Publications by authors named "Joon Wah Mak"

45 Publications

Loop-mediated isothermal amplification (LAMP) test for diagnosis of uncomplicated malaria in endemic areas: a meta-analysis of diagnostic test accuracy.

Malar J 2020 Jun 19;19(1):211. Epub 2020 Jun 19.

Institute for Research, Development and Innovation (IRDI), International Medical University, Kuala Lumpur, Malaysia.

Background: The global malaria decline has stalled and only a few countries are pushing towards pre-elimination. The aim of the malaria elimination phase is interruption of local transmission of a specified malaria parasite in a defined geographical area. New and improved screening tools and strategies are required for detection and management of very low-density parasitaemia in the field. The objective of this study was to synthesize evidence on the diagnostic accuracy of loop-mediated isothermal amplification (LAMP) test for the detection of malaria parasites among people living in endemic areas.

Methods: This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis for Diagnostic Test Accuracy (PRISMA-DTA) guideline. Relevant studies in the health-related electronic databases were searched. According to the criteria set for this study, eligible studies were identified. The quality of included studies was evaluated with the use of a quality assessment checklist. A summary performance estimates such as pooled sensitivity and specificity were stratified by type of LAMP. Bivariate model for data analyses was applied. Summary receiver operating characteristics plots were created to display the results of individual studies in a receiver operating characteristics space. Meta-regression analysis was performed to investigate the sources of heterogeneity among individual studies.

Results: Twenty-seven studies across 17 endemic countries were identified. The vast majority of studies were with unclear risk of bias in the selection of index test. Overall, the pooled test performances were high for Pan LAMP (sensitivity: 0.95, 95% CI 0.91 to 0.97; specificity: 0.98, 95% CI 0.95 to 0.99), Plasmodium falciparum (Pf) LAMP (sensitivity: 0.96, 95% CI 0.94 to 0.98; specificity: 0.99, 95% CI 0.96 to 1.00) or for Plasmodium vivax (Pv) LAMP from 6 studies (sensitivity: 0.98, 95% CI 0.92 to 0.99; specificity: 0.99, 95% CI 0.72 to 1.00). The area under the curve for Pan LAMP (0.99, 95% CI 0.98-1.00), Pf LAMP (0.99, 95% CI 0.97-0.99) and Pv LAMP was (1.00, 95% CI 0.98-1.00) indicated that the diagnostic performance of these tests were within the excellent accuracy range. Meta-regression analysis showed that sample size had the greatest impact on test performance, among other factors.

Conclusions: The current findings suggest that LAMP-based assays are appropriate for detecting low-level malaria parasite infections in the field and would become valuable tools for malaria control and elimination programmes. Future well-designed larger sample studies on LAMP assessment in passive and active malaria surveillances that use PCR as the reference standard and provide sufficient data to construct 2 × 2 diagnostic table are needed.
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http://dx.doi.org/10.1186/s12936-020-03283-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305603PMC
June 2020

Association between long-term exposure to ambient air pollution and prevalence of diabetes mellitus among Malaysian adults.

Environ Health 2020 04 3;19(1):37. Epub 2020 Apr 3.

Department of Environment, Ministry of Energy, Technology, Science, Environment and Climate Change, 62662, Putrajaya, Malaysia.

Background: Malaysia has the highest rate of diabetes mellitus (DM) in the Southeast Asian region, and has ongoing air pollution and periodic haze exposure.

Methods: Diabetes data were derived from the Malaysian National Health and Morbidity Surveys conducted in 2006, 2011 and 2015. The air pollution data (NO, NO, SO, O and PM) were obtained from the Department of Environment Malaysia. Using multiple logistic and linear regression models, the association between long-term exposure to these pollutants and prevalence of diabetes among Malaysian adults was evaluated.

Results: The PM concentration decreased from 2006 to 2014, followed by an increase in 2015. Levels of NO decreased while O increased annually. The air pollutant levels based on individual modelled air pollution exposure as measured by the nearest monitoring station were higher than the annual averages of the five pollutants present in the ambient air. The prevalence of overall diabetes increased from 11.4% in 2006 to 21.2% in 2015. The prevalence of known diabetes, underdiagnosed diabetes, overweight and obesity also increased over these years. There were significant positive effect estimates of known diabetes at 1.125 (95% CI, 1.042, 1.213) for PM, 1.553 (95% CI, 1.328, 1.816) for O, 1.271 (95% CI, 1.088, 1.486) for SO, 1.124 (95% CI, 1.048, 1.207) for NO, and 1.087 (95% CI, 1.024, 1.153) for NO for NHMS 2006. The adjusted annual average levels of PM [1.187 (95% CI, 1.088, 1.294)], O [1.701 (95% CI, 1.387, 2.086)], NO [1.120 (95% CI, 1.026, 1.222)] and NO [1.110 (95% CI, 1.028, 1.199)] increased significantly from NHMS 2006 to NHMS 2011 for overall diabetes. This was followed by a significant decreasing trend from NHMS 2011 to 2015 [0.911 for NO, and 0.910 for NO].

Conclusion: The findings of this study suggest that long-term exposure to O is an important associated factor of underdiagnosed DM risk in Malaysia. PM, NO and NO may have mixed effect estimates towards the risk of DM, and their roles should be further investigated with other interaction models. Policy and intervention measures should be taken to reduce air pollution in Malaysia.
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http://dx.doi.org/10.1186/s12940-020-00579-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7119016PMC
April 2020

Efficacy of antimalarial drugs for treatment of uncomplicated falciparum malaria in Asian region: A network meta-analysis.

PLoS One 2019 19;14(12):e0225882. Epub 2019 Dec 19.

International Medical University, Kuala Lumpur, Malaysia.

Background: The WHO recommends artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated falciparum malaria. Hence, monitoring the efficacy of antimalarial drugs is a key component of malaria control and elimination. The published randomized trials that assessed comparisons of ACTs for treating uncomplicated falciparum malaria reported conflicting results in treatment efficacy. A network meta-analysis is an extension of pairwise meta-analysis that can synthesize evidence simultaneously from both direct and indirect treatment comparisons. The objective was to synthesize evidence on the comparative efficacy of antimalarial drugs for treatment of uncomplicated falciparum malaria in Asian region.

Methods: Relevant randomized trials that assessed efficacy of antimalarial drugs for patients having uncomplicated falciparum malaria in Asian region were searched in health-related databases. We evaluated the methodological quality of the included studies with the Cochrane risk of bias tool. Main outcome was treatment success at day 28 as determined by the absence of parasiteamia. We performed network meta-analysis of the interventions in the trials, and assessed the overall quality of evidence using the GRADE approach.

Results: Seventeen randomized trials (n = 5043) were included in this network meta-analysis study. A network geometry was formed with 14 antimalarial treatment options such as artemether-lumefantrine (AL), artemisinin-piperaquine, artesunate-amodiaquine, artesunate-mefloquine (ASMQ), artesunate-chloroquine, artesunate-mefloquine home treatment, artesunate-mefloquine 2-day course, artesunate plus sulfadoxine-pyrimethamine, chloroquine, dihydroartemisinin-piperaquine (DHP), dihydroartemisinin-piperaquine home treatment, dihydroartemisinin-piperaquine 4-day course, dihydroartemisinin-piperaquine and added artesunate, sulfadoxine-pyrimethamine. A maximum number of trials included was DHP compared to ASMQ (n = 5). In general, DHP had better efficacy than AL at day 28 (DHP vs AL: OR 2.5, 95%CI:1.08-5.8). There is low certainty evidence due to limited number of studies and small trials.

