Citations

ABSTRACT As the number of cerebral aneurysms treated with flow diverters continues to increase, it is important to understand what factors influence not only thrombus formation within the aneurysm cavity but also fibrin accumulation across the device and its associated disruption and blockage of the inflow stream. Both processes contribute to the eventual occlusion of the aneurysm or its continued patency and incomplete occlusion which may require future re‐treatment. To investigate fibrin accumulation on flow diverters placed across the neck of cerebral aneurysms, a previously developed computational model that couples flow and fibrin dynamics is used in combination with experimental in vitro models of cerebral aneurysms treated with flow diverters. Fibrin accumulation was previously investigated in four glass models of cerebral aneurysms with varying parent artery geometries placed in a flow loop at different flow rates. Corresponding computational models were constructed and compared with the experimental findings. The computational model based on fibrin production stimulated from flow shear stress and subsequent adhesion to device wires was able to reproduce and explain the fibrin accumulation patterns observed in the experimental aneurysms treated with flow diverters. Specifically, these models indicated that increasing vessel curvature, flow rate, and thrombin concentration induced faster fibrin accumulation and associated aneurysm inflow disruption and blockage. The models described and tested in this paper are valuable to understand the detailed mechanisms leading to aneurysm occlusion and healing or incomplete occlusions after treatment with flow diverting devices.

Abstract Objective There is a dearth of research on neuropsychological functioning and the validity of assessment measures in American Indian (AI) older adults. The present study sought to comprehensively examine neuropsychological functioning in cognitively normal AI older adults in the southwestern USA (i.e., Arizona). Participants and Methods Ninety predominantly female participants (45 AIs and 45 non-Hispanic Whites) aged 44 years and older (mean age of mid-60s) were matched on age, decade, gender, and assessment battery. Participants were enrolled in the Arizona Alzheimer’s Disease Center database. Data obtained included demographics, medical history, psychiatric variables, and raw neuropsychological scores. Analyses included ANCOVAs, chi-square, and stepwise multiple regression. Results AIs generally had lower performance across all neuropsychological measures compared with matched Whites, even after controlling for demographic variables. Performance between groups was most discrepant on several measures of global cognition, attention, executive functioning, and language, while performance was statistically comparable on measures of memory and visuospatial abilities. The AI group had higher proportions of diabetes and obesity, but results showed that higher cardiovascular risk was not predictive of lower cognitive performance with the exception of the Clinical Dementia Rating Scale–Sum of Boxes. Conclusions Findings suggest that older AIs perform lower on many neuropsychological measures compared with non-Hispanic Whites, even after controlling for demographic variables. This suggests that other factors, including language, culture, educational quality, overall health, socioeconomic status, and level of acculturation may be impacting test scores and need to be considered when assessing and diagnosing older AIs.

Introduction: To analyze the association of patient characteristics on operating room (OR) times for robotic-assisted partial nephrectomies (RAPNs). Methods: In total, 248 consecutive RAPNs were performed by a single surgeon from October 2018 to August 2022. Data were collected on the following patient factors: sex, age, race, weight, body mass index (BMI), diabetes, hypertension (HTN), tumor side, tumor mass, and American Society of Anesthesiologists (ASA) score. Total fixed OR times were evaluated as the sum of in-room time to anesthesia-release time (IRAT), anesthesia-release time to cut time (ARCT), close time to wheels out time (CTWO), and in-room time to cut time (IRAT + ARCT). Total variable OR times were defined as cut time to close time (CTCT). Total operative time was defined as wheels into wheel out (WIWO). Results: Median OR time was 265 minutes (interquartile range [IQR]: 247–298 minutes) for WIWO, 191 minutes (IQR: 170–225 minutes) for CTCT, and 75 minutes (IQR: 68–83 minutes) for total fixed time. There was a significant increase in WIWO with the following patient variables: male sex (18.0 minutes, 95% confidence interval [CI]: 6.3–29.7 minutes), weight (5.6 minutes, 95% CI: 2.8–8.4 minutes), BMI (14.3 minutes, 95% CI: 4.2–24.4 minutes), HTN (15.1 minutes, 95% CI: 3.7–26.5 minutes), pathology tumor size (cm) (6.4 minutes, 95% CI: 2.2–10.6 minutes), and ASA score (13.8 minutes, 95% CI: 3.1–24.4 minutes). Sex, age, BMI, weight, HTN, and pathology tumor size significantly impacted CTCT ( P < 0.05). Total fixed OR time was only affected by ASA score ( P = 0.02). Conclusions: Patient variables significantly affect total OR time and variable OR time. These variables do not impact total fixed OR times, confirming fixed OR time as a viable OR efficiency point.

