Displaying publications 81 - 100 of 201 in total

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  1. 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.
  2. 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.
  3. 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.
  4. Khurana RK, Beg S, Burrow AJ, Vashishta RK, Katare OP, Kaur S, et al.
    Eur J Pharm Biopharm, 2017 Dec;121:42-60.
    PMID: 28887099 DOI: 10.1016/j.ejpb.2017.09.001
    The aim of this study was to develop polyunsaturated fatty acid (PUFA) long chain glyceride (LCG) enriched self-nanoemulsifying lipidic nanomicelles systems (SNELS) for augmenting lymphatic uptake and enhancing oral bioavailability of docetaxel and compare its biopharmaceutical performance with a medium-chain fatty acid glyceride (MCG) SNELS. Equilibrium solubility and pseudo ternary phase studies facilitated the selection of suitable LCG and MCG. The critical material attributes (CMAs) and critical process parameters (CPPs) were earmarked using Placket-Burman Design (PBD) and Fractional Factorial Design (FFD) for LCG- and MCG-SNELS respectively, and nano micelles were subsequently optimized using I- and D-optimal designs. Desirability function unearthed the optimized SNELS with Temul <5min, Dnm <100nm, Rel15min >85% and Perm45min >75%. The SNELS demonstrated efficient biocompatibility and energy dependent cellular uptake, reduced P-gp efflux and increased permeability using bi-directional Caco-2 model. Optimal PUFA enriched LCG-SNELS exhibited distinctly superior permeability and absorption parameters during ex vivo permeation, in situ single pass intestinal perfusion, lymphatic uptake and in vivo pharmacokinetic studies over MCG-SNELS.
  5. Vipin, Singh A, Sharma V, Tripathi NK, Dixit R, Singh B, et al.
    Acta Parasitol, 2022 Dec;67(4):1756-1766.
    PMID: 36306015 DOI: 10.1007/s11686-022-00626-1
    PURPOSE: Avian haemosporidian may affect the host from body damage to the extinction of a population. Knowledge of their status may help in future avifauna conservation plans. Hence, their status in two bird groups of India and their phylogenetic relationships with other known lineages of the world were examined.

    METHODS: Cytochrome b gene sequences (479 bp) generated from India and available at MalAvi database were used to study the avian haemosporidian prevalence and phylogenetic analysis of lineages at local and world levels.

    RESULTS: One common (COLL2) and only once in the study (CYOPOL01, CHD01, CYORUB01, EUMTHA01, GEOCIT01) haemosporidian lineages were discovered. 5.88% prevalence of haemosporidian infection was found in 102 samples belonging to 6 host species. Haemoproteus prevalence was 4.90% across five host species (Phylloscopus trochiloides, Cyornis poliogenys, C. hainanus dialilaemus, C. rubeculoides, Eumiyas thalassinus) and Plasmodium prevalence was 0.98% in Geokichla citrina. Spatial phylogeny at the global level showed that COLL2 lineage, found in C. poliogenys in India, was genetically identical to H. pallidus lineages (COLL2) in parts of Africa, Europe, North America, Malaysia, and the Philippines. The Plasmodium lineage (GEOCIT01) was related to PADOM16 in Egypt, but the sequences were only 93.89% alike.

    CONCLUSIONS: Four new lineages of Haemoproteus and one of Plasmodium were reported. COLL2 similarity with other H. pallidus lineages may suggest their hosts as possible infection sources.

