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Drought poses a significant challenge to plant growth and productivity, particularly in arid regions like northern Kazakhstan. Dehydration-responsive element-binding (DREB) transcription factors play an important role in plant response to drought and other abiotic stresses. In Arabidopsis thaliana, the DREB subfamily consists of six groups, designated DREB1 to DREB6. Among these, DREB2 is primarily associated with drought and salinity tolerance. In the chickpea genome, two DREB genes, CaDREB2c and CaDREB2h, have been identified, exhibiting high sequence similarity to Arabidopsis DREB2 genes. We investigated the nucleotide sequences of CaDREB2c and CaDREB2h genes in several chickpea cultivars commonly grown in northern Kazakhstan. Interestingly, the CaDREB2h gene sequence was identical across all varieties and corresponded to the sequence deposited in the GenBank. However, the CaDREB2c gene sequence exhibited variations among the studied varieties, categorized into three groups: the first group (I), comprising 20 cultivars, contained a CaDREB2c gene sequence identical to the GenBank (Indian cultivar CDC Frontier). The second group (II), consisting of 4 cultivars, had a single synonymous substitution (T to C) compared to the deposited CaDREB2c gene sequence. The third group, encompassing 5 cultivars, displayed one synonymous substitution (C to T) and two non-synonymous substitutions (G to T and G to A). Furthermore, we assessed the gene expression patterns of CaDREB2c and CaDREB2h in different chickpea varieties under drought conditions. Chickpea cultivars 8 (III), 37 (I), 6 (III), and 43 (I) exhibited the highest drought resistance. Our analysis revealed a strong positive correlation between drought resistance and CaDREB2h gene expression under drought stress. Our findings suggest that the chickpea’s adaptive responses to water deprivation are associated with changes in CaDREB2 gene expression. To further elucidate the mechanisms underlying drought tolerance, we propose future research directions that will delve into the molecular interactions and downstream targets of CaDREB2 genes.

Background: Non-optimum temperatures are associated with a considerable mortality burden. However, there is a lack of evaluation of labour productivity losses related to premature deaths due to non-optimum temperatures. This study aimed to quantify the labour productivity burden associated with premature deaths related to non-optimum temperatures and explore the potential socio-economic vulnerabilities., Methods: Daily all-cause mortality data were collected from 1,066 locations in 7 countries (Australia, Brazil, Canada, Chile, New Zealand, South Korea, and Thailand). Productivity-Adjusted Life-Year (PALY) loss due to each premature death was calculated to measure the labour productivity loss, by multiplying the years of working life lost by the proportion of the equivalent full-time (EFT) workers. A two-stage times series design and the generalized linear regression model with a quasi-Poisson family were applied to assess the association between non-optimum temperatures and the PALY loss due to premature deaths., Results: We observed a U-shaped relationship between temperature and PALY lost due to premature mortality. We estimated that 2.51% (95% eCI: 2.05%, 2.92%) of PALY losses could be attributed to non-optimal temperatures, with cold-related deaths contributing 1.26% (95% eCI: 0.94%, 1.54%) and heat-related deaths contributing 1.25% (95% eCI: 0.96%, 1.51%). Cold temperature contributed to the most PALYs lost in those aged 45-54 and 55-64, while heat-related losses predominated among the 15-44 age group. We also observed that the fractions of PALY lost attributed to extreme heat were positively associated with the relative deprivation index, while negatively associated with GDP per capita., Conclusion: This multi-country study highlights that non-optimum temperatures led to a considerable labour productivity loss and socioeconomically disadvantaged communities experience greater losses., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: This study aimed to quantify the burden of eight non-communicable conditions on productivity-adjusted life year (PALY) at work and within the household among the Finnish general adult population., Methods: Survey data on 18-79-year-old Finnish respondents collected in 2022 was used to calculate age- and sex-specific productivity indices at work and within the household using zero- and one-inflated beta regression for individuals with and without a certain condition (asthma or chronic obstructive pulmonary disease, cardiovascular disease, depression or other mental health problem, diabetes, gastrointestinal disease, hypothyroidism or other thyroid disease, migraine or other chronic headache, and musculoskeletal disease). Age and sex distributions of the Finnish population obtained from Statistics Finland together with the prevalence of the condition and the estimated productivity indices were used to produce the population-level one-year losses in PALYs at work and within the household., Results: Among eight conditions, depression and other mental health problems had the highest PALY losses (99 570 PALY loss burden at work, 256 086 PALY loss at home, and 250 980 PALY loss in general adult populations), with diabetes having the lowest (3 666 PALY loss burden at work, 46 344 PALY loss at home, and 43 443 PALY loss in general adult populations). All the examined conditions were as significant in affecting both the productivity at work and the within-household productivity., Conclusions: Depression and other mental health problems have a major effect on self-reported work ability and productivity when compared with other chronic conditions., (Copyright © 2024. Published by Elsevier Inc.)

