Deakin University

BACKGROUND: The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. METHODS: We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors-the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). FINDINGS: Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6-58·8) of global deaths and 41·2% (39·8-42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. INTERPRETATION: Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. FUNDING: Bill & Melinda Gates Foundation.

OBJECTIVE: To update and expand the 2013 Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the ICU. DESIGN: Thirty-two international experts, four methodologists, and four critical illness survivors met virtually at least monthly. All section groups gathered face-to-face at annual Society of Critical Care Medicine congresses; virtual connections included those unable to attend. A formal conflict of interest policy was developed a priori and enforced throughout the process. Teleconferences and electronic discussions among subgroups and whole panel were part of the guidelines' development. A general content review was completed face-to-face by all panel members in January 2017. METHODS: Content experts, methodologists, and ICU survivors were represented in each of the five sections of the guidelines: Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption). Each section created Population, Intervention, Comparison, and Outcome, and nonactionable, descriptive questions based on perceived clinical relevance. The guideline group then voted their ranking, and patients prioritized their importance. For each Population, Intervention, Comparison, and Outcome question, sections searched the best available evidence, determined its quality, and formulated recommendations as "strong," "conditional," or "good" practice statements based on Grading of Recommendations Assessment, Development and Evaluation principles. In addition, evidence gaps and clinical caveats were explicitly identified. RESULTS: The Pain, Agitation/Sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) panel issued 37 recommendations (three strong and 34 conditional), two good practice statements, and 32 ungraded, nonactionable statements. Three questions from the patient-centered prioritized question list remained without recommendation. CONCLUSIONS: We found substantial agreement among a large, interdisciplinary cohort of international experts regarding evidence supporting recommendations, and the remaining literature gaps in the assessment, prevention, and treatment of Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) in critically ill adults. Highlighting this evidence and the research needs will improve Pain, Agitation/sedation, Delirium, Immobility (mobilization/rehabilitation), and Sleep (disruption) management and provide the foundation for improved outcomes and science in this vulnerable population.

BACKGROUND: The burden of cardiovascular diseases (CVDs) remains unclear in many regions of the world. OBJECTIVES: The GBD (Global Burden of Disease) 2015 study integrated data on disease incidence, prevalence, and mortality to produce consistent, up-to-date estimates for cardiovascular burden. METHODS: CVD mortality was estimated from vital registration and verbal autopsy data. CVD prevalence was estimated using modeling software and data from health surveys, prospective cohorts, health system administrative data, and registries. Years lived with disability (YLD) were estimated by multiplying prevalence by disability weights. Years of life lost (YLL) were estimated by multiplying age-specific CVD deaths by a reference life expectancy. A sociodemographic index (SDI) was created for each location based on income per capita, educational attainment, and fertility. RESULTS: In 2015, there were an estimated 422.7 million cases of CVD (95% uncertainty interval: 415.53 to 427.87 million cases) and 17.92 million CVD deaths (95% uncertainty interval: 17.59 to 18.28 million CVD deaths). Declines in the age-standardized CVD death rate occurred between 1990 and 2015 in all high-income and some middle-income countries. Ischemic heart disease was the leading cause of CVD health lost globally, as well as in each world region, followed by stroke. As SDI increased beyond 0.25, the highest CVD mortality shifted from women to men. CVD mortality decreased sharply for both sexes in countries with an SDI >0.75. CONCLUSIONS: CVDs remain a major cause of health loss for all regions of the world. Sociodemographic change over the past 25 years has been associated with dramatic declines in CVD in regions with very high SDI, but only a gradual decrease or no change in most regions. Future updates of the GBD study can be used to guide policymakers who are focused on reducing the overall burden of noncommunicable disease and achieving specific global health targets for CVD.

Promotion of good mental health, prevention, and early intervention before/at the onset of mental disorders improve outcomes. However, the range and peak ages at onset for mental disorders are not fully established. To provide robust, global epidemiological estimates of age at onset for mental disorders, we conducted a PRISMA/MOOSE-compliant systematic review with meta-analysis of birth cohort/cross-sectional/cohort studies, representative of the general population, reporting age at onset for any ICD/DSM-mental disorders, identified in PubMed/Web of Science (up to 16/05/2020) (PROSPERO:CRD42019143015). Co-primary outcomes were the proportion of individuals with onset of mental disorders before age 14, 18, 25, and peak age at onset, for any mental disorder and across International Classification of Diseases 11 diagnostic blocks. Median age at onset of specific disorders was additionally investigated. Across 192 studies (n = 708,561) included, the proportion of individuals with onset of any mental disorders before the ages of 14, 18, 25 were 34.6%, 48.4%, 62.5%, and peak age was 14.5 years (k = 14, median = 18, interquartile range (IQR) = 11-34). For diagnostic blocks, the proportion of individuals with onset of disorder before the age of 14, 18, 25 and peak age were as follows: neurodevelopmental disorders: 61.5%, 83.2%, 95.8%, 5.5 years (k = 21, median=12, IQR = 7-16), anxiety/fear-related disorders: 38.1%, 51.8%, 73.3%, 5.5 years (k = 73, median = 17, IQR = 9-25), obsessive-compulsive/related disorders: 24.6%, 45.1%, 64.0%, 14.5 years (k = 20, median = 19, IQR = 14-29), feeding/eating disorders/problems: 15.8%, 48.1%, 82.4%, 15.5 years (k = 11, median = 18, IQR = 15-23), conditions specifically associated with stress disorders: 16.9%, 27.6%, 43.1%, 15.5 years (k = 16, median = 30, IQR = 17-48), substance use disorders/addictive behaviours: 2.9%, 15.2%, 48.8%, 19.5 years (k = 58, median = 25, IQR = 20-41), schizophrenia-spectrum disorders/primary psychotic states: 3%, 12.3%, 47.8%, 20.5 years (k = 36, median = 25, IQR = 20-34), personality disorders/related traits: 1.9%, 9.6%, 47.7%, 20.5 years (k = 6, median = 25, IQR = 20-33), and mood disorders: 2.5%, 11.5%, 34.5%, 20.5 years (k = 79, median = 31, IQR = 21-46). No significant difference emerged by sex, or definition of age of onset. Median age at onset for specific mental disorders mapped on a time continuum, from phobias/separation anxiety/autism spectrum disorder/attention deficit hyperactivity disorder/social anxiety (8-13 years) to anorexia nervosa/bulimia nervosa/obsessive-compulsive/binge eating/cannabis use disorders (17-22 years), followed by schizophrenia, personality, panic and alcohol use disorders (25-27 years), and finally post-traumatic/depressive/generalized anxiety/bipolar/acute and transient psychotic disorders (30-35 years), with overlap among groups and no significant clustering. These results inform the timing of good mental health promotion/preventive/early intervention, updating the current mental health system structured around a child/adult service schism at age 18.

