Higher Plasma Viremia in the Febrile Phase Is Associated With Adverse Dengue Outcomes Irrespective of Infecting Serotype or Host Immune Status: An Analysis of 5642 Vietnamese Cases.

BACKGROUND: One of the generally accepted constructs of dengue pathogenesis is that clinical disease severity is at least partially dependent upon plasma viremia, yet data on plasma viremia in primary versus secondary infections and in relation to clinically relevant endpoints remain limited and contradictory. METHODS: Using a large database comprising detailed clinical and laboratory characterization of Vietnamese participants enrolled in a series of research studies executed over a 15-year period, we explored relationships between plasma viremia measured by reverse transcription-polymerase chain reaction and 3 clinically relevant endpoints-severe dengue, plasma leakage, and hospitalization-in the dengue-confirmed cases. All 4 dengue serotypes and both primary and secondary infections were well represented. In our logistic regression models we allowed for a nonlinear effect of viremia and for associations between viremia and outcome to differ by age, serotype, host immune status, and illness day at study enrollment. RESULTS: Among 5642 dengue-confirmed cases we identified 259 (4.6%) severe dengue cases, 701 (12.4%) patients with plasma leakage, and 1441 of 4008 (40.0%) patients recruited in outpatient settings who were subsequently hospitalized. From the early febrile phase onwards, higher viremia increased the risk of developing all 3 endpoints, but effect sizes were modest (ORs ranging from 1.12-1.27 per 1-log increase) compared with the effects of a secondary immune response (ORs, 1.67-7.76). The associations were consistent across age, serotype, and immune status groups, and in the various sensitivity and subgroup analyses we undertook. CONCLUSIONS: Higher plasma viremia is associated with increased dengue severity, regardless of serotype or immune status.

Survey of knowledge, attitude and practice of healthcare professionals on dengue transmission, diagnosis and clinical classification.

BACKGROUND: To investigate the knowledge, attitudes, and practices of the healthcare professionals (HCPs) including physicians and nurses regarding dengue transmission, diagnosis and clinical classification using the warning signs of World Health Organization (WHO) 2009 classification. RESULTS: Out of 471 respondents from three countries, 80.9% of physicians and 74% of nurses did not receive previous training regarding the dengue infection. The majority of respondents could identify the primary dengue vector (86%), while only a third of HCPs knew the biting time of dengue mosquitoes. Only half of our respondents knew about immunity induced by serotypes; Moreover, half of our participants could determine the diagnostic tests. On the other hand, about 90% of the respondents took responsibility for talking to the patients about preventive measures. Our respondents also showed wide variations in definition of warning signs listed in the WHO 2009 classification. Multivariate analysis linked the impact of different cofactors including prior training on dengue infection, type of profession, frequency of taking care of dengue patients and country on how HCPs defined these warning signs. CONCLUSIONS: This study could declare the variation in employing the warning signs listed in the WHO 2009 classification. We have figured that most of the HCPs did not take prior training on the dengue viral infection; Also, we found gaps in the knowledge regarding various topics in dengue fever. This paper recommends the gathering of efforts to establish the proper knowledge of dengue infection and the warning signs listed by the WHO.

Association between low serum prealbumin levels and carpal tunnel syndrome in maintenance hemodialysis patients.

AIMS: Carpal tunnel syndrome (CTS) and low serum prealbumin concentration are common in maintenance hemodialysis patients. In this study, we focused on the association between low serum prealbumin levels and carpal tunnel syndrome in maintenance hemodialysis (MHD) patients using low-flux dialysis reuse. MATERIALS AND METHODS: Serum prealbumin levels were assessed to determine the association between low serum prealbumin levels and CTS in 373 prevalent MHD patients (the mean age was 45 years old, hemodialysis duration was 46 months). The patients were divided into 2 groups: the CTS group with 44 patients and the non-CTS group with 329 patients. RESULTS: The prevalence of CTS was 11.8%. Serum prealbumin showed a good prognostic value to predict CTS in MHD patients using low-flux dialysis reuse (the Area Under the Curve = 0.841, p < .001; cutoff value: 26.5 mg/dL with sensitivity = 72.7% and specificity = 79.9%). CONCLUSIONS: Serum prealbumin was a good prognostic biomarker of CTS in MHD patients using low-flux dialysis reuse.

