David M. Vock

Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner

Hepatitis C virus (HCV) subverts host cholesterol metabolism for key processes in its lifecycle. How this interference results in the frequently observed, genotype‐dependent clinical sequelae of hypocholesterolemia, hepatic steatosis, and insulin resistance (IR) remains incompletely understood. Hypocholesterolemia typically resolves after sustained viral response (SVR), implicating viral interference in host lipid metabolism. Using a targeted cholesterol metabolomic platform we evaluated paired HCV genotype 2 (G2) and G3 patient sera for changes in in vivo HCV sterol pathway metabolites. We compared HCV genotypic differences in baseline metabolites and following antiviral treatment to assess whether sterol perturbation resolved after HCV eradication. We linked these metabolites to IR and urine oxidative stress markers. In paired sera from HCV G2 (n = 13) and G3 (n = 20) patients, baseline sterol levels were lower in G3 than G2 for distal metabolites (7‐dehyrocholesterol (7DHC) 0.017 versus 0.023 mg/dL; Padj = 0.0524, cholesterol 140.9 versus 178.7 mg/dL; Padj = 0.0242) but not the proximal metabolite lanosterol. In HCV G3, SVR resulted in increased levels of distal metabolites (cholesterol [Δ55.2 mg/dL; Padj = 0.0015], 7DHC [Δ0.0075 mg/dL; Padj = 0.0026], lathosterol [Δ0.0430 mg/dL Padj = 0.0405]). In contrast, lanosterol was unchanged after SVR (P = 0.9515). Conclusion: HCV G3, but not G2, selectively interferes with the late cholesterol synthesis pathway, evidenced by lower distal sterol metabolites and preserved lanosterol levels. This distal interference resolves with SVR. Normal lanosterol levels provide a signal for the continued proteolysis of 3‐hydroxyl‐3‐methylglutaryl coenzyme A reductase, which may undermine other host responses to increase cholesterol synthesis. These data may provide a hypothesis to explain why hypocholesterolemia persists in chronic HCV infection, particularly in HCV G3, and is not overcome by host cholesterol compensatory mechanisms. (HEPATOLOGY 2012;56:49–56)

Inosine triphosphatase deficiency helps predict anaemia, anaemia management and response in chronic hepatitis C therapy

Anaemia frequently complicates peginterferon/ribavirin therapy for chronic hepatitis C infection. Better prediction of anaemia, ribavirin dose reduction or erythropoietin (EPO) need, may enhance patient management. Inosine triphosphatase (ITPA) genetic variants are associated with ribavirin‐induced anaemia and dose reduction; however, their impact in real‐life clinic patient cohorts remains to be defined. We studied 193 clinic patients with chronic hepatitis C infection of mixed viral genotype (genotype 1/4 n = 123, genotype 2/3, n = 70) treated with peginterferon/ribavirin. Patients were genotyped for ITPA polymorphisms rs1127354 and rs7270101 using Taqman primers. Hardy–Weinberg equilibrium was present. Estimated ITPA deficiency was graded on severity (0–3, no deficiency/mild/moderate/severe, n = 126/40/24/3, respectively). Multivariable models tested the association with anaemia at 4 weeks of treatment [including decline in haemoglobin (g/dL); haemoglobin <10 g/dL and haemoglobin decline >3 g/dL]; ribavirin dose reduction and EPO use and explored sustained viral response (SVR) to peginterferon/ribavirin. More severe ITPA deficiency was associated with less reduction in haemoglobin level (P < 0.001; R2 = 0.34), less ribavirin dose reduction (OR 0.42; (95% CI = 0.23–0.77); P = 0.005) and less EPO use [OR 0.53; (0.30–0.94); P = 0.029]. ITPA deficiency was associated with SVR [OR: 1.70; (1.02–2.83); P = 0.041] independently of clinical covariates (adjusted R2 = 0.31). In this clinical cohort, ITPA deficiency helped predict the risk of on‐treatment anaemia, ribavirin dose reduction, need for EPO support and was associated with SVR. For patients on HCV regimens including peginterferon/ribavirin, testing for ITPA deficiency may have clinical utility.

