Participants' views of ultra-low dose combination therapy for high blood pressure: a mixed-methods study from the QUARTET trial.

Single-pill combination therapy containing four quarter-dose medications for high blood pressure improves BP control compared to monotherapy, however patient-reported acceptance of the quadpill as a treatment strategy remains undescribed. We collected within-trial feedback and interviewed participants from the quadruple ultra-low-dose treatment for hypertension (QUARTET) trial to characterise patient attitudes to this intervention. All trial participants were asked about ease and preference for the quadpill and provided an opportunity to give further comments on the trial at 12 weeks (trial primary endpoint) and 52 weeks extended follow-up. Separately, we used purposive and quota sampling for the semi-structured telephone interviews, with the resultant verbatim transcripts analysed using an inductive thematic analysis approach. Themes were re-evaluated after each successive interview, and at suspected data saturation, an additional interview conducted for confirmation. At 12 weeks follow-up, 502 of 591 (85%) participants responded to acceptability questions, and 359 of 417 (86%) responded at week 52. Most reported the trial capsule easy or very easy to take. From eight sites, 16 participants were interviewed between 5 August 2020 and 19 November 2020. All described a positive experience, preferred once-daily morning dosing and found routine facilitated adherence. Participants valued individual responsibility for adherence, and involvement of the general practitioner in blood-pressure management. Most reported capsule size did not deter adherence but desired a smaller capsule. Participants described a preference for minimising number and dosage of medications, reduced capsule size, and once-daily morning dosing. These findings suggest a preference for single-pill combination therapy for blood pressure lowering.

Fast magnetization transfer saturation imaging of the brain using MP2RAGE T1 mapping.

PURPOSE: Magnetization transfer saturation (MTsat) mapping is commonly used to examine the macromolecular content of brain tissue. This study compared variable flip angle (VFA) T1 mapping against compressed-sensing MP2RAGE (csMP2RAGE) T1 mapping for accelerating MTsat imaging. METHODS: VFA, MP2RAGE, and csMP2RAGE were compared against inversion-recovery T1 in an aqueous phantom at 3 T. The same 1-mm VFA, MP2RAGE, and csMP2RAGE protocols were acquired in 4 healthy subjects to compare T1 and MTsat. Bloch-McConnell simulations were used to investigate differences between the phantom and in vivo T1 results. Ten healthy controls were imaged twice with the csMP2RAGE MTsat protocol to quantify repeatability. RESULTS: The MP2RAGE and csMP2RAGE protocols were 13.7% and 32.4% faster than the VFA protocol, respectively. At these scan times, all approaches provided strong repeatability and accurate T1 times (< 5% difference) in the phantom, but T1 accuracy was more impacted by T2 for VFA than for MP2RAGE. In vivo, VFA estimated longer T1 times than MP2RAGE and csMP2RAGE. Simulations suggest that the differences in the T1 measured using VFA, MP2RAGE, and inversion recovery could be explained by the magnetization-transfer effects. In the test-retest experiment, we found that the csMP2RAGE has a minimum detectable change of 2.3% for T1 mapping and 7.8% for MTsat imaging. CONCLUSIONS: We demonstrated that MP2RAGE can be used in place of VFA T1 mapping in an MTsat protocol. Furthermore, a shorter scan time and high repeatability can be achieved using the csMP2RAGE sequence.

Assessing, communicating and managing cardiovascular disease risk: a practical summary of the 2023 guideline.

