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McCartney, Borras et al. analyse the metabolites present in breath samples collected from people with or without COVID-19. The authors find that the breath metabolite signature differs based on the predominant SARS-CoV-2 variant circulating at the time, and that breath test accuracy improves when modelling samples from each variant wave separately.

Cunningham-Burley, McCartney, Campbell, Flaig, Orange et al. assess the ethics and potential benefit of secondary data use from newborn blood spot archives for research in a Citizen’s jury that agreed this was in the public interest. They also investigate and demonstrate the feasibility of using the archives for research purposes.

Abstract Background The world is facing an unprecedented systemic shock to population health, the economy and society due to the devastating impact of the COVID-19 pandemic. As with most economic shocks, this is expected to disproportionately impact vulnerable groups in society such as those in poverty and those in precarious employment as well as marginalised groups such as women, the elderly, Black, Asian and Minority Ethnic (BAME) groups and those with health conditions. The current literature is rich in normative recommendations on plural ownership as a key building block of an inclusive economy rooted in communities and their needs. There is, however, a need for a rigorous synthesis of the available evidence on what impact (if any) plural ownership may potentially have on the inclusivity of the economy. This review seeks to synthesise and compare the available evidence across the three economic sectors (private, public and third). Methods We will search eight bibliographic databases (Sociological abstracts, EBSCO Econlit, OVID Embase, OVID Medline, Applied Social Sciences Index and Abstracts (ASSIA), ProQuest Public Health, Web of Science, Research Papers in Economics (Repec) – EconPapers) from the earliest data available in each database until January 2021. Grey literature will be identified from Google (advanced), Google Scholar and 37 organisational websites identified as relevant to the research question. We will include comparative studies of plural ownership from high-income countries that report outcomes on access to opportunities, distribution of benefits, poverty, and discrimination. A bespoke search strategy will be used for each website to account for the heterogeneity in content and search capabilities and will be fully documented. A standardised data extraction template based on the Population-Intervention-Context-Outcome (PICO) template will be developed. We will assess the strength of evidence for different forms of economic ownership identified in relation to the impact of each on the four economic outcomes of interest, paying particular attention to the role of wider contextual factors as they emerge through the evidence. Discussion The findings of this review are intended to inform policymaking at local, national and international level that prioritises and supports the development of different economic and business models. Systematic review registration Open Science Framework registration DOI: https://doi.org/10.17605/OSF.IO/BYH5A

Abstract Background Income inequality has been linked to health and mortality. While there has been extensive research exploring the relationship, the evidence for whether the relationship is causal remains disputed. We describe the methods for a systematic review that will transparently assess whether a causal relationship exists between income inequality and mortality and self-rated health. Methods We will identify relevant studies using search terms relating to income inequality, mortality, and self-rated health (SRH). Four databases will be searched: MEDLINE, ISI Web of Science, EMBASE, and the National Bureau of Economic Research. The inclusion criteria have been developed to identify the study designs best suited to assess causality: multilevel studies that have conditioned upon individual income (or a comparable measure, such as socioeconomic position) and natural experiment studies. Risk of bias assessment of included studies will be conducted using ROBINS-I. Where possible, we will convert all measures of income inequality into Gini coefficients and standardize the effect estimate of income inequality on mortality/SRH. We will conduct random-effects meta-analysis to estimate pooled effect estimates when possible. We will assess causality using modified Bradford Hill viewpoints and assess certainty using GRADE. Discussion This systematic review protocol lays out the complexity of the relationship between income inequality and individual health, as well as our approach for assessing causality. Understanding whether income inequality impacts the health of individuals within a population has major policy implications. By setting out our methods and approach as transparently as we can, we hope this systematic review can provide clarity to an important topic for public policy and public health, as well as acting as an exemplar for other “causal reviews”.

Objectives The rate of improvement in all-cause mortality rates has slowed in the UK since around 2012. While evidence suggests that UK Government ‘austerity’ policies have been largely responsible, it has been proposed that rising obesity may also have contributed. The aim here was to estimate this contribution for Scotland and England.Methods We calculated population attributable fractions (PAFs) resulting from changes in Body Mass Index (BMI) between the mid-1990s and late 2000s for all-cause mortality among 35–89-year olds in 2017–2019. We used BMI data from national surveys (the Scottish Health Survey and the Health Survey for England), and HRs from a meta-analysis of 89 European studies. PAFs were applied to mortality data for 2017–2019 (obtained from national registries), enabling comparison of observed rates, BMI-adjusted rates and projected rates. Uncertainty in the estimates is dominated by the assumptions used and biases in the underlying data, rather than random variation. A series of sensitivity analyses and bias assessments were therefore undertaken to understand the certainty of the estimates.Results In Scotland, an estimated 10% (males) and 14% (females) of the difference between observed and predicted mortality rates in 2017–2019 may be attributable to previous changes in BMI. The equivalent figures for England were notably higher: 20% and 35%, respectively. The assessments of bias suggest these are more likely to be overestimates than underestimates.Conclusions Some of the recent stalled mortality trends in Scotland and England may be associated with earlier increases in obesity. Policies to reduce the obesogenic environment, including its structural and commercial determinants, and reverse the impacts of austerity, are needed.

Introduction Prehabilitation is a high-priority intervention for patients, the public, clinicians and health systems. However, existing knowledge syntheses are generally low quality and do not provide insights regarding the relative efficacy of different prehabilitation components (eg, exercise, nutrition, psychosocial or cognitive interventions). The objective of the planned review is to evaluate the relative efficacy of different prehabilitation components to inform current care, implementation and future research.Methods and analysis We will perform a systematic review and component network meta-analysis (CNMA). We will use a peer-reviewed search strategy to identify all randomised trials of prehabilitation in adult surgical patients from Ovid Medline, Embase, the CINAHL, PsycINFO, Web of Science and the Cochrane Central Register of Controlled Trials, along with grey literature. All stages of the review and data extraction process will be performed in duplicate, following recommended best practices. To compare the relative efficacy of different prehabilitation components (prespecified as exercise, nutrition, psychosocial or cognitive interventions), we will use CNMA, an extension of network meta-analysis that allows estimation of the contributions to efficacy of each component of a multicomponent intervention through direct and indirect comparisons. We will use additive CNMA models for critical outcomes (postoperative complications, patient-reported recovery, physical recovery and length of stay); standard care will be the common reference condition. Pre-specified sensitivity and subgroup analyses will be conducted.Ethics and dissemination This review of published data does not require ethical review. Results will be disseminated via scientific conferences, peer-reviewed publications, social and traditional media and via our research network to target partners and organisations.

