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1.  A morphometric and histological study of placental malaria shows significant changes to villous architecture in both Plasmodium falciparum and Plasmodium vivax infection 
Malaria Journal  2014;13:4.
Background
Malaria in pregnancy remains a major health problem. Placental malaria infection may cause pathophysiological changes in pregnancy and result in morphological changes to placental villi. Quantitative histomorphological image analysis of placental biopsies was performed to compare placental villous architecture between active or treated placental malaria cases and controls.
Methods
A total of 67 placentas were studied from three clinical groups: control patients who did not have malaria (n = 27), active (n = 14) and treated (n=26) malaria cases, including both Plasmodium falciparum and Plasmodium vivax infections. Image analysis of histological placental sections was performed using ImageJ software to measure the number and size (area) of terminal villi, perimeter measurement per villus and total perimeter per unit area, and number of capillaries per villus (vascularity). Histological features of placental malaria were scored and these results were correlated with malaria status and clinical outcomes.
Results
Villous size correlated with vascularity (p <0.0001) but was inversely correlated with observed villi per unit area, (p = 0.0001). Significantly greater villous area and vascularity was observed in UK controls. Indices of histological malaria infection were significantly greater in active versus treated malaria cases. Active placental malaria cases showed significantly smaller villous area (p <0.0084), vascularity (p <0.0139) and perimeter (p <0.0006) than treated malaria cases or controls, but significantly more villi per unit area (p <0.0001). Villous size in treated malaria cases was significantly larger than active placental malaria cases (p <0.001) and similar to controls. There was a significant relationship between villous number and anaemia at the time of infection (p <0.0034), but not placental weight, birth weight or gestational age at delivery. No differences were found between histology or villous morphology comparing infections with P. falciparum or P. vivax.
Conclusions
These results imply that villous size, perimeter and vascularity are acutely decreased during active placental malaria, decreasing the surface area available for gas exchange per villus. However the increased number of villi per unit area offsets this change and persists after treatment. Histopathological and villous architectural changes may be reversed by early detection and appropriate anti-malarial treatment.
doi:10.1186/1475-2875-13-4
PMCID: PMC3900675  PMID: 24386908
Malaria; Placenta; Pregnancy; Pathophysiology; Morphometry; Image analysis; Villi
2.  Inter- and Intra-Operator Variability in the Reading of Indirect Immunofluorescence Assays for the Serological Diagnosis of Scrub Typhus and Murine Typhus 
Inter- and intra-observer variation was examined among six microscopists who read 50 scrub typhus (ST) and murine typhus (MT) indirect immunofluorescence assay (IFA) immunoglobulin M (IgM) slides. Inter-observer agreement was moderate (κ = 0.45) for MT and fair (κ = 0.32) for ST, and was significantly correlated with experience (P = 0.03 and P = 0.004, respectively); κ-scores for intra-observer agreement between morning and afternoon readings (range = 0.35–0.86) were not correlated between years of experience for ST and MT IFAs (Spearman's ρ = 0.31, P = 0.54 and P = 0.14, respectively; P = 0.78). Storage at 4°C for 2 days showed a change from positive to negative in 20–32% of slides. Although the titers did not dramatically change after 14 days of storage, the final interpretation (positive to negative) did change in 36–50% of samples, and it, therefore, recommended that slides should be read as soon as possible after processing.
doi:10.4269/ajtmh.12-0325
PMCID: PMC3752761  PMID: 23478577
3.  Sequestration and Microvascular Congestion Are Associated With Coma in Human Cerebral Malaria 
The Journal of Infectious Diseases  2011;205(4):663-671.
The pathogenesis of coma in severe Plasmodium falciparum malaria remains poorly understood. Obstruction of the brain microvasculature because of sequestration of parasitized red blood cells (pRBCs) represents one mechanism that could contribute to coma in cerebral malaria. Quantitative postmortem microscopy of brain sections from Vietnamese adults dying of malaria confirmed that sequestration in the cerebral microvasculature was significantly higher in patients with cerebral malaria (CM; n = 21) than in patients with non-CM (n = 23). Sequestration of pRBCs and CM was also significantly associated with increased microvascular congestion by infected and uninfected erythrocytes. Clinicopathological correlation showed that sequestration and congestion were significantly associated with deeper levels of premortem coma and shorter time to death. Microvascular congestion and sequestration were highly correlated as microscopic findings but were independent predictors of a clinical diagnosis of CM. Increased microvascular congestion accompanies coma in CM, associated with parasite sequestration in the cerebral microvasculature.
doi:10.1093/infdis/jir812
PMCID: PMC3266137  PMID: 22207648
5.  Effect of High-Dose or Split-Dose Artesunate on Parasite Clearance in Artemisinin-Resistant Falciparum Malaria 
New treatment strategies are needed for artemisinin-resistant falciparum malaria. This randomized trial shows that neither increasing nor splitting the standard once-daily artesunate dose reverses the markedly reduced parasite clearance rate in patients with artemisinin-resistant falciparum malaria.
Background. The emergence of Plasmodium falciparum resistance to artemisinins on the Cambodian and Myanmar-Thai borders poses severe threats to malaria control. We investigated whether increasing or splitting the dose of the short-half-life drug artesunate improves parasite clearance in falciparum malaria in the 2 regions.
