Jenny X. Chen

Inefficient Reprogramming of Fibroblasts into Cardiomyocytes Using Gata4, Mef2c, and Tbx5

Rationale: Direct reprogramming of fibroblasts into cardiomyocytes is a novel strategy for cardiac regeneration. However, the key determinants involved in this process are unknown. Objective: To assess the efficiency of direct fibroblast reprogramming via viral overexpression of GATA4, Mef2c, and Tbx5 (GMT). Methods and Results: We induced GMT overexpression in murine tail tip fibroblasts (TTFs) and cardiac fibroblasts (CFs) from multiple lines of transgenic mice carrying different cardiomyocyte lineage reporters. We found that the induction of GMT overexpression in TTFs and CFs is inefficient at inducing molecular and electrophysiological phenotypes of mature cardiomyocytes. In addition, transplantation of GMT infected CFs into injured mouse hearts resulted in decreased cell survival with minimal induction of cardiomyocyte genes. Conclusions: Significant challenges remain in our ability to convert fibroblasts into cardiomyocyte-like cells and a greater understanding of cardiovascular epigenetics is needed to increase the translational potential of this strategy.

Risk of Malignancy Associated with Head and Neck CT in Children: A Systematic Review

Objective To perform a systematic review to evaluate the risk of malignancy associated with computed tomography (CT) of the head and/or neck in infants, children, and adolescents. Data Sources Pubmed, EMBASE, and the Cochrane Library were assessed from the date of their inception to January 2014. Additionally, manual searches of bibliographies were performed and topic experts were contacted. Review Methods Data were obtained from studies measuring or estimating the risks of malignancy associated with radiation from head and/or neck CT in pediatric populations according to an a priori protocol. Two independent evaluators corroborated the extracted data. Results There were 16 criterion-meeting studies that included data from n = 858,815 patients. The radiation-related risk of malignancy was estimated using primary patient data for both the exposure and outcome in a minority of studies, with most analyses utilizing mathematical modeling techniques. The data regarding otolaryngology-specific studies were limited and suggested a borderline significant increase in the risk of all combined cancers after facial CT (incidence rate ratio [IRR] = 1.14; 95% CI, 1.01-1.28) and neck/spine CT (IRR = 1.13; 95% CI, 1.00-1.28). Cohort data suggest that 1 excess brain malignancy occurred after 4000 brain CTs (40 mSv per scan) and that the estimated risk in the 10 years following CT exposure was 1 brain tumor per 10,000 patients exposed to a 10 mGy scan at less than 10 years of age. Conclusion Detailed understanding of any potential malignancy risk associated with pediatric imaging of the head and neck furthers our ability to engage in rational, shared, informed decision making with families considering CT scan.

Diagnostic Yield of MRI for Pediatric Hearing Loss: A Systematic Review

Objective To perform a systematic review to analyze the diagnostic yield of magnetic resonance imaging (MRI) for pediatric hearing loss, including comparison to computed tomography (CT) and subgroup evaluation according to impairment severity and specific diagnostic findings (cochlear anomalies, enlarged vestibular aqueduct, cochlear nerve abnormalities, and brain findings). Data Sources Pubmed, EMBASE, and the Cochrane library were assessed from their inception through December 2013. Manual searches were also performed, and topic experts were contacted. Review Methods Data from studies describing the use of MRI with or without comparison to CT in the diagnostic evaluation of pediatric patients with hearing loss were evaluated, according to a priori inclusion/exclusion criteria. Two independent evaluators corroborated the extracted data. Heterogeneity was evaluated according to the I2 statistic. Results There were 29 studies that evaluated 2434 patients with MRIs and 1451 patients with CTs that met inclusion/exclusion criteria. There was a wide range of diagnostic yield from MRI. Heterogeneity among studies was substantial but improved with subgroup analysis. Meta-analysis of yield differences demonstrated that CT had a greater yield than MRI for enlarged vestibular aqueduct (yield difference 16.7% [95% CI, 9.1%-24.4%]) and a borderline advantage for cochlear anomalies (4.7% [95% CI, 0.1%-9.5%]). Studies were more likely to report brain findings with MRI. Conclusions These data may be utilized in concert with that from studies of risks of MRI and risk/yield of CT to inform the choice of diagnostic testing.

