Faculty Bibliography

BACKGROUND:The purpose of this study was to compare narcotic use in the 90-day postoperative period across orthopaedic trauma, spine, and adult reconstruction patients and examine whether patient-reported pain scores at discharge correlate with narcotic use during the 90-day postoperative period. METHODS:Electronic medical record query was done between 2012 and 2015 using diagnosis-related groups for spine, adult reconstruction, and trauma procedures. Demographics, length of stay (LOS), visual analog scale pain scores during hospitalization, and narcotics prescribed in the 90-day postoperative period were collected. Multivariate analysis and linear regression were done. RESULTS:Five thousand thirty patients were analyzed. Spine patients had the longest LOS, highest mean pain during LOS, and were prescribed the most morphine in the 90-day postoperative period. Linear regression revealed that pain scores at discharge markedly influence the quantity of narcotics prescribed in the 90-day postoperative period. DISCUSSION/CONCLUSIONS:Patient-reported pain at hospital discharge was associated with increased narcotic use in the 90-day postoperative period.

Down Syndrome Cell Adhesion Molecules (dscam and dscaml1) are essential regulators of neural circuit assembly, but their roles in vertebrate neural circuit function are still mostly unexplored. We investigated the functional consequences of dscaml1 deficiency in the larval zebrafish (sexually undifferentiated) oculomotor system, where behavior, circuit function, and neuronal activity can be precisely quantified. Genetic perturbation of dscaml1 resulted in deficits in retinal patterning and light adaptation, consistent with its known roles in mammals. Oculomotor analyses revealed specific deficits related to the dscaml1 mutation, including severe fatigue during gaze stabilization, reduced saccade amplitude and velocity in the light, greater disconjugacy, and impaired fixation. Two-photon calcium imaging of abducens neurons in control and dscaml1 mutant animals confirmed deficits in saccade-command signals (indicative of an impairment in the saccadic premotor pathway), while abducens activation by the pretectum-vestibular pathway was not affected. Together, we show that loss of dscaml1 resulted in impairments in specific oculomotor circuits, providing a new animal model to investigate the development of oculomotor premotor pathways and their associated human ocular disorders.SIGNIFICANCE STATEMENTDscaml1 is a neural developmental gene with unknown behavioral significance. Using the zebrafish model, this study shows that dscaml1 mutants have a host of oculomotor (eye movement) deficits. Notably, the oculomotor phenotypes in dscaml1 mutants are reminiscent of human ocular motor apraxia, a neurodevelopmental disorder characterized by reduced saccade amplitude and gaze stabilization deficits. Population-level recording of neuronal activity further revealed potential subcircuit-specific requirements for dscaml1 during oculomotor behavior. These findings underscore the importance of dscaml1 in the development of visuomotor function and characterize a new model to investigate potential circuit deficits underlying human oculomotor disorders.

After mastectomy, breast reconstruction is increasingly performed using autologous tissue with the aim of improving quality of life. During this procedure, autologous tissue is excised, relocated, and reattached using vascular anastomoses at the site of the extirpated breast. The period during which the tissue is ex vivo may allow genetic modification without any systemic exposure to the vector. Could such access be used to deliver therapeutic agents using the tissue flap as a vehicle? Such delivery may be more efficient than systemic treatment, in terms of oncological outcomes. The cytokine interferon gamma (IFNγ) has antitumor effects, but systemic toxicity that could be circumvented if its effect can be localized by delivery of the IFNγ gene via gene therapy to autologous tissue used for breast reconstruction, which then releases IFNγ and exerts anti-tumor effects. In a rat model of loco-regional recurrence (LRR) using both MADB-106-Luc and MAD-MB-231-Luc breast cancer cells, autologous tissue was transduced ex vivo with an adeno-associated viral vector (AAV) encoding IFNγ. The therapeutic reconstruction released IFNγ at the LRR site and eliminated cancer cells, significantly decreased tumor burden (P<0.05), and increased survival by 33% (P<0.05) compared to sham reconstruction. Mechanistically, localized IFNγ immunotherapy stimulated M1 macrophages to target cancer cells within the regional confines of the modified tumor environment. This concept of therapeutic breast reconstruction using ex vivo gene therapy of autologous tissue offers a new application for immunotherapy in breast cancer with a dual therapeutic effect of both reconstructing the ablative defect and delivering local adjuvant immunotherapy.

