Amodiaquine dosage and tolerability for intermittent preventive treatment to prevent malaria in children.

Sulfadoxine-pyrimethamine with amodiaquine (SP-AQ) is a highly efficacious regimen for intermittent preventive treatment to prevent malaria in children (IPTc), but the amodiaquine component is not always well tolerated. We determined the association between amodiaquine dosage by body weight and mild adverse events (AEs) and investigated whether alternative age-based regimens could improve dosing accuracy and tolerability, using data from two trials of IPTc in Senegal, one in which AQ dose was determined by age and the other in which it was determined by weight category. Both dosage strategies resulted in some children receiving AQ doses above the recommended therapeutic range. The odds of vomiting increased with increasing amodiaquine dosage. In one study, incidence of fever also increased with increasing dosage. Anthropometric data from 1,956 children were used to predict the dosing accuracy of existing and optimal alternative regimens. Logistic regression models describing the probability of AEs by dosage were used to predict the potential reductions in mild AEs for each regimen. Simple amendments to current AQ dosing schedules based on the child's age could substantially increase dosing accuracy and thus improve the tolerability of IPTc using SP-amodiaquine in situations where weighing the child is impractical.

Gastric and small intestinal ileus as a cause of acute colic in the post parturient mare.

REASONS FOR PERFORMING STUDY: Ileus (functional obstruction of aboral gastrointestinal transit) is an uncommon cause of gastrointestinal dysfunction and colic in the horse. A number of specific conditions have been previously reported in association with ileus. This report describes the recognition of primary gastric and small intestinal ileus of undetermined cause in a series of post parturient mares. OBJECTIVES: To describe the clinical features, treatment and outcome of a series of episodes of primary gastric and small intestinal ileus. METHODS: A retrospective study was performed of colic episodes seen in an equine practice in Newmarket, UK over a 6 year period (2002-2007). RESULTS: Seventeen episodes of gastric and small intestinal ileus were identified, which occurred in 15 horses. All episodes occurred in post parturient mares. No previously reported cause of ileus was identified in any of the episodes. Fifteen of the 17 episodes received medical treatment (medical support and nasogastric decompression) and, in addition, surgical decompression was performed in 9 episodes. Two mares were subjected to euthanasia before treatment due to the presence of gastric rupture and the remaining 13 mares survived with a follow-up period of at least 10 months. Two mares suffered a further episode of gastric and small intestinal ileus, one 4 days and the other 2 years after the initial episode. CONCLUSIONS: Gastric and small intestinal ileus of, as yet, unknown aetiology appears to be a potential cause of acute colic in the post parturient mare. The outcome following treatment by decompression is good.

Safety of Seasonal Malaria Chemoprevention (SMC) with Sulfadoxine-Pyrimethamine plus Amodiaquine when Delivered to Children under 10 Years of Age by District Health Services in Senegal: Results from a Stepped-Wedge Cluster Randomized Trial.

BACKGROUND: It is recommended that children aged 3 months to five years of age living in areas of seasonal transmission in the sub-Sahel should receive Seasonal Malaria Chemoprevention (SMC) with sulfadoxine-pyrimethamine plus amodiaquine (SPAQ) during the malaria transmission season. The purpose of this study was to evaluate the safety of SMC with SPAQ in children when delivered by community health workers in three districts in Senegal where SMC was introduced over three years, in children from 3 months of age to five years of age in the first year, then in children up to 10 years of age. METHODS: A surveillance system was established to record all deaths and all malaria cases diagnosed at health facilities and a pharmacovigilance system was established to detect adverse drug reactions. Health posts were randomized to introduce SMC in a stepped wedge design. SMC with SPAQ was administered once per month from September to November, by nine health-posts in 2008, by 27 in 2009 and by 45 in 2010. RESULTS: After three years, 780,000 documented courses of SMC had been administered. High coverage was achieved. No serious adverse events attributable to the intervention were detected, despite a high level of surveillance. CONCLUSIONS: SMC is being implemented in countries of the sub-Sahel for children under 5 years of age, but in some areas the age distribution of cases of malaria may justify extending this age limit, as has been done in Senegal. Our results show that SMC is well tolerated in children under five and in older children. However, pharmacovigilance should be maintained where SMC is implemented and provision for strengthening national pharmacovigilance systems should be included in plans for SMC implementation. TRIAL REGISTRATION: ClinicalTrials.gov NCT 00712374.

Correction: Safety of Seasonal Malaria Chemoprevention (SMC) with Sulfadoxine-Pyrimethamine plus Amodiaquine when Delivered to Children under 10 Years of Age by District Health Services in Senegal: Results from a Stepped-Wedge Cluster Randomized Trial.

