Antibiotic prescribing practices of medical doctors in a resource-limited setting and the influence of individual perceptions and stewardship support: a survey in three tertiary hospitals in Vietnam.

Objectives: To understand antibiotic prescribing and influencing factors to inform antimicrobial stewardship (AMS) interventions to reduce unwanted consequences of antibiotic use in hospitals in Vietnam, a lower-middle-income country in Asia. Methods: We conducted a cross-sectional study of doctors at three tertiary hospitals using non-probability convenience sampling, through a paper-based (Hospitals 1 and 2) or electronic (Hospital 3) survey. Questions included items on perceptions regarding antibiotic resistance and AMS, prescribing practices, knowledge, demographics and training. We used principal components analysis and mixed-effects models to examine practices and identify influencing factors. Results: Among 314 surveyed participants, 61%, 57% and 59% in Hospitals 1, 2 and 3, respectively, felt certain about the appropriateness of their antibiotic prescriptions. In total, 9% reported sometimes prescribing antibiotics when not needed to meet patients' expectations, and 13% reported doing so to avoid perceived complications. Higher prescribing confidence was found among those with positive perceptions about AMS (P < 0.0001), whereas negative perceptions about colleagues' practices reduced this confidence (P < 0.0001). Individual preference for branded antibiotics was associated with more unnecessary prescribing whereas having higher prescribing confidence decreased the habits of prescribing when not needed. Conclusions: This study provides important implications for design of hospital interventions to address influencing factors on antibiotic prescribing in Vietnam and similar resource-limited settings. Specific interventions should target improving knowledge through education and training for doctors, enhancing the support from the AMS team, and promoting guidelines and policies for appropriate antibiotic use in hospital.

Aortic regurgitation progression after mitral valve replacement for rheumatic heart disease.

OBJECTIVES: Little is known about the fate of untreated moderate aortic regurgitation after mitral valve replacement for rheumatic heart disease. The aim of this study was to compare the progression to significant aortic valve disease of untreated moderate and mild aortic regurgitation after mitral valve replacement for rheumatic heart disease. METHODS: Among patients who underwent mitral valve replacement for rheumatic heart disease without concomitant aortic valve intervention at our institution between January 2005 and December 2017, we selected 338 patients with pure aortic regurgitation (273 patients with mild and 65 patients with moderate aortic regurgitation). RESULTS: After a median follow-up of 10.0 years, 16 patients developed significant aortic valve disease. Freedom from significant aortic valve disease at 3 years, 8 years, and 14 years was 100%, 97.8 ± 1.1%, and 93.5 ± 2.3% in patients with mild aortic regurgitation, and 98.5 ± 1.5%, 94.5 ± 3.2%, and 80.6 ± 7.5% in patients with moderate aortic regurgitation (log-rank test: p = 0.007). Seven patients with mild aortic regurgitation and two patients with moderate aortic regurgitation underwent aortic valve replacement. CONCLUSIONS: After mitral valve replacement for rheumatic heart disease, untreated moderate aortic regurgitation progressed more frequently to significant aortic valve disease compared to untreated mild aortic regurgitation. A marked difference in freedom from significant aortic valve disease occurred after eight years. Aortic valve replacement was rarely needed.

Metal-Oxide FET Biosensor for Point-of-Care Testing: Overview and Perspective.

Metal-oxide semiconducting materials are promising for building high-performance field-effect transistor (FET) based biochemical sensors. The existence of well-established top-down scalable manufacturing processes enables the reliable production of cost-effective yet high-performance sensors, two key considerations toward the translation of such devices in real-life applications. Metal-oxide semiconductor FET biochemical sensors are especially well-suited to the development of Point-of-Care testing (PoCT) devices, as illustrated by the rapidly growing body of reports in the field. Yet, metal-oxide semiconductor FET sensors remain confined to date, mainly in academia. Toward accelerating the real-life translation of this exciting technology, we review the current literature and discuss the critical features underpinning the successful development of metal-oxide semiconductor FET-based PoCT devices that meet the stringent performance, manufacturing, and regulatory requirements of PoCT.

Simple clinical and laboratory predictors to improve empirical treatment strategies in areas of high scrub typhus and dengue endemicity, central Vietnam.

