TASK DEFINITION: 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.
PROBLEM: Context: Proprotein convertase subtilisin kexin-like 9 (PCSK9) is a secreted glycoprotein that is transcriptionally regulated by cholesterol status. It modulates levels of circulating low density lipoprotein cholesterol (LDLC) by negatively regulating low density lipoprotein receptor (LDLR) levels. PCSK9 variants that result in 'gain of function' have been linked to autosomal dominant hypercholesterolemia, while significant protection from coronary artery disease has been documented in individuals who carry 'loss of function' PCSK9 variants. PCSK9 circulates in human plasma, and we previously reported that plasma PCSK9 is positively correlated with total cholesterol and LDLC in men.", 'Herein, we report the effects of two lipid-modulating therapies, namely statins and fibrates, on PCSK9 plasma levels in human subjects. We also document their effects on endogenous PCSK9 and LDLR expression in a human hepatocyte cell line, HepG2, using immunoprecipitation and immunoblot analyses. Changes in plasma PCSK9 following fenofibrate or gemfibrozil treatments (fibric acid derivatives) were inversely correlated with changes in LDLC levels (r = -0.558, p = 0.013). Atorvastatin administration (HMGCoA reductase inhibitor) significantly increased plasma PCSK9 (7.40%, p = 0.033) and these changes were inversely correlated with changes in LDLC levels (r = -0.393, p = 0.012). Immunoblot analyses of endogenous PCSK9 and LDLR expression by HepG2 cells in response to statins and fibrates showed that LDLR is more upregulated than PCSK9 by simvastatin (2.6x vs 1.5x, respectively at 10 muM), while fenofibrate did not induce changes in either.
Answer: These results suggest that in vivo (1) statins directly increase PCSK9 expression while (2) fibrates affect PCSK9 expression indirectly through its modulation of cholesterol levels and (3) that these therapies could be improved by combination with a PCSK9 inhibitor, constituting a novel hypercholesterolemic therapy, since PCSK9 was significantly upregulated by both treatments.

SOLUTION: Are plasma PCSK9 levels significantly modified by statins and fibrates in humans?

PROBLEM: Context: Evidence suggests that induction of heme oxygenase-1 (HO-1) inhibits proliferation of vascular smooth muscle cells and intimal thickening after arterial injury, and therapeutic molecules induce HO-1. Probucol is the only oral drug that inhibits restenosis in humans and intimal thickening in animals, although its underlying mechanism remains unclear.', 'Aortas were harvested from New Zealand White rabbits fed normal or 0.75% (wt/wt) probucol-fortified chow, with or without endothelial denudation of the abdominal aorta on day 21, and analyzed for heme oxygenase and apoptosis. Uninjured aortas were harvested on day 21 and balloon-injured aortas on days 22 and 25. Probucol significantly increased mRNA of HO-1 assessed by real-time PCR and HO activity in aortas at all time points. Probucol also enhanced apoptosis of medial cells in the injured aorta, as evidenced by the TUNEL assay. Furthermore, probucol (100 micromol/L) increased HO-1 mRNA and HO activity when added to rabbit aortic smooth muscle cells (RASMCs) cultured in serum-free medium for 24 hours. Induction of HO-1 mRNA was inhibited by actinomycin D and was associated with inhibition of RASMC proliferation. This probucol-induced increase in HO-1 mRNA and inhibition of RASMC proliferation was prevented by the HO inhibitor Sn(IV) protoporphyrin or transfection with small interference RNA (siRNA) to knockdown HO-1, but not by inactive Cu(II) protoporphyrin or scrambled siRNA.
Answer: Probucol induces HO-1, and this contributes to the inhibition of vascular SMC proliferation. This novel finding may explain how probucol inhibits restenosis and highlights HO-1 as a target for therapeutic intervention against occlusive vascular disease.

SOLUTION: Does probucol protect against smooth muscle cell proliferation by upregulating heme oxygenase-1?

PROBLEM: Context: Substantial country differences in neurosurgical training throughout Europe have recently been described, ranging from subjective rating of training quality to objective working hours per week. The aim of this study was to analyse whether these differences translate into the results of the written and oral part of the European Board Examination in Neurological Surgery (EBE-NS).', 'Country-specific composite scores for satisfaction with quality of theoretical and practical training, as well as working hours per week, were obtained from an electronic survey distributed among European neurosurgical residents between June 2014 and March 2015. These were related to anonymous country-specific results of the EBE-NS between 2009 and 2016, using uni- and multivariate linear regression analysis.', 'A total of n\u2009=\u20091025 written and n\u2009=\u200963 oral examination results were included. There was a significant linear relationship between the country-specific EBE-NS result in the written part and the country-specific composite score for satisfaction with quality of theoretical training [adjusted regression coefficient (RC) -3.80, 95\xa0% confidence interval (CI) -5.43-7\u2009-2.17, p\u2009<\u20090.001], but not with practical training or working time. For the oral part, there was a linear relationship between the country-specific EBE-NS result and the country-specific composite score for satisfaction with quality of practical training (RC 9.47, 95\xa0% CI 1.47-17.47, p\u2009=\u20090.021), however neither with satisfaction with quality of theoretical training nor with working time.
Answer: With every one-step improvement on the country-specific satisfaction score for theoretical training, the score in the EBE-NS Part 1 increased by 3.8 %. With every one-step improvement on the country-specific satisfaction score for practical training, the score in the EBE-NS Part 2 increased by 9.47 %. Improving training conditions is likely to have a direct positive influence on the knowledge level of trainees, as measured by the EBE-NS. The effect of the actual working time on the theoretical and practical knowledge of neurosurgical trainees appears to be insignificant.

SOLUTION:
Do residency program trainee-satisfaction correlate with results of the European board examination in neurosurgery?