Precision Medicine for Sepsis Management in Low- and Middle-Income Countries - Melioidosis as a Model?

Advances in translational critical care has revealed limitations in the current clinical management of critical illness which is syndrome based (1). Studies evaluating the host response using immunoassays, multi-omics platforms and bioinformatics analysis have identified heterogenous subgroups (subphenotypes) as well as distinct pathogenic features (endotypes) among patients diagnosed with sepsis (2, 3). This has led to the aim of utilizing a precision medicine approach where targeted therapeutic management is based on utilization of assays to identify subphenotypes or clinical correlates of endotypes. This approach has been used in oncology with significant improvement in outcomes by targeting the underlying biological mechanism in individual patients (1)

Avian Influenza (H7N9) Virus Infection in Chinese Tourist in Malaysia, 2014

Of the ≈400 cases of avian influenza (H7N9) diagnosed in China since 2003, the only travel-related cases have been in Hong Kong and Taiwan. Detection of a case in a Chinese tourist in Sabah, Malaysia, highlights the ease with which emerging viral respiratory infections can travel globally

Antimicrobial Resistance in the Asia Pacific region: a meeting report.

The Asia Pacific region, home to two-thirds of the world's population and ten of the least developed countries, is considered a regional hot-spot for the emergence and spread of antimicrobial resistance (AMR). Despite this, there is a dearth of high-quality regional data on the extent of AMR. Recognising the urgency to close this gap, Singapore organised a meeting to discuss the problems in the region and frame a call for action. Representatives from across the region and beyond attended the meeting on the "Antimicrobial Resistance in the Asia Pacific & its impact on Singapore" held in November 2018. This meeting report is a summary of the discussions on the challenges and progress in surveillance, drivers and levers of AMR emergence, and the promising innovations and technologies that could be used to combat the increasing threat of AMR in the region. Enhanced surveillance and research to provide improved evidence-based strategies and policies are needed. The major themes that emerged for an action plan are working towards a tailored solution for the region by harnessing the One Health approach, enhancing inter-country collaborations, and collaboratively leverage upon new emerging technologies. A regionally coordinated effort that is target-driven, sustainable and builds on a framework facilitating communication and governance will strengthen the fight against AMR in the Asia Pacific region

A Prospective Study of Tuberculosis Drug Susceptibility in Sabah, Malaysia, and an Algorithm for Management of Isoniazid Resistance

Introduction. The burden of tuberculosis is high in eastern Malaysia, and rates of Mycobacterium tuberculosis drug resistance are poorly defined. Our objectives were to determine M. tuberculosis susceptibility and document management after receipt of susceptibility results. Methods. Prospective study of adult outpatients with smear-positive pulmonary tuberculosis (PTB) in Sabah, Malaysia. Additionally, hospital clinicians accessed the reference laboratory for clinical purposes during the study. Results. 176 outpatients were enrolled; 173 provided sputum samples. Mycobacterial culture yielded M. tuberculosis in 159 (91.9%) and nontuberculous Mycobacterium (NTM) in three (1.7%). Among outpatients there were no instances of multidrug resistant M. tuberculosis (MDR-TB). Seven people (4.5%) had isoniazid resistance (INH-R); all were switched to an appropriate second-line regimen for varying durations (4.5-9 months). Median delay to commencement of the second-line regimen was 13 weeks. Among 15 inpatients with suspected TB, 2 had multidrug resistant TB (one extensively drug resistant), 2 had INH-R, and 4 had NTM. Conclusions. Current community rates of MDR-TB in Sabah are low. However, INH-resistance poses challenges, and NTM is an important differential diagnosis in this setting, where smear microscopy is the usual diagnostic modality. To address INH-R management issues in our setting, we propose an algorithm for the treatment of isoniazid-resistant PTB

Genetic polymorphism and natural selection in the C-terminal 42 kDa region of merozoite surface protein-1 (MSP-1) among Plasmodium knowlesi samples from Malaysia

