Doctor of Philosophy

dissertationMedical knowledge learned in medical school can become quickly outdated given the tremendous growth of the biomedical literature. It is the responsibility of medical practitioners to continuously update their knowledge with recent, best available clinical evidence to make informed decisions about patient care. However, clinicians often have little time to spend on reading the primary literature even within their narrow specialty. As a result, they often rely on systematic evidence reviews developed by medical experts to fulfill their information needs. At the present, systematic reviews of clinical research are manually created and updated, which is expensive, slow, and unable to keep up with the rapidly growing pace of medical literature. This dissertation research aims to enhance the traditional systematic review development process using computer-aided solutions. The first study investigates query expansion and scientific quality ranking approaches to enhance literature search on clinical guideline topics. The study showed that unsupervised methods can improve retrieval performance of a popular biomedical search engine (PubMed). The proposed methods improve the comprehensiveness of literature search and increase the ratio of finding relevant studies with reduced screening effort. The second and third studies aim to enhance the traditional manual data extraction process. The second study developed a framework to extract and classify texts from PDF reports. This study demonstrated that a rule-based multipass sieve approach is more effective than a machine-learning approach in categorizing document-level structures and iv that classifying and filtering publication metadata and semistructured texts enhances the performance of an information extraction system. The proposed method could serve as a document processing step in any text mining research on PDF documents. The third study proposed a solution for the computer-aided data extraction by recommending relevant sentences and key phrases extracted from publication reports. This study demonstrated that using a machine-learning classifier to prioritize sentences for specific data elements performs equally or better than an abstract screening approach, and might save time and reduce errors in the full-text screening process. In summary, this dissertation showed that there are promising opportunities for technology enhancement to assist in the development of systematic reviews. In this modern age when computing resources are getting cheaper and more powerful, the failure to apply computer technologies to assist and optimize the manual processes is a lost opportunity to improve the timeliness of systematic reviews. This research provides methodologies and tests hypotheses, which can serve as the basis for further large-scale software engineering projects aimed at fully realizing the prospect of computer-aided systematic reviews

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

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

Multiresidue Pesticides Analysis of Vegetables in Vietnam by Ultrahigh-Performance Liquid Chromatography in Combination with High-Resolution Mass Spectrometry (UPLC-Orbitrap MS)

An ultrahigh-performance liquid chromatography in combination with high-resolution mass spectrometry Thermo Q-Extractive Focus Orbitrap MS has been introduced for analysis of multiclass pesticides in vegetable samples collected in Hanoi, Vietnam. Multiclass pesticides were separated on the Thermo Hypersil Gold PFP column utilizing a gradient of the mobile phase consisting of 5 mM ammonium formate, 0.1% formic acid in deionized water, and methanol. The target analytes were detected in the full-scan mode on Thermo Scientific Q-Exactive Focus Orbitrap MS for quantitation at the optimum operating conditions. These conditions included, but not limit to, the resolution of 70000 at the full width at half maximum in both positive and negative mode, mass range from 80 to 1000 m/z, and optimized parameters for the heated electrospray ionization source. The identification of the analytes in real samples was based on retention times, mass to charge ratios, mass accuracies, and MS/MS spectra at the confirmation mode with the inclusion list of target analytes. The mass accuracies of target analytes were from −4.14 ppm (dinotefuran) to 1.42 ppm (cinosulfuron) in the neat solvent and from −3.91 ppm (spinosad D) to 1.29 ppm (cinosulfuron) in the matrix-matched solution. Target analytes in the vegetable-based matrix were extracted by the QuEChERS method. Some critical parameters of the analytical method such as linearity, repeatability, limit of detection, and limit of quantitation have been evaluated and implemented. Excellent LOD and LOQ of the developed method were achieved at the range of 0.04–0.85 and 0.13–2.9 μg·kg−1, respectively. Intraday and interday repeatability of the analytical signal (peak area, n=6) of the developed method were below 3% and 10%, correspondingly. The matrix effect, extraction recovery, and overall recovery were fully investigated by spiking experiments. Experimental results demonstrated that the ionization suppression or enhancement was the main contribution on the overall recoveries of target analytes. Finally, the in-house validated method was applied to pesticides screening in vegetables samples in local villages in Hanoi, Vietnam. The concentrations of all target analytes were below limit of quantitation and lower than US-FDA or EU maximum residue levels

Evaluation of a liquid biopsy protocol using ultra-deep massive parallel sequencing for detecting and quantifying circulation tumor DNA in colorectal cancer patients

The identification and quantification of actionable mutations are critical for guiding targeted therapy and monitoring drug response in colorectal cancer. Liquid biopsy (LB) based on plasma cell-free DNA analysis has emerged as a non-invasive approach with many clinical advantages over conventional tissue sampling. Here, we developed a LB protocol using ultra-deep massive parallel sequencing and validated its clinical performance for detection and quantification of actionable mutations in three major driver genes ( and ). The assay showed a 92% concordance for mutation detection between plasma and paired tissues and great reliability in quantification of variant allele frequency

Prevalence and Associated Factors of <i>optrA</i>-Positive-<i>Enterococcus faecalis</i> in Different Reservoirs around Farms in Vietnam

Linezolid is an antibiotic of last resort for the treatment of infections caused by Gram-positive bacteria, including vancomycin-resistant enterococci. Enterococcus faecalis, a member of enterococci, is a significant pathogen in nosocomial infections. E. faecalis resistance to linezolid is frequently related to the presence of optrA, which is often co-carried with fex, phenicol exporter genes, and erm genes encoding macrolide resistance. Therefore, the common use of antibiotics in veterinary might promote the occurrence of optrA in livestock settings. This is a cross-sectional study aiming to investigate the prevalence of optrA positive E. faecalis (OPEfs) in 6 reservoirs in farms in Ha Nam province, Vietnam, and its associated factors and to explore genetic relationships of OPEfs isolates. Among 639 collected samples, the prevalence of OPEfs was highest in flies, 46.8% (51/109), followed by chickens 37.3% (72/193), dogs 33.3% (17/51), humans 18.7% (26/139), wastewater 16.4% (11/67) and pigs 11.3%, (14/80). The total feeding area and total livestock unit of the farm were associated with the presence of OPEfs in chickens, flies, and wastewater. Among 186 OPEfs strains, 86% were resistant to linezolid. The presence of optrA was also related to the resistant phenotype against linezolid and levofloxacin of E. faecalis isolates. Close genotypic relationships identified by Pulsed Field Gel Electrophoresis between OPEfs isolates recovered from flies and other reservoirs including chickens, pigs, dogs, and wastewater suggested the role of flies in the transmission of antibiotic-resistant pathogens. These results provided warnings of linezolid resistance although it is not used in livestock