Objective To understand arrangements for healthcare organisations’ declarations of staff interest in Scotland and England in the context of current recommendations.Design Cross-sectional study of a random selection of National Health Service (NHS) hospital registers of interest by two independent observers in England, all NHS Boards in Scotland and a random selection of Clinical Commissioning Groups (CCGs) in England.Setting NHS Trusts in England (NHSE), NHS Boards in Scotland, CCGs in England, and private healthcare organisations.Participants Registers of declarations of interest published in a random sample of 67 of 217 NHS Trusts, a random sample of 15 CCGs of in England, registers held by all 14 NHS Scotland Boards and a purposeful selection of private hospitals/clinics in the UK.Main outcome measures Adherence to NHSE guidelines on declarations of interests, and comparison in Scotland.Results 76% of registers published by Trusts did not routinely include all declaration of interest categories recommended by NHS England. In NHS Scotland only 14% of Boards published staff registers of interest. Of these employee registers (most obtained under Freedom of Information), 27% contained substantial retractions. In England, 96% of CCGs published a Gifts and Hospitality register, with 67% of CCG staff declaration templates and 53% of governor registers containing full standard NHS England declaration categories. Single organisations often held multiple registers lacking enough information to interpret them. Only 35% of NHS Trust registers were organised to enable searching. None of the private sector organisations studied published a comparable declarations of interest register.Conclusion Despite efforts, the current system of declarations frequently lacks ability to meaningfully obtain complete healthcare professionals’ declaration of interests.

Objectives The enormous toll of the COVID-19 pandemic has heightened the urgency of collecting and analysing population-scale datasets in real time to monitor and better understand the evolving pandemic. The objectives of this study were to examine the relationship of risk factors to COVID-19 susceptibility and severity and to develop risk models to accurately predict COVID-19 outcomes using rapidly obtained self-reported data.Design A cross-sectional study.Setting AncestryDNA customers in the USA who consented to research.Participants The AncestryDNA COVID-19 Study collected self-reported survey data on symptoms, outcomes, risk factors and exposures for over 563 000 adult individuals in the USA in just under 4 months, including over 4700 COVID-19 cases as measured by a self-reported positive test.Results We replicated previously reported associations between several risk factors and COVID-19 susceptibility and severity outcomes, and additionally found that differences in known exposures accounted for many of the susceptibility associations. A notable exception was elevated susceptibility for men even after adjusting for known exposures and age (adjusted OR=1.36, 95% CI=1.19 to 1.55). We also demonstrated that self-reported data can be used to build accurate risk models to predict individualised COVID-19 susceptibility (area under the curve (AUC)=0.84) and severity outcomes including hospitalisation and critical illness (AUC=0.87 and 0.90, respectively). The risk models achieved robust discriminative performance across different age, sex and genetic ancestry groups within the study.Conclusions The results highlight the value of self-reported epidemiological data to rapidly provide public health insights into the evolving COVID-19 pandemic.

Objectives Social determinants of health (SDoH) contribute to health outcomes. We identified SDoH that were modified by critical illness, and the effect of such modifications on recovery from critical illness.Design In-depth semistructured interviews following hospital discharge. Interview transcripts were mapped against a pre-existing social policy framework: money and work; skills and education; housing, transport and neighbourhoods; and family, friends and social connections.Setting 14 hospital sites in the USA, UK and Australia.Participants Patients and caregivers, who had been admitted to critical care from three continents.Results 86 interviews were analysed (66 patients and 20 caregivers). SDoH, both financial and non-financial in nature, could be negatively influenced by exposure to critical illness, with a direct impact on health-related outcomes at an individual level. Financial modifications included changes to employment status due to critical illness-related disability, alongside changes to income and insurance status. Negative health impacts included the inability to access essential healthcare and an increase in mental health problems.Conclusions Critical illness appears to modify SDoH for survivors and their family members, potentially impacting recovery and health. Our findings suggest that increased attention to issues such as one’s social network, economic security and access to healthcare is required following discharge from critical care.

Introduction Frailty is a strong predictor of adverse postoperative outcomes. Prehabilitation may improve outcomes after surgery for older people with frailty by addressing physical and physiologic deficits. The objective of this trial is to evaluate the efficacy of home-based multimodal prehabilitation in decreasing patient-reported disability and postoperative complications in older people with frailty having major surgery.Methods and analysis We will conduct a multicentre, randomised controlled trial of home-based prehabilitation versus standard care among consenting patients >60 years with frailty (Clinical Frailty Scale>4) having elective inpatient major non-cardiac, non-neurologic or non-orthopaedic surgery. Patients will be partially blinded; clinicians and outcome assessors will be fully blinded. The intervention consists of >3 weeks of prehabilitation (exercise (strength, aerobic and stretching) and nutrition (advice and protein supplementation)). The study has two primary outcomes: in-hospital complications and patient-reported disability 30 days after surgery. Secondary outcomes include survival, lower limb function, quality of life and resource utilisation. A sample size of 750 participants (375 per arm) provides >90% power to detect a minimally important absolute difference of 8 on the 100-point patient-reported disability scale and a 25% relative risk reduction in complications, using a two-sided alpha value of 0.025 to account for the two primary outcomes. Analyses will follow intention to treat principles for all randomised participants. All participants will be followed to either death or up to 1 year.Ethics and dissemination Ethical approval has been granted by Clinical Trials Ontario (Project ID: 1785) and our ethics review board (Protocol Approval #20190409-01T). Results will be disseminated through presentation at scientific conferences, through peer-reviewed publication, stakeholder organisations and engagement of social and traditional media.Trial registration number NCT04221295.

