Biomedical subjects
Publications and source records attributed to M S Chan.
Posterior fossa dural arteriovenous fistulae in children are rare lesions that are difficult to treat effectively. We report a case of a 2-year-old girl with such a fistula, who presented clinically with progressive neurological deficit. The lesion was treated by endovascular occlusion, resulting in radiological and clinical cure.
The identification of clones within bacterial populations is often taken as evidence for a low rate of recombination, but the validity of this inference is rarely examined. We have used statistical tests of congruence between gene trees to examine the extent and significance of recombination in six bacterial pathogens. For Neisseria meningitidis, Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus, the congruence between the maximum likelihood trees reconstructed using seven house-keeping genes was in most cases no better than that between each tree and trees of random topology. The lack of congruence between gene trees in these four species, which include both naturally transformable and nontransformable species, is in three cases supported by high ratios of recombination to point mutation during clonal diversification (estimates of this parameter were not possible for Strep. pyogenes). In contrast, gene trees constructed for Hemophilus influenzae and pathogenic isolates of Escherichia coli showed a higher degree of congruence, suggesting lower rates of recombination. The impact of recombination therefore varies between bacterial species but in many species is sufficient to obliterate the phylogenetic signal in gene trees.
Human populations are often infected with more than one species of parasite, especially in developing countries where overall rates of parasitism are high. Infections with multiple parasite species may not necessarily be independent within an individual as physiological, immunological or ecological factors may result in positive or negative associations between infections with different parasite species. A general framework for estimation of these associations is presented. Data from over 215000 individuals are analysed and the associations between geohelminth (Ascaris lumbricoides, Trichuris trichiura and hookworm) and malaria species are investigated. A method is presented for analysing data from multiple communities and testing whether the associations in different communities are equal. Overall estimates of the associations between species are obtained for each country and continent where data were available. Associations between geohelminth species were, in general, found to be positive whilst both positive and negative associations were found between the different Plasmodium species. There was evidence for significant geographical heterogeneity between the associations. A method for using these parameter estimates to predict the distribution of multiple infections when only marginal prevalence data are available is described and demonstrated.
MOTIVATION: Multi Locus Sequence Typing (MLST) is a newly developed typing method for bacteria based on the sequence determination of internal fragments of seven house-keeping genes. It has proved useful in characterizing and monitoring disease-causing and antibiotic resistant lineages of bacteria. The strength of this approach is that unlike data obtained using most other typing methods, sequence data are unambiguous, can be held on a central database and be queried through a web server. RESULTS: A database-driven software system (mlstdb) has been developed, which is used by public health laboratories and researchers globally to query their nucleotide sequence data against centrally held databases over the internet. The mlstdb system consists of a set of perl scripts for defining the database tables and generating the database management interface and dynamic web pages for querying the databases. AVAILABILITY: http://www.mlst.net.
UNLABELLED: The 32-bit Windows application START is implemented using Visual Basic and C(++) and performs analyses to aid in the investigation of bacterial population structure using multilocus sequence data. These analyses include data summary, lineage assignment, and tests for recombination and selection. AVAILABILITY: START is available at http://outbreak.ceid.ox.ac.uk/software.htm. CONTACT: keith.jolley@ceid.ox.ac.uk
UNLABELLED: We sought to correlate in vivo microvascular, systemic function, hemodynamic, and oxygenation changes in autologous shed blood (n = 4) and hemoglobin glutamer-200 (Hb-200) (n = 4) resuscitations in hypovolemic dogs. Hemorrhage (approximately 40% blood loss) reduced mean arterial pressure to approximately 50 mm Hg and caused significant (P < 0.01) decreases in hematocrit, total hemoglobin, mean pulmonary arterial pressure, cardiac output, and oxygen delivery and significant (P < 0.01) increases in heart rate, systemic vascular resistance, and lactic acidosis. Significant (P < 0.01) changes in conjunctival microvascular variables also occurred, including a 19% decrease in venular diameter and 79% increase in average blood flow velocity. Shed blood resuscitation returned microvascular, systemic function, hemodynamic, and oxygenation variables to prehemorrhagic baseline values. In contrast, Hb-200 failed to restore hematocrit, total hemoglobin, cardiac output, oxygen delivery index, and systemic venous resistance to baseline, but it restored other systemic functions and all hemodynamic and microvascular changes. In addition, Hb-200 resuscitation in hypovolemic dogs (approximately 40% blood loss) did not cause extreme hemodilution or fatal outcome. This study confirms that real-time (in vivo) microvascular studies, which were conducted only in small rodent models in the past, can be performed simultaneously with systemic function, hemodynamic, and oxygenation studies in a large animal model for relevant data correlation. IMPLICATIONS: This is the first time that changes in the blood circulation have been studied, quantified, and correlated with systemic function, hemodynamic, and oxygenation changes in shock and during shock treatment in a large animal model. This study was performed by a new technology developed in-house to noninvasively and quantitatively study blood vessels in real time.
