Antibiotic combinations to tackle Gram-negative bacterial pathogens : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Biochemistry at Massey University, Manawatu Campus, New Zealand

Antimicrobial resistance, especially in Gram-negative bacterial pathogens, is one of the most serious threats with which humans have been confronted. Coordinated efforts from industrial, academic and government sectors have been called and executed to introduce novel antibiotics into the market to meet clinical demand. Despite that, the rate of successful antibiotic development appears to be lagging behind the emergence of antibiotic resistant pathogens in the arms race between humans and super-bugs. In this dire context, alternative approaches are required to tackle Gram-negative bacterial infections. This thesis reports synergistic interaction between a secondary bile salt, sodium deoxycholate (DOC), and 5-nitrofuran pro-drugs, an old class of synthetic antibiotics, in inhibiting/killing Gram-negative enterobacteria, such as Escherichia coli, Salmonella enterica and Citrobacter gillenii. Using a genetic approach, the underlying mechanism of the synergy between the two drugs was found to involve 5-nitrofuran-mediated inhibition of TolC-associated efflux pumps that otherwise exclude DOC from bacterial cells. This synergistic combination provides a promising tool to combat infections caused by enterobacterial pathogens. The mechanism of action of individual drugs, DOC and 5-nitrofurans, was also investigated using whole-genome sequence analyses of selected resistant mutants, followed by genetic and biochemical studies. A novel nitrofuran-activating enzyme, AhpF, was identified in E. coli that reduces 5-nitrofuran prodrugs in a manner different from that of an established 5-nitrofuran activation enzyme NfsB. This discovery opens new avenues to counteract nitrofuran-resistant clinical isolates by screening for molecules that upregulate AhpF expression or catalytic activity, or designing nitrofuran analogues activated at high efficiency by the AhpF enzyme. Also, this thesis identified mutations that cause a low-level resistance to DOC in efflux-pump-deficient genetic background. These all resulted in growth-slowing phenotype, the majority of which were involved in cAMP signaling. Singe mutations conferring high-level DOC-resistance were not identified in the mutant screen, supporting the use of DOC/nitrofuran combinations

Serum interleukin 6 concentration in patients with pemphigus

Pemphigus is a rare autoimmune blistering disease that detrimentally affects the integumentary system and decreases patients’ quality of life. Recent studies have shown that interleukin 6 (IL-6) is closedly involved in the immunophathogenesis of pemphigus. Therefore, this study was performed to evaluate the role of IL-6 in the pathogenesis and severity of pemphigus disease. The case-series study was conducted in Ho Chi Minh City Hospital of Dermato-Venereology from January 2022 to August 2022, involving 26 patients with pemphigus vulgaris (PV), 4 patients with pemphigus foliaceus (PF), and 20 healthy volunteers. The serum IL-6 concentrations of patients with PV and PF were significantly higher than those of the healthy volunteers (P < 0.001). Serum IL-6 concentrations were significantly higher in patients with a positive than a negative Nikolsky sign (P < 0.001). A significant correlation was found between the serum IL-6 concentration and the pemphigus disease area index (r = 0.8, P < 0.001). Our results suggest that IL-6 may play an important role in the pathogenesis and severity of pemphigus. Therefore, new therapies targeting IL-6 may be a promising choice for treating pemphigus, especially in its severe forms

The Status of Educational Sciences In Vietnam: A Bibliometric Analysis From Clarivate Web Of Science Database Between 1991 And 2018

Since 2013, Vietnam has implemented a plan to reform the whole education sector. However, there is little understanding on the status of educational research in Vietnam, which may lay the foundation for such plan. Thus, this research aims to analyze the whole picture of educational research from Vietnam, as seen from the Clarivate Web of Science (WOS) database: 215 publications were recorded, ranging from 1991 to 2018. These 215 publications were further analyzed from five perspectives: 1) number of publications by year; 2) research fields and levels of education; 3) top institutions with the highest number of publications; 4) international collaboration; and 5) quality. Some of the most notable results are: 1) the educational sciences in Vietnam have been still under-developed until recently; 2) among different research topics research among educational sciences, some (e.g., Vocational Education and Training or Early Childhood Education) seemed to be overlooked whereas others (e.g., Higher Education and Teaching and Learning) seemed to receive more attention from educational scholars; 3) all the most major education – specialized universities did not appear among the top five institutions with highest number of publications; 4) Australia, Thailand, the USA, New Zealand and China were the countries with the highest number of co-publications with Vietnamese researchers; and 5) The majority of publications belonged to low-ranked journals. Implications would be withdrawn for Vietnamese policymakers, education leaders, educational researchers and teachers in order to adjust their policies and/or action plans; thus, enhancing the performance and impacts of educational research in the future