Large carnivores face serious threats and are experiencing massive declines in their populations and geographic ranges around the world. We highlight how these threats have affected the conservation status and ecological functioning of the 31 largest mammalian carnivores on Earth. Consistent with theory, empirical studies increasingly show that large carnivores have substantial effects on the structure and function of diverse ecosystems. Significant cascading trophic interactions, mediated by their prey or sympatric mesopredators, arise when some of these carnivores are extirpated from or repatriated to ecosystems. Unexpected effects of trophic cascades on various taxa and processes include changes to bird, mammal, invertebrate, and herpetofauna abundance or richness; subsidies to scavengers; altered disease dynamics; carbon sequestration; modified stream morphology; and crop damage. Promoting tolerance and coexistence with large carnivores is a crucial societal challenge that will ultimately determine the fate of Earth's largest carnivores and all that depends upon them, including humans.

BACKGROUND: Many causes of vision impairment can be prevented or treated. With an ageing global population, the demands for eye health services are increasing. We estimated the prevalence and relative contribution of avoidable causes of blindness and vision impairment globally from 1990 to 2020. We aimed to compare the results with the World Health Assembly Global Action Plan (WHA GAP) target of a 25% global reduction from 2010 to 2019 in avoidable vision impairment, defined as cataract and undercorrected refractive error. METHODS: We did a systematic review and meta-analysis of population-based surveys of eye disease from January, 1980, to October, 2018. We fitted hierarchical models to estimate prevalence (with 95% uncertainty intervals [UIs]) of moderate and severe vision impairment (MSVI; presenting visual acuity from <6/18 to 3/60) and blindness (<3/60 or less than 10° visual field around central fixation) by cause, age, region, and year. Because of data sparsity at younger ages, our analysis focused on adults aged 50 years and older. FINDINGS: Global crude prevalence of avoidable vision impairment and blindness in adults aged 50 years and older did not change between 2010 and 2019 (percentage change -0·2% [95% UI -1·5 to 1·0]; 2019 prevalence 9·58 cases per 1000 people [95% IU 8·51 to 10·8], 2010 prevalence 96·0 cases per 1000 people [86·0 to 107·0]). Age-standardised prevalence of avoidable blindness decreased by -15·4% [-16·8 to -14·3], while avoidable MSVI showed no change (0·5% [-0·8 to 1·6]). However, the number of cases increased for both avoidable blindness (10·8% [8·9 to 12·4]) and MSVI (31·5% [30·0 to 33·1]). The leading global causes of blindness in those aged 50 years and older in 2020 were cataract (15·2 million cases [9% IU 12·7-18·0]), followed by glaucoma (3·6 million cases [2·8-4·4]), undercorrected refractive error (2·3 million cases [1·8-2·8]), age-related macular degeneration (1·8 million cases [1·3-2·4]), and diabetic retinopathy (0·86 million cases [0·59-1·23]). Leading causes of MSVI were undercorrected refractive error (86·1 million cases [74·2-101·0]) and cataract (78·8 million cases [67·2-91·4]). INTERPRETATION: Results suggest eye care services contributed to the observed reduction of age-standardised rates of avoidable blindness but not of MSVI, and that the target in an ageing global population was not reached. FUNDING: Brien Holden Vision Institute, Fondation Théa, The Fred Hollows Foundation, Bill & Melinda Gates Foundation, Lions Clubs International Foundation, Sightsavers International, and University of Heidelberg.