The outdated cardiovascular disease risk calculator has been reported to overestimate cardiovascular disease risk for a contemporary Australian population, and does not include relevant variables, such as socioeconomic disadvantage, which has been shown to increase the incidence of both heart attack and stroke. The 2023 Australian Guideline for Assessing and Managing Cardiovascular Disease Risk marks a major milestone as the first update to Australia's cardiovascular disease prevention guideline in over a decade. The new guideline may help to refine and recategorise risk estimates, hence improving the discriminatory and predictive value of the new calculator. The new Australian Cardiovascular Disease Risk Calculator expresses risk scores as a percentage estimate of a person's probability of dying or being hospitalised due to cardiovascular disease within the next 5 years. The new calculator expresses risk scores as low (less than 5%), intermediate (5% to less than 10%), or high (10% or higher) risk over 5 years. Reclassification factors built into the new calculator are designed to help clinicians individualise risk estimates. These factors include ethnicity (e.g. First Nations status), family history of premature cardiovascular disease, severe mental illness, kidney disease and coronary artery calcium score. The new calculator also uses optional diabetes-specific variables (supporting a more granular cardiovascular disease risk assessment of people with type 2 diabetes). People who meet the clinically determined high-risk criteria (chronic kidney disease, familial hypercholesterolaemia) should not progress through the Australian Cardiovascular Disease risk calculator, but move straight to management. For a person with a cardiovascular disease risk score recorded from the outdated calculator, clinicians may want to reassess their risk using the new calculator the next time the person attends.

Storylines of family medicine VII: family medicine across the lifespan.

Storylines of Family Medicine is a 12-part series of thematically linked mini-essays with accompanying illustrations that explore the many dimensions of family medicine as interpreted by individual family physicians and medical educators in the USA and elsewhere around the world. In 'VII: family medicine across the lifespan', authors address the following themes: 'Family medicine maternity care', 'Seeing children as patients brings joy to work', 'Family medicine and the care of adolescents', 'Reproductive healthcare across the lifespan', 'Men's health', 'Care of older adults', and 'Being with dying'. May readers appreciate the range of family medicine in these essays.

How do general practitioners manage patient health literacy differences in cardiovascular disease prevention consultations? An interview study.

OBJECTIVES: Low health literacy is associated with worse health outcomes, including for cardiovascular disease (CVD). However, general practitioners (GPs) have limited support to identify and address patient health literacy needs in CVD prevention consultations. This study explored GPs' experiences of patient health literacy needs during CVD risk assessment and management consultations. METHODS: Semi-structured interviews with 18 GPs in Tasmania, Australia in 2021. A Framework Analysis approach was used to code transcripts to a thematic framework. RESULTS: GPs perceptions on patient health literacy informed three themes: 1. Methods of estimating health literacy; 2. GPs' perceptions about the impact of health literacy on CVD prevention including risk factor knowledge and behaviours; and 3. Strategies for communicating with patients experiencing health literacy challenges. The findings show that while no formal tools were used to assess health literacy in this sample, perceived health literacy can change GPs' communication and prevention strategies. CONCLUSION: The findings raise concerns about the equity of choices made available to patients, based on subjective perceptions of their health literacy level. PRACTICE IMPLICATION: GPs could be better supported to assess and address patient health literacy needs in CVD prevention consultations.

2023 Australian guideline for assessing and managing cardiovascular disease risk.

INTRODUCTION: The 2023 Australian guideline for assessing and managing cardiovascular disease risk provides updated evidence-based recommendations for the clinical assessment and management of cardiovascular disease (CVD) risk for primary prevention. It includes the new Australian CVD risk calculator (Aus CVD Risk Calculator), based on an equation developed from a large New Zealand cohort study, customised and recalibrated for the Australian population. The new guideline replaces the 2012 guideline that recommended CVD risk assessment using the Framingham risk equation. MAIN RECOMMENDATIONS: The new guideline recommends CVD risk assessment in people without known CVD: all people aged 45-79 years, people with diabetes from 35 years, and First Nations people from 30 years. The new Aus CVD Risk Calculator should be used to estimate and categorise CVD risk into low (< 5% risk over five years), intermediate (5% to < 10% risk over five years) or high risk (≥ 10% over five years). The following reclassification factors may be applied to recategorise calculated risk to improve accuracy of risk prediction, particularly in individuals close to a risk threshold: Indigenous status/ethnicity, estimated glomerular filtration rate, urine albumin to creatinine ratio measurements, severe mental illness, coronary artery calcium score and family history of premature CVD. A variety of communication formats is available to communicate CVD risk to help enable shared decision making. Healthy lifestyle modification, including smoking cessation, nutrition, physical activity and limiting alcohol, is encouraged for all individuals. Blood pressure-lowering and lipid-modifying pharmacotherapies should be prescribed for high risk and considered for intermediate risk individuals, unless contraindicated or clinically inappropriate. Reassessment of CVD risk should be considered within five years for individuals at low risk and within two years for those with intermediate risk. Reassessment of CVD risk is not recommended for individuals at high risk. CHANGES IN ASSESSMENT AND MANAGEMENT AS A RESULT OF THE GUIDELINE: The updated guideline recommends assessment over a broader age range and uses the Aus CVD Risk Calculator, which replaces the previous Framingham-based equation. It incorporates new variables: social disadvantage, diabetes-specific risk markers, diagnosis of atrial fibrillation and use of blood pressure-lowering and lipid-modifying therapies. Reclassification factors are also a new addition. Updated risk categories and thresholds are based on the new Aus CVD Risk Calculator. The proportion of the population in the high risk category (≥ 10% over five years) is likely to be broadly comparable to more than 15% risk from the Framingham-based equation. The full guideline and Aus CVD Risk Calculator can be accessed at www.cvdcheck.org.au.

