Faculty Bibliography

A growing number of patients are seeking answers for their health concerns online. This study assesses the reliability, quality, and readability of online materials patients have access to through the Internet and evaluates the social media presence of information providers. An online search was conducted for facial rejuvenation by utilizing three ubiquitously used web search engines: Google, Bing, and Yahoo. The first 25 result pages were collected from each search engine, and exclusionary criteria were applied to exclude online stores and advertisements. Website reliability and quality were assessed via the DISCERN method. Readability was measured through six measurements: Flesch-Kincaid Grade Level (FKGL), Gunning Fox score, SMOG index, Coleman Liau index, and automated readability index. Social media presence and profile followers on Facebook, Twitter, and Instagram were determined to gauge social media presence. Exclusionary criteria yielded 41 unique websites, with the majority of websites authored by physicians (54%) followed by professional organizations (19%). The DISCERN method demonstrated that journal websites yielded the highest overall quality (4.00) and physician websites yielded the lowest (2.72). Readability analysis demonstrated that online forums proved the most challenging to read, and encyclopedia articles were the least challenging. Physician websites maintained the highest social media presence (95%) followed by professional organizations (75%). However, professional organizations had more social media followers in comparison to physician websites. Physician websites and professional organizations overwhelmingly command social media presence compared to other information providers and provide information with serious deficits in reliability and quality. A strong majority of online information also surpasses the health care literacy of patients. This poses a serious concern for physicians who need to provide and guide patients to high quality and reliable information.

Reduced laryngeal sensation and accumulated pharyngeal secretions are known predictors of aspiration. Yet, their association with residue has not been fully explored. One Hundred and ten fiberoptic endoscopic examination of swallowing (FEES) examinations were retrospectively analyzed. Murray's secretion scale (MSS) for secretion stasis and laryngeal sensation were tested for association with residue severity (Yale pharyngeal residue severity rating scale, YPR-SRS) and the number of swallows required to clear the bolus. The bolus challenges of each consistency (liquid, purée and solid) with the highest PAS and YPR-SRS scores were analyzed. Impaired laryngeal sensation (ILS) and MSS were both independently significantly associated with higher YPR-SRS for all consistencies examined. Mean YPR-SRS for patients with both ILS and secretion stasis was respectively 2.4 ± 1.1, 2.5 ± 1.2, 2.4 ± 1.2 for liquid, purée and solids in the vallecula, and 2.9 ± 1.3, 2.3 ± 1.1, 2 ± 1 for pyriform sinuses residue compared to 1.8 ± 0.7, 1.6 ± 1, 1.6 ± 1 for vallecular residue and 1.8 ± 0.8, 1.4 ± 0.8, 1.3 ± 0.7 for pyriform sinus residue of patients with normal laryngeal sensation and no stasis (p < 0.05 for all except liquids in vallecula). The combined findings of both ILS and MSS ≥ 1 had a sensitivity of 25.9%, specificity of 94.2%, positive predictive value (PPV) of 83.3% and negative predictive value (NPV) of 53.3% for prediction of pharyngeal residue and a sensitivity of 58.3%, specificity of 88.8%, PPV of 39.9% and a NPV of 94.6% for prediction of aspiration. Both ILS and MSS were significantly associated with increased number of swallows required to clear a bolus. Abnormal laryngeal sensation and secretion stasis are associated with pharyngeal residue severity and reduced residue clearing on FEES.

