Publications

Polymerase chain reaction for the detection of Burkholderia pseudomallei

Melioidosis is a potentially lethal infection of humans and animals in Southeast Asia and northern Australia. Current methods for detection of the causative organism, Burkholderia pseudomallei, lack both speed and sensitivity. We report the development of a highly sensitive polymerase chain reaction-based method that can detect as few as 35 colony-forming units of B. pseudomallei/mL in saline suspensions. This polymerase chain reaction test also detected the presence of B. pseudomallei DNA in culture-negative splenic tissue obtained from mice infected with the organism, but without clinical evidence of disease. Specificity has been confirmed using a variety of pathogenic and nonpathogenic organisms, including B. mallei, B. cepacia, and Pseudomonas species. The clinical usefulness of this test should be assessed prospectively and compared with conventional diagnostic techniques.

Optimal sampling designs for accurate estimation of parasite clearance in the context of artemisinin resistance

Background The emergence of artemisinin resistance in South East Asia threatens the efficacy of artemisinin derivatives (AD). Since the pharmacodynamic hallmark of AD is rapid parasite clearance, the clinical phenotype of slow clearance characterises resistance. This indicator remains critically important to monitor the extent of the problem in the absence of molecular marker(s) associated with artemisinin resistance and lack of sensitivity of current in vitro tests. Frequent parasite counts are needed to define clearance rate but it is uncertain what sampling frequency is required to ensure reliable estimates.

Conclusion

Abstract The concluding chapter sets the findings of the individual chapters into the wider context of global history and the history of globalization. It argues that shipping as both an engine and an example of globalizing processes helps understand and illustrate the dynamics and periodization of globalization, in particular through its entanglements with the transformation of states and borders over the post-war period. This is examined first through an analysis of the context within which shipping developed, in particular the shift of the global economic balance towards Asia, decolonization, and changes in international governance. Second, the role of shipping companies in these processes is examined in a comparative perspective. Third, the obvious and less obvious connections resulting from shipping are discussed.

Red cell deformability, splenic function and anaemia in thalassaemia

Red cell deformability (RCD) was measured in 38 patients with α‐thalassaemia and 48 patients with β‐thalassaemia, of whom 13 had undergone splenectomy. All splenectomized patients, but none of those with intact spleens, had very rigid erythrocytes with an elongation index <0.45 at a high shear stress of 30 Pa suggesting a splenic recognition threshold for removal of rigid red cells. At this shear stress RCD correlated strongly with the degree of anaemia in both the splenectomized ( r = 0.81, P < 0.001) and non‐splenectomized β‐thalassaemic patients (all patients r = 0.81, P < 0.001; homozygous β‐thalassaemic patients r = 0.51, P = 0.01). These data suggest that reduced RCD is a major determinant of anaemia in thalassaemia.

Prolongation of the QTc interval in African children treated for falciparum malaria.

No abstract is provided for this article.

Sun-Earth, Sun-Earth-Moon, and idealized system datasets paper_c_sunearth_log2aubound06_meshlevel04_ic_whitenoise_randseed9.mat

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Submicroscopic malaria in pregnancy and associated adverse pregnancy events: A case-cohort study of 4,352 women on the Thailand–Myanmar border

Malaria in pregnancy detected by microscopy is associated with maternal anaemia, reduced fetal growth, and preterm birth, but the effects of lower density (i.e., submicroscopic) malaria infections are poorly characterised. This analysis was undertaken to investigate associations between submicroscopic malaria at the first antenatal care (ANC) visit and these adverse pregnancy events on the Thailand-Myanmar border. Blood samples taken from refugee and migrant pregnant women presenting for their first ANC visit were analysed retrospectively for malaria using ultrasensitive PCR (uPCR, limit of detection 22 parasites/mL). The relationships between submicroscopic malaria and subsequent microscopically detectable malaria, anaemia, birth weight, and preterm birth were evaluated using inverse probability weighting for stratified random sampling. First ANC visit samples from 4,352 asymptomatic women (median gestational age 16.5 weeks) attending between October 1st 2012 and December 31st 2015 were analysed. The weighted proportion of women with submicroscopic malaria infection was 4.6% (95% CI 3.9-5.6), comprising 59.8% (49.5-69.4) Plasmodium vivax, 6.5% (4.0-10.5) Plasmodium falciparum, 1.8% (0.9-3.6) mixed, and 31.9% (22.2-43.5) infections which could not be speciated. Submicroscopic parasitaemia at first ANC visit was associated with subsequent microscopically detected malaria (adjusted hazard ratio [HR] 12.9, 95% CI 8.8-18.8, p < 0.001) and lower birth weight (adjusted predicted mean difference -275 g, 95% CI -510 to -40, p = 0.022). There was no association with preterm birth. Submicroscopic P. falciparum mono-infection (adjusted HR 2.8, 95% CI 1.2-6.6, p = 0.023) and coinfection with P. falciparum and P. vivax (adjusted HR 10.3, 95% CI 2.6-40.4, p = 0.001) was associated with increased risk of maternal anaemia, but submicroscopic P. vivax mono-infection was not. That uPCR was conducted for only a part of the cohort due to cost constraints is a limitation. In low transmission settings, uPCR identifies substantially more malaria infections at antenatal screening than conventional diagnostic methods. On the Thailand-Myanmar border, submicroscopic malaria at first antenatal consultation was associated with higher risks of microscopically diagnosed malaria later in pregnancy, anaemia, and reduced birth weight.