Hearing the light: neural and perceptual encoding of optogenetic stimulation in the central auditory pathway

Optogenetics provides a means to dissect the organization and function of neural circuits. Optogenetics also offers the translational promise of restoring sensation, enabling movement or supplanting abnormal activity patterns in pathological brain circuits. However, the inherent sluggishness of evoked photocurrents in conventional channelrhodopsins has hampered the development of optoprostheses that adequately mimic the rate and timing of natural spike patterning. Here, we explore the feasibility and limitations of a central auditory optoprosthesis by photoactivating mouse auditory midbrain neurons that either express channelrhodopsin-2 (ChR2) or Chronos, a channelrhodopsin with ultra-fast channel kinetics. Chronos-mediated spike fidelity surpassed ChR2 and natural acoustic stimulation to support a superior code for the detection and discrimination of rapid pulse trains. Interestingly, this midbrain coding advantage did not translate to a perceptual advantage, as behavioral detection of midbrain activation was equivalent with both opsins. Auditory cortex recordings revealed that the precisely synchronized midbrain responses had been converted to a simplified rate code that was indistinguishable between opsins and less robust overall than acoustic stimulation. These findings demonstrate the temporal coding benefits that can be realized with next-generation channelrhodopsins, but also highlight the challenge of inducing variegated patterns of forebrain spiking activity that support adaptive perception and behavior.

Diagnostic yield of computed tomography scan for pediatric hearing loss: a systematic review.

Background Computed tomography (CT) has been used in the assessment of pediatric hearing loss, but concern regarding radiation risk and increased utilization of magnetic resonance imaging (MRI) have prompted us toward a more quantitative and sophisticated understanding of CT’s potential diagnostic yield. Objective To perform a systematic review to analyze the diagnostic yield of CT for pediatric hearing loss, including subgroup evaluation according to impairment severity and laterality, as well as the specific findings of enlarged vestibular aqueduct and narrow cochlear nerve canal. Data Sources PubMed, EMBASE, and the Cochrane Library were assessed from the date of their inception to December 2013. In addition, manual searches of bibliographies were performed and topic experts were contacted. Review Methods Data from studies describing the use of CT in the diagnostic evaluation of pediatric patients with hearing loss of unknown etiology were evaluated, according to a priori inclusion/exclusion criteria. Two independent evaluators corroborated the extracted data. Heterogeneity was evaluated according to the I2 statistic. Results In 50 criteria-meeting studies, the overall diagnostic yield of CT ranged from 7% to 74%, with the strongest and aggregate data demonstrating a point estimate of 30%. This estimate corresponded to a number needed to image of 4 (range, 2-15). The most commonly identified findings were enlarged vestibular aqueduct and cochlear anomalies. The largest studies showed a 4% to 7% yield for narrow cochlear nerve canal. Conclusion These data, along with similar analyses of radiation risk and risks/benefits of sedated MRI, may be used to help guide the choice of diagnostic imaging.

Oral Steroid Usage for Otitis Media with Effusion, Eustachian Tube Dysfunction, and Tympanic Membrane Retraction:

Objectives Avoiding oral steroids for otitis media with effusion (OME) is endorsed as a performance measure by the National Quality Foundation, but data regarding current gaps and practice patterns are lacking. Our objectives were to evaluate oral steroid use for OME and the related diagnoses of eustachian tube dysfunction (ETD) and tympanic membrane retraction (TMR), to assess variations by visit setting, and to identify opportunities for measurable performance improvement. Study Design Cross-sectional analysis of a national database. Setting Ambulatory visits in the United States. Subjects Children and adults in the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey (2005-2010). Methods Data were coded for patient demographic information, potential confounders (eg, concurrent conditions managed by oral steroids), and diagnosis of OME, ETD, or TMR (OME/ETD/TMR). The latter 2 diagnoses were included to meet minimum numbers for reliability of weighted estimates, but OME constituted the majority of cases. Multivariate regression was used to determine the variables associated with oral steroid use. Results Among 590,772 observations representing 7,191,711,480 visits for OME/ETD/TMR, 3.2% resulted in a new prescription for oral steroid medication (2.3% for children, 7.0% for adults). Adults were more likely to receive steroids (odds ratio = 3.50, P < .001) than those with other diagnoses, but a similar association was not found for children. Patients seen by an otolaryngologist or in the emergency department were less likely to receive steroids than those seen in other settings. Conclusions OME/ETD/TMR is infrequently treated with oral steroids, particularly in children. Opportunities for performance improvement are limited.

