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Fulltext Three Divergent Subpopulations of the Malaria Parasite Plasmodium knowlesi

Divis PC, Lin LC, Rovie-Ryan JJ, Kadir KA, Anderios F, Hisam S, et al.

Emerg Infect Dis, 2017 04;23(4):616-624.
PMID: 28322705 DOI: 10.3201/eid2304.161738

Multilocus microsatellite genotyping of Plasmodium knowlesi isolates previously indicated 2 divergent parasite subpopulations in humans on the island of Borneo, each associated with a different macaque reservoir host species. Geographic divergence was also apparent, and independent sequence data have indicated particularly deep divergence between parasites from mainland Southeast Asia and Borneo. To resolve the overall population structure, multilocus microsatellite genotyping was conducted on a new sample of 182 P. knowlesi infections (obtained from 134 humans and 48 wild macaques) from diverse areas of Malaysia, first analyzed separately and then in combination with previous data. All analyses confirmed 2 divergent clusters of human cases in Malaysian Borneo, associated with long-tailed macaques and pig-tailed macaques, and a third cluster in humans and most macaques in peninsular Malaysia. High levels of pairwise divergence between each of these sympatric and allopatric subpopulations have implications for the epidemiology and control of this zoonotic species.
Fulltext Efficient Surveillance of Plasmodium knowlesi Genetic Subpopulations, Malaysian Borneo, 2000-2018

Divis PCS, Hu TH, Kadir KA, Mohammad DSA, Hii KC, Daneshvar C, et al.

Emerg Infect Dis, 2020 07;26(7):1392-1398.
PMID: 32568035 DOI: 10.3201/eid2607.190924

Population genetic analysis revealed that Plasmodium knowlesi infections in Malaysian Borneo are caused by 2 divergent parasites associated with long-tailed (cluster 1) and pig-tailed (cluster 2) macaques. Because the transmission ecology is likely to differ for each macaque species, we developed a simple genotyping PCR to efficiently distinguish between and survey the 2 parasite subpopulations. This assay confirmed differences in the relative proportions in areas of Kapit division of Sarawak state, consistent with multilocus microsatellite analyses. Analyses of 1,204 human infections at Kapit Hospital showed that cluster 1 caused approximately two thirds of cases with no significant temporal changes from 2000 to 2018. We observed an apparent increase in overall numbers in the most recent 2 years studied, driven mainly by increased cluster 1 parasite infections. Continued monitoring of the frequency of different parasite subpopulations and correlation with environmental alterations are necessary to determine whether the epidemiology will change substantially.
Fulltext Naturally Acquired Human Plasmodium cynomolgi and P. knowlesi Infections, Malaysian Borneo

Raja TN, Hu TH, Kadir KA, Mohamad DSA, Rosli N, Wong LL, et al.

Emerg Infect Dis, 2020 08;26(8):1801-1809.
PMID: 32687020 DOI: 10.3201/eid2608.200343

To monitor the incidence of Plasmodium knowlesi infections and determine whether other simian malaria parasites are being transmitted to humans, we examined 1,047 blood samples from patients with malaria at Kapit Hospital in Kapit, Malaysia, during June 24, 2013-December 31, 2017. Using nested PCR assays, we found 845 (80.6%) patients had either P. knowlesi monoinfection (n = 815) or co-infection with other Plasmodium species (n = 30). We noted the annual number of these zoonotic infections increased greatly in 2017 (n = 284). We identified 6 patients, 17-65 years of age, with P. cynomolgi and P. knowlesi co-infections, confirmed by phylogenetic analyses of the Plasmodium cytochrome c oxidase subunit 1 gene sequences. P. knowlesi continues to be a public health concern in the Kapit Division of Sarawak, Malaysian Borneo. In addition, another simian malaria parasite, P. cynomolgi, also is an emerging cause of malaria in humans.
Sex estimation of Malaysian sub-adults using craniometrics: A computed tomography study

Syed Mohd Hamdan SN, Rahmat RA, Abdul Razak F, Abd Kadir KA, Mohd Faizal Abdullah ER, Ibrahim N

Leg Med (Tokyo), 2023 Sep;64:102275.
PMID: 37229938 DOI: 10.1016/j.legalmed.2023.102275

