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Biomedical subjects

R M Anderson

Publications and source records attributed to R M Anderson.

At least 19 recordsLinked to original sources
PubMed2006

Seroprevalence of IgG antibodies to SARS-coronavirus in asymptomatic or subclinical population groups.

We systematically reviewed the current understanding of human population immunity against SARS-CoV in different groups, settings and geography. Our meta-analysis, which included all identified studies except those on wild animal handlers, yielded an overall seroprevalence of 0.10% [95% confidence interval (CI) 0.02-0.18]. Health-care workers and others who had close contact with SARS patients had a slightly higher degree of seroconversion (0.23%, 95% CI 0.02-0.45) compared to healthy blood donors, others from the general community or non-SARS patients recruited from the health-care setting (0.16%, 95% CI 0-0.37). When analysed by the two broad classes of testing procedures, it is clear that serial confirmatory test protocols resulted in a much lower estimate (0.050%, 95% CI 0-0.15) than single test protocols (0.20%, 95% CI 0.06-0.34). Potential epidemiological and laboratory pitfalls are also discussed as they may give rise to false or inconsistent results in measuring the seroprevalence of IgG antibodies to SARS-CoV.

Antibody Formation↗
PubMed2006

Chromosome breakpoint distribution of damage induced in peripheral blood lymphocytes by densely ionizing radiation.

PURPOSE: To assess the chromosomal breakpoint distribution in human peripheral blood lymphocytes (PBL) after exposure to a low dose of high linear energy transfer (LET) alpha-particles using the technique of multiplex fluorescence in situ hybridization (m-FISH). MATERIALS AND METHODS: Separated PBL were exposed in G0 to 0.5 Gy 238Pu alpha-particles, stimulated to divide and harvested approximately 48 - 50 hours after exposure. Metaphase cells were assayed by m-FISH and chromosome breaks identified. The observed distribution of breaks were then compared with expected distributions of breaks, calculated on the assumption that the distribution of breaks is random with regard to either chromosome volume or chromosome surface area. RESULTS: More breaks than expected were observed on chromosomes 2 and 11, however no particular region of either chromosome was identified as significantly contributing to this over-representation. The identification of hot or cold chromosome regions (pter,p,cen,q,qter) varied depending on whether the data were compared according to chromosome volume or surface area. CONCLUSIONS: A deviation from randomness in chromosome breakpoint distribution was observed, and this was greatest when data were compared according to the relative surface area of each individual chromosome (or region). The identification of breaks by m-FISH (i.e., more efficient observation of interchanges than intrachanges) and importance of territorial boundaries on interchange formation are thought to contribute to these differences. The significance of the observed non-random distribution of breaks on chromosomes 2 and 11 in relation to chromatin organization is unclear.

Alpha Particles↗
PubMed2006

Increased complexity of radiation-induced chromosome aberrations consistent with a mechanism of sequential formation.

Complex chromosome aberrations (any exchange involving three or more breaks in two or more chromosomes) are effectively induced in peripheral blood lymphocytes (PBL) after exposure to low doses (mostly single particles) of densely ionising high-linear energy transfer (LET) alpha-particle radiation. The complexity, when observed by multiplex fluorescence in situ hybridisation (m-FISH), shows that commonly four but up to eight different chromosomes can be involved in each rearrangement. Given the territorial organisation of chromosomes in interphase and that only a very small fraction of the nucleus is irradiated by each alpha-particle traversal, the aim of this study is to address how aberrations of such complexity can be formed. To do this, we applied theoretical "cycle" analyses using m-FISH paint detail of PBL in their first cell division after exposure to high-LET alpha-particles. In brief, "cycle" analysis deconstructs the aberration "observed" by m-FISH to make predictions as to how it could have been formed in interphase. We propose from this that individual high-LET alpha-particle-induced complex aberrations may be formed by the misrepair of damaged chromatin in single physical "sites" within the nucleus, where each "site" is consistent with an "area" corresponding to the interface of two to three different chromosome territories. Limited migration of damaged chromatin is "allowed" within this "area". Complex aberrations of increased size, reflecting the path of alpha-particle nuclear intersection, are formed through the sequential linking of these individual sites by the involvement of common chromosomes.

