Research Priorities for Atrial Fibrillation in Australia: A Statement From the Australian Cardiovascular Alliance Clinical Arrhythmia Theme.

Atrial fibrillation (AF) is highly prevalent in the Australian community, ranking amongst the highest globally. The consequences of AF are significant. Stroke, dementia and heart failure risk are increased substantially, hospitalisations are amongst the highest for all cardiovascular causes, and Australians living with AF suffer from substantial symptoms that impact quality of life. Australian research has made a significant impact at the global level in advancing the care of patients living with AF. However, new strategies are required to reduce the growing incidence of AF and its associated healthcare demand. The Australian Cardiovascular Alliance (ACvA) has led the development of an arrhythmia clinical theme with the objective of tackling major research priorities to achieve a reduction in AF burden across Australia. In this summary, we highlight these research priorities with particular focus on the strengths of Australian research and the strategies needed to move forward in reducing incident AF and improving outcomes for those who live with this chronic condition.

Mechanistic insights and knowledge gaps in the effects of radiation therapy on cardiac arrhythmias.

Stereotactic body radiation therapy (SBRT) is an innovative modality for treatment of refractory ventricular arrhythmias (VA). Phase I/II clinical trials have demonstrated the remarkable efficacy of SBRT at reducing VA burden(by>85%) in patients with good short-term safety. SBRT as an option for VA treatment delivered in an ambulatory, non-sedated patient in a single fraction, during an outpatient session of 15-30 minutes, without added risks of anesthetic or surgery is clinically relevant. However, the underlying mechanism remains unclear. Currently used clinical dosing of SBRT has been derived from preclinical studies aimed to induce transmural fibrosis in the atria. The propitious clinical effects of SBRT appear earlier than the time-course for fibrosis. This review addresses the plausible mechanisms by which radiation alters the electrophysiological properties of myocytes and myocardial conduction to impart an anti-arrhythmic effect to elucidate clinical observations and point the direction for further research in this promising area.

Reduced connexin-43 expression, slow conduction and repolarisation dispersion in a model of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an inherited heart muscle disease that is characterised by left ventricular wall thickening, cardiomyocyte disarray and fibrosis, and is associated with arrhythmias, heart failure and sudden death. However, it is unclear to what extent the electrophysiological disturbances that lead to sudden death occur secondary to structural changes in the myocardium or as a result of HCM cardiomyocyte electrophysiology. In this study, we used an induced pluripotent stem cell model of the R403Q variant in myosin heavy chain 7 (MYH7) to study the electrophysiology of HCM cardiomyocytes in electrically coupled syncytia, revealing significant conduction slowing and increased spatial dispersion of repolarisation - both well-established substrates for arrhythmia. Analysis of rhythmonome protein expression in MYH7 R403Q cardiomyocytes showed reduced expression of connexin-43 (also known as GJA1), sodium channels and inward rectifier potassium channels - a three-way hit that reduces electrotonic coupling and slows cardiac conduction. Our data represent a previously unreported, biophysical basis for arrhythmia in HCM that is intrinsic to cardiomyocyte electrophysiology. Later in the progression of the disease, these proarrhythmic phenotypes may be accentuated by myocyte disarray and fibrosis to contribute to sudden death.

Associations between Social Capital and Self-Rated Health among Men Who Have Sex with Men in Japan.

Men who have sex with men (MSM) are significantly more likely to report poor health compared to the general population in Japan and internationally. Social capital has been observed as an important component of positive health and well-being outcomes among MSM. However, there is limited research investigating how alter sexuality (possessors of actual resources embedded in social capital networks) mitigates health outcomes. In an online survey of 1564 MSM in Japan, we investigated social correlates of poor self-rated health among MSM, including MSM and heterosexual social networks. Multiple logistic regression revealed that poor health was associated with older age, lower education, and part-time and unemployment. Poor health was inversely correlated with bisexual behavior and high MSM or heterosexual social capital. In order to decrease health disparities among MSM in Japan, interventions focusing on increasing social capital among deprived groups, such as those with lower socio-economic status, older MSM, and those whose sex partners are exclusively male, may be effective.