Neurofibromatosis type 2 (NF2) is an autosomal-dominant disorder characterized by the development of bilateral vestibular schwannomas. The NF2 gene encodes the tumor suppressor merlin, and loss of merlin activity promotes tumorigenesis and causes NF2. Cellular redox signaling has been implicated in different stages of tumor development. Among reactive nitrogen species, peroxynitrite is the most powerful oxidant produced by cells. We recently showed that peroxynitrite-mediated tyrosine nitration down-regulates mitochondrial metabolism in tumor cells. However, whether peroxynitrite supports a metabolic shift that could be exploited for therapeutic development is unknown. Here, we show that vestibular schwannomas from NF2 patients and human, merlin-deficient (MD) Schwann cells have high levels of endogenous tyrosine nitration, indicating production of peroxynitrite. Further, scavenging or inhibiting peroxynitrite formation significantly and selectively decreased survival of human and mouse MD-Schwann cells. Using multiple complementary methods, we also found that merlin deficiency leads to a reprogramming of energy metabolism characterized by a peroxynitrite-dependent decrease of oxidative phosphorylation and increased glycolysis and glutaminolysis. In MD Schwann cells, scavenging of peroxynitrite increased mitochondrial oxygen consumption and membrane potential, mediated by the up-regulation of the levels and activity of mitochondrial complex IV. This increase in mitochondrial activity correlated with a decrease in the glycolytic rate and glutamine dependency. This is the first demonstration of a peroxynitrite-dependent reprogramming of energy metabolism in tumor cells. Oxidized proteins constitute a novel target for therapeutic development not only for the treatment of NF2 schwannomas but also other tumors in which peroxynitrite plays a regulatory role.

BACKGROUND/UNASSIGNED:Improved player safety is an important goal of professional baseball. Prevention of mild traumatic brain injury (concussion) is an area of emphasis because of the potential for long-term as well as short-term sequelae. HYPOTHESIS/UNASSIGNED:A rule change can lower the incidence of concussions and other injuries in professional baseball. STUDY DESIGN/UNASSIGNED:Cohort study; Level of evidence, 3. METHODS/UNASSIGNED:This study included a retrospective review of data entered concurrently into professional baseball's electronic medical record system. All minor and major league teams are required to use this system. All injuries are captured by creation of a new record in the system at the time of the injury. All active minor and major league players from 2011 to 2017 were included. The 30 major league clubs have 1200 roster players and play 162 games per season. The approximately 200 minor league clubs have about 7500 active players and play 56 to 144 games annually that combine for approximately 330,000 athlete-exposures per season. Before the 2014 season, Major League Baseball, in conjunction with its players association, instituted a rule limiting home plate collisions between base runners and catchers that applied to both Major League Baseball and Minor League Baseball. All concussions and other injuries at home plate from 2011 to 2017 were analyzed by mechanism and player position. RESULTS/UNASSIGNED:= .0001). CONCLUSION/UNASSIGNED:This rule change was associated with significant reductions in the numbers of concussions and other injuries caused by collisions at home plate as well as significant decreases in time lost from play.

Head and neck squamous cell carcinomas (HNSCC) represent a group of epithelial neoplasms that exhibit considerable heterogeneity in clinical behavior. Here, we examined the stromal and vascular heterogeneity in a panel of patient-derived xenograft (PDX) models of HNSCC and the impact on therapeutic response. Tumor sections from established tumors were stained for p16 (surrogate for human papillomavirus (HPV) infection), stromal (Masson's trichrome) and vascular (CD31) markers. All PDX models retained the HPV/p16 status of the original patient tumor. Immunohistochemical evaluation revealed the presence of multiple vessel phenotypes (tumor, stromal or mixed) in the PDX panel. Vascular phenotypes identified in the PDX models were validated in a tissue microarray of human HNSCC. Treatment with a microtubule targeted vascular disrupting agent (VDA) resulted in a heterogeneous antivascular and antitumor response in PDX models. The PDX with the tumor vessel phenotype that exhibited higher CD31+ vessel counts and leaky vasculature on magnetic resonance imaging (MRI) was sensitive to VDA treatment while the PDX with the stromal vessel phenotype was resistant to therapy. Collectively, our results demonstrate the phenotypic and functional vascular heterogeneity in HNSCC and highlight the impact of this heterogeneity on response to antivascular therapy in PDX models of HNSCC.