Penfluridol as a Candidate of Drug Repurposing for Anticancer Agent.

Penfluridol has robust antipsychotic efficacy and is a first-generation diphenylbutylpiperidine. Its effects last for several days after a single oral dose and it can be administered once a week to provide better compliance and symptom control. Recently; strong antitumour effects for penfluridol were discovered in various cancer cell lines; such as breast; pancreatic; glioblastoma; and lung cancer cells via several distinct mechanisms. Therefore; penfluridol has drawn much attention as a potentially novel anti-tumour agent. In addition; the anti-cancer effects of penfluridol have been demonstrated in vivo: results showed slight changes in the volume and weight of organs at doses tested in animals. This paper outlines the potential for penfluridol to be developed as a next-generation anticancer drug.

Design, synthesis and evaluation of novel N-hydroxybenzamides/N-hydroxypropenamides incorporating quinazolin-4(3H)-ones as histone deacetylase inhibitors and antitumor agents.

In our search for novel small molecules targeting histone deacetylases, we have designed and synthesized several series of novel N-hydroxybenzamides/N-hydroxypropenamides incorporating quinazolin-4(3H)-ones (4a-h, 8a-d, 10a-d). Biological evaluation showed that these hydroxamic acids were generally cytotoxic against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI-H23, lung cancer). It was found that the N-hydroxypropenamides (10a-d) were the most potent, both in term of HDAC inhibition and cytotoxicity. Several compounds, e.g. 4e, 8b-c, and 10a-c, displayed up to 4-fold more potent than SAHA (suberoylanilide hydroxamic acid, vorinostat) in term of cytotoxicity. These compounds also comparably inhibited HDACs with IC50 values in sub-micromolar range. Docking experiments on HDAC2 isozyme revealed some important features contributing to the inhibitory activity of synthesized compounds, especially for propenamide analogues. Importantly, the free binding energy computed was found to have high quantitative correlation (R2 ∼ 95%) with experimental results.

Genetic variants of MICB and PLCE1 and associations with the laboratory features of dengue.

BACKGROUND: A previous genome-wide association study identified 2 susceptibility loci for severe dengue at MICB rs3132468 and PLCE1 rs3740360 and further work showed these mutations to be also associated with less severe clinical presentations. The aim of this study was to determine if these specific loci were associated with laboratory features of dengue that correlate with clinical severity with the aim of elucidating the functional basis of these genetic variants. METHODS: This was a case-only analysis of laboratory-confirmed dengue patients obtained from 2 prospective cohort studies and 1 randomised clinical trial in Vietnam (Trial registration: ISRCTN ISRCTN03147572. Registered 24th July 2012). 2742 dengue cases were successfully genotyped at MICB rs3132468 and PLCE1 rs3740360. Laboratory variables were compared between genotypes and stratified by DENV serotype. RESULTS: The analysis showed no association between MICB and PLCE1 genotype and early viraemia level, platelet nadir, white cell count nadir, or maximum haematocrit in both overall analysis and in analysis stratified by serotype. DISCUSSION: The lack of an association between genotype and viremia level may reflect the sampling procedures within the included studies. The study findings mean that the functional basis of these mutations remains unclear. TRIAL REGISTRATION: ISRCTN ISRCTN03147572 . Registered 24th July 2012.

Social marketing of low dead space syringes in Vietnam: findings from a 1-year pilot program in Hanoi, Thai Nguyen, and Ho Chi Minh City.

