Research Spotlight

Serper, M. and S. K. Asrani (2020). “Liver transplantation and chronic disease management: Moving beyond patient and graft survival.” Am J Transplant 20(3): 629-630.

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With advances in surgical techniques, multidisciplinary care, and immunosuppression, patient and graft survival continue to improve in liver transplantation (LT). Excellent patient and graft survival have translated into an aging liver transplant recipient (LTRs) cohort that resembles a general chronic disease population. LTRs are becoming more medically complex related to LT indication (e.g., nonalcoholic fatty liver disease) and with increased prevalence of relevant chronic conditions such as chronic kidney disease (CKD). Hence a paradigm shift is needed, whereby care provided by LT centers needs to focus not only on survival but also optimizing long‐term management and overall health of the LTR. In the current issue of the American Journal of Transplantation, Dr. VanWagner and colleagues examine an important and understudied aspect of posttransplant care, namely, blood pressure (BP) control. In a single‐center, retrospective cohort of 602 LTRs transplanted from 2010 to 2016 that survived more than 6 months after LT, 54% of patients had preexisting hypertension (HTN) and 84% had uncontrolled BP of 140/90 mm Hg or greater. Patients with uncontrolled BP had the expected risk factors: higher body mass index, higher prevalence of nonalcoholic fatty liver disease, pretransplant HTN, and atherosclerotic cardiovascular disease, and higher corticosteroid and mycophenolate use. Only 16% of LTRs achieved at least one BP of <140/<90 mm Hg within the first posttransplant year and only 29% achieved this goal at 5‐year posttransplant. Adherence to guideline‐recommended BP targets of <130/<80 for groups at higher risk for cardiovascular events (CVEs) such those with CKD and diabetes were dismal; less than 5% in the first year post‐LT and less than 10% at year 5. Rates of discussing initiation of antihypertensives during clinical visits were all below 50% whereas utilization of guideline‐recommended calcium channel blockers was only 14%. (Excerpt from text, p. 629; no abstract available.)

Schaffer, J. M. and W. T. Brinkman (2020). “Invited Commentary.” Ann Thorac Surg 109(3): 686-687.

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In this issue of The Annals of Thoracic Surgery, the aortic team at the University of Maryland led by Dr Bradley S. Taylor presents a series of patients treated endovascularly for ascending aortic pathology. All patients in their series were considered to have a prohibitive risk for open ascending aortic aneurysm repair, and thus would have been treated medically if not for the off-label use of endovascular technology that the authors describe in this study. It is laudable that the “heart team concept” was used to evaluate, risk stratify, and treat these patients. Cardiovascular surgeons, vascular surgeons, and interventional cardiologists were all important members of their aortic team. The study was limited by significant heterogeneity of underlying pathology and patient anatomy. Patient risk stratification was somewhat arbitrary, and the follow-up was short term (median, 388 days). Despite these limitations, we believe that the results presented in this study are excellent, and that Ghoreishi and colleagues are appropriately finding solutions to address the unmet clinical need in patients with ascending aortic (zone 0) pathology at high risk or ineligible for traditional surgical treatment. (Excerpt from text, p. 686; no abstract available.)

Savage, S. A., M. Viard, C. O’HUigin, W. Zhou, M. Yeager, S. A. Li, T. Wang, V. Ramsuran, N. Vince, A. Vogt, B. Hicks, L. Burdett, C. Chung, M. Dean, K. C. de Andrade, N. D. Freedman, S. I. Berndt, N. Rothman, Q. Lan, J. R. Cerhan, S. L. Slager, Y. Zhang, L. R. Teras, M. Haagenson, S. J. Chanock, S. R. Spellman, Y. Wang, A. Willis, M. Askar, S. J. Lee, M. Carrington and S. M. Gadalla (2020). “Genome-wide Association Study Identifies HLA-DPB1 as a Significant Risk Factor for Severe Aplastic Anemia.” Am J Hum Genet 106(2): 264-271.