Methods. In Pailin, western Cambodia (from 2008 to 2010), and Wang Pha, northwestern Thailand (2009–2010), patients with uncomplicated falciparum malaria were randomized to oral artesunate 6 mg/kg/d as a once-daily or twice-daily dose for 7 days, or artesunate 8 mg/kg/d as a once-daily or twice-daily dose for 3 days, followed by mefloquine. Parasite clearance and recrudescence for up to 63 days of follow-up were assessed.
Results. A total of 159 patients were enrolled. Overall median (interquartile range [IQR]) parasitemia half-life (half-life) was 6.03 (4.89–7.28) hours in Pailin versus 3.42 (2.20–4.85) hours in Wang Pha (P = .0001). Splitting or increasing the artesunate dose did not shorten half-life in either site. Pharmacokinetic profiles of artesunate and dihydroartemisinin were similar between sites and did not correlate with half-life. Recrudescent infections occurred in 4 of 79 patients in Pailin and 5 of 80 in Wang Pha and was not different between treatment arms (P = .68).
Conclusions. Increasing the artesunate treatment dose up to 8 mg/kg/d or splitting the dose does not improve parasite clearance in either artemisinin resistant or more sensitive infections with P. falciparum.
Clinical Trials Registration. ISRCTN15351875.
doi:10.1093/cid/cis958
PMCID: PMC3563392  PMID: 23175556
artemisinins; drug resistance; Plasmodium falciparum; neutropenia; reticulocytopenia
6.  Artemisinin Resistance in Plasmodium falciparum Malaria 
The New England journal of medicine  2009;361(5):455-467.
BACKGROUND
Artemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in all countries with endemic disease. There are recent concerns that the efficacy of such therapies has declined on the Thai–Cambodian border, historically a site of emerging antimalarial-drug resistance.
METHODS
In two open-label, randomized trials, we compared the efficacies of two treatments for uncomplicated falciparum malaria in Pailin, western Cambodia, and Wang Pha, northwestern Thailand: oral artesunate given at a dose of 2 mg per kilogram of body weight per day, for 7 days, and artesunate given at a dose of 4 mg per kilogram per day, for 3 days, followed by mefloquine at two doses totaling 25 mg per kilogram. We assessed in vitro and in vivo Plasmodium falciparum susceptibility, artesunate pharmacokinetics, and molecular markers of resistance.
RESULTS
We studied 40 patients in each of the two locations. The overall median parasite clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours (interquartile range, 36 to 66) in Wang Pha (P<0.001). Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients (30%) receiving artesunate monotherapy and 1 of 20 (5%) receiving artesunate–mefloquine therapy in Pailin, as compared with 2 of 20 (10%) and 1 of 20 (5%), respectively, in Wang Pha (P = 0.31). These markedly different parasitologic responses were not explained by differences in age, artesunate or dihydroartemisinin pharmacokinetics, results of isotopic in vitro sensitivity tests, or putative molecular correlates of P. falciparum drug resistance (mutations or amplifications of the gene encoding a multidrug resistance protein [PfMDR1] or mutations in the gene encoding sarco–endoplasmic reticulum calcium ATPase6 [PfSERCA]). Adverse events were mild and did not differ significantly between the two treatment groups.
CONCLUSIONS
P. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thailand. Resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing. Containment measures are urgently needed. (ClinicalTrials.gov number, NCT00493363, and Current Controlled Trials number, ISRCTN64835265.)
doi:10.1056/NEJMoa0808859
PMCID: PMC3495232  PMID: 19641202
7.  Comparison of Performance of Serum and Plasma in Panbio Dengue and Japanese Encephalitis Virus Enzyme-Linked Immunosorbent Assays 
We examined the comparative performance of serum and plasma (in dipotassium EDTA) in Panbio Dengue enzyme-linked immunosorbent assays (ELISAs) for detection of non-structural protein 1 (NS1), IgM, and IgG, and a dengue/Japanese encephalitis virus (JEV) combination IgM ELISA in a prospective series of 201 patients with suspected dengue in Laos. Paired comparisons of medians from serum and plasma samples were not significantly different for Dengue IgM, and NS1 which had the highest number of discordant pairs (both 2%; P = 0.13 and P = 0.25, respectively). Comparison of qualitative final diagnostic interpretations for serum and plasma samples were not significantly different: only 1.5% (3 of 201 for Dengue/JEV IgM and Dengue IgG) and 2.0% (4 of 201; IgM and NS1) showed discordant pairs. These results demonstrate that plasma containing EDTA is suitable for use in these ELISAs.