BACKGROUND: Although a growing body of evidence suggests that low dead space syringes may reduce the risk of human immunodeficiency virus (HIV) and Hepatitis C virus infection associated with sharing syringes among people who inject drugs, there is little evidence of effective approaches to motivate people who inject drugs (PWID) to shift from high to low dead space syringes. METHODS: Using a mix of consumer and trade marketing approaches, informed by rapid assessments of both the syringe market and PWID preferences, practices, and behaviors in Hanoi and Ho Chi Minh City, Population Services International (PSI) Vietnam piloted an intervention to increase the use of low dead space syringes (LDSS) in the three provinces of Hanoi, Ho Chi Minh City, and Thai Nguyen, where an estimated 31% of PWID are HIV positive and 58% are living with hepatitis C virus (HCV). RESULTS: This paper provides a summary of the social marketing activities implemented and results achieved by PSI Vietnam during an initial 1-year pilot period from December 2012 to December 2013 in these three provinces to explore their effectiveness in motivating PWID to use low dead space syringes. We found major increases in sales of LDSS accompanied by increases in reported use and consistent use of LDSS among PWID in the three provinces included in the pilot program and a positive and independent association (odds ratio (OR) 21.08; 95% confidence interval (CI) 10.6-27.3) between LDSS use and exposure to social marketing activities. We also found that LDSS use had a stronger association with perceptions of LDSS product quality than with perceptions regarding LDSS potential to reduce HIV transmission risk and use. CONCLUSIONS: We conclude that social marketing interventions have an important role to play in widening access to and the use of LDSS for PWID, as they address the need for PWID to find LDSS when and where they need them and also promote the benefits of LDSS use to PWID. High coverage of these activities among PWID appears to be the key in achieving these successes.

Giant scrotal lipoma in Madelung's disease: A case report.

INTRODUCTION AND IMPORTANCE: Madelung disease is a rare condition of unknown etiology, characterized by large masses of subcutaneous fat in the upper body bilaterally. It rarely affects the lower extremities and genital region. CASE PRESENTATION: Here, we report a patient with Donhouser's type III Madelung's disease. A 47-year-old male patient presented with a giant fatty scrotal tumor that caused deformation of the scrotum and penis, made it difficult to perform daily activities, and hindered sexual activity. The adipose tumor was completely removed using a midline scrotal incision. The scrotum was reconstructed with bilateral anterior and posterior scrotal skin flaps. The excess skin was cut into a wedge shape between the anterior and posterior scrotal regions. CLINICAL DISCUSSION: At 3 months postoperatively, the scrotum was normal in shape and size, and the patient was able to perform personal activities and normal sexual activity. The surgical options, lipectomy results, and experiences drawn from the clinical cases have been discussed. CONCLUSION: Giant scrotal lipomas are very rare in Madelung's disease. Lipectomy and scrotal reconstruction are required. Wedge-shaped scrotal skin excision in the midsection on each side of the scrotum removes excess skin, which could restore the shape and function of the penis and scrotum.

Transition practice for primary immunodeficiency diseases in Southeast Asia: a regional survey.

Introduction: With increased diagnostic capabilities and treatment modalities in the field of primary immunodeficiencies (PID), many pediatric patients survive beyond childhood and experience a change of care to the adult-oriented healthcare system. Unfortunately, the transition pathways for PID are less clearly defined, resulting in deterioration of quality of care in adulthood. Hence, this is the first regional study to address PID clinicians' opinions on practices and challenges of transition care in 7 Southeast Asia (SEA) countries. Methods: We adopted a cross-sectional study design through an online survey platform to enquire opinions of transition practices from expert representatives in 7 SEA countries. Results: Regionally, 3 out 7 countries reported having no practice of transition care. Among cited challenges were reluctant adaptation by patients and caregivers to unfamiliarized adult healthcare systems, inadequate ratio of adult immunologists to patients and lack of facilities for transfer. Discussion and conclusion: Our study provides evidence to advocate policy makers on the importance of standardized integration of transition practice towards betterment of transiting PID patients into adulthood.

The timing setting in kinetic dengue studies: A systematic review.