Sex estimation is crucial in biological profiling of skeletal human remains. Methods used for sex estimation in adults are less effective for sub-adults due to varied cranium patterns during the growth period. Hence, this study aimed to develop a sex estimation model for Malaysian sub-adults using craniometric measurements obtained through multi-slice computed tomography (MSCT). A total of 521 cranial MSCT dataset of sub-adult Malaysians (279 males, 242 females; 0-20 years old) were collected. Mimics software version 21.0 (Materialise, Leuven, Belgium) was used to construct three-dimensional (3D) models. A plane-to-plane (PTP) protocol was utilised to measure 14 selected craniometric parameters. Discriminant function analysis (DFA) and binary logistic regression (BLR) were used to statistically analyze the data. In this study, low level of sexual dimorphism was observed in cranium below 6 years old. The level was then increased with age. For sample validation data, the accuracy of DFA and BLR in estimating sex improved with age from 61.6% to 90.3%. All age groups except 0-2 and 3-6 showed high accuracy percentage (≥75%) when tested using DFA and BLR. DFA and BLR can be utilised to estimate sex for Malaysian sub-adult using MSCT craniometric measurements. However, BLR showed higher accuracy than DFA in sex estimation of sub-adults.
Generation of fluoroscopy-alike radiographs as alternative datasets for deep learning in interventional radiology

Fum WKS, Md Shah MN, Raja Aman RRA, Abd Kadir KA, Wen DW, Leong S, et al.

Phys Eng Sci Med, 2023 Dec;46(4):1535-1552.
PMID: 37695509 DOI: 10.1007/s13246-023-01317-5

In fluoroscopy-guided interventions (FGIs), obtaining large quantities of labelled data for deep learning (DL) can be difficult. Synthetic labelled data can serve as an alternative, generated via pseudo 2D projections of CT volumetric data. However, contrasted vessels have low visibility in simple 2D projections of contrasted CT data. To overcome this, we propose an alternative method to generate fluoroscopy-like radiographs from contrasted head CT Angiography (CTA) volumetric data. The technique involves segmentation of brain tissue, bone, and contrasted vessels from CTA volumetric data, followed by an algorithm to adjust HU values, and finally, a standard ray-based projection is applied to generate the 2D image. The resulting synthetic images were compared to clinical fluoroscopy images for perceptual similarity and subject contrast measurements. Good perceptual similarity was demonstrated on vessel-enhanced synthetic images as compared to the clinical fluoroscopic images. Statistical tests of equivalence show that enhanced synthetic and clinical images have statistically equivalent mean subject contrast within 25% bounds. Furthermore, validation experiments confirmed that the proposed method for generating synthetic images improved the performance of DL models in certain regression tasks, such as localizing anatomical landmarks in clinical fluoroscopy images. Through enhanced pseudo 2D projection of CTA volume data, synthetic images with similar features to real clinical fluoroscopic images can be generated. The use of synthetic images as an alternative source for DL datasets represents a potential solution to the application of DL in FGIs procedures.
Fulltext Glycyrrhizic acid can attenuate metabolic deviations caused by a high-sucrose diet without causing water retention in male Sprague-Dawley rats

Fernando HA, Chandramouli C, Rosli D, Lam YL, Yong ST, Yaw HP, et al.

Nutrients, 2014 Nov 04;6(11):4856-71.
PMID: 25375630 DOI: 10.3390/nu6114856

Glycyrrhizic acid (GA) ameliorates many components of the metabolic syndrome, but its potential therapeutic use is marred by edema caused by inhibition of renal 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2). We assessed whether 100 mg/kg per day GA administered orally could promote metabolic benefits without causing edema in rats fed on a high-sucrose diet. Groups of eight male rats were fed on one of three diets for 28 days: normal diet, a high-sucrose diet, or a high-sucrose diet supplemented with GA. Rats were then culled and renal 11β-HSD2 activity, as well as serum sodium, potassium, angiotensin II and leptin levels were determined. Histological analyses were performed to assess changes in adipocyte size in visceral and subcutaneous depots, as well as hepatic and renal tissue morphology. This dosing paradigm of GA attenuated the increases in serum leptin levels and visceral, but not subcutaneous adipocyte size caused by the high-sucrose diet. Although GA decreased renal 11β-HSD2 activity, it did not affect serum electrolyte or angiotensin II levels, indicating no onset of edema. Furthermore, there were no apparent morphological changes in the liver or kidney, indicating no toxicity. In conclusion, it is possible to reap metabolic benefits of GA without edema using the current dosage and treatment time.
Fulltext Cardio-metabolic health risks in indigenous populations of Southeast Asia and the influence of urbanization

Phipps ME, Chan KK, Naidu R, Mohamad NW, Hoh BP, Quek KF, et al.

