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Background The oleaginous, carotenogenic yeast Rhodotorula toruloides has been increasingly explored as a platform organism for the production of terpenoids and fatty acid derivatives. Fatty alcohols, a fatty acid derivative widely used in the production of detergents and surfactants, can be produced microbially with the expression of a heterologous fatty acyl-CoA reductase. Due to its high lipid production, R. toruloides has high potential for fatty alcohol production, and in this study several metabolic engineering approaches were investigated to improve the titer of this product. Results Fatty acyl-CoA reductase from Marinobacter aqueolei was co-expressed with SpCas9 in R. toruloides IFO0880 and a panel of gene overexpressions and Cas9-mediated gene deletions were explored to increase the fatty alcohol production. Two overexpression targets ( ACL1 and ACC1 , improving cytosolic acetyl-CoA and malonyl-CoA production, respectively) and two deletion targets (the acyltransferases DGA1 and LRO1 ) resulted in significant (1.8 to 4.4-fold) increases to the fatty alcohol titer in culture tubes. Combinatorial exploration of these modifications in bioreactor fermentation culminated in a 3.7 g/L fatty alcohol titer in the LRO1 Δ mutant. As LRO1 deletion was not found to be beneficial for fatty alcohol production in other yeasts, a lipidomic comparison of the DGA1 and LRO1 knockout mutants was performed, finding that DGA1 is the primary acyltransferase responsible for triacylglyceride production in R. toruloides , while LRO1 disruption simultaneously improved fatty alcohol production, increased diacylglyceride and triacylglyceride production, and increased glucose consumption. Conclusions The fatty alcohol titer of fatty acyl-CoA reductase-expressing R. toruloides was significantly improved through the deletion of LRO1 , or the deletion of DGA1 combined with overexpression of ACC1 and ACL1 . Disruption of LRO1 surprisingly increased both lipid and fatty alcohol production, creating a possible avenue for future study of the lipid metabolism of this yeast.

Background Higher cruciferous vegetable intake is associated with lower cardiovascular disease risk in observational studies. The pathways involved remain uncertain. We aimed to determine whether cruciferous vegetable intake (active) lowers 24-h brachial systolic blood pressure (SBP; primary outcome) compared to root and squash vegetables (control) in Australian adults with mildly elevated BP (SBP 120–160 mmHg inclusive). Methods In this randomized, controlled, crossover trial, participants completed two 2-week dietary interventions separated by a 2-week washout. Cruciferous vegetables were compared to root and squash vegetables (~ 300 g/day) consumed with lunch and dinner meals. Participants were blinded to which interventions were the active and control. Adherence was assessed using food diaries and biomarkers (S-methyl cysteine sulfoxide (SMCSO, active) and carotenoids (control)). Twenty-four-hour brachial ambulatory SBP and secondary outcomes were assessed pre- and post each intervention. Differences were tested using linear mixed effects regression. Results Eighteen participants were recruited (median (IQR) age: 68 (66–70); female: n  = 16/18; mean ± SD clinic SBP: 135.9 ± 10.0 mmHg). For both interventions, 72% participants had 100% adherence (IQR: 96.4–100%). SMCSO and carotenoids were significantly different between interventions (mean difference active vs. control SMCSO: 22.93 mg/mL, 95%CI 15.62, 30.23, P  < 0.0001; carotenoids: − 0.974 mg/mL, 95%CI − 1.525, − 0.423, P  = 0.001). Twenty-four-hour brachial SBP was significantly reduced following the active vs. control (mean difference − 2.5 mmHg, 95%CI − 4.2, − 0.9, P  = 0.002; active pre: 126.8 ± 12.6 mmHg, post: 124.4 ± 11.8 mmHg; control pre: 125.5 ± 12.1 mmHg, post: 124.8 ± 13.1 mmHg, n  = 17), driven by daytime SBP (mean difference − 3.6 mmHg, 95%CI − 5.4, − 1.7, P  < 0.001). Serum triglycerides were significantly lower following the active vs. control (mean difference − 0.2 mmol/L, 95%CI − 0.4, − 0.0, P  = 0.047). Conclusions Increased intake of cruciferous vegetables resulted in reduced SBP compared to root and squash vegetables. Future research is needed to determine whether targeted recommendations for increasing cruciferous vegetable intake benefits population health. Trial registration Clinical trial registry ACTRN12619001294145.  https://www.anzctr.org.au

