Penalty for Switching Implants? Assessing the Learning Curve With a Collarless, Tapered Wedge Cementless Femoral Component.

Background: Surgeon learning curve associated with a tapered wedge femoral implant as measured by early femoral component subsidence and 90-day risk of reoperation was evaluated. Methods: The first 451 patients undergoing primary, cementless total hip arthroplasty by a single, fellowship-trained arthroplasty surgeon with a tapered wedge stem design were retrospectively reviewed. Early radiographic femoral component subsidence during the first 6 weeks postoperatively and 90-day reoperations was recorded. Results: When stratified by approach, there was no association between date of surgery and femoral component subsidence in the posterior approach (P-value for linear trend over time = 0.44). In the direct anterior approach, there was a significant association between date of surgery and early femoral component subsidence (P-value for linear trend over time = 0.01). For both approaches, there was an increase in implanted stem size relative to templated stem size over time (P < .01 and P = .03, respectively). There was no association between the date of surgery and risk of 90-day reoperation (P = .45). Conclusions: In a single surgeon's initial use of a tapered cementless wedge stem, early femoral component subsidence was not impacted by the surgeon's learning curve when the posterior approach was utilized. Although subsidence was associated with date of surgery in the direct anterior cohort, this was not associated with increased risk of 90-day reoperation. Should a surgeon adopt a new tapered-wedge stem, these findings suggest that the stem is forgiving both in relation to subsidence and 90-day reoperation risk when appropriate surgical technique is utilized.

APOΕ4 lowers energy expenditure in females and impairs glucose oxidation by increasing flux through aerobic glycolysis.

BACKGROUND: Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimer's disease (AD), as well as in young cognitively normal carriers of the Ε4 allele of Apolipoprotein E (APOE), the strongest genetic predictor of late-onset AD. While this clinical feature has been described for over two decades, the mechanism underlying these changes in cerebral glucose metabolism remains a critical knowledge gap in the field. METHODS: Here, we undertook a multi-omic approach by combining single-cell RNA sequencing (scRNAseq) and stable isotope resolved metabolomics (SIRM) to define a metabolic rewiring across astrocytes, brain tissue, mice, and human subjects expressing APOE4. RESULTS: Single-cell analysis of brain tissue from mice expressing human APOE revealed E4-associated decreases in genes related to oxidative phosphorylation, particularly in astrocytes. This shift was confirmed on a metabolic level with isotopic tracing of 13C-glucose in E4 mice and astrocytes, which showed decreased pyruvate entry into the TCA cycle and increased lactate synthesis. Metabolic phenotyping of E4 astrocytes showed elevated glycolytic activity, decreased oxygen consumption, blunted oxidative flexibility, and a lower rate of glucose oxidation in the presence of lactate. Together, these cellular findings suggest an E4-associated increase in aerobic glycolysis (i.e. the Warburg effect). To test whether this phenomenon translated to APOE4 humans, we analyzed the plasma metabolome of young and middle-aged human participants with and without the Ε4 allele, and used indirect calorimetry to measure whole body oxygen consumption and energy expenditure. In line with data from E4-expressing female mice, a subgroup analysis revealed that young female E4 carriers showed a striking decrease in energy expenditure compared to non-carriers. This decrease in energy expenditure was primarily driven by a lower rate of oxygen consumption, and was exaggerated following a dietary glucose challenge. Further, the stunted oxygen consumption was accompanied by markedly increased lactate in the plasma of E4 carriers, and a pathway analysis of the plasma metabolome suggested an increase in aerobic glycolysis. CONCLUSIONS: Together, these results suggest astrocyte, brain and system-level metabolic reprogramming in the presence of APOE4, a 'Warburg like' endophenotype that is observable in young females decades prior to clinically manifest AD.

Lipid Droplets in Neurodegenerative Disorders.

Knowledge of lipid droplets (LDs) has evolved from simple depots of lipid storage to dynamic and functionally active organelles involved in a variety of cellular functions. Studies have now informed significant roles for LDs in cellular signaling, metabolic disease, and inflammation. While lipid droplet biology has been well explored in peripheral organs such as the liver and heart, LDs within the brain are relatively understudied. The presence and function of these dynamic organelles in the central nervous system has recently gained attention, especially in the context of neurodegeneration. In this review, we summarize the current understanding of LDs within the brain, with an emphasis on their relevance in neurodegenerative diseases.