Search PubMed⌕ Search

Biomedical subjects

N M Ferguson

Publications and source records attributed to N M Ferguson.

At least 37 records · Page 2Linked to original sources
PubMed2000

Slower decline of plasma HIV-1 RNA following highly suppressive antiretroviral therapy in primary compared with chronic infection.

OBJECTIVES: To study the effect of highly suppressive antiretroviral therapy on the slopes of HIV-1 RNA decline in primary compared with chronic HIV-1 infection. METHODS: Slopes of HIV-1 RNA decline in plasma were compared before and after the start of highly suppressive antiretroviral therapy from five acutely infected patients who started treatment 2 to 5 weeks following the onset of clinical symptoms. Slopes of decline after the initiation of therapy were also compared with those found in 12 chronically infected individuals on the same therapy. Numbers and percentages of activated CD4 and CD8 T cells at baseline were compared as well. RESULTS: The pre-treatment slopes of HIV-1 RNA decline in the acutely infected individuals increased significantly (P = 0.0001) after the start of anti-retroviral therapy. However, these post-treatment slopes were lower than those found in the chronically infected individuals (P= 0.012). Slopes were inversely correlated (P= 0.012) with baseline HIV-1 RNA. Although the number of CD38+HLA-DR+ CD4 cells was higher in primary infection (P= 0.02), the percentage did not differ between primary and chronic infection. CONCLUSIONS: These findings indicate that antiretroviral therapy contributes significantly to the clearance of HIV-1 during primary infection. Based on the mathematical model the less steep RNA slope following the start of treatment in primary infection can be predicted to be the result of lower clearance of productively infected cells and higher burst size per cell per unit time. This may indicate a growing immune response to HIV-1 in this very early stage of infection.

Acute Disease↗
PubMed2000

Reduction of the HIV-1-infected T-cell reservoir by immune activation treatment is dose-dependent and restricted by the potency of antiretroviral drugs.

BACKGROUND: Treatments combining T-cell activating agents and potent antiretroviral drugs have been proposed as a possible means of reducing the reservoir of long-lived HIV-1 infected quiescent CD4 T-cells. OBJECTIVE: To analyse the effect of such therapies on HIV-1 dynamics and T-cell homeostasis. DESIGN AND METHODS: A mathematical framework describing HIV-1 dynamics and T-cell homeostasis was developed. Three patients who were kept on a particularly potent course of highly active antiretroviral therapy (HAART) were treated with the anti-CD3 monoclonal antibody OKT3 and interleukin (IL)-2. Plasma HIV-RNA, and HIV-RNA and DNA in peripheral blood mononuclear cells and lymph node mononuclear cells were measured. These results and other published studies on the use of IL-2 alone were assessed using our mathematical framework. RESULTS: We show that outcome of treatment is determined by the relative rates of depletion of the infected quiescent T-cell population by activation and of its replenishment through new infection. Which of these two processes dominates is critically dependent on both the potency of HAART and also the degree of T-cell activation induced. We demonstrate that high-level T-cell stimulation is likely to produce negative outcomes, both by failing to reduce viral reservoirs and by depleting the CD4 T-cell pool and disrupting CD4/CD8 T-cell homeostasis. In contrast, repeated low-level stimulation may both aid CD4 T-cell pool expansion and achieve a substantial reduction in the long-lived HIV-1 reservoir. CONCLUSIONS: Our analysis suggests that although treatment that activates T-cells can reduce the long-lived HIV-1 reservoir, caution should be used as high-level stimulation may result in a negative outcome.

Anti-HIV Agents↗
PubMed2000

Feed-borne transmission and case clustering of BSE.

An unresolved issue in the epidemiology of bovine spongiform encephalopathy (BSE) in the UK is what precisely determines the degree to which cases of disease in cattle are clustered within herds throughout the course of the epidemic. This paper presents an analysis of feed-borne transmission at the herd level and tests various models of case-clustering mechanisms, associated with heterogeneity in exposure to infectious feed, against observed epidemic pattern. We use an age-structured metapopulation framework in which the recycling of animal tissue between herds via feed producers is explicitly described. We explore two alternative assumptions for the scaling with herd size of the within-herd risk of exposure of an animal to infectious material. We find that whereas exposure heterogeneity caused by variation in feed and offal processing methods and by variation in per-animal feed uptake can explain the pattern of case clustering seen in the BSE epidemic, exposure heterogeneity due to the aggregation of infectivity within feed cannot.

