Achieving cardiac rehabilitation uptake targets: What is the value case for commissioners? A UK case-study.

Cardiac Rehabilitation (CR) has become an established intervention to support patient recovery after a cardiac event, with evidence supporting its effectiveness and cost-effectiveness in improving patient health and reducing future burden on healthcare systems. However, this evidence has focussed on the national value case for CR rather than at the point at which it is commissioned. This analysis uses the UK as a case-study to explore variation in current CR engagement and disassemble the value case from a commissioner perspective. Using data collected by the National Audit of CR (NACR), and an existing model of cost-effectiveness, we present details on the current level of CR uptake by commissioning region (Specialist Clinical Networks) in light of the current UK target of achieving 85% uptake. We then interrogate the value case for achieving the target at a commissioner level, highlighting the expected profile of health benefits and healthcare system costs over the long-term. Importantly we consider where this may differ from the national value case. Each commissioning region has a unique level of CR uptake and sociodemographic profile. Concurrently, the value case for commissioning CR relies on the upfront cost of the service being offset by long-term healthcare savings, and health improvements. The shift in the UK and internationally to more localised commissioning necessitates evidence of cost-effectiveness that better reflects the realities of those decision makers. This paper provides vital additional data to facilitate such commissioners to understand the value case in increasing CR uptake in line with national policy.

Systematic development and feasibility testing of a multibehavioural digital prehabilitation intervention for patients approaching major surgery (iPREPWELL): A study protocol.

Improving outcomes for people undergoing major surgery, specifically reducing perioperative morbidity and mortality remains a global health challenge. Prehabilitation involves the active preparation of patients prior to surgery, including support to tackle risk behaviours that mediate and undermine physical and mental health and wellbeing. The majority of prehabilitation interventions are delivered in person, however many patients express a preference for remotely-delivered interventions that provide them with tailored support and the flexibility. Digital prehabilitation interventions offer scalability and have the potential to benefit perioperative healthcare systems, however there is a lack of robustly developed and evaluated digital programmes for use in routine clinical care. We aim to systematically develop and test the feasibility of an evidence and theory-informed multibehavioural digital prehabilitation intervention 'iPREPWELL' designed to prepare patients for major surgery. The intervention will be developed with reference to the Behaviour Change Wheel, COM-B model, and the Theoretical Domains Framework. Codesign methodology will be used to develop a patient intervention and accompanying training intervention for healthcare professionals. Training will be designed to enable healthcare professionals to promote, support and facilitate delivery of the intervention as part of routine clinical care. Patients preparing for major surgery and healthcare professionals involved with their clinical care from two UK National Health Service centres will be recruited to stage 1 (systematic development) and stage 2 (feasibility testing of the intervention). Participants recruited at stage 1 will be asked to complete a COM-B questionnaire and to take part in a qualitative interview study and co-design workshops. Participants recruited at stage 2 (up to twenty healthcare professionals and forty participants) will be asked to take part in a single group intervention study where the primary outcomes will include feasibility, acceptability, and fidelity of intervention delivery, receipt, and enactment. Healthcare professionals will be trained to promote and support use of the intervention by patients, and the training intervention will be evaluated qualitatively and quantitatively. The multifaceted and systematically developed intervention will be the first of its kind and will provide a foundation for further refinement prior to formal efficacy testing.

Multiple interventions following an acute coronary syndrome event increase uptake into cardiac rehabilitation.

AIMS: Cardiac rehabilitation (CR) improves morbidity and mortality. Uptake varies for patients following acute coronary syndrome (ACS). Entry into CR is often dependent on the management strategy received, lower following percutaneous coronary intervention (PCI), higher following coronary artery bypass grafting (CABG). This study sought to investigate differences in CR uptake following an ACS event for those patients receiving multiple treatments. METHODS: Data was from the National Audit of CR between 2016 and 2019. Patients with ACS were categorised as: no intervention; one treatment (such as any PCI, CABG, any valve surgery and any device therapy); two treatments; or three or more treatments. Baseline demographics and logistic regression were used to analyse the effect of multiple treatment intervention on uptake into CR. RESULTS: A total of 6833 ACS patients were included in the analysis (0 treatments 2014, 1 treatment 3104, ≥2 treatments 2799). Patients who received ≥2 therapeutic interventions were more likely to be male, partnered and >2 comorbidities. Logistic regression showed a positive relationship between uptake total intervention. Similar associations were seen: being younger, male, partnered and having any comorbidity. The hospital stay, history of angina, diabetes and stroke was negatively correlated with an uptake. CONCLUSION: This study showed for the first time that multiple interventions following ACS is a significant predictor of uptake into CR. The findings align with recent trends with medically managed myocardial infarction uptake. Our findings identify factors associated with poor uptake to CR which should be considered as part of strategy to increase participation.