COVID-19, lockdowns, and the mental wellbeing of LGBTQ people in Australia.

LGBTQ communities around the world entered the COVID-19 pandemic with generally high rates of poor mental health and faced additional challenges including stigma, discrimination, and barriers to care. This study sample was drawn from a survey of 3135 LGBTQ adults residing in Australia during the pandemic. Regression analysis was used to explore individual differences in psychological distress and perceived change in mental wellbeing since the onset of the pandemic as well as the impact of lockdowns, by taking advantage of a natural experiment comparing the states that experienced more extensive lockdowns (Victoria and New South Wales) to the rest of Australia. The burden of mental health was found to vary across gender, sexual orientation, age, and area of residence. While no impact of lockdowns on psychological distress was observed, participants living in the states of Victoria (ß = -0.15; 95% CI = -0.23, -0.07) and New South Wales (ß = -0.13; 95% CI = -0.21, -0.05) self-reported a more negative impact of the pandemic on their mental wellbeing compared to the rest of the country. The findings suggest that the COVID-19 pandemic had a negative impact on the mental wellbeing of LGBTQ populations, particularly among those who experienced extensive lockdowns and highlight the need for increased efforts to enable access to mental health supports during times of crisis.

Airway clearance management in people with bronchiectasis: data from the European Bronchiectasis Registry (EMBARC).

BACKGROUND: International guidelines recommend airway clearance management as one of the important pillars of bronchiectasis treatment. However, the extent to which airway clearance is used for people with bronchiectasis in Europe is unclear. The aim of the study was to identify the use of airway clearance management in patients with bronchiectasis across different countries and factors influencing airway clearance use. METHODS: This was a prospective observational study using data from the European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC) Registry between January 2015 and April 2022. Prespecified options for airway clearance management were recorded, including airway clearance techniques, devices and use of mucoactive drugs. RESULTS: 16 723 people with bronchiectasis from 28 countries were included in the study. The mean age was 67 years (interquartile range 57-74 years, range 18-100 years) and 61% were female. 72% of the participants reported daily sputum expectoration and 52% (95% CI 51-53%) of all participants reported using regular airway clearance management. Active cycle of breathing technique was used by 28% of the participants and airway clearance devices by 16% of participants. The frequency of airway clearance management and techniques used varied significantly between different countries. Participants who used airway clearance management had greater disease severity and worse symptoms, including a higher daily sputum volume, compared to those who did not use it regularly. Mucoactive drugs were also more likely to be used in participants with more severe disease. Access to specialist respiratory physiotherapy was low throughout Europe, but particularly low in Eastern Europe. CONCLUSIONS: Only a half of people with bronchiectasis in Europe use airway clearance management. Use of and access to devices, mucoactive drugs and specialist chest physiotherapy appears to be limited in many European countries.

Objective sputum colour assessment and clinical outcomes in bronchiectasis: data from the European Bronchiectasis Registry (EMBARC).