[This corrects the article DOI: 10.1371/journal.pone.0162563.].

Factors determining the outcome of treatment of adult smear-positive tuberculosis cases in The Gambia.

SETTING: Health centres in The Gambia, West Africa. OBJECTIVES: To identify factors determining the outcome of treatment of adult tuberculosis cases in a Tuberculosis Control Programme using directly observed treatment. DESIGN: Information on the outcome of treatment was collected on all tuberculosis cases registered with the Tuberculosis Control Programme in 1994 and 1995 and treated under supervision by tuberculosis control staff, nurses or village health workers. Treatment outcome was recorded as cured, completed treatment, failed, defaulted or died. Transferred-out patients were traced and their treatment outcome recorded at the health centre where they had last been seen. RESULTS: Data were analysed for 1357 adult smear-positive tuberculosis cases. Sputum smear conversion 2 months after the start of treatment was observed in 90% of smear-positive cases and was more likely to occur if the initial bacterial load in the sputum was low. The total cure rate was 74.6%. Female tuberculosis patients were more likely to achieve cure than males. Adjusting for sex, the cure rate was higher when treatment was provided by tuberculosis control staff in the main health centres rather than by nurses or village health workers at the peripheral level (odds ratio [OR] = 1.60, 95% confidence interval [CI] 1.23-2.09). The absence of sputum smear conversion after 2 months of chemotherapy was associated with defaulting later during treatment (OR = 2.0, 95% CI 1.15-3.57). Adjusting for age and sex, the death rate during treatment was higher in human immunodeficiency virus (HIV) positive than in HIV-negative tuberculosis patients. CONCLUSION: Directly observed treatment is an effective intervention for improving adherence of tuberculosis patients to treatment in a resource-poor country, provided that drugs are effectively delivered to the most peripheral level, and that health staff are adequately trained and regularly supervised. Patients with high bacterial load in initial sputum smears need to be closely supervised, as they are more likely to default from treatment.

Geographical variation in prevalence of hypertension within The Gambia.

Hypertension has become an important public health problem for sub-Sahara Africa. In a previous nationwide study, we observed a high degree of geographical variation in the prevalence of diastolic hypertension. Geographical variation provides essential background information for the development of community randomised trials could suggest aetiological mechanisms, inform control strategies and prompt further research questions. We designed a follow-up study from the nine high-prevalence communities, and from 18 communities where hypertension was found least prevalent (controls). In each community, 50 households were randomly selected. In each household, an (unrelated) man and woman were enrolled. The risk for hypertension (blood pressure > or =160/95 mm Hg) was higher in the high prevalence communities compared to the control villages (adjusted OR = 1.7, 95% CI 1.3-2.2). The observed coefficient of variation in hypertension prevalence, k, was 0.30. Thus we confirmed significant geographical variation in prevalence of hypertension over time, which has implications for planning of interventions.

Blood pressure patterns and cardiovascular risk factors in rural and urban gambian communities.

Hypertension is emerging as an important public health problem in sub-Saharan Africa. We studied blood pressure (BP) patterns, hypertension and other cardiovascular risk factors in a rural and an urban area of The Gambia. A total of 5389 adults (> or =15 years) were selected by cluster sampling in the capital Banjul and a rural area around Farafenni. A questionnaire was completed, BP, pulse rate, height and weight were recorded. Glucose was measured 2 h after a 75 g glucose load among participants > or =35 years (n = 2301); total cholesterol, triglycerides, creatinine and uric acid were measured among a stratified subsample (n = 1075). A total of 7.1% of the study participants had a BP > or =160/95 mm Hg; 18.4% of them had a BP > or =140/90 mm Hg. BP was significantly higher in the urban area. BP increased with age in both sexes in both areas. Increasing age was the major independent risk factor for hypertension. Related cardiovascular risk factors (obesity, diabetes and hyperlipidaemia) were significantly more prevalent in the urban area and among hypertensives; 17% of measured hypertensives were aware of this, 73% of people who reported to have been diagnosed as hypertensive before had discontinued treatment; 56% of those who reported being on treatment were normotensive. We conclude that hypertension is no longer rare in either urban or rural Gambians. In the urban site hypertension and related cardiovascular risk factors were more prevalent. Compliance with treatment was low. Interventions aimed at modifying risk factors at the population level, and at improving control of diagnosed hypertension are essential to prevent future increases of cardiovascular morbidity and mortality. In view of limited resources and feasibility of intervention in rural Gambia, these could initially be directed towards urbanised populations.

Placental antibody transfer: influence of maternal HIV infection and placental malaria.

