Caffeine consumed prior to cardiac stress testing may affect diagnostic accuracy of nuclear medicine myocardial imaging of myocardial ischemia: A systematic review and meta-analysis.

BACKGROUND: Myocardial perfusion imaging (MPI) is a well-established, non-invasive imaging procedure for the diagnosis and evaluation of patients with known or suspected coronary artery disease. With the increasing use of pharmacologic stress agents in myocardial perfusion imaging, strict preparation, including caffeine abstinence, is required. The aim of this review was to determine the effect of caffeine consumed prior to nuclear cardiac stress testing on the diagnostic accuracy. METHODS: Medline, Embase and CINAHL were searched from the earliest available time until August 2022. Methodological quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies version 2. Data pertaining to diagnostic accuracy were analysed using meta-analysis where appropriate and overall certainty of evidence evaluated using the Grades of Research, Assessment, Development and Evaluation approach. RESULTS: Six studies (307 participants) from a yield of 735 articles were identified. Meta-analysis of two studies found no difference in the left ventricular ejection fraction of patients pre and post caffeine consumption (MD -0.31 %, 95% CI -4.32% to 3.7%). Meta-analysis of three studies found there was uncertainty as to whether caffeine consumption affected reversibility (MD -2.16 segments 95% CI -4.61 to 0.28) and descriptive summary of three studies found mixed results for size of stress defects. CONCLUSION: The low quality evidence synthesized in this systematic review suggests caffeine may affect the diagnostic accuracy in myocardial perfusion imaging for ischemia detection in patients with chest pain and intermediate-to-high risk of coronary artery disease.

Development of Highly Potent Clinical Candidates for Theranostic Applications against Cholecystokinin-2 Receptor Positive Cancers.

Peptide receptor radionuclide therapy (PRRT) is a promising form of systemic radiation therapy designed to eradicate cancer. Cholecystokinin-2 receptor (CCK2R) is an important molecular target that is highly expressed in a range of cancers. This study describes the synthesis and in vivo characterization of a novel series of 177Lu-labeled peptides ([177Lu]Lu-2b-4b) in comparison with the reference CCK2R-targeting peptide CP04 ([177Lu]Lu-1b). [177Lu]Lu-1b-4b showed high chemical purity (HPLC ≥ 94%), low Log D7.4 (-4.09 to -4.55) with strong binding affinity to CCK2R (KD 0.097-1.61 nM), and relatively high protein binding (55.6-80.2%) and internalization (40-67%). Biodistribution studies of the novel 177Lu-labeled peptides in tumors (AR42J and A431-CCK2R) showed uptake one- to eight-fold greater than the reference compound CP04 at 1, 24, and 48 h. Rapid clearance and high tumor uptake and retention were established for [177Lu]Lu-2b-4b, making these compounds excellent candidates for theranostic applications against CCK2R-expressing tumors.

Targeting HIV-1 Reverse Transcriptase Using a Fragment-Based Approach.

Human immunodeficiency virus type I (HIV-1) is a retrovirus that infects cells of the host's immune system leading to acquired immunodeficiency syndrome and potentially death. Although treatments are available to prevent its progression, HIV-1 remains a major burden on health resources worldwide. Continued emergence of drug-resistance mutations drives the need for novel drugs that can inhibit HIV-1 replication through new pathways. The viral protein reverse transcriptase (RT) plays a fundamental role in the HIV-1 replication cycle, and multiple approved medications target this enzyme. In this study, fragment-based drug discovery was used to optimize a previously identified hit fragment (compound B-1), which bound RT at a novel site. Three series of compounds were synthesized and evaluated for their HIV-1 RT binding and inhibition. These series were designed to investigate different vectors around the initial hit in an attempt to improve inhibitory activity against RT. Our results show that the 4-position of the core scaffold is important for binding of the fragment to RT, and a lead compound with a cyclopropyl substitution was selected and further investigated. Requirements for binding to the NNRTI-binding pocket (NNIBP) and a novel adjacent site were investigated, with lead compound 27-a minimal but efficient NNRTI-offering a starting site for the development of novel dual NNIBP-Adjacent site inhibitors.

Exploring the role of medical imaging assistants in Australian medical imaging departments: A mixed-methods study.

INTRODUCTION: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

Delegation of patient related tasks to allied health assistants: a time motion study.

