Patient Frailty is Correlated With Increased Adverse Events and Costs After Revision Knee Arthroplasty.

BACKGROUND: Frailty can predict adverse outcomes after various orthopaedic procedures, but is not well-studied in revision total knee arthroplasty (rTKA). We investigated the correlation between the Hospital Frailty Risk Score (HFRS) and post-rTKA outcomes. METHODS: Using the Nationwide Readmissions Database, we identified rTKA patients discharged from January 2017 to November 2019 for the most common diagnoses (mechanical loosening, infection, and instability). Using HFRS, we compared 30-day readmission rate, length of stay, and hospitalization cost between frail and nonfrail patients with multivariate and binomial regressions. The 30-day complication and reoperation rates were compared using univariate analyses. We identified 25,177 mechanical loosening patients, 12,712 infection patients, and 9,458 instability patients. RESULTS: Frail patients had higher rates of 30-day readmission (7.8 versus 3.7% for loosening, 13.5 versus 8.1% for infection, 8.7 versus 3.9% for instability; P < .01), longer length of stay (4.1 versus 2.4 days for loosening, 8.1 versus 4.4 days for infection, 4.9 versus 2.4 days for instability; P < .01), and greater cost ($32,082 versus $27,582 for loosening, $32,898 versus $28,115 for infection, $29,790 versus $24,164 for instability; P < .01). Frail loosening patients had higher 30-day complication (6.8 versus 2.9%, P < .01) and reoperation rates (1.8 versus 1.2%, P = .01). Frail infection patients had higher 30-day complication rates (14.0 versus 8.3%, P < .01). Frail instability patients had higher 30-day complication (8.0 versus 3.5%, P < .01) and reoperation rates (3.2 versus 1.6%, P < .01). CONCLUSIONS: The HFRS may identify patients at risk for adverse events and increased costs after rTKA. Further research is needed to determine causation and mitigate complications and costs.

Brain Specific Estrogen Ameliorates Cognitive Effects of Surgical Menopause in Mice.

Menopause is a major endocrinological shift that leads to an increased vulnerability to the risk factors for cognitive impairment and dementia. This is thought to be due to the loss of circulating estrogens, which exert many potent neuroprotective effects in the brain. Systemic replacement of estrogen post-menopause has many limitations, including increased risk for estrogen-sensitive cancers. A more promising therapeutic approach therefore might be to deliver estrogen only to the brain thus limiting adverse peripheral side effects. We examined whether we could enhance cognitive performance by delivering estrogen exclusively to the brain in post-menopausal mice. We modeled surgical menopause via bilateral ovariectomy (OVX). We treated mice with the pro-drug 10ß,17ß-dihydroxyestra-1,4-dien-3-one (DHED), which can be administered systemically but is converted to 17ß-estradiol only in the brain. Young (2.5-month) and middle-aged (11-month-old) female C57BL/6J mice received ovariectomy and a subcutaneous implant containing vehicle (cholesterol) or DHED. At 3.5 months old (young group) and 14.5 months old (middle-aged group), mice underwent behavior testing to assess memory. DHED did not significantly alter metabolic status in middle-aged, post-menopausal mice. In both young and middle-aged mice, the brain-specific estrogen DHED improved spatial memory. Additional testing in middle-aged mice also showed that DHED improved working and recognition memory. These promising results lay the foundation for future studies aimed at determining if this intervention is as efficacious in models of dementia that have comorbid risk factors.

Sex differences in the effects of high fat diet on underlying neuropathology in a mouse model of VCID.

BACKGROUND: Damage to the cerebral vasculature can lead to vascular contributions to cognitive impairment and dementia (VCID). A reduction in blood flow to the brain leads to neuropathology, including neuroinflammation and white matter lesions that are a hallmark of VCID. Mid-life metabolic disease (obesity, prediabetes, or diabetes) is a risk factor for VCID which may be sex-dependent (female bias). METHODS: We compared the effects of mid-life metabolic disease between males and females in a chronic cerebral hypoperfusion mouse model of VCID. C57BL/6J mice were fed a control or high fat (HF) diet starting at ~ 8.5 months of age. Three months after diet initiation, sham or unilateral carotid artery occlusion surgery (VCID model) was performed. Three months later, mice underwent behavior testing and brains were collected to assess pathology. RESULTS: We have previously shown that in this VCID model, HF diet causes greater metabolic impairment and a wider array of cognitive deficits in females compared to males. Here, we report on sex differences in the underlying neuropathology, specifically white matter changes and neuroinflammation in several areas of the brain. White matter was negatively impacted by VCID in males and HF diet in females, with greater metabolic impairment correlating with less myelin markers in females only. High fat diet led to an increase in microglia activation in males but not in females. Further, HF diet led to a decrease in proinflammatory cytokines and pro-resolving mediator mRNA expression in females but not males. CONCLUSIONS: The current study adds to our understanding of sex differences in underlying neuropathology of VCID in the presence of a common risk factor (obesity/prediabetes). This information is crucial for the development of effective, sex-specific therapeutic interventions for VCID.

Reduced blood flow to the brain resulting from damaged blood vessels can lead to vascular dementia. Neuroinflammation and white matter damage are characteristics of vascular dementia. Middle-age is a time when obesity and prediabetes can increase risk for vascular dementia. This increase in risk is greater for women. A high fat diet causes obesity and prediabetes in mice. We compared the effects of diet-induced obesity in middle-age between males and females in a mouse model of vascular dementia. We have previously shown that a high fat diet causes greater obesity and prediabetes and a wider array of learning and memory problems in females compared to males. Here, we report on sex differences in the damage to the brain. White matter was negatively impacted by vascular dementia in males and high fat diet in females, with more severe prediabetes correlating with less white matter markers in females only. High fat diet led to an increase in activation of microglia (immune cells in the brain) in males but not in females. High fat diet also led to a decrease in pro-inflammatory and pro-resolving mediators expression in females but not males. The current study adds to our understanding of sex differences in underlying damage to the brain caused by vascular dementia in the presence of common risk factors (obesity and prediabetes). This information is needed for the development of effective, sex-specific treatments for vascular dementia.