Regulation of Sterol Transport by Dietary Phytosterol Esters

LDL cholesterol is associated with the development of atherosclerosis and is therefore considered an important target for intervention to prevent cardiovascular diseases. The inhibition of cholesterol absorption in the small intestine is an attractive approach to lowering plasma cholesterol, one that is exploited by drug therapy as well as dietary supplementation with plant sterols. The mechanism of action of plant sterol esters (PSE) is still incompletely understood, therefore this study was conducted to test the hypothesis that hydrolysis of plant sterol esters is necessary for their cholesterol-lowering effects to be realized. Male Syrian hamsters were fed diets containing no PSE, PSE containing stearic acid, palmitic acid, oleic acid or plant sterol ethers containing stearic acid. Treatment compounds were added at 5% of the diet (g/g). Diets were high is cholesterol and saturated fat to induce hyperlipidemia. The treatments effectively created a spectrum of PSE hydrolysis across which cholesterol metabolism could be compared. Stearate ethers, Stearate Esters and Palmitate Esters were poorly hydrolyzed (1.69-4.12%), while oleate sters were hydrolyzed at 88.29%, and cholesterol absorption correlated negatively with percent hydrolysis with a correlation coefficient of -0.8504. These results suggest that PSE hydrolysis plays a necessary role in the cholesterol-lowering effects of PSE. In addition, these data also suggest that poorly hydrolyzed plant sterol esters may act through an alternative mechanism than that of competition with cholesterol for micelle incorporation. We suggest that these PSE that are not well hydrolyzed may lower cholesterol by forming an oil phase into which cholesterol is solubilized making it unavailable for absorption into enterocytes. In summary, our results demonstrated that PSE hydrolysis is necessary for cholesterol-lowering. Additionally, poorly hydrolyzed PSE may function through an alternative pathway than micelle competition with cholesterol. Advisor: Timothy P. Car

Cronbach’s Alpha Under Insufficient Effort Responding: An Analytic Approach

Surveys commonly suffer from insufficient effort responding (IER). If not accounted for, IER can cause biases and lead to false conclusions. In particular, Cronbach’s alpha has been empirically observed to either deflate or inflate due to IER. This paper will elucidate how IER impacts Cronbach’s alpha in a variety of situations. Previous results concerning internal consistency under mixture models are extended to obtain a characterization of Cronbach’s alpha in terms of item validities, average variances, and average covariances. The characterization is then applied to contaminating distributions representing various types of IER. The discussion will provide commentary on previous simulation-based investigations, confirming some previous hypotheses for the common types of IER, but also revealing possibilities from newly considered responding patterns. Specifically, it is possible that the bias can change from negative to positive (and vice versa) as the proportion of contamination increases

Dietary Plant Sterol Esters Must Be Hydrolyzed to Reduce Intestinal Cholesterol Absorption in Hamsters

Background: Elevated concentrations of LDL cholesterol are associated with the development of atherosclerosis and therefore are considered an important target for intervention to prevent cardiovascular diseases. The inhibition of cholesterol absorption in the small intestine is an attractive approach to lowering plasma cholesterol, one that is addressed by drug therapy as well as dietary supplementation with plant sterols and plant sterol esters (PSEs). Objective: This study was conducted to test the hypothesis that the cholesterol-lowering effects of PSE require hydrolysis to free sterols (FSs). Methods: Male Syrian hamsters were fed atherogenic diets (AIN-93M purified diet containing 0.12% cholesterol and 8% coconut oil) to which one of the following was added: no PSEs or ethers (control), 5% sterol stearate esters, 5% sterol palmitate esters (PEs), 5% sterol oleate esters (OEs), 5% sterol stearate ethers (STs; to mimic nonhydrolyzable PSE), or 3% FSs plus 2% sunflower oil. The treatments effectively created a spectrum of PSE hydrolysis across which cholesterol metabolism could be compared. Metabolic measurements included cholesterol absorption, plasma and liver lipid concentration, and fecal neutral sterol and bile acid excretion. Results: The STs and the PEs and SEs were poorly hydrolyzed (1.69–4.12%). In contrast,OEs were 88.3% hydrolyzed. The percent hydrolysis was negatively correlated with cholesterol absorption (r=20.85; P \u3c 0.0001) and positively correlated with fecal cholesterol excretion (r = 0.92; P \u3c 0.0001), suggesting that PSE hydrolysis plays a central role in the cholesterol-lowering properties of PSE. Conclusions: Our data on hamsters suggest that PSE hydrolysis and the presence of FSs is necessary to induce an optimum cholesterol-lowering effect and that poorly hydrolyzed PSEs may lower cholesterol through an alternative mechanism than that of competition with cholesterol for micelle incorporation