Portopulmonary hypertension (POPH), a form of pulmonary artery hypertension, occurs because of portal hypertension. Pulmonary hemodynamics and right heart function are key entities that are considered when diagnosing and treating POPH. Medical management, combined with liver transplantation, offers a unique opportunity for POPH “cure”; however, transplant risk can be significant as it relates to the severity of POPH. In addition to recent POPH practice guidelines, continued efforts can be suggested to improve our understanding of prognostic factors, investigate newer medical treatments, and improve outcomes of POPH. Herein, we identify specific “unmet needs” that focus on expanding and complementing current POPH practice guidelines.

Importance Molecular techniques, including next-generation sequencing, genomic copy number profiling, fusion transcript detection, and genomic DNA methylation arrays, are now indispensable tools for the workup of central nervous system (CNS) tumors. Yet there remains a great deal of heterogeneity in using such biomarker testing across institutions and hospital systems. This is in large part because there is a persistent reluctance among third-party payers to cover molecular testing. The objective of this Review is to describe why comprehensive molecular biomarker testing is now required for the accurate diagnosis and grading and prognostication of CNS tumors and, in so doing, to justify more widespread use by clinicians and coverage by third-party payers. Observations The 5th edition of the World Health Organization (WHO) classification system for CNS tumors incorporates specific molecular signatures into the essential diagnostic criteria for most tumor entities. Many CNS tumor types cannot be reliably diagnosed according to current WHO guidelines without molecular testing. The National Comprehensive Cancer Network also incorporates molecular testing into their guidelines for CNS tumors. Both sets of guidelines are maximally effective if they are implemented routinely for all patients with CNS tumors. Moreover, the cost of these tests is less than 5% of the overall average cost of caring for patients with CNS tumors and consistently improves management. This includes more accurate diagnosis and prognostication, clinical trial eligibility, and prediction of response to specific treatments. Each major group of CNS tumors in the WHO classification is evaluated and how molecular diagnostics enhances patient care is described. Conclusions and Relevance Routine advanced multidimensional molecular profiling is now required to provide optimal standard of care for patients with CNS tumors.

ABSTRACT Background Inclusion body myositis (IBM) is the most prevalent muscle disease in adults for which no current treatment exists. The pathogenesis of IBM remains poorly defined. In this study, we aimed to explore the interplay between inflammation and mitochondrial dysfunction in IBM. Methods The study population consisted of 38 IBM patients and 22 age‐ and sex‐matched controls without a myopathy. Mean age was 62.9 years (SD = 9) in IBM group and 59.7 (10) in controls. Bulk RNA sequencing, Meso Scale Discovery electrochemiluminescence (ECL), western blotting, histochemistry and immunohistochemistry were performed on frozen muscle samples from the study participants. Results We demonstrated activation of the NLRP3 inflammasome in IBM muscle samples, with the NLRP3 inflammasome being the most upregulated pathway on RNA sequencing, along with increased expression of NLRP3 and ASC proteins in IBM group. NLRP3 RNA levels most strongly correlated with TLR7 (correlation coefficient ρ = 0.91) and complement activation‐related genes, and inversely correlated with several mitochondria‐related genes among others. On muscle histopathology, there was increased NRLP3 immunoreactivity in both inflammatory cells and muscle fibres. Mitophagy is critical for removing damaged mitochondria and preventing the formation of a vicious cycle of mitochondrial dysfunction—NLRP3 inflammasome activation. Herein, we showed altered mitophagy, as witnessed by the elevated levels of p‐S65‐Ubiquitin, a mitophagy marker, in muscle lysates from IBM patients compared to controls (median of 114.3 vs. 81.25 ECL units, p = 0.005). The p‐S65‐Ubiquitin levels were most significantly elevated in IBM males compared to male controls (136 vs. 83.5 ECL units; p = 0.013), whereas IBM females had milder nonsignificant elevation compared to female controls (97.25 vs. 69 ECL units, p = 0.31). On muscle histopathology, p‐S65‐Ubiquitin aggregates accumulated in muscle fibres that were mostly Type 2 and devoid of cytochrome‐c‐oxidase reactivity. NLRP3 RNA levels correlated with p‐S65‐Ubiquitin levels in both sexes (males: ρ = 0.48, females: ρ = 0.54) but with loss of muscle strength, as reflected by the manual motor test score, only in males (males: ρ = 0.62, females: ρ = −0.14). Lastly, we identified sex‐specific molecular pathways in IBM. Females had upregulation of pathways related to response to stress, which could conceivably offset some of the pathomechanisms of IBM, while males had upregulation of pathways related to cell adhesion and migration. Conclusions There is activation of the NLRP3 inflammasome in IBM, along with altered mitophagy, particularly in males, which is of potential therapeutic significance. These findings suggest sex‐specific mechanisms in IBM that warrant further investigation.