Cell Cycle↗
PubMed2005

Adherence to antiretroviral therapy and its impact on clinical outcome in HIV-infected patients.

We analyse data on patient adherence to prescribed regimens and surrogate markers of clinical outcome for 168 human immunodeficiency virus infected patients treated with antiretroviral therapy. Data on patient adherence consisted of dose-timing measurements collected for an average of 12 months per patient via electronic monitoring of bottle opening events. We first discuss how such data can be presented to highlight suboptimal adherence patterns and between-patient differences, before introducing two novel methods by which such data can be statistically modelled. Correlations between adherence and subsequent measures of viral load and CD4+T-cell counts are then evaluated. We show that summary measures of short-term adherence, which incorporate pharmacokinetic and pharmacodynamic data on the monitored regimen, predict suboptimal trends in viral load and CD4+T-cell counts better than measures based on adherence data alone.

Antiretroviral Therapy, Highly Active↗
PubMed2005

Methods for estimating the case fatality ratio for a novel, emerging infectious disease.

During the course of an epidemic of a potentially fatal disease, it is important that the case fatality ratio be well estimated. The authors propose a novel method for doing so based on the Kaplan-Meier survival procedure, jointly considering two outcomes (death and recovery), and evaluate its performance by using data from the 2003 epidemic of severe acute respiratory syndrome in Hong Kong, People's Republic of China. They compare this estimate obtained at various points in the epidemic with the case fatality ratio eventually observed; with two commonly quoted, naïve estimates derived from cumulative incidence and mortality statistics at single time points; and with estimates in which a parametric mixture model is used. They demonstrate the importance of patient characteristics regarding outcome by analyzing subgroups defined by age at admission to the hospital.

Communicable Diseases, Emerging↗
PubMed2005

HIV infection and reproductive health in teenage women orphaned and made vulnerable by AIDS in Zimbabwe.

AIDS has increased the number of orphans and vulnerable children (OVCs) in sub-Saharan Africa who could suffer detrimental life experiences. We investigated whether OVCs have heightened risks of adverse reproductive health outcomes including HIV infection. Data on HIV infection, sexually transmitted infection (STI) symptoms and pregnancy, and common risk factors were collected for OVCs and non-OVCs in a population survey of 1523 teenage children in eastern Zimbabwe between July 2001 and March 2003. Multivariate logistic regression was used to test for statistical association between OVC status, adverse reproductive health outcomes and suspected risk factors. Amongst women aged 15-18 years, OVCs had higher HIV prevalence than non-OVCs (3.2% versus 0.0%; p = 0.002) and more common experience of STI symptoms (5.9% versus 3.3%; adjusted odds ratio = 1.75, 95% CI 0.80-3.80) and teenage pregnancy (8.3% versus 1.9%; 4.25, 1.58-11.42). OVCs (overall), maternal orphans and young women with an infected parent were more likely to have received no secondary school education and to have started sex and married, which, in turn, were associated with poor reproductive health. Amongst men aged 17-18 years, OVC status was not associated with HIV infection (0.5% versus 0.0%; p = 1.000) or STI symptoms (2.7% versus 1.6%; p = 0.529). No association was found between history of medical injections and HIV risk amongst teenage women and men. High proportions of HIV infections, STIs and pregnancies among teenage girls in eastern Zimbabwe can be attributed to maternal orphanhood and parental HIV. Many of these could be averted through further female secondary school education. Predicted substantial expanded increases in orphanhood could hamper efforts to slow the acquisition of HIV infection in successive generations of young adults, perpetuating the vicious cycle of poverty and disease.

Adolescent↗
PubMed2005

Gender difference in HIV-1 RNA viral loads.