Proteases sustain hyperexcitability and pain by cleaving protease-activated receptor-2 (PAR₂) on nociceptors through distinct mechanisms. Whereas trypsin induces PAR₂ coupling to Gα_q, Gα_s, and β-arrestins, cathepsin-S (CS) and neutrophil elastase (NE) cleave PAR₂ at distinct sites and activate it by biased mechanisms that induce coupling to Gα_s, but not to Gα_q or β-arrestins. Because proteases activate PAR₂ by irreversible cleavage, and activated PAR₂ is degraded in lysosomes, sustained extracellular protease-mediated signaling requires mobilization of intact PAR₂ from the Golgi apparatus or de novo synthesis of new receptors by incompletely understood mechanisms. We found here that trypsin, CS, and NE stimulate PAR₂-dependent activation of protein kinase D (PKD) in the Golgi of HEK293 cells, in which PKD regulates protein trafficking. The proteases stimulated translocation of the PKD activator Gβγ to the Golgi, coinciding with PAR₂ mobilization from the Golgi. Proteases also induced translocation of a photoconverted PAR₂-Kaede fusion protein from the Golgi to the plasma membrane of KNRK cells. After incubation of HEK293 cells and dorsal root ganglia neurons with CS, NE, or trypsin, PAR₂ responsiveness initially declined, consistent with PAR₂ cleavage and desensitization, and then gradually recovered. Inhibitors of PKD, Gβγ, and protein translation inhibited recovery of PAR₂ responsiveness. PKD and Gβγ inhibitors also attenuated protease-evoked mechanical allodynia in mice. We conclude that proteases that activate PAR₂ by canonical and biased mechanisms stimulate PKD in the Golgi; PAR₂ mobilization and de novo synthesis repopulate the cell surface with intact receptors and sustain nociceptive signaling by extracellular proteases.

Background: Abnormal blood glucose (BG) levels during hematopoietic cell transplantation (HCT) are associated with increased infections, delayed engraftment, and prolonged hospitalization, though little is known about these associations. Materials and Methods: We retrospectively evaluated mean BG levels in the week prior to HCT and subsequent outcomes for 852 HCTs at our hospital from 1/2009 - 12/2013 pertaining to 745 patients. Outcomes included infections (pneumonia, C. difficile, positive cultures, administration of antimicrobials, or neutropenic fever), time-to-engraftment (TTE), and quality indicators (30- and 90-day readmission rates [RR] and median length-of-stay [LOS]). Results: 404 patients met the criteria for involvement in this study. The population was 55% male and was racially and ethnically mixed (White 38%, African American 23%, Hispanic 6%, Asian 7%, Other 21%). Mean age was 57+14 years. Significantly more patients in Group 2 were diagnosed with pneumonia (19%) compared with the Group 1 (7%) and Group 3 (10%) [p=.0054]. Patients in Group 2 also had significantly longer median LOS: Group 1-23 days, Group 2-26 days, Group 3-22 days [p = .0157]. No significant differences were noted in terms of the other infectious complications or in time-to-engraftment or readmissions. Conclusion: Pre-HCT BG trends may be a prognostic biomarker for adverse outcomes, and thus can help improve quality of care for HCT patients.

BACKGROUND:Injection medialization is performed to improve glottic closure, thereby airway protection. Overall objective to determine if unilateral injection medialization changes glottal area with concomitant adjustments in penetration/aspiration scale (PAS) scores and pharyngeal high-resolution manometry (HRM) parameters. METHODS:Enrolled 17 adults with unilateral vocal fold paralysis/paresis and aspiration/penetration. Fiberoptic endoscopic evaluation of swallowing and pharyngeal HRM completed at (1) baseline (within 1 week before injection), (2) postinjection (within 1 week post injection), and (3) 1-month postinjection. Comparisons between time points for PAS scores, glottal area, pharyngeal pressure, and timing. RESULTS:No significant differences in normalized glottal area. No significant differences in PAS scores, for any consistency. Significantly increased rate of mesopharynx pressure rise and maximum pressure at 1 month postinjection (P = .01 and .02, respectively) compared to baseline. Significant decrease in mesopharynx integral from baseline to 1 week postoperative (P = .03). CONCLUSION/CONCLUSIONS:Findings suggest unilateral vocal fold injection medialization had limited effect on swallow function.