Discussion/ Conclusions: The findings suggest the superiority of DHP (3-day course) to AL and other comparator ACTs are with the overall low/very low quality of evidence judgements. Moreover, one drug regimen is better than another is only if current drug-resistance patterns are at play. For example, the AL might be better than DHP in areas where both artemisinin and piperaquine resistance patterns are prevalent. For substantiation, well-designed larger trials from endemic countries are needed. In the light of benefit versus harm concept, future analysis with safety information is recommended.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225882PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6922314PMC
March 2020

Gene expression changes in human bronchial epithelial cells (BEAS-2B) and human pulmonary alveolar epithelial cells (HPAEpiC) after interaction with Cladosporium sphaerospermum.

Med Mycol 2020 Apr;58(3):333-340

Department of Medical Microbiology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.

Cladosporium is one of the most abundant spore. Fungi of this genus can cause respiratory allergy and intrabronchial lesion. We studied the differential expression of host genes after the interaction of Cladosporium sphaerospermum conidia with Human Bronchial Epithelial Cells (BEAS-2B) and Human Pulmonary Alveolar Epithelial Cells (HPAEpiC). C. sphaerospermum conidia were harvested and co-cultured with BEAS-2B cells or HPAEpiC cells for 48 hours respectively. This culture duration was chosen as it was associated with high germination rate. RNA was extracted from two biological replicates per treatment. RNA of BEAS-2B cells was used to assess changes in gene expression using AffymetrixGeneChip® Human Transcriptome Array 2.0. After co-culture with Cladosporium spores, 68 individual genes were found differentially expressed (P ≤ 0.05) and up-regulated ≥ 1.5 folds while 75 genes were found differentially expressed at ≤ -1.5 folds compared with controls. Reverse transcription and qPCR were performed on the RNA collected from both BEAS-2B cells and HPAEpiC cells to validate the microarray results with 7 genes. Based on the findings, infected pulmonary epithelial cells exhibited an increase in cell death-related genes and genes associated with innate immunity.
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http://dx.doi.org/10.1093/mmy/myz061DOI Listing
April 2020

Identification and ultrastructural characterization of Acanthamoeba bacterial endocytobionts belonging to the Alphaproteobacteria class.

PLoS One 2018 24;13(10):e0204732. Epub 2018 Oct 24.

Medical Sciences, School of Medicine, International Medical University, Kuala Lumpur, Malaysia.

The detection and identification of two endocytobiotic bacterial strains, one affiliated to the "Candidatus Caedibacter acanthamoebae"/"Ca. Paracaedimonas acanthamoeba", and another to the endosymbiont of Acanthamoeba UWC8 and "Ca. Jidaibacter acanthamoeba" are described. For endocytobiont screening, we developed a PCR method with a set of broad-range bacterial 16S rRNA primers to substitute the commonly used but technically demanding fluorescent in situ hybridization technique. Our PCR test alone without sequencing failed to discriminate the endocytobiont-containing and endocytobiont-free Acanthamoeba sp. due to the presence of mismatched primers to host mitochondrial DNA. We highlighted the need to perform bacterial primer checking against the Acanthamoeba genome to avoid false positive detection in PCR. Although the genetic aspect of "Ca. Caedibacter acanthamoebae"/"Ca. Paracaedimonas acanthamoeba" and the endosymbiont of Acanthamoeba UWC8/"Ca. Jidaibacter acanthamoeba" are well studied, knowledge pertaining to their morphologies are quite vague. Hence, we used transmission electron microscopy to examine our endocytobionts which are affiliated to previously described intracellular bacteria of Acanthamoeba sp. We used good-quality TEM images for the localization and the fate of the current endocytobionts inside different life stages of the hosts. Furthermore, to the best of our knowledge, our TEM findings are the first to provide morphological evidence for the clearance of defective Acanthamoeba endocytobionts via an autophagic-like process.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0204732PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200196PMC
March 2019

Association of tumour necrosis factor-α (TNF-α) gene polymorphisms (-308 G>A and -238 G>A) and the risk of severe dengue: A meta-analysis and trial sequential analysis.

PLoS One 2018 9;13(10):e0205413. Epub 2018 Oct 9.

Institute for Research, Development and Innovation (IRDI), International Medical University, Kuala Lumpur, Malaysia.

Individual studies have assessed the association between TNF-α-308G>A and TNF-α-238 G>A polymorphisms and severity of dengue infection. However, the results are inconclusive and most studies had small sample sizes. The objective of this study was to summarize the evidence of association between TNF-α-308 G>A and TNF-α-238 G>A and severity of dengue infection. This study follows the preferred reporting items for systematic reviews and meta- analyses of genetic association studies, recommended by PLOS One. We calculated pooled odds ratio and its 95% confidence interval (CI) to estimate the association between TNF-α-308 G>A or TNF-α-238 G>A and the risk of severe dengue infections. To determine the information size required for this meta-analysis study, a trial sequential analysis (TSA) was done. Eight studies (640 cases and 1275 controls), which assessed the association of TNF-α-308 G>A or TNF-α-238 G>A and the risk of DHF were included. Overall, we found no significant association between TNF-α-308 G>A and the DHF risk in the allelic model (OR, 0.91; 95% CI, 0.51-1.63), the recessive model (OR,1.32;95%CI,0.73-2.37), the dominant model (OR,0.93;95%CI:0.59-1.47) or the additive model (OR,1.43,95;95%CI:0.79-2.59). There was also no significant association between TNF-α-238 G>A and DHF risk under the allele contrast model (OR:1.51;95%CI:0.88-2.58), the recessive model (OR,1.48,95% CI:0.33-6.58), the dominant model (OR,1.48;95%CI:0.56-3.92), or the additive model (OR:1.5;95%CI:0.34-6.69). On subgroup analysis, neither the Asian population nor the non-Asian population showed significant association between TNF-α-308 G>A/TNF-α-238 G>A and the DHF risk under any genetic models. Leave-one-out meta-analysis showed stability of the results. TSA plots suggested that the sample size in this meta-analysis study was below the required information size. The findings suggest an inclusive evidence of the association between TNF-α-308/ TNF-α-238 G>A and the risk of developing severe dengue infection. Large studies with evidence of Hardy-Weinberg equilibrium, assessing gene-gene interactions are recommended.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0205413PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6177181PMC
March 2019

Immediately modifiable risk factors attributable to colorectal cancer in Malaysia.

BMC Public Health 2017 08 4;17(1):637. Epub 2017 Aug 4.

School of Postgraduate Studies, International Medical University, 57000, Kuala Lumpur, Malaysia.

Background: This study aimed to estimate potential reductions in case incidence of colorectal cancer attributable to the modifiable risk factors such as alcohol consumption, overweight and physical inactivity amongst the Malaysian population.

Methods: Gender specific population-attributable fractions (PAFs) for colorectal cancer in Malaysia were estimated for the three selected risk factors (physical inactivity, overweight, and alcohol consumptions). Exposure prevalence were sourced from a large-scale national representative survey. Risk estimates of the relationship between the exposure of interest and colorectal cancer were obtained from published meta-analyses. The overall PAF was then estimated, using the 2013 national cancer incidence data from the Malaysian Cancer Registry.

