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Background: \ud Crimean-Congo Haemorrhagic Fever (CCHF) is an emerging human-health threat causing sporadic outbreaks in livestock farming communities. However, the full extent and the risks associated with exposure of such communities has not previously been well-described.\ud \ud Methods: \ud We collected blood samples from 800 humans, 666 cattle, 549 goats and 32 dogs in districts within and outside Ugandan cattle corridor in a cross-sectional survey, and tested for CCHFV-specific IgG antibodies using Enzyme-Linked Immunosorbent Assays. Sociodemographic and epidemiological data were recorded using structured questionnaire. Ticks were collected to identify circulating nairoviruses by metagenomic sequencing.\ud \ud Results: \ud CCHFV seropositivity was in 221/800 (27·6%) in humans, 612/666 (91·8%) in cattle, 413/549 (75·2%) in goats and 18/32 (56·2%) in dogs. Human seropositivity was associated with livestock farming (AOR=5·68, p50 ticks: AOR=3·52, p=0·004). CCHFV was identified in multiple tick pools of Rhipicephalus appendiculatus.\ud \ud Interpretation: \ud The very high CCHF seropositivity especially among livestock farmers and multiple regional risk factors associated exposures, including collecting/eating engorged ticks previously unrecognised, highlights need for further surveillance and sensitisation and control policies against the disease.

Summary The hepatitis C virus (HCV) is an extremely diverse virus, subtypes of which are distributed variably around the world. Viral genotypes may be divided into epidemic subtypes; those that have become prevalent globally, and endemic subtypes that have a more limited distribution, mainly in Africa and Asia. The high variability of endemic strains reflects evolutionary origins in the locations where they are found. This increased genetic diversity raises the possibility of resistance to pan-genotypic direct-acting antiviral regimens. While many endemic subtypes respond well to direct-acting antiviral therapies, others, for example genotypes 1l, 3b and 4r, do not respond as well as predicted. Many genotypes that are rare in high-income countries but common in other parts of the world have not yet been fully assessed in clinical trials. Further sequencing and clinical studies in sub-Saharan Africa and Asia are indicated to monitor response to treatment and to facilitate the World Health Organization’s 2030 elimination strategy.

Background: \ud 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.\ud \ud Methods: \ud 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.\ud \ud Findings: \ud 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.\ud \ud Interpretation: \ud 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.\ud \ud Funding: \ud Medical Research Council; UK Research and Innovation; Department of Health and Social Care; and National Institute for Health Research.

Uranium carbide is a candidate fuel for Generation IV nuclear reactors. However, like any candidate fuel, a reprocessing route should be established before implementation. One proposed method involves a pre-oxidation step, where the carbide fuel is oxidized to an oxide and then reprocessed as normal. A mathematical model has been developed to simulate such an oxidation using finite difference approximations of the heat and mass transfer processes occurring. Available literature was consulted to provide coefficients for the reaction rates and importantly the diffusion of oxygen through the adherent oxide layer that forms on the carbide: the rate limiting step. The transient temperature, oxygen and carbon monoxide distributions through the system are modeled in order to predict oxidation completion times and the temperatures reached. It was found that for a spherical pellet of radius 0.935 cm, the oxidation can take from 1 to 19 h depending on the oxidation conditions and reach temperatures of up to 1556 °C. A robust model results that offers increased understanding of a process crucial to the sustainable use of carbide fuels in energy generation.

Uranium/mixed carbide fuels are a candidate fuel for future nuclear reactors. However, in order to be implemented, a clear outline for their reprocessing must be formed so as to reduce the volume of nuclear waste produced as much as possible. One proposed method is to oxidise the uranium carbide into uranium oxide which can then be reprocessed using current infrastructure. A mathematical model has been constructed to simulate such an oxidation from a combination of finite-difference approximations of the relevant equations describing the heat and mass transfer processes involved. Available literature was consulted for reaction coefficients and information on reaction products, however the behaviour of the produced oxide is uncertain. The model was built accounting for this uncertainty and the resultant predictions will assist in characterising the proposed reprocessing method for carbide fuels.