Background: The widespread use of pneumococcal conjugate vaccines (PCV) has changed the epidemiology of invasive pneumococcal disease (IPD) in children globally., Methods: Multicentre prospective audit of IPD episodes from five paediatric hospitals in Australia over 5.5 years between 2016 and June 2021. Children (<18 years) with Streptococcus pneumoniae isolated from a sterile site were included., Results: There were 377 IPD episodes in 375 children: 338 (90%) had received ≥3 PCV doses; 42 (11%) had IPD risk factors. The most common presentations were complicated pneumonia (254, 67%), bacteraemia (65, 17%) and meningitis (29, 8%). Five (1%) children died.Serotype information was available for 230 (61%) episodes; 140 (61%) were 13vPCV vaccine serotypes (VTs). The majority (85%) of episodes of complicated pneumonia were due to a VT; predominantly 3, 19A, 19F. Children with risk factors were more likely to present with bacteraemia ± sepsis (42% vs 12%) and to have a non-vaccine serotype (NVT) (74% vs 32%). Resistance to ceftriaxone (meningitis cut-off) occurred in 17% of 23B isolates (n=12) and accounted for 22% (5/23) of meningitis cases., Conclusions: Complicated pneumonia is the most common IPD presentation. NVTs account for the majority of bacteraemia and meningitis episodes. High rates of ceftriaxone resistance for NVT 23B support the addition of vancomycin for empiric treatment of suspected meningitis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Structured education and exercise therapy programs have been proposed to reduce reliance on total knee replacement (TKR) surgery and improve health care sustainability. The long-term cost-effectiveness of these programs is unclear., Objectives: To estimate the lifetime cost-effectiveness of implementing a national structured education and exercise therapy program for individuals with knee osteoarthritis with the option for future TKR compared with usual care (TKR for all)., Design, Setting, and Participants: This economic evaluation used a life table model in combination with a Markov model to compare costs and health outcomes of a national education and exercise therapy program vs usual care in the Australian health care system. Subgroup, deterministic, and probabilistic sensitivity analyses were completed. A hypothetical cohort of adults aged 45 to 84 years who would undergo TKR was created., Exposure: Structured education and exercise therapy intervention provided by physiotherapists. The comparator was usual care where all people undergo TKR without accessing the program in the first year., Main Outcomes and Measures: Incremental net monetary benefit (INMB), with an incremental cost-effectiveness ratio threshold of 28 033 Australian dollars (A$) per quality-adjusted life-year (QALY) gained, was calculated from a health care perspective. Transition probabilities, costs, and utilities were estimated from national registries and a randomized clinical trial., Results: The hypothetical cohort included 61 394 individuals (53.9% female; 93.6% aged ≥55 years). Implementation of an education and exercise therapy program resulted in a lifetime cost savings of A$498 307 942 (US $339 922 227), or A$7970 (US $5537) per individual, and resulted in fewer QALYs (0.43 per individual) compared with usual care. At a population level, education and exercise therapy was not cost-effective at the lifetime horizon (INMB, -A$4090 [-US $2841]). Subgroup analysis revealed that the intervention was cost-effective only for the first 9 years and over a lifetime only in individuals with no or mild pain at baseline (INMB, A$11 [US $8]). Results were robust to uncertainty around model inputs., Conclusions and Relevance: In this economic evaluation of structured education and exercise therapy compared with usual care, the intervention was not cost-effective over the lifetime for all patients but was for the first 9 years and for those with minimal pain. These findings point to opportunities to invest early cost savings in additional care or prevention, including targeted implementation to specific subgroups.

Aim: Clinical guidelines recommend secondary prevention medications following myocardial infarction (MI) regardless of revascularisation strategy. Studies suggest that there is variation in post-MI medication use following percutaneous coronary intervention (PCI) and coronary artery bypass grafts (CABG). We investigated initial dispensing and 12-month patterns of medication use according to revascularisation strategy following non-ST-elevation MI (NSTEMI)., Method: We included all public and private hospital admissions for NSTEMI for patients aged ≥30 years in Victoria, Australia, between July 2012 and June 2017. We investigated initial dispensing of P2Y 12 inhibitors (P2Y 12 i), statins (total and high intensity), angiotensin-converting-enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB), and beta blockers within 60 days after discharge. Twelve-month post-MI medication use was estimated as the proportion of days covered (PDC) over a 12-month period from the date of hospital discharge. Analyses were performed using adjusted regression models, stratified by revascularisation strategy., Results: There were 15,399 admissions for NSTEMI: 11,754 with PCI and 3,645 with CABG. Following adjustments, predicted probability of initial dispensing in the PCI and CABG groups, respectively, was 0.94 (95% confidence interval 0.93-0.95) vs 0.17 (0.13-0.21) for P2Y 12 i; 0.69 (0.66-0.71) vs 0.42 (0.37-0.48) for ACEi/ARB; 0.59 (0.57-0.62) vs 0.69 (0.64-0.74) for beta blockers; 0.89 (0.87-0.91) vs 0.89 (0.85-0.92) for statins; and 0.60 (0.57-0.62) vs 0.69 (0.63-0.73) for high intensity statins. The 12-month PDC in the PCI and CABG groups, respectively, was 0.82 (0.80-0.83) vs 0.12 (0.09-0.15) for P2Y 12 i; 0.62 (0.60-0.65) vs 0.43 (0.39-0.48) for ACEi/ARB; 0.53 (0.51-0.55) vs 0.632 (0.58-0.66) for beta blockers; 0.79 (0.78-0.81) vs 0.78 (0.74-0.81) for statins; and 0.49 (0.47-0.51) vs 0.55 (0.50-0.59) for high intensity statins., Conclusions: Post-discharge dispensing of secondary prevention medications differed with respect to revascularisation strategy from 2012 to 2017, despite clear evidence of benefit during this period. Interventions may be needed to address possible clinician and patient uncertainty about the benefits of secondary prevention medications, regardless of revascularisation strategy., Competing Interests: Conflicts of Interest A.C.L. reports consulting for Sanofi, Boehringer Ingelheim, and Novartis. J.I. has received grants from the National Health and Medical Research Council (NHMRC), National Breast Cancer Foundation, Dementia Australia Research Foundation, AstraZeneca, and Amgen. A.J.N. reports consulting for AstraZeneca, Boehringer Ingelheim, Novartis, Amgen, Novo Nordisk, and Lilly. J.S.B. is supported by a NHMRC Boosting Dementia Research Leadership Fellowship and has received grant funding or consulting funds from the NHMRC, Medical Research Future Fund, Victorian Government Department of Health, Dementia Australia Research Foundation, Yulgilbar Foundation, Aged Care Quality and Safety Commission, Dementia Centre for Research Collaboration, Pharmaceutical Society of Australia, Society of Hospital Pharmacists of Australia, GlaxoSmithKline Supported Studies Programme, Amgen, and several aged care provider organisations unrelated to