Animal Feed↗
PubMed2000

Assessment of the prevalence of vCJD through testing tonsils and appendices for abnormal prion protein.

The objective of this study was to determine the age group or groups which will provide the most information on the potential size of the vCJD epidemic in Great Britain via the sampling of tonsil and appendix material to detect the presence of abnormal prion protein (PrP(Sc)). A subsidiary aim was to determine the degree to which such an anonymous age-stratified testing programme will reduce current uncertainties in the size of the epidemic in future years. A cohort- and time-stratified model was used to generate epidemic scenarios consistent with the observed vCJD case incidence. These scenarios, together with data on the age distribution of tonsillectomies and appendectomies, were used to evaluate the optimal age group and calendar time for undertaking testing and to calculate the range of epidemic sizes consistent with different outcomes. The analyses suggested that the optimal five-year age group to test is 25-29 years, although a random sample of appendix tissue from all age groups is nearly as informative. A random sample of tonsil tissue from all age groups is less informative, but the information content is improved if sampling is restricted to tissues removed from those over ten years of age. Based on the assumption that the test is able to detect infection in the last 75% of the incubation period, zero detected infections in an initial random sample of 1000 tissues would suggest that the epidemic will be less than 870,000 cases. If infections are detected, then the model prediction suggests that both relatively small epidemics (800+ cases if one is detected or 8300+ if two are detected) and larger epidemics (21,000+ cases if three or more are detected) are possible. It was concluded that testing will be most informative if undertaken using appendix tissues or tonsil tissues removed from those over ten years of age. Large epidemics can only be excluded if a small number of infections are detected and the test is able to detect infection early in the incubation period.

Adolescent↗
PubMed2000

The transmission dynamics of the aetiological agent of scrapie in a sheep flock.

We formulate and investigate the properties of a model framework to mimic the transmission dynamics of the aetiological agent of scrapie in a sheep flock. We derive expressions for summary parameters that characterize transmission scenarios, notably the basic reproduction number R(0) and the mean generation time T(g). The timescale of epidemic outbreaks is expressed in terms of R(0) and cumulants of the generation time distribution. We discuss the relative contributions to the overall rate of transmission of horizontal and vertical routes during invasion and in endemicity. Simplified models are used to obtain analytical insight into the characteristics of the endemic state.

Animals↗
PubMed2000

More realistic models of sexually transmitted disease transmission dynamics: sexual partnership networks, pair models, and moment closure.

BACKGROUND: Mathematical models of sexually transmitted disease transmission have proven powerful tools for interpreting observed epidemiologic pattern. However, the most commonly used formulation of such models largely fail to capture the effect of partnership concurrency and contact network structure on transmission. GOAL: The development of a compartmental model of partnership formation and dissolution that includes approximations for the influence of the sexual-partner network. STUDY DESIGN: Theoretical analysis of ordinary differential equation models for sexually transmitted disease transmission within sex-partner networks. RESULTS: The approach developed advances earlier pair models, allows for the influence of concurrent sexual partnerships, and illustrates the importance of concurrency to the persistence of diseases with relatively short durations of infectiousness. The authors also illustrate that heterogeneity in risk is possible even in model populations in which all individuals follow the same behavioral rules. CONCLUSION: Deterministic extended pair models offer a powerful approach to modelling sexually transmitted disease transmission that usefully complement computationally intensive microsimulation models.

Female↗
PubMed1999

Antigen-driven CD4+ T cell and HIV-1 dynamics: residual viral replication under highly active antiretroviral therapy.

Antigen-induced stimulation of the immune system can generate heterogeneity in CD4+ T cell division rates capable of explaining the temporal patterns seen in the decay of HIV-1 plasma RNA levels during highly active antiretroviral therapy. Posttreatment increases in peripheral CD4+ T cell counts are consistent with a mathematical model in which host cell redistribution between lymph nodes and peripheral blood is a function of viral burden. Model fits to patient data suggest that, although therapy reduces HIV replication below replacement levels, substantial residual replication continues. This residual replication has important consequences for long-term therapy and the evolution of drug resistance and represents a challenge for future treatment strategies.

Anti-HIV Agents↗
PubMed1999

Transmission dynamics and epidemiology of dengue: insights from age-stratified sero-prevalence surveys.

