Isaac Alden Bernstein

All Publications

• Automated Recognition of Visual Acuity Measurements in Ophthalmology Clinical Notes Using Deep Learning. Ophthalmology science Bernstein, I. A., Koornwinder, A., Hwang, H. H., Wang, S. Y. 2024; 4 (2): 100371

  Abstract

  Visual acuity (VA) is a critical component of the eye examination but is often only documented in electronic health records (EHRs) as unstructured free-text notes, making it challenging to use in research. This study aimed to improve on existing rule-based algorithms by developing and evaluating deep learning models to perform named entity recognition of different types of VA measurements and their lateralities from free-text ophthalmology notes: VA for each of the right and left eyes, with and without glasses correction, and with and without pinhole.Cross-sectional study.A total of 319 756 clinical notes with documented VA measurements from approximately 90 000 patients were included.The notes were split into train, validation, and test sets. Bidirectional Encoder Representations from Transformers (BERT) models were fine-tuned to identify VA measurements from the progress notes and included BERT models pretrained on biomedical literature (BioBERT), critical care EHR notes (ClinicalBERT), both (BlueBERT), and a lighter version of BERT with 40% fewer parameters (DistilBERT). A baseline rule-based algorithm was created to recognize the same VA entities to compare against BERT models.Model performance was evaluated on a held-out test set using microaveraged precision, recall, and F1 score for all entities.On the human-annotated subset, BlueBERT achieved the best microaveraged F1 score (F1 = 0.92), followed by ClinicalBERT (F1 = 0.91), DistilBERT (F1 = 0.90), BioBERT (F1 = 0.84), and the baseline model (F1 = 0.83). Common errors included labeling VA in sections outside of the examination portion of the note, difficulties labeling current VA alongside a series of past VAs, and missing nonnumeric VAs.This study demonstrates that deep learning models are capable of identifying VA measurements from free-text ophthalmology notes with high precision and recall, achieving significant performance improvements over a rule-based algorithm. The ability to recognize VA from free-text notes would enable a more detailed characterization of ophthalmology patient cohorts and enhance the development of models to predict ophthalmology outcomes.Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

  View details for DOI 10.1016/j.xops.2023.100371

  View details for PubMedID 37868799

  View details for PubMedCentralID PMC10587603

• Social Determinants of Health and Perceived Barriers to Care in Diabetic Retinopathy Screening. JAMA ophthalmology Ravindranath, R., Bernstein, I. A., Fernandez, K. S., Ludwig, C. A., Wang, S. Y. 2023

  Abstract

  Regular screening for diabetic retinopathy often is crucial for the health of patients with diabetes. However, many factors may be barriers to regular screening and associated with disparities in screening rates.To evaluate the associations between visiting an eye care practitioner for diabetic retinopathy screening and factors related to overall health and social determinants of health, including socioeconomic status and health care access and utilization.This retrospective cross-sectional study included adults aged 18 years or older with type 2 diabetes who answered survey questions in the All of Us Research Program, a national multicenter cohort of patients contributing electronic health records and survey data, who were enrolled from May 1, 2018, to July 1, 2022.The associations between visiting an eye care practitioner and (1) demographic and socioeconomic factors and (2) responses to the Health Care Access and Utilization, Social Determinants of Health, and Overall Health surveys were investigated using univariable and multivariable logistic regressions.The primary outcome was whether patients self-reported visiting an eye care practitioner in the past 12 months. The associations between visiting an eye care practitioner and demographic and socioeconomic factors and responses to the Health Care Access and Utilization, Social Determinants of Health, and Overall Health surveys in All of Us were investigated using univariable and multivariable logistic regression.Of the 11 551 included participants (54.55% cisgender women; mean [SD] age, 64.71 [11.82] years), 7983 (69.11%) self-reported visiting an eye care practitioner in the past year. Individuals who thought practitioner concordance was somewhat or very important were less likely to have seen an eye care practitioner (somewhat important: adjusted odds ratio [AOR], 0.83 [95% CI, 0.74-0.93]; very important: AOR, 0.85 [95% CI, 0.76-0.95]). Compared with financially stable participants, individuals with food or housing insecurity were less likely to visit an eye care practitioner (food insecurity: AOR, 0.75 [95% CI, 0.61-0.91]; housing insecurity: AOR, 0.86 [95% CI, 0.75-0.98]). Individuals who reported fair mental health were less likely to visit an eye care practitioner than were those who reported good mental health (AOR, 0.84; 95% CI, 0.74-0.96).This study found that food insecurity, housing insecurity, mental health concerns, and the perceived importance of practitioner concordance were associated with a lower likelihood of receiving eye care. Such findings highlight the self-reported barriers to seeking care and the importance of taking steps to promote health equity.