Estimating the health loss due to poor engagement with cardiac rehabilitation in Australia.

BACKGROUND: Cardiac rehabilitation (CR) programs are effective in reducing cardiovascular mortality and readmissions. However, most patients are denied the benefits of CR due to low referral rates. Of those patients referred, commencement rates vary from 28.4% to 60%. This paper quantifies the scale of health loss in Australia due to poor engagement with the program, and estimates how much public funding can be justifiably reallocated to address the problem. METHODS: Economic decision modelling was undertaken to estimate the expected lifetime health loss and costs to Medicare. Key parameters were derived from Australian databases, CR registries and meta-analyses. Population health gains associated with uptake rates of 60%, and 85% were calculated. RESULTS: CR was associated with a 99.9% probability of being cost-effective, even at a cost-effectiveness threshold lower than conventionally applied. Importantly, an average of 0.52 years of life expectancy are lost due to national uptake being below 60% achieved in some best performing programs in Australia, equivalent to 0.28 quality adjusted life years. The analysis indicates that $12.9 million/year could be justifiably reallocated from public funds to achieve a national uptake rate of 60%, while maintaining cost-effectiveness of CR due to the large health gains that would be expected. CONCLUSION: CR is a cost-effective service for patients with coronary heart disease. In Australia, less than a third of patients commence CR, potentially resulting in avoidable patient harm. Additional investment in CR is vital and should be a national priority as the health gains for patients far outweigh the costs.

Subtotal colectomy and ileorectal anastomosis for slow transit constipation: clinical follow-up at median of 15 years.

BACKGROUND: Slow transit constipation is characterised by prolonged colonic transit and reliance on laxatives. The pathophysiology is poorly understood and in its most severe form, total colectomy with ileorectal anastomosis is the final treatment option. We present a follow-up study of the long-term function in patients who had surgery for laxative-resistant slow transit constipation. METHODS: A postal survey was sent to assess bowel frequency, abdominal pain, St Mark's continence score, satisfaction with procedure, likelihood to choose the procedure again, and long-term rates of small bowel obstruction and ileostomy. Longitudinal data from a subgroup studied 23 years previously are reported. RESULTS: Forty-two patients (male = 2) were available for follow-up out of an initial cohort of 102. Mean time since surgery was 15.9 years (range 1.7-29.7) years. Fifty percent had < 4 bowel motions per day, most commonly Bristol stool 6, mean St Mark's score 7.45. Twenty-one percent had severe incontinence. Satisfaction and likelihood to choose surgery were high (median 10/10). There was a high rate of small bowel obstruction, suggesting pan-intestinal dysmotility in some cases. Conversion to ileostomy occurred in 8 patients. In the longitudinal follow-up in 15 subjects, continence deteriorated (p < 0.01), stool consistency softened (p < 0.01), and stool frequency fell (p < 0.01). CONCLUSIONS: Satisfactory stool frequency was achieved in the long term, and although 21% had incontinence scores > 12, patient satisfaction was high. This is the longest reported follow-up of colectomy for slow transit constipation, with longitudinal outcomes reported. There was considerable attrition of patients, so larger, longitudinal studies are required to better ascertain the functional outcomes of these patients.

In their own words: investigating the preparedness of final year dental students in the UK for independent general dental practice.