Papillary thyroid carcinoma with tall cell features is as aggressive as tall cell variant: a meta-analysis

There are still ongoing debates as to which cut-off percentage of tall cell (TC) should be used to define tall cell variant (TCV) papillary thyroid carcinoma (PTC). In this meta-analysis, we aimed to investigate the clinicopathological significance of PTC with tall cell features (PTC-TCF, PTC with 10–50% of TCs) in comparison with classical PTC and TCVPTC (PTC with more than 50% of TCs) to clarify the controversial issue. Four electronic databases including PubMed, Web of Science, Scopus and Virtual Health Library were accessed to search for relevant articles. We extracted data from published studies and pooled into odds ratio (OR) and its corresponding 95% confidence intervals (CIs) using random-effect modeling. Nine studies comprising 403 TCVPTCs, 325 PTC-TCFs and 3552 classical PTCs were included for meta-analyses. Overall, the clinicopathological profiles of PTC-TCF including multifocality, extrathyroidal extension, lymph node metastasis, distant metastasis and patient mortality were not statistically different from those of TCVPTC. Additionally, PTC-TCF and TCVPTC were both associated with an increased risk for aggressive clinical courses as compared to classical PTC. The prevalence of BRAF mutation in PTC-TCF and TCVPTC was comparable and both were significantly higher than that in classical PTC. The present meta-analysis demonstrated that even a PTC comprising only 10% of TCs might be associated with a poor clinical outcome. Therefore, the proportions of PTC in PTC should be carefully estimated and reported even when the TC component is as little as 10%

Pragmatic economic valuation of adaptation risk and responses across scales Case study in Vietnam

Vietnam is one of the countries particularly vulnerable to climate change. Increased temperatures, increased salinity intrusion due to sea-level rise and altering precipitation patterns significantly affect livelihood options of smallholder farmers, resulting in losses in agricultural production. These impacts are projected to become increasingly severe, hence, adaptation to climate change and sensitivity needs to be assessed and adaptation measures taken. This study provides a vulnerability assessment based on the results for exposure, sensitivity and adaptive capacity. This includes present and projected future climatic conditions and hazards, crop suitability analyses and socioeconomic assessments on a district scale. In addition, a case study is presented focusing on the two provinces of Tra Vinh and Ben Tre, identified as highly vulnerable in the Mekong Delta area. The case study shows opportunities, economic trade-offs and barriers of adoption of climate-smart agriculture (CSA) practices to adapt to progressive climate change

Assessing the efficacy and safety of magnesium sulfate for management of autonomic nervous system dysregulation in Vietnamese children with severe hand foot and mouth disease.

BACKGROUND: Brainstem encephalitis is a serious complication of hand foot and mouth disease (HFMD) in children. Autonomic nervous system (ANS) dysregulation and hypertension may occur, sometimes progressing to cardiopulmonary failure and death. Vietnamese national guidelines recommend use of milrinone if ANS dysregulation with Stage 2 hypertension develops. We wished to investigate whether magnesium sulfate (MgSO4) improved outcomes in children with HFMD if used earlier in the evolution of the ANS dysregulation (Stage 1 hypertension). METHODS: During a regional epidemic we conducted a randomized, double-blind, placebo-controlled trial of MgSO4 in children with HFMD, ANS dysregulation and Stage 1 hypertension, at the Hospital for Tropical Diseases in Ho Chi Minh city. Study participants received an infusion of MgSO4 or matched placebo for 72 h. We also reviewed data from non-trial HFMD patients in whom milrinone failed to control hypertension, some of whom received MgSO4 as second line therapy. The primary outcome for both analyses was a composite of disease progression within 72 h - addition of milrinone (trial participants only), need for ventilation, shock, or death. RESULTS: Between June 2014 and September 2016, 14 and 12 participants received MgSO4 or placebo respectively, before the trial was stopped due to futility. Among 45 non-trial cases with poorly controlled hypertension despite high-dose milrinone, 33 received MgSO4 while 12 did not. There were no statistically significant differences in the composite outcome between the MgSO4 and the placebo/control groups in either study (adjusted relative risk (95%CI) of [6/14 (43%) vs. 6/12 (50%)], 0.84 (0.37, 1.92), p = 0.682 in the trial and [1/33 (3%) vs. 2/12 (17%)], 0.16 (0.01, 1.79), p = 0.132 in the observational cohort). The incidence of adverse events was similar between the groups. Potentially toxic magnesium levels occurred very rarely with the infusion regime used. CONCLUSION: Although we could not demonstrate efficacy in these studies, there were no safety signals associated with use of 30-50 mg/kg/hr. MgSO4 in severe HFMD. Intermittent outbreaks of HFMD are likely to continue across the region, and an adequately powered trial is still needed to evaluate use of MgSO4 in controlling hypertension in severe HFMD, potentially involving a higher dose regimen. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01940250 (Registered 22 AUG 2013). Trial sponsor: University of Oxford

