Faculty Bibliography

Protein"“protein interactions are essential for normal cellular processes and signaling events. Defining these interaction networks is therefore crucial for understanding complex cellular functions and interpretation of disease-associated gene variants. We need to build a comprehensive picture of the interactions, their affinities and interdependencies in the specific organ to decipher hitherto poorly understood signaling mechanisms through ion channels. Here we report the experimental identification of the ensemble of protein interactors for 13 types of ion channels in murine cardiac tissue. Of these, we validated the functional importance of ten interactors on cardiac electrophysiology through genetic knockouts in zebrafish, gene silencing in mice, super-resolution microscopy and patch clamp experiments. Furthermore, we establish a computational framework to reconstruct human cardiomyocyte ion channel networks from deep proteome mapping of human heart tissue and human heart single-cell gene expression data. Finally, we integrate the ion channel interactome with human population genetics data to identify proteins that influence the electrocardiogram (ECG). We demonstrate that the combined channel network is enriched for proteins influencing the ECG, with 44% of the network proteins significantly associated with an ECG phenotype. Altogether, we define interactomes of 13 major cardiac ion channels, contextualize their relevance to human electrophysiology and validate functional roles of ten interactors, including two regulators of the sodium current (epsin-2 and gelsolin). Overall, our data provide a roadmap for our understanding of the molecular machinery that regulates cardiac electrophysiology.

Although robotic surgery has been routinely established in other surgical disciplines, robotic technologies have been less readily adopted in plastic surgery. Despite a strong demand for innovation and cutting-edge technology in plastic surgery, most reconstructive procedures, including microsurgery, have continued to necessitate an open approach. Recent advances in robotics and artificial intelligence, however, are gaining momentum and have shown significant promise to improve patient care in plastic surgery. These next-generation surgical robots have the potential to enable surgeons to perform complex procedures with greater precision, flexibility, and control than previously possible with conventional techniques. Successful integration of robotic technologies into clinical practice in plastic surgery requires achieving key milestones, including implementing appropriate surgical education and garnering patient trust.

OBJECTIVES/OBJECTIVE:Obesity is characterized by local and systemic low-grade inflammatory responses. Adipose tissue macrophages (ATM) play decisive roles in inflammation, insulin signaling, and various metabolic dysfunctions. Diets enriched with ω-3 polyunsaturated fatty acids (PUFAs) have been shown to improve health and mitigate pathologic conditions. However, the effects of ω-3 PUFA on adipose tissue inflammation, ATM number, and phenotype are poorly defined in human obesity. The aim of this study was to examine differences in expression of metabolic-inflammatory markers in omental, mesenteric, and subcutaneous fat depots of obese women supplemented with ω-3 PUFAs for 4 wk compared with a low-calorie diet before bariatric surgery. METHODS:In a randomized controlled trial, inflammatory markers in the abdominal adipose tissue and the systemic response in obese women were studied. Patients were treated with a 2-wk low-calorie diet (LCD) or a 4-wk ω-3 PUFA-enriched diet (920 mg eicosapentaenoic acid, 760 mg docosahexaenoic acid daily) before laparoscopic bypass surgery. Omental, mesenteric, and subcutaneous adipose tissue biopsies were collected during surgery and analyzed for quantity and phenotype of ATMs, and profiled for adipokines, cytokines, and signal transduction molecules. RESULTS:The chronic inflammatory state characterized by ATM markers was mostly improved by ω-3 PUFAs in visceral adipose tissue. We observed a decreased expression of CD45, CCL2, and CD68, indicating a lower inflammatory state. In patients with type 2 diabetes, ω-3 PUFAs lowered the expression of Netrin-1. CONCLUSIONS:Compared with an LCD, a diet enriched with ω-3 PUFAs influences the inflammatory state in different adipose tissue depots, by affecting markers of adipose tissue inflammation, macrophage phenotype, and retention. However, this was not reflected in clinical parameters such as insulin resistance and inflammatory cytokines. Subcutaneous adipose tissue and visceral adipose tissue have different responses to an LCD or a ω-3 PUFA-enriched diet. The presence of diabetes modifies the expression of inflammatory markers.