<h3>Importance</h3> Cancer and other noncommunicable diseases (NCDs) are now widely recognized as a threat to global development. The latest United Nations high-level meeting on NCDs reaffirmed this observation and also highlighted the slow progress in meeting the 2011 Political Declaration on the Prevention and Control of Noncommunicable Diseases and the third Sustainable Development Goal. Lack of situational analyses, priority setting, and budgeting have been identified as major obstacles in achieving these goals. All of these have in common that they require information on the local cancer epidemiology. The Global Burden of Disease (GBD) study is uniquely poised to provide these crucial data. <h3>Objective</h3> To describe cancer burden for 29 cancer groups in 195 countries from 1990 through 2017 to provide data needed for cancer control planning. <h3>Evidence Review</h3> We used the GBD study estimation methods to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life-years (DALYs). Results are presented at the national level as well as by Socio-demographic Index (SDI), a composite indicator of income, educational attainment, and total fertility rate. We also analyzed the influence of the epidemiological vs the demographic transition on cancer incidence. <h3>Findings</h3> In 2017, there were 24.5 million incident cancer cases worldwide (16.8 million without nonmelanoma skin cancer [NMSC]) and 9.6 million cancer deaths. The majority of cancer DALYs came from years of life lost (97%), and only 3% came from years lived with disability. The odds of developing cancer were the lowest in the low SDI quintile (1 in 7) and the highest in the high SDI quintile (1 in 2) for both sexes. In 2017, the most common incident cancers in men were NMSC (4.3 million incident cases); tracheal, bronchus, and lung (TBL) cancer (1.5 million incident cases); and prostate cancer (1.3 million incident cases). The most common causes of cancer deaths and DALYs for men were TBL cancer (1.3 million deaths and 28.4 million DALYs), liver cancer (572 000 deaths and 15.2 million DALYs), and stomach cancer (542 000 deaths and 12.2 million DALYs). For women in 2017, the most common incident cancers were NMSC (3.3 million incident cases), breast cancer (1.9 million incident cases), and colorectal cancer (819 000 incident cases). The leading causes of cancer deaths and DALYs for women were breast cancer (601 000 deaths and 17.4 million DALYs), TBL cancer (596 000 deaths and 12.6 million DALYs), and colorectal cancer (414 000 deaths and 8.3 million DALYs). <h3>Conclusions and Relevance</h3> The national epidemiological profiles of cancer burden in the GBD study show large heterogeneities, which are a reflection of different exposures to risk factors, economic settings, lifestyles, and access to care and screening. The GBD study can be used by policy makers and other stakeholders to develop and improve national and local cancer control in order to achieve the global targets and improve equity in cancer care.

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Despite a growing body of epidemiological evidence in recent years documenting the health impacts of racism, the cumulative evidence base has yet to be synthesized in a comprehensive meta-analysis focused specifically on racism as a determinant of health. This meta-analysis reviewed the literature focusing on the relationship between reported racism and mental and physical health outcomes. Data from 293 studies reported in 333 articles published between 1983 and 2013, and conducted predominately in the U.S., were analysed using random effects models and mean weighted effect sizes. Racism was associated with poorer mental health (negative mental health: r = -.23, 95% CI [-.24,-.21], k = 227; positive mental health: r = -.13, 95% CI [-.16,-.10], k = 113), including depression, anxiety, psychological stress and various other outcomes. Racism was also associated with poorer general health (r = -.13 (95% CI [-.18,-.09], k = 30), and poorer physical health (r = -.09, 95% CI [-.12,-.06], k = 50). Moderation effects were found for some outcomes with regard to study and exposure characteristics. Effect sizes of racism on mental health were stronger in cross-sectional compared with longitudinal data and in non-representative samples compared with representative samples. Age, sex, birthplace and education level did not moderate the effects of racism on health. Ethnicity significantly moderated the effect of racism on negative mental health and physical health: the association between racism and negative mental health was significantly stronger for Asian American and Latino(a) American participants compared with African American participants, and the association between racism and physical health was significantly stronger for Latino(a) American participants compared with African American participants. Protocol PROSPERO registration number: CRD42013005464.

Uncertainty quantification (UQ) methods play a pivotal role in reducing the impact of uncertainties during both optimization and decision making processes. They have been applied to solve a variety of real-world problems in science and engineering. Bayesian approximation and ensemble learning techniques are two widely-used types of uncertainty quantification (UQ) methods. In this regard, researchers have proposed different UQ methods and examined their performance in a variety of applications such as computer vision (e.g., self-driving cars and object detection), image processing (e.g., image restoration), medical image analysis (e.g., medical image classification and segmentation), natural language processing (e.g., text classification, social media texts and recidivism risk-scoring), bioinformatics, etc. This study reviews recent advances in UQ methods used in deep learning, investigates the application of these methods in reinforcement learning, and highlights fundamental research challenges and directions associated with UQ.

Student feedback literacy denotes the understandings, capacities and dispositions needed to make sense of information and use it to enhance work or learning strategies. In this conceptual paper, student responses to feedback are reviewed and a number of barriers to student uptake of feedback are discussed. Four inter-related features are proposed as a framework underpinning students’ feedback literacy: appreciating feedback; making judgments; managing affect; and taking action. Two well-established learning activities, peer feedback and analysing exemplars, are discussed to illustrate how this framework can be operationalized. Some ways in which these two enabling activities can be re-focused more explicitly towards developing students’ feedback literacy are elaborated. Teachers are identified as playing important facilitating roles in promoting student feedback literacy through curriculum design, guidance and coaching. The implications and conclusion summarise recommendations for teaching and set out an agenda for further research

