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News Article | May 9, 2017
Site: www.eurekalert.org

Researchers have identified a metabolite 'signature' that can accurately distinguish typhoid from other fever-inducing tropical diseases using patient blood samples. The research, published in the journal eLife, builds on previous results from 2014 showing that metabolite markers can distinguish between typhoid infection caused by different organisms. Many tropical diseases, such as typhoid and malaria, present with similar symptoms, making accurate diagnosis challenging and delaying effective treatment. A further problem with diagnosing typhoid is that currently available tests are not sensitive enough, and some patients are later found to have the disease, even though an organism cannot be cultured from their blood. The researchers used an approach called 'metabolomics', which involves measuring many small metabolites in a biological sample, to try and identify patterns that are unique to different diseases. In a previous study, they used this method to identify metabolic 'signatures' that could successfully differentiate between typhoid caused by two closely related organisms -- Salmonella Typhi and Salmonella Paratyphi A. "We wanted to assess if metabolomics could accurately diagnose typhoid in patients from different regions with a wider range of tropical diseases," says senior author Professor Stephen Baker, molecular microbiologist at Oxford University Clinical Research Unit, Vietnam. "We thought that this approach would more closely reflect the real situation where patients with fever-inducing diseases present with non-specific symptoms." Baker and his research collaborators collected blood samples from multiple patients from Bangladesh, who fell into three groups: patients who had Salmonella Typhi in their blood, those who were suspected of having typhoid from their symptoms, and a third group who were suspected of having a different tropical disease characterised by fever (a 'fever-control' group). Using mass spectrometry, the team analysed the metabolites in each patient blood sample to generate a metabolic 'signature' for two patient groups: those whose blood tested positive for typhoid, and fever controls. They then used this as a model to predict the identity of individual samples in a third group: patients suspected of having typhoid from their symptoms. They found that the model had excellent predictive power for distinguishing between culture-positive typhoid patients and patients with other types of tropical disease. "A major challenge in typhoid diagnosis is diagnosing true typhoid patients who have a negative blood culture result," explains first author Elin Näsström, a graduate student at Umeå University, Sweden. "We wanted to see if the detected metabolomics could help further distinguish these groups." As hoped, their predictive model pinpointed five out of nine blood-test-negative samples that were actually typhoid positive. And three out of five patients who were suspected of typhoid from their symptoms were also indicated to be typhoid-positive by their metabolite signature. To validate the signature further, the team studied an additional collection of blood samples from patients in Bangladesh and Senegal. They then compared these profiles against the original data from Nepal patients, published in the 2014 study by Näsström et al. From these combined analyses, they identified 24 metabolites that were consistently different between patients who had typhoid, and those who had other diseases including malaria. "Our results demonstrated a metabolite panel that can distinguish typhoid from other fever-inducing diseases, providing a new approach for typhoid diagnostics," Baker concludes. "The next challenges are to corroborate these metabolites in larger patient numbers and try and incorporate them into simple diagnostic test formats. This approach could be potentially expanded into other tropical diseases, eventually allowing for more accurate diagnosis and more effective treatment, and hopefully reducing the use of unnecessary antimicrobials." The paper, 'Reproducible diagnostic metabolites in plasma from typhoid fever patients in Asia and Africa', can be freely accessed online at http://dx. . It builds upon the previous study, 'Salmonella Typhi and Salmonella Paratyphi A elaborate distinct systemic metabolite signatures during enteric fever', which can be freely accessed at http://dx. . Contents, including text, figures and data, are free to reuse under a CC BY 4.0 license. eLife is a unique collaboration between the funders and practitioners of research to improve the way important research is selected, presented, and shared. eLife publishes outstanding works across the life sciences and biomedicine -- from basic biological research to applied, translational, and clinical studies. All papers are selected by active scientists in the research community. Decisions and responses are agreed by the reviewers and consolidated by the Reviewing Editor into a single, clear set of instructions for authors, removing the need for laborious cycles of revision and allowing authors to publish their findings quickly. eLife is supported by the Howard Hughes Medical Institute, the Max Planck Society, and the Wellcome Trust. Learn more at elifesciences.org. The Oxford University Clinical Research Unit (OUCRU) is a large-scale clinical and public health research unit with campuses in Ho Chi Minh City and Hanoi in Vietnam. OUCRU is hosted by the Hospital of Tropical Diseases (HTD) in Ho Chi Minh City, and the National Hospital for Tropical Diseases (NHTD) in Hanoi. As a Wellcome Trust Major Overseas Programme, OUCRU has received considerable support from the Trust since its establishment in 1991. The work of the unit covers clinical and public health research and includes work in immunology, host and pathogen genetics, molecular biology, virology, mathematical modelling, bioinformatics, biostatistics and epidemiology. Overall, OUCRU aims to have a positive and significant impact on global health and, in particular, the prevention, diagnosis and treatment of infectious diseases. This is being achieved via an integrated long-term research programme, contributions to training, the scientific literature, national and international meetings and membership of national and international committees. Priority is given to health issues important to the hospitals, and to Vietnam as a whole. All work is intended not only to benefit the patients seen daily at our host hospitals, but also to help improve patient care throughout the country. http://www.