Impact of Lung Transplantation on Recipient Quality of Life: A Serial, Prospective, Multicenter Analysis Through the First Posttransplant Year

BACKGROUND Quality of life (QOL) is an important but understudied outcome after lung transplantation. Previous cross-sectional, single-center studies suggest improved QOL, but few prior longitudinal multicenter data exist regarding the effect of transplantation on the patient’s QOL. METHODS We hypothesized that lung transplantation confers a 1-year QOL benefit in both physical and psychologic well-being; we further hypothesized that the magnitude of benefit would vary by sex, native disease, age, or type of transplant operation. To test these hypotheses, we conducted a secondary analysis using QOL data prospectively and serially measured with the Medical Outcomes Study 36-Item Short-Form Health Survey, version 2 (SF-36) in a multicenter cytomegalovirus prevention clinical trial. Linear mixed-effects models were used to assess the impact of transplantation on the recipient’s QOL. RESULTS Over the first year after lung transplantation, the SF-36 Physical Component Score significantly increased an average of 10.9 points from baseline levels (P < .0001). A positive benefit was observed for all native diseases; however, the magnitude varied slightly by native disease (P = .04) but not by sex (P = .35), age (P = .06), or transplant type (P = .30). In contrast, the SF-36 Mental Component Score did not change from baseline (P = .36) and remained well below population norms. CONCLUSIONS Our results demonstrate that lung transplantation confers clinically important QOL benefits in physical domains but not in psychologic well-being. A better understanding of the barriers to psychologic well-being after transplant is critical to enhancing the benefits of lung transplantation.

Interleukin 28B polymorphisms are the only common genetic variants associated with low-density lipoprotein cholesterol (LDL-C) in genotype-1 chronic hepatitis C and determine the association between LDL-C and treatment response

Summary.  Low‐density lipoprotein cholesterol (LDL‐C) levels and interleukin 28B (IL28B) polymorphism are associated with sustained viral response (SVR) to peginterferon/ribavirin (pegIFN/RBV) for chronic hepatitis C (CHC) infection. IL28B has been linked with LDL‐C levels using a candidate gene approach, but it is not known whether other genetic variants are associated with LDL‐C, nor how these factors definitively affect SVR. We assessed genetic predictors of serum lipid and triglyceride levels in 1604 patients with genotype 1 (G1) chronic hepatitis C virus (HCV) infection by genome‐wide association study and developed multivariable predictive models of SVR. IL28B polymorphisms were the only common genetic variants associated with pretreatment LDL‐C level in Caucasians (rs12980275, P = 4.7 × 10−17, poor response IL28B variants associated with lower LDL‐C). The association was dependent on HCV infection, IL28B genotype was no longer associated with LDL‐C in SVR patients after treatment, while the association remained significant in non‐SVR patients (P < 0.001). LDL‐C was significantly associated with SVR for heterozygous IL28B genotype patients (P < 0.001) but not for homozygous genotypes. SVR modelling suggested that IL28B heterozygotes with LDL‐C > 130 mg/dL and HCV RNA ≤600 000 IU/mL may anticipate cure rates >80%, while the absence of these two criteria was associated with an SVR rate of <35%. IL28B polymorphisms are the only common genetic variants associated with pretreatment LDL‐C in G1‐HCV. LDL‐C remains significantly associated with SVR for heterozygous IL28B genotype patients, where LDL‐C and HCV RNA burden may identify those patients with high or low likelihood of cure with pegIFN/RBV therapy.