OBJECTIVES/OBJECTIVE:To evaluate the causes of 30-day readmissions following orthopedic trauma surgery and classify them based on their relation to the index admission. DESIGN/METHODS:Retrospective chart review. SETTING/METHODS:One large, academic medical center. PARTICIPANTS/METHODS:Patients admitted to a large, academic medical center for a traumatic fracture injury over a nine-year period. INTERVENTION/METHODS:Assignment of readmission classification. MAIN OUTCOME MEASUREMENTS/METHODS:Readmissions within 30 days of discharge were identified and classified into: orthopedic complications; medical complications; and non-complications. A chi-square test was performed to assess any difference in the proportion of readmissions between the hospital-reported readmission rate and the orthopedic complication readmission rate. RESULTS:1,955 patients who were admitted between 2011-2018 for an acute orthopedic trauma fracture injury were identified. Eighty-nine patients were readmitted within 30 days of discharge with an overall readmission rate of 4.55%. Within the 30-day readmission cohort, 30 (33.7%) were the direct result of orthopedic treatment complications, 36 (40.4%) were unrelated medical conditions, and 23 (25.8%) were non-complications. Thus, the readmission rate directly due to orthopedic treatment complications was 1.53%. A chi-square test of homogeneity revealed a statistically significant difference between the hospital-reported readmission rate and the orthopedic-treatment complication readmission rate, p < .0005. CONCLUSION/CONCLUSIONS:The use of 30-day readmissions as a measure of hospital quality of care overreports the number of preventable readmissions and penalizes surgeons and hospitals for caring for patients with less optimal health. LEVEL OF EVIDENCE/METHODS:Diagnostic Level III.

OBJECTIVES/OBJECTIVE:This study aims to investigate the role and mechanism of FGFR3 in macrophages and their biological effects on the pathology of arthritis. METHODS:Mice with conditional knockout of FGFR3 in myeloid cells (R3cKO) were generated. Gait behaviours of the mice were monitored at different ages. Spontaneous synovial joint destruction was evaluated by digital radiographic imaging and μCT analysis; changes of articular cartilage and synovitis were determined by histological analysis. The recruitment of macrophages in the synovium was examined by immunostaining and monocyte trafficking assay. RNA-seq analysis, Western blotting and chemotaxis experiment were performed on control and FGFR3-deficient macrophages. The peripheral blood from non-osteoarthritis (OA) donors and patients with OA were analysed. Mice were treated with neutralising antibody against CXCR7 to investigate the role of CXCR7 in arthritis. RESULTS:R3cKO mice but not control mice developed spontaneous cartilage destruction in multiple synovial joints at the age of 13 months. Moreover, the synovitis and macrophage accumulation were observed in the joints of 9-month-old R3cKO mice when the articular cartilage was not grossly destructed. FGFR3 deficiency in myeloid cells also aggravated joint destruction in DMM mouse model. Mechanically, FGFR3 deficiency promoted macrophage chemotaxis partly through activation of NF-κB/CXCR7 pathway. Inhibition of CXCR7 could significantly reverse FGFR3-deficiency-enhanced macrophage chemotaxis and the arthritic phenotype in R3cKO mice. CONCLUSIONS:Our study identifies the role of FGFR3 in synovial macrophage recruitment and synovitis, which provides a new insight into the pathological mechanisms of inflammation-related arthritis.

This retrospective, matched-cohort study analyzed 1,556 patients with diabetic ulcers treated at 470 wound centers throughout the United States to determine the effectiveness of a cryopreserved bioactive split-thickness skin allograft plus standard of care when compared to standard of care alone. There were 778 patients treated with the graft in the treatment cohort, who were paired with 778 patients drawn from a pool of 126,864 candidates treated with standard of care alone (controls), by using propensity matching to create nearly identical cohorts. Both cohorts received standard wound care, including surgical debridement, moist wound care, and offloading. Logistic regression analysis of healing rates according to wound size, wound location, wound duration, volume reduction, exposed deep structures, and Wagner grade was performed. Amputation rates and recidivism at 3 months, 6 months, and 1 year after wound closure were analyzed. Diabetic ulcers were 59% more likely to close in the treatment cohort compared to the control cohort (p = .0045). The healing rate with the graft was better than standard of care across multiple subsets, but the most significant improvement was noted in the worst wounds that had a duration of 90-179 days prior to treatment (p =.0073), exposed deep structures (p = .036), and/or Wagner Grade 4 ulcers (p = 0.04). Furthermore, the decrease in recidivism was statistically significant at 3 months, 6 months, and 1 year, with and without initially exposed deep structures (p < .05). The amputation rate in the treatment cohort was 41.7% less than that of the control cohort at 20 weeks (0.9% vs 1.5%, respectively). This study demonstrated that diabetic ulcers treated with a cryopreserved bioactive split-thickness skin allograft were more likely to heal and remain closed compared to ulcers treated with standard of care alone. This article is protected by copyright. All rights reserved.