Results: Overall, the mean incidence rate for colorectal cancer in Malaysia from 2008 to 2013 was 21.3 per 100,000 population, with the mean age of 61.6 years (±12.7) and the majority were men (56.6%). Amongst 369 colorectal cancer cases in 2013, 40 cases (20 men, 20 women), 10 cases (9 men, 1 woman) or 20 cases (16 men,4 women) would be prevented, if they had done physical exercises, could reduce their body weight to normal level or avoided alcohol consumption, assuming that these factors are causally related to colorectal cancer. It was estimated that 66 (17.8%;66/369) colorectal cancer cases (42 men, 24 women) who had all these three risk factors for the last 10 years would have been prevented, if they could control these three risk factors through effective preventive measures.

Conclusions: Findings suggest that approximately 18% of colorectal cancer cases in Malaysia would be prevented through appropriate preventive measures such as doing regular physical exercises, reducing their body weight to normal level and avoiding alcohol consumption, if these factors are causally related to colorectal cancer. Scaling-up nationwide public health campaigns tailored to increase physical activity, controlling body weight within normal limits and avoid alcohol intake are recommended. Future studies with other site-specific cancers and additional risk factors are needed.
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http://dx.doi.org/10.1186/s12889-017-4650-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5544995PMC
August 2017

Salivary glucose in monitoring glycaemia in patients with type 1 diabetes mellitus: a systematic review.

J Diabetes Metab Disord 2017 21;16. Epub 2017 Jan 21.

Institute for Research, Development and Innovation (IRDI), International Medical University, Kuala Lumpur, 57000 Malaysia.

Background: Incidence of type 1 diabetes mellitus is increasing worldwide. Monitoring glycaemia is essential for control of diabetes mellitus. Conventional blood-based measurement of glucose requires venepuncture or needle prick, which is not free from pain and risk of infection. The non-invasiveness, ease and low-cost in collection made saliva an attractive alternative sample. The objective of this review was to systematically review the evidence on the relationship between salivary glucose level and blood glucose level in monitoring glycaemia in patients with type 1 diabetes mellitus.

Methods: We searched studies which evaluate salivary glucose levels and serum glycaemia in type 1 diabetes mellitus in electronic databases of MEDLINE, EMBASE, Ovid and Google Scholar. We selected the eligible studies, following the inclusion criteria set for this review. Due to heterogeneity of studies, we conducted qualitative synthesis of studies.

Results: Ten observational studies were included in this review, including a total of 321 cases and 323 controls with ages between 3 and 61 years and the majority were males (62%). Two studies were done exclusively on children below 17 years old. The significant difference between salivary glucose levels in type 1 diabetes mellitus and controls were reported in 6 studies with 8 data sets. Five studies with 7 datasets reported the correlation coefficient between salivary glucose and blood glucose in patients with diabetes.

Conclusions: Findings suggest that salivary glucose concentrations may be helpful in monitoring glycaemia in type 1 diabetes mellitus. However, the utility of using salivary glucose level to monitor glycaemia should be evaluated in future well designed, prospective studies with adequate number of participants with type 1 diabetes mellitus.
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http://dx.doi.org/10.1186/s40200-017-0287-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5251294PMC
January 2017

Association between telomere length and the risk of colorectal cancer: a meta-analysis of observational studies.

BMC Cancer 2017 01 5;17(1):24. Epub 2017 Jan 5.

School of Postgraduate Studies, International Medical University (IMU), Kuala Lumpur, 57000, Malaysia.

Background: Human chromosomes are capped and stabilized by telomeres. Telomere length regulates a 'cellular mitotic clock' that defines the number of cell divisions and hence, cellular life span. This study aimed to synthesize the evidence on the association between peripheral blood leucocytes (PBL) telomere length and the risk of colorectal cancer (CRC).

Methods: We searched relevant studies in electronic databases. When two or more observational studies reported the same outcome measures, we performed pooled analysis. All the analyses were performed on PBL using PCR. The odds ratio (OR) and its 95% confidence interval (CI) were used to assess the strength of association.

Results: Seven studies (with 8 datasets) were included in this meta-analysis; 3 prospective studies, 3 retrospective studies and 1 study with a separate prospective and retrospective designs. The pooled analysis of 4 prospective studies (summary OR 1.01, 95% CI: 0.77-1.34, I :30%) and 4 retrospective studies (summary OR 1.65, 95% CI: 0.96-2.83, I :96%) showed no relationship between PBL telomere length and the CRC risk. A subgroup analysis of 2 prospective studies exclusively on females also showed no association between PBL telomere length and the CRC risk (summary OR, 1.17, 95% CI:0.72-1.91, I :57%).

Conclusion: The current analysis is insufficient to provide evidence on the relationship between PBL telomere length and the risk of CRC. Findings suggest that there may be a complex relationship between PBL telomere length and the CRC risk or discrepancy between genetics, age of patients and clinical studies. Future well powered, large prospective studies on the relationship between telomere length and the risk of CRC, and the investigations of the biologic mechanisms are recommended.
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http://dx.doi.org/10.1186/s12885-016-2997-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216529PMC
January 2017

The correlation of Acanthamoeba from the ventilation system with other environmental parameters in commercial buildings as possible indicator for indoor air quality.

Ind Health 2017 Feb 29;55(1):35-45. Epub 2016 Jul 29.

School of Postgraduate Studies, Institute for Research, Development and Innovation (IRDI), International Medical University, Malaysia.

The free-living protozoan Acanthamoeba is an opportunistic pathogen that is ubiquitous in our environment. However, its role in affecting indoor air quality and ill-health of indoor occupants is relatively unknown. The present study investigated the presence of Acanthamoeba from the ventilation system and its correlation with other indoor air quality parameters, used in the industry code of practice and its potential as an indicator for indoor air quality. Indoor air quality assessments were carried out in nine commercial buildings with approval from the building management, and the parameters assessed were as recommended by the Department of Occupational Safety and Health. The presence of Acanthamoeba was determined through dust swabs from the ventilation system and indoor furniture. Logistic regression was performed to study the correlation between assessed parameters and occupants' complaints. A total of 107 sampling points were assessed and 40.2% of the supplying air diffuser and blowing fan and 15% of the furniture were positive for cysts. There was a significant correlation between Acanthamoeba detected from the ventilation system with ambient total fungus count (r=0.327; p=0.01) and respirable particulates (r=0.276; p=0.01). Occupants' sick building syndrome experience also correlated with the presence of Acanthamoeba in the ventilation system (r=0.361; p=0.01) and those detected on the furniture (r=0.290; p=0.01). Logistic regression showed that there was a five-fold probability of sick building syndrome among occupants when Acanthamoeba was detected in the ventilation system.
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http://dx.doi.org/10.2486/indhealth.2015-0218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5285312PMC
February 2017

A systematic review of the efficacy of a single dose artemisinin-naphthoquine in treating uncomplicated malaria.

Malar J 2015 Oct 6;14:392. Epub 2015 Oct 6.

School of Medicine, International Medical University, Kuala Lumpur, Malaysia.

Background: This study aimed to synthesize the existing evidence on the efficacy and safety of a single dose artemisinin-naphthoquine (ASNQ) for treatment of uncomplicated malaria in endemic countries.

Methods: A meta-analysis of randomized, controlled trials (RCT), assessing efficacy and safety of single dose ASNQ was carried out. Comparator drugs included artemether-lumefentrine (AL), chloroquine plus sulfadoxine-pyrimethamine (CQSP) and dihydroartemisinin-piperaquine (DHP). The efficacy and safety profile of non-comparator, single-arm studies on the single dose ASNQ was also assessed. The primary endpoint was efficacy defined as an absence of PCR-confirmed parasitaemia. The methodological quality of the included studies was assessed using the six domains for the risk of bias.