Dietary Plant Sterol Esters Must Be Hydrolyzed to Reduce Intestinal Cholesterol Absorption in Hamsters

Background: Elevated concentrations of LDL cholesterol are associated with the development of atherosclerosis and therefore are considered an important target for intervention to prevent cardiovascular diseases. The inhibition of cholesterol absorption in the small intestine is an attractive approach to lowering plasma cholesterol, one that is addressed by drug therapy as well as dietary supplementation with plant sterols and plant sterol esters (PSEs). Objective: This study was conducted to test the hypothesis that the cholesterol-lowering effects of PSE require hydrolysis to free sterols (FSs). Methods: Male Syrian hamsters were fed atherogenic diets (AIN-93M purified diet containing 0.12% cholesterol and 8% coconut oil) to which one of the following was added: no PSEs or ethers (control), 5% sterol stearate esters, 5% sterol palmitate esters (PEs), 5% sterol oleate esters (OEs), 5% sterol stearate ethers (STs; to mimic nonhydrolyzable PSE), or 3% FSs plus 2% sunflower oil. The treatments effectively created a spectrum of PSE hydrolysis across which cholesterol metabolism could be compared. Metabolic measurements included cholesterol absorption, plasma and liver lipid concentration, and fecal neutral sterol and bile acid excretion. Results: The STs and the PEs and SEs were poorly hydrolyzed (1.69–4.12%). In contrast,OEs were 88.3% hydrolyzed. The percent hydrolysis was negatively correlated with cholesterol absorption (r=20.85; P \u3c 0.0001) and positively correlated with fecal cholesterol excretion (r = 0.92; P \u3c 0.0001), suggesting that PSE hydrolysis plays a central role in the cholesterol-lowering properties of PSE. Conclusions: Our data on hamsters suggest that PSE hydrolysis and the presence of FSs is necessary to induce an optimum cholesterol-lowering effect and that poorly hydrolyzed PSEs may lower cholesterol through an alternative mechanism than that of competition with cholesterol for micelle incorporation

Hospital admission and emergency care attendance risk for SARS-CoV-2 delta (B.1.617.2) compared with alpha (B.1.1.7) variants of concern: a cohort study