IMPORTANCE: The Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019) provided systematic estimates of incidence, morbidity, and mortality to inform local and international efforts toward reducing cancer burden. OBJECTIVE: To estimate cancer burden and trends globally for 204 countries and territories and by Sociodemographic Index (SDI) quintiles from 2010 to 2019. EVIDENCE REVIEW: The GBD 2019 estimation methods were used to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life years (DALYs) in 2019 and over the past decade. Estimates are also provided by quintiles of the SDI, a composite measure of educational attainment, income per capita, and total fertility rate for those younger than 25 years. Estimates include 95% uncertainty intervals (UIs). FINDINGS: In 2019, there were an estimated 23.6 million (95% UI, 22.2-24.9 million) new cancer cases (17.2 million when excluding nonmelanoma skin cancer) and 10.0 million (95% UI, 9.36-10.6 million) cancer deaths globally, with an estimated 250 million (235-264 million) DALYs due to cancer. Since 2010, these represented a 26.3% (95% UI, 20.3%-32.3%) increase in new cases, a 20.9% (95% UI, 14.2%-27.6%) increase in deaths, and a 16.0% (95% UI, 9.3%-22.8%) increase in DALYs. Among 22 groups of diseases and injuries in the GBD 2019 study, cancer was second only to cardiovascular diseases for the number of deaths, years of life lost, and DALYs globally in 2019. Cancer burden differed across SDI quintiles. The proportion of years lived with disability that contributed to DALYs increased with SDI, ranging from 1.4% (1.1%-1.8%) in the low SDI quintile to 5.7% (4.2%-7.1%) in the high SDI quintile. While the high SDI quintile had the highest number of new cases in 2019, the middle SDI quintile had the highest number of cancer deaths and DALYs. From 2010 to 2019, the largest percentage increase in the numbers of cases and deaths occurred in the low and low-middle SDI quintiles. CONCLUSIONS AND RELEVANCE: The results of this systematic analysis suggest that the global burden of cancer is substantial and growing, with burden differing by SDI. These results provide comprehensive and comparable estimates that can potentially inform efforts toward equitable cancer control around the world.

Diet, nutrition and the prevention of chronic diseases

Urbanization and climate change are together exacerbating water scarcity-where water demand exceeds availability-for the world's cities. We quantify global urban water scarcity in 2016 and 2050 under four socioeconomic and climate change scenarios, and explored potential solutions. Here we show the global urban population facing water scarcity is projected to increase from 933 million (one third of global urban population) in 2016 to 1.693-2.373 billion people (one third to nearly half of global urban population) in 2050, with India projected to be most severely affected in terms of growth in water-scarce urban population (increase of 153-422 million people). The number of large cities exposed to water scarcity is projected to increase from 193 to 193-284, including 10-20 megacities. More than two thirds of water-scarce cities can relieve water scarcity by infrastructure investment, but the potentially significant environmental trade-offs associated with large-scale water scarcity solutions must be guarded against.

Ionic liquids offer a unique suite of properties that make them important candidates for a number of energy related applications. Cation–anion combinations that exhibit low volatility coupled with high electrochemical and thermal stability, as well as ionic conductivity, create the possibility of designing ideal electrolytes for batteries, super-capacitors, actuators, dye sensitised solar cells and thermo-electrochemical cells. In the field of water splitting to produce hydrogen they have been used to synthesize some of the best performing water oxidation catalysts and some members of the protic ionic liquid family co-catalyse an unusual, very high energy efficiency water oxidation process. As fuel cell electrolytes, the high proton conductivity of some of the protic ionic liquid family offers the potential of fuel cells operating in the optimum temperature region above 100 °C. Beyond electrochemical applications, the low vapour pressure of these liquids, along with their ability to offer tuneable functionality, also makes them ideal as CO2 absorbents for post-combustion CO2 capture. Similarly, the tuneable phase properties of the many members of this large family of salts are also allowing the creation of phase-change thermal energy storage materials having melting points tuned to the application. This perspective article provides an overview of these developing energy related applications of ionic liquids and offers some thoughts on the emerging challenges and opportunities.

Deep autoencoder has been extensively used for anomaly detection. Training on the normal data, the autoencoder is expected to produce higher reconstruction error for the abnormal inputs than the normal ones, which is adopted as a criterion for identifying anomalies. However, this assumption does not always hold in practice. It has been observed that sometimes the autoencoder "generalizes" so well that it can also reconstruct anomalies well, leading to the miss detection of anomalies. To mitigate this drawback for autoencoder based anomaly detector, we propose to augment the autoencoder with a memory module and develop an improved autoencoder called memory-augmented autoencoder, i.e. MemAE. Given an input, MemAE firstly obtains the encoding from the encoder and then uses it as a query to retrieve the most relevant memory items for reconstruction. At the training stage, the memory contents are updated and are encouraged to represent the prototypical elements of the normal data. At the test stage, the learned memory will be fixed, and the reconstruction is obtained from a few selected memory records of the normal data. The reconstruction will thus tend to be close to a normal sample. Thus the reconstructed errors on anomalies will be strengthened for anomaly detection. MemAE is free of assumptions on the data type and thus general to be applied to different tasks. Experiments on various datasets prove the excellent generalization and high effectiveness of the proposed MemAE.

