32 research outputs found

    Adjunctive dexamethasone for the treatment of HIV-uninfected adults with tuberculous meningitis stratified by Leukotriene A4 hydrolase genotype (LAST ACT): Study protocol for a randomised double blind placebo controlled non-inferiority trial [version 1; referees: 2 approved]

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    Background: Tuberculosis kills more people than any other bacterial infection worldwide. In tuberculous meningitis (TBM), a common functional promoter variant (C/T transition) in the gene encoding leukotriene A4 hydrolase (LTA4H), predicts pre-treatment inflammatory phenotype and response to dexamethasone in HIV-uninfected individuals. The primary aim of this study is to determine whether LTA4H genotype determines benefit or harm from adjunctive dexamethasone in HIV-uninfected Vietnamese adults with TBM. The secondary aim is to investigate alternative management strategies in individuals who develop drug induced liver injury (DILI) that will enable the safe continuation of rifampicin and isoniazid therapy.  Methods: We will perform a parallel group, randomised (1:1), double blind, placebo-controlled,  multi-centre Phase III non-inferiority trial, comparing dexamethasone versus placebo for 6-8 weeks in addition to standard anti-tuberculosis treatment in HIV-uninfected patients with TBM stratified by LTA4H genotype. The primary endpoint will be death or new neurological event. The trial will enrol approximately 720 HIV-uninfected adults with a clinical diagnosis of TBM, from two hospitals in Ho Chi Minh City, Vietnam. 640 participants with CC or CT- LTA4H genotype will be randomised to either dexamethasone or placebo, and the remaining TT- genotype participants will be treated with standard-of-care dexamethasone. We will also perform a randomised comparison of three management strategies for anti-tuberculosis DILI. An identical ancillary study will also be perfomed in the linked randomised controlled trial of dexamethasone in HIV-infected adults with TBM (ACT HIV).  Discussion: Previous data have shown that LTA4H genotype may be a critical determinant of inflammation and consequently of adjunctive anti-inflammatory treatment response in TBM. We will stratify dexamethasone therapy according to LTA4H genotype in HIV-uninfected adults, which may indicate a role for targeted anti-inflammatory therapy according to variation in LTA4H C/T transition. A comparison of DILI management strategies may allow the safe continuation of rifampicin and isoniazid

    Viral Etiology of Encephalitis in Children in Southern Vietnam: Results of a One-Year Prospective Descriptive Study

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    Viral encephalitis is associated with high morbidity and mortality in Vietnam. However little is known about the causes of the disease due to a lack of diagnostic facilities in this relatively resource-poor setting. Knowledge about the etiologies and clinical outcome of viral encephalitis is necessary for future design of intervention studies targeted at improvement of clinical management, treatment and prevention of the disease. We report the viral agents, clinical outcome and prognostic factors of mortality of encephalitis in children admitted to a referral hospital for children in southern Vietnam. We show that about one third of the enrolled patients die acutely, and that mortality is independently associated with patient age and Glasgow Coma Scale on admission. Japanese encephalitis, dengue virus and enterovirus (including enterovirus 71) are the major viruses detected in our patients. However, more than half of the patients remain undiagnosed, while mortality in this group is as high as in the diagnosed group. This study will benefit clinicians and public health in terms of clinical management and prevention of childhood encephalitis in Vietnam

    The Vietnam Initiative on Zoonotic Infections (VIZIONS): A Strategic Approach to Studying Emerging Zoonotic Infectious Diseases

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    The effect of newly emerging or re-emerging infectious diseases of zoonotic origin in human populations can be potentially catastrophic, and large-scale investigations of such diseases are highly challenging. The monitoring of emergence events is subject to ascertainment bias, whether at the level of species discovery, emerging disease events, or disease outbreaks in human populations. Disease surveillance is generally performed post hoc, driven by a response to recent events and by the availability of detection and identification technologies. Additionally, the inventory of pathogens that exist in mammalian and other reservoirs is incomplete, and identifying those with the potential to cause disease in humans is rarely possible in advance. A major step in understanding the burden and diversity of zoonotic infections, the local behavioral and demographic risks of infection, and the risk of emergence of these pathogens in human populations is to establish surveillance networks in populations that maintain regular contact with diverse animal populations, and to simultaneously characterize pathogen diversity in human and animal populations. Vietnam has been an epicenter of disease emergence over the last decade, and practices at the human/animal interface may facilitate the likelihood of spillover of zoonotic pathogens into humans. To tackle the scientific issues surrounding the origins and emergence of zoonotic infections in Vietnam, we have established The Vietnam Initiative on Zoonotic Infections (VIZIONS). This countrywide project, in which several international institutions collaborate with Vietnamese organizations, is combining clinical data, epidemiology, high-throughput sequencing, and social sciences to address relevant one-health questions. Here, we describe the primary aims of the project, the infrastructure established to address our scientific questions, and the current status of the project. Our principal objective is to develop an integrated approach to the surveillance of pathogens circulating in both human and animal populations and assess how frequently they are exchanged. This infrastructure will facilitate systematic investigations of pathogen ecology and evolution, enhance understanding of viral cross-species transmission events, and identify relevant risk factors and drivers of zoonotic disease emergence

    Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double-blind, placebo-controlled trial

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    Background Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population. Methods AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2–15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921. Findings Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76–1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [<1%]; p=0·038) at 6 months. Interpretation Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke

    Substitution to Position Number 2 of 4(3<i>H</i>)-Quinazolinone to Create New Derivatives and to Test the Antibacterial or Antifungal Effects

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    The campaign “No action today, no cure tomorrow” against antimicrobial resistance proposed by the World Health Organization (WHO) has not only propeled people to take action to prevent antimicrobial resistance, but has also encouraged researchers to develop new antimicrobial agents. 4(3H)-quinazolinone and its derivatives belong to a group of compounds with many potential applications; this study was conducted to find new derivatives of heterocyclic 4(3H)-quinazolinone with biological effects, contributing to research on antibacterial and antifungal compounds. Using the closed-loop method between anthranilic acid and acetic anhydride, followed by reaction with aniline derivatives, a substituted product of position 3 of 4(3H)-quinazolinone was obtained, along with bromizing to replace the hydrogen of the methyl group in position 2 with dibromo. Heterocyclic derivatives such as imidazole, triazole, and thiazole were replaced from this dibromo product to obtain 19 derivatives. The structures of these derivatives were checked by modern methods such as IR, 1H-NMR, and MS. The results indicated that all of the structures were as expected, so the process of creating new derivatives from 4(3H)-quinazolinone was achieved in this study. Fourteen of the derivatives, namely 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3m, 3o, 3p, 3q, 3r, and 3s, had antibacterial or antifungal effects. Among these, there were five potential derivatives: Antifungal activity was observed on A. niger by 3j and 3f (MIC: 32 μg/mL) and 3s (MIC: 64 μg/mL), and on C. albicans by 3f (MIC: 8 μg/mL); antibacterial activity was observed on S. aureus by 3p (MIC: 16 μg/mL) and 3f and 3r (MIC: 32 μg/mL), on MRSA by 3f and 3r (MIC: 32 μg/mL), and on E. coli by 3f (MIC: 32 μg/mL)

    Substitution to Position Number 2 of 4(3H)-Quinazolinone to Create New Derivatives and to Test the Antibacterial or Antifungal Effects

    No full text
    The campaign &ldquo;No action today, no cure tomorrow&rdquo; against antimicrobial resistance proposed by the World Health Organization (WHO) has not only propeled people to take action to prevent antimicrobial resistance, but has also encouraged researchers to develop new antimicrobial agents. 4(3H)-quinazolinone and its derivatives belong to a group of compounds with many potential applications; this study was conducted to find new derivatives of heterocyclic 4(3H)-quinazolinone with biological effects, contributing to research on antibacterial and antifungal compounds. Using the closed-loop method between anthranilic acid and acetic anhydride, followed by reaction with aniline derivatives, a substituted product of position 3 of 4(3H)-quinazolinone was obtained, along with bromizing to replace the hydrogen of the methyl group in position 2 with dibromo. Heterocyclic derivatives such as imidazole, triazole, and thiazole were replaced from this dibromo product to obtain 19 derivatives. The structures of these derivatives were checked by modern methods such as IR, 1H-NMR, and MS. The results indicated that all of the structures were as expected, so the process of creating new derivatives from 4(3H)-quinazolinone was achieved in this study. Fourteen of the derivatives, namely 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3m, 3o, 3p, 3q, 3r, and 3s, had antibacterial or antifungal effects. Among these, there were five potential derivatives: Antifungal activity was observed on A. niger by 3j and 3f (MIC: 32 &mu;g/mL) and 3s (MIC: 64 &mu;g/mL), and on C. albicans by 3f (MIC: 8 &mu;g/mL); antibacterial activity was observed on S. aureus by 3p (MIC: 16 &mu;g/mL) and 3f and 3r (MIC: 32 &mu;g/mL), on MRSA by 3f and 3r (MIC: 32 &mu;g/mL), and on E. coli by 3f (MIC: 32 &mu;g/mL)
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