Biomedical subjects

R M Anderson

Publications and source records attributed to R M Anderson.

At least 127 records · Page 7Linked to original sources

PubMed1996

Persistence and dynamics in lattice models of epidemic spread.

We present a simple epidemic model representing the spread of a communicable disease in a spatially extended host population. The model falls into the general class of techniques which utilise lattice based simulation as a way of incorporating spatial effects. The factors relating to the persistence and dynamics of the disease are investigated. There exists a clear population threshold below which the disease dies out and above which it settles to an endemically stable state. The rate of population mixing is shown to affect this threshold density. Equations which accurately account for the mean-field limit of the model are introduced and the relevance to the epidemiological modelling of measles is discussed.

Communicable Diseases↗

PubMed1996

Estimates of the axonal refractory period of midbrain dopamine neurons: their relevance to brain stimulation reward.

Psychophysical studies have shown that the directly activated neurons subserving the rewarding effect produced by electrical stimulation of the medial forebrain bundle (MFB) have refractory periods (RPs) shorter than those of dopaminergic (DA) neurons: this suggests that the directly stimulated substrate for the rewarding effect does not include DA neurons. Comparison of RP estimates. however, is difficult since those of DA neurons were obtained with the standard electrophysiological technique that characterizes cell body/initial segment rather than the directly stimulated axonal segment. Using electrophysiological recording techniques in urethane anesthetized rats, we re-estimated and compared the RP of DA neurons that project to the MFB and the ventral striatum (VST) with two stimulation procedures: one that characterizes the axonal segment near the stimulation electrode and the standard one that characterizes the cell body/initial segment near the recording electrode. Results showed that DA axonal RPs range from 1.0 to 2.2 ms, whereas cell body/initial segment RPs range from 1.0 to 3.0 ms. The axonal RP was equal to or shorter (mean difference = 0.22 ms, n = 15) than the cell body/initial segment RP. Axonal RP estimates for MFB sites range from 1.3 to 2.1 ms. values that slightly overlap with the late recovery from refractoriness reported in psychophysical studies for reward-relevant neurons. Axonal RP estimates obtained for VST sites were very similar (mean = 1.66, LH and 1.62 ms, VST) suggesting that the excitability of DA axons does not differ along their path. These results further support the hypothesis that DA axons are unlikely to constitute a major component of the directly-stimulated reward-relevant axons in the MFB. They also suggest that the direct contribution of DA axons to reward produced by VST stimulation is more important than by the MFB.

Action Potentials↗

PubMed1996

Antigenic variation and the within-host dynamics of parasites.

Many parasites exhibit antigenic variation within their hosts. We use mathematical models to investigate the dynamical interaction between an antigenically varying parasite and the host's immune system. The models incorporate antigenic variation in the parasite population and the generation of immune responses directed against (i) antigens specific to individual parasite variants and (ii) antigens common to all the parasite variants. Analysis of the models allows us to evaluate the relative importance of variant-specific and cross-reactive immune responses in controlling the parasite. Early in the course of infection within the host, when parasite diversity is below a defined threshold value (the value is determined by the biological properties of the parasite and of the host's immune response), the variant-specific immune responses are predominant. Later, when the parasite diversity is high, the cross-reactive immune response is largely responsible for controlling the parasitemia. It is argued that increasing antigenic diversity leads to a switch from variant-specific to cross-reactive immune responses. These simple models mimic various features of observed infections recorded in the experimental literature, including an initial peak in parasitemia, a long and variable duration of infection with fluctuating parasitemia that ends with either the clearance of the parasite or persistent infection.

Animals↗

PubMed1996

Dynamic aspects of morbidity and acquired immunity in schistosomiasis control.

In schistosomiasis control, rational planning of chemotherapy programmes is complicated by the dynamic interactions between treatment and levels of acquired immunity and morbidity in the community. In this paper, mathematical models that address the development of acquired immunity and the prevalence of morbidity are incorporated within an age-structured transmission framework to explore some of the dynamic complexities of long-term chemotherapy programmes. As well as illustrating some of the potential problems inherent in predicting the consequences of control measures, the model provides insights into the dynamics of schistosomiasis transmission and the parameters that need to be measured to further improve the design of community-based control programmes.

Humans↗

PubMed1996

Dynamical complexity in age-structured models of the transmission of the measles virus: epidemiological implications at high levels of vaccine uptake.