doi:10.4269/ajtmh.2012.12-0043
PMCID: PMC3435366  PMID: 22826488
8.  Single Nucleotide Polymorphisms in the Toll-Like Receptor 3 and CD44 Genes Are Associated with Persistence of Vaccine-Induced Immunity to the Serogroup C Meningococcal Conjugate Vaccine 
The rate of decay of antibody concentration following serogroup C meningococcal (MenC) polysaccharide-protein conjugate vaccination varies between individuals. This depends partly on vaccination age but may be influenced by human genetics. We studied 721 single nucleotide polymorphisms (SNPs) across 131 candidate genes in a first cohort of 905 Caucasians (11 to 21 years old; mean time after vaccination, 4.9 years) and 30 SNPs across 17 genes in a replication study using 155 children, aged 6 to 12 years (mean time after vaccination, 6.7 years), and 196 infants (1 year old; mean time after vaccination, 8 months). Individuals were classified as responders or nonresponders for total MenC IgG concentration and MenC serum bactericidal antibody (SBA) measurements. Associated genes were examined further for quantitative outcome measures. Fifty-nine SNPs in 37 genes were associated with IgG persistence (adjusted for age at measurement), and 56 SNPs in 36 genes were associated with SBA persistence (adjusted for age at measurement and vaccine used). Three SNPs each within the Toll-like receptor 3 (TLR3) (rs3775291, rs3775292, and rs5743312) and CD44 (rs11033013, rs353644, and rs996076) genes were associated with IgG (adjusted for age at measurement) or SBA (adjusted for age at measurement and vaccine used) persistence in the initial genetic study (P, 0.02 to 0.04). Single SNPs within the TLR3 (rs7657186) (P = 0.004 [unadjusted]) and CD44 (rs12419062) (P = 0.01 [unadjusted]) genes were associated with IgG persistence in the replication study. These results suggest that genetic polymorphisms in the TLR3 and CD44 genes are associated with the persistence of the immune response to MenC vaccines 1 to 6 years after vaccination.
doi:10.1128/CVI.05379-11
PMCID: PMC3294616  PMID: 22205660
9.  Is areca innocent? The effect of areca (betel) nut chewing in a population of pregnant women on the Thai–Myanmar border 
International Health  2012;4-172(3):204-209.
Eight manuscripts have specifically examined the effects of areca (betel) nut use in pregnant women, seven of which have documented adverse effects on birth weight, newborn neurological status, gender ratio and pregnancy outcomes such as anaemia and miscarriage following areca nut use during pregnancy. A retrospective cohort analysis of migrant and refugee pregnant women attending antenatal clinics along the Thai–Myanmar border (July 1997 to November 2006) was conducted to examine the adverse effects of areca nut use routinely recorded on enrolment. Of 7685 women, 2284 (29.7%) never used areca or smoked (cheroots), 2484 (32.3%) only used areca, 438 (5.7%) only smoked cheroots and 2479 (32.3%) used both areca and cheroots. Pieces of ripe areca nut in a leaf with lime, without tobacco, were used particularly among older multigravid women. Adverse pregnancy effects were not observed in areca nut users compared with non-users. Smoking, but not areca nut use, had a dose-related effect on miscarriage. Areca nut use in conjunction with smoking reduced the adverse effects of smoking on birth weight, further supporting a lack of effect of areca nut. Areca (betel) nut-related adverse pregnancy outcomes were not observed in this population, whereas smoking was clearly harmful. Differences from previous reports may result from the amount or types of areca nut, or quid content, consumed between countries. Smoking, but not areca nut, reduction is likely to improve pregnancy outcomes on the Thai–Myanmar border.
doi:10.1016/j.inhe.2012.05.001
PMCID: PMC3442179  PMID: 24029401
Areca nut; Smoking; Pregnancy; Maternal outcome; Neonatal outcome
10.  Diagnosing Severe Falciparum Malaria in Parasitaemic African Children: A Prospective Evaluation of Plasma PfHRP2 Measurement 
PLoS Medicine  2012;9(8):e1001297.
Arjen Dondorp and colleagues investigate whether the plasma level of Plasmodium falciparum histidine-rich protein 2 can be used to distinguish between severe malaria and other severe febrile illness in African children with malaria.
Background
In African children, distinguishing severe falciparum malaria from other severe febrile illnesses with coincidental Plasmodium falciparum parasitaemia is a major challenge. P. falciparum histidine-rich protein 2 (PfHRP2) is released by mature sequestered parasites and can be used to estimate the total parasite burden. We investigated the prognostic significance of plasma PfHRP2 and used it to estimate the malaria-attributable fraction in African children diagnosed with severe malaria.
Methods and Findings
Admission plasma PfHRP2 was measured prospectively in African children (from Mozambique, The Gambia, Kenya, Tanzania, Uganda, Rwanda, and the Democratic Republic of the Congo) aged 1 month to 15 years with severe febrile illness and a positive P. falciparum lactate dehydrogenase (pLDH)-based rapid test in a clinical trial comparing parenteral artesunate versus quinine (the AQUAMAT trial, ISRCTN 50258054). In 3,826 severely ill children, Plasmadium falciparum PfHRP2 was higher in patients with coma (p = 0.0209), acidosis (p<0.0001), and severe anaemia (p<0.0001). Admission geometric mean (95%CI) plasma PfHRP2 was 1,611 (1,350–1,922) ng/mL in fatal cases (n = 381) versus 1,046 (991–1,104) ng/mL in survivors (n = 3,445, p<0.0001), without differences in parasitaemia as assessed by microscopy. There was a U-shaped association between log10 plasma PfHRP2 and risk of death. Mortality increased 20% per log10 increase in PfHRP2 above 174 ng/mL (adjusted odds ratio [AOR] 1.21, 95%CI 1.05–1.39, p = 0.009). A mechanistic model assuming a PfHRP2-independent risk of death in non-malaria illness closely fitted the observed data and showed malaria-attributable mortality less than 50% with plasma PfHRP2≤174 ng/mL. The odds ratio (OR) for death in artesunate versus quinine-treated patients was 0.61 (95%CI 0.44–0.83, p = 0.0018) in the highest PfHRP2 tertile, whereas there was no difference in the lowest tertile (OR 1.05; 95%CI 0.69–1.61; p = 0.82). A limitation of the study is that some conclusions are drawn from a mechanistic model, which is inherently dependent on certain assumptions. However, a sensitivity analysis of the model indicated that the results were robust to a plausible range of parameter estimates. Further studies are needed to validate our findings.
