Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Gen Y consumers' perceptions of quick service restaurant and the mediating role of purchase intentions : a case study of McDonald's in Singapore

This paper examines purchase intentions and brand loyalty with five dimensions of Quick Service Restaurant. The objectives of the study are to investigate the associations between consumers' perceptions of Quick Service Restaurant and brand loyalty, and whether purchase intentions mediate these relationships. The measures used for the constructs were adapted from past studies and our hypotheses were tested using online survey data. This research was conducted from the perspective of Generation Y consumers in Singapore and we used McDonald's, the market leader in the Singapore fast food industry, as the context for this study. The findings provided support for all the hypotheses, namely, that consumers' perceptions of location, product menu, food quality, service crew and collectibles were positively related to purchase intentions. Moreover, the results indicate that the purchase intention variable played a mediating role in the relationship between location, product menu, food quality and brand loyalty. The findings have some useful managerial implications for the foodservice industry.Published versio

Delineating the contributors towards brand loyalty for fast food restaurants : the case of McDonald’s Singapore.

Using data obtained from self-administrated surveys, this study examined the attributes that motivates consumers to patronize McDonald’s in Singapore. Specifically, we seek to investigate the relative significance of these operational attributes in influencing purchase intention, and subsequently brand loyalty. Using factor analysis and regression analysis, our study uncovers five components that appear instrumental in instilling brand loyalty. We found that strong purchase intention, efficient service crew, extensive menu and reasonably priced food contribute towards loyalty for, and continued patronage at McDonald’s. In addition, purchase intention not only instills brand loyalty, to some extent, it also mediates the influence of other factors on brand loyalty. Notably, our study found that positive service crew attributes and strong purchase intention jointly exerts considerable impact in determining one’s brand loyalty. In sum, while our study focused solely on McDonald’s in Singapore, it has also unveiled relevant insights into areas which local fast food operators can work on to strengthen loyalty among its consumers.BUSINES

An exploration of the political, social, economic and cultural factors affecting how different global regions initially reacted to the COVID-19 pandemic

Responses to the early (February-July 2020) COVID-19 pandemic varied widely, globally. Reasons for this are multiple but likely relate to the healthcare and financial resources then available, and the degree of trust in, and economic support provided by, national governments. Cultural factors also affected how different populations reacted to the various pandemic restrictions, like masking, social distancing and self-isolation or self-quarantine. The degree of compliance with these measures depended on how much individuals valued their needs and liberties over those of their society. Thus, several themes may be relevant when comparing pandemic responses across different regions. East and Southeast Asian populations tended to be more collectivist and self-sacrificing, responding quickly to early signs of the pandemic and readily complied with most restrictions to control its spread. Australasian, Eastern European, Scandinavian, some Middle Eastern, African and South American countries also responded promptly by imposing restrictions of varying severity, due to concerns for their wider society, including for some, the fragility of their healthcare systems. Western European and North American countries, with well-resourced healthcare systems, initially reacted more slowly, partly in an effort to maintain their economies but also to delay imposing pandemic restrictions that limited the personal freedoms of their citizens

The origin of the alpha-domain intermediate in the folding of hen lysozyme

Stopped-flow fluorescence and circular dichroism spectroscopy have been used in conjunction with quenched-flow hydrogen exchange labelling, monitored by electrospray ionization mass spectrometry, to compare the refolding kinetics of hen egg-white lysozyme at 20 degrees C and 50 degrees C. At 50 degrees C there is clear evidence for distinct fast and slow refolding populations, as observed at 20 degrees C, although folding occurs significantly more rapidly. The folding process is, however, substantially more cooperative at the higher temperature. In particular, the transient intermediate on the major refolding pathway at 20 degrees C, having persistent native-like structure in the alpha-helical domain of the protein, is not detected by hydrogen exchange labelling at 50 degrees C. Ln addition, the characteristic maximum in negative ellipticity and the minimum in fluorescence intensity observed in far UV CD and intrinsic fluorescence experiments at 20 degrees C, respectively, are not seen at 50 degrees C. Addition of 2 M NaCl to the refolding buffer at 50 degrees C, however, regenerates both the hydrogen exchange and optical properties associated with the alpha-domain intermediate but has no significant effect on the overall refolding kinetics. Together with previous findings, these results indicate that non-native interactions within the alpha-domain intermediate are directly responsible for the unusual optical properties observed during refolding, and that this intermediate accumulates as a consequence of its intrinsic stability in a folding process where the formation of stable structure in the beta-domain constitutes the rate-limiting step for the majority of molecules. (C) 1998 Academic Press Limited

Trajectory of immune evasion and cancer progression in hepatocellular carcinoma

Immune evasion is key to cancer initiation and later at metastasis, but its dynamics at intermediate stages, where potential therapeutic interventions could be applied, is undefined. Here we show, using multi-dimensional analyses of resected tumours, their adjacent non-tumour tissues and peripheral blood, that extensive immune remodelling takes place in patients with stage I to III hepatocellular carcinoma (HCC). We demonstrate the depletion of anti-tumoural immune subsets and accumulation of immunosuppressive or exhausted subsets along with reduced tumour infiltration of CD8 T cells peaking at stage II tumours. Corresponding transcriptomic modification occur in the genes related to antigen presentation, immune responses, and chemotaxis. The progressive immune evasion is validated in a murine model of HCC. Our results show evidence of ongoing tumour-immune co-evolution during HCC progression and offer insights into potential interventions to reverse, prevent or limit the progression of the disease.National Medical Research Council (NMRC)National Research Foundation (NRF)Published versionThis work was supported by the National Medical Research Council (NMRC), Singapore (ref numbers: NMRC/TCR/015-NCC/2016, NMRC/CIRG/1460/2016, NMRC/ CSA-SI/0013/2017, NMRC/CSA-SI/0018/2017, NMRC/OFLCG/003/2018, NMRC/ STaR/020/2013, NMRC/CG/M003/2017, LCG17MAY004 and NMRC/OFIRG/0064/ 2017) and National Research Foundation, Singapore (ref number: NRF-NRFF2015-04)