Abstract Expansion of various types of water infrastructure is critical to water security in Africa. To date, analysis of adverse disease impacts has focused mainly on large dams. The aim of this study was to examine the effect of both small and large dams on malaria in four river basins in sub-Saharan Africa (i.e., the Limpopo, Omo-Turkana, Volta and Zambezi river basins). The European Commission’s Joint Research Center (JRC) Yearly Water Classification History v1.0 data set was used to identify water bodies in each of the basins. Annual malaria incidence data were obtained from the Malaria Atlas Project (MAP) database for the years 2000, 2005, 2010 and 2015. A total of 4907 small dams and 258 large dams in the four basins, with 14.7million people living close (

Abstract Background DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach. Methods The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses. Results We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development. Conclusions We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context.

TeenCovidLife is part of Generation Scotland’s CovidLife projects, a set of longitudinal observational studies designed to assess the psychosocial and health impacts of the COVID-19 pandemic. TeenCovidLife focused on how adolescents in Scotland were coping during the pandemic. As of September 2021, Generation Scotland had conducted three TeenCovidLife surveys. Participants from previous surveys were invited to participate in the next, meaning the age ranges shifted over time. TeenCovidLife Survey 1 consists of data from 5,543 young people age 12 to 17, collected from 22 May to 5 July 2020, during the first school closures period in Scotland. TeenCovidLife Survey 2 consists of data from 2,245 young people aged 12 to 18, collected from 18 August to 14 October 2020, when the initial lockdown measures were beginning to ease, and schools reopened in Scotland. TeenCovidLife Survey 3 consists of data from 597 young people age 12 to 19, collected from 12 May to 27 June 2021, a year after the first survey, after the schools returned following the second lockdown in 2021. A total of 316 participants took part in all three surveys. TeenCovidLife collected data on general health and well-being, as well as topics specific to COVID-19, such as adherence to COVID-19 health guidance, feelings about school closures, and the impact of exam cancellations. Limited work has examined the impact of the COVID-19 pandemic on young people. TeenCovidLife provides relevant and timely data to assess the impact of the pandemic on young people in Scotland. The dataset is available under authorised access from Generation Scotland; see the Generation Scotland website for more information.

Located in northwestern South China Sea (SCS), the Beibu Gulf constitutes an environmentally sensitive region shaped by land-ocean-atmosphere interactions in Asia between the western Pacific and eastern Indian Oceans. This study aims to provide a comprehensive view of the sub-fossil diatom biogeography, distribution pattern and oceanographic environmental controls with support of multivariate methods based on Beibu Gulf core-top samples. Cluster analysis of diatom assemblages divides the distribution pattern into four subclusters. Sea surface salinity (SSS), temperature (SST), trophic state (chlorophyll a concentration in this study) and water depth constrain the diatom distribution pattern through canonical redundancy analysis although only partly support an interpretation of the relationship between these various variables. Chlorophyll a has a strong correlation to diatom distribution, and responds to Paralia sulcata occurrence, while SSS and SST also have significant influence and indicate warm water invasion from the open SCS. Water depth is a subordinate factor in terms of Beibu Gulf diatom distribution. The ca. 25 m water-depth marks the upper extent of Paralia sulcata dominance in the northern Beibu Gulf. A strong mixing area with a complex diatom distribution exists below this water depth in the middle of Beibu Gulf. Coastal currents from north of SCS invade Beibu Gulf through Qiongzhou Strait and south of Hainan Island, as recorded by higher percentages of Paralia sulcata and Cyclotella striata at these sites. Our results provide a selection of evaluation method for a marine ecological red-line definition for sustainable development. This study highlights the perspective relationships between the spatial distribution of sub-fossil diatom assemblages in surface sediments and oceanographic variables, which could serve as a model for paleoenvironmental and paleoclimatic reconstruction in future marginal sea geoscience research for the Beibu Gulf, northwestern SCS.

Abstract Background The molecular factors which control circulating levels of inflammatory proteins are not well understood. Furthermore, association studies between molecular probes and human traits are often performed by linear model-based methods which may fail to account for complex structure and interrelationships within molecular datasets. Methods In this study, we perform genome- and epigenome-wide association studies (GWAS/EWAS) on the levels of 70 plasma-derived inflammatory protein biomarkers in healthy older adults (Lothian Birth Cohort 1936; n = 876; Olink® inflammation panel). We employ a Bayesian framework (BayesR+) which can account for issues pertaining to data structure and unknown confounding variables (with sensitivity analyses using ordinary least squares- (OLS) and mixed model-based approaches). Results We identified 13 SNPs associated with 13 proteins (n = 1 SNP each) concordant across OLS and Bayesian methods. We identified 3 CpG sites spread across 3 proteins (n = 1 CpG each) that were concordant across OLS, mixed-model and Bayesian analyses. Tagged genetic variants accounted for up to 45% of variance in protein levels (for MCP2, 36% of variance alone attributable to 1 polymorphism). Methylation data accounted for up to 46% of variation in protein levels (for CXCL10). Up to 66% of variation in protein levels (for VEGFA) was explained using genetic and epigenetic data combined. We demonstrated putative causal relationships between CD6 and IL18R1 with inflammatory bowel disease and between IL12B and Crohn’s disease. Conclusions Our data may aid understanding of the molecular regulation of the circulating inflammatory proteome as well as causal relationships between inflammatory mediators and disease.