STUDY QUESTION: What is the recommended assessment and management of women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise and consumer preference? SUMMARY ANSWER: International evidence-based guidelines, including 166 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of women with PCOS. WHAT IS KNOWN ALREADY: Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. Diagnosis of PCOS remains controversial, and assessment and management are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist. STUDY DESIGN, SIZE, DURATION: International evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Appraisal of Guidelines for Research and Evaluation (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength. PARTICIPANTS/MATERIALS, SETTING, METHODS: Governance included a six continent international advisory and a project board, five guideline development groups, and consumer and translation committees. Extensive health professional and consumer engagement informed guideline scope and priorities. Engaged international society-nominated panels included pediatrics, endocrinology, gynecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, public health and other experts, alongside consumers, project management, evidence synthesis and translation experts. In total, 37 societies and organizations covering 71 countries engaged in the process. Twenty face-to-face meetings over 15 months addressed 60 prioritized clinical questions involving 40 systematic and 20 narrative reviews. Evidence-based recommendations were developed and approved via consensus voting within the five guideline panels, modified based on international feedback and peer review, with final recommendations approved across all panels. MAIN RESULTS AND THE ROLE OF CHANCE: The evidence in the assessment and management of PCOS is generally of low to moderate quality. The guideline provides 31 evidence based recommendations, 59 clinical consensus recommendations and 76 clinical practice points all related to assessment and management of PCOS. Key changes in this guideline include: (i) considerable refinement of individual diagnostic criteria with a focus on improving accuracy of diagnosis; (ii) reducing unnecessary testing; (iii) increasing focus on education, lifestyle modification, emotional wellbeing and quality of life; and (iv) emphasizing evidence based medical therapy and cheaper and safer fertility management. LIMITATIONS, REASONS FOR CAUTION: Overall evidence is generally low to moderate quality, requiring significantly greater research in this neglected, yet common condition, especially around refining specific diagnostic features in PCOS. Regional health system variation is acknowledged and a process for guideline and translation resource adaptation is provided. WIDER IMPLICATIONS OF THE FINDINGS: The international guideline for the assessment and management of PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program. STUDY FUNDING/COMPETING INTEREST(S): The guideline was primarily funded by the Australian National Health and Medical Research Council of Australia (NHMRC) supported by a partnership with ESHRE and the American Society for Reproductive Medicine. Guideline development group members did not receive payment. Travel expenses were covered by the sponsoring organizations. Disclosures of conflicts of interest were declared at the outset and updated throughout the guideline process, aligned with NHMRC guideline processes. Full details of conflicts declared across the guideline development groups are available at https://www.monash.edu/medicine/sphpm/mchri/pcos/guideline in the Register of disclosures of interest. Of named authors, Dr Costello has declared shares in Virtus Health and past sponsorship from Merck Serono for conference presentations. Prof. Laven declared grants from Ferring, Euroscreen and personal fees from Ferring, Euroscreen, Danone and Titus Healthcare. Prof. Norman has declared a minor shareholder interest in an IVF unit. The remaining authors have no conflicts of interest to declare. The guideline was peer reviewed by special interest groups across our partner and collaborating societies and consumer organizations, was independently assessed against AGREE-II criteria, and underwent methodological review. This guideline was approved by all members of the guideline development groups and was submitted for final approval by the NHMRC.

Staying at the top is getting tougher and more challenging due to the fast-growing and changing digital technologies and AI-based solutions. The world of technology, mass customization, and advanced manufacturing is experiencing a rapid transformation. Robots are becoming even more important as they can now be coupled with the human mind by means of brain–machine interface and advances in artificial intelligence. A strong necessity to increase productivity while not removing human workers from the manufacturing industry is imposing punishing challenges on the global economy. To counter these challenges, this article introduces the concept of Industry 5.0, where robots are intertwined with the human brain and work as collaborator instead of competitor. This article also outlines a number of key features and concerns that every manufacturer may have about Industry 5.0. In addition, it presents several developments achieved by researchers for use in Industry 5.0 applications and environments. Finally, the impact of Industry 5.0 on the manufacturing industry and overall economy is discussed from an economic and productivity point of view, where it is argued that Industry 5.0 will create more jobs than it will take away.

This paper develops a general service sector model of repurchase intention from the consumer theory literature. A key contribution of the structural equation model is the incorporation of customer perceptions of equity and value and customer brand preference into an integrated repurchase intention analysis. The model describes the extent to which customer repurchase intention is influenced by seven important factors – service quality, equity and value, customer satisfaction, past loyalty, expected switching cost and brand preference. The general model is applied to customers of comprehensive car insurance and personal superannuation services. The analysis finds that although perceived quality does not directly affect customer satisfaction, it does so indirectly via customer equity and value perceptions. The study also finds that past purchase loyalty is not directly related to customer satisfaction or current brand preference and that brand preference is an intervening factor between customer satisfaction and repurchase intention. The main factor influencing brand preference was perceived value with customer satisfaction and expected switching cost having less influence.

