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The World Health Organisation declared the coronavirus disease 2019 (COVID-19) a pandemic on March 11, 2020. While globally, the relative caseload has been high, Australia's has been relatively low. During the pandemic, radiology services have seen significant changes in workflow across modalities and a reduction in imaging volumes.To investigate differences in modality imaging volumes during the COVID-19 pandemic across a large Victorian public health network.A retrospective analysis from January 2019 to December 2020 compared imaging volumes across two periods corresponding to the pandemic's first and second waves. Weekly volumes across patient class, modality and mobile imaging were summed for periods: wave 1 (weeks 11 to 16 for 2019; weeks 63 to 68 for 2020) and wave 2 (weeks 28 to 43 for 2019; weeks 80 to 95 for 2020). Microsoft Power Business Intelligence linked to the radiology information system was used to mine all completed examinations.Summed weekly data during the pandemic's first wave showed the greatest decrease of 29.8% in adult outpatient imaging volumes and 46.3% in paediatric emergency department imaging volumes. Adult nuclear medicine demonstrated the greatest decrease of 37.1% for the same period. Paediatric nuclear medicine showed the greatest decrease of 47.8%, with angiography increasing by 50%. The pandemic's second wave demonstrated the greatest decrease of 23.5% in adult outpatient imaging volumes, with an increase of 18.2% in inpatient imaging volumes. The greatest decrease was 28.5% in paediatric emergency department imaging volumes. Nuclear medicine showed the greatest decrease of 37.1% for the same period. Paediatric nuclear medicine showed the greatest decrease of 36.7%. Mobile imaging utilisation increased between 57.8% and 135.1% during the first and second waves. A strong correlation was observed between mobile and non-mobile imaging in the emergency setting (Spearman's correlation coefficient = -0.743,Nuclear medicine was most impacted, while computed tomography and angiography were the least affected by the pandemic. The impact was less during the pandemic's second wave. Mobile imaging shows continuous growth during both waves.

Allied health assistants (AHAs) are important members of the health workforce and key to meeting population health needs. Previous studies exploring the role and utility of AHAs from multiple stakeholder perspectives suggest AHAs remain poorly utilised in many healthcare settings. This qualitative study explores the experiences and perspectives of AHAs working in healthcare settings to determine the contextual factors influencing their role, and mechanisms to maximise their utility. We conducted semi-structured interviews using purposive sampling with 21 AHAs, from one regional and three metropolitan health services in Australia, between February and July 2021. We used a team-based framework approach to analyse the data. Four major themes were identified: 1) AHAs' interpersonal relationships, 2), clarity and recognition of AHA roles and role boundaries, 3) AHAs accessing education and professional development, and 4) the professional identity of the AHA workforce. Underpinning each of these themes were relationships between AHAs and other healthcare professionals, their patients, health services, and the wider AHA workforce. This study may inform initiatives to optimise the utility of AHAs and increase their role in, and impact on, patient care. Such initiatives include the development and implementation of guidelines and competencies to enhance the clarity of AHAs' scope of practice, the establishment of standardised educational pathways for AHAs, and increased engagement with the AHA workforce to make decisions about their scope of practice. These initiatives may precede strategies to advance the AHA career structure.

Allied health assistants are support staff who assist medical imaging professionals in their clinical and non-clinical role. Assistants can improve efficiency of medical imaging services; however, little is known about the specific tasks they perform.A two-phase explanatory, sequential mixed-methods study design comprising a time motion survey and qualitative interviews was conducted across three health services in Victoria, Australia. Participants were medical imaging assistants supporting medical imaging professionals. Participants recorded tasks completed on a time motion proforma across two working days. Time spent on tasks was categorised into patient related and non-patient related tasks. Semi-structured interviews were conducted to explore assistants' perspectives about tasks, their roles and any responsibilities. Time motion data was descriptively analysed. Qualitative data were audiotaped, transcribed verbatim and analysed using the framework analysis method. Quantitative and qualitative findings were integrated using data triangulation.Four medical imaging assistants participated, providing 4170 min of time motion data and 138 min of interview data. Integration of time motion and interview data revealed the medical imaging assistant role is predominantly non-patient facing; autonomous and critical to workflow; diverse and requires flexibility; has the potential to expand into a more patient-facing role.Medical imaging assistants make significant contributions to workflow management. Their role is predominantly non-patient facing but there appear opportunities for the clinical role to expand. Realizing these opportunities will require careful consideration of the challenges and benefits of extending their scope of practice.

