Faculty Bibliography

In recent history, human life expectancy has increased significantly, resulting in a high burden of late-life morbidity and geriatric fractures. Changes to the body as a result of aging, such as degeneration of the bone marrow, osteoblast apoptosis, and a decline in hormone production, coupled with sarcopenia, are only a few factors that predispose the elderly to fractures. In addition, these factors further complicate surgical management, as they increase the risk of fixation failure, nonunion, malunion, and wound complications. As a result, the standards of geriatric fracture fixation must account for variables that are rarely included when planning for surgery in the younger population. Operative fixation should provide a stable limb to allow for early mobilization and weight bearing, lowering the risk of medical complications. Therefore, early mobility is of the utmost importance in the setting of most fragility fractures. However, early mobility in some, such as the pelvic fragility fracture, may lead to an increased risk for bleeding and death. Geriatric fractures carry significant morbidity, mortality, and financial risk, which indicates that there should be a continuing review and understanding of the multifactorial process leading toward and treatment strategies employed after geriatric fractures. The purpose of this review is to summarize the biology of aging, the causes, effects, and treatments of sarcopenia, the current fixation strategies of geriatric fractures, and the importance of mobility in the geriatric patient.

INTRODUCTION/BACKGROUND:Several types of fifth metatarsal (MT) fractures exist and are treated with various methods of immobilization, weight bearing restrictions, and occasionally operative procedures. This study evaluated the differences in clinical and radiographic outcomes among pseudo-Jones fractures (Zones 1 and 2), true Jones fractures (Zone 3), and fifth metatarsal shaft and neck fractures. METHODS:A retrospective review of a consecutive series of patients presenting to a single academic medical center with a fifth metatarsal fracture between 2012 and 2022 was conducted. Radiographs obtained at the initial presentation were reviewed, and fracture patterns were categorized as either Zone 1, Zone 2, Zone 3, shaft, neck, or head fractures. RESULTS:In total, 1314 patients with isolated fifth metatarsal fractures were treated (mean age = 49.6 ± 18.0 years). In total, 1217 fractures (92.5%) were initially treated nonoperatively, and 97 fractures (7.5%) were treated operatively. The overall time to clinical and radiographic healing for all fifth metatarsal fractures treated nonoperatively was 9.9 ± 8.7 weeks and 17.9 ± 15.6 weeks, respectively (P = .245, P = .088). Immediate weightbearing led to a faster time to clinical healing by (P = .035). There was no statistically significant difference in time to clinical or radiographic union among the different fracture types (P = .496, P = .400). Likewise, there was no evidence of any difference in time to clinical or radiographic union for patients treated operatively versus nonoperatively (P > .05). CONCLUSION/CONCLUSIONS:.

While weight loss is highly recommended for those with obesity, >60% will regain their lost weight. This weight cycling is associated with elevated risk of cardiovascular disease, relative to never having lost weight. How weight loss/regain directly influence atherosclerotic inflammation is unknown. Thus, we studied short-term caloric restriction (stCR) in obese hypercholesterolemic mice, without confounding effects from changes in diet composition. Weight loss was found to promote atherosclerosis resolution independent of plasma cholesterol. From single-cell RNA-sequencing and subsequent mechanistic studies, this can be partly attributed to a unique subset of macrophages accumulating with stCR in epididymal white adipose tissue (eWAT) and atherosclerotic plaques. These macrophages, distinguished by high expression of Fcgr4, help to clear necrotic cores in atherosclerotic plaques. Conversely, weight regain (WR) following stCR accelerated atherosclerosis progression with disappearance of Fcgr4+ macrophages from eWAT and plaques. Furthermore, WR caused reprogramming of immune progenitors, sustaining hyper-inflammatory responsiveness. In summary, we have developed a model to investigate the inflammatory effects of weight cycling on atherosclerosis and the interplay between adipose tissue, bone marrow, and plaques. The findings suggest potential approaches to promote atherosclerosis resolution in obesity and weight cycling through induction of Fcgr4+ macrophages and inhibition of immune progenitor reprogramming.