Duong A.T.,Ministry of Health | Kato M.,World Health Organization | Bales S.,National University of Singapore | Do N.T.,Ministry of Health | And 3 more authors.
Journal of Acquired Immune Deficiency Syndromes | Year: 2014

Background: Vietnam achieved rapid scale-up of antiretroviral therapy (ART), although external funds are declining sharply. To achieve and sustain universal access to HIV services, evidence-based planning is essential. To date, there had been limited HIV treatment and care cost data available in Vietnam. Methods: Cost data of outpatient and inpatient HIV care were extracted at 21 sentinel facilities (17 adult and 4 pediatric) that epitomize the national program. Step-down costing for administration costs and bottom-up resource costing for drugs, diagnostics, and labor were used. Records of 1401 adults and 527 pediatric patients were reviewed. Results: Median outpatient care costs per patient-year for pre-ART, first year ART, later year ART, and second-line ART were US 100, US 316, US 303, and US 1557 for adults; and US 171, US 387, US 320, and US 1069 for children, respectively. Median inpatient care cost per episode was US 162 for adults and US 142 for children. Non-antiretroviral (ARV) costs in adults at stand-alone facilities were 44% (first year ART) and 24% (later year ART) higher than those at integrated facilities. Adults who started ART with CD4 count #100 cells per cubic millimeter had 47% higher non-ARV costs in the first year ART than those with CD4 count .100 cells per cubic millimeter. Adult ARV drug costs at government sites were from 66% to 85% higher than those at donor-supported sites in the first year ART. Conclusions: The study found that HIV treatment and care costs in Vietnam are economical, yet there is potential to further promote efficiency through strengthening competitive procurement, integrating HIV services, and promoting earlier ART initiation. Copyright © 2013 by Lippincott Williams & Wilkins.


Gong M.M.,King's College | Macdonald B.D.,University of Ontario Institute of Technology | Nguyen T.V.,Hanoi Medical University | Van Nguyen K.,National Hospital for Tropical Diseases | Sinton D.,King's College
Lab on a Chip - Miniaturisation for Chemistry and Biology | Year: 2014

We present a low cost, simple and integrated device for medical diagnostics in low-resource settings called the lab-in-a-pen. Finger pricking, and sample collection and processing, are integrated with commercially available paper-based assays in a pen format. This approach ensures safety (i.e. biological sample and sharps containment) and can be used by untrained end users across multiple settings. The pen format also leverages existing low cost, high volume manufacturing and assembly methods. We characterize sample wicking in the lab-in-a-pen using porcine whole blood. The clinical diagnostic utility and usability of the lab-in-a-pen is established by testing of patients for Hepatitis B surface antigen (HBsAg) and Hepatitis B 'e' antigen (HBeAg) by medical staff at the National Hospital for Tropical Diseases in Hanoi, Vietnam. This journal is © The Royal Society of Chemistry 2014.


Gong M.M.,King's College | MacDonald B.D.,University of Ontario Institute of Technology | Vu Nguyen T.,Hanoi Medical University | Van Nguyen K.,National Hospital for Tropical Diseases | Sinton D.,King's College
Biomicrofluidics | Year: 2013

In this paper, we present a low cost and equipment-free blood filtration device capable of producing plasma from blood samples with mL-scale capacity and demonstrate its clinical application for hepatitis B diagnosis. We report the results of in-field testing of the device with 0.8-1 ml of undiluted, anticoagulated human whole blood samples from patients at the National Hospital for Tropical Diseases in Hanoi, Vietnam. Blood cell counts demonstrate that the device is capable of filtering out 99.9% of red and 96.9% of white blood cells, and the plasma collected from the device contains lower red blood cell counts than plasma obtained from a centrifuge. Biochemistry and immunology testing establish the suitability of the device as a sample preparation unit for testing alanine transaminase (ALT), aspartate transaminase (AST), urea, hepatitis B "e" antigen (HBeAg), hepatitis B "e" antibody (HBe Ab), and hepatitis B surface antibody (HBs Ab). The device provides a simple and practical front-end sample processing method for point-of-care microfluidic diagnostics, enabling sufficient volumes for multiplexed downstream tests. © 2013 AIP Publishing LLC.