BACKGROUND: A validated 4-point sputum colour chart can be used to objectively evaluate the levels of airway inflammation in bronchiectasis patients. In the European Bronchiectasis Registry (EMBARC), we tested whether sputum colour would be associated with disease severity and clinical outcomes. METHODS: We used a prospective, observational registry of adults with bronchiectasis conducted in 31 countries. Patients who did not produce spontaneous sputum were excluded from the analysis. The Murray sputum colour chart was used at baseline and at follow-up visits. Key outcomes were frequency of exacerbations, hospitalisations for severe exacerbations and mortality during up to 5-year follow-up. RESULTS: 13 484 patients were included in the analysis. More purulent sputum was associated with lower forced expiratory volume in 1 s (FEV1), worse quality of life, greater bacterial infection and a higher bronchiectasis severity index. Sputum colour was strongly associated with the risk of future exacerbations during follow-up. Compared to patients with mucoid sputum (reference group), patients with mucopurulent sputum experienced significantly more exacerbations (incident rate ratio (IRR) 1.29, 95% CI 1.22-1.38; p<0.0001), while the rates were even higher for patients with purulent (IRR 1.55, 95% CI 1.44-1.67; p<0.0001) and severely purulent sputum (IRR 1.91, 95% CI 1.52-2.39; p<0.0001). Hospitalisations for severe exacerbations were also associated with increasing sputum colour with rate ratios, compared to patients with mucoid sputum, of 1.41 (95% CI 1.29-1.56; p<0.0001), 1.98 (95% CI 1.77-2.21; p<0.0001) and 3.05 (95% CI 2.25-4.14; p<0.0001) for mucopurulent, purulent and severely purulent sputum, respectively. Mortality was significantly increased with increasing sputum purulence, hazard ratio 1.12 (95% CI 1.01-1.24; p=0.027), for each increment in sputum purulence. CONCLUSION: Sputum colour is a simple marker of disease severity and future risk of exacerbations, severe exacerbations and mortality in patients with bronchiectasis.

Factors associated with help-seeking regarding sexual orientation concerns among Japanese gay and bisexual men: results from a cross-sectional survey.

OBJECTIVE: This study investigates Japanese gay and bisexual men's experiences of seeking help for emotional support from others regarding their sexual orientation concerns. It examines the relationship between their help-seeking and presence of gay and bisexual peers, duration between questioning their sexual orientation and accepting it, and experience of coming out to family members by multiple logistic regression analysis. RESULTS: We conducted a cross-sectional survey using a self-reported paper questionnaire. There were 360 valid responses. Eighty-two respondents (22.8%) had experience of help-seeking for emotional support, and this was associated with age, occupation, presence of gay/bisexual friends, and experience of coming out to family members about their sexual orientation. Respondents sought the most help from their male friends (70.0%), followed by female friends (25.0%), mothers (17.5%), and the Internet (16.3%). Even after controlling for age and occupation, experience of help-seeking for emotional support was higher among participants who had gay/bisexual friends when they were aware of their sexual orientation, took < 1 year from questioning to realizing their sexual orientation, and had come out to their family about their sexual orientation.

Development of a pharmaceutical database as an aid to the nonclinical detection of drug-induced cardiac toxicity.

The Health and Environmental Sciences Institute (HESI) Cardiac Safety Committee designed and created a publicly accessible database with an initial set of 128 pharmacologically defined pharmaceutical agents, many with known cardiotoxic properties. The database includes specific information about each compound that could be useful in evaluating hypotheses around mechanisms of drug-induced cardiac toxicity or for development of novel cardiovascular safety assays. Data on each of the compounds was obtained from published literature and online sources (e.g., DrugBank.ca and International Union of Basic and Clinical Pharmacology (IUPHAR) / British Pharmacological Society (BPS) Guide to PHARMACOLOGY) and was curated by 10 subject matter experts. The database includes information such as compound name, pharmacological mode of action, characterized cardiac mode of action, type of cardiac toxicity, known clinical cardiac toxicity profile, animal models used to evaluate the cardiotoxicity profile, routes of administration, and toxicokinetic parameters (i.e., Cmax). Data from both nonclinical and clinical studies are included for each compound. The user-friendly web interface allows for multiple approaches to search the database and is also intended to provide a means for the submission of new data/compounds from relevant users. This will ensure that the database is constantly updated and remains current. Such a data repository will not only aid the HESI working groups in defining drugs for use in any future studies, but safety scientists can also use the database as a vehicle of support for broader cardiovascular safety studies or exploring mechanisms of toxicity associated with certain pharmacological modes of action.

Bronchiectasis and asthma: Data from the European Bronchiectasis Registry (EMBARC).