In this paper we address the question of detecting immunity to helminth infections from patterns of infection in endemic communities. We use stochastic simulations to investigate whether it would be possible to detect patterns predicted by theoretical models, using typical field data. Thus, our technique is to simulate a theoretical model, to generate the data that would be obtained in field surveys and then to analyse these data using methods usually employed for field data. The general behaviour of the model, and in particular the levels of variability of egg counts predicted, show that the model is capturing most of the variability present in field data. However, analysis of the data in detail suggests that detection of immunity patterns in real data may be very difficult even if the underlying patterns are present. Analysis of a real data set does show patterns consistent with acquired immunity and the implications of this are discussed.
This paper presents a first attempt at modelling the possible cost and effectiveness of reaching non-enrolled children through school-based programmes using empirical data from Egypt. A sex/school-attendance/age-structured population dynamic model was used to predict trends in infection and early disease. Four treatment delivery strategies were compared: school-based (coverage of 85 %) and school-aged targeted (coverage of 25, 50 and 85 %). The school-aged targeted strategies also included the school-based programme. For each alternative strategy, the maximum unit cost was calculated to obtain a cost-effectiveness ratio equal or smaller to the one obtained with the school-based programme (unit cost of US$ 0.60). The analysis showed that, for S. mansoni in Lower Egypt, a programme where only 85% of children attending school were treated would still prevent 77 % of the early disease cases prevented with a programme where 85 % of all school-age children were treated. However, using the school-aged targeted strategy, from US $ 0.06 to US $ 1.03 extra unit costs could be spent to reach non-enrolled children and still be more cost-effective. Treating non-enrolled children is an important consideration in maximizing the effectiveness of treatment programmes while maintaining a cost-effectiveness comparable to school-based delivery.
Mathematical models of transmission dynamics of infectious diseases provide a useful tool for investigating the impact of community based control measures. Previously, we used a dynamic (constant force-of-infection) model for lymphatic filariasis to describe observed patterns of infection and disease in endemic communities. In this paper, we expand the model to examine the effects of control options against filariasis by incorporating the impact of age structure of the human community and by addressing explicitly the dynamics of parasite transmission from and to the vector population. This model is tested using data for Wuchereria bancrofti transmitted by Culex quinquefasciatus in Pondicherry, South India. The results show that chemotherapy has a larger short-term impact than vector control but that the effects of vector control can last beyond the treatment period. In addition we compare rates of recrudescence for drugs with different macrofilaricidal effects.
BACKGROUND: Currently, more than 600,000 immigrants enter the United States each year from countries where intestinal parasites are endemic. At entry persons with parasitic infections may be asymptomatic, and stool examinations are not a sensitive method of screening for parasitosis. Albendazole is a new, broad-spectrum antiparasitic drug, which was approved recently by the Food and Drug Administration. International trials have shown albendazole to be safe and effective in eradicating many parasites. In the United States there is now disagreement about whether to screen all immigrants for parasites, treat all immigrants presumptively, or do nothing unless they have symptoms. METHODS: We compared the costs and benefits of no preventive intervention (watchful waiting) with those of universal screening or presumptive treatment with 400 mg of albendazole per day for five days. Those at risk were defined as immigrants to the United States from Asia, the Middle East, sub-Saharan Africa, Eastern Europe, and Latin America and the Caribbean. Cost effectiveness was expressed both in terms of the cost of treatment per disability-adjusted life-year (DALY) averted (one DALY is defined as the loss of one year of healthy life to disease) and in terms of the cost per hospitalization averted. RESULTS: As compared with watchful waiting, presumptive treatment of all immigrants at risk for parasitosis would avert at least 870 DALYs, prevent at least 33 deaths and 374 hospitalizations, and save at least $4.2 million per year. As compared with watchful waiting, screening would cost $159,236 per DALY averted. CONCLUSIONS: Presumptive administration of albendazole to all immigrants at risk for parasitosis would save lives and money. Universal screening, with treatment of persons with positive stool examinations, would save lives but is less cost effective than presumptive treatment.