BACKGROUND:The purpose of this study was to compare outcomes following surgical treatment of tibial plateau fractures in an elderly (≥ 65y) and non-elderly (< 65) population. METHODS:Patients with tibial plateau fractures were prospectively followed. Patients were included if they were operatively treated, had an Injury Severity Score of < 16, and had follow-up through 12 months. Clinical, radiographic, and functional outcomes were evaluated at the 3, 6, and 12-month follow-up points. RESULTS:Mean time to radiographic fracture union was by 4.68 and 5.26 months in young and elderly patients, respectively (p = 0.25). There was no difference in self-reported baseline SMFA (p = 0.617). SMFA scores were better in younger patients at 3 months (p = 0.031), however this did not hold when multivariate modeling controlled for other factors. There was no difference at 6 and 12 months (p = 0.475, 0.392). There was no difference in range of knee motion at 3 months. At 6 and 12 months, young patients had statistically but not clinically better range of knee motion (p = 0.045, 0.007). There were no differences in overall reoperation rates, conversion arthroplasty, post-traumatic osteoarthritis or wound complications. CONCLUSIONS:Age greater than 65 does not appear to portend poorer outcomes after surgical repair of a tibial plateau fracture. The complication profiles are similar. Elderly and younger patients had similar function at 12 months compared to their baseline. These data suggest that age should not be a disqualifying factor when considering whether a patient with a tibial plateau fracture should be treated operatively.

PURPOSE/OBJECTIVE:To determine if the type of approach used for treatment of lateral split-depression tibial plateau fractures affects clinical outcome and complications rate. METHODS:This is a retrospective review of 169 patients who presented between 01/2005 and 12/2020 to a Level-I trauma center for operative management of an isolated lateral Schatzker II tibial plateau fractures (AO/OTA Type 41B3.1) treated through a single anterolateral approach: a 90-degree "L" (L), longitudinal vertical (V), or "lazy S" (S). Postoperative radiographic, clinical, and functional outcomes were assessed at 3, 6, 12 months, and beyond. RESULTS:Average time to radiographic healing was longer in the S incision cohort (p < 0.05). Furthermore, patients within the S incision cohort developed more postoperative wound complications at follow-up when compared to those within the L and V incision cohorts (p < 0.05). Additionally, reoperation rates were greater in the S incision cohort (p < 0.05). Lastly, on physical examination of the knee, patients within the S incision cohort had significantly poorer knee range of motion (p < 0.05). CONCLUSIONS:Our study demonstrates that skin incision type in the anterolateral approach to the proximal tibia has an association with outcomes following operative repair of tibial plateau fractures. The information from this study can be used to inform surgeons about the potential complications and long-term outcomes that patients may experience when undergoing operative repair of a tibial plateau fracture through a specific incision type. LEVEL OF EVIDENCE/METHODS:III.

Platelet-rich plasma (PRP) has garnered widespread and increasing attention in recent years. We aimed to characterize the most influential articles in PRP research while clarifying controversies surrounding its use and clinical efficacy and identifying important areas on which to focus future research efforts. The Science Citation Index Expanded subsection of the Web of Science Core Collection was systematically searched to identify the top 50 cited publications on orthopedic PRP research. Publication and study characteristics were extracted, and Spearman's correlations were calculated to assess the relationship between citation data and level of evidence. The top 50 articles were published between the years 2005 and 2016, with 68% published in the year 2010 or later. Of the 33 studies for which level of evidence was assessed, the majority were of level I or II (18, 54.5%). Seventeen articles (34%) were classified as basic science. All clinical studies were prospective, and most (12 studies, 60%) included a high number of metrics related to the PRP preparation protocol and composition. Knee osteoarthritis was the most common topic among clinical studies in the top 50 cited articles (11 studies, 34%). More recent articles were associated with higher citation rates (ρ = 0.46, p < 0.001). The most influential articles on orthopaedic PRP research are recent and consist of high-level of evidence studies mostly. Randomized controlled trials were the most common study type, while basic science articles were relatively less common. The most influential clinical studies reported a high number of metrics related to their PRP preparation protocol and the final PRP composition. These results suggest a rapidly evolving field with the potential to better explain inconsistent clinical results with improved understanding and documentation of basic science concepts such as PRP composition, preparation, and combination techniques.

PURPOSE/OBJECTIVE:The purpose of this study is to compare medium to long term patient reported outcomes to one-year data for patients treated surgically for an aseptic fracture nonunion. METHODS:305 patients surgically treated for a fracture-nonunion were prospectively followed. Data collected included pain scores measured by the Visual Analog Scale (VAS), clinical outcomes assessed by the Short Musculoskeletal Functional Assessment (SMFA), and range of motion. 75% of patients in this study had lower extremity fracture nonunions and 25% had upper extremity fracture nonunions. Femur fracture nonunions were the most common. Data at latest follow-up was compared to one-year follow-up using the independent t-test. RESULTS:Sixty-two patients were available for follow-up data at an average of eight years. There were no differences in patient reported outcomes between one and eight years according to the standardized total SMFA (p = 0.982), functional index SMFA (p = 0.186), bothersome index SMFA (p = 0.396), activity index SMFA (p = 0.788), emotional index SMFA (p = 0.923), or mobility index SMFA (p = 0.649). There was also no difference in reported pain (p = 0.534). Range of motion data was collected for patients who followed up in clinic for an average of eight years after their surgical treatment. 58% of these patients reported a slight increase in range of motion at an average of eight years. CONCLUSION/CONCLUSIONS:Patient functional outcomes, range of motion, and reported pain all normalize after one year following surgical treatment for fracture nonunion and do not change significantly at an average of eight years. Surgeons can feel confident in counseling patients that their results will last and they do not need to follow up beyond one year, barring pain or other complications. LEVEL OF EVIDENCE/METHODS:Level IV.

