An online wideband acoustic immittance (WAI) database and corresponding website. No abstract available

Discrepancies in Hearing Thresholds between Pure-Tone Audiometry and Auditory Steady-State Response in Non-Malingerers Objectives: To evaluate discrepancies between pure-tone audiometry (PTA) and auditory steady state response (ASSR) tests in non-malingerers and investigate brain lesions that may explain the discrepancies, especially in cases where the PTA threshold was worse than the estimated ASSR threshold. Design: PTA, speech audiometry, auditory brainstem response, ASSR, and neuroimaging tests were carried out on individuals selected from 995 cases of hearing impairment. Among these, medical records of 25 subjects (19 males, 6 females; mean age = 46.5 ± 16.0 years) with significant discrepancy between PTA and estimated ASSR thresholds were analyzed retrospectively. To define acceptable levels of discrepancy in PTA and ASSR hearing thresholds, 56 patients (27 males, 29 females; mean age = 53.0 ± 13.6 years) were selected for the control group. Magnetic resonance images, magnetic resonance angiograms, and positron emission tomograms were reviewed to identify any neurologic abnormalities. Results: Pathologic brain lesions were found in 20 cases (80%) in the study group, all of which showed a significant discrepancy in hearing threshold between PTA and ASSR. Temporal lobe lesions were found in 14 cases (70%), frontal lobe lesions in 12 (60%), and thalamic lesions without the frontal or temporal lobe in 2 cases (10%). On repeated PTA and ASSR tests a few months later, the discrepancy between ASSR and behavioral hearing thresholds was reduced or resolved in 6 cases (85.7%). Temporal lobe lesions were found in all 3 cases in which the estimated ASSR threshold worsened with unchanged PTA threshold, and frontal lobe lesions were found in all 3 cases in which the PTA threshold improved but the estimated ASSR threshold was unchanged. No neurological lesions were found in 5 cases (20%) of patients with a discrepancy between ASSR and behavioral hearing thresholds. Conclusions: Clinicians should not rely exclusively on ASSR, especially in cases of central nervous system including temporal, frontal lobe, or thalamus lesions. If no lesions are found in a neuroimaging study of a patient with a discrepancy between PTA thresholds and estimated ASSR thresholds, further functional studies of the brain may be needed. If clinicians encounter patients with a discrepancy between PTA thresholds and estimated ASSR thresholds, an evaluation of brain lesions and repeat audiologic tests are recommended in lieu of relying solely on ASSR. The authors have no conflicts of interest to declare. Received January 7, 2019; accepted July 15, 2019. Address for correspondence: Dong-Hee Lee, Department of Otolaryngology-Head and Neck Surgery, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 271 Cheonbo Street, Uijeongbu City, Gyeonggi-do, 11765, Republic of Korea. E-mail: leedh0814@catholic.ac.kr. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Deep Learning in Automated Region Proposal and Diagnosis of Chronic Otitis Media Based on Computed Tomography Objectives: The purpose of this study was to develop a deep-learning framework for the diagnosis of chronic otitis media (COM) based on temporal bone computed tomography (CT) scans. Design: A total of 562 COM patients with 672 temporal bone CT scans of both ears were included. The final dataset consisted of 1147 ears, and each of them was assigned with a ground truth label from one of the 3 conditions: normal, chronic suppurative otitis media, and cholesteatoma. A random selection of 85% dataset (n = 975) was used for training and validation. The framework contained two deep-learning networks with distinct functions: a region proposal network for extracting regions of interest from 2-dimensional CT slices; and a classification network for diagnosis of COM based on the extracted regions. The performance of this framework was evaluated on the remaining 15% dataset (n = 172) and compared with that of 6 clinical experts who read the same CT images only. The panel included 2 otologists, 3 otolaryngologists, and 1 radiologist. Results: The area under the receiver operating characteristic curve of the artificial intelligence model in classifying COM versus normal was 0.92, with sensitivity (83.3%) and specificity (91.4%) exceeding the averages of clinical experts (81.1% and 88.8%, respectively). In a 3-class classification task, this network had higher overall accuracy (76.7% versus 73.8%), higher recall rates in identifying chronic suppurative otitis media (75% versus 70%) and cholesteatoma (76% versus 53%) cases, and superior consistency in duplicated cases (100% versus 81%) compared with clinical experts. Conclusions: This article presented a deep-learning framework that automatically extracted the region of interest from two-dimensional temporal bone CT slices and made diagnosis of COM. The performance of this model was comparable and, in some cases, superior to that of clinical experts. These results implied a promising prospect for clinical application of artificial intelligence in the diagnosis of COM based on CT images. ACKNOWLEDGMENTS: We appreciate the suggestions provided to improve our methodology by Dayi Bian, Shunxing Bao, Yiyuan Zhao from Vanderbilt University, and Chenghua Tao from Indiana University at Bloomington. We acknowledge Maria Powell from Vanderbilt University Medical Center for her invaluable opinions in manuscript writing. Supported by the National Key Research and Development Program of China (2016YFC0905200, 2016YFC0905202) to F.-L.C.; the National Natural Science Foundation of China (NSFC) (Grant Nos. 81420108010 to F.-L.C. and 81771017 and 81570920 to D.-D.R.); the “Zhuo-Xue Plan” of Fudan University to D.-D.R.; the Shanghai Outstanding Young Medical Talent Program to D.-D.R.. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Y.L. conceptualized and designed the study, reviewed and analyzed the data, performed computer programming, evaluated the AI model, wrote and edited the manuscript; Y.-M.W. retrieved and validated the data; Y.-S.C. retrieved the data and evaluated the AI model; Z.-Y.H. retrieved and validated the data; J.-M.Y., J.-H.X., and Z.-C.C. evaluated the AI model; F.-l.C. provided funding support and data resources; D.-D.R. conceptualized the study, provided funding support and data resources, administered the project and edited the manuscript. All authors have reviewed, discussed, and approved the manuscript. The authors have no conflicts of interest to disclose. Received May 28, 2019; accepted July 22, 2019. Address for correspondence: Yike Li, Department of Otolaryngology, Vanderbilt University Medical Center, 1313 21st Avenue South, 602 Oxford House, Nashville, TN 37232, USA. E-mail: yike.li.1@vumc.org; Dong-Dong Ren, Department of Otorhinolaryngology, Eye and ENT Hospital, 83 Fenyang Road, Shanghai, 200031, China. E-mail: dongdongren@fudan.edu.cn This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Association Between Saccule and Semicircular Canal Impairments and Cognitive Performance Among Vestibular Patients Objectives: Growing evidence suggests that vestibular function impacts higher-order cognitive ability such as visuospatial processing and executive functioning. Despite evidence demonstrating vestibular functional impairment impacting cognitive performance, it is unknown whether cognitive ability is differentially affected according to the type of vestibular impairment (semicircular canal [SCC] versus saccule) among patients with diagnosed vestibular disease. Design: Fifty-four patients who presented to an academic neurotologic clinic were recruited into the study. All patients received a specific vestibular diagnosis. Forty-one patients had saccule function measured with the cervical vestibular-evoked myogenic potential, and 43 had SCC function measured using caloric irrigation. Cognitive tests were administered to assess cognitive performance among patients. One hundred twenty-five matched controls were recruited from the Baltimore Longitudinal Study of Aging to compare cognitive performance in patients relative to age-matched healthy controls. Results: Using multivariate linear regression analyses, patients with bilaterally absent cervical vestibular-evoked myogenic potential responses (i.e., bilateral saccular impairments) were found to take longer in completing the Trail-Making test (β = 25.7 sec, 95% confidence interval = 0.3 to 51.6) and to make significantly more errors on the Benton Visual Retention test part-C (β = 4.5 errors, 95% confidence interval [CI] = 1.2 to 7.8). Patients with bilateral SCC impairment were found to make significantly more errors on the Benton Visual Retention test part-C (β = 9.8 errors, 95% CI = 0.2 to 19.4). From case–control analysis, for each SD difference in Trail-Making test part-B time, there was a corresponding 142% increase in odds of having vestibular impairment (odds ratio = 2.42, 95% CI = 1.44 to 4.07). Conclusions: These data suggest that bilateral saccule and SCC vestibular impairments may significantly affect various domains of cognitive performance. Notably, the cognitive performance in patients in this study was significantly poorer relative to age-matched healthy adults. Cognitive assessment may be considered in patients with saccule and SCC impairments, and cognitive deficits in vestibular patients may represent an important