  View details for DOI 10.1001/jamaophthalmol.2023.5287

  View details for PubMedID 37971726

• The Association Between Frailty and Visual Field Loss in U.S. Adults. American journal of ophthalmology Bernstein, I. A., Fisher, A. C., Singh, K., Wang, S. Y. 2023

  Abstract

  To describe the association between visual field loss and frailty in a nationally representative cohort of U.S. adults.Retrospective cross-sectional study.The cohort included adults 40 years or older with complete eye examination data from the 2005-2006 and 2007-2008 National Health and Nutrition Examination Surveys (NHANES). Visual field loss (VFL) was determined by frequency doubling technology and a 2-2-1 algorithm. A 36-item deficit accumulation-based frailty index was used to divide subjects into 4 categories of increasing frailty severity.Of the 4,897 participants, 4,402 (93.2%) participants had no VFL, 301 (4.1%) had unilateral VFL, and 194 (2.73%) had bilateral VFL. Within the sample, 2,197 (53.1%) subjects were categorized as non-frail, 1,659 (31.3%) as vulnerable, 732 (11.3%) as mildly frail, and 312 (4.3%) as most frail. In multivariable models adjusted for demographics, visual acuity, and history of cataract surgery, subjects with unilateral VFL had higher adjusted odds of being in a more frail category (adjusted odds ratio [aOR], 2.07; 95% CI, 1.42-3.02) than subjects without VFL. Subjects with bilateral VFL also had higher odds of a more frail category compared to subjects without VFL (aOR, 1.74; 95% CI, 1.20-2.52).In the 2005-2008 NHANES adult population, VFL is associated with higher odds of frailty, independent of central visual acuity loss. Frail individuals may be more susceptible to diseases which can cause VFL and/or VFL may predispose to frailty. Additional studies are needed to determine the directionality of this relationship and to assess potential interventions.

  View details for DOI 10.1016/j.ajo.2023.09.008

  View details for PubMedID 37714282

• Comparison of Ophthalmologist and Large Language Model Chatbot Responses to Online Patient Eye Care Questions. JAMA network open Bernstein, I. A., Zhang, Y. V., Govil, D., Majid, I., Chang, R. T., Sun, Y., Shue, A., Chou, J. C., Schehlein, E., Christopher, K. L., Groth, S. L., Ludwig, C., Wang, S. Y. 2023; 6 (8): e2330320