  6. Yunos NE, Sharkawi HM, Hii KC, Hu TH, Mohamad DSA, Rosli N, et al.
    Sci Rep, 2022 Oct 14;12(1):17284.
    PMID: 36241678 DOI: 10.1038/s41598-022-21439-2
    Plasmodium knowlesi infections in Malaysia are a new threat to public health and to the national efforts on malaria elimination. In the Kapit division of Sarawak, Malaysian Borneo, two divergent P. knowlesi subpopulations (termed Cluster 1 and Cluster 2) infect humans and are associated with long-tailed macaque and pig-tailed macaque hosts, respectively. It has been suggested that forest-associated activities and environmental modifications trigger the increasing number of knowlesi malaria cases. Since there is a steady increase of P. knowlesi infections over the past decades in Sarawak, particularly in the Kapit division, we aimed to identify hotspots of knowlesi malaria cases and their association with forest activities at a geographical scale using the Geographic Information System (GIS) tool. A total of 1064 P. knowlesi infections from 2014 to 2019 in the Kapit and Song districts of the Kapit division were studied. Overall demographic data showed that males and those aged between 18 and 64 years old were the most frequently infected (64%), and 35% of infections involved farming activities. Thirty-nine percent of Cluster 1 infections were mainly related to farming surrounding residential areas while 40% of Cluster 2 infections were associated with activities in the deep forest. Average Nearest Neighbour (ANN) analysis showed that humans infected with both P. knowlesi subpopulations exhibited a clustering distribution pattern of infection. The Kernel Density Analysis (KDA) indicated that the hotspot of infections surrounding Kapit and Song towns were classified as high-risk areas for zoonotic malaria transmission. This study provides useful information for staff of the Sarawak State Vector-Borne Disease Control Programme in their efforts to control and prevent zoonotic malaria.
  7. Sansom K, Reynolds A, McVeigh J, Mazzotti DR, Dhaliwal SS, Maddison K, et al.
    Sleep Adv, 2023;4(1):zpad028.
    PMID: 37485312 DOI: 10.1093/sleepadvances/zpad028
    Comparisons of actigraphy findings between studies are challenging given differences between brand-specific algorithms. This issue may be minimized by using open-source algorithms. However, the accuracy of actigraphy-derived sleep parameters processed in open-source software needs to be assessed against polysomnography (PSG). Middle-aged adults from the Raine Study (n = 835; F 58%; Age 56.7 ± 5.6 years) completed one night of in-laboratory PSG and concurrent actigraphy (GT3X+ ActiGraph). Actigraphic measures of total sleep time (TST) were analyzed and processed using the open-source R-package GENEActiv and GENEA data in R (GGIR) with and without a sleep diary and additionally processed using proprietary software, ActiLife, for comparison. Bias and agreement (intraclass correlation coefficient) between actigraphy and PSG were examined. Common PSG and sleep health variables associated with the discrepancy between actigraphy, and PSG TST were examined using linear regression. Actigraphy, assessed in GGIR, with and without a sleep diary overestimated PSG TST by (mean ± SD) 31.0 ± 50.0 and 26.4 ± 69.0 minutes, respectively. This overestimation was greater (46.8 ± 50.4 minutes) when actigraphy was analyzed in ActiLife. Agreement between actigraphy and PSG TST was poor (ICC = 0.27-0.44) across all three methods of actigraphy analysis. Longer sleep onset latency and longer wakefulness after sleep onset were associated with overestimation of PSG TST. Open-source processing of actigraphy in a middle-aged community population, agreed poorly with PSG and, on average, overestimated TST. TST overestimation increased with increasing wakefulness overnight. Processing of actigraphy without a diary in GGIR was comparable to when a sleep diary was used and comparable to actigraphy processed with proprietary algorithms in ActiLife.
  8. Sansom K, Reynolds A, Windred D, Phillips A, Dhaliwal SS, Walsh J, et al.
    Sleep, 2024 Jan 05.
    PMID: 38180870 DOI: 10.1093/sleep/zsae001
    STUDY OBJECTIVES: Little is known about the inter-relationships between sleep regularity, obstructive sleep apnea (OSA) and important health markers. This study examined whether irregular sleep is associated with OSA and hypertension, and if this modifies the known association between OSA and hypertension.

    METHODS: 602 adults (age mean(SD) =56.96(5.51) years, female=60%) from the Raine Study who were not evening or night shift workers were assessed for OSA (in-laboratory polysomnography; apnea hypopnea index (AHI) ≥15events/hour), hypertension (doctor diagnosed; or systolic blood pressure ≥140mmHg and/or diastolic ≥90mmHg) and sleep (wrist actigraphy for ≥5 days). A sleep regularity index (SRI) was determined from actigraphy. Participants were categorised by tertiles as severely irregular, mildly irregular, or regular sleepers. Logistic regression models examined the interrelationships between SRI, OSA and hypertension. Covariates included age, sex, body mass index, actigraphy sleep duration, insomnia, depression, activity, alcohol, smoking, and anti-hypertensive medication.