The relationship between infection with the four major serotypes of dengue virus and the occurrence of different forms of disease is complex and not fully understood. Interpreting longitudinal records of the incidence of serious disease to gain insight into the transmission dynamics and epidemiology of the virus is therefore complicated. Since age reflects duration of exposure, age-stratified, strain-specific serological surveys carried out at one point in time, or over a short time interval, can potentially provide a rich source of information on longitudinal patterns. This paper describes the development and application (to data collected in Thailand) of statistically rigorous methods designed to estimate time-varying, strain-specific forces of infection, and thus basic reproduction numbers, from cross-sectional serological data. The analyses provide support for the hypothesis that antibody-dependent enhancement of transmission influences observed epidemiological pattern. Age-stratified serological data also reveal evidence of a propensity for the annual incidence of infection to oscillate over time with a frequency of several years. The latter observation is consistent with the predictions of simple mathematical models of the transmission dynamics of the virus. The estimates of the basic reproduction numbers obtained are similar in magnitude for each dengue serotype, being in the range of four to six. Such values are higher than those obtained from earlier analyses, and the implications of this for dengue control are discussed.

Dengue↗
PubMed1999

Estimation of the basic reproduction number of BSE: the intensity of transmission in British cattle.

The basic reproduction number, R0, of an infectious agent is a key factor determining the rate of spread and the proportion of the host population affected. We formulate a general mathematical framework to describe the transmission dynamics of long incubation period diseases with complex pathogenesis. This is used to derive expressions for R0 of bovine spongiform encephalopathy (BSE) in British cattle, and back-calculation methods are used to estimate R0 throughout the time-course of the BSE epidemic. We show that the 1988 meat and bonemeal ban was effective in rapidly reducing R0 below 1, and demonstrate that this indicates that BSE will be unable to become endemic in the UK cattle population even when case clustering is taken into account. The analysis provides some insight into absolute infectiousness for bovine-to-bovine transmission, indicating maximally infectious animals may have infected up to 400 animals each. The relationship between R0 and the early stages of the BSE epidemic and the requirements for additional research are also discussed.

Animal Feed↗
PubMed1998

Epidemiological determinants of the pattern and magnitude of the vCJD epidemic in Great Britain.

Understanding the epidemiology and aetiology of new-variant Creutzfeldt-Jakob (vCJD) disease in humans has become increasingly important given the scientific evidence linking it to bovine spongiform encephalopathy (BSE) in cattle and hence the wide exposure of the population of Great Britain (GB) to potentially infectious tissue. The recent analysis undertaken to determine the risk to the population from dorsal route ganglia illustrated the danger in presenting point estimates rather than ranges of scenarios in the face of uncertainty. We present a mathematical template that relates the past pattern of the BSE epidemic in cattle to the future course of any vCJD epidemic in humans, and use extensive scenario analysis to explore the wide range of possible outcomes given the uncertainty in epidemiological determinants. We demonstrate that the average number of humans infected by one infectious bovine and the incubation period distribution are the two epidemiological factors that have the greatest impact on epidemic size and duration. Using the time-series of the BSE epidemic and the cases seen to date, we show that the minimum length of the incubation period is approximately nine years, and that at least 20% of the cases diagnosed to date were exposed prior to 1986. We also demonstrate that the current age distribution of vCJD cases can only arise if younger people were either exposed to a greater extent, more susceptible to infection, or have shorter incubation periods. Extensive scenario analyses show that given the information currently available, the very high degree of uncertainty in the future size of the epidemic will remain for the next 3-5 years. Furthermore, we demonstrate that this uncertainty is unlikely to be reduced by mass screening for late-stage infection.

Creutzfeldt-Jakob Syndrome↗
PubMed1998

BSE in Northern Ireland: epidemiological patterns past, present and future.

By 30 January 1998, there had been 170,259 confirmed cases of BSE in Great Britain (GB), 1766 confirmed cases in Northern Ireland (NI) (2 January 1998), and 276 confirmed cases in the Republic of Ireland (31 January 1998). Analysis of the epidemiological patterns in the NI epidemic reveals significant clustering of cases in herds and counties. The observed clustering of cases within herds results in lower per capita incidence of BSE in previously unaffected herds, providing support for the introduction of a certified herd scheme in NI. By fitting a backcalculation model to the case data, we can estimate the number of animals infected with the aetiological agent of BSE and project the number of future cases. We predict that the epidemic will decline rapidly, with approximately 99 cases (95% confidence interval 30,504) occurring in the five year period 1997-2001.