this work. J.I.M. has no conflicts to declare relevant to this publication. All grants and consulting funds were paid to the employing institution., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: To assess the effectiveness of Clinical Decision Support Tools (CDSTs) in enhancing the quality of care outcomes in primary cardiovascular disease (CVD) prevention., Methods: A systematic review was undertaken in accordance with PRISMA guidelines, and included searches in Ovid Medline, Ovid Embase, CINAHL, and Scopus. Eligible studies were randomized controlled trials of CDSTs comprising digital notifications in electronic health systems (EHS/EHR) in various primary healthcare settings, published post-2013, in patients with CVD risks and without established CVD. Two reviewers independently assessed risk of bias using the Cochrane RoB-2 tool. Attainment of clinical targets was analysed using a Restricted Maximum Likelihood random effects meta-analysis. Other relevant outcomes were narratively synthesised due to heterogeneity of studies and outcome metrics., Results: Meta-analysis revealed CDSTs showed improvement in systolic (Mean Standardised Difference (MSD)=0.39, 95 %CI=-0.31, -1.10) and diastolic blood pressure target achievement (MSD=0.34, 95 %CI=-0.24, -0.92), but had no significant impact on lipid (MSD=0.01; 95 %CI=-0.10, 0.11) or glucose target attainment (MSD=-0.19, 95 %CI=-0.66, 0.28). The CDSTs with active prompts increased statin initiation and improved patients' adherence to clinical appointments but had minimal effect on other medications and on enhancing adherence to medication., Conclusion: CDSTs were found to be effective in improving blood pressure clinical target attainments. However, the presence of multi-layered barriers affecting the uptake, longer-term use and active engagement from both clinicians and patients may hinder the full potential for achieving other quality of care outcomes., Lay Summary: The study aimed to evaluate how Clinical Decision Support Tools (CDSTs) impact the quality of care for primary cardiovascular disease (CVD) management. CDSTs are tools designed to support healthcare professionals in delivering the best possible care to patients by providing timely and relevant information at the point of care (ie. digital notifications in electronic health systems). Although CDST are designed to improve the quality of healthcare outcomes, the current evidence of their effectiveness is inconsistent. Therefore, we conducted a systematic review with meta-analysis, to quantify the effectiveness of CDSTs. The eligibility criteria targeted patients with CVD risk factors, but without diagnosed CVD. The meta-analysis found that CDSTs showed improvement in systolic and diastolic blood pressure target achievement but did not significantly impact lipid or glucose target attainment. Specifically, CDSTs showed effectiveness in increasing statin prescribing but not antihypertensives or antidiabetics prescribing. Interventions with CDSTs aimed at increasing screening programmes were effective for patients with kidney diseases and high-risk patients, but not for patients with diabetes or teenage patients with hypertension. Alerts were effective in improving patients' adherence to clinical appointments but not in medication adherence. This study suggests CDSTs are effective in enhancing a limited number of quality of care outcomes in primary CVD prevention, but there is need for future research to explore the mechanisms and context of multiple barriers that may hinder the full potential for cardiovascular health outcomes to be achieved., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier B.V.)

Aims: To quantify the productivity burden of cardiovascular disease (CVD) in type 2 diabetes and the potential benefits of improved CVD risk factor control., Methods: We designed models to quantify the productivity burden (using the productivity-adjusted life-year; PALY) of CVD in Australians with type 2 diabetes aged 40-69 years from 2023-2032. PALYs were ascribed a financial value equivalent to gross domestic product (GDP) per full-time worker (AU$204,167 (€124,542)). The base-case model was designed to quantify the productivity burden of CVD in the target population. Then, other hypothetical scenarios were simulated to estimate the potential productivity gains resulting from improved control of risk factors. These scenarios included reductions in systolic blood pressure (SBP), number of smokers, total cholesterol, and incidence of type 2 diabetes. All future costs and outcomes were discounted at an annual rate of 5%., Results: In the base-case (i.e. current projections), the estimated total PALYs lost due to CVD in type 2 diabetes were 1.21 million (95%CI (1.10-1.29 million), contributing to an AU$258.93 (€157.94) billion (95%CI (AU$258.73-261.69 (€157.83-159.63) billion) lost in the country's GDP. If there were reductions in SBP, number of smokers, total cholesterol, and incidence of type 2 diabetes, there would be gains of 7,889, 28,971, 7,117, and 320,124 PALYs, respectively. These improvements would also lead to economic gains of AU$1.72 (€1.05) billion, AU$6.21 (€3.79) billion, AU$1.55 billion (€947.33 million), and AU$68.34 (€41.69) billion, respectively., Conclusions: Targeted "early lifestyle" strategies that can prevent CVD in Australians with type 2 diabetes are likely positively impact Australian health and work productivity., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Olpasiran and pelacarsen are gene-silencing therapies that lower lipoprotein(a). Cardiovascular outcome trials are ongoing. Mendelian randomisation studies estimated clinical benefits from lipoprotein(a) lowering., Objective: Our study estimated prices at which olpasiran and pelacarsen, in addition to standard-of-care, would be deemed cost-effective in reducing risk of recurrent coronary heart disease (CHD) events in the Australian healthcare system., Methods: We developed a decision tree and lifetime Markov model. For olpasiran, participants had CHD and lipoprotein(a) 260 nmol/L at baseline and three-monthly injections, profiled on OCEAN(a) Outcomes trial (NCT05581303). Baseline risks of CHD, costs and utilities were obtained from published sources. Clinical trial data were used to derive reductions in lipoprotein(a) from treatment. Mendelian randomisation study data were used to estimate downstream clinical benefits. Annual discounting was 5 %. For pelacarsen, participants had CHD and lipoprotein(a) 226 nmol/L at baseline and one- monthly injections, profiled on Lp(a) HORIZON (NCT04023552) trial., Results: Olpasiran in addition to standard-of-care saved 0.87 discounted quality-adjusted life years (QALYs) per person. Olpasiran in addition to standard-of-care would be cost- effective at annual prices of AU$1867 (AU$467 per dose) at threshold AU$28,000 per QALY. Pelacarsen would be cost-effective at annual prices of AU$984 (AU$82 per dose). For ICER threshold AU$50,000 per QALY, olpasiran and pelacarsen would be cost-effective at annual prices AU$4207 and AU$2464 respectively., Conclusion: This early health technology assessment model used inclusion criteria from clinical trials. Olpasiran and pelacarsen would be cost-effective if annual treatment prices were AU$1867 and AU$984 respectively, from the Australian healthcare perspective., Competing Interests: Declaration of