target for intervention. ACKNOWLEDGMENTS: Supported in part by the National Institutes of Health (NIDCD K23 DC013056, NIDCD T32 DC000023). K.P. interviewed clinic patients, collected data, assisted in analysis, and wrote the article. D.P. recruited and interviewed clinic patients and collected data. E.W., R.K., and B.K. assisted in editing the article. E.W. performed most of the analyses. Y.A. designed the project and edited the entire article. The authors have no conflicts of interest to disclose. Received March 29, 2019; accepted July 25, 2019. Address for correspondence: Kevin Pineault, Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, 2308 E. Fairmount Ave., Baltimore, MD 21224, USA. E-mail: kpineau1@jhmi.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Cochlear Implant Use Remains Consistent Over Time in Children With Single-Sided Deafness Objectives: To measure the acceptance of a cochlear implant by children with single-sided deafness (SSD) using datalogging technology in the cochlear implant processor. Design: Datalogs from follow-up clinical audiology appointments for 23 children with SSD were extracted from their cochlear implant processors ranging from 1 to 8 visits (M = 3.74, SD = 1.79). The number of hours the cochlear implant was in use per day, the number of times the coil disconnected from the internal device, and the percentage of daily cochlear implant use in different auditory environments were collected from the datalogs. Linear mixed-effects regressions were used to analyze the relationship between age, hearing experience, cochlear implant use, and coil-offs per day. Nonlinear regressions were conducted to evaluate cochlear implant use in different environments. Results: Children with SSD wore their cochlear implants for 6.22 (SD = 2.81; range = 0.0004 to 14.74) hours per day on average. No significant change in cochlear implant use was seen as the children grew older or gained more hearing experience. As hearing experience increased, the number of coil-offs per day was reduced. Preschoolers spent more time in “music” and “speech” and less time in “noise” and “quiet” than older and younger children while older children spent more time in “speech-in-noise.” Conclusions: Children with SSD consistently wear their cochlear implants. However, the auditory environments to which they are exposed vary over time. Regular cochlear implant use by this population suggests that it does not detract from a normal-hearing ear and that children with SSD appreciate access to bilateral input. ACKNOWLEDGMENTS: The authors have no conflicts of interest to disclose. Received November 20, 2018; accepted July 7, 2019. Address for correspondence: Hillary V. Ganek, Archie’s Cochlear Implant Laboratory, The Hospital for Sick Children, 555 University Ave., Toronto, ON M5G 1X8, Canada. E-mail: hillary.ganek@sickkids.ca Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Word Identification With Temporally Interleaved Competing Sounds by Younger and Older Adult Listeners Objectives: The purpose of this experiment was to contribute to our understanding of the nature of age-related changes in competing speech perception using a temporally interleaved task. Design: Younger and older adults (n = 16/group) participated in this study. The target was a five-word sentence. The masker was one of the following: another five-word sentence; five brief samples of modulated noise; or five brief samples of environmental sounds. The stimuli were presented in a temporally interleaved manner, where the target and masker alternated in time, always beginning with the target. Word order was manipulated in the target (and in the masker during trials with interleaved words) to compare performance when the five words in each stream did versus did not create a syntactically correct sentence. Talker voice consistency also was examined by contrasting performance when each word in the target was spoken by the same talker or by different talkers; a similar manipulation was used for the masker when it consisted of words. Participants were instructed to repeat back the target words and ignore the intervening words or sounds. Participants also completed a subset of tests from the NIH Cognitive Toolbox. Results: Performance on this interleaved task was significantly associated with listener age and with a metric of cognitive flexibility, but it was not related to the degree of high-frequency hearing loss. Younger adults’ performance on this task was better than that of older adults, especially for words located toward the end of the sentence. Both groups of participants were able to take advantage of correct word order in the target, and both were negatively affected, to a modest extent, when the masker words were