  Abstract

  Importance: Large language models (LLMs) like ChatGPT appear capable of performing a variety of tasks, including answering patient eye care questions, but have not yet been evaluated in direct comparison with ophthalmologists. It remains unclear whether LLM-generated advice is accurate, appropriate, and safe for eye patients.Objective: To evaluate the quality of ophthalmology advice generated by an LLM chatbot in comparison with ophthalmologist-written advice.Design, Setting, and Participants: This cross-sectional study used deidentified data from an online medical forum, in which patient questions received responses written by American Academy of Ophthalmology (AAO)-affiliated ophthalmologists. A masked panel of 8 board-certified ophthalmologists were asked to distinguish between answers generated by the ChatGPT chatbot and human answers. Posts were dated between 2007 and 2016; data were accessed January 2023 and analysis was performed between March and May 2023.Main Outcomes and Measures: Identification of chatbot and human answers on a 4-point scale (likely or definitely artificial intelligence [AI] vs likely or definitely human) and evaluation of responses for presence of incorrect information, alignment with perceived consensus in the medical community, likelihood to cause harm, and extent of harm.Results: A total of 200 pairs of user questions and answers by AAO-affiliated ophthalmologists were evaluated. The mean (SD) accuracy for distinguishing between AI and human responses was 61.3% (9.7%). Of 800 evaluations of chatbot-written answers, 168 answers (21.0%) were marked as human-written, while 517 of 800 human-written answers (64.6%) were marked as AI-written. Compared with human answers, chatbot answers were more frequently rated as probably or definitely written by AI (prevalence ratio [PR], 1.72; 95% CI, 1.52-1.93). The likelihood of chatbot answers containing incorrect or inappropriate material was comparable with human answers (PR, 0.92; 95% CI, 0.77-1.10), and did not differ from human answers in terms of likelihood of harm (PR, 0.84; 95% CI, 0.67-1.07) nor extent of harm (PR, 0.99; 95% CI, 0.80-1.22).Conclusions and Relevance: In this cross-sectional study of human-written and AI-generated responses to 200 eye care questions from an online advice forum, a chatbot appeared capable of responding to long user-written eye health posts and largely generated appropriate responses that did not differ significantly from ophthalmologist-written responses in terms of incorrect information, likelihood of harm, extent of harm, or deviation from ophthalmologist community standards. Additional research is needed to assess patient attitudes toward LLM-augmented ophthalmologists vs fully autonomous AI content generation, to evaluate clarity and acceptability of LLM-generated answers from the patient perspective, to test the performance of LLMs in a greater variety of clinical contexts, and to determine an optimal manner of utilizing LLMs that is ethical and minimizes harm.

  View details for DOI 10.1001/jamanetworkopen.2023.30320

  View details for PubMedID 37606922

• Automated Radiomic Analysis of Vestibular Schwannomas and Inner Ears Using Contrast-Enhanced T1-Weighted and T2-Weighted Magnetic Resonance Imaging Sequences and Artificial Intelligence. Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology Neves, C. A., Liu, G. S., El Chemaly, T., Bernstein, I. A., Fu, F., Blevins, N. H. 2023

  Abstract

  To objectively evaluate vestibular schwannomas (VSs) and their spatial relationships with the ipsilateral inner ear (IE) in magnetic resonance imaging (MRI) using deep learning.Cross-sectional study.A total of 490 adults with VS, high-resolution MRI scans, and no previous neurotologic surgery.MRI studies of VS patients were split into training (390 patients) and test (100 patients) sets. A three-dimensional convolutional neural network model was trained to segment VS and IE structures using contrast-enhanced T1-weighted and T2-weighted sequences, respectively. Manual segmentations were used as ground truths. Model performance was evaluated on the test set and on an external set of 100 VS patients from a public data set (Vestibular-Schwannoma-SEG).Dice score, relative volume error, average symmetric surface distance, 95th-percentile Hausdorff distance, and centroid locations.Dice scores for VS and IE volume segmentations were 0.91 and 0.90, respectively. On the public data set, the model segmented VS tumors with a Dice score of 0.89 ± 0.06 (mean ± standard deviation), relative volume error of 9.8 ± 9.6%, average symmetric surface distance of 0.31 ± 0.22 mm, and 95th-percentile Hausdorff distance of 1.26 ± 0.76 mm. Predicted VS segmentations overlapped with ground truth segmentations in all test subjects. Mean errors of predicted VS volume, VS centroid location, and IE centroid location were 0.05 cm3, 0.52 mm, and 0.85 mm, respectively.A deep learning system can segment VS and IE structures in high-resolution MRI scans with excellent accuracy. This technology offers promise to improve the clinical workflow for assessing VS radiomics and enhance the management of VS patients.

