Isaac Alden Bernstein

All Publications

• 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