    RESULTS: Compared to regular sleepers, participants with mildly irregular (OR 1.97, 95% CI 1.20-3.27) and severely irregular (OR 2.06, 95% CI 1.25-3.42) sleep had greater odds of OSA. Compared to those with no OSA and regular sleep, OSA and severely irregular sleep combined had the highest odds of hypertension (OR 2.34 95% CI 1.07-5.12; p for interaction=0.02) while those with OSA and regular/mildly irregular sleep were not at increased risk (p for interaction=0.20).

    CONCLUSIONS: Sleep irregularity may be an important modifiable target for hypertension among those with OSA.

  9. Fatih FA, Staines HM, Siner A, Ahmed MA, Woon LC, Pasini EM, et al.
    Malar J, 2013;12:425.
    PMID: 24245918 DOI: 10.1186/1475-2875-12-425
    Evidence suggests that Plasmodium knowlesi malaria in Sarawak, Malaysian Borneo remains zoonotic, meaning anti-malarial drug resistance is unlikely to have developed in the absence of drug selection pressure. Therefore, adequate response to available anti-malarial treatments is assumed.
  10. Zhang S, Singh B, Rodriguez DA, Chasnoits AR, Hussin A, Ching CK, et al.
    Europace, 2015 Nov;17(11):1720-6.
    PMID: 26037794 DOI: 10.1093/europace/euv103
    This study aims to demonstrate that primary prevention (PP) patients with one or more additional risk factors are at a similar risk of life-threatening ventricular arrhythmias when compared with secondary prevention (SP) patients, and would receive similar benefit from an implantable cardioverter defibrillator (ICD), or cardiac resynchronization therapy-defibrillator (CRT-D) implant. The study evaluates the benefits of therapy for high-risk patients in countries where defibrillation therapy for PP of SCA is underutilized.
  11. Faber BW, Abdul Kadir K, Rodriguez-Garcia R, Remarque EJ, Saul FA, Vulliez-Le Normand B, et al.
    PLoS One, 2015;10(4):e0124400.
    PMID: 25881166 DOI: 10.1371/journal.pone.0124400
    Infection with Plasmodium knowlesi, a zoonotic primate malaria, is a growing human health problem in Southeast Asia. P. knowlesi is being used in malaria vaccine studies, and a number of proteins are being considered as candidate malaria vaccine antigens, including the Apical Membrane Antigen 1 (AMA1). In order to determine genetic diversity of the ama1 gene and to identify epitopes of AMA1 under strongest immune selection, the ama1 gene of 52 P. knowlesi isolates derived from human infections was sequenced. Sequence analysis of isolates from two geographically isolated regions in Sarawak showed that polymorphism in the protein is low compared to that of AMA1 of the major human malaria parasites, P. falciparum and P. vivax. Although the number of haplotypes was 27, the frequency of mutations at the majority of the polymorphic positions was low, and only six positions had a variance frequency higher than 10%. Only two positions had more than one alternative amino acid. Interestingly, three of the high-frequency polymorphic sites correspond to invariant sites in PfAMA1 or PvAMA1. Statistically significant differences in the quantity of three of the six high frequency mutations were observed between the two regions. These analyses suggest that the pkama1 gene is not under balancing selection, as observed for pfama1 and pvama1, and that the PkAMA1 protein is not a primary target for protective humoral immune responses in their reservoir macaque hosts, unlike PfAMA1 and PvAMA1 in humans. The low level of polymorphism justifies the development of a single allele PkAMA1-based vaccine.
  12. Zhang X, Meng Y, Houghton P, Liu M, Kanthaswamy S, Oldt R, et al.
    J Med Primatol, 2017 04;46(2):31-41.
    PMID: 28266719 DOI: 10.1111/jmp.12256
    BACKGROUND: Most cynomolgus macaques (Macaca fascicularis) used in the United States as animal models are imported from Chinese breeding farms without documented ancestry. Cynomolgus macaques with varying rhesus macaque ancestry proportions may exhibit differences, such as susceptibility to malaria, that affect their suitability as a research model.