WHO COVID-19 therapeutic guidelines Reply

Rosette formation by Plasmodium vivax

In contrast to Plasmodium falciparum, infections with P. vivax are seldom fatal. Red blood cells containing mature forms of P. falciparum sequester in the microvasculature of vital organs, and adhere to vascular endothelium (cytoadherence) and to uninfected red cells (rosetting). Rosetting of P. falciparum has been associated with the lethal syndrome of cerebral malaria. We have studied the rosetting properties of red blood cells infected with P. vivax obtained from adults with acute malaria in Thailand. Of 35 parasite isolates studied, 25 (71%) showed rosetting with a mean proportion of 41% of infected red cells (sd 34%, range 14–100%). Rosetting of P. vivax was related to maturation of the parasite; only cells containing parasites with visible malaria pigment rosetted. Rosetting and parasitaemia were not correlated. However, unlike P. falciparum, cells infected with P. vivax did not adhere to human umbilical vein endothelial cells, to C32 melanoma cells, to platelets, or to purified adhesion receptor molecule CD36. These findings suggest that thrombocytopenia in vivax malaria is not related to platelet-red cell attachment, and that rosetting alone is insufficient to cause the syndrome of cerebral malaria.

Resistance to antimicorbial agents in <em>Salmonella typhi</em> in Vietnam: clinical response to therapy and molecular mechanisms

ING & INDEXING

IFN-γ at the Site of Infection Determines Rate of Clearance of Infection in Cryptococcal Meningitis

In animal models, immunity to cryptococcal infection, as in many chronic fungal and bacterial infections, is associated with a granulomatous inflammatory response, intact cell-mediated immunity, and a Th1 pattern of cytokine release. To examine the correlates of human immunity to cryptococcal infection in vivo, we analyzed immune parameters at the site of infection over time and assessed the rate of clearance of infection by serial quantitative cerebrospinal fluid (CSF) fungal cultures in 62 patients in a trial of antifungal therapy for HIV-associated cryptococcal meningitis. CSF IL-6, IFN-γ, TNF-α, and IL-8 were significantly higher in survivors compared with nonsurvivors. There were negative correlations between log TNF-α, IFN-γ, and IL-6 levels and baseline cryptococcal CFU. Log IFN-γ, G-CSF, TNF-α, and IL-6 were correlated positively with the rate of fall in log CFU/ml CSF/day. In a linear regression model including antifungal treatment group, baseline CFU, and these cytokines, only treatment group and log IFN-γ remained independently associated with rate of clearance of infection. The results provide direct in vivo evidence for the importance of quantitative differences in IFN-γ secretion in human immune control of granulomatous infections, and increase the rationale for adjunctive IFN-γ in the treatment of refractory HIV-associated cryptococcosis.

Famous Fathers and Grumpy Daughters

No abstract is provided for this article.

Ethics, Economics, and the Use of Primaquine to Reduce Falciparum Malaria Transmission in Asymptomatic Populations

Yoel Lubell and colleagues consider ethical and economic perspectives on mass drug administration of primaquine to limit transmission of P. falciparum malaria. Please see later in the article for the Editors' Summary

Posterior Calvarial Distraction in older paediatric population: single centre paediatric neurosurgery craniofacial unit outcomes

No abstract is provided for this article.

A comparison of the dynamics of the ionized and neutral gas in NGC 281

Splitting of the [N II] line of up to 26 km s−1 has been found over much of the H II region NGC 281. These observations have been correlated with distinct features in the associated neutral clouds mapped by recent radio observations.

