Citations

OBJECTIVE The formation and propagation of intraneural ganglion cysts (INGCs) is being elucidated by the unified articular theory. Its principles include a connection for joint fluid to egress from a synovial joint via an articular branch to a parent nerve and cyst following the path of least resistance, dependent on pressures and pressure fluxes. The occurrence of so-called extreme peroneal or tibial INGCs in the popliteal fossa extending to the sciatic nerve has been reported. One rarely described variant with a circumferential cyst within the subparaneurial compartment outside the epineurium of nerve(s) has been previously illustrated, but its mechanism and morphology have not been clarified. In this study, the authors aimed to investigate this type of cyst to challenge the principles of the unified articular theory. METHODS Four novel cases of patients with peroneal INGCs and "extreme subparaneurial cyst(s)" of the sciatic nerve and its distal branches were investigated: 3 arose from the superior tibiofibular joint (STFJ) and 1 from the knee joint. Three other cases of recognized extreme subparaneurial cyst (2 peroneal and 1 tibial from the STFJ) and 1 case of a peroneal subparaneurial cyst in the literature were reinterpreted. Data on clinical presentation, MR images, and surgical results were analyzed. RESULTS In all 8 cases, subparaneurial extension was observed to different degrees along the sciatic, tibial, common peroneal, sural, and deep and superficial peroneal nerves, as was subparaneurial-to-subparaneurial communication at the sciatic nerve bifurcation (i.e., crossover). Sequential MRI performed in 7 patients showed variable dynamic changes, including extreme ascent and descent. Extraneural rupture of the subparaneurial cyst, with spread into the surrounding tissue, was present at the sciatic nerve bifurcation in 6 cases. CONCLUSIONS The authors provide pathoanatomical and pathophysiological evidence supporting that extreme subparaneurial cysts follow the principles of the articular theory. They propose a distribution pattern that explains the occurrence and evolution of extreme subparaneurial cysts along the sciatic nerve and its distal branches in patients with peroneal or tibial INGCs and subepineurial cysts. Crossover in the subparaneurial compartment allows potentially extensive circumferential distribution within connected nerves. Also, dynamic factors can lead to dramatic changes in cyst size and appearance from reabsorption or extraneural rupture. In Part 2 of this study, the authors provide evidence showing that a fenestration in the epineurium allows cysts to pass from the subepineurial-to-subparaneurial, subparaneurial-to-subparaneurial, and subparaneurial-to-subepimyseal compartments.

OBJECTIVE Extreme subparaneurial ganglion cysts are poorly understood. In Part 1, the authors demonstrated that patterns of distribution in the subparaneurial space are consistent with the principles of the articular theory for intraneural ganglion cysts (INGCs). How a cyst transfers from the subepineurial to the subparaneurial compartment remains to be determined. In this part, the authors provide evidence supporting that cyst transfer occurs at the sciatic nerve bifurcation based on MRI and histological analysis, and introduce the geyser theory as an explanation for the redistribution of cysts. METHODS The authors analyze MR images obtained in patients with extreme subparaneurial cysts as well as newly identified cases of nearly extreme subparaneurial cysts (i.e., cysts visible in the subparaneurial compartment but not to the extreme degree as defined in Part 1) for potential crossover sites. They also analyze histological sections from 10 cadavers around the sciatic nerve bifurcation for the presence of openings in the epineurium and paraneurium. RESULTS MRI studies performed in 8 patients in Part 1 and 8 newly identified examples with nearly extreme subparaneurial INGCs showed evidence to support communication between different compartments at the sciatic nerve bifurcation (subepineurial-to-subparaneurial and subparaneurial-to-neighboring soft tissues). Openings in the epineurium of the common peroneal and tibial nerves at the sciatic nerve bifurcation were consistently found in all 10 cadaver specimens, as were openings in the paraneurium. CONCLUSIONS The authors expand on the evidence to support cyst redistribution at the sciatic nerve bifurcation for INGCs in the knee region. They put forth a logical explanation for the development of a spectrum of extreme INGCs (ranging from a faint amount of cyst around the epineurium [wedding ring sign] to extreme subparaneurial INGCs [owl eyes]) based on principles seen in a geyser. The authors believe that radiological occurrence of crossover can be explained by the presence of fenestrations in both the epineurium and paraneurium at the sciatic nerve bifurcation, allowing cyst crossover in two steps: from the subepineurial to the subparaneurial space ("cross") and between a shared subparaneurial space of different nerves ("over"). Finally, the frequent occurrence of extraneural rupture ("cross-out") is due to cyst transfer into the soft tissue compartment via an opening in the outermost circumneurial layer.