BACKGROUND: Allied health assistants (AHAs) are support staff who complete patient and non-patient related tasks under the delegation of an allied health professional. Delegating patient related tasks to AHAs can benefit patients and allied health professionals. However, it is unclear whether the AHA workforce is utilised optimally in the provision of patient care. The purpose of this study was to determine the proportion of time AHAs spend on patient related tasks during their working day and any differences across level of AHA experience, clinical setting, and profession delegating the task. METHODS: A time motion study was conducted using a self-report, task predominance work sampling method. AHAs were recruited from four publicly-funded health organisations in Victoria, Australia. AHAs worked with dietitians, occupational therapists, physiotherapists, podiatrists, social workers, speech pathologists, psychologists, and exercise physiologists. The primary outcome was quantity of time spent by AHAs on individual task-categories. Tasks were grouped into two main categories: patient or non-patient related activities. Data were collected from July 2020 to May 2021 using an activity capture proforma specifically designed for this study. Logistic mixed-models were used to investigate the extent to which level of experience, setting, and delegating profession were associated with time spent on patient related tasks. RESULTS: Data from 51 AHAs showed that AHAs spent more time on patient related tasks (293 min/day, 64%) than non-patient related tasks (167 min/day, 36%). Time spent in community settings had lower odds of being delegated to patient related tasks than time in the acute hospital setting (OR 0.44, 95%CI 0.28 to 0.69, P < 0.001). Time delegated by exercise physiologists and dietitians was more likely to involve patient related tasks than time delegated by physiotherapists (exercise physiology: OR 3.77, 95% 1.90 to 7.70, P < 0.001; dietetics: OR 2.60, 95%CI 1.40 to 1.90, P = 0.003). Time delegated by other professions (e.g. podiatry, psychology) had lower odds of involving patient related tasks than physiotherapy (OR 0.37, 95%CI 0.16 to 0.85, P = 0.02). CONCLUSION: AHAs may be underutilised in community settings, and by podiatrists and psychologists. These areas may be targeted to understand appropriateness of task delegation to optimise AHAs' role in providing patient care.

Imaging volumes during COVID-19: A Victorian health service experience.

BACKGROUND: 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. AIM: To investigate differences in modality imaging volumes during the COVID-19 pandemic across a large Victorian public health network. METHODS: 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. RESULTS: 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, P = 0.000). No correlation was observed in the inpatient setting (Spearman's correlation coefficient = -0.059, P = 0.554). CONCLUSION: 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' perspectives of their role in healthcare settings: A qualitative study.

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.

A synthetic lipopeptide targeting top-priority multidrug-resistant Gram-negative pathogens.

The emergence of multidrug-resistant (MDR) Gram-negative pathogens is an urgent global medical challenge. The old polymyxin lipopeptide antibiotics (polymyxin B and colistin) are often the only therapeutic option due to resistance to all other classes of antibiotics and the lean antibiotic drug development pipeline. However, polymyxin B and colistin suffer from major issues in safety (dose-limiting nephrotoxicity, acute toxicity), pharmacokinetics (poor exposure in the lungs) and efficacy (negligible activity against pulmonary infections) that have severely limited their clinical utility. Here we employ chemical biology to systematically optimize multiple non-conserved positions in the polymyxin scaffold, and successfully disconnect the therapeutic efficacy from the toxicity to develop a new synthetic lipopeptide, structurally and pharmacologically distinct from polymyxin B and colistin. This resulted in the clinical candidate F365 (QPX9003) with superior safety and efficacy against lung infections caused by top-priority MDR pathogens Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae.

COVID-19 pandemic and the effect of increased utilisation of mobile X-ray examinations on radiation dose to radiographers.

INTRODUCTION: The use of ionising radiation results in occupational exposure to medical imaging professionals, requiring routine monitoring. This study aims to assess the effect of increased utilisation of mobile X-ray units, mobile imaging of non-routine body regions and radiographer work practice changes for impact on staff radiation dose during the early stages of the COVID-19 pandemic. METHODS: A retrospective analysis of general radiology departments across two metropolitan hospitals was performed. Personal radiation monitor exposure reports between January 2019 and December 2020 were analysed. Statistical analysis was conducted using a Mann-Whitney U test when comparing each quarter, from 2019 to 2020. Categorical data were compared using a Chi-squared test. RESULTS: Mobile X-ray use during the pandemic increased approximately 1.7-fold, with the peak usage observed in September 2020. The mobile imaging rate per month of non-routine body regions increased from approximately 6.0-7.8%. Reported doses marginally increased during Q2, Q3 and Q4 of 2020 (in comparison to 2019 data), though was not statistically significant (Q2: P = 0.13; Q3: P = 0.31 and Q4 P = 0.32). In Q1, doses marginally decreased and were not statistically significant (P = 0.22). CONCLUSION: Increased utilisation and work practice changes had no significant effect on reported staff radiation dose. The average reported dose remained significantly lower than the occupational dose limits for radiation workers of 20 mSv.

Abstract-To-Publication Rates From Australian Society of Medical Imaging and Radiation Therapy Conferences.

PURPOSE: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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. CONCLUSION: 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.

CT Attenuation correction and its impact on image quality of myocardial perfusion imaging in coronary artery disease: A systematic review.