A mathematical model, based on a deterministic differential equation framework, has been developed to predict the impact of community chemotherapy programmes for human schistosomiasis. Here, this model is validated using data collected from a long-term control programme for urinary schistosomiasis on the island of Pemba, Zanzibar, United Republic of Tanzania, initiated in 1986 and still ongoing, in which schoolchildren were offered praziquantel chemotherapy every 6 months. Prevalence of infection and blood in urine were monitored in all the schools (total 26000 children from 60 schools) and more detailed data were collected in selected evaluation schools. Model predictions were run by using the initial prevalence as input. The predictions were very close to the observed decreases in prevalence and in prevalence of blood in urine. The correspondence improved further when the data were combined, going from single school level to district, and when the entire data set was combined. The accuracy of the predictions suggests that this model could be used as a tool to predict the consequences of chemotherapy control programmes. It is currently in press as a Windows software package under the name of 'EpiSchisto'.
Schistosomiasis is a helminth (worm) infection with approximately 200 million people infected worldwide. There is still controversy on whether differing worm burdens between individuals is a result of differing contact rates or of acquired immunity. In this paper, we present a stochastic modelling framework to address these issues. By using appropriate approximations for the higher moments of the joint distributions, differential equations for the means, variances and co-variances of infection and immunity can be obtained. Numerical solutions of these equations to obtain age profiles of the above properties were compared with Monte Carlo simulations of the stochastic process. Simulations showed that the results depended on whether between host heterogeneity was generated by differing contact rates or differing immune responses. Heterogeneity in contact rates produced a highly aggregated distribution of parasites with a large variance/mean ratio. Heterogeneity in the immune response had very little effect on the overall dynamics. This agrees with the predominant field evidence which would suggest that infection is mainly determined by ecology with a smaller contribution of immunity.
Few health-related quality of life (HRQOL) survey instruments are available to the Chinese, although many have been developed for Western populations. This article describes the testing of the acceptability, conceptual equivalence, scaling assumptions and construct validity of a Chinese (HK [Hong Kong]) version fo the MOS SF-36 Health Survey. A Chinese (HK) SF-36 survey form was developed by an iterative translation process. It was administered to 236 Chinese subjects who also rated the understanding, difficulty, relevance, and acceptability of each question. The scores were tested against the original scaling assumptions. The SF-36 profile of our subjects was compared to U.S. results for conceptual equivalence. Most subjects did not have any problem in understanding and answering the SF-36. Item means were generally clustered as hypothesized. All but a few items satisfied all scaling assumptions. The shape of the eight-scale SF-36 profile was similar to that of American patients, suggesting conceptual equivalence. We conclude that the Chinese (HK) version of the SF-36 Health Survey has achieved conceptual equivalence and satisfied the psychometric scaling assumptions well enough to warrant further use and testing, using the standard scoring algorithms.
A population dynamic model of schistosome transmission was used to investigate the interaction between drug efficacy and drug price of different brands of praziquantel in determining the cost-effectiveness of school-targeted treatment for Schistosoma mansoni. In this analysis, costs were affected by coverage, drug price and distance travelled, and effectiveness by coverage and drug efficacy. Four effectiveness measures were assessed: the number of infection case-years prevented, heavy infection case-years prevented, hepatomegaly case-years prevented and fibrosis case-years prevented. The interactions between drug efficacy and drug price were complex. In particular, there was a highly nonlinear relationship between drug efficacy and cost-effectiveness, with drugs of low efficacy producing high and variable cost-effectiveness ratios, particularly when other programme costs related to distance travelled were high. The results suggest that given the current price range of praziquantel, a drug with less than a 50% chance of killing the worms is not to be recommended. This has important practical implications for the widespread use of praziquantel, since most international agencies procure praziquantel purely on the basis of price. There is clearly a need for studies which evaluate the efficacy of new brands of praziquantel, and more credence should be given to the use of high efficacy brands, not only in terms of maximizing the cost-effectiveness of the intervention programme, but also in delaying the onset of drug resistance.