  View details for DOI 10.1097/MAO.0000000000003959

  View details for PubMedID 37464458

• Association between insurance status and hearing healthcare use in the United States. American journal of otolaryngology Bernstein, I. A., Megwalu, U. C. 2023; 44 (6): 103993

  Abstract

  Despite the high prevalence and morbidity of hearing loss, many individuals with hearing loss do not have access to hearing healthcare. This study aims to assess the relationship between insurance status and prior audiogram, and hearing aid use among subjects with hearing loss.This cross-sectional study of the 2009-10, 2011-12, and 2015-16 cycles of the U.S. National Health and Nutrition Examination Survey (NHANES) included 5270 adult subjects 18 years or older with subjective or audiometric hearing loss. Subjects were stratified by insurance: Medicare, Medicaid, private, uninsured, and 'other or unspecified'.After adjusting for covariates, among subjects with audiometric hearing loss, prior audiogram was not associated with insurance type, including no insurance (OR 0.80, 95 % CI 0.45 to 1.42), Medicare (OR 1.34, 95 % CI 0.69 to 2.59), Medicaid (OR 1.27, 95 % CI 0.55 to 2.93), or 'other or unspecified' (OR 1.73, 95 % CI 0.67 to 4.47). Hearing aid use was not associated with insurance type, including no insurance (OR 0.20, 95 % CI 0.03 to 1.29), Medicare (OR 0.56, 95 % CI 0.27 to 1.14), Medicaid (OR 2.03, 95 % CI 0.47 to 8.71), or 'other or unspecified' (OR 1.76, 95 % CI 0.59 to 5.23).Health insurance status was not associated with hearing healthcare use in our nationally-representative sample of individuals with hearing loss. Given variations in hearing coverage by Medicaid between states, future studies should compare the impact of Medicaid insurance on hearing aid use between states that cover hearing aids and those that do not.

  View details for DOI 10.1016/j.amjoto.2023.103993

  View details for PubMedID 37454432

• Seeing What Patients See: Identifying Visual Acuity from Ophthalmology Clinical Notes Using Deep Learning and Natural Language Processing Bernstein, I., Koornwinder, A., Hwang, H., Wang, S. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2023

  View details for Web of Science ID 001053795606125

• Otolaryngic sensory loss as a measure of frailty among older US adults. International forum of allergy & rhinology Hura, N., Bernstein, I. A., Mady, L. J., Agrawal, Y., Lane, A. P., Rowan, N. R. 2021

  Abstract

  BACKGROUND: Frailty is a syndrome characterized by reduced physiologic reserve and increased vulnerability to poor health outcomes. Disruption of sensorineural function appears to serve as a novel biomarker of frailty. Using population-level data, we sought to characterize the association between otolaryngic sensory dysfunction and frailty.METHODS: A cross-sectional analysis of the 2011-2012 US National Health and Nutrition Examination Survey was performed on adults ≥40 years of age (n=2138). Participants were grouped by subjective gustatory dysfunction (sGD), olfactory dysfunction (sOD), hearing loss (sHL), and measured hearing loss (mHL) with pure tone averages (PTAs). Frailty was operationalized using a continuous 36-item frailty index (FI) scored from 0 to 1, stratified in 4 categories ("non-frail," "vulnerable," "frail," or "most frail").RESULTS: All sensory loss groups had significantly higher FI scores than those without sensory loss (sGD = 0.15; sOD = 0.14; sHL = 0.15; low-frequency mHL = 0.16; high-frequency mHL = 0.14vs control = 0.11; p<0.007 for all). "Vulnerable" individuals had increased odds of sOD (adjusted odds ratio [aOR], 1.45; 95% confidence interval [CI], 1.05-2.00), whereas "frail" individuals had increased odds of sOD (aOR, 1.85; 95% CI, 1.26-2.71) and low-frequency mHL (aOR, 4.01; 95% CI, 1.27-12.63). The "most frail" individuals had increased odds of sHL (aOR, 11.72; 95% CI, 2.88-47.66) and high-frequency mHL (aOR 5.10; 95% CI, 1.72-15.12). PTAs were linearly associated with FI (low: beta=10.15; 95% CI, 1.78-18.51; high: beta=19.85; 95% CI, 5.19-34.53).CONCLUSION: Otolaryngic sensory loss is associated with increased frailty. Independent association of frailty with measures of olfaction and hearing suggests that olfactory and hearing assessments may help identify at-risk individuals with modifiable risk factors.