Background: The SARS-CoV-2 delta (B.1.617.2) variant was first detected in England in March, 2021. It has since rapidly become the predominant lineage, owing to high transmissibility. It is suspected that the delta variant is associated with more severe disease than the previously dominant alpha (B.1.1.7) variant. We aimed to characterise the severity of the delta variant compared with the alpha variant by determining the relative risk of hospital attendance outcomes. Methods: This cohort study was done among all patients with COVID-19 in England between March 29 and May 23, 2021, who were identified as being infected with either the alpha or delta SARS-CoV-2 variant through whole-genome sequencing. Individual-level data on these patients were linked to routine health-care datasets on vaccination, emergency care attendance, hospital admission, and mortality (data from Public Health England's Second Generation Surveillance System and COVID-19-associated deaths dataset; the National Immunisation Management System; and NHS Digital Secondary Uses Services and Emergency Care Data Set). The risk for hospital admission and emergency care attendance were compared between patients with sequencing-confirmed delta and alpha variants for the whole cohort and by vaccination status subgroups. Stratified Cox regression was used to adjust for age, sex, ethnicity, deprivation, recent international travel, area of residence, calendar week, and vaccination status. Findings: Individual-level data on 43 338 COVID-19-positive patients (8682 with the delta variant, 34 656 with the alpha variant; median age 31 years [IQR 17–43]) were included in our analysis. 196 (2·3%) patients with the delta variant versus 764 (2·2%) patients with the alpha variant were admitted to hospital within 14 days after the specimen was taken (adjusted hazard ratio [HR] 2·26 [95% CI 1·32–3·89]). 498 (5·7%) patients with the delta variant versus 1448 (4·2%) patients with the alpha variant were admitted to hospital or attended emergency care within 14 days (adjusted HR 1·45 [1·08–1·95]). Most patients were unvaccinated (32 078 [74·0%] across both groups). The HRs for vaccinated patients with the delta variant versus the alpha variant (adjusted HR for hospital admission 1·94 [95% CI 0·47–8·05] and for hospital admission or emergency care attendance 1·58 [0·69–3·61]) were similar to the HRs for unvaccinated patients (2·32 [1·29–4·16] and 1·43 [1·04–1·97]; p=0·82 for both) but the precision for the vaccinated subgroup was low. Interpretation: This large national study found a higher hospital admission or emergency care attendance risk for patients with COVID-19 infected with the delta variant compared with the alpha variant. Results suggest that outbreaks of the delta variant in unvaccinated populations might lead to a greater burden on health-care services than the alpha variant. Funding: Medical Research Council; UK Research and Innovation; Department of Health and Social Care; and National Institute for Health Research

Changes in symptomatology, reinfection, and transmissibility associated with the SARS-CoV-2 variant B.1.1.7: an ecological study

Background The SARS-CoV-2 variant B.1.1.7 was first identified in December, 2020, in England. We aimed to investigate whether increases in the proportion of infections with this variant are associated with differences in symptoms or disease course, reinfection rates, or transmissibility. Methods We did an ecological study to examine the association between the regional proportion of infections with the SARS-CoV-2 B.1.1.7 variant and reported symptoms, disease course, rates of reinfection, and transmissibility. Data on types and duration of symptoms were obtained from longitudinal reports from users of the COVID Symptom Study app who reported a positive test for COVID-19 between Sept 28 and Dec 27, 2020 (during which the prevalence of B.1.1.7 increased most notably in parts of the UK). From this dataset, we also estimated the frequency of possible reinfection, defined as the presence of two reported positive tests separated by more than 90 days with a period of reporting no symptoms for more than 7 days before the second positive test. The proportion of SARS-CoV-2 infections with the B.1.1.7 variant across the UK was estimated with use of genomic data from the COVID-19 Genomics UK Consortium and data from Public Health England on spike-gene target failure (a non-specific indicator of the B.1.1.7 variant) in community cases in England. We used linear regression to examine the association between reported symptoms and proportion of B.1.1.7. We assessed the Spearman correlation between the proportion of B.1.1.7 cases and number of reinfections over time, and between the number of positive tests and reinfections. We estimated incidence for B.1.1.7 and previous variants, and compared the effective reproduction number, Rt, for the two incidence estimates. Findings From Sept 28 to Dec 27, 2020, positive COVID-19 tests were reported by 36 920 COVID Symptom Study app users whose region was known and who reported as healthy on app sign-up. We found no changes in reported symptoms or disease duration associated with B.1.1.7. For the same period, possible reinfections were identified in 249 (0·7% [95% CI 0·6–0·8]) of 36 509 app users who reported a positive swab test before Oct 1, 2020, but there was no evidence that the frequency of reinfections was higher for the B.1.1.7 variant than for pre-existing variants. Reinfection occurrences were more positively correlated with the overall regional rise in cases (Spearman correlation 0·56–0·69 for South East, London, and East of England) than with the regional increase in the proportion of infections with the B.1.1.7 variant (Spearman correlation 0·38–0·56 in the same regions), suggesting B.1.1.7 does not substantially alter the risk of reinfection. We found a multiplicative increase in the Rt of B.1.1.7 by a factor of 1·35 (95% CI 1·02–1·69) relative to pre-existing variants. However, Rt fell below 1 during regional and national lockdowns, even in regions with high proportions of infections with the B.1.1.7 variant. Interpretation The lack of change in symptoms identified in this study indicates that existing testing and surveillance infrastructure do not need to change specifically for the B.1.1.7 variant. In addition, given that there was no apparent increase in the reinfection rate, vaccines are likely to remain effective against the B.1.1.7 variant. Funding Zoe Global, Department of Health (UK), Wellcome Trust, Engineering and Physical Sciences Research Council (UK), National Institute for Health Research (UK), Medical Research Council (UK), Alzheimer's Society