    METHODS: DNA of 400 cynomolgus macaques from 10 Chinese breeding farms was genotyped to characterize their regional origin and rhesus ancestry proportion. A nested PCR assay was used to detect Plasmodium cynomolgi infection in sampled individuals.

    RESULTS: All populations exhibited high levels of genetic heterogeneity and low levels of inbreeding and genetic subdivision. Almost all individuals exhibited an Indochinese origin and a rhesus ancestry proportion of 5%-48%. The incidence of P. cynomolgi infection in cynomolgus macaques is strongly associated with proportion of rhesus ancestry.

    CONCLUSIONS: The varying amount of rhesus ancestry in cynomolgus macaques underscores the importance of monitoring their genetic similarity in malaria research.

  13. Singh B, Zhang S, Ching CK, Huang D, Liu YB, Rodriguez DA, et al.
    Pacing Clin Electrophysiol, 2018 12;41(12):1619-1626.
    PMID: 30320410 DOI: 10.1111/pace.13526
    BACKGROUND: Despite available evidence that implantable cardioverter defibrillators (ICDs) reduce all-cause mortality among patients at risk for sudden cardiac death, utilization of ICDs is low especially in developing countries.

    OBJECTIVE: To summarize reasons for ICD or cardiac resynchronization therapy defibrillator implant refusal by patients at risk for sudden cardiac arrest (Improve SCA) in developing countries.

    METHODS: Primary prevention (PP) and secondary prevention (SP) patients from countries where ICD use is low were enrolled. PP patients with additional risk factors (syncope, ejection fraction 

  14. 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.
  15. Sugiarto SR, Natalia D, Mohamad DSA, Rosli N, Davis WA, Baird JK, et al.
    Sci Rep, 2022 Nov 03;12(1):18546.
    PMID: 36329096 DOI: 10.1038/s41598-022-21570-0
    The simian parasite Plasmodium knowlesi is the predominant species causing human malaria infection, including hospitalisations for severe disease and death, in Malaysian Borneo. By contrast, there have been only a few case reports of knowlesi malaria from Indonesian Borneo. This situation seems paradoxical since both regions share the same natural macaque hosts and Anopheles mosquito vectors, and therefore have a similar epidemiologically estimated risk of infection. To determine whether there is a true cross-border disparity in P. knowlesi prevalence, we conducted a community-based malaria screening study using PCR in Kapuas Hulu District, West Kalimantan. Blood samples were taken between April and September 2019 from 1000 people aged 6 months to 85 years attending health care facilities at 27 study sites within or close to jungle areas. There were 16 Plasmodium positive samples by PCR, five human malarias (two Plasmodium vivax, two Plasmodium ovale and one Plasmodium malariae) and 11 in which no species could be definitively identified. These data suggest that, if present, simian malarias including P. knowlesi are rare in the Kapuas Hulu District of West Kalimantan, Indonesian Borneo compared to geographically adjacent areas of Malaysian Borneo. The reason for this discrepancy, if confirmed in other epidemiologically similar regions of Indonesian Borneo, warrants further studies targeting possible cross-border differences in human activities in forested areas, together with more detailed surveys to complement the limited data relating to monkey hosts and Anopheles mosquito vectors in Indonesian Borneo.
  16. Wan SA, Tiong IK, Chuah SL, Cheong YR, Singh BSM, Lee KH, et al.
    Med J Malaysia, 2023 Mar;78(2):207-212.
    PMID: 36988532
    INTRODUCTION: Osteoporosis and osteoporotic fracture pose a major public health problem in our ageing population, and particularly concerning is the increased morbidity and mortality associated with osteoporotic hip fractures. While overall diagnosis and treatment for osteoporosis have improved, osteoporosis in men remains underdiagnosed and undertreated. We aim to describe the difference in clinical characteristics between elderly men and women with osteoporotic hip fractures in Sarawak General Hospital.

    MATERIALS AND METHODS: All patients diagnosed with osteoporotic hip fracture admitted to Sarawak General Hospital from June 2019 to March 2021 were recruited, and demographic data and clinical features were obtained.