Introduction: There is relatively little data on the preparedness of UK dental graduates for independent general dental practice. Two recent studies have indicated that graduates appear well prepared, but although quantifying the level of preparedness, they provide limited understanding of the underlying factors contributing to preparedness. This study aims to more deeply understand the contributing factors leading to assertions of graduate preparedness using focus groups of final year dental students, and semi-structured interviews of senior faculty members. Materials and methods: Three UK dental schools were visited in order to conduct both study elements. Focus groups and semi-structured interviews were audio recorded and fully transcribed. Thematic analysis of the transcripts resulted in the production of a thematic matrix. Results: The major categories of the thematic matrix were classified as extrinsic; including the role of educators and features of the course, and intrinsic; relating to fear of the unknown, the development of adult learning abilities and less easily identifiable attributes in the development of competence, which became known as 'bricks and mortar'. Discussion: Students felt that the most important factor affecting their preparation was clinical exposure. Outreach placements were felt to be particularly useful, the simulation of general dental practice being highly valued by final year students. The interaction with educators was also felt to be a key influence on preparedness, with the involvement of general practitioners in dental school teaching felt to be helpful, perhaps giving students an extended exposure to general practice. Conclusion: It is hoped that the rich data derived from this study may allow an invaluable insight into factors contributing to preparedness of new dental graduates, which may then be considered in the light of any proposed changes in the curricula or syllabi.

How prepared are foundation dentists in England and Wales for independent general dental practice?

Introduction The Graduate Assessment of Preparedness for Practice (GAPP) questionnaire has been shown to be valid and reliable in assessing the preparedness of foundation dentists (FDs) for independent general dental practice (GDP). In this study it is used to establish preparedness at six weeks of dental foundation training (DFT) across England and Wales.Method GAPP questionnaires were sent to all FDs and ESs in England and Wales in mid-September 2012. Part 1 of the GAPP questionnaire collected the descriptive data of respondents. Part 2 comprised 34 'competence areas' designed to reflect the breadth of Preparing for Practice allowing respondents a 7-category Likert style response. Part 3 comprised open questions designed to allow respondents to expand on their views. Quantitative categorical data from Part 2 was analysed using IBM SPSS (version 20). Median scores were analysed and mean rank scores were generated in order to compare FD and ES responses. Part 2 results were cross-tabulated with the Part 1 descriptors and analysed using the Mann Whitney U and Kruskal Wallis H non-parametric tests. Mean rank scores were considered to be statistically significant if P ≤0.05. Part 3 data was analysed thematically using NVivo (version 10).Results FDs and ESs felt that FDs were generally well prepared for independent GDP, although FDs rated their preparedness significantly higher than ESs in all areas. FDs who graduated from 4-year courses felt significantly more prepared across most of the curriculum than those from 5-year courses, and graduates from outside the UK felt less prepared for GDP than those from a UK school.Conclusions FDs appear to be well prepared for independent GDP at six weeks of DFT. FDs rated their preparedness significantly higher than ESs across the curriculum. Coupled with the finding that the more experienced ESs felt their FDs were less well prepared, that may indicate FDs potentially overstate their level of preparedness. FDs who completed 4-year courses were generally more prepared across a range of curricular areas, some of which may reflect differences in the courses they completed, while others may relate to the individual being a graduate on entry to the course. Distribution of questionnaires through DFT schemes has resulted in a large number of respondents which may allow valuable generalisations to be made about the preparedness of graduates entering DFT in the UK.

Effects of Sildenafil and Tadalafil on Edema and Reactive Oxygen Species Production in an Experimental Model of Lung Ischemia-Reperfusion Injury.

BACKGROUND: Lung ischemia-reperfusion injury is characterized by formation of reactive oxygen species and cellular swelling leading to pulmonary edema and primary graft dysfunction. Phosphodiesterase 5 inhibitors could ameliorate lung ischemia-reperfusion injury by interfering in many molecular pathways. The aim of this work was to evaluate and compare the effects of sildenafil and tadalafil on edema and reactive oxygen species formation in an ex vivo nonhuman animal model of lung ischemia-reperfusion injury. METHODS: Thirty-two Wistar rats were distributed, treated, perfused and the cardiopulmonary blocks were managed as follows: control group: immediate excision and reperfusion without pretreatment; ischemia reperfusion group: treatment with dimethylsulfoxide 0.9% and excision 1 hour later; sildenafil group: treatment with sildenafil (0.7 mg/kg) and excision 1 hour later; and tadalafil group: treatment with tadalafil (0.15 mg/kg) and excision 2 hours later. All cardiopulmonary blocks except control group were preserved for 8 hours and then reperfused. Pulmonary arterial pressure, pulmonary venous pressure, and capillary filtration coefficient were measured. Reactive oxygen species were measured. RESULTS: Edema was similar between control and sildenafil groups, but significantly greater in the ischemia-reperfusion (P ≤ .04) and tadalafil (P ≤ .003) groups compared with the sildenafil group. The malondialdehyde levels were significantly lower in the sildenafil (P ≤ .001) and tadalafil (P ≤ .001) groups than the ischemia-reperfusion group. CONCLUSIONS: Administration of sildenafil, but not tadalafil, decreased edema in lung ischemia-reperfusion injury. Both drugs decreased reactive oxygen species formation in a lung ischemia-reperfusion injury model.