BACKGROUND: Asthma is commonly reported in patients with a diagnosis of bronchiectasis. OBJECTIVE: The aim of this study was to evaluate whether patients with bronchiectasis and asthma (BE+A) had a different clinical phenotype and different outcomes compared with patients with bronchiectasis without concomitant asthma. METHODS: A prospective observational pan-European registry (European Multicentre Bronchiectasis Audit and Research Collaboration) enrolled patients across 28 countries. Adult patients with computed tomography-confirmed bronchiectasis were reviewed at baseline and annual follow-up visits using an electronic case report form. Asthma was diagnosed by the local investigator. Follow-up data were used to explore differences in exacerbation frequency between groups using a negative binomial regression model. Survival analysis used Cox proportional hazards regression. RESULTS: Of 16,963 patients with bronchiectasis included for analysis, 5,267 (31.0%) had investigator-reported asthma. Patients with BE+A were younger, were more likely to be female and never smokers, and had a higher body mass index than patients with bronchiectasis without asthma. BE+A was associated with a higher prevalence of rhinosinusitis and nasal polyps as well as eosinophilia and Aspergillus sensitization. BE+A had similar microbiology but significantly lower severity of disease using the bronchiectasis severity index. Patients with BE+A were at increased risk of exacerbation after adjustment for disease severity and multiple confounders. Inhaled corticosteroid (ICS) use was associated with reduced mortality in patients with BE+A (adjusted hazard ratio 0.78, 95% CI 0.63-0.95) and reduced risk of hospitalization (rate ratio 0.67, 95% CI 0.67-0.86) compared with control subjects without asthma and not receiving ICSs. CONCLUSIONS: BE+A was common and was associated with an increased risk of exacerbations and improved outcomes with ICS use. Unexpectedly we identified significantly lower mortality in patients with BE+A.

Pneumococcal serotypes and risk factors in adult community-acquired pneumonia 2018-20; a multicentre UK cohort study.

Background: Higher-valency pneumococcal vaccines are anticipated. We aimed to describe serotype distribution and risk factors for vaccine-serotype community-acquired pneumonia (CAP) in the two years pre-SARS-CoV-2 pandemic. Methods: We conducted a prospective cohort study of adults hospitalised with CAP at three UK sites between 2018 and 2020. Pneumococcal serotypes were identified using a 24-valent urinary-antigen assay and blood cultures. Risk factors associated with vaccine-type pneumonia caused by serotypes in the 13-, 15- and 20-valent pneumococcal conjugate vaccines (PCV13, PCV15, PCV20) and 23-valent pneumococcal polysaccharide vaccine (PPV23) were determined from multivariable analysis. Findings: Of 1921 adults hospitalised with CAP, 781 (40.7%, 95% confidence intervals (CI) 38.5-42.9%) had pneumococcal pneumonia. A single PCV13-serotype was detected in 242 (31.0%, 95% CI 27.8-34.3%) pneumococcal CAP patients, mostly serotype 3 (171/242, 70.7%, 95% CI 64.5-76.0%). The additional two PCV15-serotypes were detected in 31 patients (4%, 95% CI 2.8-5.6%), and PCV20-non13-serotypes in 192 (24.6%), with serotype 8 most prevalent (123/192, 64.1%, 95% CI 57.1-70.5%). Compared to PCV13-serotype CAP, people with PCV20-non13 CAP were younger (median age 62 versus 72 years, p < 0.001) and less likely to be male (44% versus 61%, p = 0.01). PPV23-non13-serotypes were found in 252 (32.3%, 95% CI 29.1-35.6%) pneumococcal CAP patients. Interpretation: Despite mature infant pneumococcal programmes, the burden of PCV13-serotype pneumonia remains high in older adults, mainly due to serotype 3. PCV20-non13-serotype pneumonia is more likely in younger people with fewer pneumococcal risk factors. Funding: Unrestricted investigator-initiated research grant from Pfizer, United Kingdom; support from National Institute for Health Research (NIHR) Biomedical Research Centre, Nottingham.

The influence of care continuity and disclosure of sexual orientation in general practice on lesbian, bi+ and queer cisgender women's engagement with mental health services.