Time-dependent localized patterns in a predator-prey model.

Numerical continuation is used to compute solution branches in a two-component reaction-diffusion model of Leslie-Gower type. Two regimes are studied in detail. In the first, the homogeneous state loses stability to supercritical spatially uniform oscillations, followed by a subcritical steady state bifurcation of Turing type. The latter leads to spatially localized states embedded in an oscillating background that bifurcate from snaking branches of localized steady states. Using two-parameter continuation, we uncover a novel mechanism whereby disconnected segments of oscillatory states zip up into a continuous snaking branch of time-periodic localized states, some of which are stable. In the second, the homogeneous state loses stability to supercritical Turing patterns, but steady spatially localized states embedded either in the homogeneous state or in a small amplitude Turing state are nevertheless present. We show that such behavior is possible when sideband Turing states are strongly subcritical and explain why this is so in the present model. In both cases, the observed behavior differs significantly from that expected on the basis of a supercritical primary bifurcation.

Therapeutic Inertia With Initial Low-Dose Quadruple Combination Therapy for Hypertension: Results From the QUARTET Trial.

BACKGROUND: Low-dose combinations are a promising intervention for improving blood pressure (BP) control but their effects on therapeutic inertia are uncertain. METHODS: Analysis of 591 patients randomized to an ultra-low-dose quadruple pill or initial monotherapy. The episode of therapeutic inertia was defined as a patient visit with a BP of >140/90 mm Hg without intensification of antihypertensive treatment. We compared the frequency of therapeutic inertia episodes between Quadpill and initial monotherapy as a proportion of the total population (intention-to-treat analysis with the denominator being all participants randomized) and as a proportion of people with uncontrolled BP (with the denominator being participants with uncontrolled BP). RESULTS: Therapeutic inertia occurred in fewer participants randomized to Quadpill compared with monotherapy. For example, among the 390 participants with a 6-month follow-up, therapeutic inertia according to unattended BP was 21/192 (11%) versus 45/192 (23%), P=0.002. There were similar rates of therapeutic inertia among those with uncontrolled unattended BP in each group (all P>0.4). Consistent observations were seen with the use of attended office BP measures. The major determinants of not intensifying treatment during follow-up were BP readings that were close to target and large improvements in BP compared with the previous visit. CONCLUSIONS: Among all treated individuals, low-dose Quadpill reduced the number of therapeutic inertia episodes compared with initial monotherapy. After the first follow-up visit, most high BP values did not lead to treatment intensification in both groups. Education is needed about the importance of treatment intensification despite a significant improvement in BP or BP being close to target. REGISTRATION: URL: https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=ACTRN12616001144404; Unique identifier: ACTRN12616001144404.

Age and sex disparities in cardiovascular risk factor management prior to stroke: Linked registry and general practice data.