Long-term satellite tracking reveals variable seasonal migration strategies of basking sharks in the north-east Atlantic.

Animal migration is ubiquitous in nature with individuals within a population often exhibiting varying movement strategies. The basking shark (Cetorhinus maximus) is the world's second largest fish species, however, a comprehensive understanding of their long-term wider-ranging movements in the north-east Atlantic is currently lacking. Seventy satellite tags were deployed on basking sharks over four years (2012-2015) off the west coast of Scotland and the Isle of Man. Data from 28 satellite tags with attachment durations of over 165 days reveal post-summer ranging behaviours. Tagged sharks moved a median minimum straight-line distance of 3,633 km; achieving median displacement of 1,057 km from tagging locations. Tagged individuals exhibited one of three migration behaviours: remaining in waters of UK, Ireland and the Faroe Islands; migrating south to the Bay of Biscay or moving further south to waters off the Iberian Peninsula, and North Africa. Sharks used both continental shelf areas and oceanic habitats, primarily in the upper 50-200 m of the water column, spanning nine geo-political zones and the High Seas, demonstrating the need for multi-national cooperation in the management of this species across its range.

Rehabilitation Enablement in Chronic Heart Failure-a facilitated self-care rehabilitation intervention in patients with heart failure with preserved ejection fraction (REACH-HFpEF) and their caregivers: rationale and protocol for a single-centre pilot randomised controlled trial.

INTRODUCTION: The Rehabilitation EnAblement in CHronic Heart Failure in patients with Heart Failure (HF) with preserved ejection fraction (REACH-HFpEF) pilot trial is part of a research programme designed to develop and evaluate a facilitated, home-based, self-help rehabilitation intervention to improve self-care and quality of life (QoL) in heart failure patients and their caregivers. We will assess the feasibility of a definitive trial of the REACH-HF intervention in patients with HFpEF and their caregivers. The impact of the REACH-HF intervention on echocardiographic outcomes and bloodborne biomarkers will also be assessed. METHODS AND ANALYSIS: A single-centre parallel two-group randomised controlled trial (RCT) with 1:1 individual allocation to the REACH-HF intervention plus usual care (intervention) or usual care alone (control) in 50 HFpEF patients and their caregivers. The REACH-HF intervention comprises a REACH-HF manual with supplementary tools, delivered by trained facilitators over 12 weeks. A mixed methods approach will be used to assess estimation of recruitment and retention rates; fidelity of REACH-HF manual delivery; identification of barriers to participation and adherence to the intervention and study protocol; feasibility of data collection and outcome burden. We will assess the variance in study outcomes to inform a definitive study sample size and assess methods for the collection of resource use and intervention delivery cost data to develop the cost-effectiveness analyses framework for any future trial. Patient outcomes collected at baseline, 4 and 6 months include QoL, psychological well-being, exercise capacity, physical activity and HF-related hospitalisation. Caregiver outcomes will also be assessed, and a substudy will evaluate impact of the REACH-HF manual on resting global cardiovascular function and bloodborne biomarkers in HFpEF patients. ETHICS AND DISSEMINATION: The study is approved by the East of Scotland Research Ethics Service (Ref: 15/ES/0036). Findings will be disseminated via journals and presentations to clinicians, commissioners and service users. TRIAL REGISTRATION NUMBER: ISRCTN78539530; Pre-results .

The development and piloting of the graduate assessment of preparedness for practice (GAPP) questionnaire.

