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.

Q: 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.

A: Are plasma PCSK9 levels significantly modified by statins and fibrates in humans?
****
Q: Context: This study evaluated risk factors for acute wheeze in preschool children and investigated whether subnormal levels of vitamin D were associated with increased risk for acute wheeze, atopy or viral/bacterial respiratory infections.', 'We recruited 130 children with acute wheeze, aged 6\xa0months to 4\xa0years, from paediatric emergency departments in Stockholm, Sweden, and 101 age-matched controls with no history of wheeze or sensitisation to airborne allergens. Parents answered standardised questionnaires, and blood samples were analysed for specific IgE to airborne and food allergens and levels of 25 hydroxyvitamin D (25(OH)D). Nasopharyngeal virus samples were collected during the emergency department visit in the group of children with wheeze, and a subset were also tested for bacteria.', 'Vitamin D insufficiency (25(OH)D\xa0<\xa075\xa0nmol/L (30\xa0ng/mL)) was associated with an odds ratio of 2.7 (95% confidence interval 1.1-6.2) for acute wheeze. However, no association was found between vitamin D insufficiency and atopy, presence of virus or bacteria or recurrent infections. Children older than 24\xa0months were particularly at risk of subnormal vitamin D levels, irrespective of wheezing history.
Answer: Our findings support the hypothesis that subnormal levels of vitamin D are associated with acute wheeze in young children.

A: Are subnormal levels of vitamin D associated with acute wheeze in young children?
****
Q: Context: Several studies have shown that contralateral prophylactic mastectomy (CPM) provides a disease-free and overall survival (OS) benefit in young women with estrogen receptor (ER)-negative breast cancer. We utilized the National Cancer Data Base to evaluate CPM's survival benefit for young women with early -stage breast cancer in the years that ER status was available.", 'We selected 14,627 women ≤45 years of age with American Joint Committee on Cancer stage I-II breast cancer who underwent unilateral mastectomy or CPM from 2004 to 2006. Five-year OS was compared between those who had unilateral mastectomy and CPM using the Kaplan-Meier method and Cox regression analysis.', 'A total of 10,289 (70.3 %) women underwent unilateral mastectomy and 4,338 (29.7 %) women underwent CPM. Median follow up was 6.1 years. After adjusting for patient age, race, insurance status, co-morbidities, year of diagnosis, ER status, tumor size, nodal status, grade, histology, facility type, facility location, use of adjuvant radiation and chemohormonal therapy, there was no difference in OS in women <45 years of age who underwent CPM compared towith those who underwent unilateral mastectomy (hazard ratio [HR] = 0.93; p = 0.39). In addition, Tthere was no improvement in OS in women <45 years of age with T1N0 tumors who underwent CPM versus unilateral mastectomy (HR = 0.85; p = 0.37) after adjusting for the aforementioned factors. Among women ≤45 years of age with ER-negative tumors who underwent CPM, there was no improvement in OS compared with women who underwent unilateral mastectomy (HR = 1.12; p = 0.32) after adjusting for the same aforementioned factors.
Answer: CPM provides no survival benefit to young patients with early-stage breast cancer, and no benefit to ER-negative patients. Future studies with longer follow-up are required in this cohort of patients.

A:
Does contralateral prophylactic mastectomy provide no survival benefit in young women with estrogen receptor-negative breast cancer?
****