Faculty Bibliography

This study compares outcomes of patients with Lisfranc injuries treated with screw only fixation constructs to those treated with dorsal plate and screw constructs. Seventy patients who underwent surgical treatment for acute Lisfranc injury without arthrodesis and minimum 6-month (mean >1-year) follow-up were identified. Demographics, surgical information, and radiographic imaging were reviewed. Cost data were compared. The primary outcome measure was the American Orthopedic Foot and Ankle Surgery (AOFAS) midfoot score. Univariate analysis through independent sample t tests, Mann-Whitney U, and chi-squared compared the populations. Twenty-three (33%) patients were treated with plate constructs and 47 (67%) with screw only fixation. The plate group was older (49 ± 18 vs 40 ± 16 years, p = .029). More screw constructs treated isolated medial column injuries compared to plate constructs (92% vs 65%, p = .006). At latest follow-up (mean 14 ± 13 months), all tarsometatarsal joints were aligned. There was no difference in AOFAS midfoot scores. Plate patients experienced longer operations (131 ± 70 vs 75 ± 31 minutes, p < .001) and tourniquet time (101 ± 41 vs 69 ± 25 minutes, p = .001). Plate constructs were more expensive than screw ($2.3X ± $2.3X vs $X ± $0.4X, p < .001) ($X is the mean cost of screws alone). Plate patients had a higher incidence of wound complications (13% vs 0%, p = .012). Treatment of Lisfranc fracture dislocation injuries with screws only demonstrated a higher value procedure as similar outcomes were found amidst lower implant costs. Screw only fixation required a shorter operative and tourniquet time with less frequent wound complications. Screw only fixations proved mechanically sound enough to achieve goals of repair without inferior outcomes.

Specific and effective treatments for autism spectrum disorder (ASD) are lacking due to a poor understanding of disease mechanisms. Here we test the idea that similarities between diverse ASD mouse models are caused by deficits in common molecular pathways at neuronal synapses. To do this, we leverage the availability of multiple genetic models of ASD that exhibit shared synaptic and behavioral deficits and use quantitative mass spectrometry with isobaric tandem mass tagging (TMT) to compare their hippocampal synaptic proteomes. Comparative analyses of mouse models for Fragile X syndrome (Fmr1 knockout), cortical dysplasia focal epilepsy syndrome (Cntnap2 knockout), PTEN hamartoma tumor syndrome (Pten haploinsufficiency), ANKS1B syndrome (Anks1b haploinsufficiency), and idiopathic autism (BTBR+) revealed several common altered cellular and molecular pathways at the synapse, including changes in oxidative phosphorylation, and Rho family small GTPase signaling. Functional validation of one of these aberrant pathways, Rac1 signaling, confirms that the ANKS1B model displays altered Rac1 activity counter to that observed in other models, as predicted by the bioinformatic analyses. Overall similarity analyses reveal clusters of synaptic profiles, which may form the basis for molecular subtypes that explain genetic heterogeneity in ASD despite a common clinical diagnosis. Our results suggest that ASD-linked susceptibility genes ultimately converge on common signaling pathways regulating synaptic function and propose that these points of convergence are key to understanding the pathogenesis of this disorder.

BACKGROUND/UNASSIGNED:Locking plate technology was developed approximately 25-years-ago and has been successfully used since. Newer designs and material properties have been used to modify the original design, but these changes have yet to be correlated to improved patient outcomes. The purpose of this study was to evaluate the outcomes of first-generation locking plate (FGLP) and screw systems at our institution over an 18 year period. METHODS/UNASSIGNED:Between 2001 to 2018, 76 patients with 82 proximal tibia and distal femur fractures (both acute fracture and nonunions) who were treated with a first-generation titanium, uniaxial locking plate with unicortical screws (FGLP), also known as a LISS plate (Synthes Paoli Pa), were identified and compared to 198 patients with 203 similar fracture patterns treated with 2nd and 3rd generation locking plates, or Later Generation Locking Plates (LGLP). Inclusion criteria was a minimum of 1-year follow-up. At latest follow-up, outcomes were assessed using radiographic analysis, Short Musculoskeletal Functional Assessment (SMFA), VAS pain scores, and knee ROM. All descriptive statistics were calculated using IBM SPSS (Armonk, NY). RESULTS/UNASSIGNED:A total of 76 patients with 82 fractures had a mean 4-year follow-up available for analysis. There were 76 patients with 82 fractures fixed with a First-generation locking plate. The mean age at time of injury for all patients was 59.2 and 61.0% were female. Mean time to union for fractures about the knee fixed with FGLP was by 5.3 months for acute fractures and 6.1 months for nonunions. At final follow-up, the mean standardized SMFA for all patients was 19.9, mean knee range of motion was 1.6°-111.9°, and mean VAS pain score was 2.7. When compared to a group of similar patients with similar fractures and nonunions treated with LGLPs there were no differences in outcomes assessed. CONCLUSION/UNASSIGNED:.