Dengue is classified as an endemic infectious disease, which is transmitted by Aedes mosquitos. Kinetic studies, which monitor the viral load of the disease, have been the mainstay for several decades in humanity's quest to control this disease. Our study aims to systematically evaluate the usage of different timing systems in dengue kinetic studies. A search in nine electronic databases and manual search of reference and citation lists were conducted to find relevant studies. A quality assessment using the National Institute of Health tools for observational cohort and cross-sectional studies was performed. The protocol was registered in PROSPERO with number CRD42018086435. As results, among included 87 studies, 71 studies (81.6%) use a timing system which is based on the day of illness onset, of which, 11 studies designate the day of illness onset as "day 0″ (type 1A) while 60 studies designate it as "day 1″ (type 1B). Only ten articles (11.5%) designate the day of defervescence as "day 0″, the day before and after defervescence as "day -1″ and "day +1″, respectively. Four articles (4.6%) use a timing system based on the day of hospital admission. Lastly, two studies (2.3%) designate the day of hemorrhagic manifestation as "day 0″ and two studies (2.3%) designate the day of pharmacological treatment as "day 1″. Therefore, the timing system which designates the day of illness onset as "day 1″ (type 1B) was most commonly used. Inconsistent definitions of "day 0″ and "day 1″ may lead to disparities in results across the studies and may have a negative impact on treatment guidelines implementation.

Applied machine learning for the risk-stratification and clinical decision support of hospitalised patients with dengue in Vietnam.

BACKGROUND: Identifying patients at risk of dengue shock syndrome (DSS) is vital for effective healthcare delivery. This can be challenging in endemic settings because of high caseloads and limited resources. Machine learning models trained using clinical data could support decision-making in this context. METHODS: We developed supervised machine learning prediction models using pooled data from adult and paediatric patients hospitalised with dengue. Individuals from 5 prospective clinical studies in Ho Chi Minh City, Vietnam conducted between 12th April 2001 and 30th January 2018 were included. The outcome was onset of dengue shock syndrome during hospitalisation. Data underwent random stratified splitting at 80:20 ratio with the former used only for model development. Ten-fold cross-validation was used for hyperparameter optimisation and confidence intervals derived from percentile bootstrapping. Optimised models were evaluated against the hold-out set. FINDINGS: The final dataset included 4,131 patients (477 adults and 3,654 children). DSS was experienced by 222 (5.4%) of individuals. Predictors were age, sex, weight, day of illness at hospitalisation, indices of haematocrit and platelets over first 48 hours of admission and before the onset of DSS. An artificial neural network model (ANN) model had best performance with an area under receiver operator curve (AUROC) of 0.83 (95% confidence interval [CI], 0.76-0.85) in predicting DSS. When evaluated against the independent hold-out set this calibrated model exhibited an AUROC of 0.82, specificity of 0.84, sensitivity of 0.66, positive predictive value of 0.18 and negative predictive value of 0.98. INTERPRETATION: The study demonstrates additional insights can be obtained from basic healthcare data, when applied through a machine learning framework. The high negative predictive value could support interventions such as early discharge or ambulatory patient management in this population. Work is underway to incorporate these findings into an electronic clinical decision support system to guide individual patient management.

Role of Anillin in Tumour: From a Prognostic Biomarker to a Novel Target.

Anillin (ANLN), an actin-binding protein, reportedly plays a vital role in cell proliferation and migration, particularly in cytokinesis. Although there have been findings pointing to a contribution of ANLN to the development of cancer, the association of ANLN to cancer remains not fully understood. Here, we gather evidence to determine the applicability of ANLN as a prognostic tool for some types of cancer, and the impact that ANLN has on the hallmarks of cancer. We searched academic repositories including PubMed and Google Scholar to find and review studies related to cancer and ANLN. The conclusion is that ANLN could be a potent target for cancer treatment, but the roles ANLN, other than in cytokinesis and its influence on tumour microenvironment remodeling in cancer development, must be further elucidated, and specific ANLN inhibitors should be found.

Interleukin 6 is a better predictor of 5-year cardiovascular mortality than high-sensitivity C-reactive protein in hemodialysis patients using reused low-flux dialyzers.

