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.].

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.

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.

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

Efficacy of RTS,S/AS02 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in The Gambia: a randomised trial.

BACKGROUND: RTS,S/AS02 is a pre-erythrocytic malaria vaccine based on the circumsporozoite surface protein of Plasmodium falciparum fused to HBsAg, incorporating a new adjuvant (AS02). We did a randomised trial of the efficacy of RTS,S/AS02 against natural P. falciparum infection in semi-immune adult men in The Gambia. METHODS: 306 men aged 18-45 years were randomly assigned three doses of either RTS,S/AS02 or rabies vaccine (control). Volunteers were given sulfadoxine/pyrimethamine 2 weeks before dose 3, and kept under surveillance throughout the malaria transmission season. Blood smears were collected once a week and whenever a volunteer developed symptoms compatible with malaria. The primary endpoint was time to first infection with P. falciparum. Analysis was per protocol. FINDINGS: 250 men (131 in the RTS,S/AS02 group and 119 in the control group) received three doses of vaccine and were followed up for 15 weeks. RTS,S/AS02 was safe and well tolerated. P. falciparum infections occurred significantly earlier in the control group than the RTS,S/AS02 group (Wilcoxon's test p=0.018). Vaccine efficacy, adjusted for confounders, was 34% (95% CI 8.0-53, p=0.014). Protection seemed to wane: estimated efficacy during the first 9 weeks of follow-up was 71% (46-85), but decreased to 0% (-52 to 34) in the last 6 weeks. Vaccination induced strong antibody responses to circumsporozoite protein and strong T-cell responses. Protection was not limited to the NF54 parasite genotype from which the vaccine was derived. 158 men received a fourth dose the next year and were followed up for 9 weeks; during this time, vaccine efficacy was 47% (4-71, p=0.037). INTERPRETATION: RTS,S/AS02 is safe, immunogenic, and is the first pre-erythrocytic vaccine to show significant protection against natural P. falciparum infection.

Asthma, smoking and chronic cough in rural and urban adult communities in The Gambia.

BACKGROUND: Asthma is reported to be rare in traditional rural communities, but is thought to be increasing as lifestyles become more urbanized or 'western'. OBJECTIVES: A community-based survey of non-communicable diseases was conducted from October 1996 to June 1997, and included comparison of the prevalence of asthma, smoking and chronic cough in rural and urban Gambia. METHODS: A cluster sample survey was conducted in a random sample of rural and urban adults (> or = 15 years of age). Subjects were asked about respiratory symptoms using a locally adapted version based on the IULTD questionnaire. Spirometry (basal, methacholine provocation and reversibility with a bronchodilator) and skin prick tests were performed on a randomly selected subsample of all subjects and those who, when interviewed, said they wheezed or had been diagnosed as asthmatic by a doctor. RESULTS: Out of 2166 participants in the urban population, 4.1% reported having had wheezing or whistling in the chest in the previous 12 months, 3.6% reported doctor-diagnosed asthma, and 0.6% chronic cough. In the rural population with 3223 participants these figures were 3.3%, 0.7% and 1.2%, respectively. Wheeze was more common in women, cough for 3 months of the year was more common in the age-groups 45+. Those who reported that they currently smoked accounted for 34% in urban and 42% in rural men. Figures were much lower for women (1.5% and 6.0%). Seven out of 574 randomly selected subjects (1.4%) exhibited bronchial hyper-responsiveness to methacholine challenge. Four of 133 (3.0%) people with self-reported wheeze and 3/69 (4.3%) participants with doctor-diagnosed asthma reacted positively on bronchial provocation with methacholine. There was a remarkably high prevalence of positive skin prick tests to aeroallergens: 38% in participants with a history of wheeze and 27% in those without. CONCLUSION: The prevalence of wheeze (particularly in association with bronchial hyper-responsiveness) was low in both rural and urban Gambia. This is in contrast to the relatively high prevalence of positive skin prick tests to aeroallergens (in both wheezers and non-wheezers), questioning the mechanisms of interaction between allergy and asthma and the presence of protective factors against asthma in this West African population. The high smoking rates justify international concern about tobacco marketing in developing societies.

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.

Obesity and undernutrition and cardiovascular risk factors in rural and urban Gambian communities.

OBJECTIVES: This study documented the prevalence of and cardiovascular risk factors associated with obesity and undernutrition in the Gambia. METHODS: Adults (> or =15 years; N = 5373) from rural and urban areas completed a questionnaire; their height, weight, and waist and hip circumferences were measured, and their cardiovascular risk factors were assessed. RESULTS: Prevalence of undernutrition (body mass index < 18 kg/m(2)) was 18.0%; all strata of society were affected. Prevalence of obesity (body mass index > or =30 kg/m(2)) was 4.0% but was higher (32.6%) among urban women 35 years or older. Cardiovascular risk factors were more prevalent among obese participants. CONCLUSIONS: Undernutrition coexists with obesity, demonstrating a "double burden of disease." Differential interventions should focus on high-risk groups; prevention needs a multisectorial approach.

Family history: an opportunity for early interventions and improved control of hypertension, obesity and diabetes.

