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Background Severe dengue has been linked to the presence of atypical lymphocytes, which can be quantified using the Q-flag parameter on a hematology analyzer. A higher atypical lymphocyte count has previously been associated with severe dengue. We aimed to evaluate the feasibility of the atypical lymphocyte score to provide an early prognosis for dengue severity. Method A prospective observational study enrolled adult patients admitted to the Infectious Disease ward with a febrile illness of less than 7 days. Blood samples obtained daily until discharge, were processed with XN-20 hematology analyzer with specific attention given to atypical lymphocyte score. Severe dengue cases were classified according to the 2009 World Health Organization Classification. Results A total of 287 cases of laboratory-confirmed dengue, including 25 severe cases, were included. Dengue fever compared to non-dengue patients manifested increased lymphocytes within the high fluorescent zone on Day 6, The atypical lymphocyte score (ALS) of severe dengue showed an early rise, reaching a saturation point of 300 and remaining stable within the timeframe of days 4 to 8 post-fever onset. All but one severe dengue patient had a score exceeding 100 on day 4 post fever onset. Conclusion An atypical lymphocyte score below 100 on day 4 post fever onset, may serve as a predictive indicator that severe dengue is less likely to develop, potentially allowing for a lower level of medical intervention. These findings may contribute to more efficient resource allocation during outbreaks. Trial registration The study was registered under National Medical Research Registration of Malaysia, (NMRR-18–3347-45473, 1 Sept 2019).

Silver nanoparticles (AgNPs) were synthesized using apple extract as a reducing agent and aqueous silver nitrate as the precursor. The AgNPs formation was observed as a color change of the mixture from colorless to dark-brownish. The X-ray diffraction pattern confirmed the presence of only Ag crystallites, and the dynamic light scattering estimates the average sizes of the AgNPs to be 30.25 ± 5.26 nm. Furthermore, Fourier Transform Infrared as well as UV-vis spectroscopy identifies ethylene groups as the reducing agent and capping agent for the formation of the AgNPs. This green synthesis provides an economic, eco-friendly, and clean synthesis route to AgNPs. AgNPs in suspension showed activity against Gram-negative and Gram-positive bacteria with minimum bactericidal concentrations (MBCs) to be in the range from 125 μg/mL to 1000 μg/mL.

Context: The resistance of bacteria to antibiotics is raising serious concern globally. Asian medicinal plants could improve the current treatment strategies for bacterial infections. The antibacterial properties of medicinal plants used by the Khyang tribe in Bangladesh have not been investigated. Objective: The present study examines the antibacterial properties of 18 medicinal plants used by the Khyang tribe in day-to-day practice against human pathogenic bacteria. Materials and methods: Leaves, bark, fruits, seeds, roots and rhizomes from collected plants were successively extracted with hexane, ethyl acetate and ethanol. The corresponding 54 extracts were tested against six human pathogenic bacteria by broth microdilution assay. The antibacterial mode of actions of phytoconstituents and their synergistic effect with vancomycin and cefotaxime towards MRSA was determined by time-killing assay and synergistic interaction assay, respectively. Results and discussion: Hexane extract of bark of Cinnamomum cassia (L.) J. Presl. (Lauraceae) inhibited the growth of MRSA, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii with MIC values below 100 µg/mL. From this plant, cinnamaldehyde evoked at 4 × MIC in 1 h an irreversible decrease of MRSA count Log10 (CFU/mL) from 6 to 0, and was synergistic with vancomycin for MRSA with fractional inhibitory concentration index of 0.3. Conclusions: Our study provides evidence that the medicinal plants in Bangladesh have high potential to improve the current treatment strategies for bacterial infection.