OBJECTIVES: To test and characterize the dependence of viral load on gender in different countries and racial groups as a function of CD4 T-cell count. METHODS: Plasma viral load data were analysed for > 30,000 HIV-infected patients attending clinics in the USA [HIV Insight (Cerner Corporation, Vienna, VA, USA) and Plum Data Mining LLC (East Meadow, NY, USA) databases] and the Netherlands (Athena database; HIV Monitoring Foundation, Amsterdam, Netherlands). Log-normal regression models were used to test for an effect of gender on viral load while adjusting for covariates and allowing the effect to depend on CD4 T-cell count. Sensitivity analyses were performed to test the robustness of conclusions to assumptions regarding viral loads below the lower limit of quantification (LLOQ). RESULTS: After adjusting for covariates, women had (nonsignificantly) lower viral loads than men (HIV Insight: -0.053 log(10) HIV-1 RNA copies/mL, P = 0.202; Athena: -0.005 log(10) copies/mL, P = 0.667; Plum: -0.072 log(10) copies/mL, P = 0.273). However, further investigation revealed that the gender effect depended on CD4 T-cell count. Women had consistently higher viral loads than men when CD4 T-cell counts were at most 50 cells/microL, and consistently lower viral loads than men when CD4 T-cell counts were greater than 350 cells/microL. These effects were remarkably consistent when estimated independently for the racial groups with sufficient data available in the HIV Insight and Plum databases. CONCLUSIONS: The consistent relationship between gender-related differences in viral load and CD4 T-cell count demonstrated here explains the diverse findings previously published.

Adult↗
PubMed2005

Vitamin D-dependent rickets type II in a cat.

A cat with clinical signs Indicating rickets was diagnosed as having a defect of vitamin D receptors. Clinical signs had been seen from four months of age. Treatment with calcium supplementation and various forms of vitamin D did not alter plasma calcium levels or reverse skeletal lesions of lateral antebrachial bowing, lumbar spinal lordosis and costochondral beading. Analgesics were effective for relieving skeletal pain during the bone growth phase and were withdrawn when the animal reached skeletal maturity. Therapy for hip osteoarthritis was given from five years of age until the cat was euthanased at nine years of age as a result of refractory hip pain.

Analgesics↗
PubMed2003

Dynamics of a scrapie outbreak in a flock of Romanov sheep--estimation of transmission parameters.

Knowledge of epidemiological mechanisms and parameters underlying scrapie transmission in sheep flocks remains very limited at present. Here we introduce a method for fitting stochastic transmission models to outbreak data to estimate bounds on key transmission parameters. We apply this method to data describing an outbreak of scrapie in a closed flock of Romanov sheep. The main findings are that the relative infectiousness of infected animals in this outbreak becomes appreciable early into disease incubation and that the mean incubation period is less than 1.5 years. We also find that the data are consistent with a broad range of values for the basic reproduction number R0 and describe how the boundaries of this range depend on assumptions about the mean incubation period and the contribution to transmission of a long-lived environmental reservoir of infectivity.

Animals↗
PubMed2003

Patterns of antiretroviral use in the United States of America: analysis of three observational databases.

OBJECTIVE: To characterize patterns of antiretroviral use in HIV-infected patients and explore variation by patient characteristics and disease stage. METHODS: Three large patient databases recording information derived from routine clinical attendance were analyzed: HIV Insight (n = 10 873), Target Management Services (n = 2226) and Clinical Partners (n = 1505). Each database records the dates of starting and stopping individual antiretroviral agents over time, measurements of CD4 T-cell counts and HIV-RNA levels at approximately 6-monthly intervals, and the demographic characteristics of patients. The number, frequency and duration of different antiretroviral combinations over time and their relationship to stage of HIV-disease and demographic characteristics were explored. RESULTS: Over 2000 different combinations of antiretroviral agents are recorded. From 1987 onwards, the use of zidovudine increased, with 23% of patients receiving monotherapy by 1990. The majority of treated patients remained on monotherapy until the introduction of highly active antiretroviral therapy (HAART) in 1996. By 1999, the standard of care was HAART, with 84% of patients beginning antiretroviral therapy with HAART. Those of African American race (odds ratio 0.59) and funded by Medicaid (odds ratio 0.72) were significantly less likely to begin antiretroviral therapy on HAART. Until 1995, there was a significant decrease in CD4 T-cell count when starting antiretroviral therapy. No significant trend was observed in either CD4 T-cell count or viral load after this time. Those starting on HAART therapies were significantly less likely to stop or switch regimens than those on nucleoside reverse transcriptase inhibitor (NRTI)-only therapies (P < 0.001). CONCLUSIONS: Complex patterns of antiretroviral treatment are observed in this large population. Changes over time mirror the introduction of the new antiretroviral agents.