Background: Epigenetic clocks have been associated with cancer risk in several observational studies. Nevertheless, it is unclear whether they play a causal role in cancer risk or if they act as a non-causal biomarker. Methods: We conducted a two-sample Mendelian randomization (MR) study to examine the genetically predicted effects of epigenetic age acceleration as measured by HannumAge (nine single-nucleotide polymorphisms (SNPs)), Horvath Intrinsic Age (24 SNPs), PhenoAge (11 SNPs), and GrimAge (4 SNPs) on multiple cancers (i.e. breast, prostate, colorectal, ovarian and lung cancer). We obtained genome-wide association data for biological ageing from a meta-analysis (N = 34,710), and for cancer from the UK Biobank (N cases = 2671–13,879; N controls = 173,493–372,016), FinnGen (N cases = 719–8401; N controls = 74,685–174,006) and several international cancer genetic consortia (N cases = 11,348–122,977; N controls = 15,861–105,974). Main analyses were performed using multiplicative random effects inverse variance weighted (IVW) MR. Individual study estimates were pooled using fixed effect meta-analysis. Sensitivity analyses included MR-Egger, weighted median, weighted mode and Causal Analysis using Summary Effect Estimates (CAUSE) methods, which are robust to some of the assumptions of the IVW approach. Results: Meta-analysed IVW MR findings suggested that higher GrimAge acceleration increased the risk of colorectal cancer (OR = 1.12 per year increase in GrimAge acceleration, 95% CI 1.04–1.20, p = 0.002). The direction of the genetically predicted effects was consistent across main and sensitivity MR analyses. Among subtypes, the genetically predicted effect of GrimAge acceleration was greater for colon cancer (IVW OR = 1.15, 95% CI 1.09–1.21, p = 0.006), than rectal cancer (IVW OR = 1.05, 95% CI 0.97–1.13, p = 0.24). Results were less consistent for associations between other epigenetic clocks and cancers. Conclusions: GrimAge acceleration may increase the risk of colorectal cancer. Findings for other clocks and cancers were inconsistent. Further work is required to investigate the potential mechanisms underlying the results. Funding: FMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (224982/Z/22/Z which is part of grant 218495/Z/19/Z). KKT was supported by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme) and by the Hellenic Republic’s Operational Programme ‘Competitiveness, Entrepreneurship & Innovation’ (OΠΣ 5047228). PH was supported by Cancer Research UK (C18281/A29019). RMM was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). RMM is a National Institute for Health Research Senior Investigator (NIHR202411). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. GDS and CLR were supported by the Medical Research Council (MC_UU_00011/1 and MC_UU_00011/5, respectively) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). REM was supported by an Alzheimer’s Society project grant (AS-PG-19b-010) and NIH grant (U01 AG-18-018, PI: Steve Horvath). RCR is a de Pass Vice Chancellor’s Research Fellow at the University of Bristol.

Increasingly, communicating science to the public is recognized as the responsibility of professional scientists; however, these skills are not always included in graduate training. In addition, most research on science communication training during graduate school, which is limited, has been program evaluation or literature reviews and does not report on or seek to understand graduate student perspectives. This research study provides a comprehensive analysis of graduate-level science communication training from the perspective of STEM graduate students. Using a mixed-methods approach, this study aimed to investigate where graduate students are receiving science communication training (if at all), what this training looks like from the student's point of view, and, for graduate students that are engaging in science communication, what do these experiences look like. This study also explores how graduate students define science communication. Taken together, these results will give graduate students a voice in the development of science communication trainings and will remove barriers and increase equity in science communication training.

Background: Circulating S100 calcium-binding protein (S100β) is a marker of brain inflammation that has been associated with a range of neurological conditions. To provide insight into the molecular regulation of S100β and its potential causal associations with Alzheimer’s disease, we carried out genome- and epigenome-wide association studies (GWAS/EWAS) of serum S100β levels in older adults and performed Mendelian randomisation with Alzheimer’s disease. Methods: GWAS (N=769, mean age 72.5 years, sd = 0.7) and EWAS (N=722, mean age 72.5 years, sd = 0.7) of S100β levels were performed in participants from the Lothian Birth Cohort 1936. Conditional and joint analysis (COJO) was used to identify independent loci. Expression quantitative trait locus (eQTL) analyses were performed for lead loci that had genome-wide significant associations with S100β. Bidirectional, two-sample Mendelian randomisation was used to test for causal associations between S100β and Alzheimer’s disease. Colocalisation between S100β and Alzheimer’s disease GWAS loci was also examined. Results: We identified 154 SNPs from chromosome 21 that associated (P

Protein biomarkers have been identified across many age-related morbidities. However, characterising epigenetic influences could further inform disease predictions. Here, we leverage epigenome-wide data to study links between the DNA methylation (DNAm) signatures of the circulating proteome and incident diseases. Using data from four cohorts, we trained and tested epigenetic scores (EpiScores) for 953 plasma proteins, identifying 109 scores that explained between 1% and 58% of the variance in protein levels after adjusting for known protein quantitative trait loci (pQTL) genetic effects. By projecting these EpiScores into an independent sample (Generation Scotland; n = 9537) and relating them to incident morbidities over a follow-up of 14 years, we uncovered 130 EpiScore-disease associations. These associations were largely independent of immune cell proportions, common lifestyle and health factors, and biological aging. Notably, we found that our diabetes-associated EpiScores highlighted previous top biomarker associations from proteome-wide assessments of diabetes. These EpiScores for protein levels can therefore be a valuable resource for disease prediction and risk stratification.