This article explores the effect of increasingly finely stratified age structure on the dynamical properties of deterministic metapopulation models of the transmission of the measles virus. The dynamical simplicity of earlier age-structured models is shown to break down once the age-specific force of infection is no longer assumed to be constant across all child age classes below 5 years of age. While the biennial epidemics characteristic of earlier models are still observed, additional higher period stable cycles arise and coexist with the biennial cycle. The existence of multiple stable limit cycles necessarily implies model sensitivity on initial conditions, and for certain parameter values, chaotic dynamics are observed. Using a novel parameterization of the magnitude of seasonal forcing we are also able to make more biologically relevant comparisons between the dynamics of age- and non-age-structured models than have hitherto been possible. The epidemiological significance of these results is discussed, and we demonstrate that perturbations of the kind produced by intensive vaccination programs can shift transmission dynamics between biennial and triennial cycles. The possible implications of this work for studies of intermittency and infection persistence are also considered.

Adolescent↗

PubMed1996

The within-host cellular dynamics of bloodstage malaria: theoretical and experimental studies.

The properties of a mathematical model of bloodstage infection with a single strain of malaria were investigated. Analysing the cell population dynamics in the absence of a host immune response we demonstrate a relationship between host and parasite parameters that defines a criterion for the successful invasion and persistence of the parasite. Important parameters are the rates of merozoite production and death and those of erythrocyte production, death and invasion. We present data from experiments designed to evaluate the erythrocyte invasion rate in a rodent malaria system. The model generates patterns of parasitaemia in good qualitative agreement with those seen in Plasmodium berghei infections. The sole force behind the rise and fall in parasitaemia in the model without immunity is the density of susceptible erythrocytes, suggesting that resource availability is an important determinant of the initial pattern of infection in vivo. When we incorporate a simple immune response into the model we find that immunity against the infected cell is much more effective at suppressing parasite abundance than immunity against the merozoite. Simulations reveal oscillating temporal patterns of parasite abundance similar to P. c. chabaudi infection, challenging the concept that antigenic variation is the sole mechanism behind recrudescing patterns of infection.

Animals↗

PubMed1996

Immunodominance, competition and evolution in immunological responses to helminth parasite antigens.

The paper describes the development and analysis of a mathematical framework for the study of the within-host population dynamics of the interaction between macroparasites and the human immune system. Simple models of this interaction based on the proliferation of T cell clones specific to parasite antigen, and the impact of clonal expansion on parasite survival, capture the basic features of age-related changes in worm loads within human communities. The model is generalized to multiple epitopes on a single antigen, and reveals competitive exclusion amongst T cells, with a single clone becoming immunodominant in the absence of cross-reactive responses and genetic variation. The introduction of genetic heterogeneity and concomitant variability in the immunogenicity of specific epitopes induces additional complexity into the dynamical interaction. Most importantly, multiple epitope models with antigenic variation suggest that the immunodominant response may not necessarily be targeted at the epitope at which some strains show the greatest immunogenicity. High immunogenicity at a particular epitope can be masked by genetic variability even though many of the variants are more immunogenic at this epitope by comparison with the epitope to which the immunodominant immunological response is directed.

Animals↗

PubMed1996

Density-dependent processes in the transmission of human onchocerciasis: relationship between microfilarial intake and mortality of the simuliid vector.