Henk D.A.,Imperial College London | Shahar-Golan R.,Imperial College London | Devi K.R.,Regional Institute of Medical science | Boyce K.J.,University of Melbourne | And 14 more authors.
PLoS Pathogens | Year: 2012

Molecular genetic approaches typically detect recombination in microbes regardless of assumed asexuality. However, genetic data have shown the AIDS-associated pathogen Penicillium marneffei to have extensive spatial genetic structure at local and regional scales, and although there has been some genetic evidence that a sexual cycle is possible, this haploid fungus is thought to be genetically, as well as morphologically, asexual in nature because of its highly clonal population structure. Here we use comparative genomics, experimental mixed-genotype infections, and population genetic data to elucidate the role of recombination in natural populations of P. marneffei. Genome wide comparisons reveal that all the genes required for meiosis are present in P. marneffei, mating type genes are arranged in a similar manner to that found in other heterothallic fungi, and there is evidence of a putatively meiosis-specific mutational process. Experiments suggest that recombination between isolates of compatible mating types may occur during mammal infection. Population genetic data from 34 isolates from bamboo rats in India, Thailand and Vietnam, and 273 isolates from humans in China, India, Thailand, and Vietnam show that recombination is most likely to occur across spatially and genetically limited distances in natural populations resulting in highly clonal population structure yet sexually reproducing populations. Predicted distributions of three different spatial genetic clusters within P. marneffei overlap with three different bamboo rat host distributions suggesting that recombination within hosts may act to maintain population barriers within P. marneffei. © 2012 Henk et al.


Dunne M.P.,Queensland University of Technology | Kato M.,World Health Organization | Nguyen K.V.,National Hospital for Tropical Diseases
BMC Infectious Diseases | Year: 2013

Background: Optimal adherence to antiretroviral therapy (ART) is necessary for people living with HIV/AIDS (PLHIV). There have been relatively few systematic analyses of factors that promote or inhibit adherence to antiretroviral therapy among PLHIV in Asia. This study assessed ART adherence and examined factors associated with suboptimal adherence in northern Viet Nam.Methods: Data from 615 PLHIV on ART in two urban and three rural outpatient clinics were collected by medical record extraction and from patient interviews using audio computer-assisted self-interview (ACASI).Results: The prevalence of suboptimal adherence was estimated to be 24.9% via a visual analogue scale (VAS) of past-month dose-missing and 29.1% using a modified Adult AIDS Clinical Trial Group scale for on-time dose-taking in the past 4 days. Factors significantly associated with the more conservative VAS score were: depression (p < 0.001), side-effect experiences (p < 0.001), heavy alcohol use (p = 0.001), chance health locus of control (p = 0.003), low perceived quality of information from care providers (p = 0.04) and low social connectedness (p = 0.03). Illicit drug use alone was not significantly associated with suboptimal adherence, but interacted with heavy alcohol use to reduce adherence (p < 0.001).Conclusions: This is the largest survey of ART adherence yet reported from Asia and the first in a developing country to use the ACASI method in this context. The evidence strongly indicates that ART services in Viet Nam should include screening and treatment for depression, linkage with alcohol and/or drug dependence treatment, and counselling to address the belief that chance or luck determines health outcomes. © 2013 Do et al.; licensee BioMed Central Ltd.


Mustafa M.,Hospital Raja Perempuan Zainab II | Chan W.M.,University of Hong Kong | Lee C.,Hospital Sungai Buloh | Harijanto E.,Dr Cipto Mangunkusumo Hospital | And 4 more authors.
International Journal of Antimicrobial Agents | Year: 2014

Doripenem is approved in the Asia-Pacific (APAC) region for treating nosocomial pneumonia (NP) including ventilator-associated pneumonia (VAP), complicated intra-abdominal infections (cIAIs) and complicated urinary tract infections (cUTIs). Clinical usage of doripenem (500 mg intravenously, infused over 1 h or 4 h every 8 h for 5-14 days) in APAC was evaluated in a prospective, open-label, non-comparative, multicentre study of inpatients (=18 years) with NP, VAP, cIAI or cUTI. A total of 216 [intention-to-treat (ITT)] patients received doripenem: 53 NP (24.5%); 77 VAP (35.6%); 67 cIAI (31.0%); and 19 cUTI (8.8%). Doripenem MIC90 values for Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli and Klebsiella pneumoniae were 32, 32, 0.094 and 0.64 μg/mL, respectively. Doripenem was used most commonly as monotherapy (86.6%) and as second-line therapy (62.0%). The clinical cure rate in clinically evaluable patients was 86.7% at the end of therapy (EOT) and 87.1% at test of cure (TOC) (7-14 days after EOT). In the ITT population, overall clinical cure rates were 66.2% at EOT and 56.5% at TOC. The median duration of hospital stay, intensive care unit (ICU) stay and mechanical ventilation was 20, 12 and 10 days, respectively. Of 146 discharged patients, 7 were re-admitted within 28 days of EOT; 1 VAP patient was re-admitted to the ICU. The all-cause mortality rate was 22.7% (49/216). The most common treatment-related adverse events were diarrhoea (1.4%) and vomiting (1.4%). Doripenem is a viable option for treating APAC patients with NP, VAP, cIAI or cUTI. [ClinicalTrials.gov: NCT 00986102]. © 2014 Elsevier B.V. and the International Society of Chemotherapy.