To review authorship details of Australian Society of Medical Imaging and Radiation Therapy (ASMIRT) conference accepted abstracts for medical imaging and radiation therapy disciplines; identify the Australian or international institutions that submitted abstracts; and to determine the rates of ASMIRT conference abstracts to papers and their citation number.Retrospective analysis of oral and poster conference abstracts published in the Journal of Medical Radiation Sciences (JMRS) from 2015 through 2017 identified 581 Australian and international abstracts. Of these, 513 Australian abstracts were analyzed using Google Scholar, PubMed, and Google databases. Abstracts were allocated to medical imaging or radiation therapy disciplines. Abstract titles, key words, institutions, and author names were used to search for peer-reviewed papers. Papers were authenticated through open access, publicly available author information, or library access.During a 3-year period, medical imaging and radiation therapy averaged 12.7 ± 7.8 and 12.7 ± 2.8 abstracts and posters, respectively. Oral abstracts averaged 70.0 ± 26.9 (medical imaging) and 76.3 ± 24.0 (radiation therapy). A total of 111 publications from 117 Australian conference presentations were distributed across 53 journals or books between the 2 disciplines. ASMIRT conference presentation to full publication rate was 18.3% (medical imaging) and 24.7% (radiation therapy). The citation number exceeded 270 for medical imaging publications and 540 for radiation therapy publications at the time of writing.Many factors affect whether medical radiation practitioners present their research at conferences. Conferences in Australia have smaller audiences compared with well-known journals such as JMRS, which limits the dissemination of data and the research impact. Research collaborations can improve publication opportunity and build research capacity, while the publication citation number can reflect the impact of the published research. The publication of research findings is a challenging process but essential to sharing medical knowledge and improving clinical practice.The rate of ASMIRT conference abstract to full publication was at the lower end of reported literature. This finding provides a benchmark for future studies on abstract-to-publication rates in Australia and globally.

A series of PI3Kδ inhibitors derived from the pan-PI3K inhibitor ZSTK474 was prepared that target a non-conserved region of the catalytic site. Dependent upon the substituents present, these analogues show different levels of isoform selectivity and sensitivity to the mutation N836D in PI3Kδ. As a marker of ‘on-target’ activity and permeability, a selection of the most potent PI3Kδ inhibitors were shown to inhibit pAkt production in the Nawalma Burkitt lymphoma cell line.

A series of amino-substituted triazines were developed and examined for PI3Kβ inhibition and anti-platelet function. Structural adaptations of a morpholine ring of the prototype pan-PI3K inhibitor ZSTK474 yielded PI3Kβ selective compounds, where the selectivity largely derives from an interaction with the non-conserved Asp862 residue, as shown by site directed mutagenesis. The most PI3Kβ selective inhibitor from the series was studied in detail through a series of in vitro and in vivo functional studies. MIPS-9922, 10 potently inhibited ADP-induced washed platelet aggregation. It also inhibited integrin αIIbβ3 activation and αIIbβ3 dependent platelet adhesion to immobilized vWF under high shear. It prevented arterial thrombus formation in the in vivo electrolytic mouse model of thrombosis without inducing prolonged bleeding or excess blood loss.

