Faculty Bibliography

INTRODUCTION/BACKGROUND:The purpose of this study was to assess the effect of an acute traumatic meniscus tear that required repair in association with a tibial plateau fracture repair on outcomes. METHODS:Over a 17-year period, 843 patients presented with a tibial plateau fracture and were followed prospectively. 721 patients with Schatzker I-VI fractures were treated operatively via a standardized algorithm. 161 tibial plateau fractures (22.3 %) had an associated meniscus tear that underwent acute repair at the time of bony fixation. These patients were compared to operatively repaired tibial plateau fracture patients with no meniscus injury (NMR). Demographics were collected and outcomes including: radiographic healing, knee range of motion (ROM), and complication rates, were recorded. In addition, re-operation rates were compared and any reoperation for meniscus repair failure identified. All patients had a minimum of 1 year follow up. RESULTS:A total of 524 patients with a mean of 21.4 (range: 12-120) months follow up met inclusion criteria. Patients in the meniscus repair (MR) cohort had poorer knee extension (1.01 degrees, range: 0-30 degrees) compared to the NMR cohort (0.07 degrees, range: 0-10 degrees) (p < 0.001), in addition to poorer knee flexion (123 degrees, range: 0-145 degrees, p = 0.024). Additionally, MR patients reported higher pain scores (mean: 3 and range: 0-8, p = 0.005) at latest follow up. Finally, MR patients had higher rates of infection (8.1 % vs. 3.3 %, p = 0.025) and lateral collapse of the joint (p = 0.032). CONCLUSION/CONCLUSIONS:Patients who had a meniscus repair at the time of tibial plateau fracture repair were found to have poorer knee ROM, more patient reported pain at minimum 12 (mean 24) months post-operation. Additionally, these patients developed more post-operative complications than those patients who did not undergo a meniscus repair.

Stress-induced dinucleoside tetraphosphates (Np₄Ns, where N is adenosine, guanosine, cytosine or uridine) are ubiquitous in living organisms, yet their function has been largely elusive for over 50 years. Recent studies have revealed that RNA polymerase can influence the cellular lifetime of transcripts by incorporating these alarmones into RNA as 5'-terminal caps. Here we present structural and biochemical data that reveal the molecular basis of noncanonical transcription initiation from Np₄As by Escherichia coli and Thermus thermophilus RNA polymerases. Our results show the influence of the first two nucleotide incorporation steps on capping efficiency and the different interactions of Np₄As with transcription initiation complexes. These data provide critical insights into the substrate selectivity that dictates levels of Np₄ capping in bacterial cells.

Astrocytic Ca²⁺ activity regulates activity-dependent synaptic plasticity, but its role in learning-related synaptic changes in the living brain remains unclear. We found that motor training induced synaptic potentiation on apical dendrites of layer 5 pyramidal neurons, as well as astrocytic Ca²⁺ rises in the mouse motor cortex. Reducing astrocytic Ca²⁺ led to synaptic depotentiation during motor training and subsequent impairment in performance improvement. Notably, synaptic depotentiation occurred on a fraction of dendrites with repetitive dendritic Ca²⁺ activity. On those dendrites, dendritic spines that were active before dendritic Ca²⁺ activity underwent CaMKII-dependent size reduction. In addition, the activation of adenosine receptors prevented repetitive dendritic Ca²⁺ activity and synaptic depotentiation caused by the reduction of astrocytic Ca²⁺, suggesting the involvement of ATP released from astrocytes and adenosine signaling in the processes. Together, these findings reveal the function of astrocytic Ca²⁺ in preventing synaptic depotentiation by limiting repetitive dendritic activity during learning.