Adult↗
PubMed2003

Extending backcalculation to analyse BSE data.

We review the origins of backcalculation (or back projection) methods developed for the analysis of AIDS (acquired immunodeficiency syndrome) incidence data. These techniques have been used extensively for >15 years to deconvolute clinical case incidence, given knowledge of the incubation period distribution, to obtain estimates of past HIV (human immunodeficiency virus) infection incidence and short-term predictions of future AIDS incidence. Adaptations required for the analysis of bovine spongiform encephalopathy (BSE) incidence included: stratification of BSE incidence by age as well as birth cohort; allowance for incomplete survival between infection and the onset of clinical signs of disease; and decomposition of the age- and time-related infection incidence into a time-dependent feed risk component and an age-dependent exposure/susceptibility function. The most recent methodological developments focus on the incorporation of data from clinically unaffected cattle screened using recently developed tests for preclinical BSE infection. Backcalculation-based predictions of future BSE incidence obtained since 1996 are examined. Finally, future directions of epidemiological analysis of BSE epidemics are discussed taking into account ongoing developments in the science of BSE and possible changes in BSE-related policies.

Animals↗
PubMed2002

Estimating the human health risk from possible BSE infection of the British sheep flock.

Following the controversial failure of a recent study and the small numbers of animals yet screened for infection, it remains uncertain whether bovine spongiform encephalopathy (BSE) was transmitted to sheep in the past via feed supplements and whether it is still present. Well grounded mathematical and statistical models are therefore essential to integrate the limited and disparate data, to explore uncertainty, and to define data-collection priorities. We analysed the implications of different scenarios of BSE spread in sheep for relative human exposure levels and variant Creutzfeldt-Jakob disease (vCJD) incidence. Here we show that, if BSE entered the sheep population and a degree of transmission occurred, then ongoing public health risks from ovine BSE are likely to be greater than those from cattle, but that any such risk could be reduced by up to 90% through additional restrictions on sheep products entering the food supply. Extending the analysis to consider absolute risk, we estimate the 95% confidence interval for future vCJD mortality to be 50 to 50,000 human deaths considering exposure to bovine BSE alone, with the upper bound increasing to 150,000 once we include exposure from the worst-case ovine BSE scenario examined.

Animals↗
PubMed2001

The BMP antagonists Chordin and Noggin have essential but redundant roles in mouse mandibular outgrowth.

Here we investigate the roles of the Bone Morphogenetic Protein (BMP) antagonists Chordin and Noggin in development of the mandible, which is derived from the first branchial arch (BA1). Both genes are expressed in the pharynx during early mandibular outgrowth and later in the mandibular process. Mice mutant for either Nog or Chd have only mild mandibular defects; however, pups of the genotype Chd(-/-);Nog(+/-) exhibit a range of mandibular truncation phenotypes, from normal to agnathia. A few embryos homozygous null for both genes survive to late gestation; many are agnathic, though a few have significant mandibular outgrowth. In mandibular explants, ectopic BMP4 rapidly induces expression of both Chd and Nog, consistent with results obtained in vivo with mutant embryos. Previous work has shown that FGF8 is a survival factor for cells populating the mandibular bud. We find that excess BMP4 represses Fgf8 transcription in mandibular explants. Embryos lacking these BMP antagonists often show a strong reduction in Fgf8 expression in the pharyngeal ectoderm, and increased cell death in the mandibular bud. We suggest that the variable mandibular hypoplasia in double mutants involves increased BMP activity downregulating Fgf8 expression in the pharynx, decreasing cell survival during mandibular outgrowth.

Animals↗
PubMed2001

Quantification of intrinsic residual viral replication in treated HIV-infected patients.