Conclusions
Plasma PfHRP2 has prognostic significance in African children with severe falciparum malaria and provides a tool to stratify the risk of “true” severe malaria-attributable disease as opposed to other severe illnesses in parasitaemic African children.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Malaria is a life-threatening disease caused by parasites that are transmitted to people through the bites of infected mosquitoes. In 2010, malaria caused an estimated 655,000 deaths worldwide, mostly in Africa, where according to the World Health Organization, one African child dies every minute from the disease. There are four Plasmodium parasite species that cause malaria in humans, with one species, Plasmodium falciparum, causing the most severe disease. However, diagnosing severe falciparum malaria in children living in endemic areas is problematic, as many semi-immune children may have the malaria parasites in their blood (described as being parasitaemic) but do not have clinical disease. Therefore, a positive malaria blood smear may be coincidental and not be diagnostic of severe malaria, and unfortunately, neither are the clinical symptoms of severe malaria, such as shock, acidosis, or coma, which can also be caused by other childhood infections. For these reasons, the misdiagnosis of falciparum malaria in severely ill children is an important problem in sub-Saharan Africa, and may result in unnecessary child deaths.
Why Was This Study Done?
Previous studies have suggested that a parasite protein—P. falciparum histidine-rich protein-2 (PfHRP2)—is a measure of the total number of parasites in the patient. Unlike the circulating parasites detected on a blood film, which do not represent the parasites that get stuck in vital organs, PfHRP2 is distributed equally through the total blood plasma volume, and so can be considered a measure of the total parasite burden in the previous 48 hours. So in this study, the researchers assessed the prognostic value of plasma PfHRP2 in African children with severe malaria and whether this protein could distinguish children who really do have severe malaria from those who have severe febrile illness but coincidental parasitaemia, who may have another infection.
What Did the Researchers Do and Find?
The researchers assessed levels of plasma PfHRP2 in 3,826 out of a possible 5,425 African children who participated in a large multinational trial (in Mozambique, The Gambia, Rwanda, Tanzania, Kenya, Uganda, and the Democratic Republic of Congo) that compared the anti-malarial drugs quinine and artesunate for the treatment of severe malaria. All children had a clinical diagnosis of severe malaria confirmed by a rapid diagnostic test, and the researchers used clinical signs to define the severity of malaria. The researchers assessed the relationship between plasma PfHRP2 concentrations and risk of death taking other well established predictors of death, such as coma, convulsions, hypoglycaemia, respiratory distress, and shock, into account.
The researchers found that PfHRP2 was detectable in 3,800/3,826 (99%) children with severe malaria and that the average plasma PfHRP2 levels was significantly higher in the 381 children who died from malaria than in children who survived (1,611 ng/mL versus 1,046 ng/mL). Plasma PfHRP2 was also significantly higher in children with severe malaria signs and symptoms such as coma, acidosis, and severe anaemia. Importantly, the researchers found that high death rates were associated with either very low or very high values of plasma PfHRP2: the odds (chance) of death were 20% higher per unit increase in PfHRP2 above a specific threshold (174 ng/ml), but below this concentration, the risk of death increased with decreasing levels, probably because at lower levels disease was caused by a severe febrile disease other than malaria, like septicemia. Finally, the researchers found that in children within the highest PfHRP2 tertile, the chance of death when treated with the antimalarial drug artesunate versus quinine was 0.61 but that there was no difference in death rates in the lowest tertile, which supports that patients with very low plasma PfHRP2 have a different severe febrile illness than malaria. The researchers use mathematical modeling to provide cut-off values for plasma PfHRP2 denoting the proportion of patients with a diagnosis other than severe malaria.
What Do These Findings Mean?
These findings suggest that in areas of moderate or high malaria transmission where a high proportion of children are parasitaemic, plasma PfHRP2 levels taken on admission to hospital can differentiate children at highest risk of death from severe falciparum malaria from those likely to have alternative causes of severe febrile illness. Therefore, plasma PfHRP2 could be considered a valuable additional diagnostic tool and prognostic indicator in African children with severe falciparum malaria. This finding is important for clinicians treating children with severe febrile illnesses in malaria-endemic countries: while high levels of plasma PfHRP2 is indicative of severe malaria which needs urgent antimalarial treatment, low levels suggest that another severe infective disease should be considered, warranting additional investigations and urgent treatment with antibiotics.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001297.