competing interest GFW has received research grants and fees for advisory boards or lectures from Amgen, Arrowhead, Novartis, Esperion, NovoNordisk. ZA is a member of the Lp(a) International Task Force. There are no other interests to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Background: Myocardial infarction (MI) remains a major health burden in Australia. Yet the future burden of MI has not been extensively studied for the Australian population., Methods and Results: A multistate lifetable model was constructed to estimate the lifetime risk of MI and project the health burden of MI for the Australian population aged between 40 and 100 years over a 20-year period (2019-2038). Data for the model were primarily sourced from the Victorian-linked dataset and supplemented with other national data. The lifetime risk of MI at age 40 was estimated as 24.4% for males and 13.2% for females in 2018. From 2019 to 2038, 891 142 Australians were projected to develop incident MI. By 2038, the model estimated there would be 702 226 people with prevalent MI, 51 262 incident non-fatal MI, and 3717 incident fatal MI; these numbers represent a significant increase compared to the 2019 estimates, with a 27.0% (148 827), 62.0% (19 629), and 104.7% (1901) rise, respectively. Projected years of life lived (YLL) (5% discount) accrued by the Australian population was 174 795 232 (84 356 304 in males and 90 438 928 in females), with 7 657 423 YLL among people with MI (4 997 009 in males and 2 660 414 in females)., Conclusion: The burden of MI was projected to increase between 2019 and 2038 in Australia. The outcomes of the model provide important information for decision-makers to prioritize population-wide prevention strategies to reduce the burden of MI., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: Online education games are gaining ground in health profession education, yet there is limited literature on its costs. This study is an economic evaluation of the substitution of a face-to-face (F2F) workshop with an online escape room game teaching the same content., Methods: A traditional F2F workshop on hepatitis management was conducted with 364 students in 2021 and was compared with a virtual self-run escape room game called Hepatitiscape™, which was used by 417 students in 2022. The outcomes were final examination and objective structured clinical examination (OSCE) scores for hepatitis stations. An incremental cost-effectiveness ratio was used to compare costs and outcomes. Student perceptions of the delivery of Hepatitiscape™ were also captured using an online questionnaire., Results: Delivering the hepatitis case workshop via Hepatitiscape™ yielded an additional 4.77% increase in the final examination score and a 21.04% increase in the OSCE score at an additional cost of AUD $4212 in the first year compared with F2F delivery. This equated to an incremental cost-effectiveness ratio of AUD 883 per additional score of final examination and AUD 200 per additional score of OSCE for hepatitis stations. Hepatitiscape™ became cost saving from the second year onward. Student perception data revealed their recall of content was higher owing to the iterative design of the gaming elements., Conclusions: Hepatitiscape™ is likely to be a cost-effective strategy to deliver workshops that are routinely delivered F2F to test knowledge-based constructs. In addition, virtual gaming has a logistical advantage over F2F delivery in that it enhances student participation from remote locations and allows for better control and flexibility of content delivery with increasing or decreasing cohort sizes, and can have potential long-term sustainable savings., Competing Interests: The authors report no conflict of interest., (Copyright © 2024 Society for Simulation in Healthcare.)

Objectives: Our objective was to design and develop an open-source model capable of simulating interventions for primary prevention of cardiovascular disease (CVD) that incorporated the cumulative effects of risk factors (eg, cholesterol years or blood-pressure years) to enhance health economic modeling in settings which clinical trials are not possible., Methods: We reviewed the literature to design the model structure by selecting the most important causal risk factors for CVD-low-density lipoprotein-cholesterol (LDL-C), systolic blood pressure (SBP), smoking, diabetes, and lipoprotein (a) (Lp(a))-and most common CVDs-myocardial infarction and stroke. The epidemiological basis of the model involves the simulation of risk factor trajectories, which are used to modify CVD risk via causal effect estimates derived from Mendelian randomization. LDL-C, SBP, Lp(a), and smoking all have cumulative impacts on CVD risk, which were incorporated into the health economic model. The data for the model were primarily sourced from the UK Biobank study. We calibrated the model using clinical trial data and validated the model against the observed UK Biobank data. Finally, we performed an example health economic analysis to demonstrate the utility of the model. The model is open source., Results: The model performed well in all validation tests. It was able to produce interpretable and plausible (consistent with expectations of the existing literature) results from an example health economic analysis., Conclusions: We have constructed an open-source health economic model capable of incorporating the cumulative effect of LDL-C (ie, cholesterol years), SBP (SBP-years), Lp(a), and smoking on lifetime CVD risk., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024. Published by Elsevier Inc.)

Objectives: To evaluate the population health returns from investment in the Victorian Cancer Biobank (VCB), a research consortium including five hospital-integrated sample repositories located in Melbourne, Australia. Methods: This economic evaluation assigned monetary values to the health gains attributable to VCB-supported research. These were then compared with the total investment in VCB infrastructure since inception (2006-2022) to determine the return on investment (ROI). A time lag of 40 years was incorporated, recognizing the delay from investment to impact in scientific research. Health gains were therefore measured for the years 2046-2066, with a 3% discount rate applied. Health gains were measured in terms of disability-adjusted life years (DALYs) attributable to VCB-associated research, with monetary cost assigned via the standardized value of a statistical life year (AU$227,000). The age-standardized DALY rate attributable to cancer was modeled for two standpoints (1) extrapolating the current decreasing trajectory and (2) assuming nil future improvement from current rates, with 33% of the difference attributed to scientific innovation. The proportion of the aggregate health gain attributable to VCB-supported research was estimated from the number of VCB-credited scientific publications as a proportion of total oncology publications over the same period. Results: The AU$32,628,016 of public funding invested in VCB activities over the years 2006-2022 is projected to generate AU$84,561,373 in total (discounted) savings. ROI was AU$1.59 for each AU$1 invested. Conclusions: The VCB offers a strong ROI in terms of impacts on health, justifying the expenditure of public funds and supporting the use of biobanks to advance scientific research.