Renal denervation (RDN) is an adjunct therapy for resistant hypertension, reducing blood pressure (BP) by inhibiting both afferent sensory and efferent sympathetic renal nerve activity. The resulting reduction in central sympathetic outflow including that directed toward the heart may beneficially impact cardiac remodeling, left ventricular hypertrophy (LVH) and atrial fibrillation (AF). RDN has been shown to reduce left ventricular mass and AF burden but long‐term data is sparse. Forty patients (72.5% male, 69.2 ± 9.6 years) underwent 12‐lead ECG at baseline prior to RDN and at a mean long‐term follow‐up (LTFU) of 8.3 ± 0.9 years post‐intervention. A 24‐h ambulatory blood pressure monitor (ABPM) was obtained at both time points. Cornell voltage indices were calculated at baseline and LTFU, then converted to left ventricular mass based on validated formulae accounting for sex. ECGs underwent cardiologist review for determination of AF at both time‐points. There was no difference in Cornell voltages or left ventricular mass index (LVMI) between baseline and long‐term follow‐up in neither males ( p  = 0.89) nor females ( p  = 0.91). BP lowering at LTFU was correlated with a more pronounced reduction in LVMI ( r  = 0.50, p  = 0.0011) No change was observed in the incidence of atrial fibrillation between baseline or long‐term follow‐up ( p  = 0.99). There was no reduction in mean Cornell voltage or LVMI across the cohort between baseline and long‐term follow‐up. However, changes in ambulatory systolic BP correlated with reduction in LVMI suggestive of an RDN‐induced BP dependent long‐term reduction in LVMI out to eight years post‐RDN.

Background A diet rich in fruits and vegetables is recommended for cardiovascular health. However, the majority of Australians do not consume the recommended number of vegetable servings each day. Furthermore, intakes of vegetables considered to have the greatest cardiovascular benefit are often very low. Results from prospective observational studies indicate that a higher consumption of cruciferous vegetables (e.g. broccoli, cabbage, cauliflower) is associated with lower cardiovascular disease risk. This may be due to the presence of specific nutrients and bioactive compounds found almost exclusively, or at relatively high levels, in cruciferous vegetables. Therefore, the aim of this randomised controlled crossover trial is to determine whether regular consumption of cruciferous vegetables results in short-term improvement in measures related to cardiovascular disease risk, including ambulatory blood pressure, arterial stiffness, glycaemic control, and circulating biomarkers of oxidative stress and inflammation. Methods Twenty-five participants (50–75 years) with mildly elevated blood pressure (systolic blood pressure 120–160 mmHg) will complete two 2-week intervention periods in random order, separated by a 2-week washout period. During the intervention period, participants will consume 4 servings (~ 300 g) of cruciferous vegetables per day as a soup (~ 500–600 mL/day). The ‘control’ soup will consist of other commonly consumed vegetables (potato, sweet potato, carrot, pumpkin). Both soups will be approximately matched for energy, protein, fat, and carbohydrate content. All measurements will be performed at the beginning and end of each intervention period. Discussion The findings of this study will provide evidence regarding the potential cardiometabolic health benefits of cruciferous vegetables, which may contribute to the revision of dietary and clinical guidelines. Trial registration The trial was registered with the Australian New Zealand Clinical Trial Registry on 19th September 2019 ( ACTRN12619001294145 ).