Results: Five RCTs and three single-arm studies were included in this review. As RCT studies did not compare the same anti-malarial drugs, it was difficult to do a pooled analysis. At day 28, a pooled analysis of two RCTs (n = 271) showed a comparable efficacy on PCR-confirmed parasitaemia between ASNQ and AL. Another RCT, which compared ASNQ and CQSP or ASNQ and DHP, also showed comparable efficacy. At day 42, one RCT comparing ASNQ and DHP and another RCT comparing ASNQ and AL reported comparable levels of efficacy. The proportion of parasite clearance was faster in the ASNQ groups than the comparators at day 1, and almost all parasites were cleared by day 3 in the ASNQ groups.

Conclusions: The present review provides some evidence to support that there is similar efficacy and safety of the single dose ASNQ compared to other anti-malarial drugs in treating uncomplicated malaria. Larger, adequately powered, well-designed studies are recommended to substantiate the efficacy and safety in different populations and in different epidemiological settings. As the potential evolution of drug resistance is a great concern and this cannot be addressed in a short-term study, the use of single dose ASNQ needs further evaluation.
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http://dx.doi.org/10.1186/s12936-015-0919-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596557PMC
October 2015

Culture and molecular identification of fungal contaminants in edible bird nests.

Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2015 4;32(12):2138-47. Epub 2015 Nov 4.

a School of Medical Sciences , International Medical University , Kuala Lumpur , Malaysia.

Widespread food poisoning due to microbial contamination has been a major concern for the food industry, consumers and governing authorities. This study is designed to determine the levels of fungal contamination in edible bird nests (EBNs) using culture and molecular techniques. Raw EBNs were collected from five house farms, and commercial EBNs were purchased from five Chinese traditional medicine shops (companies A-E) in Peninsular Malaysia. The fungal contents in the raw and commercial EBNs, and boiled and unboiled EBNs were determined. Culturable fungi were isolated and identified. In this study, the use of these methods revealed that all EBNs had fungal colony-forming units (CFUs) that exceeded the limit set by Standards and Industrial Research Institute of Malaysia (SIRIM) for yeast and moulds in EBNs. There was a significant difference (p < 0.05) in the number of types of fungi isolated from raw and commercial EBNs, but no significant difference in the reduction of the number of types of fungi after boiling the EBNs (p > 0.05). The types of fungi isolated from the unboiled raw EBNs were mainly soil, plant and environmental fungi, while the types of fungi isolated from the boiled raw EBNs, unboiled and boiled commercial EBNs were mainly environmental fungi. Aspergillus sp., Candida sp., Cladosporium sp., Neurospora sp. and Penicillum sp. were the most common fungi isolated from the unboiled and boiled raw and commercial EBNs. Some of these fungi are mycotoxin producers and cause opportunistic infections in humans. Further studies to determine the mycotoxin levels and methods to prevent or remove these contaminations from EBNs for safe consumption are necessary. The establishment and implementation of stringent regulations for the standards of EBNs should be regularly updated and monitored to improve the quality of the EBNs and consumer safety.
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http://dx.doi.org/10.1080/19440049.2015.1101494DOI Listing
September 2016

A Systematic Review and Meta-Analysis of Medical Students' Perspectives on the Engagement in Research.

Medicine (Baltimore) 2015 Jul;94(28):e1089

From the Institute for Research, Development and Innovation (IRDI) (CN, JWM), International Medical University (IMU), Kuala Lumpur, Malaysia; School of Medicine (VNW, KA), International Medical University (IMU), Kuala Lumpur, Malaysia; School of Public Health (JD, MAW), University of Queensland, Brisbane, Australia; and School of Health Sciences (NNW), International Medical University (IMU), Kuala Lumpur, Malaysia.

Engaging students in active learning lies at the center of effective higher education. In medical schools, students' engagement in learning and research has come under increasing attention. The objective of this study was to synthesize evidence on medical students' perspectives on the engagement in research. We performed a systematic review and meta-analysis. Relevant studies were searched in electronic databases. The methodological quality of the included studies was assessed. Overall, 14 observational studies (with 17 data sets) were included. In general, many studies did not use the same questionnaires and the outcome measurements were not consistently reported; these presented some difficulties in pooling the results. Whenever data permitted, we performed pooled analysis for the 4 education outcomes. A Bayesian meta-analytical approach was supplemented as a measure of uncertainty. A pooled analysis showed that 74% (95% confidence interval [CI]: 1.57%-11.07%; I2: 95.2%) of those students who engaged in research (while at the medical school) had positive attitudes toward their research experiences, whereas 49.5% (95% CI: 36.4%-62.7%; I2: 93.4%) had positive attitudes toward the study of medical sciences, 62.3% (95% CI: 46.7%-77.9%; I2: 96.3%) had self-reported changes in their practices, and 64% (95% CI: 30.8%-96.6%; I2: 98.5%) could have published their work. There was substantial heterogeneity among studies. We acknowledged the caveats and the merit of the current review. Findings showed that engagement in research resulted in favorable reactions toward research and academic learning. Future well-designed studies using standardized research tools on how to engage students in research are recommended.
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http://dx.doi.org/10.1097/MD.0000000000001089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617066PMC
July 2015

Cost-utility analysis of an adjunctive recombinant activated factor VIIa for on-demand treatment of bleeding episodes in dengue haemorrhagic fever.

Blood Coagul Fibrinolysis 2015 Jun;26(4):403-7

aInstitute for Research, Development and Innovation, International Medical University, Kuala Lumpur, Malaysia bChulalongkorn University, Bangkok, Thailand cSchool of Medicine, International Medical University, Kuala Lumpur, Malaysia *Cho Naing and Yong Poovorawan contributed equally to the writing of this article.

The present study aimed to assess the cost-utility analysis of using an adjunctive recombinant activated factor VIIa (rFVIIa) in children for controlling life-threatening bleeding in dengue haemorrhagic fever (DHF)/dengue shock syndrome (DSS). We constructed a decision-tree model, comparing a standard care and the use of an additional adjuvant rFVIIa for controlling life-threatening bleeding in children with DHF/DSS. Cost and utility benefit were estimated from the societal perspective. The outcome measure was cost per quality-adjusted life years (QALYs). Overall, treatment with adjuvant rFVIIa gained QALYs, but the total cost was higher. The incremental cost-utility ratio for the introduction of adjuvant rFVIIa was $4241.27 per additional QALY. Sensitivity analyses showed the utility value assigned for calculation of QALY was the most sensitive parameter. We concluded that despite high cost, there is a role for rFVIIa in the treatment of life-threatening bleeding in patients with DHF/DSS.
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http://dx.doi.org/10.1097/MBC.0000000000000280DOI Listing
June 2015

In vitro effect of important herbal active constituents on human cytochrome P450 1A2 (CYP1A2) activity.

Phytomedicine 2014 Oct 16;21(12):1645-50. Epub 2014 Sep 16.

