Research Spotlight

Iribarne, A., S. Pan, J. N. McCullough, J. P. Mathew, J. Hung, X. Zeng, P. Voisine, P. T. O’Gara, N. M. Sledz, A. C. Gelijns, W. C. Taddei-Peters, S. R. Messe, A. J. Moskowitz, V. H. Thourani, M. Argenziano, M. A. Groh, G. Giustino, J. R. Overbey, J. M. DiMaio and P. K. Smith (2020). “Impact of Aortic Atherosclerosis Burden on Outcomes of Surgical Aortic Valve Replacement.” Ann Thorac Surg 109(2): 465-471.

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BACKGROUND: Epiaortic ultrasound detects and localizes ascending aortic atherosclerosis. In this analysis we investigated the association between epiaortic ultrasound-based atheroma grade during surgical aortic valve replacement (SAVR) and perioperative adverse outcomes. METHODS: SAVR patients in a randomized trial of 2 embolic protection devices underwent a protocol-defined 5-view epiaortic ultrasound read at a core laboratory. Aortic atherosclerosis was quantified with the Katz atheroma grade, and patients were categorized as mild (grade I-II) or moderate/severe (grade III-V). Multivariable logistic regression was used to estimate associations between atheroma grade and adverse outcomes, including death, clinically apparent stroke, cerebral infarction on diffusion-weighted magnetic resonance imaging, delirium, and acute kidney injury (AKI) by 7 and 30 days. RESULTS: Precannulation epiaortic ultrasound data were available for 326 of 383 randomized patients (85.1%). Of these, 106 (32.5%) had moderate/severe Katz atheroma grade at any segment of the ascending aorta. Although differences in the composite of death, stroke, or cerebral infarction on diffusion-weighted magnetic resonance imaging by 7 days were not statistically significant, moderate/severe atheroma grade was associated with a greater risk of AKI by 7 days (adjusted odds ratio, 2.63; 95% confidence interval, 1.24-5.58; P = .01). At 30 days, patients with moderate/severe atheroma grade had a greater risk of death, stroke, or AKI (adjusted odds ratio, 1.97; 95% confidence interval, 1.04-3.71; P = .04). CONCLUSIONS: Moderate/severe aortic atherosclerosis was associated with an increased risk of adverse events after SAVR. Epiaortic ultrasound may serve as a useful adjunct for identifying patients who may benefit from strategies to reduce atheroembolic complications during SAVR.

Huo, X., K. B. Dunbar, X. Zhang, Q. Zhang, S. J. Spechler and R. F. Souza (2020). “In Barrett’s Epithelial Cells, Weakly Acidic Bile Salt Solutions Cause Oxidative DNA Damage with Response and Repair Mediated by p38.” Am J Physiol Gastrointest Liver Physiol Jan 27. [Epub ahead of print].

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The frequency of esophageal adenocarcinoma is rising despite widespread use of PPIs, which heal reflux esophagitis but do not prevent reflux of weakly acidic gastric juice and bile in Barrett’s esophagus patients. We aimed to determine if weakly acidic (pH 5.5) bile salt medium (WABM) causes DNA damage in Barrett’s cells. Since p53 is inactivated frequently in Barrett’s esophagus and p38 can assume p53 functions, we explored p38’s role in DNA damage response and repair. We exposed Barrett’s cells with or without p53 knockdown to WABM, and evaluated DNA damage, its response and repair, and whether these effects are p38-dependent. We also measured phospho-p38 in biopsies of Barrett’s metaplasia exposed to deoxycholic acid (DCA). WABM caused phospho-H2AX increases that were blocked by a reactive oxygen species (ROS) scavenger. WABM increased phospho-p38 and reduced BrdU incorporation (an index of S phase entry). Repair of WABM-induced DNA damage proceeded through p38-mediated base excision repair (BER) associated with Ref-1/APE1. Cells treated with WABM supplemented with ursodeoxycholic acid (UDCA) exhibited enhanced p38-mediated responses to DNA damage. All these effects were observed in p53-intact and p53-deficient Barrett’s cells. In patients, esophageal DCA perfusion significantly increased phospho-p38 in Barrett’s metaplasia. WABM exposure generates ROS causing oxidative DNA damage in Barrett’s cells, a mechanism possibly underlying the rising frequency of esophageal adenocarcinoma despite PPI usage. p38 plays a central role in oxidative DNA damage response and Ref-1/APE1-associated BER, suggesting potential chemopreventive roles for agents like UDCA that increase p38 activity in Barrett’s esophagus.

Hinkley, S. B., S. C. Holub and A. Menter (2020). “The Validity of Cutaneous Body Image as a Construct and as a Mediator of the Relationship Between Cutaneous Disease and Mental Health.” Dermatol Ther (Heidelb) 10(1): 203-211.