Patients with ST-elevation myocardial infarction (STEMI) with no standard modifiable risk factors (SMuRFs: hypertension, diabetes mellitus, hypercholesterolemia, and smoking) have worse short-term mortality than those with SMuRFs. Whether this association extends to younger patients is unclear. A retrospective cohort study was performed of patients aged 18 to 45 years with STEMI at 3 Australian hospitals between 2010 and 2020. Nonatherosclerotic causes of STEMI were excluded. The primary outcome was 30-day all-cause mortality. Secondary outcomes included 1 and 2-year mortality. Cox proportional hazards analysis was used. Of 597 patients, the median age was 42 (interquartile range 38 to 44) years, 85.1% were men and 8.4% were SMuRF-less. Patients who are SMuRF-less were >2 times more likely to have cardiac arrest (28.0% vs 12.6%, p = 0.003); require vasopressors (16.0% vs 6.8%, p = 0.018), mechanical support (10.0% vs 2.3%, p = 0.046), or intensive care admission (20.0% vs 5.7%, p <0.001); and have higher rate of left anterior descending artery infarcts than those with SMuRFs (62.0% vs 47.2%, p = 0.045). No significant differences in thrombolysis or percutaneous intervention were observed. Guideline-directed medical therapy at discharge was high (>90%), and not different in the SMuRF-less. 30-day mortality was almost fivefold higher in the SMuRF-less (hazard ratio 4.70, 95% confidence interval 1.66 to 13.35, p = 0.004), remaining significant at 1 and 2 years. In conclusion, young patients who are SMuRF-less have a higher 30-day mortality after STEMI than their counterparts with SMuRFs. This may be partially mediated by higher rates of cardiac arrest and left anterior descending artery territory events. These findings further highlight the need for improved prevention and management of SMuRF-less STEMI.

ABSTRACT Rhodotorula toruloides has been increasingly explored as a host for bioproduction of lipids, fatty acid derivatives and terpenoids. Various genetic tools have been developed, but neither a centromere nor an autonomously replicating sequence (ARS), both necessary elements for stable episomal plasmid maintenance, has yet been reported. In this study, cleavage under targets and release using nuclease (CUT&RUN), a method used for genome-wide mapping of DNA–protein interactions, was used to identify R. toruloides IFO0880 genomic regions associated with the centromeric histone H3 protein Cse4, a marker of centromeric DNA. Fifteen putative centromeres ranging from 8 to 19 kb in length were identified and analyzed, and four were tested for, but did not show, ARS activity. These centromeric sequences contained below average GC content, corresponded to transcriptional cold spots, were primarily nonrepetitive and shared some vestigial transposon-related sequences but otherwise did not show significant sequence conservation. Future efforts to identify an ARS in this yeast can utilize these centromeric DNA sequences to improve the stability of episomal plasmids derived from putative ARS elements. The centromeres of R. toruloidesIFO0880 were identified by using CUT&RUN to identify the chromosomal regions bound by the centromeric histone Cse4.

Objectives To compare the diagnostic performance and radiation exposure of 128-slice dual-source CT coronary angiography (CTCA) protocols to detect coronary stenosis with more than 50 % lumen obstruction. Methods We prospectively included 459 symptomatic patients referred for CTCA. Patients were randomized between high-pitch spiral vs. narrow-window sequential CTCA protocols (heart rate below 65 bpm, group A), or between wide-window sequential vs. retrospective spiral protocols (heart rate above 65 bpm, group B). Diagnostic performance of CTCA was compared with quantitative coronary angiography in 267 patients. Results In group A (231 patients, 146 men, mean heart rate 58 ± 7 bpm), high-pitch spiral CTCA yielded a lower per-segment sensitivity compared to sequential CTCA (89 % vs. 97 %, P  = 0.01). Specificity, PPV and NPV were comparable (95 %, 62 %, 99 % vs. 96 %, 73 %, 100 %, P  > 0.05) but radiation dose was lower (1.16 ± 0.60 vs. 3.82 ± 1.65 mSv, P  < 0.001). In group B (228 patients, 132 men, mean heart rate 75 ± 11 bpm), per-segment sensitivity, specificity, PPV and NPV were comparable (94 %, 95 %, 67 %, 99 % vs. 92 %, 95 %, 66 %, 99 %, P  > 0.05). Radiation dose of sequential CTCA was lower compared to retrospective CTCA (6.12 ± 2.58 vs. 8.13 ± 4.52 mSv, P  < 0.001). Diagnostic performance was comparable in both groups. Conclusion Sequential CTCA should be used in patients with regular heart rates using 128-slice dual-source CT, providing optimal diagnostic accuracy with as low as reasonably achievable (ALARA) radiation dose. Key Points • 128-slice dual-source CT coronary angiography offers several different acquisition protocols. • Randomized comparison of protocols reveals an optimal protocol selection strategy. • Appropriate CTCA protocol selection lowers radiation dose, while maintaining high quality. • CTCA protocol selection should be based on individual patient characteristics. • A prospective sequential protocol is preferred for CTCA.