An Acute Change in Lung Allocation Score and Survival After Lung Transplantation: A Cohort Study

BACKGROUND Lung transplantation is an effective treatment for patients with advanced lung disease. In the United States, lungs are allocated on the basis of the lung allocation score (LAS), a composite measure of transplantation urgency and utility. Clinical deteriorations result in increases to the LAS; however, whether the trajectory of the LAS has prognostic significance is uncertain. OBJECTIVE To determine whether an acute increase in the LAS before lung transplantation is associated with reduced posttransplant survival. DESIGN Retrospective cohort study of adult lung transplant recipients listed for at least 30 days between 4 May 2005 (LAS implementation) and 31 December 2010 in the United Network for Organ Sharing registry. An acute increase in the LAS was defined as an LAS change (LASΔ) greater than 5 units between the 30 days before and the time of transplantation. Multivariable Cox proportional hazard models were used to examine the relationship between an LASΔ >5 and posttransplant graft survival. SETTING All U.S. lung transplantation centers. PATIENTS 5749 lung transplant recipients. MEASUREMENTS Survival time after lung transplantation. RESULTS 702 (12.2%) patients experienced an LASΔ >5. These patients had significantly worse posttransplant survival (hazard ratio, 1.31 [95% CI, 1.11 to 1.54]; P = 0.001]) after adjustment for the LAS at transplantation (LAS-T) and other clinical covariates. The effect of an LASΔ >5 was independent of the LAS-T, underlying diagnosis, center volume, or donor characteristics. LIMITATION Analysis was based on center-reported data. CONCLUSION An acute increase in LAS before transplantation is associated with posttransplant survival after adjustment for LAS-T. Further emphasis on serial assessment of the LAS could improve the ability to offer accurate prediction of survival after transplantation. PRIMARY FUNDING SOURCE National Institutes of Health.

Changes to Polymer Surface of Drug-Eluting Stents During Balloon Expansion

Form for Disclosure of Potential Conflicts of Interest and reported being a member of the board of directors of the American Social Health Association; receiving payment from the American Social Health Association for developing educational materials on HPV prevention through an unrestricted grant to the association from Merck; recently completing a term as a member of Merck’s Gardasil Male Population Advisory Committee; and receiving royalties from McGraw-Hill for his book, Color Atlas and Synopsis of Sexually Transmitted Diseases, 2nd and 3rd editions.

Survival Benefit of Lung Transplantation in the Modern Era of Lung Allocation

Rationale: Lung transplantation is an accepted and increasingly employed treatment for advanced lung diseases, but the anticipated survival benefit of lung transplantation is poorly understood. Objectives: To determine whether and for which patients lung transplantation confers a survival benefit in the modern era of U.S. lung allocation. Methods: Data on 13,040 adults listed for lung transplantation between May 2005 and September 2011 were obtained from the United Network for Organ Sharing. A structural nested accelerated failure time model was used to model the survival benefit of lung transplantation over time. The effects of patient, donor, and transplant center characteristics on the relative survival benefit of transplantation were examined. Measurements and Main Results: Overall, 73.8% of transplant recipients were predicted to achieve a 2‐year survival benefit with lung transplantation. The survival benefit of transplantation varied by native disease group (P = 0.062), with 2‐year expected benefit in 39.2 and 98.9% of transplants occurring in those with obstructive lung disease and cystic fibrosis, respectively, and by lung allocation score at the time of transplantation (P < 0.001), with net 2‐year benefit in only 6.8% of transplants occurring for lung allocation score less than 32.5 and in 99.9% of transplants for lung allocation score exceeding 40. Conclusions: A majority of adults undergoing transplantation experience a survival benefit, with the greatest potential benefit in those with higher lung allocation scores or restrictive native lung disease or cystic fibrosis. These results provide novel information to assess the expected benefit of lung transplantation at an individual level and to enhance lung allocation policy.

Evolution of Living Donor Nephrectomy at a Single Center: Long-term Outcomes With 4 Different Techniques in Greater Than 4000 Donors Over 50 Years.