AIM: To determine the influence of placental malaria, maternal HIV infection, and maternal hypergammaglobulinaemia on transplacental IgG antibody transfer. METHODS: One hundred and eighty materno-neonatal pairs from a Malawian population were assessed. Cord and maternal serum samples were tested for total serum IgG antibody titres using nephelometry, and for specific IgG antibody titres to Streptococcus pneumoniae, measles, and tetanus toxoid antibodies using an enzyme linked immunosorbent assay (ELISA). RESULTS: Multiple regression analyses showed that placental malaria was associated with a decrease in placental IgG antibody transfer to S pneumoniae and measles to 82% and 81%, respectively. Maternal HIV infection was associated with a reduction in IgG antibody transfer to S pneumoniae to 79%; raised maternal total serum IgG titres were correlated with S pneumoniae and measles IgG antibody transfer reduction to 86% and 87%, respectively. No effect was seen with tetanus toxoid antibody transfer. CONCLUSION: The combined influence of placental malaria, maternal HIV infection, and maternal hypergammaglobulinaemia seems to be linked to the low transplacental antibody transfer observed in the Malawian population.

Association of spatial distribution of childhood respiratory morbidity with environmental dust pollution.

The objective of this study was to investigate the spatial distribution of respiratory morbidity and asthma in children in relation to high levels of airborne dust pollution. A cross-sectional survey of 2035 children (aged 5-11 yr) by parent-completed questionnaire, with concurrent monitoring of dust deposition rates in the vicinity of children's homes, was performed in 15 primary schools (5 in each of 3 areas of Merseyside). The main outcome measures were (1) doctor-diagnosed asthma, (2) parent-reported respiratory symptoms of recent excess cough, wheeze, and breathlessness, and (3) school absenteeism due to respiratory ill health. Proximity to the source of dust pollution was associated with increased prevalence of excess cough, breathlessness, school absence due to respiratory ill health, and doctor-diagnosed asthma, after adjusting for a range of socioeconomic, environmental, and other confounding factors. The adjusted odds for excess cough and breathlessness for children living within 2 km of the source (dock area) are estimated to be almost twice those for children living more than 2 km away: excess cough 1.9 (95% CI 1.4-2.6); breathlessness 1.9 (1.3-2.7); school absence 1.5 (1.2-1.9); and doctor-diagnosed asthma 1.5 (1.1-2.0). Excess cough was significantly associated with the mean annual dust deposition recorded in the vicinity of the child's home. The adjusted odds ratio for excess cough corresponding to an increase in mean annual dust deposition of 50 mg/m2/d was 3.1 (95% CI 1.1-8.2). These results suggest that airborne dust was associated with respiratory morbidity in these children, which could relate to the high prevalence of childhood doctor-diagnosed asthma in this community.

Cuticular hydrocarbons, isoenzymes and behavior of three populations of Anopheles darlingi from Brazil.

Three populations of Anopheles darlingi were studied for cuticular hydrocarbons, isoenzymes and patterns of peak biting activity. Differences were found in specimens from Costa Marques, a malaria endemic area; Dourado, a site with a very exophilic population and Juturnaíba, located near the type locality. Twelve hour collections from sunset to sunrise showed that An. darlingi from Costa Marques had a bimodal biting activity profile with a major peak at sunset and a minor peak at sunrise. At Dourado, the pattern was trimodal, with peaks at both morning and evening periods of twilight and near midnight. The Juturnaíba population showed a slight increase in activity near 2000 and 0100 h. Nei's genetic distances, determined by isoenzyme electrophoresis between pairs of populations, were low (D < or = 0.049). Using discriminant analysis for the cuticular hydrocarbons, 92.4% of the specimens from Costa Marques, 91.2% of the specimens from Dourado and 61.3% from Juturnaíba were correctly identified. Cuticular hydrocarbon and isoenzyme results matched very well: the smaller the Nei's distance, the more misidentifications occurred in the jackknife estimator used in the cuticular hydrocarbon analysis. This is the first report of cuticular hydrocarbon analysis in combination with isoenzymes to investigate neotropical anopheline species.

Epizootiology of trypanosomiases: some aspects of mathematical modelling.

The formulation of trypanosomiasis transmission models is complicated by heterogeneity, due to (a) different feeding preferences of vectors for a range of host species, (b) the presence of different genetic lines in the parasite population, and (c) variations in susceptibility and infectivity among hosts and vectors. Simple models are used to explore qualitative effects of changes in host range of vectors on the basic reproductive rate (section 1), of migration of vectors on disease persistence (section 2), and of gradual acquisition of immunity to different trypanosome serodemes (section 3). Many implicit and explicit assumptions need to be validated by fitting models to field data as part of multidisciplinary projects.