A previous small study in PLOS ONE explores the relationship between plasma PfHRP2 and severe malaria in Tanzanian children
The WHO website and the website of Malaria No More have comprehensive information about malaria
doi:10.1371/journal.pmed.1001297
PMCID: PMC3424256  PMID: 22927801
11.  Diagnosis, Clinical Presentation, and In-Hospital Mortality of Severe Malaria in HIV-Coinfected Children and Adults in Mozambique 
Background. Severe falciparum malaria with human immunodeficiency virus (HIV) coinfection is common in settings with a high prevalence of both diseases, but there is little information on whether HIV affects the clinical presentation and outcome of severe malaria.
Methods. HIV status was assessed prospectively in hospitalized parasitemic adults and children with severe malaria in Beira, Mozambique, as part of a clinical trial comparing parenteral artesunate versus quinine (ISRCTN50258054). Clinical signs, comorbidity, complications, and disease outcome were compared according to HIV status.
Results. HIV-1 seroprevalence was 11% (74/655) in children under 15 years and 72% (49/68) in adults with severe malaria. Children with HIV coinfection presented with more severe acidosis, anemia, and respiratory distress, and higher peripheral blood parasitemia and plasma Plasmodium falciparum histidine-rich protein-2 (PfHRP2). During hospitalization, deterioration in coma score, convulsions, respiratory distress, and pneumonia were more common in HIV-coinfected children, and mortality was 26% (19/74) versus 9% (53/581) in uninfected children (P < .001). In an age- and antimalarial treatment–adjusted logistic regression model, significant, independent predictors for death were renal impairment, acidosis, parasitemia, and plasma PfHRP2 concentration.
Conclusions. Severe malaria in HIV-coinfected patients presents with higher parasite burden, more complications, and comorbidity, and carries a higher case fatality rate. Early identification of HIV coinfection is important for the clinical management of severe malaria.
doi:10.1093/cid/cis590
PMCID: PMC3447636  PMID: 22752514
12.  A Prospective Assessment of the Accuracy of Commercial IgM ELISAs in Diagnosis of Japanese Encephalitis Virus Infections in Patients with Suspected Central Nervous System Infections in Laos 
Japanese encephalitis virus (JEV) is a major cause of encephalitis in Asia. We estimated the diagnostic accuracy of two anti-JEV immunoglobulin M (IgM) enzyme-linked immunosorbent assays (ELISAs) (Panbio and XCyton JEVCheX) compared with a reference standard (AFRIMS JEV MAC ELISA) in a prospective study of the causes of central nervous system infections in Laos. Cerebrospinal fluid (CSF; 515 patients) and serum samples (182 patients) from those admitted to Mahosot Hospital, Vientiane, were tested. The CSF from 14.5% of acute encephalitis syndrome (AES) patients and 10.1% from those with AES and meningitis were positive for anti-JEV IgM in the reference ELISA. The sensitivities for CSF were 65.4% (95% confidence interval [CI] = 51–78) (Xcyton), 69.2% (95% CI = 55–81) (Panbio), however 96.2% (95% CI = 87–100) with Panbio Ravi criteria. Specificities were 89–100%. For admission sera from AES patients, sensitivities and specificities of the Panbio ELISA were 85.7% (95% CI = 42–100%) and 92.9% (95% CI = 83–98%), respectively.
doi:10.4269/ajtmh.2012.11-0729
PMCID: PMC3391045  PMID: 22764310
13.  Correction: A Randomized Controlled Trial of Chloroquine for the Treatment of Dengue in Vietnamese Adults 
PLoS Neglected Tropical Diseases  2012;6(6):10.1371/annotation/c5c14905-8792-4d2e-8179-f8c70064e773.
doi:10.1371/annotation/c5c14905-8792-4d2e-8179-f8c70064e773
PMCID: PMC3386287
14.  Correction: A Randomized Controlled Trial of Chloroquine for the Treatment of Dengue in Vietnamese Adults 
PLoS Neglected Tropical Diseases  2012;6(6):10.1371/annotation/e00ee8fb-4ab9-46db-be8e-3696bb362db4.
doi:10.1371/annotation/e00ee8fb-4ab9-46db-be8e-3696bb362db4
PMCID: PMC3386291
15.  Correction: A Randomized Controlled Trial of Chloroquine for the Treatment of Dengue in Vietnamese Adults 
PLoS Neglected Tropical Diseases  2012;6(6):10.1371/annotation/8683caec-b309-46d7-bc47-dc9cc27108e4.
doi:10.1371/annotation/8683caec-b309-46d7-bc47-dc9cc27108e4
PMCID: PMC3386292
16.  Changing Patterns of Gastrointestinal Parasite Infections in Cambodian Children: 2006–2011 
Journal of Tropical Pediatrics  2012;58(6):509-512.