This is the fourth in a series of papers describing the burden of cardiovascular disease (CVD) within Europe.1–3 CVD remains the most common cause of death worldwide, with the 2013 Global Burden of Disease (GBD) study estimating that CVD caused 17.3 million deaths globally. It accounted for 31.5% of all deaths and 45% of all non-communicable disease deaths, more than twice that caused by cancer, as well as more than all communicable, maternal, neonatal and nutritional disorders combined. The 2013 GBD also reported that CVD caused a greater number of deaths and was responsible for a greater percentage of all deaths than in 1990 when 12.3 million deaths were attributed to CVD, corresponding to 25.9% of total deaths.4 Previous publications in this series have reported that despite the decreases in CVD mortality in Europe more than 4 million people die from CVD across the continent every year, with more than 1.4 million dying prematurely, before the age of 75 years.1–3 In this article we present an updated overview of the burden of CVD in Europe, including new statistics for mortality, morbidity, and treatment. Where possible we provide statistics for all CVD and for coronary heart disease (CHD) and stroke in particular. All data included here are updated from previous publications and we present prevalence statistics for the first time. This series of publications describing the current burden and distribution of CVD and CHD in Europe has been based on the European Cardiovascular Disease Statistics 2012 report,5 the fourth in a series of Europe-wide compendia, which was published jointly by the European Heart Network and the European Society of Cardiology. Throughout this article, we present statistics from a number of data sources chosen with consideration of data quality, date of most recent update, and coverage of the European region. Rather than collected data from individual countries we utilized major data sources which make their statistics publically available. Specifically, we aimed to obtain data for as many European countries as possible from as recently as possible. In order to present data on CVD throughout Europe, with a particular focus on the two most common forms of CVD: CHD and stroke, we identified international sources that collect and report comparable data for a number of countries. Commonly, such sources are updated through routine and administrative data collections and provide an overview of the burden and distribution of CVD in Europe through the mortality, morbidity, and treatment associated with CVD across the continent. However, these data sources generally rely on individual countries to provide the data they collate, this means that in some cases the data that we obtain from a central source, in order to be consistent and comparable between countries and across Europe, may not be as up to date as could be obtained from some individual countries’ own databases. In this article, we define Europe as the 53 member states of the World Health Organization (WHO) European region. There were no ‘ideal’ data sources that provided complete, up-to-date, high-quality, and representative information for all 53 countries for any topic in this overview and comparability and quality of the data varies by topic. We also present data for EU-15 countries, those in the European Union (EU) prior to the accession of 10 candidate countries on 1 May 2004: Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, the Netherlands, Portugal, Spain, Sweden, UK, and the EU-28 countries which include these 15 countries and the 13 additional countries which have subsequently joined the EU: Bulgaria, Croatia, Cyprus, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Malta, Poland, Romania, Slovakia, Slovenia. Mortality data come from the WHO Mortality Database using the most recent (25 November 2015) update of age- and cause-specific mortality data, and age-specific population data, by country.6 All analyses, interpretations, and conclusions are those of the authors, not the WHO, which is responsible only for the provision of the original information. The WHO database collates data reported by national authorities based on their civil registration systems and contains data for 52 of 53 European countries, with no data available for Andorra. Age-standardized rates can only be calculated where data on the absolute number of an outcome and the population are available in comparable age-specific aggregates. Where rates are presented for the ‘most recent year’, this relates to the most recent data for which both mortality and population data were available. Mortality data for Turkmenistan, for example, are now available for 2013, but the most recent population data come from 1998, hence rates for this country are from the earlier year. For one country (Monaco), although mortality data were available, no population data were. These could not, therefore, be used in the presentation of age-standardized death rates (ASDRs) but were included in the calculations for total number of deaths and premature deaths in Europe. In order to calculate rates, population data from the same database were applied to these mortality data and were standardized using the 2013 European Standard Population (ESP). The 2013 ESP was developed by the European Commission for the EU27 + European Free Trade Association countries as an update to the 1976 ESP, to reflect the current age structure of the present European population.7 On average, when using the same data, CHD ASDRs for European countries calculated using the 2013 ESP are around twice as large as those calculated using the previous (1976) ESP.8 This means that although comparisons can be made within this study between countries in which ASDRs have been calculated using the same 2016 ESP, comparisons cannot be made to other studies, including earlier papers from this series, which have used the 1976 ESP to calculate standardized rates. WHO mortality and population data are relatively up to date, with the most recent data for only 11 of the 52 countries dating from 2010 or before; however, data from five countries were not available for any years more recent than 2005: Albania (2004), San Marino (2005), Tajikistan (2004), Turkmenistan (1998), and Uzbekistan (2005). Mortality rates are presented for CVD and CHD for all ages and for those under the ages of 65 and 75 years separately; deaths before these ages are often described as premature or preventable. Morbidity data come from the WHO9 and the European Social Survey.10 Disability-adjusted life years (DALYs) are available for the entire WHO European Region from the WHO’s Health Statistics and Information Systems11 and allow for a comparison of disease burden between both countries and conditions. One DALY is equivalent to 1 year of healthy life lost and is a composite measure of years of life lost due to death from a condition and years lived with disability due to a condition. The WHO has calculated DALYs for all conditions and all countries using estimates that draw on the methods used by the GBD project.9 Prevalence data come from the European Social Survey.10 This is a European Commission-funded cross-sectional survey that is repeated every 2 years with face-to-face data collection. Using random probability methods, samples are drawn from each participating country and aim to be representative of all people aged 15 and over in that country. Data are only available for selected countries that participated in the 2014 survey. The question relating to CVD prevalence was included in 2014 in the ‘health inequalities’ module and asked people to recall if they had had any health problems listed on a showcard in the last 12 months; with heart or circulation problems as an option. Hospital discharge data come from the WHO European Region’s Health for All Database.12 Data are sourced from the national