Introduction: We aimed to systematically review contemporary evidence on the barriers and enablers to implementing and sustaining short-stay arthroplasty programs for elective primary total hip and knee replacement from the perspectives of patients, health professionals, carers, healthcare administrators, funders and policymakers and to map the findings to the Theoretical Domains Framework (TDF)., Methods: Medline, Cumulative Index to Nursing and Allied Health Literature, EMBASE, and the Cochrane Central Register of Controlled Trials were searched (up to 19 August 2023). Primary qualitative or mixed-methods studies reporting on perspectives relating to the review aims that utilised a short-stay programme were eligible for inclusion. Study quality was assessed using the qualitative critical appraisal tool from the Joanna Briggs Institute. Data were analysed inductively. The final themes were mapped to the TDF. The confidence in the findings was assessed using GRADE CERQual., Results: Fifteen studies were included. Twelve barrier themes and twelve enabler themes were identified. Three themes were graded with high confidence, 10 were graded with moderate confidence, three were graded with low confidence, and eight were graded with very low confidence. The most pertinent domains that the themes were mapped to for patients were beliefs about capabilities, reinforcement, and the environmental context and resources. Health professionals identified knowledge, environmental context and resources as important domains. Two domains were identified for carers: (1) social/professional role and identity and (2) memory, attention, and decision processes., Conclusion: We identified key barrier and enabler themes linked to the TDF that can be used to guide implementation initiatives and promote the sustainability of short-stay arthroplasty programs., (© 2024 The Author(s). Musculoskeletal Care published by John Wiley & Sons Ltd.)

Background: Primary prevention programs utilising traditional risk scores fail to identify all individuals who suffer acute cardiovascular events. We aimed to model the impact and cost effectiveness of incorporating a Polygenic risk scores (PRS) into the cardiovascular disease CVD primary prevention program in Australia, using a whole-of-system model., Methods: System dynamics models, encompassing acute and chronic CVD care in the Australian healthcare setting, assessing the cost-effectiveness of incorporating a CAD-PRS in the primary prevention setting. The time horizon was 10-years., Results: Pragmatically incorporating a CAD-PRS in the Australian primary prevention setting in middle-aged individuals already attending a Heart Health Check (HHC) who are determined to be at low or moderate risk based on the 5-year Framingham risk score (FRS), with conservative assumptions regarding uptake of PRS, could have prevented 2, 052 deaths over 10-years, and resulted in 24, 085 QALYs gained at a cost of $19, 945 per QALY with a net benefit of $724 million. If all Australians overs the age of 35 years old had their FRS and PRS performed, and acted upon, 12, 374 deaths and 60, 284 acute coronary events would be prevented, with 183, 682 QALYs gained at a cost of $18, 531 per QALY, with a net benefit of $5, 780 million., Conclusions: Incorporating a CAD-PRS in a contemporary primary prevention setting in Australia would result in substantial health and societal benefits and is cost-effective. The broader the uptake of CAD-PRS in the primary prevention setting in middle-aged Australians, the greater the impact and the more cost-effective the strategy., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Stephen Vernon reports financial support was provided by National Heart Foundation of Australia. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier B.V.)

Background: There are no robust population-based Australian data on prevalence and attributed burden of migraine and medication-overuse headache (MOH) data. In this pilot cross-sectional study, we aimed to capture the participation rate, preferred response method, and acceptability of self-report questionnaires to inform the conduct of a future nationwide migraine/MOH epidemiological study., Methods: We developed a self-report questionnaire, available in hard-copy and online, including modules from the Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation (HARDSHIP) questionnaire, the Eq. 5D (quality of life), and enquiry into treatment gaps. Study invitations were mailed to 20,000 randomly selected households across Australia's two most populous states. The household member who most recently had a birthday and was aged ≥ 18 years was invited to participate, and could do so by returning a hard-copy questionnaire via reply-paid mail, or by entering responses directly into an online platform., Results: The participation rate was 5.0% (N = 1,000). Participants' median age was 60 years (IQR 44-71 years), and 64.7% (n = 647) were female. Significantly more responses were received from areas with relatively older populations and middle-level socioeconomic status. Hard copy was the more commonly chosen response method (n = 736). Females and younger respondents were significantly more likely to respond online than via hard-copy., Conclusions: This pilot study indicates that alternative methodology is needed to achieve satisfactory engagement in a future nationwide migraine/MOH epidemiological study, for example through inclusion of migraine screening questions in well-resourced, interview-based national health surveys that are conducted regularly by government agencies. Meanwhile, additional future research directions include defining and addressing treatment gaps to improve migraine awareness, and minimise under-diagnosis and under-treatment., (© 2024. The Author(s).)

