Warfarin Pharmacogenomics for Precision Medicine in Real-Life Clinical Practice in Southern Africa: Harnessing 73 Variants in 29 Pharmacogenes

Pharmacogenomics is universally relevant for worldwide modern therapeutics and yet needs further development in resource-limited countries. While there is an abundance of genetic association studies in controlled medical settings, there is a paucity of studies with a naturalistic design in real-life clinical practice in patients with comorbidities and under multiple drug treatment regimens. African patients are often burdened with communicable and noncommunicable comorbidities, yet the application of pharmacogenomics in African clinical settings remains limited. Using warfarin as a model, this study aims at minimizing gaps in precision/personalized medicine research in African clinical practice. We present, therefore, pharmacogenomic profiles of a cohort of 503 black Africans (n = 252) and Mixed Ancestry (n = 251) patients from Southern Africa, on warfarin and co-prescribed drugs in a naturalized noncontrolled environment. Seventy-three (n = 73) single nucleotide polymorphisms (SNPs) in 29 pharmacogenes were characterized using a combination of allelic discrimination, Sanger sequencing, restriction fragment length polymorphism, and Sequenom Mass Array. The common comorbidities were hypertension (43-46%), heart failure (39-45%), diabetes mellitus (18%), arrhythmia (25%), and HIV infection (15%). Accordingly, the most common co-prescribed drugs were antihypertensives, antiarrhythmic drugs, antidiabetics, and antiretroviral therapy. We observed marked variation in major pharmacogenes both at interethnic levels and within African subpopulations. The Mixed Ancestry group presented a profile of genetic variants reflecting their European, Asian, and African admixture. Precision medicine requires that African populations begin to capture their own pharmacogenetic SNPs as they cannot always infer with absolute certainty from Asian and European populations. In the current historical moment of the COVID-19 pandemic, we also underscore that the spectrum of drugs interacting with warfarin will likely increase, given the systemic and cardiovascular effects of COVID-19, and the anticipated influx of COVID-19 medicines in the near future. This observational clinical pharmacogenomics study of warfarin, together with past precision medicine research, collectively, lends strong support for incorporation of pharmacogenetic profiling in clinical settings in African patients for effective and safe administration of therapeutics

Managing a live music performance: A supply-side analysis

Purpose and objective: The purpose of this research is to determine what managers regard as important critical success factors in ensuring a memorable visitor experience at a live music performance. Problem investigated: When organising a live music performance, it is evident that the various characteristics that form part of the visitor experience have to be considered. The critical success factors of live music performances from the supply side are fundamental, since the costs of organising live music performances are high, the needs of the visitors are constantly changing and competition plays a major role in the success of such events. Management furthermore constantly needs to be aware of the ever-changing external environment by determining what factors visitors consider to be vital for a rewarding experience at a major music event. This is extremely important since the concept of experience has become more pervasive, mainly given that the event sector, such as live music performances, has adopted experience as a tool to make individual businesses more competitive, as the organisations operating within this sector exist to provide consumers with an experience. Design and/or methodology and/or approach: A qualitative research method, by means of interviews, was used to obtain the relevant information from the selected participants. All the data collected in the process were transcribed into text and presented in narrative form. The six steps of data analysis and interpretation were applied to analyse the data. Findings and impications: The following four major themes emerged from the analysis; each theme was differentiated in terms of various categories and subcategories. Theme 1:The most important aspects for a memorable visitor experience; Theme 2:Main purpose when organising a live music performance; Theme 3:Important aspects regarding the management of a live music performance; Theme 4:Timing of event management. Based on the research conducted on the critical success factors from a supply side, the following findings emerged. Firstly, it is evident that the critical success factors differ significantly from one tourism sector to another. Therefore, more qualitative research should be applied with regard to critical success factors in other tourism operations. Secondly, comparing the results of the qualitative research reveals significantly more in-depth information than those of the various quantitative research studies conducted on critical success factors. Thirdly, it is evident that the pre-event, during-event and post-event planning phases differ from event to event. Lastly, it is evident that there is no common guideline with regard to creating a memorable visitor experience. Conclusion: Determining the critical success factors for memorable live music performances (from the supply side) in South Africa enables management to improve the current management plans in order to ensure an outstanding memorable visitor experience whilst also improving the overall success rate

Managing the "wow factor" at live music performances

The aim of this article is to determine what attendees at live music performances regard as critical success factors for different music genres in order to enhance memorable visitor experiences. Surveys were conducted for various genres at live music performances. A total of 4 110 questionnaires were administered. A general profile of the visitors for the different genres was determined whereafter a factor analysis was performed to determine the critical success factors for the genres. An ANOVA was subsequently applied to compare the critical success factors identified in the factor analysis. The results indicated significant statistical differences with regard to what visitors at the different music genres regard as being important for a memorable visitor experience. Determining the differences with regard to the critical success factors contribute towards event specific education and information for current as well as future live music performance managers