Summary Health-related behaviours contribute to the global burden of cardiovascular disease (CVD). Cardiovascular imaging can be used to screen asymptomatic individuals for increased risk of CVD to enable earlier interventions to promote health-related behaviours to prevent or reduce CVD risk. Some theories of behaviour and behaviour change assume that engagement in a given behaviour is a function of individual threat appraisals, beliefs regarding the performance of behaviour, self-efficacy for performing the desired behaviour and/or dispositions to act (e.g. behavioural intentions). To date, little is known about the impact of cardiovascular imaging interventions on these constructs. This article summarises evidence related to perceived threat, efficacy beliefs, and behavioural intentions after CVD screening. We identified 10 studies (2 RCTs and 8 non-randomised studies, n = 2498) through a combination of screening citations from published systematic reviews and meta-analyses and searching electronic databases. Of these, 7 measured behavioural intentions and perceived susceptibility and 3 measured efficacy beliefs. Findings showed largely encouraging effects of screening interventions on bolstering self-efficacy beliefs and strengthening behavioural intentions. Imaging results that suggest the presence of coronary or carotid artery disease also increased perceived susceptibility to CVD. However, the review also identified some gaps in the literature, such as a lack of guiding theoretical frameworks and assessments of critical determinants of health-related behaviours. By carefully considering the key issues highlighted in this review, we can make significant strides towards reducing CVD risks and improving population health. Lay Summary This systematic narrative review sought to comprehensively report evidence related to individual responses to cardiovascular screening interventions. Theoretically, the study builds upon theories based on the cognitive perspective (e.g. Health Belief Model, Protection Motivation Theory), which supports the examination of individual perceptions of negative health-related outcomes or health risk, beliefs regarding the performance of a behaviour or outcome expectancies (e.g. perceived benefits of behavioural performance), personal control or capacity to perform a behaviour and/or willingness to invest the effort to engage in behaviour after behavioural intervention delivery. These concepts are considered key predictors of health-related behaviours and have been examined in several public health interventions. Using a variety of search strategies, studies that reported outcomes of interest were identified. Some studies showed that cardiovascular screening interventions may help people form the desired intention to engage in health-related behaviours. We also observed (largely) encouraging effects of cardiovascular screening interventions on individual confidence to engage in health-related behaviours and understanding of personal health risks. However, we identified some limitations in the design, delivery and outcomes assessed in the studies included. For future research, key recommendations to inform the design and delivery of health behaviour interventions are provided.

ObjectiveWe tested the hypothesis that patients with a potential acute coronary syndrome (ACS) and very low levels of high-sensitivity cardiac troponin I can be efficiently and safely discharged from the emergency department after a single troponin measurement.MethodsThis prospective cohort study recruited 2255 consecutive patients aged ≥18 years presenting to the Emergency Department, Royal Perth Hospital, Western Australia, with chest pain without high-risk features but requiring the exclusion of ACS. Patients were managed using a guideline-recommended pathway or our novel Single Troponin Accelerated Triage (STAT) pathway. The primary outcome was the percentage of patients discharged in <3 hours. Secondary outcomes included the duration of observation and death or acute myocardial infarction in the next 30 days.ResultsThe study enrolled 1131 patients to the standard cohort and 1124 to the STAT cohort. Thirty-eight per cent of the standard cohort were discharged directly from emergency department compared with 63% of the STAT cohort (p<0.001). The median duration of observation was 4.3 (IQR 3.3–7.1) hours in the standard cohort and 3.6 (2.6–5.4) hours in the STAT cohort (p<0.001), with 21% and 38% discharged in <3 hours, respectively (p<0.001). No patients discharged directly from the emergency department died or suffered an acute myocardial infarction within 30 days in either cohort.ConclusionsAmong low-risk patients with a potential ACS, a pathway which incorporates early discharge based on a single very low level of high-sensitivity cardiac troponin increases the proportion of patients discharged directly from the emergency department, reduces length of stay and is safe.Trial registration numberACTRN12618000797279.