Abstract Background: Refugee, immigrant, and asylee populations face significant barriers to healthcare access, including linguistic, cultural, socioeconomic, and institutional challenges. The Refugee Education and Clinic Team (REACT) is a student-run free clinic in Maricopa County, Arizona, providing subacute care and referrals to federally qualified health centers (FQHCs). This study evaluates patient demographics, clinical needs, social determinants of health (SDH), and follow-up outcomes to identify barriers to long-term care integration. Methods: A retrospective chart review of all REACT patients (2022–2024) was conducted using electronic health records. Data on demographics, SDH, chief complaints, prescriptions, referrals, and follow-up outcomes were analyzed using descriptive statistics and logistic regression. Results: The cohort (n=95) was predominantly uninsured (63%) and faced significant social barriers, including food insecurity (30.5%), employment challenges (30.5%), and language barriers (28.4%). Musculoskeletal pain and general health check-ups were the most common concerns. Older patients had higher-than-expected rates of possible hypertension. Nearly 90% received primary care provider (PCP) referrals, yet follow-up rates remained low, with only 42% attending or planning to still attend the referred visit after their initial clinic visit with us. Successful phone outreach was a significant predictor (OR: 0.5, 95% CI: 0.31-0.77) of PCP visit attendance by multivariate logistic regression. Conclusion: REACT serves a unique population with distinct barriers to care. While the clinic facilitates healthcare entry, limited follow-up adherence highlights the need for enhanced outreach, geographically optimized referrals, and integrated allied health services to improve care continuity.

Importance Tumor-infiltrating lymphocytes (TILs) are a provocative biomarker in melanoma, influencing diagnosis, prognosis, and immunotherapy outcomes; however, traditional pathologist-read TIL assessment on hematoxylin and eosin–stained slides is prone to interobserver variability, leading to inconsistent clinical decisions. Therefore, development of newer TIL scoring approaches that produce more reliable and consistent readouts is important. Objective To evaluate the analytical and clinical validity of a machine learning algorithm for TIL quantification in melanoma compared with traditional pathologist-read methods. Design, Setting, and Participants This multioperator, global, multi-institutional prognostic study compared TIL scoring reproducibility between traditional pathologist-read methods and an artificial intelligence (AI)-driven approach. The study was conducted using retrospective cohorts of patients with melanoma between January 2022 and June 2023 across 45 institutions, with tissue evaluated by participants from academic, clinical, and research institutions. Participants were selected to ensure diverse expertise and professional backgrounds. Main Outcomes and Measures Intraclass correlation coefficient (ICC) values were calculated for the manual and AI-assisted arms using log-transformed data. Kendall W values were calculated for Clark scores (brisk = 3, nonbrisk = 2, and sparse = 1). Reliabilities of ICC and W values were classified as moderate (0.40-0.60), good (0.61-0.80), or excellent (>0.80). AI TIL measurements were dichotomized using the 16.6 and median cutoffs. Univariable and multivariable Cox regression analyses assessed the prognostic value of TIL scores adjusted for clinicopathologic variables. Results There were 111 patients with melanoma in the independent testing cohort (median [range] age at diagnosis, 61.0 [25.0-87.0] years; 56 [50.5%] male) who contributed melanoma whole tissue sections. A total of 98 participants evaluated TILs on 60 hematoxylin and eosin–stained melanoma tissue sections. All 40 participants in the manual arm were pathologists, while the AI-assisted arm included 11 pathologists and 47 nonpathologists (scientists). The AI algorithm demonstrated superior reproducibility, with ICCs higher than 0.90 for all machine learning TIL variables, significantly outperforming manual assessments (ICC, 0.61 for AI-derived stromal TILs vs Kendall W , 0.44 for manual Clark TIL scoring). AI-based TIL scores showed prognostic associations with patient outcomes (n = 111) using the median cutoff approach with a hazard ratio (HR) of 0.45 (95% CI, 0.26-0.80; P = .005), and using the cutoff of 16.6, with an HR of 0.56 (95% CI, 0.32-0.98; P = .04). Conclusions and Relevance In this prognostic study of TIL quantification in melanoma, the AI algorithm demonstrated superior reproducibility and prognostic associations compared with traditional methods. Although the retrospective nature of the cohorts limits demonstration of clinical utility, the publicly available dataset and open-source AI tool offer a foundation for future validation and integration into melanoma management.