PURPOSE: In this study, we focused on the role of elevated serum interleukin 6 (IL-6) concentration in predicting 5-year cardiovascular mortality in hemodialysis patients using low-flux dialyzer reuse. MATERIALS AND METHODS: We measured serum IL-6 concentrations in 236 hemodialysis patients (138 males and 98 females) to predict 5-year cardiovascular mortality. We assessed the baseline demographics of all patients who had a mean age of 44 years and a median hemodialysis duration of 38.5 months. We divided all patients into two equal groups based on the serum IL-6 concentration: G1 (n = 118) with serum IL-6 concentration < 6.78 pg/L and G2 (n = 118) with serum IL-6 concentration ≥ 6.78 pg/L. RESULTS: After the 5-year follow-up, 45 patients died due to cardiovascular causes (19.1%). Lipid disorder, hemoglobin, serum albumin, ß2-M, and IL-6 concentration were independent risk factors for predicting cardiovascular mortality during the 60-month follow-up in hemodialysis patients. Based on the Kaplan-Meier analysis, we realized that patients with a higher interleukin 6 concentration (G2) had a significantly higher cardiovascular mortality rate than patients in G1 (log-rank test p < 0.001). Serum IL-6 concentration was a better predictor of 5-year cardiovascular mortality than high-sensitivity C-reactive protein in hemodialysis patients using low-flux dialyzer reuse (AUC = 0.818; p < 0.001; cut-off value: 8.055 pg/mL, Se = 77.8%, Sp = 78.5%). CONCLUSION: Serum IL-6 concentration was a better predictor of 5-year cardiovascular mortality than high-sensitivity C-reactive protein in maintenance hemodialysis patients using low-flux dialysis reuse.

Correction to: Interleukin 6 is a better predictor of 5-year cardiovascular mortality than high-sensitivity C-reactive protein in hemodialysis patients using reused low-flux dialyzers.

The article "Interleukin 6 is a better predictor of 5-year cardiovascular mortality than high-sensitivity C-reactive protein in hemodialysis patients using reused low-fux dialyzers".

Measuring serum beta2-microglobulin to predict long-term mortality in hemodialysis patients using low-flux dialyzer reuse.

PURPOSE: Beta2-microglobulin (ß2-M) is recognized as a surrogate marker relating to the mechanisms of dialysis-associated amyloidosis. Few studies have evaluated the association of serum ß2-M with clinical outcome in hemodialysis patients using high-flux type. However, study on patients using low-flux dialyzer reuse has not been done yet. PATIENTS AND METHODS: Using serum ß2-M level on predicting long-term mortality of hemodialysis patients was examined in 326 prevalent hemodialysis patients (45.59±14.46 years, hemodialysis duration of 47.5 (26-79) months, 186 males and 140 females). The patients were divided into 3 groups with equal number of patients, according to their serum ß2-M levels: group A (n=109, serum ß2-M concentration ≤55.7 mg/L), group B (n=109, serum ß2-M level from 55.8 mg/L to 75.4 mg/L) and group C (n=108, serum ß2-M concentration >75.4 mg/L). RESULTS: During the follow-up period of 5 years, there were 75 all-cause deaths (23.0%). Kaplan-Meier analysis revealed that all-cause mortality in the higher ß2-M group was significantly higher compared to that in the lower ß2-M groups (p<0.001). Serum ß2-M level was a significant predictor for all-cause mortality (AUC =0.898; p<0.001; Cut-off value: 74.9 mg/L, Se=93.3%, Sp=92.9%). CONCLUSION: Serum ß2-M levels were a significant predictor of long-term mortality in hemodialysis patients, who use only low-flux dialyzers and reuse 6 times.

Chikungunya and Zika Virus Cases Detected against a Backdrop of Endemic Dengue Transmission in Vietnam.

Between 2010 and 2014, four chikungunya and two Zika virus infections were identified among 8,105 febrile children in southern Vietnam. Zika viruses were linked to French Polynesian strains, chikungunya to Cambodian strains. Against a backdrop of endemic dengue transmission, chikungunya and Zika present an additional arboviral disease burden in Vietnam.

Sensitivity and specificity of a novel classifier for the early diagnosis of dengue.

BACKGROUND: Dengue is the commonest arboviral disease of humans. An early and accurate diagnosis of dengue can support clinical management, surveillance and disease control and is central to achieving the World Health Organisation target of a 50% reduction in dengue case mortality by 2020. METHODS: 5729 children with fever of <72 hrs duration were enrolled into this multicenter prospective study in southern Vietnam between 2010-2012. A composite of gold standard diagnostic tests identified 1692 dengue cases. Using statistical methods, a novel Early Dengue Classifier (EDC) was developed that used patient age, white blood cell count and platelet count to discriminate dengue cases from non-dengue cases. RESULTS: The EDC had a sensitivity of 74.8% (95%CI: 73.0-76.8%) and specificity of 76.3% (95%CI: 75.2-77.6%) for the diagnosis of dengue. As an adjunctive test alongside NS1 rapid testing, sensitivity of the composite test was 91.6% (95%CI: 90.4-92.9%). CONCLUSIONS: We demonstrate that the early diagnosis of dengue can be enhanced beyond the current standard of care using a simple evidence-based algorithm. The results should support patient management and clinical trials of specific therapies.