Classic experiments with peripheral sympathetic neurons established an absolute dependence upon NGF for survival. A forgotten problem is how these neurons become resistant to deprivation of trophic factors. The question is whether and how neurons can survive in the absence of trophic support. However, the mechanism is not understood how neurons switch their phenotype to lose their dependence on trophic factors, such as NGF and BDNF. Here, we approach the problem by considering the requirements for trophic support of peripheral sympathetic neurons and hippocampal neurons from the central nervous system. We developed cellular assays to assess trophic factor dependency for sympathetic and hippocampal neurons and identified factors that rescue neurons in the absence of trophic support. They include enhanced expression of a subunit of the NGF receptor (Neurotrophin Receptor Homolog, NRH) in sympathetic neurons and an increase of the expression of the glucocorticoid receptor in hippocampal neurons. The results are significant since levels and activity of trophic factors are responsible for many neuropsychiatric conditions. Resistance of neurons to trophic factor deprivation may be relevant to the underlying basis of longevity, as well as an important element in preventing neurodegeneration.

Loss of bone is a common medical problem and, while it can be treated with available therapies, some of these therapies have critical side effects. We have previously demonstrated that CGS21680, a selective A_2A adenosine receptor agonist, prevents bone loss, but its on-target toxicities (hypotension, tachycardia) and frequent dosing requirements make it unusable in the clinic. We therefore generated a novel alendronate-CGS21680 conjugate (MRS7216), to target the agonist to bone where it remains for long periods thereby diminishing the frequency of administration and curtailing side effects. MRS7216 was synthesized from CGS21680 by sequential activation of the carboxylic acid moiety and reacting with an appropriate amino acid (PEG, alendronic acid) under basic conditions. MRS7216 was tested on C57BL/6J (WT) mice with established osteoporosis (OP) and WT or A2A KO mice with wear particle-induced inflammatory osteolysis (OL). Mice were treated weekly with MRS7216 (10mg/kg). Bone formation was studied after in vivo labeling with calcein/Alizarin Red, and μCT and histology analyses were performed. In addition, human primary osteoblasts and osteoclasts were cultured using bone marrow discarded after hip replacement. Receptor binding studies demonstrate that MRS7216 efficiently binds the A2A adenosine receptor. MRS7216-treated OP and OL mice had significant new bone formation and reduced bone loss compared to vehicle or alendronate-treated mice. Histological analysis showed that MRS7216 treatment significantly reduced osteoclast number and increased osteoblast number in murine models. Interestingly, cultured human osteoclast differentiation was inhibited, and osteoblast differentiation was stimulated by the compound indicating that MRS7216 conjugates represent a novel therapeutic approach to treat osteoporosis and osteolysis.

Abdominal aortic aneurysms (AAA) is a multifactorial complex disease with life-threatening consequences. While Genome-wide association studies (GWAS) have revealed several single nucleotide polymorphisms (SNPs) located in the genome of individuals with AAA, the link between SNPs with the associated pathological signals, the influence of risk factors on their distribution and their combined analysis is not fully understood. We integrated 86 AAA SNPs from GWAS and clinical cohorts from the literature to determine their phenotypical vulnerabilities and association with AAA risk factors. The SNPs were annotated using snpXplorer AnnotateMe tool to identify their chromosomal position, minor allele frequency, CADD (Combined Annotation Dependent Depletion), annotation-based pathogenicity score, variant consequence, and their associated gene. Gene enrichment analysis was performed using Gene Ontology and clustered using REVIGO. The plug-in GeneMANIA in Cytoscape was applied to identify network integration with associated genes and functions. 15 SNPs affecting 20 genes with a CADD score above ten were identified. AAA SNPs were predominantly located on chromosome 3 and 9. Stop-gained rs5516 SNP obtained high frequency in AAA and associated with proinflammatory and vascular remodeling phenotypes. SNPs presence positively correlated with hypertension, dyslipidemia and smoking history. GO showed that AAA SNPs and their associated genes could regulate lipid metabolism, extracellular matrix organization, smooth muscle cell proliferation, and oxidative stress, suggesting that part of these AAA traits could stem from genetic abnormalities. We show a library of inborn SNPs and associated genes that manifest in AAA. We uncover their pathological signaling trajectories that likely fuel AAA development.

Objectives: Smoking is the commonest cause of oral cavity squamous cell carcinoma (OC-SCC), but the etiology of OC-SCC in nonsmokers is unknown. Our primary goal was to use metagenomic shotgun sequencing (MSS) to define the taxonomic composition and functional potential of oral metagenome in nonsmokers with OC-SCC. Methods: We conducted a case"“control study with 42 OC-SCC case and 45 control nonsmokers. MSS was performed on DNA extracted from mouthwash samples. Taxonomic analysis and pathway analysis were done using MetaPhlAn2 and HUMAnN2, respectively. Statistical difference was determined using the Mann"“Whitney test controlling false discovery rate. Results: There was no significant difference in age, sex, race, or alcohol consumption between OC-SCC and control patients. There was a significant difference in beta diversity between OC-SCC and controls. At the phylum level, Bacteroidetes and Synergistetes were overly represented in OC-SCC while Actinobacteria and Firmicutes were overly represented in controls. At the genus level, Fusobacterium was overly represented in OC-SCC compared with controls, while Corynebacterium, Streptococcus, Actinomyces, Cryptobacterium, and Selenomonas were overly represented in controls. Bacterial pathway analysis identified overrepresentation in OC-SCC of pathways related to metabolism of flavin, biotin, thiamin, heme, sugars, fatty acids, peptidoglycans, and tRNA and overrepresentation of nucleotides and essential amino acids in controls. Conclusions: The oral microbiome in nonsmoker patients with OC-SCC is significantly different from that of nonsmoker control patients in taxonomic compositions and functional potentials. Our study"™s MSS findings matched with previous 16S-based methods in taxonomic differentiation but varied greatly in functional differentiation of microbiomes in OC-SCC and controls.