BMC Public Health, 2015 Jan 31;15:47.
PMID: 25636170 DOI: 10.1186/s12889-015-1384-3

BACKGROUND: South East Asia (SEA) is home to over 30 tribes of indigenous population groups who are currently facing rapid socio-economic change. Epidemiological transition and increased prevalence of non-communicable diseases (NCD) has occured. In Peninsular Malaysia, the Orang Asli (OA) indigenous people comprise 0 · 6% (150,000) of the population and live in various settlements. OA comprise three distinct large tribes with smaller sub-tribes. The three large tribes include Proto-Malay (sub-tribes: Orang Seletar and Jakun), Senoi (sub-tribes: Mahmeri and Semai), and Negrito (sub-tribes: Jehai, Mendriq and Batek).
METHODS: We studied the health of 636 OA from seven sub-tribes in the Peninsular. Parameters that were assessed included height, weight, BMI and waist circumference whilst blood pressure, cholesterols, fasting blood glucose and HbA1c levels were recorded. We then analysed cardio-metabolic risk factor prevalences and performed multiple pair-wise comparisons among different sub-tribes and socio-economic clusters.
RESULTS: Cardio-metabolic risk factors were recorded in the seven sub-tribes.. Prevalence for general and abdominal obesity were highest in the urbanized Orang Seletar (31 · 6 ± 5 · 7%; 66 · 1 ± 5 · 9%). Notably, hunter gatherer Jehai and Batek tribes displayed the highest prevalence for hypertension (43 · 8 ± 9 · 29% and 51 · 2 ± 15 · 3%) despite being the leanest and most remote, while the Mendriq sub-tribe, living in the same jungle area with access to similar resources as the Batek were less hypertensive (16.3 ± 11.0%), but displayed higher prevalence of abdominal obesity (27.30 ± 13.16%).
CONCLUSIONS: We describe the cardio-metabolic risk factors of seven indigenous communities in Malaysia. We report variable prevalence of obesity, cholesterol, hypertension and diabetes in the OA in contrast to the larger ethnic majorities such as Malays, Chinese and Indians in Malaysia These differences are likely to be due to socio-economic effects and lifestyle changes. In some sub-tribes, other factors including genetic predisposition may also play a role. It is expected that the cardio-metabolic risk factors may worsen with further urbanization, increase the health burden of these communities and strain the government's resources.
Fulltext Prevalence of abnormal glucose tolerance and risk factors in urban and rural Malaysia

Mustafa N, Kamarudin NA, Ismail AA, Khir AS, Ismail IS, Musa KI, et al.

Diabetes Care, 2011 Jun;34(6):1362-4.
PMID: 21498788 DOI: 10.2337/dc11-0005

OBJECTIVE:
To determine the prevalence of prediabetes and diabetes among rural and urban Malaysians.
RESEARCH DESIGN AND METHODS:
This cross-sectional survey was conducted among 3,879 Malaysian adults (1,335 men and 2,544 women). All subjects underwent the 75-g oral glucose tolerance test (OGTT).
RESULTS:
The overall prevalence of prediabetes was 22.1% (30.2% in men and 69.8% in women). Isolated impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) were found in 3.4 and 16.1% of the study population, respectively, whereas 2.6% of the subjects had both IFG and IGT. Based on an OGTT, the prevalence of newly diagnosed type 2 diabetes was 12.6% (31.0% in men and 69.0% in women). The prediabetic subjects also had an increased prevalence of cardiovascular disease risk factors.
CONCLUSIONS:
The large proportion of undiagnosed cases of prediabetes and diabetes reflects the lack of public awareness of the disease.
Prevalence of metabolic syndrome and its risk factors in adult Malaysians: results of a nationwide survey

Mohamud WN, Ismail Aa, Khir AS, Ismail IS, Musa KI, Kadir KA, et al.