Chronic wounds affect roughly 6.5 million patients in the United States annually. Current standard of therapy entails weekly sharp debridement. However, the sharp technique is associated with significant pain, while having minimal impact on the bioburden. Our study proposes the Er:YAG laser as an alternative method of debridement that may decrease procedural pain, reduce bioburden, and potentially improve overall healing. This pilot study was performed as a prospective, randomized, controlled, crossover clinical trial, containing two groups: 1) one group underwent single laser debridement session first, followed by single sharp debridement session one week later; 2) the other group underwent single sharp debridement session first, followed by single laser debridement session one week later. Variables analyzed included pain during debridement, pre- and post-debridement wound sizes, pre- and post-debridement bacterial loads and patient preference. Twenty-two patients were enrolled (12 patients in Group 1, plus 10 patients in Group 2). The mean pain score for patients undergoing laser debridement was 3.0 ± 1.7 versus 4.8 ± 2.6 for those undergoing sharp debridement (p = 0.003). The mean percent change in wound size one-week post-laser debridement was -20.8% ± 80.1%, as compared with -36.7% ± 54.3% one-week post-sharp debridement (p = 0.6). The percentage of patients who had a bacterial load in the Low/Negative category increased from 27.3% to 59.1% immediately after laser debridement (p = 0.04), versus 54.5% to 68.2% immediately after sharp debridement (p = 0.38). Moreover, there was a sustained decrease in bacterial load one-week post-laser debridement, as compared with no sustained decrease one-week post-sharp debridement (p < 0.02). Overall, 52.9% of patients preferred laser debridement versus 35.3% for sharp debridement. We believe that Er:YAG laser serves as a promising technology in chronic wounds, functioning as a potentially superior alternative to sharp debridement, the current standard of therapy. This article is protected by copyright. All rights reserved.

The recruitment and activation of inflammatory cells in the liver delineates the transition from hepatic steatosis to steatohepatitis. We found that in steatohepatitis, γδT cells are recruited to the liver by CCR2, CCR5, and NOD2 signaling and are skewed towards an IL-17A⁺ phenotype in an ICOS-ICOSL dependent manner. γδT cells exhibit a distinct Vγ4⁺ , PD1⁺ , Ly6C⁺ CD44⁺ phenotype in steatohepatitis. Moreover, γδT cells upregulate both CD1d, which is necessary for lipid-based antigens presentation, and the free fatty acid receptor CD36. γδT cells are stimulated to express IL-17A by palmitic acid and CD1d ligation. Deletion, depletion, and targeted interruption of γδT cell recruitment protects against diet-induced steatohepatitis and accelerates disease resolution. We demonstrate that hepatic γδT cells exacerbate steatohepatitis, independent of IL-17 expression, by mitigating conventional CD4⁺ T cell expansion and modulating their inflammatory program via CD1d-dependent VEGF expression.

BACKGROUND:Pressure injury is seen across all healthcare settings and affects people of any age and health condition. It imposes a significant burden, with annual costs of up to $17.8 billion in the United States alone. Despite considerable resources it exhausts, the disease remains very prevalent, and the incidence is on the rise. This is in part due to aging population, growing number of nursing home residents, poorly understood biology, and dismal track record of clinical research in this field. METHODS:In our Review Article, we discuss the disease pathophysiology, clinical manifestation, evidence based recommendations for risk assessment, prevention and timely management, existing challenges, and directions to improve research on the field. This article encompasses dedicated sections on the full spectrum of the pressure related pathologies including "conventional pressure ulcers", "medical device related pressure injuries", "pressure injuries in mucosal membranes", "pressure injuries in pediatric population", "pressure injury at end of life", and the "role of pressure in pathogenesis of diabetic foot ulcers".