Objectives: Breast cancer (BC) remains a critical public health issue where early detection significantly improves outcomes. Despite advancements, disparities in screening awareness and access persist, particularly in underserved populations. This study evaluates a comprehensive, technology-driven educational campaign designed to empower individuals to advocate for their breast health, bridging gaps in knowledge and accessibility. Methods: Between 10/1/22 and 12/2/22, a multiplatform campaign was conducted with IRB approval. The initiative utilized traditional media, including televised ads and educational videos, and digital tools such as a mobile app and website in English and Spanish. Central to this campaign was an interactive risk calculator, offering personalized BC screening recommendations. Data collection included user demographics, platform engagement metrics, and the identification of high-risk individuals. A cost-effectiveness analysis was conducted using campaign budget data. Results: The campaign reached 673,920 individuals through televised ads and 152,672 impressions by digital ads. The website garnered 930 unique impressions, while the app recorded 2752 downloads across 131 countries. The risk calculator was completed 637 times, identifying 72 high-risk individuals. Follow-up data revealed ongoing engagement, with the calculator used an additional 1468 times. The cost per conversion was $1.62, and the cost to identify a high-risk individual was $209.27, demonstrating remarkable cost-efficiency. Conclusions: This campaign successfully increased BC awareness and early detection efforts, leveraging a cost-effective, multiplatform approach. The integration of personalized tools like the risk calculator underscores the potential of digital interventions in health education. Future efforts should build on this model to further enhance reach and health outcomes.

Age-associated muscle weakness and atrophy (sarcopenia) is prevalent in both limb and respiratory muscles. In the limb muscles, dyscoordination and sarcopenia predisposes elderly individuals to a greater risk of fall hospitalization, protracted recovery and subsequent frailty. In humans and in the Fischer 344 rat model of aging, motor neuron (MN) death occurs in old age, and the selective vulnerability of fast-fatigable motor units to loss is consistent with behavioral deficits. In many behaviors, deficits in neuromotor coordination and the timing of motor unit activations may be more pertinent than frank weakness. In MNs, the substrate for the integration of sensory, pattern, executive and reflex activations is the dendritic arbour. Currently, it is unknown whether MN dendritic and dendritic spine degenerations occur in aging and if any changes are specific to the vulnerable larger MNs. In this study of female and male Fischer 344 rats at 6- and 24-months-old, we evaluated lumbar MN dendritic arbours and dendritic spines using golgi-cox impregnation and confocal imaging approaches in thick horizontal vibratome ex vivo slices (200 µm). All data were analyzed by unpaired t-tests, 2-way ANOVAs or Pearson’s correlations, where relevant. In 24-month-old rats, lumbar MN dendritic arbour length and surface area were reduced compared to 6-month controls. In 6-month-olds, dendritic length and surface area was dependent on somal size, with bigger MN somas having longer and larger dendritic arbours, a relationship lost in 24-month old lumbar MNs. Dendritic spine density was reduced in 24- compared to 6-month-old rats. Overall, our findings suggest that lumbar MN dendritic degenerations with aging are selective to MNs of fast-fatiguable motor units. Interventions ameliorating neuromotor circuit and dendritic breakdown may preserve neuromotor function in old age. This work was supported by NIH grants: HL166204 & AG086136 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.