The human leukocyte antigen alleles have been implicated as probable genetic markers in predicting the susceptibility and/or protection to severe manifestations of dengue virus (DENV) infection. In this present study, we aimed to investigate for the first time, the genotype variants of HLA Class 1(-A and -B) of DENV infected patients against healthy individuals in Malaysia. This study was carried out with 92 dengue disease patients and 95 healthy controls from three different ethnic groups (Malay, Chinese and Indian) in Malaysia. All patients with clinical and laboratory confirmation of DENV infection were typed for the HLA-A and B loci, using polymerase chain reaction-sequence specific primer techniques. In our total population, a significant increase for HLA-B*53 (P = 0.042, Pc = 1.008) allele and a significant decrease for A*03 (P = 0.015, Pc = 0.18, OR = 5.23, 95% CI = 1.19-23.02) and B*18 (P = 0.017, Pc = 0.408) alleles were noted in DHF patients as compared to healthy donors. We also observed that in the Malay DHF patients, allele B*13 (P = 0.049, Pc = 1.176, OR = 0.18, 95% CI = 0.03-0.90) was present at a significantly higher frequency in this population while allele HLA-B*18 (P = 0.024, Pc = 0.576) was seen to be negatively associated with DHF. These are the first findings on genetic polymorphisms in our population and we conclude that: (1) In our total population, HLA-B*53 probably involve in disease susceptibility, while the HLA-A*03 and HLA-B*18 may confer protection from progression to severe disease; (2) In the Malay population, HLA-B*13 and B*18 are probably associated in disease susceptibility and protection, respectively. These results could furnish as a valuable predictive tool to identify ethnically different individuals at risk and/or protection from severe forms of DENV infection and would provide valuable informations for the design of future dengue vaccine.

The world’s first dengue vaccine [Dengvaxia; Sanofi Pasteur] was licensed in 2015 and others are in development. Real-world evaluations of dengue vaccines will therefore soon be needed. We assessed feasibility of case control (CC) and test-negative (TN) design studies for dengue vaccine effectiveness by measuring associations between socio-demographic risk factors, and hospitalized dengue outcomes, in Malaysia. Following ethical approval, we conducted hospital-based dengue surveillance for one year in three referral hospitals. Suspected cases aged 9–25 years underwent dengue virological confirmation by RT-PCR and/or NS1 Ag ELISA at a central laboratory. Two age- and geography-matched hospitalized non-dengue case-controls were recruited for a traditional CC study. Suspected cases testing negative were test-negative controls. Socio-demographic, risk factor and routine laboratory data were collected. Logistic regression models were used to estimate associations between confirmed dengue and risk factors. We recruited 327 subjects; 155 were suspected of dengue. The planned sample size was not met. 124 (80%) of suspected cases were dengue-confirmed; seven were assessed as severe. Three had missing RT-PCR results; the study recruited 28 test-negative controls. Only 172 matched controls could be recruited; 90 cases were matched with ≥1 controls. Characteristics of cases and controls were mostly similar. By CC design, two variables were significant risk factors for hospitalized dengue: recent household dengue contact (OR: 54, 95% CI: 7.3–397) and recent neighbourhood insecticidal fogging (OR: 2.1; 95% CI: 1.3–3.6). In the TN design, no risk factors were identified. In comparison with gold-standard diagnostics, routine tests performed poorly. The CC design may be more appropriate than the TN design for hospitalized dengue vaccine effectiveness studies. Selection bias in case control selection could be minimized by protocol changes more easily than increasing TN design control numbers, because early-stage dengue diagnosis in endemic countries is highly specific. MREC study approval: (39)KKM/NIHSEC/P16-1334.