Background: Circulating S100 calcium-binding protein (S100β) is a marker of brain inflammation that has been associated with a range of neurological conditions. To provide insight into the molecular regulation of S100β and its potential causal associations with Alzheimer’s disease, we carried out genome- and epigenome-wide association studies (GWAS/EWAS) of serum S100β levels in older adults and performed Mendelian randomisation with Alzheimer’s disease. Methods: GWAS (N=769, mean age 72.5 years, sd = 0.7) and EWAS (N=722, mean age 72.5 years, sd = 0.7) of S100β levels were performed in participants from the Lothian Birth Cohort 1936. Conditional and joint analysis (COJO) was used to identify independent loci. Expression quantitative trait locus (eQTL) analyses were performed for lead loci that had genome-wide significant associations with S100β. Bidirectional, two-sample Mendelian randomisation was used to test for causal associations between S100β and Alzheimer’s disease. Colocalisation between S100β and Alzheimer’s disease GWAS loci was also examined. Results: We identified 154 SNPs from chromosome 21 that associated (P

Abstract Background Advanced age is associated with cognitive and physical decline and is a major risk factor for a multitude of disorders. There is also a gap in life expectancy between males and females. DNA methylation differences have been shown to be associated with both age and sex. Here, we investigate age-by-sex differences in blood-based DNA methylation in an unrelated cohort of 2586 individuals between the ages of 18 and 87 years, with replication in a further 4450 individuals between the ages of 18 and 93 years. Methods Linear regression models were applied, with stringent genome-wide significance thresholds (p

Background: Vaccination is the cornerstone of the global public health response to the COVID-19 pandemic. Excess morbidity and mortality of COVID-19 infection is seen in people with cancer. COVID-19 vaccine hesitancy has been observed in this medically vulnerable population, although associated attitudes and beliefs remain poorly understood. Methods: An online cross-sectional survey of people with solid organ cancers was conducted through nine health services across Australia. Demographics, cancer-related characteristics and vaccine uptake were collected. Perceptions and beliefs regarding COVID-19 vaccination were assessed using the Oxford COVID-19 Vaccine Hesitancy Scale, the Oxford COVID-19 Vaccine Confidence and Complacency Scale and the Disease Influenced Vaccine Acceptance Scale-6. Results: Between June and October 2021, 2691 people with solid organ cancers completed the survey. The median age was 62.5 years (SD = 11.8; range 19–95), 40.9% were male, 71.3% lived in metropolitan areas and 90.3% spoke English as their first language. The commonest cancer diagnoses were breast (36.6%), genitourinary (18.6%) and gastrointestinal (18.3%); 59.2% had localized disease and 56.0% were receiving anti-cancer therapy. Most participants (79.7%) had at least one COVID-19 vaccine dose. Vaccine uptake was higher in people who were older, male, metropolitan, spoke English as a first language and had a cancer diagnosis for more than six months. Vaccine hesitancy was higher in people who were younger, female, spoke English as a non-dominant language and lived in a regional location, and lower in people with genitourinary cancer. Vaccinated respondents were more concerned about being infected with COVID-19 and less concerned about vaccine safety and efficacy. Conclusions: People with cancer have concerns about acquiring COVID-19, which they balance against vaccine-related concerns about the potential impact on their disease progress and/or treatment. Detailed exploration of concerns in cancer patients provides valuable insights, both for discussions with individual patients and public health messaging for this vulnerable population.

Background: COVID-19 is responsible for increasing deaths globally. As most people dying with COVID-19 are older with underlying long-term conditions (LTCs), some speculate that YLL are low. We aim to estimate YLL attributable to COVID-19, before and after adjustment for number/type of LTCs, using the limited data available early in the pandemic. Methods: We first estimated YLL from COVID-19 using WHO life tables, based on published age/sex data from COVID-19 deaths in Italy. We then used aggregate data on number/type of LTCs in a Bayesian model to estimate likely combinations of LTCs among people dying with COVID-19. We used routine UK healthcare data from Scotland and Wales to estimate life expectancy based on age/sex/these combinations of LTCs using Gompertz models from which we then estimate YLL. Results: Using the standard WHO life tables, YLL per COVID-19 death was 14 for men and 12 for women. After adjustment for number and type of LTCs, the mean YLL was slightly lower, but remained high (11.6 and 9.4 years for men and women, respectively). The number and type of LTCs led to wide variability in the estimated YLL at a given age (e.g. at ≥80 years, YLL was >10 years for people with 0 LTCs, and

As COVID-19 vaccinations became available and were proven effective in preventing serious infection, uptake amongst individuals varied, including in medically vulnerable populations. This cross-sectional multi-site study examined vaccine uptake, hesitancy, and explanatory factors amongst people with serious and/or chronic health conditions, including the impact of underlying disease on attitudes to vaccination. A 42-item survey was distributed to people with cancer, diabetes, or multiple sclerosis across ten Australian health services from 30 June to 5 October 2021. The survey evaluated sociodemographic and disease-related characteristics and incorporated three validated scales measuring vaccine hesitancy and vaccine-related beliefs generally and specific to their disease: the Oxford COVID-19 Vaccine Hesitancy Scale, the Oxford COVID-19 Vaccine Confidence and Complacency Scale and the Disease Influenced Vaccine Acceptance Scale-Six. Among 4683 participants (2548 [54.4%] female, 2108 [45.0%] male, 27 [0.6%] other; mean [SD] age, 60.6 [13.3] years; 3560 [76.0%] cancer, 842 [18.0%] diabetes, and 281 [6.0%] multiple sclerosis), 3813 (81.5%) self-reported having at least one COVID-19 vaccine. Unvaccinated status was associated with younger age, female sex, lower education and income, English as a second language, and residence in regional areas. Unvaccinated participants were more likely to report greater vaccine hesitancy and more negative perceptions toward vaccines. Disease-related vaccine concerns were associated with unvaccinated status and hesitancy, including greater complacency about COVID-19 infection, and concerns relating to vaccine efficacy and impact on their disease and/or treatment. This highlights the need to develop targeted strategies and education about COVID-19 vaccination to support medically vulnerable populations and health professionals.