in correct syntactic order. The two groups did not differ in how phonetic similarity between target and masker words influenced performance, and interleaved environmental sounds or noise had only a minimal effect for all listeners. The most robust difference between listener groups was found for the use of voice consistency: older adults, as compared with younger adults, were less able to take advantage of a consistent target talker within a trial. Conclusions: Younger adults outperformed older adults when masker words were interleaved with target words. Results suggest that this difference was unlikely to be related to energetic masking and/or peripheral hearing loss. Rather, age-related changes in cognitive flexibility and problems encoding voice information appeared to underlie group differences. These results support the contention that, in real-life competing speech situations that produce both energetic and informational masking, older adults’ problems are due to both peripheral and nonperipheral changes. ACKNOWLEDGMENTS: The authors thank Sarah Laakso, Kimberly Adamson-Bashaw, Peter Wasiuk, and Michael Rogers for their assistance with this project. This study was supported by NIH NIDCD R01 012057. The authors have no conflicts of interest to disclose. Received September 14, 2018; accepted July 1, 2019. Address for correspondence: Karen S. Helfer, Department of Communication Disorders, University of Massachusetts Amherst, 358 N. Pleasant St., Amherst, MA 01002, USA. E-mail: helfer@umass.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Neural Modulation Transmission Is a Marker for Speech Perception in Noise in Cochlear Implant Users Objectives: Cochlear implants (CIs) restore functional hearing in persons with a severe hearing impairment. Despite being one of the most successful bionic prosthesis, performance with CI (in particular speech understanding in noise) varies considerably across its users. The ability of the auditory pathway to encode temporal envelope modulations (TEMs) and the effect of degenerative processes associated with hearing loss on TEM encoding is assumed to be one of the reasons underlying the large intersubject differences in CI performance. The objective of the present study was to investigate how TEM encoding of the stimulated neural ensembles of human CI recipients is related to speech perception in noise (SPIN). Design: We used electroencephalography as a noninvasive electrophysiological measure to assess TEM encoding in the auditory pathway of CI users by means of the 40-Hz electrically evoked auditory steady state response (EASSR). Nine CI users with a wide range of SPIN outcome were included in the present study. TEM encoding was assessed for each stimulation electrode of each subject and new metrics; the CI neural modulation transmission difference (CIMTD) and the CI neural modulation transmission index (CIMTI) were developed to quantify the amount of variability in TEM encoding across the stimulated neural ensembles of the CI electrode array. Results: EASSR patterns varied across the CI electrode array and subjects. We found a strong correlation (r = 0.89, p = 0.001) between the SPIN outcomes and the variability in EASSR amplitudes across the array as assessed with CIMTD/CIMTI. Conclusions: The results of the present study show that the 40-Hz EASSR can be used to objectively assess the neural encoding of TEMs in human CI recipients. Overall reduced or largely variable TEM encoding of the neural ensembles across the electrode array, as quantified with the CIMTD/CIMTI, is highly correlated with speech perception in noise outcome with a CI. ACKNOWLEDGMENTS: The authors thank all participants for their patience and willingness to join this study, and the authors are grateful to Ann Dierckx for her help in recruiting participants. Jana van Canneyt and Hanne Deprez helped with some of the data collection. Nancy Jennings is acknowledged for her constructive comments on an earlier version of the manuscript. Robert Luke is currently at Department of Linguistics, Australian Hearing Hub, Macquarie University, Sydney, NSW 2109, Australia. The work leading to this deliverable and the results described therein has received funding from the People Programme (Marie Curie Actions) of the European Unions Seventh Framework Programme FP7/2007–2013/under REA grant agreement PITN-GA-2012–317521 (I Can Hear), and from grants from FWO (G.0662.13), IWT (IWT-150432), and the HermesFonds (IWT-141243). J.W., A.V.W., R.L, and R.G. contributed to the design of the study; R.L. contributed to the development of the programming code to obtain the behavioral results; R.G. and A.V.W. contributed to the participant recruitment; R.G. and R.L. contributed to the data