  View details for DOI 10.1002/alr.22918

  View details for PubMedID 34878232

• Predictors of academic career placement and scholarly impact in fellowship-trained rhinologists INTERNATIONAL FORUM OF ALLERGY & RHINOLOGY Vohra, V., Watley, D. C., Yan, C. H., Locke, T. B., Bernstein, I. A., Levy, J. M., Rowan, N. R. 2021: 62-70

  Abstract

  As rhinology fellowship positions outpace the availability of academic rhinology jobs, it is increasingly important to identify characteristics that are associated with academic placement after fellowship completion. In this study, we evaluated the association of academic characteristics during training with current job placement and posttraining scholarly impact.Previous rhinology fellows were identified using publicly available data. Bibliometric indices, training institutions, graduate degrees, and job placement data were used in bivariate and multivariable regression analyses to assess for association with predictors and academic trajectory.Data from 265 rhinologists, all graduating between 1991 and 2020, were included. Most surgeons (n = 185, 70%) held an academic position and 80 (30%) surgeons worked in a nonacademic setting; 93.2% had a Doctor of Medicine (MD) degree and 80.3% were male. Multivariable logistic regression indicated that a designation of MD, compared with Doctor of Osteopathic Medicine (DO; odds ratio [OR], 5.93; 95% confidence interval [CI], 1.97-21.9), number of publications during fellowship (OR, 1.19; 95% CI, 1.02-1.41), and h-index during training (OR, 1.25; 95% CI, 1.07-1.49]) were independently predictive of academic job placement. Meanwhile, number of primary authorships during fellowship (β = 1.47; 95% CI, 1.07-1.88]), h-index during training (β = 0.48; 95% CI, 0.25-0.71), and PhD (β = 4.16; 95% CI, 1.57-6.76) were associated with posttraining h-index. Medical school ranking; graduate degrees, including Master of Science (MS), Master of Business Administration (MBA), and Master of Public Health (MPH); and research metrics before residency were not associated with either academic placement or posttraining h-index.The predictors of academic job placement in rhinology are unclear, but h-index during training, and research productivity during fellowship may serve as indicators of an academic career.

  View details for DOI 10.1002/alr.22873

  View details for Web of Science ID 000678838400001

  View details for PubMedID 34309228

• Association Between Chemosensory Dysfunction and Diet Quality in United States Adults AMERICAN JOURNAL OF RHINOLOGY & ALLERGY Roxbury, C. R., Bernstein, I. A., Lin, S. Y., Rowan, N. R. 2022; 36 (1): 47-56