BACKGROUND: Lesbian, bisexual+ and queer (LBQ+) cisgender women have considerable unmet mental health needs. The aims of this study were to examine LBQ+ cisgender women's prior engagement with general practitioners (GPs), and how this relationship shaped their mental health service use. METHOD: Data from 2707 cisgender LBQ+ women were drawn from a national survey of adults who are lesbian, gay, bisexual, trans, intersex, queer or questioning, asexual and other diverse sexuality and gender identities (LGBTIQA+) in Australia. Multivariable logistic regression analyses examined demographic predictors of continuity of care with GPs and GPs' awareness of LBQ+ women's sexual orientation. The relationship between these variables and recent mental health service use was then analysed, comparing LBQ+ women's engagement with services known to be LGBTIQA+ inclusive and those without an inclusive reputation. RESULTS: LBQ+ cisgender women with a regular GP had greater odds of having accessed mental health services in the last 12months. Two-thirds had a regular GP, with the lowest odds among women aged 18-35years and highest odds among women with a disability. LBQ+ women who did not believe their regular GP knew of their sexuality had lower odds of having accessed LGBTIQA+ inclusive mental health services. These individuals were typically aged below 25years, bisexual+ or queer identified, had below undergraduate-level education, earned <$2000 AUD per week, or lived in an outer-suburban or regional area. CONCLUSION: GPs may be missing opportunities to promote continuity of care through developing trusting relationships with specific sub-populations of LBQ+ women, which in turn appears to sustain inequitable access to mental health care. To offer appropriate care and referrals for this population, GPs should provide safe and inclusive environments to enable comfortable and supportive discussions about sexual orientation when this is relevant to a person's health care.

Community connection is associated with lower psychological distress for sexual minority women who view community connection positively.

We examined factors associated with sexual minority women's evaluations of belonging to the lesbian, gay, bisexual, transgender and queer (LGBTQ) community in Australia, and assessed whether a positive view of community participation impacted levels of psychological distress. 2424 cisgender sexual minority women participated in a national, online, cross-sectional survey of LGBTIQ adult Australians' health and well-being. Multivariable regression analyses were conducted to investigate sociodemographic factors associated with sexual minority women's belonging to the LGBTQ community, feelings towards community connection, and associations between community connection and recent psychological distress. Most sexual minority women (58.9%) reported feeling that they are part of the LGBTQ community, and a majority of the participants felt positive about being connected to this community (68.5%). Participants who were bisexual, non-university educated, and who resided in an outer-suburban location were least likely to evaluate participation in the LGBTQ community positively. Feeling positive about community connection was associated with lower levels of psychological distress. Feeling a part of LGBTQ community was associated with lower psychological distress, but this link appears contingent upon positive feelings about community participation. Sexual minority women's' relationships to the LGBTQ community are often complex, and community connection and participation in and of itself is not a panacea for the negative outcomes associated with sexual minority stressors.

A core outcome set for bronchiectasis in children and adolescents for use in clinical research: an international consensus study.

Improving the treatment of non-cystic fibrosis bronchiectasis in children and adolescents requires high-quality research with outcomes that meet study objectives and are meaningful for patients and their parents and caregivers. In the absence of systematic reviews or agreement on the health outcomes that should be measured in paediatric bronchiectasis, we established an international, multidisciplinary panel of experts to develop a core outcome set (COS) that incorporates patient and parent perspectives. We undertook a systematic review from which a list of 21 outcomes was constructed; these outcomes were used to inform the development of separate surveys for ranking by parents and patients and by health-care professionals. 562 participants (201 parents and patients from 17 countries, 361 health-care professionals from 58 countries) completed the surveys. Following two consensus meetings, agreement was reached on a ten-item COS with five outcomes that were deemed to be essential: quality of life, symptoms, exacerbation frequency, non-scheduled health-care visits, and hospitalisations. Use of this international consensus-based COS will ensure that studies have consistent, patient-focused outcomes, facilitating research worldwide and, in turn, the development of evidence-based guidelines for improved clinical care and outcomes. Further research is needed to develop validated, accessible measurement instruments for several of the outcomes in this COS.

