Experiences of the SARS-CoV-2 pandemic amongst Australian healthcare workers: from stressors to protective factors.

BACKGROUND: The SARS-CoV-2 pandemic has critically challenged healthcare systems globally. Examining the experiences of healthcare workers (HCWs) is important for optimizing ongoing and future pandemic responses. OBJECTIVES: In-depth exploration of Australian HCWs' experiences of the SARS-CoV-2 pandemic, with a focus on reported stressors vis-à-vis protective factors. METHODS: Individual interviews were performed with 63 HCWs in Australia. A range of professional streams and operational staff were included. Thematic analysis was performed. RESULTS: Thematic analysis identified stressors centred on paucity of, or changing, evidence, leading to absence of, or mistrust in, guidelines; unprecedented alterations to the autonomy and sense of control of clinicians; and deficiencies in communication and support. Key protective factors included: the development of clear guidance from respected clinical leaders or recognized clinical bodies, interpersonal support, and strong teamwork, leadership, and a sense of organizational preparedness. CONCLUSIONS: This study provides insights into the key organizational sources of emotional stress for HCWs within pandemic responses and describes experiences of protective factors. HCWs experiencing unprecedented uncertainty, fear, and rapid change, rely on clear communication, strong leadership, guidelines endorsed by recognized expert groups or individuals, and have increased reliance on interpersonal support. Structured strategies for leadership and communication at team, service group and organizational levels, provision of psychological support, and consideration of the potential negative effects of centralizing control, would assist in ameliorating the extreme pressures of working within a pandemic environment.

PXR, CAR and HNF4alpha genotypes and their association with pharmacokinetics and pharmacodynamics of docetaxel and doxorubicin in Asian patients.

Previously studied candidate genes have failed to account for inter-individual variability of docetaxel and doxorubicin disposition and effects. We genotyped the transcriptional regulators of CYP3A and ABCB1 in 101 breast cancer patients from 3 Asian ethnic groups, that is, Chinese, Malays and Indians, in correlation with the pharmacokinetics and pharmacodynamics of docetaxel and doxorubicin. While there was no ethnic difference in docetaxel and doxorubicin pharmacokinetics, ethnic difference in docetaxel- (ANOVA, P=0.001) and doxorubicin-induced (ANOVA, P=0.003) leukocyte suppression was observed, with Chinese and Indians experiencing greater degree of docetaxel-induced myelosuppression than Malays (Bonferroni, P=0.002, P=0.042), and Chinese experiencing greater degree of doxorubicin-induced myelosuppression than Malays and Indians (post hoc Bonferroni, P=0.024 and 0.025). Genotyping revealed both PXR and CAR to be well conserved; only a PXR 5'-untranslated region polymorphism (-24381A>C) and a silent CAR variant (Pro180Pro) were found at allele frequencies of 26 and 53%, respectively. Two non-synonymous variants were identified in HNF4alpha (Met49Val and Thr130Ile) at allele frequencies of 55 and 1%, respectively, with the Met49Val variant associated with slower neutrophil recovery in docetaxel-treated patients (ANOVA, P=0.046). Interactions were observed between HNF4alpha Met49Val and CAR Pro180Pro, with patients who were wild type for both variants experiencing least docetaxel-induced neutropenia (ANOVA, P=0.030). No other significant genotypic associations with pharmacokinetics or pharmacodynamics of either drug were found. The PXR-24381A>C variants were significantly more common in Indians compared to Chinese or Malays (32/18/21%, P=0.035) Inter-individual and inter-ethnic variations of docetaxel and doxorubicin pharmacokinetics or pharmacodynamics exist, but genotypic variability of the transcriptional regulators PAR, CAR and HNF4alpha cannot account for this variability.

Herpesvirus saimiri pathogenicity enhanced by thymidine kinase of herpes simplex virus.

Herpesvirus saimiri can be used as an efficient gene expression vector for human T lymphocytes and thus may allow applications in experimental leukemia therapy. We constructed recombinant viruses for the functional expression of the thymidine kinase (TK) of herpes simplex virus type 1 (HSV) as a suicide gene. These viruses reliably allowed the targeted elimination of transduced nonpermissive human T cells in vitro after the administration of ganciclovir. To test the reliability of this function under the most stringent permissive conditions, in this study we analyzed the influence of the prodrugs ganciclovir and acyclovir in common marmosets on the acute leukemogenesis induced by either wild-type herpesvirus saimiri C488 or by a recombinant derivative expressing TK of HSV. Antiviral drug treatment did not influence the rapid development of acute disease. In contrast, the presence of the HSV tk gene resulted in a faster disease progression. In addition, HSV TK-expressing viruses showed faster replication than wild-type virus in culture at low serum concentrations. Thus, HSV TK accelerates the replication of herpesvirus saimiri and enhances its pathogenicity. This should be generally considered when HSV TK is applied as a transgene in replication-competent DNA virus vectors for gene therapy.

Induction of a novel cellular homolog of interleukin-10, AK155, by transformation of T lymphocytes with herpesvirus saimiri.

Although herpesvirus saimiri-transformed T lymphocytes retain multiple normal T-cell functions, only a few changes have been described. By subtractive hybridization, we have isolated a novel cellular gene, ak155, a sequence homolog of the interleukin-10 gene. Specifically herpesvirus saimiri-transformed T cells overexpress ak155 and secrete the protein into the supernatant. In other T-cell lines and in native peripheral blood cells, but not in B cells, ak155 is transcribed at low levels. AK155 forms homodimers similarly to interleukin-10. As a lymphokine, AK155 may contribute to the transformed phenotype of human T cells after infection by herpesvirus saimiri.