  Abstract

  Evidence suggests chemosensory dysfunction (CSD) patients have altered diet, but population-level evidence assessing diet quality in CSD patients is lacking.We examined the association between CSD and diet quality in a representative sample of United States adults.This cross-sectional study included 2831 adults aged greater than 40 years from the 2013-2014 National Health and Nutrition Examination Survey who completed the taste/smell questionnaire and examination. Mean nutrient intake in subjects with self-reported olfactory/gustatory dysfunction (sOD/sGD) and measured olfactory/gustatory dysfunction (mOD/mGD) were compared to those without CSD using univariate Wilcoxon rank-sum tests. The Healthy Eating Index (HEI), a validated measure of diet quality, was calculated. The proportion of subjects with CSD with bottom-quartile HEI was compared to those without CSD using multivariate logistic regression, adjusting for demographic and socioeconomic covariates.The population-weighted prevalence of sOD, sGD, mOD, and mGD was 20.1%, 14.4%, 15.9% and 25.6%, respectively. Subjects with mOD had lower mean intake of total calories, total fat, protein, sodium, and potassium compared to normal subjects (1873.4 ± 49.6 vs 2010.2 ± 24.2 kcal, 72.3 ± 2.7 vs 78.6 ± 1.0 gm, 74.0 ± 2.5 vs 80.4 ± 0.6 gm, 3122 ± 97.2 vs 3353.2 ± 37.0 mg, 2509.8 ± 69.8 vs 2684.7 ± 26.1 mg, P < 0.05 respectively). When controlling for sociodemographic factors and comorbidities, subjects with sOD were more likely to have bottom-quartile HEI compared to normal subjects (OR 1.33, 95% CI 1.04-1.70).This population-level study suggests an association between poor diet quality and variation in dietary intake in patients with CSD, which warrants further investigation and suggests the possible need for nutritional counseling for CSD patients.

  View details for DOI 10.1177/19458924211016611

  View details for Web of Science ID 000652865300001

  View details for PubMedID 34000836

• The association of frailty with olfactory and gustatory dysfunction in older adults: a nationally representative sample INTERNATIONAL FORUM OF ALLERGY & RHINOLOGY Bernstein, I. A., Roxbury, C. R., Lin, S. Y., Rowan, N. R. 2021; 11 (5): 866-876

  Abstract

  Olfaction and gustation are associated with age-related decline. Deficits in these chemosenses have been associated with significant comorbidities. Meanwhile, frailty, defined as a reduced physiological reserve, is well correlated with mortality and worse health outcomes. We sought to analyze a nationally representative patient population to determine the association between chemosensory dysfunction and frailty.Cross-sectional analysis of U.S. National Health and Nutrition Examination Survey (NHANES) 2013-2014 was performed, using multivariate logistic regression to examine the association between chemosensory dysfunction and frailty in adults aged ≥40 years (n = 3547). Self-reported olfactory dysfunction (sOD) and gustatory dysfunction (sGD), and measured olfactory dysfunction (mOD) and gustatory dysfunction (mGD) were assessed for all participants. Frailty was operationalized using a 39-item frailty index (FI) and stratified into 4 groups using validated cutoffs.Participants with sOD and mOD had significantly higher mean FI scores (sOD: 0.18 vs 0.13, p < 0.001; mOD: 0.20 vs 0.14, p < 0.001), whereas subjects with sGD, but not mGD, had higher mean FI scores (sGD: 0.21 vs 0.13, p < 0.001; mGD: 0.14 vs 0.14, p = 0.953). Multivariate logistic regression demonstrated frail participants had significantly greater odds of sGD (odds ratio [OR] 4.11; 95% confidence interval [CI], 3.46 to 4.88), sOD (OR 2.35; 95% CI, 1.98 to 2.78), and mOD (OR 1.58; 95% CI, 1.22 to 2.05), but not mGD (OR 1.21; 95% CI, 0.91 to 1.61). This association was strongest in the frailest group.Self-reported chemosensory dysfunction and mOD are independently associated with measures of frailty, suggesting a novel method to assess or predict frailty.