Diabetes Res Clin Pract, 2012 04;96(1):91-7.
PMID: 22553777 DOI: 10.1016/j.diabres.2011.11.020

Aim: To report the national prevalence of metabolic syndrome (MetS) and its risk factors among adult Malaysians (>18 years old) based on World Health Organization (WHO), the National Cholesterol Education Program Expert Panel III (ATP III), International Diabetes Federation (IDF) and the 'Harmonized' criteria.Methods: A multi-stage stratified sampling method was used to select 4341 subjects from Peninsular and East Malaysia. Subjects underwent physical and clinical examinations.Results: Based on the WHO, ATP III, IDF and Harmonized definitions, the overall crude prevalences of MetS were 32.1, 34.3, 37.1 and 42.5%, respectively. Regardless of the criteria used, MetS was higher in urban areas, in females, in the Indian population and increased significantly with age. Risk factors also increased with age; abdominal obesity was most prevalent (57.4%), was higher in females (64.2%) and was highest in Indians (68.8%).Hypertension was higher in males (56.5%) and highest among Malays (52.2%). In contrast,the Chinese had the highest prevalence of hypertriglyceridemia (47.4%).Conclusions: Malaysia has a much higher prevalence of MetS compared with other Asian countries and, unless there is immediate intervention to reduce risk factors, this may pose serious implications on the country's healthcare costs and services.
Fulltext Natural Human Infections with Plasmodium cynomolgi, P. inui, and 4 other Simian Malaria Parasites, Malaysia

Yap NJ, Hossain H, Nada-Raja T, Ngui R, Muslim A, Hoh BP, et al.

Emerg Infect Dis, 2021 08;27(8):2187-2191.
PMID: 34287122 DOI: 10.3201/eid2708.204502

We detected the simian malaria parasites Plasmodium knowlesi, P. cynomolgi, P. inui, P. coatneyi, P. inui-like, and P. simiovale among forest fringe-living indigenous communities from various locations in Malaysia. Our findings underscore the importance of using molecular tools to identify newly emergent malaria parasites in humans.
Fulltext Cerebral infarction pattern in tuberculous meningitis

Tai MS, Viswanathan S, Rahmat K, Nor HM, Kadir KA, Goh KJ, et al.

Sci Rep, 2016 12 13;6:38802.
PMID: 27958312 DOI: 10.1038/srep38802

Tuberculous meningitis (TBM) causes significant morbidity and mortality. The primary objective was to re-examine the concept of "TB zone" and "ischaemic zone" in cerebral infarction in patients with tuberculous meningitis. The secondary objective was to evaluate cerebral infarction, vasculitis and vasospasm in tuberculous meningitis infections. Between 2009 and 2014, TBM patients were recruited. Neuroimaging was performed and findings of cerebral infarction, vasculitis and vasospasm were recorded. Infarcts were classified based on arterial supply and Hsieh's classification. Fifty-one TBM patients were recruited of whom 34 patients (67%) had cerebral infarction. Based on Hsieh's classification, 20 patients (59%) had infarcts in both "TB zone" and "ischaemic zones". 12 patients (35%) had infarcts in "ischaemic zone" and two (6%) patients had infarcts in "TB zone". In terms of vascular supply, almost all patients (35/36) had infarcts involving perforators and cortical branches. 25 patients (73%) and 14 patients (41%) had infarcts supplied by lateral lenticulostriate and medial lenticulostriate arteries respectively. 15 patients (37%) had vasculitis. Vasospasm was present in six patients (15%). 29 patients (85%) with cerebral infarction also had leptomeningeal enhancement (p = 0.002). In summary, infarcts involved mainly perforators and cortical branches, rather than "TB zone" versus "ischaemic zone".
Fulltext Initiating or Switching to Insulin Degludec/Insulin Aspart in Adults with Type 2 Diabetes in Malaysia: Results from a Prospective, Non-interventional Real-World Study

Mohamed M, Lim SC, Mumtaz M, Uppal S, Mukherjee D, Kassim MSM, et al.