OBJECTIVE: To examine whether a family history of high-risk groups for major noncommunicable diseases (NCDs) was a significant risk factor for these conditions among family members in a study population in the Gambia, where strong community and family coherence are important determinants that have to be taken into consideration in promoting lifestyle changes. METHODS: We questioned 5389 adults as to any first-degree family history of major noncommunicable diseases (hypertension, obesity, diabetes and stroke), and measured their blood pressure (BP) and body mass index (BMI). Total blood cholesterol, triglyceride, uric acid, and creatinine concentrations were measured in a stratified subsample, as well as blood glucose (2 hours after ingesting 75 g glucose) in persons aged > or = 35 years. FINDINGS: A significant number of subjects reported a family history of hypertension (8.0%), obesity (5.4%), diabetes (3.3%) and stroke (1.4%), with 14.6% of participants reporting any of these NCDs. Subjects with a family history of hypertension had a higher diastolic BP and BMI, higher cholesterol and uric acid concentrations, and an increased risk of obesity. Those with a family history of obesity had a higher BMI and were at increased risk of obesity. Individuals with a family history of diabetes had a higher BMI and higher concentrations of glucose, cholesterol, triglycerides and uric acid, and their risk of obesity and diabetes was increased. Subjects with a family history of stroke had a higher BMI, as well as higher cholesterol, triglyceride and uric acid concentrations. CONCLUSIONS: A family history of hypertension, obesity, diabetes, or stroke was a significant risk factor for obesity and hyperlipidaemia. With increase of age, more pathological manifestations can develop in this high-risk group. Health professionals should therefore utilize every opportunity to include direct family members in health education.

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.

Haemophilus influenzae type b meningitis in The Gambia after introduction of a conjugate vaccine.

After the introduction of a Haemophilus Influenzae type b (Hib) conjugate vaccine into The Gambia, the annual incidence of Hib meningitis has fallen from more than 200 per 100,000 before vaccination to 21 per 100,000 during the past 12 months.

PIP: This paper reports on the impact of Haemophilus influenzae type b (Hib) conjugate vaccine on the incidence of Hib meningitis in Gambia. The incidence of Hib meningitis among infants younger than 12 months of age in Gambia is greater, and the children affected are younger, compared to children in more developed countries. Between March 1993 and December 1995, children who were administered diphtheria-tetanus-pertussis (DTP) vaccination were randomly assigned a course of Hib conjugate vaccine mixed with DTP or DTP only. In Gambia, DTP vaccinations are recommended at 2, 3, and 4 months of age. The coverage of these vaccinations has been over 85% since 1990. Hib disease has not disappeared from Gambia in the last 2 years since the national immunization program was introduced. However, the incidence rate has declined rapidly, and a longer period of vaccination may be needed to achieve a sufficient herd effect to protect unimmunized children.

Is there a role for glycosuria testing in sub-Saharan Africa?

BACKGROUND: With increasing urbanization and westernization, rates of diabetes in sub-Saharan Africa (sSA) are likely to rise. Early detection and intervention plays an important role in delaying development of complications. In sSA in particular there is need for an affordable, reliable, safe, feasible test to avert human suffering and exhausting already stressed health facilities. METHODS: Data from two large community-based studies were used to assess the value of glycosuria testing in the detection of diabetes in adults in a sub-Saharan country. A first study (A) tested participants for glycosuria by dipstick; if positive, fasting capillary glucose was measured. A later study (B) measured glucose concentration in venous blood 2 h after a 75-g glucose load; if glycaemia was > or = 10 mmol/l, urine was tested for glycosuria. RESULTS: The positive predictive value of glycosuria for a diagnosis of diabetes (fasting glucose > or = 6.7 mmol/l) was 48%. Sensitivity was 64% (57% if a 2-h-value > or = 10 mmol/l was used as gold standard). Sensitivity was higher among overweight and/or hypertensive subjects, among elderly people in the urban area, and among subjects with higher blood glucose levels. Extrapolated specificity was 99.7%, and the likelihood ratio 190. CONCLUSIONS: Glycosuria testing can identify a considerable number of undiagnosed diabetic patients when specially targeted at high-risk groups (obese, hypertensive, or elderly people). Dipstick glycosuria testing is an appropriate, safe, feasible test for sSA, where the prevalence of diabetes is expected to increase considerably in the near future.

Stereospecific analysis and enantiomeric disposition of 3, 4-methylenedioxymethamphetamine (Ecstasy) in humans.

BACKGROUND: Little is known concerning the enantioselective disposition of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) in humans. In addition, the potential of utilizing the stereochemical composition of an analyte in biological media for forensic purposes requires investigation. METHODS: The enantiomers of MDMA and its demethylated metabolite, 3,4-methylenedioxyamphetamine (MDA), present in plasma and urine extracts were derivatized with (-)-(R)-alpha-methoxy-alpha-trifluoromethylphenylacetyl chloride and analyzed by gas chromatography-mass spectrometry and gas chromatography, respectively. The enantioselective disposition of MDMA and MDA was determined following oral administration of racemic MDMA (40 mg) to eight male volunteers. RESULTS: The plasma concentrations of (R)-MDMA exceeded those of the S-enantiomer [ratio R:S of the area under the curve (AUC), 2.4 +/- 0.3], and the plasma half-life of (R)-MDMA (5.8 +/- 2.2 h) was significantly longer than that of the S-enantiomer (3.6 +/- 0.9 h). The majority of the recovered material in urine was excreted within 24 h after dosing, with the recovery of (R)-MDMA (21.4% +/- 11.6%) being significantly greater than that of (S)-MDMA (9.3% +/- 4.9%), and with (S)- and (R)-MDA accounting for 1.4% +/- 0.5% and 1.0% +/- 0.3% of the dose, respectively. Mathematical modeling of plasma enantiomeric composition vs sampling time demonstrated the applicability of using stereochemical data for the prediction of time elapsed after drug administration. CONCLUSIONS: Analytical methods for determining the enantiomeric composition of MDMA and MDA in plasma and urine were developed. The disposition of MDMA in humans is stereoselective, with the more active S-enantiomer having a reduced AUC and shorter half-life than (R)-MDMA. The determination of stereochemical composition may be applicable for forensic purposes.

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.

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.

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.