  View details for DOI 10.1002/alr.22718

  View details for Web of Science ID 000583055600001

  View details for PubMedID 33131203

• Implications of Obesity on Endoscopic Sinus Surgery Postoperative Complications: An Analysis of the NSQIP Database OTOLARYNGOLOGY-HEAD AND NECK SURGERY Wardlow, R. D., Bernstein, I. A., Orlov, C. P., Rowan, N. R. 2021; 164 (3): 675-682

  Abstract

  To evaluate the influence of body mass index on postoperative adverse events in adult patients undergoing endoscopic sinus surgery.Retrospective cohort study.Database of the American College of Surgeons NSQIP (National Surgical Quality Improvement Program) from 2006 to 2018.The NSQIP database was queried for adult patients undergoing endoscopic sinus surgery. The total sample (N = 1546) was stratified by nonobese (18.5 kg/m2≤ body mass index <30 kg/m2) and obese (≥30 kg/m2). Demographics, comorbidities, intraoperative variables, and postoperative adverse events were compared via chi-square analysis and multivariable logistic regression.Obese patients accounted for 49.7% (n = 768) of the cohort. Obese patients had a higher American Society of Anesthesiologists classification (class III, 45.1% vs 29.5%; P < .001), rate of diabetes (18.2% vs 7.2%, P < .001), and rate of hypertension requiring medication (43.1% vs 23.0%, P < .001). Nonobese patients were more likely to be >58 years of age (23.4% vs 29.0%, P = .02) and have disseminated cancer (<1% vs 3.2%, P < .001). The obese cohort had a lower frequency of surgical complications (3.0% vs 5.4%, P = .027), driven by frequency of perioperative bleeding (1.8% vs 3.7%, P = .022). There was no statistical difference in medical complications (P = .775), unplanned readmissions (P = .286), unplanned reoperations (P = .053), or 30-day mortality (P > .999). After multivariable adjustment, obese subjects had decreased odds of any surgical complication (adjusted odds ratio [aOR], 0.567; 95% CI, 0.329-0.979), perioperative bleeding (aOR, 0.474; 95% CI, 0.239-0.942), and any adverse postoperative event (aOR, 0.740; 95% CI, 0.566-0.968).Obesity does not increase the risk of 30-day adverse outcomes following endoscopic sinus surgery and may even be protective against perioperative bleeding.

  View details for DOI 10.1177/0194599820955180

  View details for Web of Science ID 000567850800001

  View details for PubMedID 32895003

• Interleukin 13 (IL-13) alters hypoxia-associated genes and upregulates CD73 INTERNATIONAL FORUM OF ALLERGY & RHINOLOGY Khalil, S., Bernstein, I., Kulaga, H., Gour, N., Rowan, N., Lajoie, S., Lane, A. P. 2020; 10 (9): 1096-1102

  Abstract

  Interleukin 13 (IL-13) is a pleiotropic cytokine that has been shown to be important in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) and other type 2 inflammation-related diseases. Increased IL-13 expression can elicit several pro-inflammatory effects, including eosinophilia, and pathology such as increased mucus secretion. Polypogenesis in chronic rhinosinusitis (CRS) can be caused by hypoxia, which can also lead to hyperpermeability of airway epithelium and epithelium-to-mesenchymal translation through the upregulation of hypoxia-associated genes, such as HIF1. Whether T-helper 2 (Th2) inflammatory cytokines, such as IL-13, can also induce sinonasal epithelial hypoxia-associated genes is currently unknown.Human air-liquid interface (ALI) sinonasal epithelial cell cultures treated with recombinant IL-13 were analyzed by real-time polymerase chain reaction (PCR) and flow cytometry to determine the effect on epithelial cells.Whole tissue from CRSwNP subjects showed increased HIF1A gene expression. Treatment of fully differentiated human ALI cultures with IL-13 resulted in a concurrent increase in HIF1A and ARNT messenger RNA (mRNA) expression. However, the level of EPAS1 expression was significantly reduced. IL-13 also had a dose-dependent response on the expression of HIF genes and the time course experiment showed peak expression of HIF1A and ARNT at 5 to 7 days poststimulation. Remarkably, CD73 surface expression also peaked at day 5 poststimulation.Our data suggests that IL-13 can induce hypoxia signaling pathway genes leading to surface expression of CD73, which has an anti-inflammatory effect.