collection; R.L. and J.W. contributed to the initial analysis; R.G. and J.W. contributed to the final analysis; J.W., A.V.W., R.L, and R.G. contributed to the interpretation of the results and conceptual advice; R.G., R.L., and J.W. contributed to the writing of the initial manuscript; R.G. and J.W. contributed to the writing of the final manuscript; J.W. and R.G. contributed to the conceptualization of the CIMTI metric; J.W. and A.V.W. contributed to the project supervision; J.W., A.V.W., and R.G. contributed to the funding acquisition. All authors read the final version of the manuscript. A.v.W. is a member of the editorial board of Ear & Hearing. Received August 21, 2018; accepted June 25, 2019. Address for correspondence: Robin Gransier, KU Leuven, Department of Neurosciences, ExpORL, Herestraat 49, P. O. Box 721, B-3000, Leuven, Belgium. E-mail: robin.gransier@kuleuven.be Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The Association Between Hearing Impairment and Problem Behaviors in 11-Year-Old Pacific Children Living in New Zealand Objectives: Hearing impairment in childhood is a serious disability that can impose a heavy social and economic burden on individuals and families. It was hypothesized that hearing loss or middle ear disease in 11-year-old Pacific children living in New Zealand would be associated with higher levels of engagement in (1) delinquent behaviors, and (2) clinical level internalizing and externalizing problem behaviors than Pacific children with no hearing loss or middle ear disease. Based on earlier findings, peer pressure, self-perception, physical punishment (slapping), sex, and ethnicity were controlled for in the association between hearing difficulties and behavioral outcomes. Design: In the school setting, pure-tone audiometry and immittance audiometry assessments were used to establish the hearing level in 11-year-old Pacific children (n = 920). These children also completed multidisciplinary questionnaires, which included questions about involvement in delinquent behaviors, peer pressure, and self-perception. In the home setting, maternal reports were gathered on internalizing and externalizing problem behaviors in their offspring, their parenting style, and sociodemographic details. Results: A significant effect of hearing level was detected for the odds of reporting mild delinquency versus no delinquency (odds ratio: 1.02, 95% CI: 1.00 to 1.05), and odds of moderate delinquency versus no delinquency (odds ratio: 0.97, 95% CI: 0.94 to 1.00). No significant effect was detected for hearing level and severe delinquency or internalizing or externalizing behavioral problems in the clinical range. Middle ear disease (abnormal tympanogram in the worse ear) was not significantly associated with delinquency at any level or with internalizing behaviors in the clinical range. However, children with middle ear disease were significantly less likely than all other participants to exhibit disruptive externalizing behavior in the clinical range. Conclusions: Relatively young children with hearing loss reported engagement in moderate levels of delinquency that represent serious antisocial and potentially violent acts. This finding provides evidence of the significant effect that hearing loss has on child behavior. This association between hearing loss and moderate delinquency requires ethnic-specific interventions that are targeted for maximum benefit at appropriate times in childhood to mitigate potentially long-term health, educational, and behavioral risks. ACKNOWLEDGMENTS: The authors thank the study participants and the Pacific Peoples Community Advisory Board. Funding to support the PIF study is from the Foundation for Research, Science & Technology, and the Health Research Council of New Zealand. J.P. wrote the article, worked with statisticians to analyze the data, and coordinated the article through to submission. S.C.P. provided expert advice and feedback through the process. R.S. and P.J.S. were the biostatisticians on the team and were responsible for the data analyses, the results section, and the tables. L.I. and E.