Mahidol University

About: Mahidol University is a education organization based out in Bangkok, Nakhon Pathom, Thailand. It is known for research contribution in the topics: Population & Malaria. The organization has 23758 authors who have published 39761 publications receiving 878781 citations.

Clopidogrel plus aspirin versus aspirin alone for reducing embolisation in patients with acute symptomatic cerebral or carotid artery stenosis (CLAIR study): a randomised, open-label, blinded-endpoint trial

Abstract: Summary Background Few randomised clinical trials have investigated the use of antithrombotic drugs for early secondary prevention of stroke or transient ischaemic attack in patients with intracranial atherosclerotic stenosis. Microembolic signals, detected by transcranial doppler, are a surrogate marker of future stroke risk and have been used to show treatment efficacy in patients with extracranial carotid stenosis. We aimed to investigate whether treatment with clopidogrel plus aspirin reduced the number of microembolic signals detected with transcranial doppler ultrasound compared with aspirin alone in patients with recent stroke. Methods The clopidogrel plus aspirin for infarction reduction in acute stroke or transient ischaemic attack patients with large artery stenosis and microembolic signals (CLAIR) trial was a randomised, open-label, blinded-endpoint trial. Between Oct 28, 2003, and Nov 19, 2008, patients with acute ischaemic stroke or transient ischaemic attack who had symptomatic large artery stenosis in the cerebral or carotid arteries and in whom microembolic signals were present on transcranial doppler were randomly assigned within 7 days of symptom onset to receive clopidogrel (300 mg for the first day, then 75 mg daily) plus aspirin (75–160 mg daily) or aspirin alone (75–160 mg daily) for 7 days. Patients were randomly assigned in blocks of four or six by use of a randomisation website. Monitoring of microembolic signals on transcranial doppler was done on days 2 and 7. The primary endpoint was the proportion of patients who had microembolic signals on day 2. Analysis was by modified intention to treat. All analyses were done by an investigator masked to both patient identity and the day the recording was taken. This trial is registered with the Centre for Clinical Trials, Chinese University of Hong Kong, number CUHK_CCT00164. Findings 100 patients were randomly assigned to clopidogrel plus aspirin (n=47) or aspirin monotherapy (n=53). 93 of 100 patients had symptomatic intracranial stenosis in either the intracranial internal carotid artery or the middle cerebral artery: 45 of 46 in the dual therapy group and 48 of 52 in the monotherapy group. At day 2, 14 of 45 patients in the dual therapy group and 27 of 50 patients in the monotherapy group for whom data were available had at least one microembolic signal on transcranial doppler (relative risk reduction 42·4%, 95% CI 4·6–65·2; p=0·025). Adverse events were similar in the two groups. No patients had intracranial or severe systemic haemorrhage, but two patients in the dual therapy group had minor haemorrhages. Interpretation Combination therapy with clopidogrel and aspirin is more effective than aspirin alone in reducing microembolic signals in patients with predominantly intracranial symptomatic stenosis. Clinical trials are now warranted to investigate whether this combination treatment also results in a reduction in stroke incidence. Funding Research Grant Council Earmarked Grant and Asian Stroke Research Grant, Chinese University of Hong Kong.

The spread of artemisinin-resistant Plasmodium falciparum in the Greater Mekong subregion: a molecular epidemiology observational study

Abstract: Summary Background Evidence suggests that the PfKelch13 mutations that confer artemisinin resistance in falciparum malaria have multiple independent origins across the Greater Mekong subregion, which has motivated a regional malaria elimination agenda. We aimed to use molecular genotyping to assess antimalarial drug resistance selection and spread in the Greater Mekong subregion. Methods In this observational study, we tested Plasmodium falciparum isolates from Myanmar, northeastern Thailand, southern Laos, and western Cambodia for PfKelch13 mutations and for Pfplasmepsin2 gene amplification (indicating piperaquine resistance). We collected blood spots from patients with microscopy or rapid test confirmed uncomplicated falciparum malaria. We used microsatellite genotyping to assess genetic relatedness. Findings As part of studies on the epidemiology of artemisinin-resistant malaria between Jan 1, 2008, and Dec 31, 2015, we collected 434 isolates. In 2014–15, a single long PfKelch13 C580Y haplotype (−50 to +31·5 kb) lineage, which emerged in western Cambodia in 2008, was detected in 65 of 88 isolates from northeastern Thailand, 86 of 111 isolates from southern Laos, and 14 of 14 isolates from western Cambodia, signifying a hard transnational selective sweep. Pfplasmepsin2 amplification occurred only within this lineage, and by 2015 these closely related parasites were found in ten of the 14 isolates from Cambodia and 15 of 15 isolates from northeastern Thailand. C580Y mutated parasites from Myanmar had a different genetic origin. Interpretation Our results suggest that the dominant artemisinin-resistant P falciparum C580Y lineage probably arose in western Cambodia and then spread to Thailand and Laos, outcompeting other parasites and acquiring piperaquine resistance. The emergence and spread of fit artemisinin-resistant P falciparum parasite lineages, which then acquire partner drug resistance across the Greater Mekong subregion, threatens regional malaria control and elimination goals. Elimination of falciparum malaria from this region should be accelerated while available antimalarial drugs still remain effective. Funding The Wellcome Trust and the Bill and Melinda Gates Foundation.