We studied gastrointestinal parasites in symptomatic Cambodian children attending a provincial hospital in Siem Reap, Cambodia between 2006 and 2011. A total of 16 372 faecal samples were examined by direct microscopy. Parasites were detected in 3121 (19.1%) samples and most common were Giardia lamblia (8.0% of samples; 47.6% disease episodes), hookworm (5.1%; 30.3%) and Strongyloides stercoralis (2.6%; 15.6%). The proportion of infected children increased, and the number of disease episodes effectively treated with a single dose of mebendazole decreased, over the 5-year period.
doi:10.1093/tropej/fms024
PMCID: PMC3739457  PMID: 22723077
Cambodia; parasite; faeces; paediatric; epidemiology
17.  A Longitudinal Study of Streptococcus pneumoniae Carriage in a Cohort of Infants and Their Mothers on the Thailand-Myanmar Border 
PLoS ONE  2012;7(5):e38271.
Background
Pneumococcal disease is a major cause of childhood death. Almost a third of the world's children live in Southeast Asia, but there are few data from the region on pneumococcal colonization or disease. Our aim was to document the dynamics of pneumococcal carriage in a rural SE Asian birth cohort.
Methods
We studied 234 Karen mother-infant pairs in Northwestern Thailand. Infants were followed from birth and nasopharyngeal swabs were taken from mother and infant at monthly intervals until 24 months old.
Results
8,386 swabs were cultured and 4,396 pneumococci characterized. Infants became colonized early (median 45.5 days; 95% confidence interval [CI] 44.5-46.0) and by 24 months had a median of seven (range 0–15) carriage episodes. Maternal smoking and young children in the house were associated with earlier colonization (hazard ratio [HR] 1.5 (95% CI 1.1–2.1) and 1.4 (95% CI 1.0–1.9)). For the four commonest serotypes and non-typeable pneumococci, previous exposure to homologous or heterologous serotypes resulted in an extended interval to reacquisition of the same serotype. Previous colonization by serotypes 14 and 19F was also associated with reduced carriage duration if subsequently reacquired (HR [first reacquisition] 4.1 (95% CI 1.4–12.6) and 2.6 (1.5–4.7)). Mothers acquired pneumococci less frequently, and carried them for shorter periods, than infants (acquisition rate 0.5 vs. 1.1 /100 person-days, p<0.001; median duration 31.0 vs. 60.5 days, p = 0.001). 55.8% of pneumococci from infants were vaccine serotypes (13-valent pneumococcal conjugate vaccine, PCV13), compared with 27.5% from mothers (p<0.001). Non-typeable pneumococcal carriage was common, being carried at least once by 55.1% of infants and 32.0% of mothers.
Conclusions
Pneumococcal carriage frequency and duration are influenced by previous exposure to both homologous and heterologous serotypes. These data will inform vaccination strategies in this population.
doi:10.1371/journal.pone.0038271
PMCID: PMC3365031  PMID: 22693610
18.  Predicting the Clinical Outcome of Severe Falciparum Malaria in African Children: Findings From a Large Randomized Trial 
Four predictors were independently associated with an increased risk of death: acidosis, cerebral manifestations of malaria, elevated blood urea nitrogen, or signs of chronic illness. The standard base deficit was found to be the single most relevant predictor of death.
Background. Data from the largest randomized, controlled trial for the treatment of children hospitalized with severe malaria were used to identify such predictors of a poor outcome from severe malaria.
Methods. African children (<15 years) with severe malaria participated in a randomized comparison of parenteral artesunate and parenteral quinine in 9 African countries. Detailed clinical assessment was performed on admission. Parasite densities were assessed in a reference laboratory. Predictors of death were examined using a multivariate logistic regression model.
Results. Twenty indicators of disease severity were assessed, out of which 5 (base deficit, impaired consciousness, convulsions, elevated blood urea, and underlying chronic illness) were associated independently with death. Tachypnea, respiratory distress, deep breathing, shock, prostration, low pH, hyperparasitemia, severe anemia, and jaundice were statistically significant indicators of death in the univariate analysis but not in the multivariate model. Age, glucose levels, axillary temperature, parasite density, heart rate, blood pressure, and blackwater fever were not related to death in univariate models.
Conclusions. Acidosis, cerebral involvement, renal impairment, and chronic illness are key independent predictors for a poor outcome in African children with severe malaria. Mortality is markedly increased in cerebral malaria combined with acidosis.
Clinical Trial Registration. ISRCTN50258054.
doi:10.1093/cid/cis034
PMCID: PMC3309889  PMID: 22412067
19.  Randomized, Double-Blind, Placebo-Controlled Trial of Monthly versus Bimonthly Dihydroartemisinin-Piperaquine Chemoprevention in Adults at High Risk of Malaria 
Intermittent preventive treatment (IPT) is increasingly used to reduce malaria morbidity and mortality in children and pregnant women. The efficacy of IPT depends on the pharmacokinetic and pharmacodynamic properties of the antimalarial drugs used. Healthy adult male volunteers whose occupation put them at high risk of malaria on the Northwest border of Thailand were randomized to receive a 3-day-treatment dose of dihydroartemisinin-piperaquine monthly (DPm) or every 2 months (DPalt) or an identical placebo with or without fat (6.4g/dose) over a 9-month period. All volunteers were monitored weekly. One thousand adults were recruited. Dihydroartemisinin-piperaquine was well tolerated. There were 114 episodes of malaria (49 Plasmodium falciparum, 63 P. vivax, and 2 P. ovale). The protective efficacy against all malaria at 36 weeks was 98% (95% confidence interval [CI], 96% to 99%) in the DPm group and 86% (95% CI, 81% to 90%) in the DPalt group (for both, P < 0.0001 compared to the placebo group). As a result, the placebo group also had lower hematocrits during the study (P < 0.0001). Trough plasma piperaquine concentrations were the main determinant of efficacy; no malaria occurred in participants with a trough concentration above 31 ng/ml. Neither plasma piperaquine concentration nor efficacy was influenced by the coadministration of fat. DPm is safe to use and is effective in the prevention of malaria in adult males living in an area where P. vivax and multidrug-resistant P. falciparum malaria are endemic.