Factors Associated With Experiences of Harassment or Abuse Among Lesbian, Gay, Bisexual, Trans, Queer, and Asexual Young People With Disability in Australia.

Lesbian, gay, bisexual, trans, queer, and asexual (LGBTQA+) young people with disability are known to experience higher rates of harassment or abuse than LGBTQA+ young people without disability. This study focused on participants in Australia and identified factors associated with harassment or abuse among LGBTQA+ adolescents and young adults who reported a disability as well as associations with mental health outcomes. Analyses were conducted from a national survey that included 2,500 LGBTQA+ people who reported a disability and were aged 14 to 21 years. Measures included experiences in the past 12 months of verbal and physical harassment or abuse due to one's sexual orientation or gender identity, sexual harassment or abuse, mental health, suicidality, and sociodemographic traits. Overall, 48.4% of participants with disability reported experiencing verbal harassment or abuse, 12.4% physical harassment or abuse, and 29.7% sexual assault or harassment. In multivariable regression analyses, verbal harassment or abuse was significantly more likely among trans men, participants with an intellectual disability, and those who were "out" to most or all of their family. Physical harassment or abuse was significantly more likely among participants with a physical or sensory disability. Sexual harassment or abuse was significantly more likely among trans women and participants with a physical or sensory disability. Participants who experienced harassment or abuse were also significantly more likely to have attempted suicide in the past 12 months. These findings will assist policymakers and practitioners in identifying contexts linked to a heightened risk of abuse among LGBTQA+ young people with disability and further underscore an immediate need to address and prevent harm in this population.

Functional coupling between Piezo1 and TRPM4 influences the electrical activity of HL-1 atrial myocytes.

The transient receptor potential melastatin 4 (TRPM4) channel contributes extensively to cardiac electrical activity, especially cardiomyocyte action potential formation. Mechanical stretch can induce changes in heart rate and rhythm, and the mechanosensitive channel Piezo1 is expressed in many cell types within the myocardium. Our previous study showed that TRPM4 and Piezo1 are closely co-localized in the t-tubules of ventricular cardiomyocytes and contribute to the Ca2+-dependent signalling cascade that underlies hypertrophy in response to mechanical pressure overload. However, there was no direct evidence showing that Piezo1 activation was related to TRPM4 activation in situ. In the present study, we employed the HL-1 mouse atrial myocyte-like cell line as an in vitro model to investigate whether Piezo1-TRPM4 coupling can affect action potential properties. We used the small molecule Piezo1 agonist, Yoda1, as a surrogate for mechanical stretch to activate Piezo1 and detected the action potential changes in HL-1 cells using FluoVolt, a fluorescent voltage sensitive dye. Our results demonstrate that Yoda1-induced activation of Piezo1 changes the action potential frequency in HL-1 cells. This change in action potential frequency is reduced by Piezo1 knockdown using small intefering RNA. Importantly knockdown or pharmacological inhibition of TRPM4 significantly affected the degree to which Yoda1-evoked Piezo1 activation influenced action potential frequency. Thus, the present study provides in vitro evidence of a functional coupling between Piezo1 and TRPM4 in a cardiomyocyte-like cell line. The coupling of a mechanosensitive Ca2+ permeable channel and a Ca2+-activated TRP channel probably represents a ubiquitous model for the role of TRP channels in mechanosensory transduction. KEY POINTS: The transient receptor potential melastatin 4 (TRPM4) and Piezo1 channels have been confirmed to contribute to the Ca2+-dependent signalling cascade that underlies cardiac hypertrophy in response to mechanical pressure overload. However, there was no direct evidence showing that Piezo1 activation was related to TRPM4 activation in situ. We employed the HL-1 mouse atrial myocyte-like cell line as an in vitro model to investigate the effect of Piezo1-TRPM4 coupling on cardiac electrical properties. The results show that both pharmacological and genetic inhibition of TRPM4 significantly affected the degree to which Piezo1 activation influenced action potential frequency in HL-1 cells. Our findings provide in vitro evidence of a functional coupling between Piezo1 and TRPM4 in a cardiomyocyte-like cell line. The coupling of a mechanosensitive Ca2+ permeable channel and a Ca2+-activated TRP channel probably represents a ubiquitous model for the role of TRP channels in mechanosensory transduction in various (patho)physiological processes.