Background The development of minimally invasive surgical approaches to donor nephrectomy (DN) has been driven by the potential advantages for the donor, with questions remaining about long-term outcomes. Methods All living DN performed from June 1963 through December 2014 at the University of Minnesota were reviewed. Outcomes were compared among 4 DN techniques. Results We performed 4286 DNs: 2759 open DN (ODNs), 1190 hand-assisted (HA) laparoscopic DNs (LDNs), 203 pure LDN (P-LDNs), and 97 robot-assisted-LDN. Laparoscopic DN was associated with an older (P < 0.001) and heavier (P < 0.001) donor population. Laparoscopic DN was associated with a higher probability of left kidney procurement (P < 0.001). All 3 LDN modalities required a longer operative time (P < 0.001); robot-assisted-LDN took significantly longer than HA-LDN or P-LDN. Laparoscopic DN decreased the need for intraoperative blood transfusion (P < 0.001) and reduced the incidence of intraoperative complications (P < 0.001) and hospital length of stay (P < 0.001). However, LDN led to a significantly higher rate of readmissions, both short-term (<30 day, P < 0.001) and long-term (>30 day, P < 0.001). Undergoing HA-LDN was associated with a higher rate of an incisional hernia compared with all other modalities (P < 0.001). For recipients, LDN seemed to be associated with lower rates of graft failure at 1 year compared with ODN (P = 0.002). The odds of delayed graft function increased for kidneys with multiple arteries procured via P-LDN compared with HA-LDN (OR 3 [1,10]) and ODN (OR 5 [2, 15]). Conclusions In our experience, LDN was associated with decreased donor intraoperative complications and hospital length of stay but higher rates of readmission and long-term complications.

Utility of high-sensitivity cardiac troponin T in patients receiving anthracycline chemotherapy

Background Anthracycline chemotherapy remains an integral part of the care for curative intent chemotherapy in breast cancer and non-Hodgkin lymphoma patients. Better tools need to be identified to predict cardiac complications of anthracycline chemotherapy. Materials and methods We investigated the utility of high-sensitivity cardiac troponin T (hscTnT), N-terminal pro-B-type natriuretic peptide, cardiac troponin T and I, and creatine kinase (CK)-MB in cancer patients receiving anthracycline-based chemotherapy, in order to determine whether baseline levels or changes in these biomarkers may help predict the onset of congestive heart failure. Results Eighteen consecutive patients with a pathologic diagnosis of breast cancer or non-Hodgkin lymphoma were enrolled. The median dose of doxorubicin exposure was 240 mg/m2 (range 240–400 mg/m2). After treatment with doxorubicin, the hscTnT increased to 19.1 pg/mL (P<0.001). CKMB and N-terminal pro-B-type natriuretic peptide levels increased to 1.1 ng/mL and 88.3 pg/mL, respectively (P=0.02). When subjects who had a decline in left ventricular ejection fraction (LVEF) by equilibrium radionuclide ventriculography were compared to those who did not have a change in LVEF, there was a suggestion that those subjects with an elevated baseline hscTnT were more likely to have a decline in LVEF (2.7 pg/mL and 0.1 pg/mL, respectively; P=0.07). Spearman correlation demonstrated that patients with higher baseline hscTnT and CKMB tended to have a greater decline in LVEF (Spearman correlation −0.54, 95% confidence interval −0.80 to −0.08 [P=0.02], and −0.49, 95% confidence interval −0.77 to −0.01 [P=0.04], respectively). Conclusion Elevations in baseline hscTnT levels are suggestive of an oncology subgroup at high risk of developing cardiac complications from their chemotherapy. Early detection by oncologists with the use of baseline biomarkers may be clinically important in designing interventions to prevent serious anthracycline-based chemotherapy complications.

Mixed model analysis of censored longitudinal data with flexible random-effects density

Mixed models are commonly used to represent longitudinal or repeated measures data. An additional complication arises when the response is censored, for example, due to limits of quantification of the assay used. While Gaussian random effects are routinely assumed, little work has characterized the consequences of misspecifying the random-effects distribution nor has a more flexible distribution been studied for censored longitudinal data. We show that, in general, maximum likelihood estimators will not be consistent when the random-effects density is misspecified, and the effect of misspecification is likely to be greatest when the true random-effects density deviates substantially from normality and the number of noncensored observations on each subject is small. We develop a mixed model framework for censored longitudinal data in which the random effects are represented by the flexible seminonparametric density and show how to obtain estimates in SAS procedure NLMIXED. Simulations show that this approach can lead to reduction in bias and increase in efficiency relative to assuming Gaussian random effects. The methods are demonstrated on data from a study of hepatitis C virus.