School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia. Electronic address:

This study was designed to investigate eight herbal active constituents (andrographolide, asiaticoside, asiatic acid, madecassic acid, eupatorin, sinensetin, caffeic acid, and rosmarinic acid) on their potential inhibitory effects on human cytochrome P450 1A2 (CYP1A2) activity. A fluorescence-based enzyme assay was performed by co-incubating human cDNA-expressed CYP1A2 with its selective probe substrate, 3-cyano-7-ethoxycoumarin (CEC), in the absence or presence of various concentrations of herbal active constituents. The metabolite (cyano-hydroxycoumarin) formed was subsequently measured in order to obtain IC50 values. The results indicated that only eupatorin and sinensetin moderately inhibited CYP1A2 with IC50 values of 50.8 and 40.2 μM, while the other active compounds did not significantly affect CYP1A2 activity with IC50 values more than 100 μM. Ki values further determined for eupatorin and sinensetin were 46.4 and 35.2 μM, respectively. Our data indicated that most of the investigated herbal constituents have negligible CYP1A2 inhibitory effect. In vivo studies however may be warranted to ascertain the inhibitory effect of eupatorin and sinensetin on CYP1A2 activity in clinical situations.
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http://dx.doi.org/10.1016/j.phymed.2014.08.003DOI Listing
October 2014

Is Plasmodium vivax malaria a severe malaria?: a systematic review and meta-analysis.

PLoS Negl Trop Dis 2014 Aug 14;8(8):e3071. Epub 2014 Aug 14.

School of Postgraduate Studies, International Medical University, Kuala Lumpur, Malaysia.

Background: Plasmodium vivax is one of the major species of malaria infecting humans. Although emphasis on P. falciparum is appropriate, the burden of vivax malaria should be given due attention. This study aimed to synthesize the evidence on severe malaria in P. vivax infection compared with that in P. falciparum infection.

Methods/principal Findings: We searched relevant studies in electronic databases. The main outcomes required for inclusion in the review were mortality, severe malaria (SM) and severe anaemia (SA). The methodological quality of the included studies was assessed using the Newcastle-Ottawa Scale. Overall, 26 studies were included. The main meta-analysis was restricted to the high quality studies. Eight studies (n = 27490) compared the incidence of SM between P. vivax infection and P. falciparum mono-infection; a comparable incidence was found in infants (OR: 0.45, 95% CI:0.04-5.68, I2:98%), under 5 year age group (OR: 2.06, 95% CI: 0.83-5.1, I2:83%), the 5-15 year-age group (OR: 0.6, 95% CI: 0.31-1.16, I2:81%) and adults (OR: 0.83, 95% CI: 0.67-1.03, I2:25%). Six studies reported the incidences of SA in P. vivax infection and P. falciparum mono-infection; a comparable incidence of SA was found among infants (OR: 3.47, 95%:0.64-18.94, I2: 92%), the 5-15 year-age group (OR:0.71, 95% CI: 0.06-8.57, I2:82%). This was significantly lower in adults (OR:0.75, 95% CI: 0.62-0.92, I2:0%). Five studies (n = 71079) compared the mortality rate between vivax malaria and falciparum malaria. A lower rate of mortality was found in infants with vivax malaria (OR:0.61, 95% CI:0.5-0.76, I2:0%), while this was comparable in the 5-15 year- age group (OR: 0.43, 95% CI:0.06-2.91, I2:84%) and the children of unspecified-age group (OR: 0.77, 95% CI:0.59-1.01, I2:0%).

Conclusion: Overall, the present analysis identified that the incidence of SM in patients infected with P. vivax was considerable, indicating that P. vivax is a major cause of SM. Awareness of the clinical manifestations of vivax malaria should prompt early detection. Subsequent treatment and monitoring of complications can be life-saving.
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http://dx.doi.org/10.1371/journal.pntd.0003071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133404PMC
August 2014

Efficacy and safety of dihydroartemisinin-piperaquine for treatment of Plasmodium vivax malaria in endemic countries: meta-analysis of randomized controlled studies.

PLoS One 2013 3;8(12):e78819. Epub 2013 Dec 3.

School of Population Health, University of Queensland, Herston, Australia ; International Medical University, Kuala Lumpur, Malaysia.

Background: This study aimed to synthesize available evidence on the efficacy of dihydroartemisinin-piperaquine (DHP) in treating uncomplicated Plasmodium vivax malaria in people living in endemic countries.

Methodology And Principal Findings: This is a meta-analysis of randomized controlled trials (RCT). We searched relevant studies in electronic databases up to May 2013. RCTs comparing efficacy of (DHP) with other artemisinin-based combination therapy (ACT), non-ACT or placebo were selected. The primary endpoint was efficacy expressed as PCR-corrected parasitological failure. Efficacy was pooled by hazard ratio (HR) and 95% CI, if studies reported time-to-event outcomes by the Kaplan-Meier method or data available for calculation of HR Nine RCTs with 14 datasets were included in the quantitative analysis. Overall, most of the studies were of high quality. Only a few studies compared with the same antimalarial drugs and reported the outcomes of the same follow-up duration, which created some difficulties in pooling of outcome data. We found the superiority of DHP over chloroquine (CQ) (at day > 42-63, HR:2.33, 95% CI:1.86-2.93, I (2): 0%) or artemether-lumefentrine (AL) (at day 42, HR:2.07, 95% CI:1.38-3.09, I (2): 39%). On the basis of GRADE criteria, further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Discussion/conclusion: Findings document that DHP is more efficacious than CQ and AL in treating uncomplicated P. vivax malaria. The better safety profile of DHP and the once-daily dosage improves adherence, and its fixed co-formulation ensures that both drugs (dihydroartemisinin and piperaquine) are taken together. However, DHP is not active against the hypnozoite stage of P. vivax. DHP has the potential to become an alternative antimalarial drug for the treatment uncomplicated P. vivax malaria. This should be substantiated by future RCTs with other ACTs. Additional work is required to establish how best to combine this treatment with appropriate antirelapse therapy (primaquine or other drugs under development).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0078819PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3848966PMC
August 2014

Malaria and soil-transmitted intestinal helminth co-infection and its effect on anemia: a meta-analysis.

Trans R Soc Trop Med Hyg 2013 Nov;107(11):672-83

School of Population Health, University of Queensland, Queensland 4006, Australia.

This study aimed to synthesize available evidence on the extent of malaria and soil-transmitted intestinal helminth (STH) co-infections in people living in endemic countries and to explore the effect of interactions between malaria and STHs on anemia. We searched relevant studies in electronic databases up to March 2013. Studies comparing malaria and STH co-infected patients with those not co-infected were included and the effect estimates were pooled using a random-effects model. We identified 30 studies for meta-analyses of which 17 were cross-sectional design. The majority of included studies (80%) were carried out in African countries. Among pregnant women, those infected with hookworm were found to have higher association with malaria infection compared with those without (summary OR: 1.36; 95% CI: 1.17-1.59; I(2): 0%). Among non-pregnant adults, the summary OR of the association between anemia and the combined malaria and STH was 2.91 (1.38-6.14). The summary OR of the association between anemia and malaria alone was 1.53 (0.97-2.42), while the association between anemia and STH alone was 0.28 (0.04-1.95). There is no good evidence to support a different effect of malaria and STH on anemia. A subgroup analysis showed a higher risk of malaria infection in the primigravidae (summary OR: 1.61; 95% CI: 1.3-1.99; I(2): 0%). In conclusion, the malaria-STH co-infection was variable with complex outcomes on anemia.
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http://dx.doi.org/10.1093/trstmh/trt086DOI Listing
November 2013

Effect of eurycomanone on cytochrome P450 isoforms CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 in vitro.

J Nat Med 2014 Apr 24;68(2):402-6. Epub 2013 Jul 24.

School of Medical Sciences, International Medical University, 126 Jalan 19/155B, Bukit Jalil, 57000, Kuala Lumpur, Malaysia.