Phyllanthus is a traditional medicinal plant that has been found to have antihepatitis, antibacterial, and anticancer properties. The present studies were to investigate the in vitro molecular mechanisms of anticancer effects of Phyllanthus (P. amarus, P. niruri, P. urinaria, and P. watsonii) plant extracts in human prostate adenocarcinoma. The cancer ten-pathway reporter array was performed and revealed that the expression of six pathway reporters were significantly decreased (Wnt, NFκB, Myc/Max, hypoxia, MAPK/ERK, and MAPK/JNK) in PC-3 cells after treatment with Phyllanthus extracts. Western blot was conducted and identified several signalling molecules that were affected in the signalling pathways including pan-Ras, c-Raf, RSK, Elk1, c-Jun, JNK1/2, p38 MAPK, c-myc, DSH, β-catenin, Akt, HIF-1α, GSK3β, NFκB p50 and p52, Bcl-2, Bax, and VEGF, in treated PC-3 cells. A proteomics-based approach, 2D gel electrophoresis, was performed, and mass spectrometry (MS/MS) results revealed that there were 72 differentially expressed proteins identified in treated PC-3 cells and were involved in tumour cell adhesion, apoptosis, glycogenesis and glycolysis, metastasis, angiogenesis, and protein synthesis and energy metabolism. Overall, these findings suggest that Phyllanthus can interfere with multiple signalling cascades involved in tumorigenesis and be used as a potential therapeutic candidate for treatment of cancer.

The Flavivirus genus is made up of viruses that are either mosquito-borne or tick-borne and other viruses transmitted by unknown vectors. Flaviviruses present a significant threat to global health and infect up to 400 million of people annually. As the climate continues to change throughout the world, these viruses have become prominent infections, with increasing number of infections being detected beyond tropical borders. These include dengue virus (DENV), West Nile virus (WNV), Japanese encephalitis virus (JEV), and Zika virus (ZIKV). Several highly conserved epitopes of flaviviruses had been identified and reported to interact with antibodies, which lead to cross-reactivity results. The major interest of this review paper is mainly focused on the serological cross-reactivity between DENV serotypes, ZIKV, WNV, and JEV. Direct and molecular techniques are required in the diagnosis of Flavivirus -associated human disease. In this review, the serological assays such as neutralization tests, enzyme-linked immunosorbent assay, hemagglutination-inhibition test, Western blot test, and immunofluorescence test will be discussed. Serological assays that have been developed are able to detect different immunoglobulin isotypes (IgM, IgG, and IgA); however, it is challenging when interpreting the serological results due to the broad antigenic cross-reactivity of antibodies to these viruses. However, the neutralization tests are still considered as the gold standard to differentiate these flaviviruses.

Dengue represents one of the most serious life-threatening vector-borne infectious diseases that afflicts approximately 50 million people across the globe annually. Whilst symptomatic infections are frequently reported, asymptomatic dengue remains largely unnoticed. Therefore, we sought to investigate the immune correlates conferring protection to individuals that remain clinically asymptomatic. We determined the levels of neutralizing antibodies (nAbs) and gene expression profiles of host immune factors in individuals with asymptomatic infections, and whose cognate household members showed symptoms consistent to clinical dengue infection. We observed broad down-regulation of host defense response (innate, adaptive and matrix metalloprotease) genes in asymptomatic individuals as against symptomatic patients, with selective up-regulation of distinct genes that have been associated with protection. Selected down-regulated genes include: TNF α (TNF), IL8, C1S, factor B (CFB), IL2, IL3, IL4, IL5, IL8, IL9, IL10 and IL13, CD80, CD28, and IL18, MMP8, MMP10, MMP12, MMP15, MMP16, and MMP24. Selected up-regulated genes include: RANTES (CCL5), MIP-1α (CCL3L1/CCL3L3), MIP-1β (CCL4L1), TGFβ (TGFB), and TIMP1. Our findings highlight the potential association of certain host genes conferring protection against clinical dengue. These data are valuable to better explore the mysteries behind the hitherto poorly understood immunopathogenesis of subclinical dengue infection.

