Adelaide Research & Scholarship

Clinicians' perspectives on diagnosing polycystic ovary syndrome in Australia: a qualitative study

2021-02-25T00:06:12Z

Title: Clinicians' perspectives on diagnosing polycystic ovary syndrome in Australia: a qualitative study Author: Copp, T.; Muscat, D.M.; Hersch, J.; McCaffery, K.J.; Doust, J.; Mol, B.W.; Dokras, A.; Jansen, J. Abstract: STUDY QUESTION: What are clinicians' views about the diagnosis of polycystic ovary syndrome (PCOS), and how do they handle any complexities and uncertainties in practice? SUMMARY ANSWER: Clinicians have to navigate many areas of complexity and uncertainty regarding the diagnosis of PCOS, related to the diagnostic criteria, limitations in current evidence and misconceptions surrounding diagnosis, and expressed concern about the risk and consequences of both under- and overdiagnosis. WHAT IS KNOWN ALREADY: PCOS is a complex, heterogeneous condition with many areas of uncertainty, raising concerns about both underdiagnosis and overdiagnosis. Quantitative studies with clinicians have found considerable variation in diagnostic criteria used and care provided, as well as a lack of awareness around the breadth of PCOS features and poor uptake of recommended screening for metabolic complications. Clinicians' views about the uncertainties and complexities of diagnosing PCOS have not been explored. STUDY DESIGN, SIZE, DURATION: Semi-structured telephone interviews were conducted with clinicians from September 2017 to July 2018 to explore their perceptions about the diagnosis of PCOS, including how they handle any complexities and uncertainties in practice. PARTICIPANTS/MATERIALS, SETTING, METHODS: A group of 36 clinicians (15 general practitioners, 10 gynaecologists and 11 endocrinologists) currently practicing in Australia, were recruited through advertising via professional organisations, contacting a random sample of endocrine and gynaecology teams across Australia and snowballing. Transcribed audio-recordings were analysed thematically using Framework analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Clinicians expressed a range of uncertainties and complexities regarding the diagnosis of PCOS, which were organised into three areas: (i) establishing diagnosis (e.g. lack of standardisation regarding diagnostic cut-offs, risk of misdiagnosis), (ii) factors influencing the diagnostic process (e.g. awareness of limitations in evidence and consideration of the benefits and harms) and (iii) strategies for handling challenges and uncertainties (e.g. using caution and communication of uncertainties). Clinicians also varied in their concerns regarding under- and overdiagnosis. Overall, most felt the diagnosis was beneficial for women provided that it was the correct diagnosis and time was taken to assess patient expectations and dispel misconceptions, particularly concerning fertility. LIMITATIONS, REASONS FOR CAUTION: There is possible selection bias, as clinicians who are more knowledgeable about PCOS may have been more likely to participate. Clinicians' views may also differ in other countries. WIDER IMPLICATIONS OF THE FINDINGS: These findings underscore the vital need to first consider PCOS a diagnosis of exclusion and use caution before giving a diagnosis in order to reduce misdiagnosis, as suggested by clinicians in our study. Until there is greater standardisation of diagnostic criteria, more transparent conversations with women may help them understand the uncertainties surrounding the criteria and limitations in the evidence. Additionally, clinicians emphasised the importance of education and reassurance to minimise the potential harmful impact of the diagnosis and improve patient-centred outcomes. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the University of Sydney Lifespan Research Network and an NHMRC Program Grant (APP1113532). T.C. is supported by an Australian Government Research Training Program (RTP) Scholarship and a Sydney Medical School Foundation Scholarship, from the The University of Sydney, Australia. B.W.M. reports consultancy for ObsEva, Merck, Merck KGaA and Guerbet. No further competing interests exist. TRIAL REGISTRATION NUMBER: N/A.

Clinical utility of stress echocardiography in remote indigenous and non-indigenous populations: a 10-year study in Central Australia