J ASEAN Fed Endocr Soc, 2023;38(1):37-44.
PMID: 37252419 DOI: 10.15605/jafes.038.01.12

OBJECTIVES: Insulin degludec (IDeg)/insulin aspart (IAsp; IDegAsp) is a co-formulation of 70% IDeg and 30% IAsp. According to several randomized controlled trials, IDegAsp is effective and safe for patients with type 2 diabetes mellitus (T2DM). A subgroup analysis of the ARISE study was conducted to explore the safety and efficacy of IDegAsp among Malaysian patients with T2DM in real-world settings.
METHODOLOGY: ARISE, an open-label, multicenter, non-interventional, prospective study was conducted between August 2019 and December 2020. Adult Malaysian patients with T2DM who were enrolled from 14 sites received IDegAsp as per the local label for 26 weeks. The primary endpoint was change in glycated hemoglobin (HbA1c) levels from baseline to end of study (EOS).
RESULTS: Of the 182 patients included in the full analysis set, 159 (87.4%) completed the study. From baseline to EOS, HbA1c (estimated difference [ED]: -1.3% [95% CI: -1.61 to -0.90]) and fasting plasma glucose levels (ED: -1.8 mmol/L [95% CI: -2.49 to -1.13]) were significantly reduced (p<0.0001). The patient-reported reduced hypoglycemic episodes (overall and nocturnal) during treatment. Overall, 37 adverse events were observed in 23 (12.6%) patients.
CONCLUSION: Switching or initiating IDegAsp treatment resulted in significant improvements in glycemic control and a reduction in hypoglycemic episodes.
Fulltext Population genomic structure and adaptation in the zoonotic malaria parasite Plasmodium knowlesi

Assefa S, Lim C, Preston MD, Duffy CW, Nair MB, Adroub SA, et al.

Proc Natl Acad Sci U S A, 2015 Oct 20;112(42):13027-32.
PMID: 26438871 DOI: 10.1073/pnas.1509534112

Malaria cases caused by the zoonotic parasite Plasmodium knowlesi are being increasingly reported throughout Southeast Asia and in travelers returning from the region. To test for evidence of signatures of selection or unusual population structure in this parasite, we surveyed genome sequence diversity in 48 clinical isolates recently sampled from Malaysian Borneo and in five lines maintained in laboratory rhesus macaques after isolation in the 1960s from Peninsular Malaysia and the Philippines. Overall genomewide nucleotide diversity (π = 6.03 × 10(-3)) was much higher than has been seen in worldwide samples of either of the major endemic malaria parasite species Plasmodium falciparum and Plasmodium vivax. A remarkable substructure is revealed within P. knowlesi, consisting of two major sympatric clusters of the clinical isolates and a third cluster comprising the laboratory isolates. There was deep differentiation between the two clusters of clinical isolates [mean genomewide fixation index (FST) = 0.21, with 9,293 SNPs having fixed differences of FST = 1.0]. This differentiation showed marked heterogeneity across the genome, with mean FST values of different chromosomes ranging from 0.08 to 0.34 and with further significant variation across regions within several chromosomes. Analysis of the largest cluster (cluster 1, 38 isolates) indicated long-term population growth, with negatively skewed allele frequency distributions (genomewide average Tajima's D = -1.35). Against this background there was evidence of balancing selection on particular genes, including the circumsporozoite protein (csp) gene, which had the top Tajima's D value (1.57), and scans of haplotype homozygosity implicate several genomic regions as being under recent positive selection.
Fulltext A comparison of the clinical, laboratory and epidemiological features of two divergent subpopulations of Plasmodium knowlesi

Hu TH, Rosli N, Mohamad DSA, Kadir KA, Ching ZH, Chai YH, et al.

Sci Rep, 2021 10 11;11(1):20117.
PMID: 34635723 DOI: 10.1038/s41598-021-99644-8

Plasmodium knowlesi, a simian malaria parasite responsible for all recent indigenous cases of malaria in Malaysia, infects humans throughout Southeast Asia. There are two genetically distinct subpopulations of Plasmodium knowlesi in Malaysian Borneo, one associated with long-tailed macaques (termed cluster 1) and the other with pig-tailed macaques (cluster 2). A prospective study was conducted to determine whether there were any between-subpopulation differences in clinical and laboratory features, as well as in epidemiological characteristics. Over 2 years, 420 adults admitted to Kapit Hospital, Malaysian Borneo with knowlesi malaria were studied. Infections with each subpopulation resulted in mostly uncomplicated malaria. Severe disease was observed in 35/298 (11.7%) of single cluster 1 and 8/115 (7.0%) of single cluster 2 infections (p = 0.208). There was no clinically significant difference in outcome between the two subpopulations. Cluster 1 infections were more likely to be associated with peri-domestic activities while cluster 2 were associated with interior forest activities consistent with the preferred habitats of the respective macaque hosts. Infections with both P. knowlesi subpopulations cause a wide spectrum of disease including potentially life-threatening complications, with no implications for differential patient management.

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