BACKGROUND: Dengue fever is highly endemic in Vietnam, but scrub typhus-although recognized as an endemic disease-remains underappreciated. These diseases together are likely to account for more than half of the acute undifferentiated fever burden in Vietnam. Scrub typhus (ST) is a bacterial disease requiring antimicrobial treatment, while dengue fever (DF) is of viral etiology and does not. The access to adequate diagnostics and the current understanding of empirical treatment strategies for both illnesses remain limited. In this study we aimed to contribute to the clinical decision process in the management of these two important etiologies of febrile illness in Vietnam. METHODS: Using retrospective data from 221 PCR-confirmed scrub typhus cases and 387 NS1 protein positive dengue fever patients admitted to five hospitals in Khanh Hoa province (central Vietnam), we defined predictive characteristics for both diseases that support simple clinical decision making with potential to inform decision algorithms in future. We developed models to discriminate scrub typhus from dengue fever using multivariable logistic regression (M-LR) and classification and regression trees (CART). Regression trees were developed for the entire data set initially and pruned, based on cross-validation. Regression models were developed in a training data set involving 60% of the total sample and validated in the complementary subsample. Probability cut points for the distinction between scrub typhus and dengue fever were chosen to maximise the sum of sensitivity and specificity. RESULTS: Using M-LR, following seven predictors were identified, that reliably differentiate ST from DF; eschar, regional lymphadenopathy, an occupation in nature, increased days of fever on admission, increased neutrophil count, decreased ratio of neutrophils/lymphocytes, and age over 40. Sensitivity and specificity of predictions based on these seven factors reached 93.7% and 99.5%, respectively. When excluding the "eschar" variable, the values dropped to 76.3% and 92.3%, respectively. The CART model generated one further variable; increased days of fever on admission, when eschar was included, the sensitivity and specificity was 95% and 96.9%, respectively. The model without eschar involved the following six variables; regional lymphadenopathy, increased days of fever on admission, increased neutrophil count, increased lymphocyte count, platelet count ≥ 47 G/L and age over 28 years as predictors of ST and provided a sensitivity of 77.4% and a specificity of 90.7%. CONCLUSIONS: The generated algorithms contribute to differentiating scrub typhus from dengue fever using basic clinical and laboratory parameters, supporting clinical decision making in areas where dengue and scrub typhus are co-endemic in Vietnam.

Collagen XI Alpha 1 (COL11A1) Expression in the Tumor Microenvironment Drives Neuroblastoma Dissemination.

BACKGROUND: Neuroblastoma (NB) is among the most common cancers in children. A highly aggressive form of cancer, NB relies on cells in the microenvironment for dissemination particularly cancer associated fibroblast (CAFs). CAFs synthesise the extracellular matrix to create a scaffold for tumor growth thus enabling the carcinogenesis of NB, Collagen, an abundant scaffold protein produced by CAFs, has been implicated in the creation of an optimal tumor microenvironment, however, the expression profile of collagen within NB is not yet known. METHODS: We characterised collagen expression within the tumor-stroma boundary by microarray and confirmed by qRT-PCR and immunohistochemistry. RESULTS: The collagen marker, COL11A1, was also upregulated in NB CD45+ cells and SMA+ CAFs. Furthermore, SMA+ CAFs led to neuroblastoma cell invasion in an in vitro co-culture system which was subsequently attenuated by gene silencing COL11A1. Immunohistochemical staining of clinical tumor samples revealed that high COL11A1 expression in the stroma adjacent to tumour site, significantly associated with advanced cancer stages, age ≥18 months, undifferentiated tumor status, relapse and poor overall survival. CONCLUSION: Collectively, these results suggest that a COL11A1 signature in the NB microenvironment could represent a novel target for therapeutic intervention.

A simplified point-of-care testing approach for preeclampsia blood biomarkers based on nanoscale field effect transistors.

Rapid diagnosis of preeclampsia is necessary to ensure timely administration of appropriate care and prevent the potentially catastrophic complications of the condition affecting both mothers and babies. While the diagnostic superiority of angiogenic blood biomarkers such as placental growth factor has recently been demonstrated, there is an urgent need to develop point-of-care (PoC) technologies that allow rapid, quantitative, and accurate testing for these markers within local communities. Towards addressing this need, here we report on a fully integrated biodiagnostic platform based on nanoscale indium oxide field effect transistor (FET) sensors. The high-performance FET sensors are integrated with blood sample processing cartridges that minimize the need for operator intervention during the assay and eliminate the need for analytical equipment. Within 40 minutes and from 30 µL of blood, the FET platform could reliably measure PlGF with a limit of detection of 0.06 pg mL-1 and a five order of magnitudes dynamic range. Pilot clinical validation in four preeclamptic pregnancies confirmed that the accuracy and reliability of the FET platform, paving the way for further development to a much-needed point-of-care preeclampsia testing.

CD40LG mutations in Vietnamese patients with X-linked hyper-IgM syndrome; catastrophic anti-phospholipid syndrome as a new complication.