A model of tsetse-transmitted animal trypanosomiasis.

The data needed to develop analytical models of trypanosomiasis transmission have become available only recently. By making some simplifying assumptions, models of the dynamics of the disease in vector, cattle and wild mammal populations can be constructed in order to determine criteria for successful disease control by mass and targetted chemotherapy, and by vector control. The heterogeneity in transmission due to tsetse fly feeding preferences and the variability of immunological characteristics among the vertebrate hosts account for differences in prevalence of Trypanosoma vivax and T. congolense, and also lead to an increase in the basic reproductive rates of the parasites and a corresponding decrease in the vector population density threshold for disease eradication or persistence. The long life-span of the vectors relative to the duration of the parasites' developmental period lead to high infection rates in the vector and high values of R0. The efficacy of chemotherapeutic regimes depends on the relationship between treatment rate and the duration of prophylaxis conferred by the drugs used. The model's predictions of the effects of vector control are shown to be in broad agreement with published field data for Mkwaja Ranch, Tanzania. Vector control programmes are frequently blighted by reinvasion, and the implications of this are discussed in terms of a model for fly immigration. With immigration of vectors, the disease is always endemic, though the infection rate in the fly population is modified by the effect of differential mortalities inside and outside the controlled area on cohorts of incubating flies. Sensitivity analysis of the model, using Monte-Carlo methods, enables an assessment of the relative importance of the parameters to be made. The results emphasize the need for studies of the wild animal reservoir to be carried out alongside entomological surveys. The relative accuracy with which field measurements need to be made in order to minimize the uncertainty in predictions of trypanosomiasis prevalence is discussed.

Trypanozoon: infectivity to humans is linked to reduced transmissibility in tsetse. I. Comparison of human serum-resistant and human serum-sensitive field isolates.

The transmissibility of recent isolates of human serum-sensitive (HSS) and human serum-resistant (HSR) Trypanozoon was compared by transmission of 37 stocks through an inbred line of Glossina m. morsitans. As in previous studies maturation was found to be dependent on fly sex with males producing significantly greater proportions of salivary gland infections than females. HSS stocks were, however, 1.8 times more likely to mature to mammalian infective form than HSR stocks in male tsetse and 2.7 times more likely to mature than HSR stocks in female tsetse. Infectivity to man has apparently evolved at the expense of transmissibility in tsetse. The likelihood of sexual processes occurring in Trypanosoma b. rhodesiense in wild flies is discussed.

Trypanozoon: infectivity to humans is linked to reduced transmissibility in tsetse. II. Genetic mechanisms.

Trypanozoon infections are less likely to mature in female tsetse than in males. Analysis of maturation data from 37 Trypanozoon isolates in Glossina m. morsitans showed that while the proportion of mature infections (salivary gland infections as a proportion of established midgut infections) varied from isolate to isolate, the proportion of mature infections in female flies was consistently smaller than the proportion in male flies. The log of the probability of maturation in females is, on average, twice the log of the probability in males (estimate of the ratio of the logged proportions is 2.09, 95% confidence interval (CI) 1.8 to 2.5). Human serum-resistant isolates were less likely to mature than human serum-sensitive isolates (ratio of logged proportions maturing was 1.5, 95% CI 1.3 to 1.8, in both male and female tsetse). Data for four other trypanosome stocks show that the probability of maturation decreases as the maturation time (the delay between the infected bloodmeal and maturation) increases. The decrease is approximately exponential with twice the half-life in male flies compared to that in female flies (estimate of the ratio of the exponential parameters is 1.97, 95% CI 0.7 to 3.3). A model is proposed to explain these observations which assumes that product(s) from an X-linked gene(s) kills or otherwise prevents migrating parasites from establishing a mature infection. Longer maturation times are associated with a heavy penalty in terms of transmissibility as measured by the vectorial capacity.

Trypanosome infections and survival in tsetse.

The effect of trypanosome infection on vector survival was observed in a line of Glossina morsitans selected for susceptibility to trypanosome infection. The differential effects of midgut and salivary gland infections on survival were examined by exposing flies to infection with either Trypanosoma congolense which colonizes midgut and mouthparts or Trypanosoma brucei rhodesiense which colonizes midgut and salivary glands. A comparison of the survival distributions of uninfected flies with those exposed to infection showed that salivary gland infection significantly reduces tsetse survival; midgut infection had little or no effect on the survival of tsetse. The significance of these findings is discussed in relation to the vectorial capacity of wild flies.

