Given a passage with a context and an answer, construct a question on the basis of the information present in the passage. Construct the question in such a way that (i) it is unambiguous, (ii) it is answerable from the passage, (iii) its answer is unique (iv) it answer uses text phrases from the passage. Avoid creating questions that (i) can't be answered correctly without actually understanding the passage and (ii) uses the same words or phrases given in the passage.

Input: Consider Input: Context: Autoimmune hepatitis type 2 (AIH-2), a severe juvenile liver disorder of unknown etiology and pathogenesis, is characterized by liver-kidney microsomal antibody type 1 targeting cytochrome P450IID6 (CYP2D6) and is associated to HLA DRB1*07. Although CYP2D6 B-cell reactivity has been extensively characterized, little is known about CYP2D6-specific T-cell responses. The aim of the present study was to characterize anti-CYP2D6 cellular immune responses and their possible pathogenic role in patients with AIH-2.', 'We investigated T-cell reactivity against 61 overlapping peptides spanning the full CYP2D6 protein using ex vivo cultures obtained at diagnosis, remission, and relapse. Moreover, CYP2D6-specific T-cell reactivity was investigated in the context of HLA restriction, peptide-binding affinity to HLA DRB1*07, cytokine profile, disease specificity, and clinical course.', 'Proliferative responses to CYP2D6 cluster to 7 antigenic regions in DRB1*07 and to 4 regions in non-DRB1*07 patients. Whereas distinct peptides induce production of interferon gamma, interleukin-4, or interleukin-10, peptides inducing interferon-gamma and proliferation overlap. There is also an overlap between sequences inducing T- and B-cell responses. The breadth (number of epitopes) and intensity (quantity of cytokine produced) of the T-cell response are directly correlated to disease activity (biochemical and histologic markers).
Answer: These data imply that the T-cell response to CYP2D6 in AIH-2 is polyclonal, involves multiple effector types targeting different epitopes, and is associated with hepatocyte damage, knowledge that should form the basis for a more refined therapeutic approach.

Output: Are polyclonal T-cell responses to cytochrome P450IID6 associated with disease activity in autoimmune hepatitis type 2?


Input: Consider Input: Context: Cardiac overexpression of the β-adrenoreceptor (βAR)-coupled stimulatory G-protein subunit Gαs enhances inotropic responses to adrenergic stimulation and improves survival in mice under βAR blockade. The authors recently identified three common haplotypes in the GNAS gene encoding Gαs, with the greatest Gαs protein expression and signal transduction in haplotype *3 carriers and less in haplotype *2 and *1 carriers. The authors tested the hypothesis that these GNAS variants result in altered mortality in patients after coronary artery bypass graft surgery, particularly in those receiving βAR blockade.', 'This prospective analysis included 1,627 European ancestry patients undergoing primary coronary artery bypass graft surgery. Patients were genotyped for two GNAS haplotype tagging single-nucleotide polymorphisms defining three major haplotypes. Up to 5-yr all-cause mortality was estimated using a Cox proportional hazard model; hazard ratios and 95% CIs were calculated while adjusting for demographics, clinical covariates, and the new EuroSCORE II.', 'Univariate analysis revealed haplotype-dependent 5-yr mortality rates (*1/*1: 18.9%, *2/*1: 13.7%, *2/*2: 9.3%, *3/*1: 10.6%, *3/*2: 9.1%, and *3/*3: 9.6%; P = 0.0006). After adjustment for other predictors of death, homozygote haplotype *1 carriers showed a doubled risk for death (hazard ratio, 2.2; 95% CI, 1.2 to 3.8; P = 0.006). Considering only patients receiving βAR blockers (n = 1,267), the adjusted risk of death even tripled (hazard ratio, 3.0; 95% CI, 1.5 to 6.1; P = 0.002).
Answer: GNAS haplotypes independently associate with an increased risk of death after primary coronary artery bypass graft surgery. These results are most pronounced in patients receiving βAR blockers, strengthening the rationale for personalized treatment, to decrease medication side effects and improve outcomes.

Output: Do gNAS gene variants affect β-blocker-related survival after coronary artery bypass grafting?


Input: Consider Input: Context: We investigated cardiac energetics in subjects with mutations in three different familial hypertrophic cardiomyopathy (HCM) disease genes, some of whom were nonpenetrant carriers without hypertrophy, using phosphorus-31 magnetic resonance spectroscopy.', 'Familial hypertrophic cardiomyopathy is caused by mutations in sarcomeric protein genes. The mechanism by which these mutant proteins cause disease is uncertain. A defect of myocyte contractility had been proposed, but in vitro studies of force generation have subsequently shown opposing results in different classes of mutation. An alternative hypothesis of "energy compromise" resulting from inefficient utilization of adenosine triphosphate (ATP) has been suggested, but in vivo data in humans with genotyped HCM are lacking.', 'The cardiac phosphocreatine (PCr) to ATP ratio was determined at rest in 31 patients harboring mutations in the genes for either beta-myosin heavy chain, cardiac troponin T, or myosin-binding protein C, and in 24 controls. Transthoracic echocardiography was used to measure left ventricular (LV) dimensions and maximal wall thickness.', 'The PCr/ATP was reduced in the HCM subjects by 30% relative to controls (1.70 +/- 0.43 vs. 2.44 +/- 0.30; p < 0.001), and the reduction was of a similar magnitude in all three disease-gene groups. The PCr/ATP was equally reduced in subjects with (n = 24) and without (n = 7) LV hypertrophy.
Answer: Our data provide evidence of a bioenergetic deficit in genotype-confirmed HCM, which is present to a similar degree in three disease-gene groups. The presence of energetic abnormalities, even in those without hypertrophy, supports a proposed link between altered cardiac energetics and development of the disease phenotype.


Output: Is hypertrophic cardiomyopathy due to sarcomeric gene mutations characterized by impaired energy metabolism irrespective of the degree of hypertrophy?