OBJECTIVE:To describe and assess intraoperative and postoperative outcomes in the insertion of osseointegrated auditory implants with a newly designed surgical instrumentation set through a punch type technique. STUDY DESIGN/METHODS:Retrospective case series. METHODS:Patients who underwent bone anchored auditory implant surgery using the Minimally Invasive Ponto Surgery (Oticon Medical, Somerset, NJ) surgical set through a punch technique at nine neurotology tertiary referral based practices were identified. Demographic data, skin thickness at implant site, implant used, duration of surgery, adverse intraoperative events, and postoperative outcomes were recorded. RESULTS:Seventy-five patients comprised the study cohort (32 males, 43 females). Most patients (57. 3%) were aged 51 to 75 years while 30.7% of the cohort comprised those aged 18 to 50 years and 12% were over 75 years. All but two patients received 4 mm fixtured implants and 68% received the Oticon Medical BioHelix implant. Two patients received 3 mm fixture implants and 32% received the Oticon Medical Wide Ponto implant. Mean surgical time was 12.2 minutes (6-45 min, standard deviation of 6.88 min). In three instances, surgery was converted to a linear incision to control brisk bleeding. Skin condition was Holgers 0 to 1 in 91.8%, while 5.5% had Holgers 2, and 2.7% had Holgers 3 at the first postoperative visit. At second postoperative visit, 94.3% had Holgers 0 to 1, 4.3% had Holgers 2, and 1.4% had Holgers 3. All instances of adverse skin reactions were treated with topical or systemic antibiotics and/or local debridement. There were no instances of implant loss. One patient had his implant traumatically displaced to a 45-degree angle necessitating implant replacement at a second site. CONCLUSION/CONCLUSIONS:Punch technique placement of osseointegrated auditory implants using the Minimally Invasive Ponto Surgery surgical set represents a safe technique that further simplifies a progressively minimally invasive surgery.

Pain is rated by oral cancer patients as the worst symptom and significantly impairs a patient's ability to eat, talk, and drink. Mediators, secreted from oral cancer microenvironment, excite primary afferent neurons, which in turn generate pain. Oral cancer cells release TNFalpha which induces acute inflammation and nociception in mice. We hypothesize that TNFalpha activates Schwann cells to amplify pain signals. First, we confirmed the involvement of TNFalpha in oral cancer pain in patients and animal models. We found that oral cancer tissues collected from patients have higher TNFalpha concentration compared to anatomically matched normal tissues. Differences in TNFalpha concentration between the tumor and anatomically matched normal tissues correlate positively with total pain scores. In a Nitroquinoline 1-oxide (4NQO) mouse oral cancer model we demonstrated reduced mechanical hypersensitivity (P<0.05, N=8) with the dolognawmeter gnawing assay when TNFalpha was neutralized with C-87. Using a non-contact co-culture model, we found that HSC-3 cells induced a more activated human primary Schwann cells phenotype with increased proliferation (P<0.05) and migration (P<0.05); introduction of C-87 in the co-culture reduced Schwann cell proliferation (P<0.05) and migration (P<0.05) induced by HSC-3 cells. After removal of the co-cultured cancer cells, cancer-activated Schwann cells secrete greater amounts of TNFalpha and nerve growth factor (NGF), another known nociceptive mediator in the oral cancer microenvironment, compared to Schwann cells initially co-cultured with DOK (P<0.05) or naive Schwann cells (P<0.05). To determine whether activated Schwann cells mediate oral cancer pain, we cultured Schwann cells in hypoxic conditions - a known cancer stimulus that induces robust Schwann cell activation. Schwann cell supernatant was then collected and injected into the mouse cheek. Supernatant from hypoxia-activated Schwann cells induced greater facial allodynia (measured with von Frey filaments) in mice (P<0.05, N=7), compared to supernatant from Schwann cells cultured in normoxic conditions (N=5). C-87 significantly reduced facial allodynia caused by hypoxiaactivated Schwann cells (P<0.05, N=5). We infer from our results that TNFalpha plays a role in the activation of Schwann cells and that cancer-activated Schwann cells are a source of nociceptive mediators in the cancer microenvironment. Inhibition of Schwann cell activation might be clinically useful for alleviating oral cancer pain