Background: Projections of the future burden of ischemic stroke (IS) has not been extensively reported for the Australian population; the availability of such data would assist in health policy planning, clinical guideline updates, and public health., Methods: First, we estimated the lifetime risk of IS (from age 40 to 100 years) using a multistate life table model. Second, a dynamic multistate model was constructed to project the burden of IS for the whole Australian population aged between 40 and 100 years over a 20-year period (2019-2038). Data for the study were primarily sourced from a large, representative Victorian linked dataset based on the Victorian Admitted Episode Dataset and National Death Index. The model projected prevalent and incident cases of nonfatal IS, fatal IS, and years of life lived (YLL) with and without IS. The YLL outcome was discounted by 5% annually; we varied the discounting rate in scenario analyses., Results: The lifetime risk of IS from age 40 years was estimated as 15.5% for males and 14.0% for females in 2018. From 2019 to 2038, 644,208 Australians were projected to develop incident IS (564,922 nonfatal and 79,287 fatal). By 2038, the model projected there would be 358,534 people with prevalent IS, 35,554 people with incident nonfatal IS and 5,338 people with fatal IS, a 14.2% (44,535), 72.9% (14,988), and 106.3% (2,751) increase compared to 2019 estimations, respectively. Projected YLL (with a 5% discount rate) accrued by the Australian population were 174,782,672 (84,251,360 in males and 90,531,312 in females), with 4,053,794 YLL among people with IS (2,320,513 in males, 1,733,281 in females)., Conclusion: The burden of IS was projected to increase between 2019 and 2038 in Australia. The outcomes of the model provide important information for decision-makers to design strategies to reduce stroke burden., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Enormous health burden has been associated with air pollution and its effects continue to grow. However, the impact of air pollution on labour productivity at the population level is still unknown. This study assessed the association between premature death due to PM 2.5 exposure and the loss of productivity-adjusted life years (PALYs), in Brazil. We applied a novel variant of the difference-in-difference (DID) approach to assess the association. Daily all-cause mortality data in Brazil were collected from 2000-2019. The PALYs lost increased by 5.11% (95% CI: 4.10-6.13%), for every 10 µg/m 3 increase in the 2-day moving average of PM 2.5 . A total of 9,219,995 (95% CI: 7,491,634-10,921,141) PALYs lost and US$ 268.05 (95% CI: 217.82-317.50) billion economic costs were attributed to PM 2.5 exposure, corresponding to 7.37% (95% CI: 5.99-8.73%) of the total PALYs lost due to premature death. This study also found that 5,005,306 PALYs could be avoided if the World Health Organization (WHO) air quality guideline (AQG) level was met. In conclusion, this study demonstrates that ambient PM 2.5 exposure is associated with a considerable labour productivity burden relating to premature death in Brazil, while over half of the burden could be prevented if the WHO AQG was met. The findings highlight the need to reduce ambient PM 2.5 levels and provide strong evidence for the development of strategies to mitigate the economic impacts of air pollution., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Epilepsy is a common and serious neurological disorder. This cross-sectional analysis addresses the burden of epilepsy at different stages of the disease., Methods: This pilot study is embedded within the Australian Epilepsy Project (AEP), aiming to provide epilepsy support through a national network of dedicated sites. For this analysis, adults aged 18-65 years with first unprovoked seizure (FUS), newly diagnosed epilepsy (NDE), or drug-resistant epilepsy (DRE) were recruited between February-August 2022. Baseline clinicodemographic data were collected from the participants who completed questionnaires to assess their quality of life (QOLIE-31, EQ-5D-5L), work productivity (Work Productivity and Activity Impairment [WPAI]), and care needs. Univariate analysis and multivariate regression was performed., Results: 172 participants formed the study cohort (median age 34, interquartile range [IQR]: 26-45), comprising FUS (n = 44), NDE (n = 53), and DRE (n = 75). Mean QOLIE-31 score was 56 (standard deviation [SD] ± 18) and median EQ-5D-5L score was 0.77 (IQR: 0.56-0.92). QOLIE-31 but not EQ-5D-5L scores were significantly lower in the DRE group compared to FUS and NDE groups (p < 0.001). Overall, 64.5% of participants participated in paid work, with fewer DRE (52.0%) compared with FUS (76.7%) and NDE (72.5%) (p < 0.001). Compared to those not in paid employment, those in paid employment had significantly higher quality of life scores (p < 0.001). Almost 5.8% of participants required formal care (median 20 h/week, IQR: 12-55) and 17.7% required informal care (median 16 h/week, IQR: 7-101)., Significance: Epilepsy is associated with a large burden in terms of quality of life, productivity and care needs., Plain Language Summary: This is a pilot study from the Australian Epilepsy Project (AEP). It reports health economic data for adults of working age who live with epilepsy. It found that people with focal drug-resistant epilepsy had lower quality of life scores and were less likely to participate in paid employment compared to people with new diagnosis epilepsy. This study provides important local data regarding the burden of epilepsy and will help researchers in the future to measure the impact of the AEP on important personal and societal health economic outcomes., (© 2024 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background and Aim: The prevalence of type 2 diabetes (T2D) is rapidly increasing in Sub-Saharan Africa (SSA). T2D increases the risk of premature death and reduces quality of life and work productivity. This population life table modelling analysis evaluated the impact of T2D in terms of productivity-adjusted life years (PALYs) on the South African working-age population., Research Design and Methods: Life table modelling was employed to simulate the follow-up of individuals aged 20-65 with T2D in South Africa (SA). Two life table models were developed to simulate health outcomes for a SA cohort with and without diabetes. The difference in the number of deaths, years of life lost (YLL), and PALYs lost between the two cohorts represented the burden of diabetes. Scenarios were simulated in which the proportions of gross domestic productivity (GDP), productivity indices, labour force dropout, and mortality risk trends were adjusted to lower and upper uncertainty bounds. Data were sourced from the International Diabetes Federation, Statistics SA, and both publicly available and published sources. We utilised the World Health Organization (WHO) standard annual discount rate of 3% for YLL and PALYs., Results: In 2019, an estimated 9.5% (7.68% men and 11.37% women) or 3.2 million total working-age people had T2D in SA. Simulated follow-up until retirement predicted 669,427 excess mortality, a loss of 6.2 million years of life (9.3%) and 13 million PALYs (30.6%) in SA. On average, this resulted in 3.1 PALYs lost per person. Based on the GDP per full-time employee in 2019, the PALYs loss equated to US$223 billion, or US$69,875 per person., Conclusions: This study emphasises the significant impact of T2D on society and the economy. Relatively modest T2D prevention and treatment management enhancement could lead to substantial economic benefits in SA., (© 2024. The Author(s).)