In order to construct an analytical model of onchocerciasis transmission, it is necessary to elucidate the functional relationships of the various population rate processes taking place within the human and vector hosts. Two previous papers have explored the evidence for density-dependent regulation in relation to microfilarial intake by, and larval development within, the Simulium host. This paper investigates the survivorship of wild-caught blackfly samples fed on subjects with different intensities of Onchocerca volvulus microfilarial infection. Analyses were based on data for Guatemalan S. ochraceum s.l. (possessing a well-developed cibarial armature), West African S. damnosum s.l. (forest species), and South Venezuelan S. guianense (the latter two lacking a toothed cibarium). The mean survival times of samples of the 3 species, kept under laboratory conditions, decreased as parasite intake increased, the rate of mortality being dependent on the fly's age (measured as time post-feeding) and on the worm load acquired. An empirical, time-dependent hazard function was fitted to observed death rates/fly/day which rose very shortly after engorgement, declined subsequently, and rose again throughout the extrinsic incubation period of the parasite. The parameters of this hazard model were all positively correlated with the density of microfilariae in the bloodmeal. Expressions of survivorship and life-expectancy as explicit functions of time post-feeding and mean parasite intake were derived. The average expectation of life at engorgement for uninfected flies in the laboratory was estimated to be around 1 week for both, armed and unarmed blackflies. Residual life-expectancy decreased with time post-feeding and microfilarial load in both categories of vectors. This decline (resulting from age- and parasite-dependent mortality rates) was much more pronounced in those species lacking a toothed fore-gut. Whilst a fraction of heavily infected S. ochraceum was able to survive the latent period of the parasite, being therefore potentially capable of transmitting the infection, equivalent worm loads in S. guianense resulted in a drastic reduction of the expectation of infective life. These results provide additional evidence to support the hypothesis that, in the case of intrinsically susceptible vectors, unarmed simuliids are more efficient at low microfilarial loads, when the transmission rate from human to vector host is higher, and parasite-induced fly mortality is negligible. The opposite takes place in armed flies, which perform poorly at low parasite burdens and better at heavier loads, with little parasite-induced vector death.

Animals↗

PubMed1996

The transmission dynamics of hepatitis B in the UK: a mathematical model for evaluating costs and effectiveness of immunization programmes.

Complex hepatitis B (HBV) epidemiology makes it difficult to evaluate and compare effectiveness of different immunization policies. A method for doing so is presented using a mathematical model of HBV transmission dynamics which can represent universal infant and adolescent vaccination strategies and those targeted at genito-urinary (GU) clinic attenders and infants born to infectious mothers. Model structure, epidemiological underpinning, and parameterization, are described. Data from the UK National Survey of Sexual Attitudes and Lifestyles is used to define patterns of sexual activity and GU clinic attendance; data deficiencies are discussed, in particular that of UK seroprevalence of HBV markers stratified by age, sex, and risk factors. General model predictions of endemic HBV marker prevalence in homosexual and heterosexual populations seem consistent with published UK data. The simulations exhibit non-linearities in the impact of different vaccination strategies. Estimated number of carriers prevented per vaccine dose for each strategy provides a measure of costs and benefits, varying temporally over the course of a programme, and with level of vaccine coverage. Screening before vaccination markedly increases payback per dose in homosexuals but not in heterosexuals; mass infant vaccination gives the poorest effectiveness ratio and vaccination of infants after antenatal screening the best; in general, increasing vaccine coverage yields lower pay-back per dose. The model provides a useful framework for evaluating costs and benefits of immunization programmes, but for precise quantitative comparison more UK epidemiological data is urgently needed.

Adolescent↗

PubMed1996

The maintenance of strain structure in populations of recombining infectious agents.

Using mathematical models that combine population genetic and epidemiological processes, we resolve the paradox that many important pathogens appear to persist as discrete strains despite the constant exchange of genetic material. We show that dominant polymorphic determinants (that is, those that elicit the most effective immune responses) will be organized into nonoverlapping combinations as a result of selection by the host immune system, thereby defining a set of discrete independently transmitted strains. By analysing 222 isolates of Neisseria meningitidis, we show that two highly polymorphic epitopes of the outer membrane protein PorA exist in nonoverlapping combinations as predicted by this general framework. The model indicates that dominant polymorphic determinants will be in linkage disequilibrium, despite frequent genetic exchange, even though they may be encoded by several unlinked genes. This suggests that the detection of nonrandom associations between epitope regions can be employed as a novel strategem for identifying dominant polymorphic antigens.

Genes, Dominant↗

PubMed1996

Sexually transmitted diseases and sexual behavior: insights from mathematical models.

The major role of mathematical models of transmission dynamics and population biology of sexually transmitted diseases is helping understand the influence of the many biologic, social, and behavioral factors that influence the incidence or prevalence of infection. Various models can examine heterogeneity in sexual behavior and determine how individual variation influences epidemiologic pattern within a population. In the cases of heterogeneity in sex acts and in sex partner numbers, heterogeneity acts to enhance the likelihood of the persistence of infection. Also important is the pattern of mixing or sexual contact within a community. Assortative mixing promotes rapid spread in high-sexual-activity classes but results in a lower endemic equilibrium state compared with random mixing. In these models, each facet of behavior is treated separately. The obvious next goal of modeling is to meld processes together into a single mathematical framework; however, quantitative epidemiologic information on each factor is still needed.