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INTRODUCTION: Cutaneous body image (CBI) is a construct encompassing how individuals perceive their hair, skin, and nails. Negative CBI has been related to negative psychological outcomes and body image concerns. The first aim of our study was to further validate CBI as a construct. Second, as individuals with dermatologic conditions are at an increased risk for anxiety and depression, the study examined CBI as a mediator of the relationships between having a skin condition and anxiety and depression. METHODS: A convenience sample of clinical participants with dermatologist-validated diagnoses of psoriasis, atopic dermatitis, or acne who were currently taking systemic medication (n = 128) were matched to a sample of comparison participants without skin conditions (n = 128) on self-reported gender, ethnicity, developmental stage, and weight status (body mass index). All participants reported on their CBI, self-esteem (global, appearance-related, and weight-related), body dissatisfaction, drive for thinness, dietary restraint, anxiety, depression, and demographic characteristics. RESULTS: Cutaneous body image was more negative in those respondents with skin conditions (regression analysis B = – 0.61, standard error 0.23, p = 0.008), demonstrating the criterion-related validity of the measure. CBI was significantly correlated with global (r = 0.39, p < 0.001) and appearance-related self-esteem (r = 0.50, p < 0.001), which establishes convergent validity. CBI was not significantly related to a drive for thinness (r = - 0.12, p = 0.06) or to dietary restraint (r = - 0.05, p = 0.39), supporting discriminant validity. CBI mediated the relationships between having a dermatologic condition and anxiety [point estimate of indirect effect 0.07, 95% confidence interval (CI) 0.02, 0.15] and depression (point estimate of indirect effect 0.04, 95% CI 0.01, 0.08). CONCLUSIONS: The measure of CBI has been further validated. Dermatologists must be aware that various dermatoses may impact patient mental health via the mechanism of negative CBI.

Helman, G., B. R. Lajoie, J. Crawford, A. Takanohashi, M. Walkiewicz, E. Dolzhenko, A. M. Gross, V. G. Gainullin, S. J. Bent, E. M. Jenkinson, S. Ferdinandusse, H. R. Waterham, I. Dorboz, E. Bertini, N. Miyake, N. I. Wolf, T. E. M. Abbink, S. M. Kirwin, C. M. Tan, G. M. Hobson, L. Guo, S. Ikegawa, A. Pizzino, J. L. Schmidt, G. Bernard, R. Schiffmann, M. S. van der Knaap, C. Simons, R. J. Taft and A. Vanderver (2020). “Genome sequencing in persistently unsolved white matter disorders.” Ann Clin Transl Neurol 7(1): 144-152.

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Genetic white matter disorders have heterogeneous etiologies and overlapping clinical presentations. We performed a study of the diagnostic efficacy of genome sequencing in 41 unsolved cases with prior exome sequencing, resolving an additional 14 from an historical cohort (n = 191). Reanalysis in the context of novel disease-associated genes and improved variant curation and annotation resolved 64% of cases. The remaining diagnoses were directly attributable to genome sequencing, including cases with small and large copy number variants (CNVs) and variants in deep intronic and technically difficult regions. Genome sequencing, in combination with other methodologies, achieved a diagnostic yield of 85% in this retrospective cohort.

Hamandi, M., W. H. Ryan, P. A. Grayburn, E. Huff, L. Mallari and M. J. Mack (2020). “Misclassification of Mitral Valve Disease and Rate of Surgical Repair in the STS Database.” Ann Thorac Surg Jan 18. [Epub ahead of print].

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BACKGROUND: Surgical repair of primary mitral regurgitation (MR) is considered an indicator of quality performance. Therefore, accurate data reporting is critical for quality assessment. During an institutional quality review, MR etiology could not be determined in 40% of operations in our Society of Thoracic Surgeons (STS) database entries and thus our true repair rate could not be reliably ascertained. Therefore, we reviewed all source documents and echocardiograms to assess our true disease etiology and repair rate. METHODS: Sourse records and echocardiograms of all operations performed in a single healthcare system for a one-year period were reviewed by an experienced MV surgeon, an echocardiographic core lab and a data manager. Disease etiology and operation were compared to data previously entered in the database by post hoc chart abstraction. RESULTS: 314 isolated MV operations were performed. MR was originally classified as primary- 163 (52%), secondary- 22 (7%), rheumatic- 37 (12%), endocarditis- 24 (8%), other- 33 (10%), and unknown- 35 (11%). Reported repair rate for primary MR was 142/163 (87.1%). After review, etiology was determined to be primary- 177 (56%), secondary-33 (11%), rheumatic- 61 (20%), endocarditis- 25 (8%), and others- 18 (5%) resulting in a change of classification in 99/314 (31.5%) patients and a true repair rate for primary MR of 165/177 (93.2%). CONCLUSIONS: Source document and imaging review of MV surgery revealed significant discordance with post hoc chart abstraction methods. A more detailed data entry methodology is necessary to accurately report the true disease etiology and repair rates for primary MR.