Introduction Most new dental graduates in the UK begin their professional career following a year in dental foundation training (DFT). There has been little investigation of how prepared they feel for independent general dental practice across all four domains of the General Dental Council's curriculum 'Preparing for practice'. This paper describes the development of the Graduate Assessment of Preparedness for Practice (GAPP) questionnaire to address this.Methodology The GAPP questionnaire was developed and piloted using a cohort of educational supervisors (ESs) and foundation dentists (FDs). The questionnaire comprised three parts, the first of which collected respondent demographic data. The second was based on Preparing for practice and was used to develop 34 'competence areas' and required a tick-box response on a 7-category Likert Scale. The third comprised free text questions in order to further explore the subject's responses.Results Pilot feedback was positive, the statements were felt to be clear and unambiguous, allowing them sufficient scope to state their position. The pilot study informed small cosmetic changes to the GAPP questionnaire and inclusion of a 'comments' column for respondents to qualify their responses. The pilot results indicated that both FDs and their ESs felt that at ten months of DFT, the FDs were very well prepared for independent general dental practice.Discussion The paper describes the important considerations relating to the reliability and validity of the GAPP questionnaire.Conclusions GAPP appears to be a suitable questionnaire to measure preparedness of new graduates with a degree of reliability and validity. The instrument is designed to be simple to complete and provides a useful analytical instrument for both self-assessment of competence and for wider use within dental education.

Lyophilized allografts without pre-treatment with glutaraldehyde are more suitable than cryopreserved allografts for pulmonary artery reconstruction.

Various methods are available for preservation of vascular grafts for pulmonary artery (PA) replacement. Lyophilization and cryopreservation reduce antigenicity and prevent thrombosis and calcification in vascular grafts, so both methods can be used to obtain vascular bioprostheses. We evaluated the hemodynamic, gasometric, imaging, and macroscopic and microscopic findings produced by PA reconstruction with lyophilized (LyoPA) grafts and cryopreserved (CryoPA) grafts in dogs. Eighteen healthy crossbred adult dogs of both sexes weighing between 18 and 20 kg were used and divided into three groups of six: group I, PA section and reanastomosis; group II, PA resection and reconstruction with LyoPA allograft; group III, PA resection and reconstruction with CryoPA allograft. Dogs were evaluated 4 weeks after surgery, and the status of the graft and vascular anastomosis were examined macroscopically and microscopically. No clinical, radiologic, or blood-gas abnormalities were observed during the study. The mean pulmonary artery pressure (MPAP) in group III increased significantly at the end of the study compared with baseline (P=0.02) and final [P=0.007, two-way repeat-measures analysis of variance (RM ANOVA)] values. Pulmonary vascular resistance of groups II and III increased immediately after reperfusion and also at the end of the study compared to baseline. The increase shown by group III vs group I was significant only if compared with after surgery and study end (P=0.016 and P=0.005, respectively, two-way RM ANOVA). Microscopically, permeability was reduced by ≤75% in group III. In conclusion, substitution of PAs with LyoPA grafts is technically feasible and clinically promising.

Lyophilized allografts without pre-treatment with glutaraldehyde are more suitable than cryopreserved allografts for pulmonary artery reconstruction

Various methods are available for preservation of vascular grafts for pulmonary artery (PA) replacement. Lyophilization and cryopreservation reduce antigenicity and prevent thrombosis and calcification in vascular grafts, so both methods can be used to obtain vascular bioprostheses. We evaluated the hemodynamic, gasometric, imaging, and macroscopic and microscopic findings produced by PA reconstruction with lyophilized (LyoPA) grafts and cryopreserved (CryoPA) grafts in dogs. Eighteen healthy crossbred adult dogs of both sexes weighing between 18 and 20 kg were used and divided into three groups of six: group I, PA section and reanastomosis; group II, PA resection and reconstruction with LyoPA allograft; group III, PA resection and reconstruction with CryoPA allograft. Dogs were evaluated 4 weeks after surgery, and the status of the graft and vascular anastomosis were examined macroscopically and microscopically. No clinical, radiologic, or blood-gas abnormalities were observed during the study. The mean pulmonary artery pressure (MPAP) in group III increased significantly at the end of the study compared with baseline (P=0.02) and final [P=0.007, two-way repeat-measures analysis of variance (RM ANOVA)] values. Pulmonary vascular resistance of groups II and III increased immediately after reperfusion and also at the end of the study compared to baseline. The increase shown by group III vs group I was significant only if compared with after surgery and study end (P=0.016 and P=0.005, respectively, two-way RM ANOVA). Microscopically, permeability was reduced by ≤75% in group III. In conclusion, substitution of PAs with LyoPA grafts is technically feasible and clinically promising.