Phosphoinositide 3-kinases (PI3K) hold significant therapeutic potential as novel targets for the treatment of cancer. ZSTK474 (4a) is a potent, pan-PI3K inhibitor currently under clinical evaluation for the treatment of cancer. Structural studies have shown that derivatisation at the 5- or 6-position of the benzimidazole ring may influence potency and isoform selectivity. However, synthesis of these derivatives by the traditional route results in a mixture of the two regioisomers. We have developed a straightforward regioselective synthesis that gave convenient access to 5- and 6-methoxysubstituted benzimidazole derivatives of ZSTK474. While 5-methoxy substitution abolished activity at all isoforms, the 6-methoxy substitution is consistently 10-fold more potent. This synthesis will allow convenient access to further 6-position derivatives, thus allowing the full scope of the structure-activity relationships of ZSTK474 to be probed.

A series of aminoacyl-triazine derivatives based upon the pan-PI3K inhibitor ZSTK474 were identified as potent and isoform-selective inhibitors of PI3Kβ. The compounds showed selectivity based upon stereochemistry with l-amino acyl derivatives preferring PI3Kβ, while their d-congeners favored PI3Kδ. The mechanistic basis of this inhibition was studied using site-directed mutants. One Asp residue, D862, was identified as a critical participant in binding to the PI3Kβ-selective inhibitors, distinguishing this class from other reported PI3Kβ-selective inhibitors. The compounds show strong inhibition of cellular Akt phosphorylation and growth of PTEN-deficient MD-MBA-468 cells.

A series of synthesized and commercially available compounds were assessed against PI3Kα for in vitro inhibitory activity and the results compared to binding calculated in silico. Using published crystal structures of PI3Kγ and PI3Kδ co-crystallized with inhibitors as a template, docking was able to identify the majority of potent inhibitors from a decoy set of 1000 compounds. On the other hand, PI3Kα in the apo-form, modeled by induced fit docking, or built as a homology model gave only poor results. A PI3Kα homology model derived from a ligand-bound PI3Kδ crystal structure was developed that has a good ability to identify active compounds. The docking results identified binding poses for active compounds that differ from those identified to date and can contribute to our understanding of structure-activity relationships for PI3K inhibitors.

Drug-induced toxicity is a leading cause of drug withdrawal from clinical development and clinical use and represents a major impediment to the development of new drugs. The mechanisms underlying drug-induced toxicities are varied; however, metabolic bioactivation to form reactive metabolites has been identified as a major contributor.1,2 These electrophilic species can covalently modify important biological macromolecules and thereby increase the risk of adverse drug reactions or idiosyncratic toxicity. Consequently, screening compounds for their propensity to form reactive metabolites has become an integral part of drug discovery programs. This screening process typically involves identification of structural alerts as well as the generation of reactive metabolites in vitro in subcellular hepatic fractions, followed by trapping the reactive species with nucleophiles and characterization via LC-MS. This article presents evidence for the bioactivation of a series of aminopyrazole derivatives via LC-MS detection of glutathione ethyl ester-trapped reactive intermediates formed in human liver microsomal incubations. These results indicate that the aminopyrazole motif, within specific contexts, may be considered a new structural alert for the potential formation of reactive metabolites.

A library of 4-iminothiazolidinones (28 examples) is synthesized by multiple pathways and their enzyme inhibitor activities are tested.

The thiazolidinedione, compound 1, has previously shown pan-inhibition of the phosphoinositide 3-kinase (PI3K) class I isoforms. We hypothesized the derivatization of the thiazolidinedione core of compound 1 could introduce isoform selectivity. We report the synthesis, characterization, and inhibitory activity of a novel series of 4-iminothiazolidin-2-ones for inhibition of the class I PI3K isoforms. Their synthesis was successfully achieved by multiple pathways described in this paper. Initial in vitro data of 28 analogues demonstrated poor inhibition of all class I PI3K isoforms. However, we identified an alternate target, the phosphodiesterases, and present preliminary screening results showing improved inhibitory activity.