Purpose of Review: Heterozygous familial hypercholesterolemia (HeFH) is one of the most common monogenic disorders and is safely treatable with lipid-lowering medication. However, most individuals with HeFH remain untreated and undetected, especially in paediatric populations where the potential for long-term therapeutic benefit is higher. Here, we review the recent literature on health economic outcomes for the detection and management of FH in children., Recent Findings: A targeted literature review identified eight studies evaluating detection and management strategies for paediatric FH populations in the last 25 years. Most studies conducted modelled cost-effectiveness analyses to understand the long-term impact of these strategies on health outcomes and the financial impact on the healthcare system. All studies reported that detection and management of HeFH in paediatric populations was cost-effective, regardless of the age of the children. However, cost-effectiveness varied depending on the method of case ascertainment - targeted screening was generally cheaper overall, but less effective, than whole-of-population screening, although both methods were generally cost-effective., Summary: Detection and management of HeFH in paediatric populations is a cost-effective way to significantly lower the burden of disease later in life for these individuals. These strategies should be implemented across healthcare systems., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To estimate the economic impact of the developed antimicrobial stewardship program (ASP) versus the preliminary ASP use, in the adults' general medicine settings in Qatar., Methods: Patient records were retrospectively reviewed during two periods: preliminary ASP was defined as the 12 months following ASP implementation (i.e. May 2015-April 2016), and developed ASP was defined as the last 12 months of a 5-year ASP implementation in Hamad Medical Corporation (HMC) (i.e. February 2019-January 2020). The economic impact was the overall cost savings in resource use, including operational costs, plus the cost avoidance associated with ASP., Results: A total of 500 patients were included in the study. The operational costs decreased with the developed ASP. Whereas antimicrobial consumption and resource utilisation, and their associated costs, appear to have declined with the developed ASP, with a cost saving of QAR458 (US$125) per 100-patient beds, the avoided cost was negative, by QAR4,807 (US$1,317) per 100-patient beds, adding to a total QAR4,224 (US$1,160) increase in the 100-patient beds cost after ASP development., Conclusions: Despite that the developed ASP attained a total cost saving QAR458 (US$125) per 100-patient beds, the avoided cost was QAR-4,807 (US$-1,317) per 100-patient beds, which exceeded the cost savings achieved., Competing Interests: No potential conflict of interest was reported by the authors.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Aims: People in remote areas may have more difficulty accessing healthcare following myocardial infarction (MI) than people in metropolitan areas. We determined whether remoteness was associated with initial and 12-month use of secondary prevention medications following MI in Victoria, Australia., Methods and Results: We included all people alive at least 90 days after discharge following MI between July 2012 and June 2017 in Victoria, Australia (n = 41 925). We investigated dispensing of P2Y12 inhibitors (P2Y12i), statins, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEIs/ARBs), and beta-blockers within 90 days after discharge. We estimated 12-month medication use using proportion of days covered (PDC). Remoteness was determined using the Accessibility/Remoteness Index of Australia (ARIA). Data were analysed using adjusted parametric regression models stratified by ST elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI). There were 10 819 STEMI admissions and 31 106 NSTEMI admissions. Following adjustment across NSTEMI and STEMI, there were no medication classes dispensed in the 90-day post-discharge that differed in a clinically significant way from the least remote (ARIA = 0) to the most remote (ARIA = 4.8) areas. The largest difference for NSTEMI was ACEI/ARB, with 71% (95% confidence interval 70-72%) vs. 80% (76-83%). For STEMI, it was statins with 89% (88-90%) vs. 95% (91-97%). Predicted PDC for STEMI and NSTEMI was not clinically significant across remoteness, with the largest difference in NSTEMI being P2Y12i with 48% (47-50%) vs. 55% (51-59%), and in STEMI, it was ACEI/ARB with 68% (67-69%) vs. 76% (70-80%)., Conclusion: Remoteness does not appear to be a clinically significant driver for medication use following MI. Possible differences in cardiovascular outcomes in metropolitan and non-metropolitan areas are not likely to be explained by access to secondary prevention medications., Competing Interests: Conflict of interest: A.C.L., Z.A., D.P., and J.I.M. have no conflicts to declare relevant to this publication. J.I. has received grants from the NHMRC, National Breast Cancer Foundation, Dementia Australia Research Foundation, AstraZeneca. and Amgen. J.S.B. is supported by a National Health and Medical Research Council (NHMRC) Boosting Dementia Research Leadership Fellowship and has received grant funding or consulting funds from the NHMRC, Medical Research Future Fund, Victorian Government Department of Health, Dementia Australia Research Foundation, Yulgilbar Foundation, Aged Care Quality and Safety Commission, Dementia Centre for Research Collaboration, Pharmaceutical Society of Australia, Society of Hospital Pharmacists of Australia, GlaxoSmithKline Supported Studies Programme, Amgen, and several aged care provider organizations unrelated to this work. All grants and consulting funds were paid to the employing institution., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Remoteness has been shown to predict poor clinical outcomes following myocardial infarction (MI). This study investigated 1-year clinical outcomes following MI by remoteness in Victoria, Australia., Methods: We included all admissions for people discharged from hospital following MI between July 2012 and June 2017 (n = 43,729). Remoteness was determined using the Accessibility/Remoteness Index of Australia (ARIA). The relationship between remoteness and major adverse cardiovascular events (MACE) and all-cause mortality over 1-year was evaluated using adjusted Poisson regression, stratified by type STEMI and NSTEMI., Results: For NSTEMI, adjusted rates of MACE were 77.5[95% confidence interval 65.1-92.1] for the most remote area versus 83.4[65.5-106.3] for the least remote area per 1000 person-years. For STEMI, rates of MACE were 28.5[18.3-44.6] for the most versus 33.5[18.9-59.4] for the least remote areas per 1000 person-years. With respect to all-cause mortality, NSTEMI mortality rates were 82.2[67.0-100.9] for the most versus 100.8[75.2-135.1] for the least remote areas per 1000 person-years. For STEMI, mortality rates were 24.7[13.7-44.7] for the most versus 22.3[9.8-50.8] for the least remote per 1000 person-years., Conclusions: Rates of MACE and all-cause mortality were similar in regardless of degree of remoteness, suggesting that initiatives to increase access to