Humans↗

PubMed1996

Antiviral therapy and the transmission dynamics of HIV-1.

The factors influencing the transmission dynamics of HIV are discussed in the context of the community wide use of antiviral therapy. A mathematical framework is constructed to examine the impact of chemotherapy on transmission, based on a description of the progressive decline of CD4 counts in infected patients. Treatment which acts to increase the incubation period before the onset of serious immunodeficiency, but has no impact on the infectiousness of a patient, is obviously beneficial to the individual. However it can act to either reduce or increase net morbidity and mortality when used on a community wide basis. When treatment prolongs the incubation period and reduces infectiousness, community based chemotherapy is invariably beneficial to the individual and the community. Heterogeneity in infectiousness over the incubation period of AIDS, with peaks in early and late stages of infection, has an important influence on the effect of treatment on the net transmission within the community. In these circumstances community wide benefit is influenced by the timing of treatment within the incubation period of AIDS. The many heterogeneities arising in the transmission dynamics of HIV argue for careful analysis of the net impact of antiviral therapy on mortality at a community wide level as well as at the level of the individual patient.

Anti-HIV Agents↗

PubMed1996

The population biology of the interaction between HIV-1 and HIV-2: coexistence or competitive exclusion?

BACKGROUND: The emergence and rapid world-wide spread of HIV provides an unusual opportunity for the study of the evolution and maintenance of virulence in a major human pathogen. OBJECTIVE: To analyse the available biological and epidemiological data on the pathogenicity, transmissibility and antigenic similarity of HIV-1 and HIV-2, and use simple mathematical models of competition between the two viral types within a defined host community. RESULTS AND CONCLUSIONS: Analysis revealed a positive association between pathogenicity and reproductive success. A mathematical model of the concomitant transmission of the two viruses suggests that HIV-1 will competitively displace HIV-2 in the longer term in areas where both viruses are being transmitted within the same sexually active population.

Female↗

PubMed1996

Demographic approaches to the estimation of incidence of HIV-1 infection among adults from age-specific prevalence data in stable endemic conditions.

OBJECTIVE: To develop methods for estimating the incidence of HIV-1 infection among adults from age-specific prevalence data derived in stable endemic conditions. METHODS: Two methods are proposed. The first method is the Cumulative Incidence and Survival Method which treats HIV-1 prevalence at any given age as the cumulative incidence of new infections at each preceding age, adjusted for mortality. A model for age-specific incidence is fitted to the data using maximum likelihood techniques. The other method is the Constant Prevalence Method whereby the incidence of new infections within a time interval (t-r, t) is calculated as the difference, after adjusting for mortality, between observed prevalence levels at two successive age intervals, whose mean ages are r years apart. The two methods were applied to data from Kampala, Uganda. RESULTS: Plausible estimates of age-specific and cumulative HIV-1 incidence were obtained from each of the methods. Estimates of HIV-1 incidence are sensitive to assumptions regarding the length of the survival period after infection and the stability of the epidemic. CONCLUSIONS: Reasonable estimates of HIV-1 incidence can be obtained from prevalence data derived in near-stable conditions. With the Constant Prevalence Method, these conditions may be relaxed if large sample sizes are available and age-reporting is good. The methods proposed could be used in the design and implementation of HIV-1 prevention trials. Cumulative incidence is a better indication of demographic impact than average age-specific incidence.

Adult↗

PubMed1996

Targeted hepatitis B vaccination--a cost effective immunisation strategy for the UK?

OBJECTIVE: To compare the potential cost effectiveness of vaccination against hepatitis B virus (HBV) targeted at genitourinary clinic (GU) attendees with that of universal infant vaccination. DESIGN: A mathematical model of sexual and perinatal transmission of HBV was used to compare the effectiveness among heterosexual and homosexual populations of programmes of mass infant vaccination and targeted immunisation of genitourinary medicine (GU) clinic attendees. Each was applied to 90% of the eligible population with differing assumptions about rates of compliance and seroconversion - problems of delivery (obtaining high compliance) was considered a significant drawback of targeted vaccination. Observed relationships between GU clinic attendance and sex partner change rates for heterosexuals and for homosexuals were used to define the rates of vaccination uptake within sexual activity risk groups. SETTING: England and Wales. RESULTS: Model results showed that for heterosexuals universal infant vaccination became more effective than clinic based vaccination only approximately 40 years after the start of the programme and that the predicted cost effectiveness of GU clinic vaccination was greater at all times. For homosexuals, clinic vaccination was always more effective over the time frame considered, but by 50 years if it were carried out without prior screening it had become appreciably less cost effective than a mass infant programme. With prior screening in GU clinics this cost effectiveness deficit was only marginal. CONCLUSIONS: Targeted vaccination might have a much greater potential than is realised at present, particularly if it were possible to improve compliance of clinic attendees. A fuller comparison between mass infant and targeted vaccination must await the specific inclusion in the model of other risk groups such as intravenous drug users. An important determinant of the relative merits of the two approaches is the relationship between rates of attendance and of changing sexual partners. Further research on this is required.