INTRODUCTION: There is limited evidence about the management of cardiovascular risk factors within 12 months before stroke/transient ischaemic attack (TIA) in Australian general practices. We evaluated whether age and sex disparities in cardiovascular risk factor management for primary prevention exist in general practice. METHODS: A retrospective cohort study using data from the Australian Stroke Clinical Registry (2014-2018) linked with general practice data from three primary health networks in Victoria, Australia. We included adults who had ≥2 encounters with a general practitioner within 12 months immediately before the first stroke/TIA. Cardiovascular risk factor management within 12 months before stroke/TIA was evaluated in terms of: assessment of risk factors (blood pressure [BP], serum lipids, blood glucose, body weight); prescription of prevention medications (BP, lipid-, glucose-lowering, antithrombotic agents); and attainment of risk factor targets. RESULTS: Of 2,880 patients included (median age 76.5 years, 48.4% women), 80.9% were assessed for BP, 49.9% serum lipids, 46.8% blood glucose, and 39.3% body weight. Compared to patients aged 65-84 years, those aged <65 or ≥85 years were less often assessed for risk factors, with women aged ≥85 years assessed for significantly fewer risk factors than their male counterparts. The most prescribed prevention medications were BP-lowering (64.9%) and lipid-lowering agents (42.0%). There were significant sex differences among those aged <65 years (34.7% women vs. 40.2% men) and ≥85 years (34.0% women vs. 44.3% men) for lipid-lowering agents. Risk factor target attainment was generally poorer in men than women, especially among those aged <65 years. CONCLUSION: Age-sex disparity exists in risk factor management for primary prevention in general practice, and this was more pronounced among younger patients and older women.

Association of serum phosphate, calcium and alkaline phosphatase with risk of incident fractures in healthy older adults.

BACKGROUND: Aging increases fracture risk through bone loss and microarchitecture deterioration due to an age-related imbalance in bone resorption and formation during bone remodelling. We examined the associations between levels of phosphate, calcium, and alkaline phosphatase, and fracture risk in initially-healthy older individuals. METHODS: A post-hoc analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial recruited 16,703 Australian participants aged ≥70 years and 2,411 US participants aged ≥65 years. Analyses were conducted on ASPREE-Fracture substudy participants from Australia with serum calcium, phosphate, and alkaline phosphatase measurement. Fracture data were collected post-randomization. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CIs). Phosphate, calcium, and alkaline phosphatase were analysed in deciles (D1-D10), with deciles 4-7 (31-70%) as the reference category. Restricted cubic spline curves were used to identify nonlinear associations. RESULTS: Of the 9915 participants, 907 (9·2%) persons had incident fractures recorded over 3·9 (SD 1·4) years. In the fully adjusted model, males in the top decile (D10) of phosphate had 78% higher risk of incident fracture (HR 1·78, 95% CI 1·25-2·54). No such association was observed for females (HR 1·09, 95% CI 0·83-1·44). The population attributable fraction in men within the D10 phosphate category is 6·9%. CONCLUSION: This result confirms that, high-normal serum phosphate levels are associated with increased fracture risk in older men.

Distinct potassium channel types in brain capillary pericytes.

Capillaries, composed of electrically coupled endothelial cells and overlying pericytes, constitute the vast majority of blood vessels in the brain. The most arteriole-proximate three to four branches of the capillary bed are covered by α-actin-expressing, contractile pericytes. These mural cells have a distinctive morphology and express different markers compared with their smooth muscle cell (SMC) cousins but share similar excitation-coupling contraction machinery. Despite this similarity, pericytes are considerably more depolarized than SMCs at low intravascular pressures. We have recently shown that pericytes, such as SMCs, possess functional voltage-dependent Ca2+ channels and ATP-sensitive K+ channels. Here, we further investigate the complement of pericyte ion channels, focusing on members of the K+ channel superfamily. Using NG2-DsRed-transgenic mice and diverse configurations of the patch-clamp technique, we demonstrate that pericytes display robust inward-rectifier K+ currents that are primarily mediated by the Kir2 family, based on their unique biophysical characteristics and sensitivity to micromolar concentrations of Ba2+. Moreover, multiple lines of evidence, including characteristic kinetics, sensitivity to specific blockers, biophysical attributes, and distinctive single-channel properties, established the functional expression of two voltage-dependent K+ channels: KV1 and BKCa. Although these three types of channels are also present in SMCs, they exhibit distinctive current density and kinetics profiles in pericytes. Collectively, these findings underscore differences in the operation of shared molecular features between pericytes and SMCs and highlight the potential contribution of these three K+ ion channels in setting pericyte membrane potential, modulating capillary hemodynamics, and regulating cerebral blood flow.