Determinants of visitor expenditure at the Tsitsikamma National Park

The Tsitsikamma National Park is Africa's oldest and largest marine reserve. It has considerable importance for the community and the region. In the face of declining government funding, it needs to attract more high spenders if it is to be sustainable. This requires an understanding of expenditure patterns and the determinants of Park visitors' spending behaviour. This study investigated the socio-demographic and behavioural determinants of visitor expenditure, using visitor surveys at the Park in 2010/2011. Correlation analysis and regression analysis established the most significant determinants. The results indicated that a longer stay, a smaller travel group and obtaining information from magazines were the variables associated with higher spending. These findings provide strategic insights for marketing the Park, with the aim of achieving a greater economic impact and competitive advantage and ultimately aiding conservation efforts.http://reference.sabinet.co.za/webx/access/electronic_journals/jefs/jefs_v5_n1_a2.pd

Corrigendum: The GRIN Meeting: A ‘third place’ for managers and scholars of social-ecological systems

Original article: https://doi.org/10.17159/sajs.2020/7598 The ORCID identifier [https://orcid.org/0000-0001-7311-3223] given for one of the authors, Stefanie Freitag (South African National Parks, South Africa), is incorrect. This ORCID identifier is assigned to a different individual also named Stefanie Freitag. The person to whom this ORCID ID corresponds, should not be attributed as a co-author of this article. The author Stefanie Freitag does not have an ORCID identifier

Processing of Candida albicans Ece1p Is Critical for Candidalysin Maturation and Fungal Virulence

Candida albicans is an opportunistic fungal pathogen responsible for superficial and life-threatening infections in humans. During mucosal infection, C. albicans undergoes a morphological transition from yeast to invasive filamentous hyphae that secrete candidalysin, a 31-amino-acid peptide toxin required for virulence. Candidalysin damages epithelial cell plasma membranes and stimulates the activating protein 1 (AP-1) transcription factor c-Fos (via p38–mitogen-activated protein kinase [MAPK]), and the MAPK phosphatase MKP1 (via extracellular signal-regulated kinases 1 and 2 [ERK1/2]–MAPK), which trigger and regulate proinflammatory cytokine responses, respectively. The candidalysin toxin resides as a discrete cryptic sequence within a larger 271-amino-acid parental preproprotein, Ece1p. Here, we demonstrate that kexin-like proteinases, but not secreted aspartyl proteinases, initiate a two-step posttranslational processing of Ece1p to produce candidalysin. Kex2p-mediated proteolysis of Ece1p after Arg61 and Arg93, but not after other processing sites within Ece1p, is required to generate immature candidalysin from Ece1p, followed by Kex1p-mediated removal of a carboxyl arginine residue to generate mature candidalysin. C. albicans strains harboring mutations of Arg61 and/or Arg93 did not secrete candidalysin, were unable to induce epithelial damage and inflammatory responses in vitro, and showed attenuated virulence in vivo in a murine model of oropharyngeal candidiasis. These observations identify enzymatic processing of C. albicans Ece1p by kexin-like proteinases as crucial steps required for candidalysin production and fungal pathogenicity. IMPORTANCE Candida albicans is an opportunistic fungal pathogen that causes mucosal infection in millions of individuals worldwide. Successful infection requires the secretion of candidalysin, the first cytolytic peptide toxin identified in any human fungal pathogen. Candidalysin is derived from its parent protein Ece1p. Here, we identify two key amino acids within Ece1p vital for processing and production of candidalysin. Mutations of these residues render C. albicans incapable of causing epithelial damage and markedly reduce mucosal infection in vivo. Importantly, candidalysin production requires two individual enzymatic events. The first involves processing of Ece1p by Kex2p, yielding immature candidalysin, which is then further processed by Kex1p to produce the mature toxin. These observations identify important steps for C. albicans pathogenicity at mucosal surfaces

Multiple HLA class I and II associations in classical Hodgkin lymphoma and EBV status defined subgroups (Retracted article. See vol. 118, pg. 5211, 2011)

The pathogenesis of classical Hodgkin lymphoma (cHL) involves environmental and genetic factors. To explore the role of the human leukocyte antigen (HLA) genes, we performed a case-control genotyping study in 338 Dutch cHL patients and more than 5000 controls using a PCR-based sequence-specific oligonucleotide probe hybridization approach. HLA-A68 and HLA-DR11 (5) were significantly increased in the cHL patient population compared with the controls. Three class II associations were observed in the EBV- cHL population with an increase of HLA-DR15 (2) and a decrease of HLA-DR4 and HLA-DR7. Allele frequencies of HLA-A1, HLA-B37, and HLA-DR10 were significantly increased in the EBV+ cHL population; these alleles are in strong linkage disequilibrium and form a common haplotype in whites. The allele frequency of HLA-A2 was significantly decreased in the EBV- cHL population. Sequence-specific oligonucleotide probe analysis revealed significant differences between EBV+ and EBV- cHL patients for 19 probes that discriminate between HLA-A*01 and HLA-A*02. In conclusion, the HLA-A1 and HLA-A2 antigens and not specific single nucleotide variants shared by multiple alleles are responsible for the association with EBV+ cHL. Furthermore, several new protective and predisposing HLA class I and II associations for the EBV+, the EBV-, and the entire cHL population were identified. (Blood. 2011;118(19):5211-5217