Background: The merozoite surface protein-1 (MSP-1) gene encodes for a leading malaria vaccine candidate antigen. However, its extensive polymorphic nature represents a major obstacle to the development of a protective vaccine. Previously, a pilot study was carried out to explore the sequence variation of the C-terminal 42 kDa fragment within P. knowlesi MSP-1 gene (PkMSP-142) based on 12 clinical samples; however, further study on an adequate sample size is vital in estimating the genetic diversity of the parasite population. Methods: In the present study, we included a larger sample size of P. knowlesi (83 samples) covering eight states of Malaysia to determine the genetic polymorphism, natural selection and haplotype groups of the gene fragment coding PkMSP-142. The region flanking PkMSP-142 was amplified by PCR and directly sequenced. Genetic diversity, haplotype diversity, population genetic differentiation and natural selection were determined in order to study the polymorphic characteristic of PkMSP-142. Results: A high level of genetic diversity (Hd = 0.970 ± 0.007; л = 0.01079 ± 0.00033) was observed among the 83 P. knowlesi samples, confirming the extensive genetic polymorphism exhibited among the P. knowlesi population found in Malaysia. A total of 18 distinct haplotypes with 17 amino acid changes were identified, whereby 15 were new haplotypes. High population differentiation values were observed within samples from Peninsular Malaysia and Malaysian Borneo. The 42 kDa fragments of P. knowlesi from Malaysian Borneo were found to be acting on balancing selection whilst purifying selection was suggested to act on isolates from Peninsular Malaysia. The separation of PkMSP-142 haplotypes into two main groups based on geographical separation has further supported the existence of two distinct P. knowlesi lineages. Conclusions: A high level of genetic diversity was observed among PkMSP-142 in Malaysia, whereby most of the polymorphisms were found within the 33 kDa region. Taken together, these data will be useful in order to understand the nature of P. knowlesi population in Malaysia as well as the design and development of a MSP-142 based knowlesi malaria vaccin

Whole genome sequencing of amplified Plasmodium knowlesi DNA from unprocessed blood reveals genetic exchange events between Malaysian Peninsular and Borneo subpopulations.

The zoonotic Plasmodium knowlesi parasite is the most common cause of human malaria in Malaysia. Genetic analysis has shown that the parasites are divided into three subpopulations according to their geographic origin (Peninsular or Borneo) and, in Borneo, their macaque host (Macaca fascicularis or M. nemestrina). Whilst evidence suggests that genetic exchange events have occurred between the two Borneo subpopulations, the picture is unclear in less studied Peninsular strains. One difficulty is that P. knowlesi infected individuals tend to present with low parasitaemia leading to samples with insufficient DNA for whole genome sequencing. Here, using a parasite selective whole genome amplification approach on unprocessed blood samples, we were able to analyse recent genomes sourced from both Peninsular Malaysia and Borneo. The analysis provides evidence that recombination events are present in the Peninsular Malaysia parasite subpopulation, which have acquired fragments of the M. nemestrina associated subpopulation genotype, including the DBPβ and NBPXa erythrocyte invasion genes. The NBPXb invasion gene has also been exchanged within the macaque host-associated subpopulations of Malaysian Borneo. Our work provides strong evidence that exchange events are far more ubiquitous than expected and should be taken into consideration when studying the highly complex P. knowlesi population structure

Malaria in 2018 : looking to the past and moving into the future

World Malaria Day is observed and commemorated annually on 25 April in recognition of the ongoing global burden and the efforts to control it. Malaria is caused by Plasmodium parasites, of which 5 species are known to cause disease in humans, namely P. falciparum, P. vivax, P. ovale, P. malariae and P. knowlesi. It is a vector borne disease and is transmitted by Anopheles mosquitoes. Although potentially life threatening, prognosis is excellent if the disease is diagnosed early, and treated promptly with effective antimalarials.Published versio

Insights into potential causes of vascular hyperpermeability in dengue

Dengue is a mosquito-borne disease caused by dengue virus (DENV), where four serotypes can infect humans. Most DENV infections are self-resolving, but in some individuals, severe dengue characterised by a sudden increase in haematocrit, rapid decrease in platelet counts, and vascular leakage is a complication [1,2]. In severe dengue, a major pathogenic mechanism is a transient increase in vascular permeability resulting in severe plasma leakage (herein referred to vascular hyperpermeability) leading to hypotension, circulatory collapse, and organ dysfunction [1]. The precise mechanism in DENV-associated vascular hyperpermeability is unclear, and several hypotheses including antibody-dependent enhancement (ADE) and “cytokine storm” have been proposed. In ADE, suboptimal DENV neutralising antibodies against a heterologous serotype (in secondary infection) promotes DENV uptake into immunological cells, increasing infection and viral replication that can exacerbate the immune response [3]. Similarly, infected monocytes release excessive amounts of proinflammatory cytokines and, if dysregulated, can lead to “cytokine storm” [4]. In this article, we present current understandings on the potential causes of dengue-associated vascular hyperpermeability, which is a consequence of complex interactions between the virus and the host endothelium immune response.Nanyang Technological UniversityNational Medical Research Council (NMRC)Published versionAT is supported by Nanyang Technological University Research Scholarship Block Fellowship of Singapore and Lee Kong Chian School of Medicine, Singapore, Start-up grant. CLLC receives support from Ministry of Education (MOE) Fundamental Research Grant Scheme of Malaysia: ID FRGS/1/2020/SKK0/TAYLOR/02/1. PYC is supported by NMRC Research Training Fellowship (NMRC/Fellowship/0056/2018). TWY is supported by Lee Kong Chian School of Medicine Singapore, Start-up grant