BACKGROUND: X-linked hyper-IgM syndrome (XHIGM) is a rare primary immunodeficiency caused by CD40 ligand defects. METHODS: We identified three patients with XHIGM in Ho Chi Minh City, Vietnam. Whole-exome sequencing, immunological analyses and western blot were performed to investigate phenotypic and genotypic features. RESULTS: Despite showing symptoms typical of XHIGM, including recurrent sinopulmonary infections, oral ulcers and otitis media, the diagnosis was significantly delayed. One patient developed anti-phospholipid syndrome, which has been documented for the first time in XHIGM syndrome. Two patients had elevated IgM levels and all of them had low IgG levels. Exome sequencing revealed mutations in the CD40LG gene: one novel splicing mutation c.156+2T>A and two previously characterised mutations (non-frameshift deletion c.436_438delTAC, stop-gain c.654C>A). Due to these mutations, the CD40 ligand was not expressed in any of the three patients, as demonstrated by western blot analysis. CONCLUSION: This is the first report of XHIGM syndrome in Vietnam indicates that an effective diagnostic strategy, such as sequencing analysis, contributes to reliable diagnosis and subsequent therapy.

Characteristics and biomarkers of patients with central nervous system infection admitted to a referral hospital in Northern Vietnam.

BACKGROUND: Laboratory facilities for etiological diagnosis of central nervous system (CNS) infection are limited in developing countries; therefore, patients are treated empirically, and the epidemiology of the pathogens is not well-known. Tubercular meningitis is one of the common causes of meningitis, which has high morbidity and mortality, but lacks sensitive diagnostic assays. The objectives of this study were to determine the causes of meningitis in adult patients by using molecular assays, to assess the risk factors associated with them, and to explore whether biomarkers can differentiate tubercular meningitis from bacterial meningitis. METHODS: We conducted a cross-sectional study in the Department of Infectious Diseases, Bach Mai Hospital, Hanoi, Vietnam, from June 2012 to May 2014. All patients who were ≥ 16 years old and who had meningoencephalitis suggested by abnormal cerebrospinal fluid (CSF) findings (CSF total cell >5/mm3 or CSF protein ≥40 mg/dL) were included in the study. In addition to culture, CSF samples were tested for common bacterial and viral pathogens by polymerase chain reaction (PCR) and for biomarkers: C-reactive protein and adenosine deaminase (ADA). RESULTS: Total number of patients admitted to the department was 7506; among them, 679 were suspected to have CNS infection, and they underwent lumbar puncture. Five hundred eighty-three patients had abnormal CSF findings (meningoencephalitis); median age was 45 (IQR 31-58), 62.6% were male, and 60.9% were tested for HIV infection. Among 408 CSF samples tested by PCR, out of them, 358 were also tested by culture; an etiology was identified in 27.5% (n=112). S. suis (8.8%), N. meningitis (3.2%), and S. pneumoniae (2.7%) were common bacterial and HSV (2.2%), Echovirus 6 (0.7%), and Echovirus 30 (0.7%) were common viral pathogens detected. M. tuberculosis was found in 3.2%. Mixed pathogens were detected in 1.8% of the CSF samples. Rural residence (aOR 4.1, 95% CI 1.2-14.4) and raised CSF ADA (≥10 IU/L) (aOR 25.5, 95% CI 3.1-212) were associated with bacterial meningitis when compared with viral meningitis; similarly, raised CSF ADA (≥10 IU/L) (aOR 42.2, 95% CI 2.0-882) was associated with tubercular meningitis. CONCLUSIONS: Addition of molecular method to the conventional culture had enhanced the identification of etiologies of CNS infection. Raised CSF ADA (≥10 IU/L) was strongly associated with bacterial and tubercular meningitis. This biomarker might be helpful to diagnose tubercular meningitis once bacterial meningitis is ruled out by other methods.

High performance indium oxide nanoribbon FETs: mitigating devices signal variation from batch fabrication.

Nanostructured field effect transistor (FET) based sensors have emerged as a powerful bioanalytical technology. However, performance variations across multiple devices and between fabrication batches inevitably exist and present a significant challenge holding back the translation of this cutting-edge technology. We report an optimized and cost-effective fabrication process for high-performance indium oxide nanoribbon FET with a steep subthreshold swing of 80 mV per decade. Through systematic electrical characterizations of 57 indium oxide nanoribbon FETs from different batches, we demonstrate an optimal operation point within the subthreshold regime that mitigates the issue of device-to-device performance variation. A non-linear pH sensing of the fabricated indium oxide nanoribbon FETs is also presented.

CMOS-Compatible Silicon Nanowire Field-Effect Transistor Biosensor: Technology Development toward Commercialization.