Objectives Previously improving life expectancy and all-cause mortality in the UK has stalled since the early 2010s. National analyses have demonstrated changes in mortality rates for most age groups and causes of death, and with deprived populations most affected. The aims here were to establish whether similar changes have occurred across different parts of the UK (countries, cities), and to examine cause-specific trends in more detail.Design Population-based trend analysis.Participants/setting Whole populations of countries and selected cities of the UK.Primary and secondary outcome measures European age-standardised mortality rates (calculated by cause of death, country, city, year (1981–2017), age group, sex and—for all countries and Scottish cities—deprivation quintiles); changes in rates between 5-year periods; summary measures of both relative (relative index of inequality) and absolute (slope index of inequality) inequalities.Results Changes in mortality from around 2011/2013 were observed throughout the UK for all adult age groups. For example, all-age female rates decreased by approximately 4%–6% during the 1980s and 1990s, approximately 7%–9% during the 2000s, but by

Background: Microvascular obstruction commonly affects patients with acute ST-segment elevation myocardial infarction and is independently associated with adverse outcomes. Objective: To determine whether or not a strategy involving low-dose intracoronary fibrinolytic therapy infused early after coronary reperfusion will reduce microvascular obstruction. Design: This was a multicentre, randomised, double-blind, parallel-group, placebo-controlled, dose-ranging trial. Setting: The trial took place at 11 hospitals in the UK between 17 March 2016 and 21 December 2017. Participants: Patients with acute ST-segment elevation myocardial infarction and a symptom onset to reperfusion time of ≤ 6 hours were eligible for randomisation. Radial artery access was a requirement, and further angiographic criteria included a proximal-to-middle coronary artery occlusion or impaired coronary flow in the presence of a definite thrombus in the culprit coronary artery. Exclusion criteria included a functional coronary collateral supply to the infarct-related artery, any contraindication to fibrinolysis and lack of informed consent. Additional exclusion criteria for safety were (1) requirement for immunosuppressive drug therapy for ≤ 3 months and (2) treatment with an antimicrobial agent. Intervention: A total of 440 participants were randomly assigned 1 : 1 : 1 to treatment with placebo (n = 151), 10 mg of alteplase (n = 144) or 20 mg of alteplase (n = 145) administered by manual infusion directly into the infarct-related coronary artery over 5–10 minutes. The intervention was scheduled to happen after reperfusion and before stent implantation. Outcomes: The primary outcome was the amount of microvascular obstruction (percentage of left ventricular mass) demonstrated by contrast-enhanced cardiac magnetic resonance imaging at 2–7 days after enrolment. The primary analysis was the comparison between the 20 mg of alteplase group and the placebo group; if this comparison was not significant, the comparison of the 10 mg of alteplase group with the placebo group was considered as a secondary analysis. Sample size: A total of 618 patients (minimum of 558 patients). Recruitment was halted on 21 December 2017 given that conditional power for the primary outcome based on a prespecified analysis of the first 267 randomised participants was

Objective Annual gains in life expectancy in Scotland were slower in recent years than in the previous two decades. This analysis investigates how deaths in different age groups and from different causes have contributed to annual average change in life expectancy across two time periods: 2000–2002 to 2012–2014 and 2012–2014 to 2015–2017.Setting Scotland.Methods Life expectancy at birth was calculated from death and population counts, disaggregated by 5 year age group and by underlying cause of death. Arriaga’s method of life expectancy decomposition was applied to produce estimates of the contribution of different age groups and underlying causes to changes in life expectancy at birth for the two periods.Results Annualised gains in life expectancy between 2012–2014 and 2015–2017 were markedly smaller than in the earlier period. Almost all age groups saw worsening mortality trends, which deteriorated for most cause of death groups between 2012–2014 and 2015–2017. In particular, the previously observed substantial life expectancy gains due to reductions in mortality from circulatory causes, which most benefited those aged 55–84 years, more than halved. Mortality rates for those aged 30–54 years and 90+ years worsened, due in large part to increases in drug-related deaths, and dementia and Alzheimer’s disease, respectively.Conclusion Future research should seek to explain the changes in mortality trends for all age groups and causes. More investigation is required to establish to what extent shortcomings in the social security system and public services may be contributing to the adverse trends and preventing mitigation of the impact of other contributing factors, such as influenza outbreaks.

Introduction There have been steady reductions in mortality rates in the majority of high-income countries, including Scotland, since 1945. However, reductions in mortality rates have slowed down since 2012–2014 in these nations; and have reversed in some cases. Deaths among those aged 55+ explain a large amount of these changing mortality trends in Scotland. Increased pressures on health and social care services have been suggested as one factor explaining these changes. This paper outlines a protocol for the approach to testing the extent to which health and social care pressures can explain recent mortality trends in Scotland. Although a slower rate of mortality improvements have affected people of all ages, certain ages have been more negatively affected than the others. The current analyses will be run by age-band to test if the service pressure-mortality link varies across age-group.Methods and analysis This will be an observational ecological study based on the Scottish population. The exposures of interest will be the absolute (primary outcome) and percentage (secondary outcome) change in real terms per capita spending on social and healthcare services between 2011 and 2017. The outcome of interest will be the absolute (primary outcome) and percentage (secondary outcome) change in age-standardised mortality rate between 2012 and 2018 for men and women separately. The units of analysis will be the 32 local authorities and the 14 territorial health boards. The analyses will be run for both all age-groups combined and for the following age bands:

Introduction Mortality rates in many high-income countries have changed from their long-term trends since around 2011. This paper sets out a protocol for testing the extent to which economic austerity can explain the variance in recent mortality trends across high-income countries.Methods and analysis This is an ecological natural experiment study, which will use regression adjustment to account for differences in exposure, outcomes and confounding. All high-income countries with available data will be included in the sample. The timing of any changes in the trends for four measures of austerity (the Alesina-Ardagna Fiscal Index, real per capita government expenditure, public social spending and the cyclically adjusted primary balance) will be identified and the cumulative difference in exposure to these measures thereafter will be calculated. These will be regressed against the difference in the mean annual change in life expectancy, mortality rates and lifespan variation compared with the previous trends, with an initial lag of 2 years after the identified change point in the exposure measure. The role of underemployment and individual incomes as outcomes in their own right and as mediating any relationship between austerity and mortality will also be considered. Sensitivity analyses varying the lag period to 0 and 5 years, and adjusting for recession, will be undertaken.Ethics and dissemination All of the data used for this study are publicly available, aggregated datasets with no individuals identifiable. There is, therefore, no requirement for ethical committee approval for the study. The study will be lodged within the National Health Service research governance system. All results of the study will be published following sharing with partner agencies. No new datasets will be created as part of this work for deposition or curation.