Ambulatory blood pressure after 12 weeks of quadruple combination of quarter doses of blood pressure medication vs. standard medication.

BACKGROUND: A combination of four ultra-low-dose blood pressure (BP) medications lowered office BP more effectively than initial monotherapy in the QUARTET trial. The effects on average ambulatory BP changes at 12 weeks have not yet been reported in detail. METHODS: Adults with hypertension who were untreated or on monotherapy were eligible for participation. Overall, 591 participants were randomized to either the quadpill (irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, and bisoprolol 2.5 mg) or monotherapy control (irbesartan 150 mg). The difference in 24-h, daytime, and night-time systolic and diastolic ambulatory BP at 12 weeks along further metrics were predefined secondary outcomes. RESULTS: Of 576 participants, 289 were randomized to the quadpill group and 287 to the monotherapy group. At 12 weeks, mean 24-h ambulatory SBP and DBP were 7.7 [95% confidence interval (95% CI) 9.6-5.8] and 5.3 (95% CI: 6.5-4.1) mmHg lower in the quadpill vs. monotherapy group ( P  < 0.001 for both). Similar reductions in the quadpill group were observed for daytime (8.1/5.7 mmHg lower) and night-time (6.3/4.0 mmHg lower) BP at 12 weeks (all P  < 0.001) compared to monotherapy. The rate of BP control (24-h average BP < 130/80 mmHg) at 12 weeks was higher in the quadpill group (77 vs. 50%; P  < 0.001). The reduction in BP load was also more pronounced with the quadpill. CONCLUSION: A quadruple quarter-dose combination compared with monotherapy resulted in greater ambulatory BP lowering across the entire 24-h period with higher ambulatory BP control rates and reduced BP variability at 12 weeks. These findings further substantiate the efficacy of an ultra-low-dose quadpill-based BP lowering strategy.

Pathogenic soluble tau peptide disrupts endothelial calcium signaling and vasodilation in the brain microvasculature.

The accumulation of the microtubule-associated tau protein in and around blood vessels contributes to brain microvascular dysfunction through mechanisms that are incompletely understood. Delivery of nutrients to active neurons in the brain relies on capillary calcium (Ca2+) signals to direct blood flow. The initiation and amplification of endothelial cell Ca2+ signals require an intact microtubule cytoskeleton. Since tau accumulation in endothelial cells disrupts native microtubule stability, we reasoned that tau-induced microtubule destabilization would impair endothelial Ca2+ signaling. We tested the hypothesis that tau disrupts the regulation of local cerebral blood flow by reducing endothelial cell Ca2+ signals and endothelial-dependent vasodilation. We used a pathogenic soluble tau peptide (T-peptide) model of tau aggregation and mice with genetically encoded endothelial Ca2+ sensors to measure cerebrovascular endothelial responses to tau exposure. T-peptide significantly attenuated endothelial Ca2+ activity and cortical capillary blood flow in vivo. Further, T-peptide application constricted pressurized cerebral arteries and inhibited endothelium-dependent vasodilation. This study demonstrates that pathogenic tau alters cerebrovascular function through direct attenuation of endothelial Ca2+ signaling and endothelium-dependent vasodilation.

Protein aggregates containing wild-type and mutant NOTCH3 are major drivers of arterial pathology in CADASIL.