Eurycomanone, an active constituent isolated from Eurycoma longifolia Jack, was examined for modulatory effects on cytochrome P450 (CYP) isoforms CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 using in vitro assays. The IC50 value was determined to assess the potencies of modulation for each CYP isoform. Our results indicated that eurycomanone did not potently inhibit any of the CYP isoforms investigated, with IC50 values greater than 250 μg/ml. Hence there appears to be little likelihood of drug-herb interaction between eurycomanone or herbal products with high content of this compound and CYP drug substrates via CYP inhibition.
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http://dx.doi.org/10.1007/s11418-013-0794-8DOI Listing
April 2014

In vitro approaches to investigate cytochrome P450 activities: update on current status and their applicability.

Expert Opin Drug Metab Toxicol 2013 Sep 17;9(9):1097-113. Epub 2013 May 17.

Monash University Sunway Campus, Jeffrey Cheah School of Medicine and Health Sciences, Jalan Lagoon Selatan, 46150 Bandar Sunway, Selangor, Malaysia.

Introduction: Cytochromes P450 (CYPs) play a central role in the Phase I metabolism of drugs and other xenobiotics. It is estimated that CYPs can metabolize up to two-thirds of drugs present in humans. Over the past two decades, there have been numerous advances in in vitro methodologies to characterize drug metabolism and interaction involving CYPs.

Areas Covered: This review focuses on the use of in vitro methodologies to examine CYPs' role in drug metabolism and interaction. There is an emphasis on their current development, applicability, advantages and limitations as well as the use of in silico approaches in complementing and supporting in vitro data. The article also highlights the challenges in extrapolating in vitro data to in vivo situations.

Expert Opinion: Advances in in vitro methodologies have been made such that data can be used for in vivo prediction with comfortable degree of confidence. Improved assay designs and analytical techniques have permitted development of miniaturized assay format and automated system with improved sensitivity and throughput capacity. High-quality experimental designs and scientifically rigorous assessment/validation protocols remain crucial in developing reliable and robust in vitro models. With continued progress made in the field, in vitro methodologies will continually be employed in evaluating CYP activities in pharmaceutical industries and laboratories.
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http://dx.doi.org/10.1517/17425255.2013.800482DOI Listing
September 2013

Prevalence, predictors and clinical significance of Blastocystis sp. in Sebha, Libya.

Parasit Vectors 2013 Apr 8;6:86. Epub 2013 Apr 8.

Department of Parasitology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia.

Background: Blastocystis sp. has a worldwide distribution and is often the most common human intestinal protozoan reported in children and adults in developing countries. The clinical relevance of Blastocystis sp. remains controversial. This study was undertaken to determine the prevalence of Blastocystis infection and its association with gastrointestinal symptoms among outpatients in Sebha city, Libya.

Methods: A total of 380 stool samples were collected from outpatients attending the Central Laboratory in Sebha, Libya for routine stool examination. The presence of Blastocystis sp. was screened comparing light microscopy of direct smears against in vitro cultivation. Demographic and socioeconomic information were collected with a standardized questionnaire.

Results: The overall prevalence of Blastocystis infection was 22.1%. The prevalence was significantly higher among patients aged ≥18 years compared to those aged < 18 years (29.4% vs 9.9%; x² = 19.746; P < 0.001), and in males compared to females (26.4% vs 17.5%; x² = 4.374; P = 0.036). Univariate analysis showed significant associations between Blastocystis infection and the occupational status (P = 0.017), family size (P = 0.023) and educational level (P = 0.042) of the participants. Multiple logistic regression analysis confirmed that the age of ≥ 18 years (OR = 5.7; 95% CI = 2.21; 9.86) and occupational status (OR = 2.2; 95% CI = 1.02, 4.70) as significant predictors of Blastocystis infection among this population. In those who had only Blastocystis infection but no other gastrointestinal parasitic infections, the prevalence of gastrointestinal symptoms was higher compared to those without Blastocystis infection (35.3% vs 13.2%; x² = 25.8; P < 0.001). The most common symptoms among these patients were abdominal pain (76.4%), flatulence (41.1%) and diarrhoea (21.5%).

Conclusions: Blastocystis sp. is prevalent and associated with gastrointestinal symptoms among communities in Sebha city, Libya. Age and occupational status were the significant predictors of infection. However, more studies from different areas in Libya are needed in order to delineate the epidemiology and clinical significance of this infection.
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http://dx.doi.org/10.1186/1756-3305-6-86DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3626707PMC
April 2013

Reporting 'number needed to treat' in meta-analyses: a cross-sectional study.

J Evid Based Med 2012 Nov;5(4):232-7

School of Postgraduate Studies and Research, International Medical University, Kuala Lumpur 57000, Malaysia.

Aim: In translating clinical research into practice, the summarization of data from randomized trials in terms of measures of effect to be readily appreciated by the point-of-care clinicians is important. In this context, the body of literature highlighted the 'number needed to treat' as a useful measure. The objectives of our study were to assess how meta-analyses described number needed to treat and corresponding 95% CI, and to explore issues related to reporting number needed to treat in the selected meta-analyses.

Method: For an illustration, we searched for the Cochrane systematic reviews and non-Cochrane systematic reviews. Two-stage selection was done to identify eligible studies. First, we fixed a date and then, we searched meta-analyses in PUBMED available on the date fixed. Secondly, we purposively selected five Cochrane systematic reviews and three non-Cochrane systematic reviews, according to our inclusion criteria. The critical appraisal of meta-analyses identified for the current study was done with the 5-item quality checklist introduced to the current analysis.

Results: A total of 8 systematic reviews, 5 Cochrane systematic reviews and 3 non-Cochrane systematic reviews/meta-analyses, were identified for the present study. Of these 8 meta-analyses, some (50%; 4/8) described number needed to treat in the method session of the study. However, the majority (87.5%; 7/8) reported number needed to treat in the results. For the details, 80% in Cochrane reviews and 66.5% in non-Cochrane reviews reported number needed to treat in the results. Only two studies (25%; 2/8) reported susceptibility to publication bias, provided simplified interpretation or discussed number needed to treat.

Conclusion: Although the Cochrane handbook for systematic reviews of interventions suggests the reviewers to include number needed to treat in reporting effect estimations, there still is a need to improve.
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http://dx.doi.org/10.1111/jebm.12002DOI Listing
November 2012

Diabetes and infections-hepatitis C: is there type 2 diabetes excess in hepatitis C infection?

Curr Diab Rep 2013 Jun;13(3):428-34

School of Postgraduate Studies and Research, International Medical University, Kuala Lumpur, Malaysia.