Growing resistant wheat (Triticum aestivum L) varieties is an important strategy for the control of leaf rust, caused by Puccinia triticina Eriks. This study sought to identify the chromosomal location and effects of leaf rust resistance loci in five Canadian spring wheat cultivars. The parents and doubled haploid lines of crosses Carberry/AC Cadillac, Carberry/Vesper, Vesper/Lillian, Vesper/Stettler and Stettler/Red Fife were assessed for leaf rust severity and infection response in field nurseries in Canada near Swift Current, SK from 2013 to 2015, Morden, MB from 2015 to 2017 and Brandon, MB in 2016, and in New Zealand near Lincoln in 2014. The populations were genotyped with the 90K Infinium iSelect assay and quantitative trait loci (QTL) analysis was performed. A high density consensus map generated based on 14 doubled haploid populations and integrating SNP and SSR markers was used to compare QTL identified in different populations. AC Cadillac contributed QTL on chromosomes 2A, 3B and 7B (2 loci), Carberry on 1A, 2B (2 loci), 2D, 4B (2 loci), 5A, 6A, 7A and 7D, Lillian on 4A and 7D, Stettler on 2D and 6B, Vesper on 1B, 1D, 2A, 6B and 7B (2 loci), and Red Fife on 7A and 7B. Lillian contributed to a novel locus QLr.spa-4A, and similarly Carberry at QLr.spa-5A. The discovery of novel leaf rust resistance QTL QLr.spa-4A and QLr.spa-5A, and several others in contemporary Canada Western Red Spring wheat varieties is a tremendous addition to our present knowledge of resistance gene deployment in breeding. Carberry demonstrated substantial stacking of genes which could be supplemented with the genes identified in other cultivars with the expectation of increasing efficacy of resistance to leaf rust and longevity with little risk of linkage drag.

Abstract Background Epigenetic age acceleration (an older methylation age compared to chronological age) correlates strongly with various age-related morbidities and mortality. Chronic systemic inflammation is thought to be a hallmark of ageing, but the relationship between an increased epigenetic age and this likely key phenotype of ageing has not yet been extensively investigated. Methods We modelled the trajectories of the inflammatory biomarkers C-reactive protein (CRP; measured using both a high- and low-sensitivity assay) and interleukin-6 (IL-6) over the eighth decade in the Lothian Birth Cohort 1936. Using linear mixed models, we investigated the association between CRP and immune cell profiles imputed from the methylation data and examined the cross-sectional and longitudinal association between the inflammatory biomarkers and two measures of epigenetic age acceleration, derived from the Horvath and Hannum epigenetic clocks. Results We found that low-sensitivity CRP declined, high-sensitivity CRP did not change, and IL-6 increased over time within the cohort. CRP levels inversely associated with CD8+T cells and CD4+T cells and positively associated with senescent CD8+T cells, plasmablasts and granulocytes. Cross-sectionally, the Hannum, but not the Horvath, measure of age acceleration was positively associated with each of the inflammatory biomarkers, including a restricted measure of CRP (≤ 10 mg/L) likely reflecting levels relevant to chronic inflammation. Conclusions We found a divergent relationship between inflammation and immune system parameters in older age. We additionally report the Hannum measure of epigenetic age acceleration associated with an elevated inflammatory profile cross-sectionally, but not longitudinally.

Background: Multiple studies have made robust associations between differential DNA methylation and exposure to cigarette smoke. But whether a DNA methylation phenotype is established immediately upon exposure, or only after prolonged exposure is less well–established. Here, we assess DNA methylation patterns from peripheral blood samples in current smokers in response to dose and duration of exposure, along with the effects of smoking cessation on DNA methylation in former smokers. Methods: Dimensionality reduction was applied to DNA methylation data at 90 previously identified smoking–associated CpG sites for over 4900 individuals in the Generation Scotland cohort. K–means clustering was performed to identify clusters associated with current and never smoker status based on these methylation patterns. Cluster assignments were assessed with respect to duration of exposure in current smokers (years as a smoker), time since smoking cessation in former smokers (years), and dose (cigarettes per day). Findings: Two clusters were specified, corresponding to never smokers (97·5% of whom were assigned to Cluster 1) and current smokers (81·1% of whom were assigned to Cluster 2). The exposure time point from which >50% of current smokers were assigned to the smoker–enriched cluster varied between 5 and 9 years in heavier smokers and between 15 and 19 years in lighter smokers. Low–dose former smokers were more likely to be assigned to the never smoker–enriched cluster in the first year following cessation. In contrast, a period of at least two years was required before the majority of former high–dose smokers were assigned to the never smoker–enriched cluster. Interpretation: Our findings suggest that smoking–associated DNA methylation changes are a result of prolonged exposure to cigarette smoke, and can be reversed following cessation. The length of time in which these signatures are established and recovered is dose dependent. Should DNA methylation–based signatures of smoking status be predictive of smoking–related health outcomes, our findings may provide an additional criterion on which to stratify risk. Keywords: DNA methylation, Epigenetics, Smoking, Epidemiology

The era of biologic agents for the treatment of Crohn’s disease has brought about significant benefits for patients, and since the introduction of infliximab at the turn of the century, the entire field has moved on rapidly. Clinicians now have multiple agents at their disposal and a choice between several different anti-inflammatory mechanisms of action. This has allowed unprecedented improvements not only in symptoms and quality of life for patients previously refractory to conventional treatments but also for demonstrated healing of the intestinal mucosa and resolution of perianal fistulation. However, despite the undisputed efficacy of these agents, there remains a significant proportion of patients who fail to gain a meaningful benefit. Through years of studying infliximab and its counterpart anti-tumour necrosis factor (anti-TNF) agent, adalimumab, we now understand that strategies such as combining use with a conventional immunomodulator or measuring serum levels can help to optimise outcomes and reduce the proportion of patients for whom treatment fails. Work is ongoing to understand whether these principles apply to newer biologics such as vedolizumab and ustekinumab. In addition, novel approaches are being investigated in an attempt to maximise the benefit that these agents could offer. In this article, we summarise these new understandings and consider ways in which they could be integrated into clinical practice for the benefit of patients.

