METHODS: We did this open-label, randomised controlled trial at three district hospitals in Sabah, Malaysia. Patients aged 1 year or older with uncomplicated P knowlesi malaria were randomly assigned, via computer-generated block randomisation (block sizes of 20), to receive oral artesunate-mefloquine (target dose 12 mg/kg artesunate and 25 mg/kg mefloquine) or chloroquine (target dose 25 mg/kg). Research nursing staff were aware of group allocation, but allocation was concealed from the microscopists responsible for determination of the primary endpoint, and study participants were not aware of drug allocation. The primary endpoint was parasite clearance at 24 h. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01708876.
FINDINGS: Between Oct 16, 2012, and Dec 13, 2014, we randomly assigned 252 patients to receive either artesunate-mefloquine (n=127) or chloroquine (n=125); 226 (90%) patients comprised the modified intention-to-treat population. 24 h after treatment, we recorded parasite clearance in 97 (84% [95% CI 76-91]) of 115 patients in the artesunate-mefloquine group versus 61 (55% [45-64]) of 111 patients in the chloroquine group (difference in proportion 29% [95% CI 18·0-40·8]; p<0·0001). Parasite clearance was faster in patients given artesunate-mefloquine than in those given chloroquine (18·0 h [range 6·0-48·0] vs 24·0 h [6·0-60·0]; p<0·0001), with faster clearance of ring stages in the artesunate-mefloquine group (mean time to 50% clearance of baseline parasites 8·6 h [95% CI 7·9-9·4] vs 13·8 h [12·1-15·4]; p<0·0001). Risk of anaemia within 28 days was lower in patients in the artesunate-mefloquine group (71 [62%; 95% CI 52·2-70·6]) than in those in the chloroquine group (83 [75%; 65·6-82·5]; p=0·035). Gametocytaemia as detected by PCR for pks25 was present in 44 (86%) of 51 patients in the artesunate-mefloquine group and 41 (84%) of 49 patients in the chloroquine group at baseline, and in three (6%) of 49 patients and two (4%) of 48 patients, respectively, at day 7. Fever clearance was faster in the artesunate-mefloquine group (mean 11·5 h [95% CI 8·3-14·6]) than in the chloroquine group (14·8 h [11·7-17·8]; p=0·034). Bed occupancy was 2426 days per 1000 patients in the artesunate-mefloquine group versus 2828 days per 1000 patients in the chloroquine group (incidence rate ratio 0·858 [95% CI 0·812-0·906]; p<0·0001). One (<1%) patient in the artesunate-mefloquine group had a serious neuropsychiatric event regarded as probably related to study drug.
INTERPRETATION: Artesunate-mefloquine is highly efficacious for treatment of uncomplicated P knowlesi malaria. The rapid therapeutic response of the drug offers significant advantages compared with chloroquine monotherapy and supports a unified treatment policy for artemisinin-based combination therapy for all Plasmodium species in co-endemic areas.
FUNDING: Malaysian Ministry of Health, Australian National Health and Medical Research Council, and Asia Pacific Malaria Elimination Network.
BACKGROUND: The Occlutech® PDA occluder is novel, self-shaping Nitinol wire device with PET (polyethylene terephthalate) patches integrated into the shank of the device to assure a better obturation of the ductus. The Occlutech® PDA occluder has undergone two design modifications.
METHODS: A prospective, non-randomized pilot study was started in November 2011. Thirty-three patients were included until April 2013. Patients weighing <6 kg or those with associated cardiac anomalies that required surgery were excluded. All patients were followed up by transthoracic echocardiography at 24 hr, 30 days, 90 days, 180 days, and 360 days after implantation. Residual shunt, left pulmonary artery (LPA) and descending aortic velocities were among the parameters assessed. All occluders were delivered via 6-8 F long sheaths and PDA closures were performed following standard techniques.
RESULTS: Thirty three patients (20 female/13 male), with a median age of 2 years (6 month to 38 years), and median weight of 9.3 kg (6-69.2 kg) were included. The narrowest median PDA diameter was 3mm (1.8-5.8 mm). All the 33 patients were closed successfully using Occlutech ductal occluder, 16 patients (48.4%) had immediate and complete closure on angiography. Within 24 hr, color Doppler revealed complete closure in 27patients (81.8%), 32patients (97%) at 30 days, and in 100% of patients at 90 days. All patients with a large PDA had immediate residual shunt which was closed at the 90-day follow-up. There was no device embolization, hemolysis, or obstruction to the LPA or descending aorta.
CONCLUSION: The new Occlutech® PDA is safe and effective. In patients with a large PDA complete closure tended to take longer time.
METHODS: This was a prospective study conducted at a tertiary hospital in Malaysia, from 1st August 2010 until 31st July 2011. Children aged between 1 mo and 12 y who were admitted for CAP and had blood cultures performed before starting intravenous antibiotics were recruited. Children with congenital pneumonia, immunodeficiency, chronic cardiac or respiratory disorders, nosocomial pneumonia or those on corticosteroids, were excluded. Decision for admission was made by the attending Accident and Emergency physician.
RESULTS: One hundred and seventy-one children were enrolled. The median age was 13 mo (range: 38 d-10 y 3 mo) and 59 % were males. Blood cultures were positive in 1.2 % (2/171) of patients while the contamination rate was 1.8 % (3/171). Doctors altered antibiotics based on blood culture results in only one patient.
CONCLUSIONS: Both the yield and the impact of blood culture results on the adjustment of empiric antibiotic treatment were very small. There was a high contamination rate. The recommended practice of performing blood cultures in all children admitted with CAP should be reviewed.
KEY MESSAGES: A number of findings with a translational and clinical focus have already emerged. In the mothers, we found that changes and differences in food consumption varied across ethnic groups, with persistence of traditional beliefs, during pregnancy and the postpartum period. During pregnancy, higher maternal glucose levels, even in the absence of gestational diabetes mellitus, had graded relations with infant adiposity. Relations between maternal emotional health and birth outcomes and neurodevelopment have been identified. Genotype (25%) and in particular gene × environment interactions (75%) shape interindividual variations in the DNA methylome at birth. The complex effects of fixed genetic variations and different in utero environments can influence the epigenetic status at birth and the later-life phenotype.
CONCLUSIONS: The richness of the clinical data in 3 ethnicities, the extent of the biospecimen collection, and the extensive infancy and preschool follow-up have allowed us to study the biological pathways that link fetal development to health outcomes. In the coming years, more sophisticated analyses of epigenotype-phenotype relationships will become possible as the children grow and develop. Our studies will lead to the development of clinical and population-based interventions to reduce the burden of NCD.