout. Providing communication tools to politely frame a refusal without jeopardizing professional relationships is essential.Methods:This narrative review provided a broad overview of existing literature on the topic across medical and nonmedical customer-service sectors, combined with the authors’ own experience. It established a context for a comprehensive summary and used the available material to create vignette-based training modules for residents and junior attendings.Results:Specifically, the traditional teaching is to always say yes to all clinical consults, no matter what they are or how overworked one already is. In contrast, publications on physician-burnout strongly recommend setting boundaries, none of which teach physicians how to do so. Although communication skills are taught during training, specific skills for politely refusing referrals, especially if inappropriate or ill-timed, are lacking.Conclusions:Using the reviewed material and our experience, a rich source of teaching materials, including clinical vignettes, was created that can be used by program leaders and younger faculty to say “no,” while maintaining honesty, professionalism, and positive referral relationships. Removing the stigma of self-guilt associated with saying “no” when appropriate, and doing so via clear and respectful communication, builds credibility, maintains professional autonomy, demonstrates integrity, and also ensures that patients receive the best possible care.