White matter hyperintensities and longitudinal cognitive decline in cognitively normal populations and across diagnostic categories: A meta-analysis, systematic review, and recommendations for future study harmonization.

INTRODUCTION: The primary aim of this paper is to improve the clinical interpretation of white matter hyperintensities (WMHs) and provide an overarching summary of methodological approaches, allowing researchers to design future studies targeting current knowledge gaps. METHODS: A meta-analysis and systematic review was performed investigating associations between baseline WMHs and longitudinal cognitive outcomes in cognitively normal populations, and populations with mild cognitive impairment (MCI), Alzheimer's disease (AD), and stroke. RESULTS: Baseline WMHs increase the risk of cognitive impairment and dementia across diagnostic categories and most consistently in MCI and post-stroke populations. Apolipoprotein E (APOE) genotype and domain-specific cognitive changes relating to strategic anatomical locations, such as frontal WMH and executive decline, represent important considerations. Meta-analysis reliability was assessed using multiple methods of estimation, and results suggest that heterogeneity in study design and reporting remains a significant barrier. DISCUSSION: Recommendations and future directions for study of WMHs are provided to improve cross-study comparison and translation of research into consistent clinical interpretation.

High Energy Transsyndesmotic Ankle Fracture Dislocation - Does Deltoid Ligament Repair Influence the Progression of Posttraumatic Arthritis in Logsplitter Injuries?

OBJECTIVE: To determine the effect of deltoid ligament repair on the development of posttraumatic arthritis in logsplitter ankle injuries. METHODS: Design: Retrospective cohort. SETTING: Academic, Level I trauma center. PATIENT SELECTION CRITERIA: Patients ≥18 years of age with logsplitter injuries (OTA/AO 44B, 44C) treated with open reduction internal fixation with or without deltoid ligament repair from January 2008 to October 2021. OUTCOME MEASURES AND COMPARISON: The rate of posttraumatic arthritis (PTOA) development at final follow-up (minimum 6 months) after open reduction internal fixation was evaluated using the Kellgren-Lawrence scale. The achievement of acceptable reduction indicated by articular reduction <2mm, and a medial clear space ≤4mm was assessed at 6 weeks postoperatively with weightbearing radiographs. The effect of deltoid ligament repair on the development of PTOA was investigated. RESULTS: Fifty-nine patients aged 49.1 ± 17.2 years met inclusion criteria with a mean follow up of 16.6 months (range = 6 to 96). Twenty-six of 59 patients (44%) had developed PTOA at final follow-up. Acceptable reduction was achieved in 83.1% (49/59) of fractures. The acceptable reduction rate in fractures undergoing deltoid ligament repair was 100% versus 78% in those without deltoid ligament repair (13/13 vs. 36/46, p=0.017). The rate of PTOA development was significantly lower in patients who underwent deltoid ligament repair (15%) compared to those who did not (52%), p=0.026. Patients who underwent deltoid ligament repair had a significantly reduced rate of PTOA development leading to arthrodesis compared to those who did not (0% vs. 17%, p=0.013). CONCLUSIONS: Logsplitter injuries resulted in a high rate of development of posttraumatic arthritis. An acceptable reduction is required to minimize risk of development of PTOA and progression to arthrodesis. Deltoid ligament repair during open reduction internal fixation may facilitate acceptable reduction, decrease the rate of PTOA and progression to arthrodesis in these injuries. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Immune Checkpoint Inhibition in GBM Primed with Radiation by Engineered Extracellular Vesicles.

The lack of safe and effective delivery across the blood-brain barrier and the profound immune suppressive microenvironment are two main hurdles to glioblastoma (GBM) therapies. Extracellular vesicles (EVs) have been used as therapeutic delivery vehicles to GBM but with limited efficacy. We hypothesized that EV delivery to GBM can be enhanced by (i) modifying the EV surface with a brain-tumor-targeting cyclic RGDyK peptide (RGD-EV) and (ii) using bursts of radiation for enhanced accumulation. In addition, EVs were loaded with small interfering RNA (siRNA) against programmed cell death ligand-1 (PD-L1) for immune checkpoint blockade. We show that this EV-based strategy dramatically enhanced the targeting efficiency of RGD-EV to murine GBM, while the loaded siRNA reversed radiation-stimulated PD-L1 expression on tumor cells and recruited tumor-associated myeloid cells, offering a synergistic effect. The combined therapy significantly increased CD8+ cytotoxic T cells activity, halting tumor growth and prolonging animal survival. The selected cell source for EVs isolation and the presented functionalization strategy are suitable for large-scale production. These results provide an EV-based therapeutic strategy for GBM immune checkpoint therapy which can be translated to clinical applications.

Feocromocitotoma bilateral maligno como componentes de adenomatosis endocrina multiple tipo II-A: presentacion de un caso y revision de la literatura / Bilateral malignant pheochromocytoma as component of multiple endocrine adenmatosis type II-A: presentation of a case and review of the literature

Se presenta el caso de un joven de 25 anos hospitalizado por un cuadro de hipertension arterial sistemica severa acompanado de bocio multinodular, a quien se le diagnostico adenomatosis endocrina multiple tipo II-A (AEM II-A). Se comprobo la presencia de feocromocitoma bilateral metastasico al encontrarse niveles elevados de acido venilmandelico en orina, dos masas suprarrenales bilaterales y una masa tumoral hepatica en el estudio tomografico de abdomen. En forma similar se evidenciaron nodulos hipocaptantes en tiroides, demostrandose que correspondian a un carcinoma medular de tiroides al realizar el estudio histopatologico. se logro el control de las cifras tensionales con la administracion de prazosin (12 mg/da) y labetalol (600 mg/dia) en el periodo preoperatorio, practicandose posteriormente la adrenalectomia subtotal bilateral y tiroidectomia total. En su evolucion postoperatoria el paciente presento episodios de hemorragia digestiva superior masiva debidos a multiples ulceras del tracto gastrointestinal, que ameritaron realizar una gastrectomia total para el control de la hemorragia. Se hace revision de la literatura con referencia particular al diagnostico y manejo del feocromocitoma maligno