The Drosophila cell-adhesion molecule Sidekick is a key component of tricellular adherens junctions in epithelia and localizes to specific synaptic layers in the optic lobes. Using mutagenesis of endogenous Sidekick, we showed that its enrichment at apical tricellular junctions and its function in cell rearrangement require its fifth and sixth immunoglobulin domains, but not the first four, although these mediate homophilic adhesion of mammalian Sidekick homologues. The C-terminal PDZ-binding motif of Sidekick contributes to localizing both Sidekick and its intracellular binding partner Canoe to tricellular adherens junctions. We found that the PAK4 homologue Mushroom bodies tiny also binds to the cytoplasmic domain of Sidekick. Its kinase activity is necessary for Sidekick accumulation at tricellular junctions, and over-activity mislocalizes Sidekick along bicellular junctions. However, mutating predicted Mushroom bodies tiny phosphorylation sites in Sidekick itself did not affect its localization. Sidekick localizes to the dendrites of T4 and T5 neurons independently of its extracellular and PDZ-binding domains, and of Mushroom bodies tiny. Our findings reveal an important role for a PAK4 family member in establishing specialized structures at tricellular adherens junctions.

Targeted therapies and immunotherapy have improved treatment outcomes for many melanoma patients. However, patients whose melanomas harbor driver mutations in the neurofibromin 1 (NF1) tumor suppressor gene often lack effective targeted treatment options when their tumors do not respond to immunotherapy. In this study, we utilized patient-derived short-term cultures (STCs) and multiomics approaches to identify molecular features that could inform the development of therapies for patients with NF1 mutant melanoma. Differential gene expression analysis revealed that the epidermal growth factor receptor (EGFR) is highly expressed and active in NF1 mutant melanoma cells, where it hyper-activates ERK and AKT, leading to increased tumor cell proliferation, survival, and growth. In contrast, genetic or pharmacological inhibition of EGFR hindered cell proliferation and survival and suppressed tumor growth in patient-derived NF1 mutant melanoma models but not in NF1 wild-type models. These results reveal a connection between NF1 loss and increased EGFR expression that is critical for the survival and growth of NF1 mutant melanoma cells in patient-derived culture and xenograft models, irrespective of their BRAF and NRAS mutation status.

BACKGROUND/UNASSIGNED:Electronic cigarettes (e-cigarettes) are the most used tobacco product among youth, and adults who smoke combustible cigarettes favor e-cigarettes over approved cessation aids. Despite the lower perceived harm of vaping compared with smoking, acute inhalation of e-cigarette aerosol elicits cardiovascular responses that may lead to persistent damage when repeated over time. METHODS/UNASSIGNED:We exposed female hypercholesterolemic mice to either pod-mod e-cigarette aerosol or filtered air daily for 24 weeks. We assessed the long-term effects of vaping on aortic stiffness and vasoreactivity while investigating the underlying cellular and molecular mechanisms of injury. RESULTS/UNASSIGNED:Chronic inhalation of e-cigarette aerosol triggered the accumulation of inflammatory signals systemically and within aortic tissues, as well as T-lymphocyte accrual in the aortic wall. Limited eNOS (endothelial nitric oxide synthase) expression and enhanced superoxide radical production curbed NO bioavailability in the aorta of mice exposed to e-cigarette aerosol despite iNOS (inducible nitric oxide synthase) induction, impairing the endothelium-dependent vasodilation that regulates blood flow distribution. Inhalation of e-cigarette aerosol thickened and stiffened aortic tissues via collagen deposition and remodeling, hindering the storage of elastic energy and limiting the cyclic distensibility that enables the aorta to function as a pressure reservoir. These effects combined contributed to raising systolic and pulse pressure above control levels. CONCLUSIONS/UNASSIGNED:Chronic inhalation of aerosol from pod-mod e-cigarettes promotes oxidative stress, inflammation, and fibrosis within aortic tissues, significantly impairing passive and vasoactive aortic functions. This evidence provides new insights into the biological processes that increase the risk of adverse cardiovascular events as a result of pod-mod e-cigarette vaping.

