The Roles of IS Project Critical Success Factors: A Relevatory Case

Research in Critical Success Factors (CSFs) of Enterprise Systems (ES) projects has identified numerous practitioner governance mechanisms for ensuring project success. However, such research has not developed a theory of why certain critical success factors encourage project success. Our research develops such theory on a case study where even though the levels of several critical success factors were weak, the project nevertheless succeeded. Specifically, the logistics ES project succeeded even though there was (1) only marginal top management support, (2) low key user commitment, and (3) change management, training and other critical aspects of user management and communication were not well done. Using a modified dialectical lens, we highlight that project team legitimacy appears to be the underlying CSF, and many heretofore identified CSFs are really manifestations of project team legitimacy

Revisiting the Role of Thiopurines in Inflammatory Bowel Disease Through Pharmacogenomics and Use of Novel Methods for Therapeutic Drug Monitoring

Azathioprine and 6-mercaptopurine, often referred to as thiopurine compounds, are commonly used in the management of inflammatory bowel disease. However, patients receiving these drugs are prone to developing adverse drug reactions or therapeutic resistance. Achieving predefined levels of two major thiopurine metabolites, 6-thioguanine nucleotides and 6-methylmercaptopurine, is a long-standing clinical practice in ensuring therapeutic efficacy; however, their correlation with treatment response is sometimes unclear. Various genetic markers have also been used to aid the identification of patients who are thiopurine-sensitive or refractory. The recent discovery of novel Asian-specific DNA variants, namely those in the NUDT15 gene, and their link to thiopurine toxicity, have led clinicians and scientists to revisit the utility of Caucasian biomarkers for Asian individuals with inflammatory bowel disease. In this review, we explore the limitations associated with the current methods used for therapeutic monitoring of thiopurine metabolites and how the recent discovery of ethnicity-specific genetic markers can complement thiopurine metabolites measurement in formulating a strategy for more accurate prediction of thiopurine response. We also discuss the challenges in thiopurine therapy, alongside the current strategies used in patients with reduced thiopurine response. The review is concluded with suggestions for future work aiming at using a more comprehensive approach to optimize the efficacy of thiopurine compounds in inflammatory bowel disease

Crossover learning through a health campaign integrated in a bachelor of pharmacy curriculum

Purpose: Continuous improvement in teaching and learning methods is vital for addressing the changing needs of pharmacy education. Many have agreed that one of the most effective approaches is crossover learning, whereby learners are actively involved in shaping their learning experiences and acquiring knowledge in both formal and informal settings. In this work, we report an ongoing initiative of facilitating a student-led health campaign, Brain Awareness Day, to promote crossover learning. Method: The campaign is included in our curriculum (Bachelor of Pharmacy with Honours) as a formal mode of learning and continuous assessment. A total of 84 pharmacy students were divided into groups of eight or nine to work on a drug addiction-themed assignment and present the result in the form of a poster exhibition. A short, online questionnaire was used to gather the students’ feedback on their learning experience and perceived gain of relevant insights from the campaign. Findings: Thirty nine out of 84 students took part in the survey. Most students agreed that their involvement in the campaign had contributed favourably to their learning experience and achievement of the pre-defined learning outcomes. The students also gave several suggestions for improving the organisation of the campaign. They suggested that more budget should be allocated for running the campaign, and that finding an off-campus venue might help to increase footfall. Significance: We concluded that the campaign had been effective in encouraging crossover learning, and it would remain an integrated sub-programme in our pharmacy curriculum. Diversifying methods of teaching and learning may help to realise Malaysia’s aim of developing well-rounded and employable graduates

Threat-Balancing in Vendor Transition

While many outsourcing contracts are expiring, and vendor transition is becoming an increasing concern, little research helps organizations manage vendor transition. This paper explores vendor transition across two case sites. In one case, the outgoing vendor cooperated with the client which resulted in the client distancing itself from interactions between vendors. In the second case, the outgoing vendor was openly hostile, with the result that the client allied with the incoming vendor to manage vendor transition. These findings mirror expectations from balance of threat theory, a political science theory about interactions between nations. Balance of threat theory predicts that outgoing vendor hostility and the capability of the client to mitigate hostility determine whether a client takes a hard or soft balancing strategy during vendor transition

Therapeutic monitoring of thiopurine metabolites : validation of an HPLC method and preliminary findings from a small cohort of Malaysian patients with inflammatory bowel disease