Pharmacokinetics of Mefloquine Combined with Artesunate in Children with Acute Falciparum Malaria

Combining artemisinin or a derivative with mefloquine increases cure rates in falciparum malaria patients, reduces transmission, and may slow the development of resistance. The combination of artesunate, given for 3 days, and mefloquine is now the treatment of choice for uncomplicated multidrug-resistant falciparum malaria acquired on the western or eastern borders of Thailand. To optimize mefloquine administration in this combination, a prospective study of mefloquine pharmacokinetics was conducted with 120 children (4 to 15 years old) with acute uncomplicated falciparum malaria, who were divided into four age- and sex-matched groups. The patients all received artesunate (4 mg/kg of body weight/day orally for 3 days and mefloquine as either (i) a single dose (25 mg/kg) on day 2 with food, (ii) a split dose (15 mg/kg on day 2 and 10 mg/kg on day 3) with food, (iii) a single dose (25 mg/kg) on day 0 without food, or (iv) a single dose (25 mg/kg) on day 2 without food. Delaying administration of mefloquine until day 2 was associated with a mean (95% confidence interval) increase in estimated oral bioavailability of 72% (36 to 109%). On day 2 coadministration with food did not increase mefloquine absorption significantly, and there were no significant differences between patients receiving split- and single-dose administration. In combination with artesunate, mefloquine administration should be delayed until the second or third day after presentation.

Acidosis and acute kidney injury in severe malaria

In severe falciparum malaria metabolic acidosis and acute kidney injury (AKI) are independent predictors of a fatal outcome in all age groups. The relationship between plasma acids, urine acids and renal function was investigated in adult patients with acute falciparum malaria.Plasma and urinary acids which previously showed increased concentrations in proportion to disease severity in patients with severe falciparum malaria were quantified. Patients with uncomplicated malaria, sepsis and healthy volunteers served as comparator groups. Multiple regression and multivariate analysis were used to assess the relationship between organic acid concentrations and clinical syndromes, in particular AKI.Patients with severe malaria (n = 90), uncomplicated malaria (n = 94), non-malaria sepsis (n = 19), and healthy volunteers (n = 61) were included. Univariate analysis showed that both plasma and creatinine-adjusted urine concentrations of p-hydroxyphenyllactic acid (pHPLA) were higher in severe malaria patients with AKI (p < 0.001). Multiple regression analysis, including plasma or creatinine-adjusted urinary acids, and PfHRP2 as parasite biomass marker as independent variables, showed that pHPLA was independently associated with plasma creatinine (β = 0.827) and urine creatinine (β = 0.226). Principal component analysis, including four plasma acids and seven urinary acids separated a group of patients with AKI, which was mainly driven by pHPLA concentrations.Both plasma and urine concentrations of pHPLA closely correlate with AKI in patients with severe falciparum malaria. Further studies will need to assess the potential nephrotoxic properties of pHPLA.

Nasal Carriage in Vietnamese Children of <i>Streptococcus pneumoniae</i> Resistant to Multiple Antimicrobial Agents

Resistance to antimicrobial agents in Streptococcus pneumoniae is increasing rapidly in many Asian countries. There is little recent information concerning resistance levels in Vietnam. A prospective study of pneumococcal carriage in 911 urban and rural Vietnamese children, of whom 44% were nasal carriers, was performed. Carriage was more common in children <5 years old than in those >/=5 years old (192 of 389 [49.4%] versus 212 of 522 [40.6%]; P, 0.01). A total of 136 of 399 isolates (34%) had intermediate susceptibility to penicillin (MIC, 0.1 to 1 mg/liter), and 76 of 399 isolates (19%) showed resistance (MIC, >1.0 mg/liter). A total of 54 of 399 isolates (13%) had intermediate susceptibility to ceftriaxone, and 3 of 399 isolates (1%) were resistant. Penicillin resistance was 21.7 (95% confidence interval, 7.0 to 67.6) times more common in urban than in rural children (35 versus 2%; P, <0.001). More than 40% of isolates from urban children were also resistant to erythromycin, trimethoprim-sulfamethoxazole, chloramphenicol, and tetracycline. Penicillin resistance was independently associated with an urban location when the age of the child was controlled for. Multidrug resistance (resistance to three or more antimicrobial agent groups) was present in 32% of isolates overall but in 39% of isolates with intermediate susceptibility to penicillin and 86% of isolates with penicillin resistance. The predominant serotypes of the S. pneumoniae isolates were 19, 23, 14, 6, and 18. Almost half of the penicillin-resistant isolates serotyped were serotype 23, and these isolates were often multidrug resistant. This study suggests that resistance to penicillin and other antimicrobial agents is common in carriage isolates of S. pneumoniae from children in Vietnam.