Spatiotemporal evolution of SARS-CoV-2 Alpha and Delta variants during large nationwide outbreak of COVID-19, Vietnam, 2021

We analyzed 1,303 SARS-CoV-2 whole-genome sequences from Vietnam, and found the Alpha and Delta variants were responsible for a large nationwide outbreak of COVID-19 in 2021. The Delta variant was confined to the AY.57 lineage and caused >1.7 million infections and >32,000 deaths. Viral transmission was strongly affected by nonpharmaceutical interventions

A Bibliometric Analysis of the Global Research Trend in Child Maltreatment

Child maltreatment remains a major health threat globally that requires the understanding of socioeconomic and cultural contexts to craft effective interventions. However, little is known about research agendas globally and the development of knowledge-producing networks in this field of study. This study aims to explore the bibliometric overview on child maltreatment publications to understand their growth from 1916 to 2018. Data from the Web of Science Core Collection were collected in May 2018. Only research articles and reviews written in the English language were included, with no restrictions by publication date. We analyzed publication years, number of papers, journals, authors, keywords and countries, and presented the countries collaboration and co-occurrence keywords analysis. From 1916 to 2018, 47, 090 papers (53.0% in 2010–2018) were published in 9442 journals. Child Abuse & Neglect (2576 papers; 5.5%); Children and Youth Services Review (1130 papers; 2.4%) and Pediatrics (793 papers, 1.7%) published the most papers. The most common research areas were Psychology (16, 049 papers, 34.1%), Family Studies (8225 papers, 17.5%), and Social Work (7367 papers, 15.6%). Among 192 countries with research publications, the most prolific countries were the United States (26, 367 papers), England (4676 papers), Canada (3282 papers) and Australia (2664 papers). We identified 17 authors who had more than 60 scientific items. The most cited papers (with at least 600 citations) were published in 29 journals, headed by the Journal of the American Medical Association (JAMA) (7 papers) and the Lancet (5 papers). This overview of global research in child maltreatment indicated an increasing trend in this topic, with the world’s leading centers located in the Western countries led by the United States. We called for interdisciplinary research approaches to evaluating and intervening on child maltreatment, with a focus on low-middle income countries (LMICs) settings and specific contexts

Awareness and preparedness of healthcare workers against the first wave of the COVID-19 pandemic: A cross-sectional survey across 57 countries.

BACKGROUND: Since the COVID-19 pandemic began, there have been concerns related to the preparedness of healthcare workers (HCWs). This study aimed to describe the level of awareness and preparedness of hospital HCWs at the time of the first wave. METHODS: This multinational, multicenter, cross-sectional survey was conducted among hospital HCWs from February to May 2020. We used a hierarchical logistic regression multivariate analysis to adjust the influence of variables based on awareness and preparedness. We then used association rule mining to identify relationships between HCW confidence in handling suspected COVID-19 patients and prior COVID-19 case-management training. RESULTS: We surveyed 24,653 HCWs from 371 hospitals across 57 countries and received 17,302 responses from 70.2% HCWs overall. The median COVID-19 preparedness score was 11.0 (interquartile range [IQR] = 6.0-14.0) and the median awareness score was 29.6 (IQR = 26.6-32.6). HCWs at COVID-19 designated facilities with previous outbreak experience, or HCWs who were trained for dealing with the SARS-CoV-2 outbreak, had significantly higher levels of preparedness and awareness (p<0.001). Association rule mining suggests that nurses and doctors who had a 'great-extent-of-confidence' in handling suspected COVID-19 patients had participated in COVID-19 training courses. Male participants (mean difference = 0.34; 95% CI = 0.22, 0.46; p<0.001) and nurses (mean difference = 0.67; 95% CI = 0.53, 0.81; p<0.001) had higher preparedness scores compared to women participants and doctors. INTERPRETATION: There was an unsurprising high level of awareness and preparedness among HCWs who participated in COVID-19 training courses. However, disparity existed along the lines of gender and type of HCW. It is unknown whether the difference in COVID-19 preparedness that we detected early in the pandemic may have translated into disproportionate SARS-CoV-2 burden of disease by gender or HCW type