Chemotherapy-induced alopecia and radiation-induced alopecia, the thinning or loss of hair due to cytotoxic chemotherapy and radiation therapy, respectively, are distressing adverse effects of cancer treatment. Chemotherapy, targeted therapies, and radiation therapy used in pediatric oncology often lead to alopecia by damaging hair follicles, with varying degrees of severity depending on the specific treatment type, mechanism of action, and damage-response pathway involved. Pediatric chemotherapy-induced alopecia, radiation-induced alopecia, and permanent alopecia, defined as hair regrowth that remains incomplete 6 months or more after treatment, have significant negative impacts on mental health, self-esteem, and social interactions, highlighting the need for further research into supportive care strategies. There are currently no standard interventions for chemotherapy-induced alopecia or radiation-induced alopecia in children, with most recommendations limited to gentle hair care and camouflaging techniques during treatment. Scalp cooling has demonstrated safety and efficacy in reducing chemotherapy-induced alopecia in adults and is currently under investigation in children and adolescents. Topical and low-dose oral minoxidil have been studied in children for other hair loss disorders and may improve hair regrowth after chemotherapy or radiation. Increased awareness and continued research into management strategies for pediatric chemotherapy-induced alopecia and radiation-induced alopecia are necessary to help mitigate its significant negative impact on quality of life.

PURPOSE/OBJECTIVE:The purpose of this study is to examine the effect of age on outcomes following repair of acute displaced patella fractures Methods: 248 patients who sustained a displaced patella fracture and underwent open reduction and internal fixation were identified. Patients included underwent a similar operative protocol, were prescribed a standard post-operative protocol of therapy, and were seen at standard follow-up intervals. Patients were divided into groups of < 65 years old (young) and ≥ 65 years old (older). Statistical analysis was run to determine if there was a significant difference in range of knee motion and rate of major complications. RESULTS:Of the 248 patients, 149 were young and 99 were older. The mean age of the older group was 74.5 ± 6.7 and the mean age of the young group was 50 ± 12. Fracture pattern and BMI were similar the groups, however the older group had a higher average CCI (p<0.001). Additionally, the groups had similar length of follow up (p=0.693) and similar mean time to radiographic healing (p=0.533). Older patients had limited knee extension at 6 months (compared young patients (p=0.031). Finally, older patients had a higher rate of all complications compared to young patients. Two percent of older patients developed a fracture related infection (FRI), 4% developed a symptomatic nonunion and 11% were underwent re-operation including removal of hardware, total knee replacement, irrigation and debridement and manipulation under anesthesia. CONCLUSION/CONCLUSIONS:Complication rates following patella fracture fixation in older patients were higher than young patients, despite having similar injury patterns, surgical treatment and follow up. These findings can better inform treating physicians during surgical intervention of older patients with patella fractures.

Age-related inflammation or 'inflammaging' increases disease burden and controls lifespan. Adipose tissue macrophages (ATMs) are critical regulators of inflammaging; however, the mechanisms involved are not well understood in part because the molecular identities of niche-specific ATMs are unknown. Using intravascular labeling to exclude circulating myeloid cells followed by single-cell sequencing with orthogonal validation via multiparametric flow cytometry, we define sex-specific changes and diverse populations of resident ATMs through lifespan in mice. Aging led to depletion of vessel-associated macrophages, expansion of lipid-associated macrophages and emergence of a unique subset of CD38⁺ age-associated macrophages in visceral adipose tissue with inflammatory phenotype. Notably, CD169⁺CD11c^- ATMs are enriched in a subpopulation of nerve-associated macrophages (NAMs) that declines with age. Depletion of CD169⁺ NAMs in aged mice increases inflammaging and impairs lipolysis suggesting catecholamine resistance in visceral adipose tissue. Our findings reveal NAMs are a specialized ATM subset that control adipose homeostasis and link inflammation to tissue dysfunction during aging.