PURPOSE/OBJECTIVE:To analyze clinical, radiographic and patient-reported outcomes of distal metaphyseal femoral nonunions treated with fixed-angle plates and screws. METHODS:All patients presenting with a distal metaphyseal femoral fracture nonunion repaired with fixed-angle plating from one urban level 1 trauma center and an orthopedic specialty hospital were identified. Baseline demographic, injury information, and outcomes (healing rates, Short Musculoskeletal Function Assessment, range of motion, and post-operative pain levels) at 12 months following nonunion repair were collected. Outcomes were evaluated between patients fixed with a blade plate and with a locking plate. RESULTS:Of these 31 patients, 27 (87.1%) healed after their index nonunion surgery, 2 (6.5%) healed after one reoperation, 1 (3.2%) healed after 2 reoperations, and 1 (3.2%) had a persistent nonunion but did not want further treatment. At one-year follow-up, the group demonstrated a significant improvement in functional recovery with a mean difference of 14.5 points (p = 0.007) when compared to status before fixed-angle fixation of the nonunion. There was also a significant change in patient-reported pain levels using the VAS scale with a mean difference of 2.0 points (p = 0.009). At one-year follow-up, 11 (39.3%) had full knee range of motion (0-130), 11 (39.3%) had flexion greater than 90 and less than 120°, and 6 (21.4%) had range of motion less than 90°. CONCLUSION/CONCLUSIONS:Patients who undergo fixed angle plating and autogenous bone grafting for distal femoral metapyseal nonunions demonstrate improved functional outcomes and VAS pain score at one year follow up.

BACKGROUND:Multiple techniques have been developed for the repair of acute quadriceps and patellar tendon ruptures with the goal of optimizing clinical outcomes while minimizing complications and costs. The purpose of this study was to evaluate the biomechanical properties of transosseous tunnels and suture anchors for the repair of quadriceps and patellar tendon ruptures. METHODS:≥25%). RESULTS:A total of 392 studies were identified from the initial literature search with 7 studies meeting the eligibility criteria for quadriceps tendon repair and 8 studies meeting the eligibility criteria for patellar tendon repair. Based on the random-effects model for total gap formation and load to failure for quadriceps tendon repair, the mean difference was 8.88 mm (95% CI, -8.31 mm to 26.06 mm; p = 0.31) in favor of a larger gap with transosseous tunnels and -117.25N (95%CI, -242.73N to 8.23N; p = 0.07) in favor of a larger load to failure with suture anchors. A similar analysis for patellar tendon repair demonstrated a mean difference of 2.86 mm (95% CI, 1.08 mm to 4.64 mm; p = 0.002) in favor of a larger gap with transosseous tunnels and -56.34N (95% CI, -226.75 to 114.07N; p = 0.52) in favor of a larger load to failure with suture anchor repair. CONCLUSIONS:Transosseous tunnels are biomechanically similar to suture anchors for quadriceps tendon repair. Patellar tendon repair may benefit from reduced gap formation after cycling with suture anchor repair, but the load to failure for both techniques is biomechanically similar. Additional studies are necessary to evaluate these and alternative repair techniques. LEVEL OF EVIDENCE/METHODS:Systematic review and meta-analysis of biomechanical studies, Level V.

RAS proteins are small GTPases that transduce signals from membrane receptors to signaling pathways that regulate growth and differentiation. Four RAS proteins are encoded by three genes - HRAS, KRAS, NRAS. Among them, KRAS is mutated in human cancer more frequently than any other oncogene. The KRAS pre-mRNA is alternatively spliced to generate two transcripts, KRAS4A and KRAS4B, that encode distinct proto-oncoproteins that differ almost exclusively in their C-terminal hypervariable regions (HVRs) that controls subcellular trafficking and membrane association. The KRAS4A isoform arose 475 million years ago in jawed vertebrates and has persisted in all vertebrates ever since, strongly suggesting non-overlapping functions of the splice variants. Because KRAS4B is expressed at higher levels in most tissues, it has been considered the principal KRAS isoform. However, emerging evidence for KRAS4A expression in tumors and splice variant-specific interactions and functions have sparked interest in this gene product. Among these findings, the KRAS4A-specific regulation of hexokinase I is a stark example. The aim of this mini-review is to provide an overview of the origin and differential functions of the two splice variants of KRAS.