doi:10.1128/AAC.05877-11
PMCID: PMC3294930  PMID: 22252804
20.  No Evidence for Spread of Plasmodium falciparum Artemisinin Resistance to Savannakhet Province, Southern Laos 
We conducted an open-label, randomized clinical trial to assess parasite clearance times (PCT) and the efficacy of 4 mg/kg (group 1, n = 22) and 2 mg/kg (group 2, n = 22) of oral artesunate for three days followed by artemether-lumefantrine in patients with uncomplicated Plasmodium falciparum malaria at Xepon Interdistrict Hospital, Savannakhet Province in southern Laos. Slides were read in duplicate. The overall mean (95% confidence interval; range) PCT in hours was 23.2 (21.2–25.3; 12–46) and 22.4 (20.3–24.5; 12–46) for the first and second microscopists, respectively (P = 0.57). Ten (23%) patients remained parasitemic on day 1 after treatment (4 [18%] in group 1 and 6 [27%] in group 2; P = 0.47). No patient had patent asexual parasitemia on the second and third days of treatment. The 42-day polymerase chain reaction–corrected cure rates were 100% in both treatment groups. Serious adverse events did not develop during or after treatment in any patients. In conclusion, no evidence of P. falciparum in vivo resistance to artesunate was found in southern Laos.
doi:10.4269/ajtmh.2012.11-0497
PMCID: PMC3284353  PMID: 22403308
21.  Central venous catheter use in severe malaria: time to reconsider the World Health Organization guidelines? 
Malaria Journal  2011;10:342.
Background
To optimize the fluid status of adult patients with severe malaria, World Health Organization (WHO) guidelines recommend the insertion of a central venous catheter (CVC) and a target central venous pressure (CVP) of 0-5 cmH2O. However there are few data from clinical trials to support this recommendation.
Methods
Twenty-eight adult Indian and Bangladeshi patients admitted to the intensive care unit with severe falciparum malaria were enrolled in the study. All patients had a CVC inserted and had regular CVP measurements recorded. The CVP measurements were compared with markers of disease severity, clinical endpoints and volumetric measures derived from transpulmonary thermodilution.
Results
There was no correlation between the admission CVP and patient outcome (p = 0.67) or disease severity (p = 0.33). There was no correlation between the baseline CVP and the concomitant extravascular lung water (p = 0.62), global end diastolic volume (p = 0.88) or cardiac index (p = 0.44). There was no correlation between the baseline CVP and the likelihood of a patient being fluid responsive (p = 0.37). On the occasions when the CVP was in the WHO target range patients were usually hypovolaemic and often had pulmonary oedema by volumetric measures. Seven of 28 patients suffered a complication of the CVC insertion, although none were fatal.
Conclusion
The WHO recommendation for the routine insertion of a CVC, and the maintenance of a CVP of 0-5 cmH2O in adults with severe malaria, should be reconsidered.
doi:10.1186/1475-2875-10-342
PMCID: PMC3228715  PMID: 22082224
22.  Estimation of gestational age from fundal height: a solution for resource-poor settings 
Many women in resource-poor settings lack access to reliable gestational age assessment because they do not know their last menstrual period; there is no ultrasound (US) and methods of newborn gestational age dating are not practised by birth attendants. A bespoke multiple-measures model was developed to predict the expected date of delivery determined by US. The results are compared with both a linear and a nonlinear model. Prospectively collected early US and serial symphysis-pubis fundal height (SFH) data were used in the models. The data were collected from Karen and Burmese women attending antenatal care on the Thai–Burmese border. The multiple-measures model performed best, resulting in a range of accuracy depending on the number of SFH measures recorded per mother (for example six SFH measurements resulted in a prediction accuracy of ±2 weeks). SFH remains the proxy for gestational age in much of the resource-poor world. While more accurate measures should be encouraged, we demonstrate that a formula that incorporates at least three SFH measures from an individual mother and the slopes between them provide a significant increase in the accuracy of prediction compared with the linear and nonlinear formulae also using multiple SFH measures.
doi:10.1098/rsif.2011.0376
PMCID: PMC3262426  PMID: 21849388
symphysis-fundal height; gestational age; estimation; formula; ultrasound
23.  Brain Swelling and Mannitol Therapy in Adult Cerebral Malaria: A Randomized Trial 
Mild cerebral swelling on CT-scan was common in adult patients with cerebral malaria, but severity of swelling was not correlated with coma depth or survival. Mannitol as adjunctive treatment for cerebral malaria prolonged coma duration and may be harmful.