Loss of arterial smooth muscle cells (SMCs) and abnormal accumulation of the extracellular domain of the NOTCH3 receptor (Notch3ECD) are the 2 core features of CADASIL, a common cerebral small vessel disease caused by highly stereotyped dominant mutations in NOTCH3. Yet the relationship between NOTCH3 receptor activity, Notch3ECD accumulation, and arterial SMC loss has remained elusive, hampering the development of disease-modifying therapies. Using dedicated histopathological and multiscale imaging modalities, we could detect and quantify previously undetectable CADASIL-driven arterial SMC loss in the CNS of mice expressing the archetypal Arg169Cys mutation. We found that arterial pathology was more severe and Notch3ECD accumulation greater in transgenic mice overexpressing the mutation on a wild-type Notch3 background (TgNotch3R169C) than in knockin Notch3R170C/R170C mice expressing this mutation without a wild-type Notch3 copy. Notably, expression of Notch3-regulated genes was essentially unchanged in TgNotch3R169C arteries. We further showed that wild-type Notch3ECD coaggregated with mutant Notch3ECD and that elimination of 1 copy of wild-type Notch3 in TgNotch3R169C was sufficient to attenuate Notch3ECD accumulation and arterial pathology. These findings suggest that Notch3ECD accumulation, involving mutant and wild-type NOTCH3, is a major driver of arterial SMC loss in CADASIL, paving the way for NOTCH3-lowering therapeutic strategies.

The ASPREE Healthy Ageing Biobank: Methodology and participant characteristics.

ASPirin in Reducing Events in the Elderly (ASPREE), a placebo-controlled prevention trial of low dose aspirin, provided the opportunity to establish a biospecimen biobank from initially healthy persons aged 70+ years for future research. The ASPREE Healthy Ageing Biobank (ASPREE Biobank) collected, processed and stored blood and urine samples at -80degC or under nitrogen vapour at two timepoints, three years apart, from a willing subset of Australian ASPREE participants. Written informed consent included separate opt-in questions for biomarker and genetic testing. Fractionated blood and urine were aliquoted into multiple low-volume, barcoded cryotubes for frozen storage within 4 hours of collection. Specially designed and outfitted mobile laboratories provided opportunities for participation by people in regional and rural areas. Detailed, high quality demographic, physiological and clinical data were collected annually through the ASPREE trial. 12,219 participants contributed blood/urine at the first timepoint, 10,617 of these older adults provided 3-year follow-up samples, and an additional 1,712 provided saliva for DNA. The mean participant age was 74 years, 54% were female and 46% lived outside major cities. Despite geographical and logistical challenges, nearly 100% of blood/urine specimens were processed and frozen within 4 hours of collection into >1.4 million aliquots. After a median of 4.7 years, major clinical events among ASPREE Biobank participants included 332 with dementia, 613 with cardiovascular disease events, 1259 with cancer, 357 with major bleeds and 615 had died. The ASPREE Biobank houses and curates a large number of biospecimens collected prior to the clinical manifestations of major disease, and 3-year follow-up samples, all linked to high quality, extensive phenotypic information. This provides the opportunity to identify or validate diagnostic, prognostic and predictive biomarkers, and potentially study biological effectors, of ageing-related diseases or maintenance of older-age good health.

Cost-effectiveness of an individualised management program after stroke: a trial-based economic evaluation.

INTRODUCTION: Evidence on the cost-effectiveness of comprehensive post-stroke programs is limited. We assessed the cost-effectiveness of an individualised management program (IMP) for stroke or transient ischaemic attack (TIA). METHODS: A cost-utility analysis alongside a randomised controlled trial with a 2-year follow-up, from both societal and health system perspectives, was conducted. Adults with stroke/TIA discharged from hospitals were randomised by primary care practice to receive either usual care (UC) or an IMP in addition to UC. An IMP included at-home stroke-specific nurse-led education and a specialist review of care plans at baseline, 3, and 12 months, and telephone reviews by nurses at 6 and 18 months. Costs in 2021 Australian dollars (AUD) and quality-adjusted life years (QALYs) were discounted by 5%. The probability of cost-effectiveness of the intervention was determined by quantifying 10,000 bootstrapped iterations of incremental costs and QALYs below the threshold of AUD50,000/QALY. RESULTS: Among the 502 participants (65% male, median age 69 years), 251 (50%) were in the intervention group. From a health system perspective, the incremental cost per QALY gained was AUD53,175 with an IMP compared to UC alone. At a willingness-to-pay threshold of AUD50,000/QALY, an IMP was preferred in 46.7% of iterations. From a societal perspective, the intervention was dominant in 52.7% of iterations with mean per-patient costs of AUD49,045 and 1.352 QALYs compared to mean per-patient costs of AUD51,394 and 1.324 QALYs in the UC group. The probability of cost-effectiveness of an IMP, from a societal perspective, was 60.5%. CONCLUSIONS: Care for people with stroke/TIA using an IMP was cost-effective from a societal perspective over two years. Economic evaluations of prevention programs need sufficient time horizons and consideration of costs beyond direct health care utilisation to demonstrate their value to society.