A multicompartmental model has been devised to explain apolipoprotein B (apoB) kinetics in very low density lipoprotein subfractions (VLDL1 Sf 60-400 and VLDL2 Sf 20-60), intermediate density (IDL Sf 12-20) and low density lipoproteins (LDL Sf 0-12). Normal and hyperlipemic subjects were given tracer doses of 131I-labeled VLDL1 and 125I-labeled VLDL2 and the metabolism of apoB in VLDL1, VLDL2, IDL, and LDL was followed over a period of 13 days. VLDL1 apoB and VLDL2 apoB clearance curves had an initial shoulder, a rapid decay, and a 'tail' of slowly metabolized lipoprotein. ApoB derived from VLDL1 appeared in IDL over 10-50 h and exhibited bi-exponential decay that was attributed to the presence of two metabolically distinct species. A further compartment was required to explain the observation that a substantial proportion of apoB from VLDL2 appeared and disappeared from the IDL density range faster than apoB derived from VLDL1 delipidation. Both of the more rapidly removed IDL species gave rise to LDL apoB that was also modeled as a heterogeneous entity with two plasma compartments. The final model, which has much in common with previous versions (M. Berman et al. 1978. J. Lipid Res. 19: 38-56), a multi-step delipidation pathway and slowly metabolized remnant compartments in VLDL, incorporates parallel delipidation routes in VLDL2, IDL, and LDL. These parallel pathways linked kinetic heterogeneity in VLDL with that in IDL and LDL.

This study was designed to investigate the response of Type III hyperlipoproteinemic subjects to bezafibrate therapy. The metabolism of apolipoprotein B was examined in four lipoprotein subclasses of Sf 60-400 (large very low density lipoprotein (VLDL)), Sf 20-60 (small VLDL), Sf 12-20 (intermediate density lipoprotein (IDL)), and Sf 0-12 (low density lipoprotein (LDL)) before and during bezafibrate therapy. Treatment reduced the plasma concentration of VLDL and raised high density lipoprotein (HDL) cholesterol. There was no net change in LDL cholesterol or its associated apolipoprotein B. The decrease in plasma VLDL derived mainly from an inhibition of synthesis of both large and small subfractions which reduced the number of particles in the circulation without normalizing their lipid composition. Catabolism of the larger VLDL also increased, presumably as a result of lipoprotein lipase activation. Although the plasma concentration of LDL was unchanged, both its synthesis and catabolism were perturbed. Its fractional catabolic rate fell by 50%, but the impact that this would have had on its steady state level in the circulation was apparently blunted by a decrease in its synthesis from Sf 12-20 IDL. In the control phase of the study, most IDL apolipoprotein B was converted to LDL. Bezafibrate therapy channelled this material towards direct catabolism.

Publisher Summary This chapter outlines the mechanism of action of the major lipid-lowering drugs that can be divided conveniently into four classes: resins, statins, fibrates, and others. Resins and statins are used mainly to lower plasma cholesterol in individuals with primary hypercholesterolemia. Fibrates are most often employed in patients with raised plasma triglyceride levels or mixed hyperlipidemia. Drugs such as nicotinic acid and maxepa are usually prescribed in situations where other compounds have failed to work, particularly in the treatment of severe hypertriglyceridemia. The chapter discusses the major effects of lipid-lowering drugs on the plasma lipoprotein profile. Correction of raised plasma lipid levels is a problem that is faced by a medical practitioner on a daily basis. Individuals with signs or symptoms of coronary heart disease require intervention to lower their plasma lipid levels.