Owing to their two-dimensional confinements, silicon nanowires display remarkable optical, magnetic, and electronic properties. Of special interest has been the development of advanced biosensing approaches based on the field effect associated with silicon nanowires (SiNWs). Recent advancements in top-down fabrication technologies have paved the way to large scale production of high density and quality arrays of SiNW field effect transistor (FETs), a critical step towards their integration in real-life biosensing applications. A key requirement toward the fulfilment of SiNW FETs' promises in the bioanalytical field is their efficient integration within functional devices. Aiming to provide a comprehensive roadmap for the development of SiNW FET based sensing platforms, we critically review and discuss the key design and fabrication aspects relevant to their development and integration within complementary metal-oxide-semiconductor (CMOS) technology.

Tenofovir-based antiretroviral therapy in HBV-HIV coinfection: results from the TREAT Asia HIV Observational Database.

BACKGROUND: The World Health Organization recommends HBV-HIV-coinfected individuals start antiretroviral therapy containing tenofovir. Here we describe first-line tenofovir use and treatment outcomes in coinfected patients in Asia. METHODS: HBV surface antigen positive patients enrolled in the TREAT Asia HIV Observational Database who started first-line antiretroviral therapy were included. Logistic regression adjusted for period of treatment initiation was used to determine factors associated with tenofovir use. Generalized estimating equations were used to evaluate factors associated with alanine transaminase levels and CD4(+) T-cell count on treatment. RESULTS: There were 548 eligible patients, of whom 149 (27.2%) started tenofovir. Patients treated in high/high-middle income countries (odds ratio 4.4 versus low/low-middle, 95% CI 2.6, 7.4; P<0.001) and those with elevated baseline alanine transaminase (odds ratio 4.2 versus normal, 95% CI 2.4, 7.2; P<0.001) were more likely to receive tenofovir. Hepatitis C antibody positive patients (odds ratio 0.4 versus negative, 95% CI 0.2, 0.8; P=0.008) were less likely. In those starting antiretroviral therapy with elevated alanine transaminase, mean reduction after tenofovir initiation was 11.2 IU/l (95% CI 0.9, 21.6; P=0.034) lower compared with those using a non-tenofovir-based regimen although this did not significantly increase the chance of alanine transaminase normalization. Tenofovir use was not associated with a superior CD4(+) T-cell response. CONCLUSIONS: HBV-HIV-coinfected patients in Asia are most likely to receive tenofovir if they are treated in a high/high-middle income country, have elevated alanine transaminase levels and are hepatitis C antibody negative. Compared to other antiretroviral therapies, tenofovir-based regimens more effectively reduce liver inflammation in HBV-HIV-coinfection but do not result in superior CD4(+) T-cell recovery.

Trends in first-line antiretroviral therapy in Asia: results from the TREAT Asia HIV observational database.

BACKGROUND: Antiretroviral therapy (ART) has evolved rapidly since its beginnings. This analysis describes trends in first-line ART use in Asia and their impact on treatment outcomes. METHODS: Patients in the TREAT Asia HIV Observational Database receiving first-line ART for ≥ 6 months were included. Predictors of treatment failure and treatment modification were assessed. RESULTS: Data from 4662 eligible patients was analysed. Patients started ART in 2003-2006 (n = 1419), 2007-2010 (n = 2690) and 2011-2013 (n = 553). During the observation period, tenofovir, zidovudine and abacavir use largely replaced stavudine. Stavudine was prescribed to 5.8% of ART starters in 2012/13. Efavirenz use increased at the expense of nevirapine, although both continue to be used extensively (47.5% and 34.5% of patients in 2012/13, respectively). Protease inhibitor use dropped after 2004. The rate of treatment failure or modification declined over time (22.1 [95%CI 20.7-23.5] events per 100 patient/years in 2003-2006, 15.8 [14.9-16.8] in 2007-2010, and 11.6 [9.4-14.2] in 2011-2013). Adjustment for ART regimen had little impact on the temporal decline in treatment failure rates but substantially attenuated the temporal decline in rates of modification due to adverse event. In the final multivariate model, treatment modification due to adverse event was significantly predicted by earlier period of ART initiation (hazard ratio 0.52 [95%CI 0.33-0.81], p = 0.004 for 2011-2013 versus 2003-2006), older age (1.56 [1.19-2.04], p = 0.001 for ≥ 50 years versus <30 years), female sex (1.29 [1.11-1.50], p = 0.001 versus male), positive hepatitis C status (1.33 [1.06-1.66], p = 0.013 versus negative), and ART regimen (11.36 [6.28-20.54], p<0.001 for stavudine-based regimens versus tenofovir-based). CONCLUSIONS: The observed trends in first-line ART use in Asia reflect changes in drug availability, global treatment recommendations and prescriber preferences over the past decade. These changes have contributed to a declining rate of treatment modification due to adverse event, but not to reductions in treatment failure.