The lack of a quantitative framework that describes the dynamic relationships between infection and morbidity has constrained efforts aimed at the community-level control of lymphatic filariasis. In this paper, we describe the development and validation of EPIFIL, a dynamic model of filariasis infection intensity and chronic disease. Infection dynamics are modeled using the well established immigration-death formulation, incorporating the acquisition of immunity to infective larvae over time. The dynamics of disease (lymphodema and hydrocele) are modeled as a catalytic function of a variety of factors, including worm load and the impact of immunopathological responses. The model was parameterized using age-stratified data collected from a Bancroftian filariasis endemic area in Pondicherry in southern India. The fitted parameters suggest that a relatively simple model including only acquired immunity to infection and irreversible progression to disease can satisfactorily explain the observed infection and disease patterns. Disease progression is assumed to be a consequence of worm induced damage and to occur at a high rate for hydrocele and a low rate for lymphodema. This suggests that immunopathology involvement may not be a necessary component of observed age-disease profiles. These findings support a central role for worm burden in the initiation and progression of chronic filarial disease.
Fields trials of new schistosomiasis vaccines are anticipated within the next few years, but there remains great uncertainty regarding the optimal design of vaccination programmes. Mathematical models are used here to explore the potential long-term consequences of vaccination, assuming that the vaccines provide partial protection for a limited period. The analysis suggests that vaccines acting to reduce infection rates or egg output will have a similar impact on levels of infection, that this impact may be highly sensitive to the duration as well as the degree of protection, that it may take several decades for the full impact to become apparent, and that one consequence will be peak levels of infection occurring in older age classes. In terms of lowering levels of infection there may be advantages in delaying vaccination until children reach school age, especially if the vaccine gives short-lived protection, or to repeat vaccination. The short-term advantages can be greatly increased by combining the introduction of a vaccination programme with initial mass chemotherapy. Continuous combined vaccination and chemotherapy programmes may also be more effective than either intervention alone. More research is needed on the consequences of vaccinating previously vaccinated, infected, and infected and treated individuals and the importance of natural boosting of vaccine-induced immunity.
This paper presents estimates of the global numbers of people at risk from morbidity related to infection with Ascaris lumbricoides and the numbers of deaths from this infection. Morbidity is classified into 4 types: deficits in growth and fitness which are contemporaneous with infection, or permanent, overt acute illness of mild to moderate severity, and complications involving hospitalization. The estimation of morbidity is based on theoretical models of parasite distributions developed in previous papers. A sensitivity analysis is carried out in which parameters of the model are varied using a Latin hypercube sampling technique. The results estimate approximately 1300 million infections globally with 59 million at risk of some morbidity. The estimate for acute illness is 12 million cases per year with approximately 10,000 deaths. Most morbidity is in children. Sensitivity analysis suggests that infection estimates will not vary greatly with changes in parameter values but that morbidity estimates may be highly variable.
BACKGROUND: This paper presents a suite of models of hookworm transmission dynamics which vary the mixing patterns and rates of contamination and infection between children and adults. In this context mixing refers to the degree of epidemiological communication between children and adults, for example, whether adults are likely to get infected from infective material passed by children. METHODS: Three models are described which represent random mixing, no mixing and restricted mixing respectively. Child, adult and population targeted chemotherapy programmes are examined and compared between these models. Data from a hookworm control programme in Zimbabwe were analysed with respect to their fit to the various models. RESULTS: The analysis suggests that some mixing does occur and that in this study location, the sites where adults deposit faeces are more likely to lead to subsequent contamination than the sites children use. CONCLUSIONS: Mixing patterns may have a profound effect on transmission dynamics and should be considered in relation to design of control programmes.