Individual epidemiologic studies as well as the pooled analysis of observational studies have indicated the association between type 2 diabetes (T2D) and hepatitis C virus infection (HCV). Whether HCV infection is the cause of diabetes or diabetic patients are more prone to get HCV infection is still in question. The objective of the present review was to provide answers to this issue, based on available evidence from epidemiologic, molecular, experimental and therapeutic studies. Our current understanding of how chronic HCV infection could induce T2D is incomplete, but it seems twofold based on both direct and indirect roles of the virus. HCV may directly induce insulin resistance (IR) through its proteins. HCV core protein was shown to stimulate suppressor of cytokine signaling, resulting in ubiquitination and degradation of tyrosine kinase phosphorylated insulin receptor substrates (IRS1/2) in proteasomes. HCV-nonstructural protein could increase protein phosphatase 2A which has been shown to inactivate the key enzyme Akt by dephosphorylating it. Insulin signaling defects in hepatic IRS-1 tyrosine phosphorylation and PI3-kinase association/activation may contribute to IR, which leads to the development of T2D in patients with HCV infection. The peroxisome proliferator-activated receptors (PPARs) are also implicated. PPARα/γ, together with their obligate partner RXR, are the main nuclear receptors expressed in the liver. PPARα upregulates glycerol-3-phosphate dehydrogenase, glycerol kinase, and glycerol transport proteins, which allows for glucose synthesis during fasting states. Decreased activity of PPARs could attribute to HCV-induced IR. Immune-mediated mechanisms may be involved in the indirect role of HCV in inducing IR. It is speculated that TNF-alpha plays a major role in the pathogenesis of IR through lowering IRS1/2. Furthermore, HCV infection- triggered ER stress could lead to the activation of PP2A, which inhibits both Akt and the AMP-activated kinase, the regulators of gluconeogenesis. In summary, we illustrate that HCV infection is accompanied by multiple defects in the upstream insulin signaling pathway in the liver that may contribute to the observed prevalence of IR and diabetes. Future studies are needed to resolve this issue.
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http://dx.doi.org/10.1007/s11892-013-0370-3DOI Listing
June 2013

Heterologous expression of human cytochrome P450 (CYP) 2C19 in Escherichia coli and establishment of RP-HPLC method to serve as activity marker.

Biomed Chromatogr 2013 Jul 6;27(7):859-65. Epub 2013 Feb 6.

School of Medical Sciences, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil, 57000, Kuala Lumpur, Malaysia.

In this study, a simple and reliable reverse-phase high-performance liquid chromatography (RP-HPLC) method was established and validated to analyze S-mephenytoin 4-hydroxylase activity of a recombinant CYP2C19 system. This system was obtained by co-expressing CYP2C19 and NADPH-CYP oxidoreductase (OxR) proteins in Escherichia coli (E. coli) cells. In addition to RP-HPLC, the expressed proteins were evaluated by immunoblotting and reduced CO difference spectral scanning. The RP-HPLC assay showed good linearity (r(2) = 1.00) with 4-hydroxymephenytoin concentration from 0.100 to 50.0 μm and the limit of detection was 5.00 × 10(-2) μm. Intraday and interday precisions determined were from 1.90 to 8.19% and from 2.20 to 14.9%, respectively. Recovery and accuracy of the assay were from 83.5 to 85.8% and from 95.0 to 105%. Enzyme kinetic parameters (Km , Vmax and Ki ) were comparable to reported values. The presence of CYP2C19 in bacterial membranes was confirmed by immunoblotting and the characteristic absorbance peak at 450 nm was determined in the reduced CO difference spectral assay. Moreover, the activity level of co-expressed OxR was found to be comparable to that of the literature. As a conclusion, the procedures described here have generated catalytically active CYP2C19 and the RP-HPLC assay developed is able to serve as CYP2C19 activity marker for pharmacokinetic drug interaction study in vitro.
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http://dx.doi.org/10.1002/bmc.2872DOI Listing
July 2013

Efficacy and safety of dihydroartemisinin-piperaquine for treatment of uncomplicated Plasmodium falciparum malaria in endemic countries: meta-analysis of randomised controlled studies.

Trans R Soc Trop Med Hyg 2013 Feb 4;107(2):65-73. Epub 2012 Dec 4.

School of Postgraduate Studies and Research, International Medical University, Kuala Lumpur 57000, Malaysia.

The present review aimed to synthesise available evidence on the efficacy of dihydroartemisinin-piperaquine (DP) in treating uncomplicated Plasmodium falciparum malaria in people living in malaria-endemic countries by performing a meta-analysis of relevant studies. We searched relevant studies in electronic data bases up to December 2011. Published results from randomised controlled trials (RCTs) comparing efficacy of DP with other artemisinin-based combination therapies (ACTs), or non-ACTs, or placebo were selected. The primary endpoint was 28-day and 42-day treatment failure. We identified 26 RCTs. Many of the studies included in the present review were of high quality. Overall, DP, artesunate-mefloquine (MAS3) and artemether-lumefentrine (AL) were equally effective for reducing the risk of recurrent parasitaemia. The PCR confirmed efficacy of DP (99.5%) and MAS3 (97.7%) at day 28 exceeded 90%; both are efficacious. Comparable efficacy was also found for DP (95.6%) and AL (94.3%). The present review has documented that DP is comparable to other currently used ACTs such as MAS3 and AL in treating uncomplicated falciparum malaria. The better safety profile of DP and once-daily dosage improves adherence and its fixed co-formulation ensures that both drugs are taken together. Our conclusion is that DP has the potential to become a first-line antimalarial drug.
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http://dx.doi.org/10.1093/trstmh/trs019DOI Listing
February 2013

Meta-analysis: the association between HIV infection and extrapulmonary tuberculosis.

Lung 2013 Feb 23;191(1):27-34. Epub 2012 Nov 23.

School of Postgraduate Studies and Research, International Medical University (IMU), 57000, Kuala Lumpur, Malaysia.

Background: Extrapulmonary tuberculosis has been an AIDS-defining condition. Individual studies that highlight the association between HIV and extrapulmonary TB are available. Our objectives were to synthesis evidence on the association between extrapulmonary tuberculosis and HIV and to explore the effective preventive measures of these two diseases.

Methods: This is a meta-analysis of observational studies reporting effect estimates on how HIV is associated with extrapulmonary tuberculosis. We searched for the eligible studies in the electronic databases using search terms related to HIV and extrapulmonary tuberculosis. Where possible, we estimated the summary odds ratios using random effects meta-analysis. We stratified analysis by the type of study design. We assessed heterogeneity of effect estimates within each group of studies was assessed using I (2) test.

Results: Nineteen studies (7 case control studies and 12 cohort studies) were identified for the present study. The pooled analysis shows a significant association between HIV and extrapulmonary tuberculosis (summary odds ratio: 1.3; 95 % confidence interval (CI) 1.05-1.6; I (2): 0 %). In a subgroup analysis with two studies, a significant association was found between CD4+ count less than 100 and the incidence of extrapulmonary tuberculosis (summary OR: 1.31; 95 % CI 1.02-1.68; I (2): 0 %).

Conclusions: Findings show evidence on the association between extrapulmonary tuberculosis and HIV, based on case control studies. Further studies to understand the mechanisms of interaction of the two pathogens are recommended.
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http://dx.doi.org/10.1007/s00408-012-9440-6DOI Listing
February 2013

Signal detection to identify serious adverse events (neuropsychiatric events) in travelers taking mefloquine for chemoprophylaxis of malaria.

Drug Healthc Patient Saf 2012 3;4:87-92. Epub 2012 Aug 3.

School of Medical Sciences, International Medical University, Kuala Lumpur, Malaysia.

Background: For all medications, there is a trade-off between benefits and potential for harm. It is important for patient safety to detect drug-event combinations and analyze by appropriate statistical methods. Mefloquine is used as chemoprophylaxis for travelers going to regions with known chloroquine-resistant Plasmodium falciparum malaria. As such, there is a concern about serious adverse events associated with mefloquine chemoprophylaxis. The objective of the present study was to assess whether any signal would be detected for the serious adverse events of mefloquine, based on data in clinicoepidemiological studies.

Materials And Methods: We extracted data on adverse events related to mefloquine chemoprophylaxis from the two published datasets. Disproportionality reporting of adverse events such as neuropsychiatric events and other adverse events was presented in the 2 × 2 contingency table. Reporting odds ratio and corresponding 95% confidence interval [CI] data-mining algorithm was applied for the signal detection. The safety signals are considered significant when the ROR estimates and the lower limits of the corresponding 95% CI are ≥2.