Vaccine-induced plasma IgA specific for the C1 region of the HIV-1 envelope blocks binding and effector function of IgG

Abstract: Analysis of correlates of risk of infection in the RV144 HIV-1 vaccine efficacy trial demonstrated that plasma IgG against the HIV-1 envelope (Env) variable region 1 and 2 inversely correlated with risk, whereas HIV-1 Env-specific plasma IgA responses directly correlated with risk. In the secondary analysis, antibody-dependent cellular cytotoxicity (ADCC) was another inverse correlate of risk, but only in the presence of low plasma IgA Env-specific antibodies. Thus, we investigated the hypothesis that IgA could attenuate the protective effect of IgG responses through competition for the same Env binding sites. We report that Env-specific plasma IgA/IgG ratios are higher in infected than in uninfected vaccine recipients in RV144. Moreover, Env-specific IgA antibodies from RV144 vaccinees blocked the binding of ADCC-mediating mAb to HIV-1 Env glycoprotein 120 (gp120). An Env-specific monomeric IgA mAb isolated from an RV144 vaccinee also inhibited the ability of natural killer cells to kill HIV-1-infected CD4(+) T cells coated with RV144-induced IgG antibodies. We show that monomeric Env-specific IgA, as part of postvaccination polyclonal antibody response, may modulate vaccine-induced immunity by diminishing ADCC effector function.

Microarrays Reveal that Each of the Ten Dominant Lineages of Staphylococcus aureus Has a Unique Combination of Surface-Associated and Regulatory Genes

Abstract: Staphylococcus aureus is a persistent resident of the human nose in 20% of the population and intermittently carried by another 60% (16). Most carriers harbor a single strain (2). S. aureus is a common cause of minor skin and wound infections, but only rarely causes severe community-acquired invasive infections such as bacteremia, endocarditis, and osteomyelitis. In contrast, S. aureus is the most common cause of hospital-acquired infection, which often occurs in association with breaches of the skin and mucous membranes in the immunocompromised host (14). Hundreds of S. aureus virulence factors and putative virulence genes have been described, including those involved in adherence to human tissue, evasion of the immune response, toxin secretion, and regulation of virulence gene expression (29). Specific toxins have also been described that play a pivotal role in toxin-mediated disease such as toxic shock syndrome (toxic shock syndrome toxin-1, encoded by tst; enterotoxins B and C, encoded by seb, sec) (5), scalded skin syndrome (exfoliative toxins A and B, encoded by eta, etb) (19), food poisoning (enterotoxin A, encoded by sea) (5), and more recently hemolytic pneumonia and skin and soft tissue infection (Panton Valentine leukocidin [PVL], encoded by the lukS-PV and lukF-PV genes) (20). Many of these genes are variably present as a result of being carried on mobile genetic elements (MGE) (22). However, critical to the development of targeted or preventive strategies is the elucidation of which if any of these genes are important in invasive infection. An important isolate collection associated with community-acquired invasive disease or carriage by healthy donors in the Oxford, United Kingdom, region (7) has been examined using multilocus sequence typing (MLST) (6), in which fragments of seven housekeeping genes were amplified and sequenced. Unique alleles at the seven loci were given an allelic number, and the allelic profile (string of seven integers) was used to define sequence type (ST) for each isolate. Isolates with an identical profile were considered to be clonal, and those with at least five of seven matching genes were considered to belong to the same clonal cluster (CC). Isolates clustered into 10 major CCs, none of which were associated with invasive disease (7). This argued against the presence of virulent genotypes but did not exclude the possibility that one or more variable genes were overrepresented in the invasive-isolate group. This possibility was examined during a study that defined the presence or absence of 33 putative virulence genes in this isolate collection using PCR (27). Seven genes were found to be present more commonly in invasive isolates, including eta and those encoding fibronectin binding protein A (fnbA), collagen binding protein (cna), serine-aspartate repeat containing protein E (sdrE), staphylococcal enterotoxin J (sej), gamma-hemolysin (hlg), and intracellular adhesin (ica). This suggested there were differences between isolates that did not correlate with lineage. It also suggested that some isolates are potentially more virulent than others. Each S. aureus isolate is thought to carry hundreds of variable genes including many putative virulence determinants. The first S. aureus comparative-genomics studies using a microarray (covering 92% of the genes found in the S. aureus COL genome) estimated that 22% of the S. aureus genome was variable (8). Many of the variable genes are known or putative virulence and resistance genes carried on MGE, and these elements are likely to transfer horizontally among staphylococci (see reference 22 for a review). The accumulation of such MGE may result in the emergence of “superbugs” that are increasingly resistant and virulent (22). The whole-genome sequencing of seven isolates of S. aureus (1, 10, 12, 18; www.genome.ou.edu/staph.html) has allowed us to design, print, and validate a multistrain PCR product S. aureus microarray carrying PCR products for every gene identified from these projects, probably the most comprehensive microarray of its kind (33). Here we describe the use of the seven-strain S. aureus microarray to investigate the Oxford collection of community-acquired S. aureus isolates. The aims were to identify which regions of the S. aureus genome vary, investigate gene distribution in a typical S. aureus population, and perform a comprehensive search for differences between invasive and carriage isolates.