The intrinsic rate of viral replication in HIV-infected patients treated with antiretroviral combination therapy is estimated by using a mathematical model of viral dynamics. This intrinsic replication is found to be episodic, varying considerably in quantity between patients (even among those achieving long-term undetectable levels of viremia) and is always reduced by increasing the potency of the antiviral drug regimen. The analysis reveals that even in conditions of perfect patient adherence and drug penetration a substantial level of residual viral replication is expected. The rate of evolution in the viral quasispecies, and thus also the probability of new drug-resistant viral strains being created, is proportional to the total amount of residual viral replication. Under most circumstances, the viral population continues to turn over rapidly during therapy, albeit at a much reduced level.

Anti-HIV Agents↗
PubMed2001

Surrogate markers for disease progression in treated HIV infection.

OBJECTIVE: To characterize the relationships among highly active antiretroviral therapy (HAART), HIV-1 RNA levels, immune system markers, and clinical outcome in a cohort of HIV-1-infected homosexual men. PATIENTS: A total of 123 men enrolled in the Amsterdam cohort study of HIV-1 infection and AIDS with a documented seroconversion for HIV-1 antibodies and known date of seroconversion were included in this study. METHODS: CD4 + /CD8 + T-cell counts and HIV-1 RNA levels in plasma were measured approximately every 6 months. Dates of starting and stopping antiretroviral therapy were also recorded. The relationship between HIV-1 RNA in plasma, CD4 + /CD8 + T-cell counts and HAART and their influence on clinical outcome were examined using a graphical chain modeling approach. Generalized estimating equations were used to examine correlations among the three disease markers. Hazards models with time-dependent covariates were used to examine the influence of HAART and the disease markers on progression to AIDS. RESULTS: HAART was significantly associated with reduced disease progression (relative hazard [RH] of AIDS, 0.20;, 95% confidence interval [CI], 0.05-0.85). The most recent HIV-1 RNA measurement and CD4 + T-cell count are independently associated with disease progression (adjusted RH for HIV-1 RNA 1.8 per log 10 increase; 95% CI, 1.2-2.6, p =.002; adjusted RH for CD4 + 0.48 per 100 x 10(6)/L increase; 95% CI, 0.40-0.58; p <.001). Depending on these measurements, HAART was no longer significantly associated with AIDS (adjusted RH, 0.81; 95% CI, 0.18-3.6; p =.78). CONCLUSIONS: HIV-1 RNA levels in plasma and CD4 + T-cell counts are currently considered as effective surrogate markers for the effect of HAART on disease progression in this cohort.

Antiretroviral Therapy, Highly Active↗
PubMed2001

The role of antigenic stimulation and cytotoxic T cell activity in regulating the long-term immunopathogenesis of HIV: mechanisms and clinical implications.

This paper develops a predictive mathematical model of cell infection, host immune response and viral replication that reproduces observed long-term trends in human immunodeficiency virus (HIV) pathogenesis. Cell activation induced by repeated exposure to many different antigens is proposed as the principal mechanism of providing target cells for HIV infection and, hence, of CD4+ T cell depletion, with regulation of the overall T cell pool size causing concomitant CD8 pool increases. The model correctly predicts the cross-patient variability in disease progression, the rate of which is found to depend on the efficacy of anti-HIV cytotoxic T lymphocyte responses, overall viral pathogenicity and random effects. The model also predicts a variety of responses to anti-viral therapy, including episodic residual viral replication and discordant responses and we find that such effects can be suppressed by increasing the potency of treatment.

Anti-HIV Agents↗
PubMed2001

Transmission intensity and impact of control policies on the foot and mouth epidemic in Great Britain.

The foot and mouth disease (FMD) epidemic in British livestock remains an ongoing cause for concern, with new cases still arising in previously unaffected areas. Epidemiological analyses have been vital in delivering scientific advice to government on effective control measures. Using disease, culling and census data on all livestock farms in Great Britain, we analysed the risk factors determining the spatiotemporal evolution of the epidemic and of the impact of control policies on FMD incidence. Here we show that the species mix, animal numbers and the number of distinct land parcels in a farm are central to explaining regional variation in transmission intensity. We use the parameter estimates thus obtained in a dynamical model of disease spread to show that extended culling programmes were essential for controlling the epidemic to the extent achieved, but demonstrate that the epidemic could have been substantially reduced in scale had the most efficient control measures been rigorously applied earlier.

Animals↗