  View details for DOI 10.1002/alr.22630

  View details for Web of Science ID 000555012700001

  View details for PubMedID 32673430

• Multiple aspects of male germ cell development and interactions with Sertoli cells require inositol hexakisphosphate kinase-1 SCIENTIFIC REPORTS Fu, C., Rojas, T., Chin, A. C., Cheng, W., Bernstein, I. A., Albacarys, L. K., Wright, W. W., Snyder, S. H. 2018; 8: 7039

  Abstract

  Inositol hexakisphosphate kinase-1 (IP6K1) is required for male fertility, but the underlying mechanisms have been elusive. Here, we report that IP6K1 is required for multiple aspects of male germ cell development. This development requires selective interactions between germ cells and Sertoli cells, namely apical ectoplasmic specialization. Spermiation (sperm release) requires tubulobulbar complexes. We found that the apical ectoplasmic specialization and tubulobulbar complexes were poorly formed or disrupted in IP6K1 KOs. Deletion of IP6K1 elicited several aberrations, including: 1, sloughing off of round germ cells; 2, disorientation and malformation of elongating/elongated spermatids; 3, degeneration of acrosomes; 4, defects in germ-Sertoli cell interactions and 5, failure of spermiation. Eventually the sperm cells were not released but phagocytosed by Sertoli cells leading to an absence of sperm in the epididymis.

  View details for DOI 10.1038/s41598-018-25468-8

  View details for Web of Science ID 000431400900019

  View details for PubMedID 29728588

  View details for PubMedCentralID PMC5935691

• Inositol Polyphosphate Multikinase Inhibits Angiogenesis via Inositol Pentakisphosphate-Induced HIF-1 alpha Degradation CIRCULATION RESEARCH Fu, C., Tyagi, R., Chin, A. C., Rojas, T., Li, R., Guha, P., Bernstein, I. A., Rao, F., Xu, R., Cha, J. Y., Xu, J., Snowman, A. M., Semenza, G. L., Snyder, S. H. 2018; 122 (3): 457-472

  Abstract

  Inositol polyphosphate multikinase (IPMK) and its major product inositol pentakisphosphate (IP5) regulate a variety of cellular functions, but their role in vascular biology remains unexplored.We have investigated the role of IPMK in regulating angiogenesis.Deletion of IPMK in fibroblasts induces angiogenesis in both in vitro and in vivo models. IPMK deletion elicits a substantial increase of VEGF (vascular endothelial growth factor), which mediates the regulation of angiogenesis by IPMK. The regulation of VEGF by IPMK requires its catalytic activity. IPMK is predominantly nuclear and regulates gene transcription. However, IPMK does not apparently serve as a transcription factor for VEGF. HIF (hypoxia-inducible factor)-1α is a major determinant of angiogenesis and induces VEGF transcription. IPMK deletion elicits a major enrichment of HIF-1α protein and thus VEGF. HIF-1α is constitutively ubiquitinated by pVHL (von Hippel-Lindau protein) followed by proteasomal degradation under normal conditions. However, HIF-1α is not recognized and ubiquitinated by pVHL in IPMK KO (knockout) cells. IP5 reinstates the interaction of HIF-1α and pVHL. HIF-1α prolyl hydroxylation, which is prerequisite for pVHL recognition, is interrupted in IPMK-deleted cells. IP5 promotes HIF-1α prolyl hydroxylation and thus pVHL-dependent degradation of HIF-1α. Deletion of IPMK in mouse brain increases HIF-1α/VEGF levels and vascularization. The increased VEGF in IPMK KO disrupts blood-brain barrier and enhances brain blood vessel permeability.IPMK, via its product IP5, negatively regulates angiogenesis by inhibiting VEGF expression. IP5 acts by enhancing HIF-1α hydroxylation and thus pVHL-dependent degradation of HIF-1α.

  View details for DOI 10.1161/CIRCRESAHA.117.311983

  View details for Web of Science ID 000423876100015

  View details for PubMedID 29279301

  View details for PubMedCentralID PMC5805644