Invasive pneumococcal disease remains an important health priority owing to increasing disease incidence caused by pneumococci expressing non-vaccine serotypes. We previously defined 621 Global Pneumococcal Sequence Clusters (GPSCs) by analysing 20 027 pneumococcal isolates collected worldwide and from previously published genomic data. In this study, we aimed to investigate the pneumococcal lineages behind the predominant serotypes, the mechanism of serotype replacement in disease, as well as the major pneumococcal lineages contributing to invasive pneumococcal disease in the post-vaccine era and their antibiotic resistant traits. We whole-genome sequenced 3233 invasive pneumococcal disease isolates from laboratory-based surveillance programmes in Hong Kong (n=78), Israel (n=701), Malawi (n=226), South Africa (n=1351), The Gambia (n=203), and the USA (n=674). The genomes represented pneumococci from before and after pneumococcal conjugate vaccine (PCV) introductions and were from children younger than 3 years. We identified predominant serotypes by prevalence and their major contributing lineages in each country, and assessed any serotype replacement by comparing the incidence rate between the pre-PCV and PCV periods for Israel, South Africa, and the USA. We defined the status of a lineage as vaccine-type GPSC (≥50% 13-valent PCV [PCV13] serotypes) or non-vaccine-type GPSC (>50% non-PCV13 serotypes) on the basis of its initial serotype composition detected in the earliest vaccine period to measure their individual contribution toward serotype replacement in each country. Major pneumococcal lineages in the PCV period were identified by pooled incidence rate using a random effects model. The five most prevalent serotypes in the PCV13 period varied between countries, with only serotypes 5, 12F, 15B/C, 19A, 33F, and 35B/D common to two or more countries. The five most prevalent serotypes in the PCV13 period varied between countries, with only serotypes 5, 12F, 15B/C, 19A, 33F, and 35B/D common to two or more countries. These serotypes were associated with more than one lineage, except for serotype 5 (GPSC8). Serotype replacement was mainly mediated by expansion of non-vaccine serotypes within vaccine-type GPSCs and, to a lesser extent, by increases in non-vaccine-type GPSCs. A globally spreading lineage, GPSC3, expressing invasive serotypes 8 in South Africa and 33F in the USA and Israel, was the most common lineage causing non-vaccine serotype invasive pneumococcal disease in the PCV13 period. We observed that same prevalent non-vaccine serotypes could be associated with distinctive lineages in different countries, which exhibited dissimilar antibiotic resistance profiles. In non-vaccine serotype isolates, we detected significant increases in the prevalence of resistance to penicillin (52 [21%] of 249 vs 169 [29%] of 575, p=0·0016) and erythromycin (three [1%] of 249 vs 65 [11%] of 575, p=0·0031) in the PCV13 period compared with the pre-PCV period. Globally spreading lineages expressing invasive serotypes have an important role in serotype replacement, and emerging non-vaccine serotypes associated with different pneumococcal lineages in different countries might be explained by local antibiotic-selective pressures. Continued genomic surveillance of the dynamics of the pneumococcal population with increased geographical representation in the post-vaccine period will generate further knowledge for optimising future vaccine design. Bill & Melinda Gates Foundation, Wellcome Sanger Institute, and the US Centers for Disease Control.

Although Streptococcus pneumoniae is a leading cause of childhood disease in South East Asia, little has previously been reported regarding the epidemiology of invasive pneumococcal disease in Malaysia and very few studies have explored pneumococcal epidemiology using multilocus sequence typing (MLST). Here we describe serotype, multilocus sequence type (ST), and penicillin susceptibility of thirty pneumococcal invasive disease isolates received by the University of Malaya Medical Centre between February 2000 and January 2007 and relate this to the serotypes included in current pneumococcal conjugate vaccines. A high level of diversity was observed; fourteen serotypes and 26 sequence types (ST), (11 of which were not previously described) were detected from 30 isolates. Penicillin non-susceptible pneumococci accounted for 33% of isolates. The extent of molecular heterogeneity within carried and disease-causing Malaysian pneumococci remains unknown. Larger surveillance and epidemiological studies are now required in this region to provide robust evidence on which to base future vaccine policy.