Background. Coma is a frequent presentation of severe malaria in adults and an important cause of death. The role of cerebral swelling in its pathogenesis, and the possible benefit of intravenous mannitol therapy to treat this, is uncertain.
Methods. A computed tomographic (CT) scan of the cerebrum and lumbar puncture with measurement of cerebrospinal fluid (CSF) pressure were performed on admission for 126 consecutive adult Indian patients with cerebral malaria. Patients with brain swelling on CT scan were randomized to adjunctive treatment with intravenous mannitol (1.5 g/kg followed by 0.5 g/kg every 8 hours; n = 30) or no adjunctive therapy (n = 31).
Results. On CT scan 80 (63%) of 126 patients had cerebral swelling, of whom 36 (29%) had moderate or severe swelling. Extent of brain swelling was not related to coma depth or mortality. CSF pressures were elevated (≥200 mm H2O) in 43 (36%) of 120 patients and correlated with CT scan findings (P for trend = .001). Mortality with mannitol therapy was 9 (30%) of 30 versus 4 (13%) of 31 without adjunctive therapy (hazard ratio, 2.4 [95% confidence interval, 0.8–7.3]; P = .11). Median coma recovery time was 90 hours (range, 22–380 hours) with mannitol versus 32 hours (range, 5–168 hours) without (P = .02).
Conclusions. Brain swelling on CT scan is a common finding in adult patients with cerebral malaria but is not related to coma depth or survival. Mannitol therapy as adjunctive treatment for brain swelling in adult cerebral malaria prolongs coma duration and may be harmful.
doi:10.1093/cid/cir405
PMCID: PMC3148260  PMID: 21810747
24.  Evaluation of a PfHRP2 and a pLDH-based Rapid Diagnostic Test for the Diagnosis of Severe Malaria in 2 Populations of African Children 
This comparative study in 1898 children in 2 different African population shows that a pfHRP2-based rapid diagnostic test is a reliable diagnostic for diagnosing severe falciparum malaria in these settings and performs better than routine microscopy or a pLDH based test.
Background. Rapid diagnostic tests (RDTs) now play an important role in the diagnosis of falciparum malaria in many countries where the disease is endemic. Although these tests have been extensively evaluated in uncomplicated falciparum malaria, reliable data on their performance for diagnosing potentially lethal severe malaria is lacking.
Methods. We compared a Plasmodium falciparum histidine-rich-protein2 (PfHRP2)–based RDT and a Plasmodium lactate dehydrogenase (pLDH)–based RDT with routine microscopy of a peripheral blood slide and expert microscopy as a reference standard for the diagnosis of severe malaria in 1898 children who presented with severe febrile illness at 2 centers in Mozambique and Tanzania.
Results. The overall sensitivity, specificity, positive predictive value, and negative predictive values of the PfHRP2-based test were 94.0%, 70.9%, 85.4%, and 86.8%, respectively, and for the pLDH-based test, the values were 88.0%, 88.3%, 93.2%, and 80.3%, respectively. At parasite counts <1000 parasites/μL (n = 173), sensitivity of the pLDH-based test was low (45.7%), compared with that of the PfHRP2-based test (69.9%). Both RDTs performed better than did the routine slide reading in a clinical laboratory as assessed in 1 of the centers.
Conclusion. The evaluated PfHRP2-based RDT is an acceptable alternative to routine microscopy for diagnosing severe malaria in African children and performed better than did the evaluated pLDH-based RDT.
doi:10.1093/cid/cir143
PMCID: PMC3070869  PMID: 21467015
25.  Glyburide Is Anti-inflammatory and Associated with Reduced Mortality in Melioidosis 
Patients with diabetes have better survival from septic melioidosis than patients who without diabetes. This difference was seen only in patients taking glyburide prior to presentation and was associated with an anti-inflammatory effect of glyburide.
Background. Patients with diabetes mellitus are more prone to bacterial sepsis, but there are conflicting data on whether outcomes are worse in diabetics after presentation with sepsis. Glyburide is an oral hypoglycemic agent used to treat diabetes mellitus. This KATP-channel blocker and broad-spectrum ATP-binding cassette (ABC) transporter inhibitor has broad-ranging effects on the immune system, including inhibition of inflammasome assembly and would be predicted to influence the host response to infection.
Methods. We studied a cohort of 1160 patients with gram-negative sepsis caused by a single pathogen (Burkholderia pseudomallei), 410 (35%) of whom were known to have diabetes. We subsequently studied prospectively diabetics with B. pseudomallei infection (n = 20) to compare the gene expression profile of peripheral whole blood leukocytes in patients who were taking glyburide against those not taking any sulfonylurea.
Results. Survival was greater in diabetics than in nondiabetics (38% vs 45%, respectively, P = .04), but the survival benefit was confined to the patient group taking glyburide (adjusted odds ratio .47, 95% confidence interval .28–.74, P = .005). We identified differential expression of 63 immune-related genes (P = .001) in patients taking glyburide, the sum effect of which we predict to be antiinflammatory in the glyburide group.
Conclusions. We present observational evidence for a glyburide-associated benefit during human melioidosis and correlate this with an anti-inflammatory effect of glyburide on the immune system.
doi:10.1093/cid/ciq192
PMCID: PMC3049341  PMID: 21293047

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