registries of each country and provide an indication of the burden of CVD on health services within European countries. In addition to discharge data, the average length of stay in hospitals (ALOS) is often regarded as a good indicator of health service efficiency. The Organization for Economic Co-operation and Development (OECD) presents the ALOS as the mean number of days that patients spend in hospital.13 ALOS is generally measured by dividing the total number of days stayed by all patients during a year by cause-specific admissions or discharges. The data cover all inpatient cases with the exception of the Netherlands where data refer to curative acute care only, resulting in an under estimation. The OECD also presents 30-day case-fatality rate as a percentage of people aged 45 and over who die within 30 days following admission to hospital for acute myocardial infarction (AMI) and ischaemic stroke (IS), which represents around 85% of all cerebrovascular disease cases. The OECD presents case fatality through ‘admission-based’ and ‘patient-based’ data.13 Admission-based data refer to deaths occurring in the same hospital as the initial admission. Rates based on patient data refer to a death occurring in the same hospital, a different hospital, or out of hospital. This indicator is more robust because it captures fatalities more comprehensively. More countries can report the same-hospital ‘admission-based’ measure, with ‘patient-based’ data requiring a unique patient identifier and linked data which are not currently available in all countries. Admissions resulting in a transfer were excluded for some countries. This exclusion generally increases the case-fatality rate compared with those countries which do not exclude these transfers.13 Using the latest available data, CVD causes more than 4 million deaths each year across Europe, accounting for 45% of all deaths. CHD and cerebrovascular disease were the most common causes of CVD deaths, accounting for 1.8 million and 1.0 million deaths, respectively. The number of deaths from CVD is higher in women (2.2 million) than men (1.8 million), with CVD accounting for 49% of all deaths in women and 40% of all deaths in men. With similar numbers of men and women dying from CHD, these sex differences arise from a greater number of women dying from cerebrovascular disease and ‘other cardiovascular diseases’ (Table1, Figure1). Proportion of all deaths due to major causes in Europe, latest available year, among men (A) and women (B). Note: No data are available for Andorra. Source: WHO Mortality Database. Number and percentage of deaths from CVDs in Europe—latest available yeara Latest available years for each country are the same as those presented in Table2, except for: Albania (2009), Lithuania (2013), Monaco (1987), Slovakia (2014), Tajikistan (2005), and Turkmenistan (2013). No data are available for Andorra. Source: WHO Mortality Database. Although more than three-fifths of all CVD deaths occur in those over the age of 75 years, 1.4 million people under the age of 75 and just under 700 000 under the age of 65 die from CVD in Europe each year. More men (0.9 million) than women (0.5 million) die from CVD before the age of 75, however due to the greater number of total premature deaths in men CVD accounts for a similar proportion of deaths before 75 years in both sexes. The observed sex differences in number of deaths are greater at younger ages, with more than twice as many men than women dying from CVD under the age of 65. The greatest differences between the sexes in number of premature deaths are found for CHD, despite similar numbers of CHD deaths for all ages in men and women (Table1). Large differences in the burden of CVD between countries in the European Region remain. Of the 3.8 million total deaths in the EU-15 countries, 33% of these were caused by CVD (1.3 million), compared with 38% of deaths in the EU-28 countries (1.9 million) and 54% of deaths in non-EU member countries (2.1 million). In countries of the EU-15, ASDRs for CVD in men, calculated using the 2013 ESP (ESP13), ranged from 275.2/100 000 men in to 000 in and women from 000 women in to 000 in In the additional countries to the EU-15 ASDRs ranged from 000 men in to 000 men in and in women from 000 women in to 000 in of the to those which had data from 2010 or had the of rates. CVD ASDRs for men in these countries ranged from 000 in to 000 in For CVD ASDRs in non-EU countries ranged from 000 in to 000 in All countries for which data from 2010 were not available were from the ASDRs from CVD and CHD by country and sex 000 rate for most recent year of data and percentage in rates over 10 years Rates are not available for Monaco due to population No mortality data are available for Andorra. Age-standardized to the 2013 European Standard not available. in rates for is over 11 years due to data for the year 10 years Source: WHO Mortality Database. in rates were found for premature In the EU-15, of deaths under the age of 75 years were from CVD million with ASDRs for this age in men from 000 men in to 000 in and in women from 000 women in to 000 in In the of deaths under the age of 75 years were from CVD million with ASDRs from additional countries to the EU-15 from 000 men in to 000 men in and from 000 women in to 000 women in In non-EU countries, of deaths under the age of 75 (1.3 million were from CVD, with ASDRs countries which had data from 2010 or from 000 men in to 000 in For women CVD ASDRs in non-EU countries ranged from 000 women in to 000 in the of CVD mortality rates under 65 years similar but at rates ASDRs calculated for the most recent year to those for 10 years as a percentage of the earlier year, most of the countries in the European decreases in ASDRs for CVD and CHD from The were which reported an in CHD ASDRs over 10 years for both sexes and the Czech that a in CHD Although other countries reported increases in rates for both CVD and CHD these were within countries recent data, latest available year of data was before such as The decreases in ASDRs over 10 years between countries. In the EU-15, decreases the latest year in CVD ASDRs in men ranged from in to in and in women from in to in In the decreases in CVD from additional countries to the EU-15 ranged from in Slovakia to in and in women from in Slovakia to in the Czech In non-EU countries, CVD decreases ranged from in to in and in women from in to in a of the observed decreases in CVD, a number of countries now a greater number of deaths from than from CVD despite accounting for than the number of deaths than CVD in Europe as a to the most recent data more men die from than CVD in 12 countries and in two countries for All of these countries are in Europe as by the GBD with of the 12 countries from the This from CVD to as the most common cause of death for men was first in in 1998, with the only other country to it before the year There were two countries in which more than CVD for both with this occurring in the same year in and years in countries in which CVD as the most common cause of death also now have higher of to CVD deaths, that of an burden of mortality compared with CVD mortality this The year the higher absolute number of deaths from CVD to by of to CVD deaths, by sex and European country. Note: and same year and similar are only included for countries in which the number of deaths from is greater than the number of deaths from CVD for women as well as and Data for all other countries, those a are for men Source: WHO Mortality Database. European countries where the number of deaths the number of deaths from CVD for men and women Disability-adjusted life years are a composite measure of years of life lost due to death from a condition and years lived with disability due to a condition. One DALY is equivalent to 1 year of healthy life rates of WHO estimates for the number of DALYs to