    RESULTS: There were 140 patients with osteoporotic hip fracture, and 40 were men (28.6%). The mean age for males was 74.1 ± 9.5 years, while the mean age for females was 77.4 ± 9.1 years (p=0.06). The types of fracture consisted of neck of femur=78, intertrochanteric=61 and subtrochanteric=1. More men were active smokers (15% vs 1%, p<0.001). There were 20 men with secondary osteoporosis (50%), while 13 women (13%) had secondary osteoporosis (p<0.001). The causes of secondary osteoporosis among the men were hypogonadism, COPD, glucocorticoid-induced osteoporosis, renal disease, androgen deprivation therapy, thyroid disorder, prostate cancer and previous gastrectomy. There were two deaths among the men and four deaths among the women during the inpatient and 3 months follow-up period. There was no statistical significance between the mortality rates between male patients (5%) and female patients (4%) (p=0.55).

    CONCLUSION: There were more females with osteoporotic hip fractures, and there were significantly more males with secondary osteoporotic hip fractures.

  17. Lin AC, Biffi M, Exner DV, Johnson WB, Gras D, Hussin A, et al.
    PMID: 29808920 DOI: 10.1111/pace.13389
    BACKGROUND: Steroid-eluting (SE) electrodes suppress local inflammation and lower pacing capture thresholds (PCT); however, their effectiveness on quadripolar left ventricular (LV) leads in the cardiac vein is not fully studied. We evaluated the effectiveness of SE on all four LV pacing electrodes in human subjects enrolled in the Medtronic Attain® Performa™ quadripolar LV lead study.

    METHODS: A total of 1,097 subjects were included in this evaluation. At each follow-up visit (1, 3, 6, and 12 months), LV PCT and pacing impedance were measured using either manual or automated testing methods. Summary statistics for PCT and impedance values were obtained for implant and each scheduled follow-up visit for all lead models.

    RESULTS: Average extended bipolar (LV electrode to right ventricular Coil) PCTs for the four LV SE pacing electrodes (LV1, LV2, LV3, and LV4) on the three shapes of the quadripolar LV leads were 1.06 ± 0.97 V, 1.38 ± 1.26 V, 1.51 ± 1.33 V, and 2.25 ± 1.63 V, respectively, at 0.5-ms pulse width. PCTs remained low and stable throughout the 12-month follow-up period.

    CONCLUSION: This clinical trial demonstrated that SE on all LV pacing electrodes is associated with low and stable PCTs for all quadripolar LV lead electrodes, resulting in multiple viable vectors for LV pacing. The large number of available vectors facilitates basal pacing, avoidance of PNS, and potentially prolongs generator longevity due to lower PCTs.

  18. Zhao S, Ching CK, Huang D, Liu YB, Rodriguez-Guerrero DA, Hussin A, et al.
    BMC Med, 2024 Mar 22;22(1):130.
    PMID: 38519982 DOI: 10.1186/s12916-024-03310-5
    BACKGROUND: Comprehensive data on patients at high risk of sudden cardiac death (SCD) in emerging countries are lacking. The aim was to deepen our understanding of the SCD phenotype and identify risk factors for death among patients at high risk of SCD in emerging countries.

    METHODS: Patients who met the class I indication for implantable cardioverter-defibrillator (ICD) implantation according to guideline recommendations in 17 countries and regions underrepresented in previous trials were enrolled. Countries were stratified by the WHO regional classification. Patients were or were not implanted with an ICD at their discretion. The outcomes were all-cause mortality and SCD.