Animals↗
PubMed1997

Analysis of dam-calf pairs of BSE cases: confirmation of a maternal risk enhancement.

We investigate whether a calf born to a dam that develops bovine spongiform encephalopathy (BSE) (prior or subsequent to the birth) is itself at an enhanced risk of developing BSE. Analyses utilize the main database on reported BSE cases in the British cattle herd maintained by the Central Veterinary Laboratory in Weybridge to trace the dams of BSE-affected animals born following the ruminant feed ban in July 1988. The data reveal a significantly enhanced risk of disease in calves born to BSE-affected dams, with the risk being greatest when birth occurs after the onset of clinical signs of disease in the dam. The dependence of the maternally enhanced risk on the maternal incubation stage at birth argues for a significant component of direct maternal transmission of the aetiological agent of BSE, and offers little support for the hypothesis of genetic predisposition. Using a statistical likelihood model, we obtain estimates of the rate of direct maternal transmission by maternal incubation stage; however, biases in the available data make these values minimum estimates.

Animals↗
PubMed1997

Vaccination and the population structure of antigenically diverse pathogens that exchange genetic material.

Populations of antigenically diverse pathogens undergoing genetic exchange may be categorized into strains on the basis of a set of principal protective antigens. The extent to which polyvalent vaccines based on these protective antigens can alter the population structure of the pathogen is determined by the degree of cross-protection between strains. In the case where there is no cross-protection, vaccinating against a particular strain will have no effect on the others. As cross-protection increases, the strains containing the antigenic variants included in the vaccine will be diminished in prevalence, and those that do not will increase in prevalence. The rise in prevalence of the latter will become more and more exaggerated as cross-protection increases. However, beyond a critical level of cross-protection, in the absence of vaccination, the steady state of the system is asymmetric in that a certain subset of strains (with non-overlapping repertoires of antigenic variants) will dominate over the others in terms of prevalence. Under these circumstances, a vaccine consisting of the most immunogenic combinations of antigenic variants can cause a dramatic increase in frequency of a subset of rare strains.

Alleles↗
PubMed1997

A genetic interpretation of heightened risk of BSE in offspring of affected dams.

An analysis is presented of the results of a cohort study designed to test whether or not the aetiological agent of bovine spongiform encephalopathy (BSE) in cattle can be transmitted maternally (vertically) from dam offspring. Various genetic models are fitted to the data under the assumption that the results could be explained entirely by genetic predisposition to disease (as opposed to maternal transmission) given exposure of offspring of diseased and unaffected dams to contaminated cattle feed. The analyses suggest that the results could be explained by the hypothesis of genetic predisposition, provided a large difference exists in the susceptibility of resistant and susceptible hosts, and explore the range of genotypic parameters and frequencies consistent with the limited currently available data. The results presented are broadly robust, even under the scenario that a portion of the observed maternally enhanced risk of BSE is due to a low level of maternal transmission in late incubation stage dams.

Alleles↗
PubMed1997

The epidemiology of BSE in cattle herds in Great Britain. I. Epidemiological processes, demography of cattle and approaches to control by culling.

This paper explores the key epidemiological processes and demographic factors that determined the pattern of transmission of the aetiological agent of bovine spongiform encephalopathy (BSE) in cattle herds in Great Britain (GB). The analyses presented utilize data from published and unpublished experimental studies and from the GB central database of confirmed BSE cases. We review the experimental and epidemiological evidence that has both confirmed indirect horizontal transmission via the consumption of infectious material as the major transmission route and provided information on the duration and variability of the dose-dependent incubation period of BSE in cattle. The epidemiological and genetic data pertaining to the possible existence of maternal transmission and/or genetically variable susceptibility to infection is discussed. The demography of British cattle is characterized and the impacts of key demographic features on the observed epidemic profile are discussed. In the main BSE case database, analyses reveal that BSE cases cluster significantly at both the holding and county scale. Furthermore, analysis of longitudinal patterns reveal substantial temporal within-holding correlation. Such clustering of cases suggests a highly heterogeneous infection process. The paper ends with a discussion of how analyses of spatio-temporal clustering inform the design of targeted culling programmes aimed at reducing future disease incidence. We show how the retrospective implementation of culling policies on the BSE case database allows the qualitative evaluation of policy performance, but that model predictions of future trends in case incidence are required to estimate the precise impact of any current or future programme.

Age Factors↗