Increased expression or dysregulation of protein arginine methyltransferase 5 (PRMT5) activity is associated with poor prognosis in many cancers. Through increased methylation of epigenetic and non-epigenetic targets, the aberrant activity of PRMT5 has been associated with many pro-tumourigenic cellular changes such as, increased levels of protein synthesis, dysregulation of cell cycle, cellular adaptation to hypoxic conditions, and suppression of normal cell death pathways. Genetic studies suggest that suppression of PRMT5 activity can reverse many of these pro-tumourigenic effects making PRMT5 an attractive drug discovery target. We screened a library of 350,000 lead-like compounds with a biochemical assay measuring the methylation of a histone H4 peptide by the recombinant human PRMT5/MEP50 complex. Biochemical and biophysical profiling of the inhibitory compounds indicated that several distinct binding modes were exhibited by the different chemical scaffolds. Inhibitors displayed competitive, noncompetitive or uncompetitive interactions with respect to S-adenosyl methionine and the peptide substrate. Medicinal chemistry developed several classes of potent, highly selective inhibitors of PRMT5 methyltransferase activity from the hit set. The optimised tool compound, CTx-034, is a potent inhibitor of PRMT5 methyl transferase activity (KD = 2 nM), which is highly selective (>100-fold) versus a panel of 18 methyltransferases (including 6 PRMT family members), 11 lysine demethylases, and 15 safety related targets (GPCRs, ion channels, enzymes). Treatment of cancer cell lines with CTx-034 reduces cellular levels of symmetrically dimethylated H4 Arginine 3 (H4R3me2s), in a dose dependent manner (IC50 = 4 nM) to levels undetectable by Western blot. Furthermore, within this chemical series the ability of compounds to reduce cellular levels of H4R3me2s closely correlates with PRMT5 inhibitory activity supporting PRMT5 as the cellular target of these compounds, and suggesting that PRMT5 is the major writer of this histone mark in many cancer cell lines. CTx-034 also inhibits the symmetric dimethylation of arginine on other histone and non-histone cellular substrates of PRMT5, including H3R2me2s and SmD1. Conversely, CTx-034 treatment does not reduce levels of H4R3 asymmetric dimethylation, a histone mark catalysed by PRMT1. Finally, CTx-034 has good oral bioavailability and pharmacokinetic properties in rodents and twice-daily dosing (10 - 100 mg/kg) over 10-14 days produces a dose dependent reduction of the H4R3me2s mark in bone marrow cells and peripheral white blood cells. This treatment is well tolerated by the mice, with no significant reduction in body weight or changes in haematological parameters observed. CTx-034 provides an excellent tool compound for cellular and in vivo proof of concept studies. Citation Format: Hendrik Falk, Richard C. Foitzik, Elizabeth Allan, Melanie deSilva, Hong Yang, Ylva E. Bozikis, Marica Nikac, Scott R. Walker, Michelle A. Camerino, Ben J. Morrow, Alexandra E. Stupple, Rachel Lagiakos, Jo-Anne Pinson, Romina Lessene, Wilhelmus JA Kersten, Danny G. Ganame, Ian P. Holmes, Gill E. Lunniss, Matthew Chung, Stefan J. Hermans, Michael W. Parker, Alison Thistlethwaite, Karen White, Susan A. Charman, Brendon J. Monahan, Patricia Pilling, Julian Grusovin, Thomas S. Peat, Stefan Sonderegger, Emma Toulmin, Stephen M. Jane, David J. Curtis, Paul A. Stupple, Ian P. Street. PRMT5 inhibitors as novel treatment for cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5371. doi:10.1158/1538-7445.AM2015-5371

PI3 kinase inhibitors are hot property. In this issue of ChemistryBiology, Williams et al. add a dual PI3Kdelta/gamma inhibitor to the collection and show that its anti-inflammatory profile in vitro is quite different from pan-PI3K inhibitors, but bears an uncanny resemblance to that of the glucocorticoid drugs.