cardiology care in more remote areas succeeded in reducing previous disparities., Competing Interests: Declaration of Competing Interest AL No conflicts to declare relevant to this publication. ZA No conflicts to declare relevant to this publication. JI has received grants from the NHMRC, National Breast Cancer Foundation, Dementia Australia Research Foundation, AstraZeneca and Amgen. DP No conflicts to declare relevant to this publication. JIM No conflicts to declare relevant to this publication. JSB is supported by a National Health and Medical Research Council (NHMRC) Boosting Dementia Research Leadership Fellowship and has received grant funding or consulting funds from the NHMRC, Medical Research Future Fund, Victorian Government Department of Health, Dementia Australia Research Foundation, Yulgilbar Foundation, Aged Care Quality and Safety Commission, Dementia Centre for Research Collaboration, Pharmaceutical Society of Australia, Society of Hospital Pharmacists of Australia, GlaxoSmithKline Supported Studies Programme, Amgen, and several aged care provider organisations unrelated to this work. All grants and consulting funds were paid to the employing institution., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Stroke remains one of the leading causes of morbidity and mortality in Australia. The objective of this study was to estimate the current and future cost burden of ischemic stroke (IS) in Australia., Method: First, the annual chronic management cost per person following IS were derived for all people aged ≥30 years discharged from a public or private hospital in Victoria, Australia between July 2012 and June 2017 (with follow-up data until June 2018 [n = 34,471]). Then extrapolated the data from from Victoria to the whole Australian population aged between 30 years and 99 years to project the total healthcare costs following IS (combination of acute event and chronic management cost) over a 20-year period (2019-2038) using a dynamic multistate life table model. Data for the dynamic model were sourced from the Victorian Admitted Episodes Dataset (VAED) and supplemented with other published data., Result: The estimated annual total chronic management cost following IS was 13,525 Australian dollars (AUD) per person (95% CI: AUD 13,380, AUD 13,670) for cohorts in the VAED between July 2012 and June 2017. The annual chronic management cost was estimated to decline following IS. The highest cost was incurred in the first year of follow-up post-IS (AUD 14,309 per person) and declined to AUD 9,776 in the sixth year of follow-up post-IS. The total healthcare cost for people aged 30-99 years was projected to be AUD 47.7 billion (95% UI: AUD 44.6 billion, AUD 51.0 billion) over the 20-year period (2019-2038) Australia-wide, of which 91.3% (AUD 43.6 billion) was attributed to chronic management costs and the remaining 8.7% (AUD 4.2 billion) were due to acute IS events., Conclusion: IS has and will continue to have a considerable financial impact in the next 2 decades on the Australian healthcare system. Our estimated and projected cost burden following IS provides important information for decision making in relation to IS., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Aims: To predict the future health and economic burden of cardiovascular disease (CVD) in type 2 diabetes (T2D) in Qatar., Materials and Methods: A dynamic multistate model was designed to simulate the progression of fatal and non-fatal CVD events among people with T2D in Qatar aged 40-79 years. First CVD events [i.e. myocardial infarction (MI) and stroke] were calculated via the 2013 Pooled Cohort Equation, while recurrent CVD events were sourced from the REACH registry. Key model outcomes were fatal and non-fatal MI and stroke, years of life lived, quality-adjusted life years, total direct medical costs and total productivity loss costs. Utility and cost model inputs were drawn from published sources. The model adopted a Qatari societal perspective. Sensitivity analyses were performed to test the robustness of estimates., Results: Over 10 years among people with T2D, model estimates 108 195 [95% uncertainty interval (UI) 104 249-112 172] non-fatal MIs, 62 366 (95% UI 60 283-65 520) non-fatal strokes and 14 612 (95% UI 14 472-14 744) CVD deaths. The T2D population accrued 4 786 605 (95% UI 4 743 454, 4 858 705) total years of life lived and 3 781 833 (95% UI 3 724 718-3 830 669) total quality-adjusted life years. Direct costs accounted for 57.85% of the total costs, with a projection of QAR41.60 billion (US$11.40 billion) [95% UI 7.53-147.40 billion (US$2.06-40.38 billion)], while the total indirect costs were expected to exceed QAR30.31 billion (US$8.30 billion) [95% UI 1.07-162.60 billion (US$292.05 million-44.55 billion)]., Conclusions: The findings suggest a significant economic and health burden of CVD among people with T2D in Qatar and highlight the need for more enhanced preventive strategies targeting this population group., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: We aimed to assess the cost effectiveness of four different lipid-lowering strategies for primary prevention of coronary heart disease initiated at ages 30, 40, 50, and 60 years from the UK National Health Service perspective., Methods: We developed a microsimulation model comparing the initiation of a lipid-lowering strategy to current standard of care (control). We included 458,692 participants of the UK Biobank study. The four lipid-lowering strategies were: (1) low/moderate-intensity statins; (2) high-intensity statins; (3) low/moderate-intensity statins and ezetimibe; and (4) inclisiran. The main outcome was the incremental cost-effectiveness ratio for each lipid-lowering strategy compared to the control, with 3.5% annual discounting using 2021 GBP (£); incremental cost-effectiveness ratios were compared to the UK willingness-to-pay threshold of £20,000-£30,000 per quality-adjusted life-year., Results: The most effective intervention, low/moderate-intensity statins and ezetimibe, was projected to lead to a gain in quality-adjusted life-years of 0.067 per person initiated at 30 and 0.026 at age 60 years. Initiating therapy at 40 years of age was the most cost effective for all lipid-lowering strategies, with incremental cost-effectiveness ratios of £2553 (95% uncertainty interval: 1270, 3969), £4511 (3138, 6401), £11,107 (8655, 14,508), and £1,406,296 (1,121,775, 1,796,281) per quality-adjusted life-year gained for strategies 1-4, respectively. Incremental cost-effectiveness ratios were lower for male individuals (vs female individuals) and for people with higher (vs lower) low-density lipoprotein-cholesterol. For example, low/moderate-intensity statin use initiated from age 40 years had an incremental cost-effectiveness ratio of £5891 (3822, 9348), £2174 (772, 4216), and was dominant (i.e. cost saving; -2,760, 350) in female individuals with a low-density lipoprotein-cholesterol of ≥ 3.0, ≥ 4.0 and ≥ 5.0 mmol/L, respectively. Inclisiran was not cost effective in any sub-group at its current price., Conclusions: Low-density lipoprotein-cholesterol lowering from early ages is a more cost-effective strategy than late intervention and cost effectiveness increased with the increasing lifetime risk of coronary heart disease., (© 2023. Crown.)