Thiopurine therapy of inflammatory bowel disease (IBD) is guided by the relative blood concentrations 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP). However, their action is altered by in vivo phosphorylation, and this is not normally measured in clinical studies. Hence, we trialled a novel method for profiling phosphorylated thiopurine metabolites and revisited the association between thiopurine metabolites and IBD treatment outcomes. We first optimised and validated a published high-performance liquid chromatography (HPLC) method for measuring the blood levels of thioguanosine monophosphate (TGMP), thioguanosine diphosphate (TGDP), thioguanosine triphosphate (TGTP), and methylthioinosine monophosphate (MeTIMP). Then, we assembled a small cohort of IBD patients (n = 20), who had been treated with azathioprine for at least three months, and obtained blood samples for analysis of the metabolites. The patients received treatments at the Universiti Kebangsaan Malaysia Specialist Centre between March 2018 and April 2019. They were classified as responders (n = 12) or non-responders (n = 6) to azathioprine based on their disease activity scores (CDAI or Mayo score). The HPLC method was precise with intraday and interday variation < 15% for all the tested metabolites, and the relative accuracy ranged from 40.2 to 114.0%. We noted that the responders had higher median 6-TGN but lower median TGTP levels than the non-responders. However, the differences were not statistically significant (Wilcoxon rank-sum tests; 6-TGN, p = 0.925; TGTP, p = 0.189). The higher median 6-TGN level detected in the responders is in keeping with the findings of prior studies, suggesting that HPLC analysis of phosphorylated thiopurine metabolites is both technically feasible and clinically useful

Correction: Comparing the genomes of Helicobacter pylori clinical strain UM032 and mice-adapted derivatives

Abstract is not available in fulltext.Published versio

Targeted gene sanger sequencing should remain the first-tier genetic test for children suspected to have the five common X-linked inborn errors of immunity

DATA AVAILABILITY STATEMENT : The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.To address inborn errors of immunity (IEI) which were underdiagnosed in resource-limited regions, our centre developed and offered free genetic testing for the most common IEI by Sanger sequencing (SS) since 2001. With the establishment of The Asian Primary Immunodeficiency (APID) Network in 2009, the awareness and definitive diagnosis of IEI were further improved with collaboration among centres caring for IEI patients from East and Southeast Asia. We also started to use whole exome sequencing (WES) for undiagnosed cases and further extended our collaboration with centres from South Asia and Africa. With the increased use of Next Generation Sequencing (NGS), we have shifted our diagnostic practice from SS to WES. However, SS was still one of the key diagnostic tools for IEI for the past two decades. Our centre has performed 2,024 IEI SS genetic tests, with in-house protocol designed specifically for 84 genes, in 1,376 patients with 744 identified to have disease-causing mutations (54.1%). The high diagnostic rate after just one round of targeted gene SS for each of the 5 common IEI (X-linked agammaglobulinemia (XLA) 77.4%, Wiskott–Aldrich syndrome (WAS) 69.2%, X-linked chronic granulomatous disease (XCGD) 59.5%, X-linked severe combined immunodeficiency (XSCID) 51.1%, and X-linked hyper-IgM syndrome (HIGM1) 58.1%) demonstrated targeted gene SS should remain the first-tier genetic test for the 5 common X-linked IEI.The Hong Kong Society for Relief of Disabled Children and Jeffrey Modell Foundation.http://www.frontiersin.org/Immunologyam2023Paediatrics and Child Healt