Adult↗

PubMed1995

Potential impact of low efficacy HIV-1 vaccines in populations with high rates of infection.

A safe and effective HIV vaccine to prevent infection and/or to moderate disease is urgently needed. Research progress has been slower than anticipated for a variety of reasons including uncertainty over which immunogen to use (i.e. recombinant subunit envelope proteins or whole HIV-1 products), confusion on which immunological markers best correlate with protection, the relevance of the HIV-1 chimpanzee model to infection in humans and the significance of the rapid evolution of HIV-1, with different clades of the virus emerging in different parts of the world. However, what some would interpret as encouraging results, from Phase I and II trials of recombinant envelope glycoprotein vaccines, have raised the question of whether the time is right to start Phase III trials in humans with immunogens that may have low to moderate efficacy. By using mathematical models and data from epidemiological studies, we examine the potential impact of such vaccines within heterosexual communities with high rates of infection. Analyses suggest that it will be difficult to block HIV-1 transmission even with very high levels of mass vaccination. The cost of sustaining high levels of herd immunity with a vaccine of short protection duration is likely to be high. However, assessments of impact over the long duration of an HIV-1 epidemic indicate that many cases of HIV infection and associated mortality can be prevented by immunogens with efficacy of 50% or less and a five year protection duration.(ABSTRACT TRUNCATED AT 250 WORDS)

AIDS Vaccines↗

PubMed1995

Strategies for limiting the spread of HIV in developing countries: conclusions based on studies of the transmission dynamics of the virus.

Possible interventions to reduce the spread of human immunodeficiency virus (HIV) include actions that attempt to alter sexual behaviour, such as education aimed at reducing the rate at which individuals acquire new sexual partners, and methods that reduce the probability of transmission between partners, such as the promotion of condom use and the treatment of so-called "cofactor" sexually transmitted diseases. A mathematical model of HIV transmission that is able to mimic different approaches to the control of HIV transmission is employed to study the relative values of different approaches, either used in isolation, or in combination. The nonlinear nature of the term that describes the per capita rate of transmission dictates that for a given degree of intervention, the benefit accruing in terms of reduced HIV spread depends on the prevalence of infection before the introduction of control. Benefit is greatest when HIV prevalence is low. Combination approaches are predicted to be effective but the outcome is less than would be expected on the basis of simply summing the benefits resulting from each type of intervention used in isolation. The success of targeted interventions, aimed at those with high rates of sexual partner change, depends on the heterogeneity in levels of sexual activity within populations and what proportion of the population HIV is able to establish itself in. Targeted interventions are predicted to be very cost effective but their overall success in reducing HIV spread by a significant degree depends on the timing of their introduction (within the time frame of the development of the epidemic) and the pattern of mixing between different risk groups or sexual activity classes.

Adolescent↗

PubMed1995

Empowerment: from philosophy to practice.

Our paper reviews the philosophical and theoretical foundations of the empowerment approach to chronic disease care and education. The fundamental differences between the compliance and empowerment approaches are elucidated. The empowerment philosophy is based on the premise that human beings have the capacity to make choices and are responsible for the consequences of their choices. Empowerment is defined as an educational process designed to help patients develop the knowledge, skills, attitudes, and degree of self-awareness necessary to effectively assume responsibility for their health-related decisions. Using empowerment as an intellectual foundation, an holistic approach to health education is presented. Topics such as well-being, self-image, motivation, adaptability, stress management, problem-solving, social support, self-awareness, and hope, are discussed. Our paper asserts that health educators have a responsibility to address the physical, emotional, cognitive, and spiritual needs of persons challenged to live with a chronic disease.

Choice Behavior↗