Clinical effectiveness and cost-effectiveness of the Rehabilitation Enablement in Chronic Heart Failure (REACH-HF) facilitated self-care rehabilitation intervention in heart failure patients and caregivers: rationale and protocol for a multicentre randomised controlled trial.

INTRODUCTION: The Rehabilitation EnAblement in CHronic Heart Failure (REACH-HF) trial is part of a research programme designed to develop and evaluate a health professional facilitated, home-based, self-help rehabilitation intervention to improve self-care and health-related quality of life in people with heart failure and their caregivers. The trial will assess the clinical effectiveness and cost-effectiveness of the REACH-HF intervention in patients with systolic heart failure and impact on the outcomes of their caregivers. METHODS AND ANALYSIS: A parallel two group randomised controlled trial with 1:1 individual allocation to the REACH-HF intervention plus usual care (intervention group) or usual care alone (control group) in 216 patients with systolic heart failure (ejection fraction <45%) and their caregivers. The intervention comprises a self-help manual delivered by specially trained facilitators over a 12-week period. The primary outcome measure is patients' disease-specific health-related quality of life measured using the Minnesota Living with Heart Failure questionnaire at 12 months' follow-up. Secondary outcomes include survival and heart failure related hospitalisation, blood biomarkers, psychological well-being, exercise capacity, physical activity, other measures of quality of life, patient safety and the quality of life, psychological well-being and perceived burden of caregivers at 4, 6 and 12 months' follow-up. A process evaluation will assess fidelity of intervention delivery and explore potential mediators and moderators of changes in health-related quality of life in intervention and control group patients. Qualitative studies will describe patient and caregiver experiences of the intervention. An economic evaluation will estimate the cost-effectiveness of the REACH-HF intervention plus usual care versus usual care alone in patients with systolic heart failure. ETHICS AND DISSEMINATION: The study is approved by the North West-Lancaster Research Ethics Committee (ref 14/NW/1351). Findings will be disseminated via journals and presentations to publicise the research to clinicians, commissioners and service users. TRIAL REGISTRATION NUMBER: ISRCTN86234930; Pre-results.

Exercise-based cardiac rehabilitation after heart valve surgery: cost analysis of healthcare use and sick leave.

BACKGROUND: Owing to a lack of evidence, patients undergoing heart valve surgery have been offered exercise-based cardiac rehabilitation (CR) since 2009 based on recommendations for patients with ischaemic heart disease in Denmark. The aim of this study was to investigate the impact of CR on the costs of healthcare use and sick leave among heart valve surgery patients over 12 months post surgery. METHODS: We conducted a nationwide survey on the CR participation of all patients having undergone valve surgery between 1 January 2011 and 30 June 2011 (n=667). Among the responders (n=500, 75%), the resource use categories of primary and secondary healthcare, prescription medication and sick leave were analysed for CR participants (n=277) and non-participants (n=223) over 12 months. A difference-in-difference analysis was undertaken. All estimates were presented as the means per patient (95% CI) based on non-parametric bootstrapping of SEs. RESULTS: Total costs during the 12 months following surgery were €16 065 per patient (95% CI 13 730 to 18 399) in the CR group and €15 182 (12 695 to 17 670) in the non-CR group. CR led to 5.6 (2.9 to 8.3, p<0.01) more outpatient visits per patient. No statistically significant differences in other cost categories or total costs €1330 (-4427 to 7086, p=0.65) were found between the groups. CONCLUSIONS: CR, as provided in Denmark, can be considered cost neutral. CR is associated with more outpatient visits, but CR participation potentially offsets more expensive outpatient visits. Further studies should investigate the benefits of CR to heart valve surgery patients as part of a formal cost-utility analysis.

Designing environmental research for impact.