2021-02-25T00:02:11Z

Title: Clinical utility of stress echocardiography in remote indigenous and non-indigenous populations: a 10-year study in Central Australia Author: Ratwatte, S.; Costello, B.; Kangaharan, N.; Bolton, K.; Kaur, A.; Corkill, W.; Kuepper, B.; Pitman, B.; Sanders, P.; Wong, C.X. Abstract: Background: Remote Central Australia has a large Indigenous population and a significant burden of cardiovascular disease. Stress echocardiography has been previously validated as a useful investigation for long-term prognostication. However, there are no prior studies assessing its utility in remote or Indigenous populations. Method: Consecutive individuals undergoing stress echocardiography in Central Australia between 2007 and 2017 were included. Stress echocardiography was performed and reported via standard protocols. Individuals were followed up for all-cause mortality. Results: One-thousand and eight patients (1,008) (54% Indigenous Australian) were included. After a mean follow-up of 3.5±2.4 years, 54 (5%) patients were deceased. Overall, 797 (79%) patients had no abnormalities during rest or stress echocardiography, with no difference according to ethnicity (p>0.05). In patients with a normal test, annual mortality averaged 1.3% over 5 years of follow-up, with annual mortality significantly higher in Indigenous compared to non-Indigenous individuals (1.8% vs 0.6% respectively). In those with an abnormal test, annual mortality was 4.4% vs 1.3% in Indigenous and non-Indigenous individuals respectively. Increasing age, Indigenous ethnicity and cardiometabolic comorbidities were associated with mortality in univariate analyses (p<0.05 for all). In multivariate models, only chronic kidney disease remained predictive of mortality, with other associations (including Indigenous ethnicity) becoming attenuated. Conclusion: This is the first study to report on the use of stress echocardiography in a remote or Indigenous population. A normal stress echocardiogram in remote Indigenous individuals was able to identify a lower risk group of patients in this setting. Although Indigenous individuals with a normal test still had a higher annual rate of mortality compared to non-Indigenous individuals, this association appeared to be mediated by cardiometabolic comorbidities. Description: Published:June 07, 2020

Clinical MDR1 inhibitors enhance Smac-mimetic bioavailability to kill murine LSCs and improve survival in AML models

2021-02-25T00:01:27Z

Title: Clinical MDR1 inhibitors enhance Smac-mimetic bioavailability to kill murine LSCs and improve survival in AML models Author: Morrish, E.; Copeland, A.; Moujalled, D.M.; Powell, J.A.; Silke, N.; Lin, A.; Jarman, K.E.; Sandow, J.J.; Ebert, G.; Mackiewicz, L.; Beach, J.A.; Christie, E.L.; Lewis, A.C.; Pomilio, G.; Fischer, K.C.; MacPherson, L.; Bowtell, D.D.L.; Webb, A.I.; Pellegrini, M.; Dawson, M.A.; et al. Abstract: The specific targeting of inhibitor of apoptosis (IAP) proteins by Smac-mimetic (SM) drugs, such as birinapant, has been tested in clinical trials of acute myeloid leukemia (AML) and certain solid cancers. Despite their promising safety profile, SMs have had variable and limited success. Using a library of more than 5700 bioactive compounds, we screened for approaches that could sensitize AML cells to birinapant and identified multidrug resistance protein 1 inhibitors (MDR1i) as a class of clinically approved drugs that can enhance the efficacy of SM therapy. Genetic or pharmacological inhibition of MDR1 increased intracellular levels of birinapant and sensitized AML cells from leukemia murine models, human leukemia cell lines, and primary AML samples to killing by birinapant. The combination of clinical MDR1 and IAP inhibitors was well tolerated in vivo and more effective against leukemic cells, compared with normal hematopoietic progenitors. Importantly, birinapant combined with third-generation MDR1i effectively killed murine leukemic stem cells (LSCs) and prolonged survival of AML-burdened mice, suggesting a therapeutic opportunity for AML. This study identified a drug combination strategy that, by efficiently killing LSCs, may have the potential to improve outcomes in patients with AML.

Preferential activation of unique motor cortical networks with transcranial magnetic stimulation: a review of the physiological, functional, and clinical evidence

2021-02-24T02:10:56Z

Title: Preferential activation of unique motor cortical networks with transcranial magnetic stimulation: a review of the physiological, functional, and clinical evidence Author: Opie, G.M.; Semmler, J.G. Abstract: Objectives: The corticospinal volley produced by application of transcranial magnetic stimulation (TMS) over primary motor cortex consists of a number of waves generated by trans-synaptic input from interneuronal circuits. These indirect (I)-waves mediate the sensitivity of TMS to cortical plasticity and intracortical excitability and can be assessed by altering the direction of cortical current induced by TMS. While this methodological approach has been conventionally viewed as preferentially recruiting early or late I-wave inputs from a given populations of neurons, growing evidence suggests recruitment of different neuronal populations, and this would strongly influence interpretation and application of these measures. The aim of this review is therefore to consider the physiological, functional, and clinical evidence for the independence of the neuronal circuits activated by different current directions. Materials and Methods: To provide the relevant context, we begin with an overview of TMS methodology, focusing on the different techniques used to quantify I-waves. We then comprehensively review the literature that has used variations in coil orientation to investigate the I-wave circuits, grouping studies based on the neurophysiological, functional, and clinical relevance of their outcomes. Results: Review of the existing literature reveals significant evidence supporting the idea that varying current direction can recruit different neuronal populations having unique functionally and clinically relevant characteristics. Conclusions: Further research providing greater characterization of the I-wave circuits activated with different current directions is required. This will facilitate the development of interventions that are able to modulate specific intracortical circuits, which will be an important application of TMS. Description: OnlinePubl.