Genome-wide association study identifies susceptibility loci for dengue shock syndrome at MICB and PLCE1.

Hypovolemic shock (dengue shock syndrome (DSS)) is the most common life-threatening complication of dengue. We conducted a genome-wide association study of 2,008 pediatric cases treated for DSS and 2,018 controls from Vietnam. Replication of the most significantly associated markers was carried out in an independent Vietnamese sample of 1,737 cases and 2,934 controls. SNPs at two loci showed genome-wide significant association with DSS. We identified a susceptibility locus at MICB (major histocompatibility complex (MHC) class I polypeptide-related sequence B), which was within the broad MHC region on chromosome 6 but outside the class I and class II HLA loci (rs3132468, P(meta) = 4.41 × 10(-11), per-allele odds ratio (OR) = 1.34 (95% confidence interval: 1.23-1.46)). We identified associated variants within PLCE1 (phospholipase C, epsilon 1) on chromosome 10 (rs3765524, P(meta) = 3.08 × 10(-10), per-allele OR = 0.80 (95% confidence interval: 0.75-0.86)). We identify two loci associated with susceptibility to DSS in people with dengue, suggesting possible mechanisms for this severe complication of dengue.

Clinical and virological features of Dengue in Vietnamese infants.

BACKGROUND: Infants account for a small proportion of the overall dengue case burden in endemic countries but can be clinically more difficult to manage. The clinical and laboratory features in infants with dengue have not been extensively characterised. METHODOLOGY/PRINCIPAL FINDINGS: This prospective, cross-sectional descriptive study of infants hospitalized with dengue was conducted in Vietnam from November 2004 to December 2007. More than two-thirds of 303 infants enrolled on clinical suspicion of dengue had a serologically confirmed dengue virus (DENV) infection. Almost all were primary dengue infections and 80% of the infants developed DHF/DSS. At the time of presentation and during hospitalization, the clinical signs and symptoms in infants with dengue were difficult to distinguish from those with other febrile illnesses, suggesting that in infants early laboratory confirmation could assist appropriate management. Detection of plasma NS1 antigen was found to be a sensitive marker of acute dengue in infants with primary infection, especially in the first few days of illness. CONCLUSIONS/SIGNIFICANCE: Collectively, these results provide a systematic description of the clinical features of dengue in infants and highlight the value of NS1 detection for diagnosis.

Dengue in Vietnamese infants--results of infection-enhancement assays correlate with age-related disease epidemiology, and cellular immune responses correlate with disease severity.

The pathogenesis of severe dengue is not well understood. Maternally derived subneutralizing levels of dengue virus-reactive IgG are postulated to be a critical risk factor for severe dengue during infancy. In this study, we found that, in healthy Vietnamese infants, there was a strong temporal association between the Fc-dependent, dengue virus infection-enhancing activity of neat plasma and the age-related epidemiology of severe dengue. We then postulated that disease severity in infants with primary infections would be associated with a robust immune response, possibly as a consequence of higher viral burdens in vivo. Accordingly, in infants hospitalized with acute dengue, the activation phenotype of peripheral-blood NK cells and CD8+ and CD4+ T cells correlated with overall disease severity, but HLA-A*1101-restricted NS3(133-142)-specific CD8+ T cells were not measurable until early convalescence. Plasma levels of cytokines/chemokines were generally higher in infants with dengue shock syndrome. Collectively, these data support a model of dengue pathogenesis in infants whereby antibody-dependent enhancement of infection explains the age-related case epidemiology and could account for antigen-driven immune activation and its association with disease severity. These results also highlight potential risks in the use of live attenuated dengue vaccines in infants in countries where dengue is endemic.