Genomic assessment of quarantine measures to prevent SARS-CoV-2 importation and transmission

Mitigation of SARS-CoV-2 transmission from international travel is a priority. We evaluated the effectiveness of travellers being required to quarantine for 14-days on return to England in Summer 2020. We identified 4,207 travel-related SARS-CoV-2 cases and their contacts, and identified 827 associated SARS-CoV-2 genomes. Overall, quarantine was associated with a lower rate of contacts, and the impact of quarantine was greatest in the 16–20 age-group. 186 SARS-CoV-2 genomes were sufficiently unique to identify travel-related clusters. Fewer genomically-linked cases were observed for index cases who returned from countries with quarantine requirement compared to countries with no quarantine requirement. This difference was explained by fewer importation events per identified genome for these cases, as opposed to fewer onward contacts per case. Overall, our study demonstrates that a 14-day quarantine period reduces, but does not completely eliminate, the onward transmission of imported cases, mainly by dissuading travel to countries with a quarantine requirement

Genomic epidemiology of SARS-CoV-2 in a UK university identifies dynamics of transmission

AbstractUnderstanding SARS-CoV-2 transmission in higher education settings is important to limit spread between students, and into at-risk populations. In this study, we sequenced 482 SARS-CoV-2 isolates from the University of Cambridge from 5 October to 6 December 2020. We perform a detailed phylogenetic comparison with 972 isolates from the surrounding community, complemented with epidemiological and contact tracing data, to determine transmission dynamics. We observe limited viral introductions into the university; the majority of student cases were linked to a single genetic cluster, likely following social gatherings at a venue outside the university. We identify considerable onward transmission associated with student accommodation and courses; this was effectively contained using local infection control measures and following a national lockdown. Transmission clusters were largely segregated within the university or the community. Our study highlights key determinants of SARS-CoV-2 transmission and effective interventions in a higher education setting that will inform public health policy during pandemics.</jats:p

Food availability of glucose and fat, but not fructose, increased in the US between 1970 and 2009: analysis of the USDA food availability data system

Background: Obesity rates in the United States have risen consistently over the last four decades, increasing from about 13% of the population in 1970 to more than 34% in 2009. Dietary fructose has been blamed as a possible contributor to the obesity increase, although the consumption pattern of fructose and other key nutrients during this 40 year period remains a topic of debate. Therefore, we analyzed the USDA Loss-Adjusted Food Availability Database in combination with the USDA Nutrient Database for Standard Reference (Release 24) to determine whether fructose consumption in the US has increased sufficiently to be a casual factor in the rise in obesity prevalence. Methods: Per capita loss-adjusted food availability data for 132 individual food items were compiled and analyzed. Nutrient profiles for each of these foods were used to determine the availability of energy as well as macronutrients and monosaccharides during the years 1970-2009. The percent change in energy from food groups and individual nutrients was determined by using the year 1970 as the baseline and area-under-the-curve analysis of food trends. Results: Our findings indicate that during this 40 year period the percent change in total energy availability increased 10.7%, but that the net change in total fructose availability was 0%. Energy available from total glucose (from all digestible food sources) increased 13.0%. Furthermore, glucose availability was more than 3-times greater than fructose. Energy available from protein, carbohydrate and fat increased 4.7%, 9.8% and 14.6%, respectively. Conclusions: These data suggest that total fructose availability in the US did not increase between 1970 and 2009 and, thus, was unlikely to have been a unique causal factor in the increased obesity prevalence. We conclude that increased total energy intake, due to increased availability of foods providing glucose (primarily as starch in grains) and fat, to be a significant contributor to increased obesity in the US