-S.T. and all other authors discussed the results and implications and commented on the manuscripts at all stages. The authors have no conflicts of interest to disclose. Received September 20, 2018; accepted May 27, 2019. Address for correspondence: Janis Paterson, School of Public Health & Psychosocial Studies, Faculty of Health & Environmental Sciences, Auckland University of Technology, Auckland, New Zealand. . E-mail: janis.paterson@aut.ac.nz Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Prediction of Unilateral Meniere’s Disease Attack Using Inner Ear Test Battery Objectives: In the clinical setting, a variety of inner ear test results are obtained from patients with unilateral Meniere’s disease (MD). In this study, the authors use inner ear test results as parameters to illustrate the relationship between inner ear function and vertigo attack frequency. Design: We retrospectively enrolled 50 unilateral MD patients. In addition to clinical symptoms, the results of pure-tone audiometry and caloric, acoustic cervical vestibular-evoked myogenic potential (cVEMP), galvanic cVEMP, vibratory ocular VEMP (oVEMP), and galvanic oVEMP tests were collected via chart review. The multiple linear regression method was used to examine which independent variables have a statistically significant influence on vertigo attacks. Results: In affected ears, the abnormal rate of the caloric, acoustic cVEMP, galvanic cVEMP, vibratory oVEMP, and galvanic oVEMP tests was 74%, 76%, 48%, 34%, and 30%, respectively. According to the regression model, the abnormal galvanic cVEMP response and abnormal galvanic oVEMP response had significantly negative correlations with the frequency of vertigo attacks after logarithmic transformation. A predictive model for disease attack frequency using significant parameters and their regression coefficients was proposed: Log10 (predicted vertigo attack frequency) = 0.25+ 0.56 × (galvanic cVEMP) +0.37 × (galvanic oVEMP). Conclusions: Using the proposed model with galvanic VEMP, clinicians could develop better strategies to manage vertigo attacks in patients with MD. ACKNOWLEDGMENTS: P.-H. W. designed the study, analyzed the data, and wrote the article; C.-M. C., W.-C. L., C.-T. W., M.-H. W., T.-W. H., and Y.-H. Y. collected and analyzed the data and revised the article; P.-W. C. designed the study and critically revise the article. This study is supported by a research grant from the Far Eastern Memorial Hospital (FEMH-2018-C-060). The authors have no conflicts of interest to disclose. Received February 8, 2019; accepted June 27, 2019. Address for correspondence: Po-Wen Cheng, Department of Otolaryngology Head and Neck Surgery, Far Eastern Memorial Hospital, 21, Section 2, Nan-Ya South Road, Pan Chiao, Taipei, Taiwan, 220. E-mail: powenjapan@yahoo.com.tw Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Recommendations for Measuring the Electrically Evoked Compound Action Potential in Children With Cochlear Nerve Deficiency Objectives: This study reports a method for measuring the electrically evoked compound action potential (eCAP) in children with cochlear nerve deficiency (CND). Design: This method was developed based on experience with 50 children with CND who were Cochlear Nucleus cochlear implant users. Results: This method includes three recommended steps conducted with recommended stimulating and recording parameters: initial screen, pulse phase duration optimization, and eCAP threshold determination (i.e., identifying the lowest stimulation level that can evoke an eCAP). Compared with the manufacturer-default parameters, the recommended parameters used in this method yielded a higher success rate for measuring the eCAP in children with CND. Conclusions: The eCAP can be measured successfully in children with CND using recommended parameters. This specific method is suitable for measuring the eCAP in children with CND in clinical settings. However, it is not suitable for intraoperative eCAP recordings due to the extensive testing time required. ACKNOWLEDGMENTS: The authors thank all subjects and their parents for participating in this study. Supported by the R03 (1R03DC013153) and the R01 (R01DC017846) grant from NIH/NIDCD. S.H. developed the method used in this study, participated in data collection and patient testing at the centers in China, Ohio, and North Carolina, drafted and approved the final version of this article. X.C., R.W., J.L., and L.X. participated in data collection and patient testing at the center in China, provided critical comments, and approved the final version of this article. M.S. and C.W. participated in patient testing at the center in Ohio, provided critical comments, and approved the final version of this article. H.F.B.T. and L.R.P. participated in patient testing at the center in North Carolina, provided critical comments, and approved the final version of this article. K.D.B., A.P., and W.J.R. provided critical comments and approved the final version of this article. H.F.B.T. is a member of a Cochlear Corp. Audiology Advisory Board. Received October 30, 2018; accepted June 21, 2019. Address for correspondence: Shuman He, Eye and Ear Institute, Department of Otolaryngology – Head and Neck Surgery, The Ohio State University, 915 Olentangy River Road, Suite 4000, Columbus, OH, USA. E-mail: shuman.he@osumc.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.