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Severe aplastic anemia (SAA) is a rare disorder characterized by hypoplastic bone marrow and progressive pancytopenia. The etiology of acquired SAA is not understood but is likely related to abnormal immune responses and environmental exposures. We conducted a genome-wide association study of individuals with SAA genetically matched to healthy controls in discovery (359 cases, 1,396 controls) and validation sets (175 cases, 1,059 controls). Combined analyses identified linked SNPs in distinct blocks within the major histocompatibility complex on 6p21. The top SNP encodes p.Met76Val in the P4 binding pocket of the HLA class II gene HLA-DPB1 (rs1042151A>G, odds ratio [OR] 1.75, 95% confidence interval [CI] 1.50-2.03, p = 1.94 x 10(-13)) and was associated with HLA-DP cell surface expression in healthy individuals (p = 2.04 x 10(-6)). Phylogenetic analyses indicate that Val76 is not monophyletic and likely occurs in conjunction with different HLA-DP binding groove conformations. Imputation of HLA-DPB1 alleles revealed increased risk of SAA associated with Val76-encoding alleles DPB1( *)03:01, (OR 1.66, p = 1.52 x 10(-7)), DPB1( *)10:01 (OR 2.12, p = 0.0003), and DPB1( *)01:01 (OR 1.60, p = 0.0008). A second SNP near HLA-B, rs28367832G>A, reached genome-wide significance (OR 1.49, 95% CI 1.22-1.78, p = 7.27 x 10(-9)) in combined analyses; the association remained significant after excluding cases with clonal copy-neutral loss-of-heterozygosity affecting class I HLA genes (8.6% of cases and 0% of controls). SNPs in the HLA class II gene HLA-DPB1 and possibly class I (HLA-B) are associated with SAA. The replacement of Met76 to Val76 in certain HLA-DPB1 alleles might influence risk of SAA through mechanisms involving DP peptide binding specificity, expression, and/or other factors affecting DP function.

Sarmast, N., G. O. Ogola, M. Kouznetsova, M. Leise, R. Bahirwani, R. Maiwall, E. Tapper, J. Trotter, J. Bajaj, L. R. Thacker, P. Tandon, F. Wong, R. Reddy, J. G. O’Leary, A. Masica, A. M. Modrykamien, P. S. Kamath and S. K. Asrani (2020). “Model for End-stage Liver Disease-Lactate and Prediction of Inpatient Mortality in Patients with Chronic Liver Disease.” Hepatology Feb 21. [Epub ahead of print].

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BACKGROUND & AIMS: As compared to other chronic diseases, patients with chronic liver disease (CLD) have significantly higher inpatient mortality; accurate models to predict inpatient mortality are lacking. Serum lactate (LA) may be elevated in patients with CLD due to both tissue hypoperfusion as well as decreased lactate clearance. We hypothesized that a parsimonious model consisting of Model for End-stage Liver Disease (MELD) and LA at admission may predict inpatient mortality in patients with CLD. APPROACH & RESULTS: We examined all CLD patients in two large and diverse healthcare systems in Texas (North Texas, NTX and Central Texas, CTX) between 2010-2015. We developed (n=3,588) and validated (n=1,804) a model containing MELD and LA measured at time of hospitalization. We further validated the model in a second cohort of 14 tertiary care hepatology centers that prospectively enrolled non-elective hospitalized patients with cirrhosis (n=726). MELD-LA was an excellent predictor of inpatient mortality in development (c-statistic =0.81, 95% CI 0.79-0.82) and both validation cohorts (CTX cohort, c=0.85, 95% CI 0.78-0.87; multicenter cohort c=0.82, 95% CI 0.74-0.88). MELD-LA performed especially well in patients with specific cirrhosis diagnoses (c=0.84, 95% CI 0.81-0.86) or sepsis (c=0.80, 95% CI 0.78-0.82). For MELD score 25, inpatient mortality was 11.2% (LA=1 mmol/L), 19.4% (LA=3 mmol/L), 34.3% (LA=5 mmol/L) and >50% (LA >8 mmol/L). A linear increase (p<0.01) was seen in MELD-LA and increasing number of organ failures. Overall, use of MELD-LA improved the risk prediction in 23.5% of the patients as compared to MELD model alone. CONCLUSION: MELD-LA is an early and objective predictor of inpatient mortality and may serve as a novel model for risk assessment and guide therapeutic options.

Sankaranarayanan, G., C. A. Odlozil, K. O. Wells, S. G. Leeds, S. Chauhan, J. W. Fleshman, D. B. Jones and S. De (2020). “Training with cognitive load improves performance under similar conditions in a real surgical task.” Am J Surg Feb 10. [Epub ahead of print].

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BACKGROUND: Enhancing cognitive load while performing a bimanual surgical task affects performance. Whether repeated training under this condition could benefit performance in an operating room was tested using a virtual reality simulator with cognitive load applied through two-digit math multiplication questions. METHOD: 11 subjects were randomized to Control, VR and VR + CL groups. After a pre-test, VR and VR + CL groups repeated the peg transfer task 150 times over 15 sessions with cognitive load applied only for the last 100 trials. After training, all groups took a post-test and two weeks later the retention test with and without cognitive load and the transfer task on a pig intestine of 150 cm long under cognitive load. RESULTS AND CONCLUSION: Mixed ANOVA analysis showed significant differences between the control and VR and VR + CL groups (p = 0.013, p = 0.009) but no differences between the VR + CL and the VR groups (p = 1.0). GOALS bimanual dexterity score on transfer test show that VR + CL group outperformed both Control and VR groups (p = 0.016, p = 0.03). Training under cognitive load benefitted performance on an actual surgical task under similar conditions.