Somatic Cell Reprogramming into Cardiovascular Lineages

Ischemic cardiac disease is the leading cause of death in the developed world. The inability of the adult mammalian heart to adequately repair itself has motivated stem cell researchers to explore various strategies to regenerate cardiomyocytes after myocardial infarction. Over the past century, progressive gains in our knowledge about the cellular mechanisms governing fate determination have led to recent advances in cellular reprogramming. The identification of specific factors capable of inducing pluripotent phenotype in somatic cells as well as factors that can directly reprogram somatic cells into cardiomyocytes suggests the potential for these approaches to translate into clinical therapies in the future. Although conceptually appealing, the field of cell lineage reprogramming is in its infancy, and further research will be needed to improve the efficiency of the reprogramming process and the fidelity of the reprogrammed cells to their in vivo counterpart.

Increased Resident Research over an 18-Year Period: A Single Institution's Experience.

Objectives (1) To evaluate changes in the resident publications over time, including before and after duty hour restrictions, and (2) to identify factors statistically associated with publications during residency. Study Design Retrospective review of bibliometric data. Subjects and Methods Residents who graduated from an otolaryngology residency program from 1996 to 2013 were evaluated. Thomson Reuters Web of Science was searched to determine the number of indexed peer-reviewed publications before and after implementation of resident duty hour restrictions in 2003. Resident demographics, PhD degrees, training tracks, and postgraduation plans were collected to determine factors associated with publication rate using multivariable regression analysis. Results During the studied period, 75 residents completed otolaryngology residency training and published a total of 294 papers, averaging 3.92 publications per resident during training. After work hour restrictions were implemented, the mean number of publications increased from 1.21 to 5.10 (P < .0001). First author publications, clinical publications, and basic science publications all increased (P < .001). In regression analysis, T32 grants (β = 6.98, standard error [SE] = 1.87, P = .0004) and the time period after duty hour restrictions were introduced (β = 4.72, SE = 1.73, P = .0083) were positively associated with resident publications. Gender, PhD degree, and pursuit of fellowship training were not associated with increased publications (P > .05). Conclusion There has been a significant increase in resident publications over time, coinciding with the implementation of work hour restrictions. T32 grants were most predictive of increased resident publications, while PhD degrees were not significantly associated.

Macrolide-associated sensorineural hearing loss: A systematic review

To investigate the potential association of macrolide antibiotics with sensorineural hearing loss (SNHL) and which agents and dosage may be related. To evaluate whether an optimal treatment exists for reversing SNHL that occurs after macrolide therapy.

Otopathologic Changes in the Cochlea following Head Injury without Temporal Bone Fracture

Objective Hearing loss following temporal bone (TB) fracture may result from direct transection of the middle and inner ear. The pathophysiology of hearing loss due to head injury without TB fracture, however, is not well understood. Few reports describe otopathologic findings. Herein, we investigate the pathologic findings of patients who sustained a head injury without evidence of a TB fracture. Study Design Otopathology study. Setting Otopathology laboratory. Subjects Subjects with a history of head injury without TB fracture. Methods The TBs of patients with head injury were evaluated by light microscopy. Inner ear anatomy was evaluated, including counts of spiral ganglion cells (SGCs), hair cells, pillar cells, atrophy of the stria vascularis, and the presence of endolymphatic hydrops. SGC counts were compared with those of historical age-matched controls. Results All cases (N = 6 TBs) had evidence of inner ear pathology. Of the 6 cases, 2 (33%) had severe loss of hair cells in all 3 turns of the cochlea, and 4 (67%) cases demonstrated moderate to severe loss at the basal turn of the cochlea. Four cases had scattered atrophy of the stria vascularis, and 3 (50%) had cochlear hydrops. The number of total SGCs was decreased, with an average 53% loss (range, 25%-79%) as compared with controls. The SGC count loss was evenly distributed along Rosenthal’s canal. Conclusions Patients with a history of head injury without TB fracture demonstrate inner ear pathology. Further studies are necessary to determine if otopathology findings are directly attributable to trauma.