Insulin resistance impairs benefits of lipid-lowering treatment as evidenced by higher cardiovascular risk in individuals with type 2 diabetes versus those without. Because platelet activity is higher in insulin-resistant patients and promotes atherosclerosis progression, we questioned whether platelets impair inflammation resolution in plaques during lipid-lowering. In mice with obesity and insulin resistance, we induced advanced plaques, then implemented lipid-lowering to promote atherosclerotic plaque inflammation-resolution. Concurrently, mice were treated with either platelet-depleting or control antibodies for 3 weeks. Platelet activation and insulin resistance were unaffected by lipid-lowering. Both antibody-treated groups showed reduced plaque macrophages, but plaque cellular and structural composition differed. In platelet-depleted mice, scRNA seq revealed dampened inflammatory gene expression in plaque macrophages and an expansion of a subset of Fcgr4+ macrophages having features of inflammation-resolving, phagocytic cells. Necrotic core size was smaller and collagen content greater, resembling stable human plaques. Consistent with the mouse results, clinical data showed that patients with lower platelet counts had decreased pro-inflammatory signaling pathways in circulating non-classical monocytes after lipid-lowering. These findings highlight that platelets hinder inflammation-resolution in atherosclerosis during lipid-lowering treatment. Identifying novel platelet-targeted therapies following lipid-lowering treatment in individuals with insulin resistance may be a promising therapeutic approach to promote atherosclerotic plaque inflammation-resolution.

BACKGROUND:The knee's inflammatory response to ligamentous, meniscal, and cartilage injuries is complex and incompletely understood, particularly in the setting of concomitant injuries. Recent research has highlighted the potential utility of synovial fluid biomarker analysis in identifying factors involved in the progression of posttraumatic osteoarthritis. PURPOSE/OBJECTIVE:To investigate if unique patterns of knee injury are associated with distinct synovial fluid biomarker profiles at the time of surgical intervention. STUDY DESIGN/METHODS:Cross-sectional study; Level of evidence, 3. METHODS:Patients undergoing arthroscopic knee surgery were prospectively enrolled and asked to complete the Lysholm Knee Scoring Scale and visual analog scale for pain preoperatively. Synovial fluid was aspirated from the operative knee before surgical incision, and the concentrations of 10 biomarkers of interest were quantified. Patients with intraoperative evidence of articular cartilage, meniscal, and/or anterior cruciate ligament (ACL) injury were identified and included for subsequent analysis. Biomarker concentrations were log-normalized and standardized. Principal component analysis (PCA) was performed using biomarker variables to reduce dimensionality and extract key patterns. Multivariable linear regression for each retained principal component (PC) was performed with the predictors of age, sex, body mass index, symptom duration, ACL injury, meniscal injury, and Outerbridge grade. A separate regression analysis was performed to assess relationships between PCs and patient-reported outcomes controlling for the same variables. RESULTS:= .001; β = -.199). CONCLUSION/CONCLUSIONS:Cartilage lesions exhibited a synovial fluid inflammatory profile distinct from ACL and meniscal injury at the time of knee arthroscopy. While ACL and meniscal injuries displayed a pro-inflammatory phenotype, more severe cartilage lesions were associated with a reduced presence of anti-inflammatory markers. The pro-inflammatory phenotype also independently correlated with worse baseline knee function. These findings contribute to the understanding of the pathophysiology of ligamentous, meniscal, and cartilage injuries and may aid in the identification of pathology-specific treatments to help alter the natural history of disease.

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:.

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.

Adipose tissue has emerged as a central regulator of human physiology, with its dysfunction driving the global rise in obesity-associated diseases, such as type 2 diabetes, cardiovascular and liver diseases, and several cancers. Once thought to be inert, adipocytes are now recognized as dynamic, responsive cells essential for energy homeostasis and interorgan communication, including the brain. Distinct adipose depots support specialized functions across development, sex, and aging. Technologies like single-cell RNA sequencing are unraveling depot-specific mechanisms, with the potential of identifying new therapeutic targets. This review highlights major scientific advancements leading to our current appreciation of the pivotal role of adipose tissue in health and disease. Many key discoveries in this field have been catalyzed by National Institutes of Health funding, particularly through the National Institute of Diabetes, Digestive and Kidney Diseases, now celebrating its 75th anniversary.

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.