    RESULTS: We enrolled 4222 patients, and 3889 patients were included in the analysis. The mean follow-up period was 21.6 ± 10.2 months. There were 433 (11.1%) instances of all-cause mortality and 117 (3.0%) cases of SCD. All-cause mortality was highest in primary prevention (PP) patients from Southeast Asia and secondary prevention (SP) patients from the Middle East and Africa. The SCD rates among PP and SP patients were both highest in South Asia. Multivariate Cox regression modelling demonstrated that in addition to the independent predictors identified in previous studies, both geographic region and ICD use were associated with all-cause mortality in patients with high SCD risk. Primary prophylactic ICD implantation was associated with a 36% (HR = 0.64, 95% CI 0.531-0.802, p 

  19. Ahmed AM, Pinheiro MM, Divis PC, Siner A, Zainudin R, Wong IT, et al.
    PLoS Negl Trop Dis, 2014 Aug;8(8):e3086.
    PMID: 25121807 DOI: 10.1371/journal.pntd.0003086
    Emerging pathogens undermine initiatives to control the global health impact of infectious diseases. Zoonotic malaria is no exception. Plasmodium knowlesi, a malaria parasite of Southeast Asian macaques, has entered the human population. P. knowlesi, like Plasmodium falciparum, can reach high parasitaemia in human infections, and the World Health Organization guidelines for severe malaria list hyperparasitaemia among the measures of severe malaria in both infections. Not all patients with P. knowlesi infections develop hyperparasitaemia, and it is important to determine why. Between isolate variability in erythrocyte invasion, efficiency seems key. Here we investigate the idea that particular alleles of two P. knowlesi erythrocyte invasion genes, P. knowlesi normocyte binding protein Pknbpxa and Pknbpxb, influence parasitaemia and human disease progression. Pknbpxa and Pknbpxb reference DNA sequences were generated from five geographically and temporally distinct P. knowlesi patient isolates. Polymorphic regions of each gene (approximately 800 bp) were identified by haplotyping 147 patient isolates at each locus. Parasitaemia in the study cohort was associated with markers of disease severity including liver and renal dysfunction, haemoglobin, platelets and lactate, (r = ≥ 0.34, p =  <0.0001 for all). Seventy-five and 51 Pknbpxa and Pknbpxb haplotypes were resolved in 138 (94%) and 134 (92%) patient isolates respectively. The haplotypes formed twelve Pknbpxa and two Pknbpxb allelic groups. Patients infected with parasites with particular Pknbpxa and Pknbpxb alleles within the groups had significantly higher parasitaemia and other markers of disease severity. Our study strongly suggests that P. knowlesi invasion gene variants contribute to parasite virulence. We focused on two invasion genes, and we anticipate that additional virulent loci will be identified in pathogen genome-wide studies. The multiple sustained entries of this diverse pathogen into the human population must give cause for concern to malaria elimination strategists in the Southeast Asian region.
  20. Moyes CL, Henry AJ, Golding N, Huang Z, Singh B, Baird JK, et al.
    PLoS Negl Trop Dis, 2014 Mar;8(3):e2780.
    PMID: 24676231 DOI: 10.1371/journal.pntd.0002780
    BACKGROUND: The simian malaria parasite, Plasmodium knowlesi, can cause severe and fatal disease in humans yet it is rarely included in routine public health reporting systems for malaria and its geographical range is largely unknown. Because malaria caused by P. knowlesi is a truly neglected tropical disease, there are substantial obstacles to defining the geographical extent and risk of this disease. Information is required on the occurrence of human cases in different locations, on which non-human primates host this parasite and on which vectors are able to transmit it to humans. We undertook a systematic review and ranked the existing evidence, at a subnational spatial scale, to investigate the potential geographical range of the parasite reservoir capable of infecting humans.

    METHODOLOGY/PRINCIPAL FINDINGS: After reviewing the published literature we identified potential host and vector species and ranked these based on how informative they are for the presence of an infectious parasite reservoir, based on current evidence. We collated spatial data on parasite occurrence and the ranges of the identified host and vector species. The ranked spatial data allowed us to assign an evidence score to 475 subnational areas in 19 countries and we present the results on a map of the Southeast and South Asia region.

    CONCLUSIONS/SIGNIFICANCE: We have ranked subnational areas within the potential disease range according to evidence for presence of a disease risk to humans, providing geographical evidence to support decisions on prevention, management and prophylaxis. This work also highlights the unknown risk status of large parts of the region. Within this unknown category, our map identifies which areas have most evidence for the potential to support an infectious reservoir and are therefore a priority for further investigation. Furthermore we identify geographical areas where further investigation of putative host and vector species would be highly informative for the region-wide assessment.

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