Assessing drug safety by identifying the axis of arrhythmia in cardiomyocyte electrophysiology.

Many classes of drugs can induce fatal cardiac arrhythmias by disrupting the electrophysiology of cardiomyocytes. Safety guidelines thus require all new drugs to be assessed for pro-arrhythmic risk prior to conducting human trials. The standard safety protocols primarily focus on drug blockade of the delayed-rectifier potassium current (IKr). Yet the risk is better assessed using four key ion currents (IKr, ICaL, INaL, IKs). We simulated 100,000 phenotypically diverse cardiomyocytes to identify the underlying relationship between the blockade of those currents and the emergence of ectopic beats in the action potential. We call that relationship the axis of arrhythmia. It serves as a yardstick for quantifying the arrhythmogenic risk of any drug from its profile of multi-channel block alone. We tested it on 109 drugs and found that it predicted the clinical risk labels with an accuracy of 88.1-90.8%. Pharmacologists can use our method to assess the safety of novel drugs without resorting to animal testing or unwieldy computer simulations.

Empirical Quantification of Predictive Uncertainty Due to Model Discrepancy by Training with an Ensemble of Experimental Designs: An Application to Ion Channel Kinetics.

When using mathematical models to make quantitative predictions for clinical or industrial use, it is important that predictions come with a reliable estimate of their accuracy (uncertainty quantification). Because models of complex biological systems are always large simplifications, model discrepancy arises-models fail to perfectly recapitulate the true data generating process. This presents a particular challenge for making accurate predictions, and especially for accurately quantifying uncertainty in these predictions. Experimentalists and modellers must choose which experimental procedures (protocols) are used to produce data used to train models. We propose to characterise uncertainty owing to model discrepancy with an ensemble of parameter sets, each of which results from training to data from a different protocol. The variability in predictions from this ensemble provides an empirical estimate of predictive uncertainty owing to model discrepancy, even for unseen protocols. We use the example of electrophysiology experiments that investigate the properties of hERG potassium channels. Here, 'information-rich' protocols allow mathematical models to be trained using numerous short experiments performed on the same cell. In this case, we simulate data with one model and fit it with a different (discrepant) one. For any individual experimental protocol, parameter estimates vary little under repeated samples from the assumed additive independent Gaussian noise model. Yet parameter sets arising from the same model applied to different experiments conflict-highlighting model discrepancy. Our methods will help select more suitable ion channel models for future studies, and will be widely applicable to a range of biological modelling problems.

Cervical screening among LGBTQ people: how affirming services may aid in achieving cervical cancer elimination targets.

To reach cervical cancer elimination targets it is necessary to increase screening rates among underserved populations such as LGBTQ communities. This paper examines rates of attendance and associated factors of cervical screening in LGBTQ communities. Data from 2,424 people aged 25 to 74 years and assigned female at birth were drawn from an online national Australian survey of LGBTQ adults. Over half of the sample had accessed cervical screening in the past 2 years. Using a multivariable logistic regression analysis, significant associations were found between screening, sociodemographic traits and health-care access. Trans men were least likely to access cervical screening, while bisexual, pansexual and queer identified participants were most likely to access screening. People who lived outside inner-suburban areas and those who had a disability were less likely to have had screening. Evidence of trusting relationships with a general practitioner (having a regular GP and GP's knowledge of the individual's LGBTQ identity) increased the likelihood that participants had screened, as did recent access to a medical service that was LGBTQ-inclusive or catered specifically to LGBTQ communities. The findings suggest the importance of training health providers, as well as targeted public health messaging for increasing uptake of cervical screening among LGBTQ people.