The kinetics of maturation of trypanosome infections in tsetse.

Estimates of the time delay between the infective bloodmeal and maturation (incubation or maturation time) for 4 trypanosome stocks (2 Trypanozoon and 2 Trypanosoma congolense) show that maturation time in tsetse is not a parasite species-specific constant. The mean incubation time of a Trypanosoma brucei rhodesiense stock (EATRO 2340 - 18 days) was not significantly different from one T. congolense stock (SIKUDA88 - 15.5 days) but was significantly greater than another (1/148 FLY9 - 12.5 days). There was no significant difference in incubation times between male and female Glossina morsitans morsitans for any of the stocks but in both of the Trypanozoon stocks the proportion of female flies producing mature infections was significantly less than in males. However, estimates of gene frequency, assuming a model in which maturation is controlled by an X-linked recessive allele, gave inconsistent results indicating that maturation cannot be controlled by a single sex-linked gene. Maturation was shown to be a tsetse sex-dependent phenomenon in Trypanozoon but not in T. congolense infections. Incubation time was quite variable even for a single trypanosome stock (e.g., standard deviation of 5 days for one Trypanozoon stock); we discuss how this variability can affect disease transmission, and the interpretation of age-prevalence data.

Tsetse-trypanosomiasis challenge to village N'Dama cattle in The Gambia: field assessments of spatial and temporal patterns of tsetse-cattle contact and the risk of trypanosomiasis infection.

The severity of the trypanosomiasis problem in a particular location is traditionally assessed in terms of a challenge index-the product of some measure of tsetse abundance and infection-rate-which is assumed to be proportional to the force of infection. However, this index masks variation in the force of infection between herds and among individuals within herds. It is also not comparable between sites since the relative abundance of tsetse to hosts may vary. We have studied spatial distribution of herds of cattle in relation to tsetse in The Gambia and calculated an index of challenge based on the ratio of vectors to hosts over the livestock ranging area. This index is strongly correlated with estimates of the force of infection calculated from the incidence of infection in susceptible zebu; and it provides information on heterogeneity in exposure of different herds to tsetse.

The possible role of Rickettsia-like organisms in trypanosomiasis epidemiology.

A simple model of human and animal trypanosomiasis is proposed in which the Ross equation for disease transmission is supplemented by a differential equation describing the inheritance of susceptibility in the vector. The model predicts an equilibrium state of balanced polymorphism for the fraction, theta, of susceptible tsetse and the occurrence of periodic epidemics at roughly the observed intervals. A loss of infectivity to tsetse of mechanically transmitted strains of trypanosome would seem to be a good evolutionary strategy for the trypanosome. The main implication for disease control is that measures initially reducing trypanosomiasis incidence could trigger off subsequent epidemics. Since theta leads incidence, monitoring theta could give several years advance warning of major epidemics. The model leads to oscillations in prevalence which are only lightly damped. Other mechanisms producing periodic epidemics would interact with this mechanism, and result in only one sequence of recurrent epidemics. With typical random variation of tsetse numbers about the seasonal norm the model shows the behaviour of a narrow-band system excited by broad-band noise, i.e. predicted trypanosomiasis incidence exhibits an undamped series of oscillations of variable amplitude and phase, similar to what is actually observed.

Cancellous bone changes in the radius of patients with rheumatoid arthritis: a cross-sectional quantitative macroradiographic study.

OBJECTIVE: Fractal signature analysis (FSA), a computerized method of textural analysis, permits the separate measurement of changes in vertical and horizontal trabeculae based on the fractal dimension over a range of trabecular widths (fractal signature). We determined whether the FSA of high-definition macroradiographs (x5 magnification) quantified radiographic changes at sites of osteopenia and erosion formation in the rheumatoid arthritis (RA) hand. METHODS: Sixty-seven RA patients had macroradiographs of the left wrist and hand. The distal radius was scored and grouped from very mild (RA1) to moderate (RA4) disease. Macroradiographs were digitized and FSA of horizontal and vertical trabecular organization was performed in the radius at sites of periarticular osteopenia, erosion formation and at a mid-metaphyseal site. The RA groups were compared with 11 healthy non-arthritic subjects using ANOVA and Dunnett's tests. RESULTS: Compared to the non-arthritic hands, FSA at the distal radius in groups RA1 to RA4 measured significantly lower (P<0.05) fractal signatures. The fractal signatures were lowest in RA4 involving small, medium to large sized vertical trabeculae at the periarticular osteopenic (0.18 to 0.84 mm, P<0.01) and mid-metaphyseal sites (0.12 to 0.60 and 0.84 to 1.02 mm, P