Wyres K.L.,IBM | Wyres K.L.,University of Melbourne | Gorrie C.,University of Melbourne | Edwards D.J.,University of Melbourne | And 8 more authors.
Genome Biology and Evolution | Year: 2015

Klebsiella pneumoniae clonal group (CG) 258, comprising sequence types (STs) 258, 11, and closely related variants, is associated with dissemination of the K.pneumoniae carbapenemase (KPC). Hospitaloutbreaks of KPC CG258infections have been observed globally and are very difficult to treat. As a consequence, there is renewed interest in alternative infection control measures such as vaccines and phage or depolymerase treatments targeting the K. pneumoniae polysaccharide capsule. To date, 78 immunologically distinct capsule variants have been described in K. pneumoniae. Previous investigations of ST258 and a small number of closely related strains suggested that capsular variation was limited within this clone; only two distinct ST258 capsule polysaccharide synthesis (cps) loci have been identified, both acquired through large-scale recombination events (>50 kb). In contrast to previous studies, we report a comparative genomic analysis of the broader K. pneumoniae CG258 (n= 39). We identified 11 different cps loci within CG258, indicating that capsular switching is actually common within the complex. We observed several insertion sequences (IS) within the cps loci, and show further intraclone diversification of two cps loci through IS activity. Our data also indicate that several large-scale recombination events have shaped the genomes of CG258, and that definition of thecomplex shouldbe broadened to include ST395 (also reported to harbor KPC). As only the second report of extensive intraclonal cps variation among Gram-negative bacterial species, our findings alter our understanding of the evolution of these organisms and have key implications for the design of control measures targeting K. pneumoniae capsules. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.


Peto L.,University of Oxford | Nadjm B.,University of Oxford | Horby P.,University of Oxford | Ngan T.T.D.,National Hospital for Tropical Diseases | And 3 more authors.
Transactions of the Royal Society of Tropical Medicine and Hygiene | Year: 2014

Background: Community-acquired pneumonia (CAP) is a major cause of adult mortality in Asia. Appropriate empirical treatment depends on knowledge of the pathogens commonly responsible. However, assessing the aetiological significance of identified organisms is often difficult, particularly with sputum isolates that might represent contamination with oropharyngeal flora. Methods: A systematic review of all adult CAP aetiology studies from Asia, excluding the Middle East, published in English between 1 January 1990 and 1 March 2012 was conducted. Forty-eight studies reporting on 10 423 patients were included, representing data from China, India, Indonesia, Japan, Malaysia, The Philippines, Singapore, South Korea, Taiwan, Thailand and Vietnam. Data from large parts of Asia were unavailable and there was substantial heterogeneity in methodology. Results: As in western studies, Streptococcus pneumoniae, Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella spp. and Haemophilus influenzae were all significant pathogens. However, compared with western studies, S. pneumoniaewas of less relative importance. Gram-negative bacilli and Mycobacterium tuberculosis were more important, and in northeast Thailand Burkholderia pseudomallei was a major pathogen. Conclusion: These data have major implications for diagnostic strategies and empirical treatment. Narrow-spectrum antibiotics targeting S. pneumoniae may be inappropriate in many Asian settings, and agents active against TB may lead to partial response and delayed TB diagnosis.


Huong V.T.L.,University of Oxford | Hoa N.T.,University of Oxford | Horby P.,University of Oxford | Bryant J.E.,University of Oxford | And 3 more authors.
Emerging Infectious Diseases | Year: 2014

We assessed consumption of raw pig blood, which is a risk factor for Streptococcus suis infection in Vietnam, by using a mix-method design. Factors associated with consumption included rural residency, age, sex, occupation, income, and marital status. We identified risk groups and practices and perceptions that should be targeted by communication programs. © 2014, Centers for Disease Control and Prevention (CDC). All Rights Reserved.

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