Myocardial perfusion imaging is a non-invasive procedure that plays an integral role in the diagnosis and management of coronary artery disease. With the routine use of computerised tomography attenuation correction (CTAC) in myocardial perfusion imaging still under debate, the aim of this review was to determine the impact of CTAC on image quality in myocardial perfusion imaging. Medline, Embase and CINAHL were searched from the earliest available time until August 2019. Methodological quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies version 2. Details pertaining to image quality and diagnostic accuracy were analysed, and results summarised descriptively. Three studies with 'unclear' risk of bias and low applicability concerns (1002 participants) from a yield of 2725 articles were identified. Two studies demonstrated an increase in image quality, and one study found no difference in image quality when using CTAC compared to no attenuation correction. Benefits of CTAC for improving image quality remain unclear. Given the potential exposure risk with the addition of CTAC, patient and clinician factors should inform decision making for use of CTAC in myocardial perfusion imaging for coronary artery disease.

Who? What? Where? A snapshot of Nuclear Medicine Research Presentations from recent ANZSNM conferences in Australia and New Zealand.

OBJECTIVES: The aims of this study were to: 1) discover location (by city) of contributors to poster and oral presentations at recent ANZSNM conferences; 2) determine the nuclear medicine themes most commonly explored; 3) establish institutions producing the highest number of oral and poster abstracts and 4) determine publication rates of conference abstracts to full papers from recent ANZSNM conferences. METHODS: Retrospective analysis of abstracts published in the Internal Medicine Journal Special Issues 2014-2019 identified 614 abstracts. Invited plenary speaker abstracts were excluded. Descriptive statistics were used in data analysis. Conference abstracts were analysed using the following criteria: poster or oral presentation, author/s, city location, hospital and subject matter. Themes defined by the ANZSNM conference committee for abstract submission were: cardiology, oncology, neurology, therapy, renal/urology, gastrointestinal, paediatrics, musculoskeletal, infection/inflammation, technology, physics, radiation safety, radiopharmacy/radiochemistry, education, or general. Retrospective analysis of 555 conference abstracts (excluding New Zealand and International, 59 abstracts) using Google Scholar, Pubmed and Google databases was undertaken. Abstract titles, key words, institutions and/or authors' names were used to find peer-reviewed papers. Identified papers were authenticated through either open access, publicly available author information or Monash University's library access. Published paper citations were also recorded (up to 1st July 2019). RESULTS: Analysis of 614 abstracts 2014 - 2019 was performed. Over five years, the average number of poster abstracts was 67.8 and oral 55.0. Sydney submitted the highest number of poster abstracts, while Melbourne the highest number of oral abstracts. Most popular abstract theme was oncology for both poster and oral abstracts. Publications found had in excess of 1250 citations.One hundred and one publications from one hundred and seven conference presentations were identified, distributed across sixty journals. Conference presentation to full publication rate was 18.2%; excluding 2019 conference abstracts the rate was 21.5%. CONCLUSION: Publishing research findings is a challenging process. A retrospective analysis of research presented at recent ANZSNM conferences by abstract content was undertaken, with conference presentation to full publication rate found to be at the lower end of reported literature findings.

Development of single and mixed isoform selectivity PI3Kδ inhibitors by targeting Asn836 of PI3Kδ.

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.

Discovery and antiplatelet activity of a selective PI3Kß inhibitor (MIPS-9922).

A series of amino-substituted triazines were developed and examined for PI3Kß inhibition and anti-platelet function. Structural adaptations of a morpholine ring of the prototype pan-PI3K inhibitor ZSTK474 yielded PI3Kß selective compounds, where the selectivity largely derives from an interaction with the non-conserved Asp862 residue, as shown by site directed mutagenesis. The most PI3Kß 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 αIIbß3 activation and αIIbß3 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.

Evidence for the in vitro bioactivation of aminopyrazole derivatives: trapping reactive aminopyrazole intermediates using glutathione ethyl ester in human liver microsomes.

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.

L-Aminoacyl-triazine derivatives are isoform-selective PI3Kß inhibitors that target non-conserved Asp862 of PI3Kß

A series of aminoacyl-triazine derivatives based upon the pan-PI3K inhibitor ZSTK474 were identified as potent and isoform selective inhibitors of PI3Kß. The compounds showed selectivity based upon stereochemistry with L-amino acyl derivatives preferring PI3Kß while their D-congeners favoured 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 PI3Kß-selective inhibitors distinguishing this class from other reported PI3Kß-selective inhibitors. The compounds show strong inhibition of cellular Akt phosphorylation and growth of PTEN-deficient MD-MBA-468 cells.

Regioselective synthesis of 5- and 6-methoxybenzimidazole-1,3,5-triazines as inhibitors of phosphoinositide 3-kinase.

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.

Synthesis and Pharmacological Evaluation of 4-Iminothiazolidinones for Inhibition of PI3 Kinase.

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.

Thiazolidinedione-based PI3Kα inhibitors: an analysis of biochemical and virtual screening methods.

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.

Inflammatory twins from PI3K gang brought to justice?

PI3 kinase inhibitors are hot property. In this issue of Chemistry & Biology, 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.