Transdisciplinary research, involving close collaboration between researchers and the users of research, has been a feature of environmental problem solving for several decades, often spurred by the need to find negotiated outcomes to intractable problems. In 2005, the Australian government allocated funding to its environment portfolio for public good research, which resulted in consecutive four-year programmes (Commonwealth Environmental Research Facilities, National Environmental Research Program). In April 2014, representatives of the funders, researchers and research users associated with these programmes met to reflect on eight years of experience with these collaborative research models. This structured reflection concluded that successful multi-institutional transdisciplinary research is necessarily a joint enterprise between funding agencies, researchers and the end users of research. The design and governance of research programmes need to explicitly recognise shared accountabilities among the participants, while respecting the different perspectives of each group. Experience shows that traditional incentive systems for academic researchers, current trends in public sector management, and loose organisation of many end users, work against sustained transdisciplinary research on intractable problems, which require continuity and adaptive learning by all three parties. The likelihood of research influencing and improving environmental policy and management is maximised when researchers, funders and research users have shared goals; there is sufficient continuity of personnel to build trust and sustain dialogue throughout the research process from issue scoping to application of findings; and there is sufficient flexibility in the funding, structure and operation of transdisciplinary research initiatives to enable the enterprise to assimilate and respond to new knowledge and situations.

Effects of metal ions and hydrogen peroxide on the phenotype of yeast hom6Δ mutant.

UNLABELLED: HOM6 is a major gene in the aspartate pathway which leads to biosynthesis of threonine and methionine. The phenotypes of the gene deletion mutant (hom6∆) in a variety of cultural conditions have previously provided meaningful insights into the biological roles of HOM6 and its upstream intermediate metabolites. Here, we conducted a survey on a spectrum of metal ions for their effect on the aspartate pathway and broader sulphur metabolism. We show that manganese (Mn(2+) ) promoted the growth of hom6∆ under both anaerobic and aerobic conditions. Unexpectedly, 4 mmol l(-1) hydrogen peroxide (H2 O2 ), a dose normally causing temporary cell growth arrest, enhanced the growth of hom6∆ under the anaerobic condition only, while it had no effect on the wild type strain BY4743. We propose that Mn(2+) and H2 O2 promote the growth of hom6∆ by reducing the accumulation of the toxic intermediate metabolite-aspartate ß-semialdehyde, via directing the aspartate pathway to the central sugar metabolism-tricarboxylic acid cycle. SIGNIFICANCE AND IMPACT OF THE STUDY: This study focuses on the yeast strain which lacks homoserine dehydrogenase encoded by HOM6 gene in aspartate metabolism. The HOM6-deletion mutant (hom6Δ) was analysed in the context of varying environmental parameters such as metal ions and oxidants, under anaerobic and aerobic conditions. We demonstrated that both manganese and hydrogen peroxide can promote the growth of hom6Δ, with the latter exerting such effect only under anaerobic condition. The findings are relevant to the research areas of ageing and anti-fungal drug development. It highlights the importance of interactions between gene expression and environmental factors as well as culture conditions.

Transcriptomic and biochemical evidence for the role of lysine biosynthesis against linoleic acid hydroperoxide-induced stress in Saccharomyces cerevisiae.

Amino acid biosynthesis forms part of an integrated stress response against oxidants in Saccharomyces cerevisiae and higher eukaryotes. Here we show an essential protective role of the l-lysine biosynthesis pathway in response to the oxidative stress condition induced by the lipid oxidant-linoleic acid hydroperoxide (LoaOOH), by means of transcriptomic profiling and phenotypic analysis, and using the deletion mutant dal80∆ and lysine auxotroph lys1∆. A comprehensive up-regulation of lysine biosynthetic genes (LYS1, LYS2, LYS4, LYS9, LYS12, LYS20 and LYS21) was revealed in dal80Δ following the oxidant challenge. The lysine auxotroph (lys1∆) exhibited a significant decrease in growth compared with that of BY4743 upon exposure to LoaOOH, albeit with the sufficient provision of lysine in the medium. Furthermore, the growth of wild type BY4743 exposed to LoaOOH was also greatly reduced in lysine-deficient conditions, despite a full complement of lysine biosynthetic genes. Amino acid analysis of LoaOOH-treated yeast showed that the level of cellular lysine remained unchanged throughout oxidant challenge, suggesting that the induced lysine biosynthesis leads to a steady-state metabolism as compared to the untreated yeast cells. Together, these findings demonstrate that lysine availability and its biosynthesis pathway play an important role in protecting the cell from lipid peroxide-induced oxidative stress, which is directly related to understanding environmental stress and industrial yeast management in brewing, wine making and baking.