CVD in 2012 for European countries were in the with only five countries CVD DALYs population of more than and countries had DALYs attributed to CVD of and More DALYs were attributed to CVD and CHD in men than women in all countries, with Tajikistan the only country in which women greater DALYs due to CVD than men. No country reported more DALYs for women than men for however this not for stroke, with similar number of countries higher DALYs for each of the sexes DALYs population for all cardiovascular coronary heart disease and stroke, WHO European Region Source: World Health Health Statistics and Information DALYs population by cause and WHO European Region 2012 Source: World Health Health Statistics and Information prevalence of people heart or circulation problems in the last 12 in the European Social for all countries was the same for both sexes at There were five countries in which more than of men reported heart or circulation the Netherlands and This was the case for women in and countries reported a prevalence for men, and the Czech and for the Czech and of population heart or circulation problems in the last 12 by country and sex Note: to for for Source: European Social Data Data Social Data and of data for of population heart or circulation problems in the last 12 by country and sex 2014 Note: to for for Source: European Social Data Data Social Data and of data for The WHO collates data on rates of hospital for CVD, CHD, and The rates of were in available year with hospital for CVD 000 this a from The of countries had an in rates from the year For CHD, the was with around of countries an in rates and the other a For stroke, of the 52 countries increases in rates. It be that the data are not therefore, in rates over and differences between countries could be due to differences and in population age Hospital for CVD, CHD, and cerebrovascular disease 000 by to latest year to Cardiovascular disease data and to CHD and cerebrovascular disease data countries from Source: World Health Organization for Europe. European Health for All Database.12 had the case standardized to the 2010 OECD population aged for both and measured through and Although were greater than for all countries and both disease countries not provide data and one country not present any data The case fatalities for were found in and and the was found in two other countries had an case fatality for and and were the only countries to have case fatality for and all reported case fatalities On average, case fatality was for than However, countries had case fatalities that were greater for than the Netherlands, UK, Spain, Finland, Germany, and rates and stroke, latest year, by country rate the percentage of people aged 45 and over who die within 30 days following admission to hospital for a acute condition. rates have been standardized to the 2010 OECD population Admission-based rates refer to death occurring in the same hospital as the initial admission. rates refer to death occurring in the same hospital as the initial a different hospital, or out of hospital. average for and Admissions resulting in a transfer are Source: OECD Health Statistics OECD European countries the average length of stay (ALOS) following was with the ALOS found in and with Slovakia the only other country to report an ALOS than days ALOS following was in Germany, the only country to report an ALOS of more than 10 days and were the only other countries to report ALOS of than days length of hospital stay following latest year, by country length of stay (ALOS) the mean number of days the patients spend in hospital. cases. Data cover all inpatient cases with the exception of the admission cases are not all inpatient cases. Source: OECD Health Statistics Mortality statistics that CVD remains the most common cause of death in Europe, accounting for 45% of all 49% of deaths among women and 40% among men. More than 4 million people die from CVD across Europe every year, with 1.4 million of these deaths before the age of 75 There remains of across Europe in the burden of CVD mortality and the in rates of death from these In this article we that with the higher rates found in Europe, as in the member countries, on average, a burden from CVD mortality, with EU-15 countries that have been of the the on average the In addition the 12 countries in which the mortality burden from CVD such that the number of deaths from CVD is than that from in men, with the two countries in which this has in are all found in Europe. Although death rates for all countries were age-standardized for and across it be that these rates are only standardized for the age structure of the population and do not other of these For example, and other of population structure may between countries and across the years of data presented but these are not accounted for when using the The burden of CVD in Europe is not to mortality and this is the first in this series of papers that we present data on DALYs and presented here as population rates, were higher in European however, as these rates are not standardized for age or some differences may be due to different population between countries. The European Social data from on they have heart or circulation problems and large in prevalence between countries. It be that prevalence estimates can be to recall and higher prevalence may also be an indication of more and of these conditions in the such that it not for CVD, which may cause a large burden to countries. In although the European Social to report they have these problems in the 12 it may not for who have CVD which provide a more measure of those who have from heart or circulation or who are it may report that they do not currently such In as is no measure of the problems in the 12 or this cannot be used as a measure of With such prevalence and data from a central the survey the data we have rates an burden of CVD in health systems despite mortality rates. between countries in rates of discharge may be a of health service and as well as CVD It is by not only the quality of care provided in hospitals but also differences in hospital average length of and of condition on number of can to including to acute of and health for and can differences between countries in length of stay following CVD In addition to the of the these are also to reflect differences in and In order to ALOS many countries have a number of including of in hospital methods, and for hospitals to the of care across treatment and The average length of stay (ALOS) in hospitals is often regarded as a good indicator of health as in a burden on the health service of that country. However, although a has been found between average hospital and ALOS following an ALOS could also cause on health that of may only or In a such as can have a on patients and they may not be for discharge at if no have In addition to the of the data described in the and the of this article is that it to be a data on CVD in Europe, to provide an overview of the burden of CVD across the continent. It therefore, some of the in CVD that are presented throughout In as the study not have to the data on many we are not to present on the of all the statistics we present In where we do report data and using or age-standardized population rates, we cannot for and other of population This latest update on the of CVD within Europe presents new on the in CVD described through mortality, morbidity, and treatment throughout Europe. This for more in and countries and the of data to make comparisons on mortality and between countries, in order that can be to In particular and prevalence data across Europe are in comparison to mortality statistics and these with data on the burden of CVD, CVD conditions that are currently not identified by health services or within national be to and those in is available at European Heart and from the Heart is by an of