Binding of human low density lipoproteins (LDL) to their specific receptor on cultured cells can be inhibited by treatment with 1,2-cyclohexanedione which blocks a number of functionally significant arginyl residues on the apolipoprotein. We have used this observation to examine the role of the receptor pathway in LDL catabolism in man. The plasma clearance rates of 125I-LDL and 131I-cyclohexanedione-treated LDL were measured in four normal and four heterozygous familial hypercholesterolemic subjects. Chemical modification of the lipoprotein significantly reduced its fractional clearance rate and permitted calculation of receptor-mediated and receptor independent catabolism in both groups. The normal subjects cleared 11% of their plasma LDL pool (corresponding to 3.0 mg/kg per day) by a receptor-independent path. In tared daily by these pathways, respectively. Because the mean apoLDL pool size in the group was increased 3-fold over normal, this gave absolute clearance rates for the apoprotein of 2.5 mg/kg per day via the receptors and 12.8 mg/kg per day by the nonreceptor pathway. We conclude that the specific LDL receptor mechanism operates in vivo and probably accounts for 33% and 16% of overall LDL catabolism in normal and heterozygous familial hypercholesterolemic subjects, respectively.

This study examines the effects of probucol (1 g/ day) on the plasma concentration, composition, and metabo- lism of low and high density lipoproteins (LDL and HDL) in eleven hyperlipidemic subjects, (seven Type I1 and four Type IV). The drug lowered plasma cholesterol in the Type I1 pa- tients by 11% (P < 0.02) without affecting triglyceride. Both LDL and HDL cholesterol levels fell by 6% and 2696, respec- tively. The small reduction in the former was not associated with a change in the composition of the lipoprotein nor with a measurable alteration in the level of circulating apoLDL. Kinetic studies revealed that probucol had no consistent effect on either the synthesis or catabolism of apoLDL. However, probucol did exert a potent influence on HDL, lowering the level of this lipoprotein in both the Type I1 and Type IV patients despite the fact that total plasma cholesterol in the latter group was unchanged by treatment. The fall in HDL mass largely affected the HDLs subfraction; HDLp, which was initially low in our subjects, did not show a consistent response to therapy. Not all of the constituents in HDL were equally affected by the drug. Specifically, the fall in total plasma apoA levels (which derived from significant reductions in the rates of synthesis of apoproteins A-I and A-11) was less than that of HDL cholesterol. Direct measurement of the composition of the lipoprotein confirmed that during therapy it carried less cholesterol per unit protein. The significance of these obser- vations in relation to the prophylaxis of ischemic heart disease is not yet clear, but it seems prudent at present to use probucol selectively in subjects who show a substantial hypocholester- olemic response that derives primarily from a reduction in circulating LDL.-Atmeh, R. F., J. M. Stewart, D. E. Boag, C. J. Packard, A. R. Lorimer, and J. Shepherd. The hypo- lipidemic action of probucol: a study of its effects on high and low density 1ipoproteins.J. Lipid Res. 1983. 24: 588-595.

The conversion of very low density (VLDL) to low density lipoproteins (LDL) is a two-step process. The first step is mediated by lipoprotein lipase, but the mechanism responsible for the second is obscure. In this study we examined the possible involvement of receptors at this stage. Apolipoprotein B (apoB)-containing lipoproteins were separated into three fractions, VLDL (Sf 100-400), an intermediate fraction IDL (Sf 12-100), and LDL (Sf 0-12). Autologous 125I-labeled VLDL and 131I-labeled 1,2-cyclohexanedione-modified VLDL were injected into the plasma of four normal subjects and the rate of transfer of apoB radioactivity was followed through IDL to LDL. Modification did not affect VLDL to IDL conversion. Thereafter, however, the catabolism of modified apoB in IDL was retarded and its appearance in LDL was delayed. Hence, functional arginine residues (and by implication, receptors) are required in this process. Confirmation of this was obtained by injecting 125I-labeled IDL and 131I-labeled cyclohexanedione-treated IDL into two additional subjects. Again, IDL metabolism was delayed by approximately 50% as a result of the modification. These data are consistent with the view that receptors are involved in the metabolism of intermediate density lipoprotein.