Cell-free DNA methylation analysis as a marker of malignancy in pleural fluid.

Diagnosis of malignant pleural effusion (MPE) is made by cytological examination of pleural fluid or histological examination of pleural tissue from biopsy. Unfortunately, detection of malignancy using cytology has an overall sensitivity of 50%, and is dependent upon tumor load, volume of fluid assessed, and cytopathologist experience. The diagnostic yield of pleural fluid cytology is also compromised by low abundance of tumor cells or when morphology is obscured by inflammation or reactive mesothelial cells. A reliable molecular marker that may complement fluid cytology for the diagnosis of malignant pleural effusion is needed. The purpose of this study was to establish a molecular diagnostic approach based on pleural effusion cell-free DNA methylation analysis for the differential diagnosis of malignant pleural effusion and benign pleural effusion. This was a blind, prospective case-control biomarker study. We recruited 104 patients with pleural effusion for the study. We collected pleural fluid from patients with: MPE (n = 48), indeterminate pleural effusion in subjects with known malignancy or IPE (n = 28), and benign PE (n = 28), and performed the Sentinel-MPE liquid biopsy assay. The methylation level of Sentinel-MPE was markedly higher in the MPE samples compared to BPE control samples (p < 0.0001) and the same tendency was observed relative to IPE (p = 0.004). We also noted that the methylation signal was significantly higher in IPE relative to BPE (p < 0.001). We also assessed the diagnostic efficiency of the Sentinel-MPE test by performing receiver operating characteristic analysis (ROC). For the ROC analysis we combined the malignant and indeterminate pleural effusion groups (n = 76) and compared against the benign group (n = 28). The detection sensitivity and specificity of the Sentinel-MPE test was high (AUC = 0.912). The Sentinel-MPE appears to have better performance characteristics than cytology analysis. However, combining Sentinel-MPE with cytology analysis could be an even more effective approach for the diagnosis of MPE. The Sentinel-MPE test can discriminate between BPE and MPE. The Sentinel-MPE liquid biopsy test can detect aberrant DNA in several different tumor types. The Sentinel-MPE test can be a complementary tool to cytology in the diagnosis of MPE.

Cost-effectiveness of a government policy to incentivise chronic disease management following stroke: a modelling study.

BACKGROUND: Little is known about the cost-effectiveness of government policies that support primary care physicians to provide comprehensive chronic disease management (CDM). AIMS: To estimate the potential cost-effectiveness of CDM policies, over a lifetime, in long-time survivors of stroke. METHODS: A Markov model, using three health states (stable, hospitalised, dead), was developed to simulate the costs and benefits of CDM policies over 30 years (with 1-year cycles). Transition probabilities and costs from a health system perspective were obtained from the linkage of data between the Australian Stroke Clinical Registry (cohort n=12,368, 42% female, median age 70 years, 45% had a claim) and government-held hospital, Medicare, and pharmaceutical claims datasets. Quality-adjusted life years (QALYs) were obtained from a comparable cohort (n=512, 34% female, median age 69.6 years, 52% had a claim) linked with Medicare claims and death data. A 3% discount rate was applied to costs in Australian dollars (AUD, 2016) and QALYs beyond 12 months. Probabilistic sensitivity analyses were used to understand uncertainty. RESULTS: Per-person average total lifetime costs were AUD142,939 and 8.97 QALYs for those with a claim, and AUD103,889 and 8.98 QALYs for those without a claim. This indicates that these CDM policies were costlier without improving QALYs. The probability of cost-effectiveness of CDM was 26.1%, at a willingness-to-pay threshold of AUD50,000/QALY. CONCLUSION: CDM policies, designed to encourage comprehensive care, are unlikely to be cost-effective for stroke compared to care without CDM. Further research to understand how to deliver such care in a cost-effective manner is needed.