Results: Two datasets addressing adverse events of mefloquine chemoprophylaxis (one from a published article and one from a Cochrane systematic review) were included for analyses. Reporting odds ratio 1.58, 95% CI: 1.49-1.68 based on published data in the selected article, and 1.195, 95% CI: 0.94-1.44 based on data in the selected Cochrane review. Overall, in both datasets, the reporting odds ratio values of lower 95% CI were less than 2.

Conclusion: Based on available data, findings suggested that signals for serious adverse events pertinent to neuropsychiatric event were not detected for mefloquine. Further studies are needed to substantiate this.
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http://dx.doi.org/10.2147/DHPS.S34493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3426259PMC
October 2012

Inhibitory effects of cytochrome P450 enzymes CYP2C8, CYP2C9, CYP2C19 and CYP3A4 by Labisia pumila extracts.

J Ethnopharmacol 2012 Sep 31;143(2):586-91. Epub 2012 Jul 31.

School of Pharmacy and Health Sciences, International Medical University, 126, Jalan 19/155B, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.

Ethnopharmacological Relevance: Labisa pumila (LP), popularly known with its local name, Kacip Fatimah, is a well known herb grown in Indochina and Southeast Asia and is traditionally used to regain energy after giving birth in women. The propensity of LP to cause drug-herb interaction via cytochrome P450 (CYP) enzyme system has not been investigated.

Aim Of The Study: To evaluate the in vitro inhibitory effects of various LP extracts (aqueous, ethanol, dichloromethane (DCM) and hexane) on cytochrome P450 2C8 (CYP2C8), CYP2C9, CYP2C19 and CYP3A4 activities.

Materials And Methods: Probe substrate-based high performance liquid chromatography (HPLC) methods were established for CYP2C9, CYP2C19 and CYP3A4 whereas a fluorescence-based enzyme assay was established for CYP2C8. The metabolite formations were examined after incubation of probe substrate with respective CYP isoform in the present or absent of LP extracts. The inhibitory effect of LP was characterized with kinetic parameters IC(50) and K(i) values.

Results: LP extracts showed differential effect of CYP activities with the order of inhibitory potency as follows: dichloromethane>hexane>ethanol>aqueous. This differential effect was only observed in CYP2C isoforms but not CYP3A4. Both the hexane and DCM extracts exhibited moderate to potent inhibition towards CYP2C activities in different modes including non-competitive, competive and mixed-type. The DCM effect was notably strong for CYP2C8 and CYP2C9 showing K(i) values of below 1 μg/ml. The selectivity of LP for CYP2C isoforms rather than CYP3A4 may be attributed to the presence of relatively small, lipophilic yet slightly polar compounds within the LP extracts.

Conclusions: The results of our study revealed that phytoconstituents contained in LP, particularly in hexane and dichloromethane extracts, were able to selectively inhibit CYP2C isoforms. The inactivation was characterized by low K(i) values, in particular, in CYP2C8 and CYP2C9. These in vitro data indicate that LB preparations contain constituents that can potently inhibit CYP2C activities and suggest that this herb should be examined for potential pharmacokinetic drug interactions in vivo.
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http://dx.doi.org/10.1016/j.jep.2012.07.024DOI Listing
September 2012

Relationship between hepatitis C virus infection and type 2 diabetes mellitus: meta-analysis.

World J Gastroenterol 2012 Apr;18(14):1642-51

Faculty of Medicine and Health, International Medical University, Kuala Lumpur 57000, Malaysia.

Aim: To investigate the association between hepatitis C infection and type 2 diabetes mellitus.

Methods: Observational studies assessing the relationship between hepatitis C infection and type 2 diabetes mellitus were identified via electronic and hand searches. Studies published between 1988 to March 2011 were screened, according to the inclusion criteria set for the present analysis. Authors performed separate analyses for the comparisons between hepatitis C virus (HCV) infected and not infected, and HCV infected and hepatitis B virus infected. The included studies were further subgrouped according to the study design. Heterogenity was assessed using I(2) statistics. The summary odds ratios with their corresponding 95% CIs were calculated based on a random-effects model. The included studies were subgrouped according to the study design. To assess any factor that could potentially affect the outcome, results were further stratified by age group (proportion of ≥ 40 years), gender (proportion of male gender), body mass index (BMI) (proportion of BMI ≥ 27), and family history of diabetes (i.e., self reported). For stability of results, a sensitivity analysis was conducted including only prospective studies.

Results: Combining the electronic database and hand searches, a total of 35 observational studies (in 31 articles) were identified for the final analysis. Based on random-effects model, 17 studies (n = 286,084) compared hepatitis C-infected patients with those who were uninfected [summary odds ratio (OR): 1.68, 95% CI: 1.15-2.45]. Of these 17 studies, 7 were both a cross-sectional design (41.2%) and cohort design (41.2%), while 3 were case-control studies (17.6%). Nineteen studies (n = 51,156) compared hepatitis C-infected participants with hepatitis B-infected (summary OR: 1.92, 95% CI: 1.41-2.62). Of these 19 studies, 4 (21.1%), 6 (31.6%) and 9 (47.4%) were cross-sectional, cohort and case-control studies, respectively. A sensitivity analysis with 3 prospective studies indicated that hepatitis C-infected patients had a higher risk of developing type 2 diabetes compared with uninfected controls (summary odds ratio: 1.41, 95% CI: 1.17-1.7; I(2) = 0%). Among hepatitis C-infected patients, male patients (OR: 1.26, 95% CI: 1.03-1.54) with age over 40 years (summary OR: 7.39, 95% CI: 3.82-9.38) had an increased frequency of type 2 diabetes. Some caution must be taken in the interpretation of these results because there may be unmeasured confounding factors which may introduce bias.

Conclusion: The findings support the association between hepatitis C infection and type 2 diabetes mellitus. The direction of association remains to be determined, however. Prospective studies with adequate sample sizes are recommended.
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http://dx.doi.org/10.3748/wjg.v18.i14.1642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325531PMC
April 2012

Drinking water is a significant predictor of Blastocystis infection among rural Malaysian primary schoolchildren.

Parasitology 2012 Jul 23;139(8):1014-20. Epub 2012 Mar 23.

Department of Parasitology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.

Blastocystis infection has a worldwide distribution especially among the disadvantaged population and immunocompromised subjects. This study was carried out to determine the prevalence and the association of Blastocystis infection with the socio-economic characteristics among 300 primary schoolchildren, living in rural communities in Lipis and Raub districts of Pahang state, Malaysia. Stool samples were collected and examined for the presence of Blastocystis using direct smear microscopy after in vitro cultivation in Jones' medium. The overall prevalence of Blastocystis infection was found to be as high as 25.7%. The prevalence was significantly higher among children with gastrointestinal symptoms as compared to asymptomatic children (x2 =4.246; P=0.039). Univariate and multivariate analyses showed that absence of a piped water supply (OR=3.13; 95% CI=1.78, 5.46; P<0.001) and low levels of mothers' education (OR=3.41; 95% CI=1.62, 7.18; P<0.01) were the significant predictors of Blastocystis infection. In conclusion, Blastocystis is prevalent among rural children and the important factors that determine the infection were the sources of drinking water and mothers' educational level. Interventions with provision of clean water supply and health education especially to mothers are required.
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http://dx.doi.org/10.1017/S0031182012000340DOI Listing
July 2012