Understanding Adverse Drug Reactions Using Genomic Sequencing

New opportunities for better understanding of drug responses and adverse drug reactions have been created through the rapid evolution of high-throughput genotyping and next-generation DNA sequencing technologies. The main goals of this thesis were to establish a framework for collecting patient samples to enable the study of unusual drug responses and adverse drug reactions, and to explore the application of next-generation DNA sequencing methods in a range of pharmacogenetic and pharmacogenomic studies. At the outset of this project, the pharmacogenetic aspects of international, direct-to-consumer genetic testing companies were reviewed. This revealed that the services provided by these companies were patchy and each company covered a varied range of drug-gene pairs. The chip- or PCR-based methodology employed by the companies also meant that only the most common variants were genotyped and this could affect the accuracy of phenotype prediction across different ethnic groups. The value of these services was also limited by a lack of clear evidence supporting their utility in the clinical setting. Nevertheless, it was concluded that these direct-to-consumer companies have played a useful role in educating the public - and indirectly the health professionals - with regard to the potential, clinical application of pharmacogenetics. A prototype biobank (called Understanding Adverse Drug Reactions Using Genomic Sequencing, or UDRUGS) for the study of adverse drug reactions and unusual drug responses was established. Via this biobank, samples were sourced by various routes and subjects were consented for genetic analysis that ranged from candidate-gene to whole-exome sequencing. High-throughput genomic sequencing generates incidental findings that could be of health significance; thus a method for returning such findings to patients who agreed to it was established. UDRUGS cases formed the basis of the genetic and genomic studies in this thesis. Subject recruitment is an actively ongoing process. At the time of writing this thesis, a total of 37 participants had been recruited and in the majority of the cases, metabolic deficiency (for instance defects in the cytochrome P450 enzymes) appeared to be culpable for the reported adverse reactions. Targeted Sanger DNA sequencing analysis proved revealing in a case of poor tolerance towards the administration of venlafaxine monotherapy, and that of a combined regimen of nortriptyline and fluoxetine. Novel CYP2D6*81 and CYP2C19*34 alleles were identified by Sanger sequencing. CYP2D6*81 creates a premature stop signal in the fifth exon of the CYP2D6 gene, probably causing the formation of a non-functional, truncated protein. The effect of CYP2C19*34 was less clear-cut, as the allele is composed of an upstream variant and two non-synonymous variants located near the translation start site. This allele was co-identified alongside the common CYP2C19*2 null allele. Long-range haplotype analysis, spanning a 19.5-kb region, showed that the three variants occurred on a separate allele from CYP2C19*2. It was noteworthy that this participant was of Gujarati descent and it is possible that the identified variants may represent CYP2D6 and CYP2C19 alleles specific to this population. Recognising the important roles of CYP2D6 and CYP2C19 in drug response, a next-generation amplicon sequencing assay was designed for the comprehensive genotyping of the two genes in large numbers of clinical samples. CYP2D6 was contiguously amplified by long-range PCRs (6.6-kb) whereas three triplex PCRs were set up to amplify nine short amplicons covering the promoter region and all exons of the CYP2C19 gene. A total of 96 samples were included in the first assessment of the assay, which was run on the MiSeq® platform. High-quality data were generated with 100% agreement with the Sanger sequencing data for 19 control samples that were also included. However, several drawbacks of the assay, namely the tedious and costly nature of the PCR-based library construction steps and the coverage variation observed for CYP2D6, need to be addressed in follow-up experiments. The compatibility of this assay with a novel sequencing device, the MinIONTM (Oxford Nanopore Technologies, Oxford, UK), which detects DNA bases by disruptions of ionic current as the DNA strands are drawn through an array of nano-scale membrane pores, was also partially tested. The choice of PCR microtubes was found to have a significant impact on the success of long-range PCRs used for examining the CYP2D6 gene. Coloured microtubes purchased from Neptune Scientific (Biotix, Inc., San Diego, CA, USA) performed poorly in comparison with those obtained from other suppliers. It is possible that chemical compound(s) leached from the microtubes upon heating and inhibited PCR amplification, although a definitive conclusion was not possible. Whole-exome sequencing and array-based comparative genomic hybridisation were applied to explore the hypothesis that rare coding variants or structural variants contribute to a thiopurine hypermethylation phenotype seen in a proportion of inflammatory bowel disease patients treated with thiopurine drugs. In the exome data of twelve patients, four genes (SLC17A4, RCC2, NFS1 and ENOSF1) were noted to harbour rare and potentially deleterious variants that occurred at a higher-than-expected frequency (p <0.05). The role of pathogenic copy-number aberrations and the contribution of 52 a priori candidate genes to the phenotype was found to be insignificant. Further understanding of the genetic architecture of this trait would likely require the collection of many more cases and controls, in the context of a genome-wide association study. In a New Zealand cohort of acute coronary syndrome patients, CYP2C19*2 was shown to have a substantive influence on clopidogrel responsiveness whereas the effect of *17 was less obvious. Eleven outliers with at least one intact CYP2C19 gene copy but very high residual platelet reactivity (≥90 U) were selected for whole-gene sequencing; no additional mutations were identified. Overall this suggested that in certain instances, non-genetic factors predominated over the effect of CYP2C19 polymorphisms. This work has demonstrated that a variety of DNA sequencing technologies can be valuable tools for elucidating the genetic underpinnings of unusual ADRs or complex drug responses. It is foreseeable that the progressive advancement of next-generation sequencing technologies will continue to generate new knowledge in pharmacogenetics or pharmacogenomics, and perhaps make possible the pre-emptive identification of genetic variants that predispose to unusual drug responses or adverse reactions