Brain decoding-the process of inferring a person's momentary cognitive state from their brain activity-has enormous potential in the field of human-computer interaction. In this study we propose a zero-shot EEG-to-image brain decoding approach which makes use of state-of-the-art EEG preprocessing and feature selection methods, and which maps EEG activity to biologically inspired computer vision and linguistic models. We apply this approach to solve the problem of identifying viewed images from recorded brain activity in a reliable and scalable way. We demonstrate competitive decoding accuracies across two EEG datasets, using a zero-shot learning framework more applicable to real-world image retrieval than traditional classification techniques.

BackgroundIncreasingly Burden of Disease (BOD) measures are being used to influence policy decisions because they summarise the complete effects of morbidity and mortality in an equitable manner. An important element of producing non-fatal BOD estimates are severity distributions. The Global Burden of Disease (GBD) study use the same severity distributions across countries due to a lack of available country-specific data. In the Scottish BOD (SBOD) study we developed national severity distributions for cancer types. The main aim of this study was to consider the extent to which the use of worldwide severity distributions in BOD studies are influencing cross-country comparisons, by comparing weighted-average disability weights (DW) based on GBD severity distributions with nationally derived severity distributions in Scotland for cancer types.MethodsWe obtained individual records from the Scottish Cancer Registry for 21 cancer types and linked these to registered deaths. We estimated prevalent cancer cases for 2016 and assigned each case to sequelae using GBD 2016 study definitions. We compared the impact of using severity distributions based on GBD 2016, a Scotland-wide distribution, and distributions specific to deprivation strata in Scotland, on the weighted-average DW for each cancer type.ResultsThe relative difference in point estimates of weighted-average DW based on GBD 2016 worldwide severity distributions compared with Scottish national severity distributions resulted in overestimates in the majority of cancers (17 out of 21 cancer types). The largest overestimates were for gallbladder and biliary tract cancer (70.8%), oesophageal cancer (31.6%) and pancreatic cancer (31.2%). Furthermore, the use of weighted-average DW based on Scottish national severity distributions rather than sub-national Scottish severity distributions stratified by deprivation quintile overestimated weighted-average DW in the least deprived areas (16 out of 18 cancer types), and underestimated in the most deprived areas (16 out of 18 cancer types).ConclusionOur findings illustrate a bias in point estimates of weighted-average DW created using worldwide severity distributions. This bias would have led to the misrepresentation of non-fatal estimates of the burden of individual cancers, and underestimated the scale of socioeconomic inequality in this non-fatal burden. This highlights the importance of not interpreting non-fatal estimates of burden of disease too precisely, especially for sub-national estimates and those comparing populations when relying on data inputs from other countries. It is essential to ensure that any estimates are based upon country-specific data as far as possible.

BackgroundThe availability of robust evidence to inform effective public health decision making is becoming increasingly important, particularly in a time of competing health demands and limited resources. Comparative Risk Assessments (CRA) are useful in this regard as they quantify the contribution of modifiable exposures to the disease burden in a population. The aim of this study is to assess the contribution of a range of modifiable exposures to the burden of disease due to stroke, an important public health problem in Scotland.MethodsWe used individual-level response data from eight waves (1995-2012) of the Scottish Health Survey linked to acute hospital discharge records from the Scottish Morbidity Record 01 (SMR01) and cause of death records from the death register. Stroke was defined using the International Classification of Disease (ICD) 9 codes 430-431, 433-4 and 436; and the ICD10 codes I60-61 and I63-64 and stroke incidence was defined as a composite of an individual's first hospitalisation or death from stroke. A literature review identified exposures causally linked to stroke. Exposures were mapped to the layers of the Dahlgren & Whitehead model of the determinants of health and Population Attributable Fractions were calculated for each exposure deemed a significant causal risk of stroke from a Cox Proportional Hazards Regression model. Population Attributable Fractions were not summed as they may add to more than 100% due to the possibility of a person being exposed to more than one exposure simultaneously.ResultsOverall, the results suggest that socioeconomic factors explain the largest proportion of incident stroke hospitalisations and deaths, after adjustment for confounding. After DAG adjustment, low education explained 38.8% (95% Confidence Interval 26.0% to 49.4%, area deprivation (as measured by the Scottish Index of Multiple Deprivation) 34.9% (95% CI 26.4 to 42.4%), occupational social class differences 30.3% (95% CI 19.4% to 39.8%), high systolic blood pressure 29.6% (95% CI 20.6% to 37.6%), smoking 25.6% (95% CI 17.9% to 32.6%) and area deprivation (as measured by the Carstairs area deprivation Index) 23.5% (95% CI 14.4% to 31.7%), of incident strokes in Scotland after adjustment.ConclusionThis study provides evidence for prioritising interventions that tackle socioeconomic inequalities as a means of achieving the greatest reduction in avoidable strokes in Scotland. Future work to disentangle the proportion of the effect of deprivation transmitted through intermediate mediators on the pathway between socioeconomic inequalities and stroke may offer additional opportunities to reduce the incidence of stroke in Scotland.

In social animals, scent secretions and marking behaviors play critical roles in communication, including intraspecific signals, such as identifying individuals and group membership, as well as interspecific signaling. Anal sacs are an important odor producing organ found across the carnivorans (species in the mammalian Order Carnivora). Secretions from the anal sac may be used as chemical signals by animals for behaviors ranging from defense to species recognition to signaling reproductive status. In addition, a recent study suggests that domestic cats utilize short-chain free fatty acids in anal sac secretions for individual recognition. The fermentation hypothesis is the idea that symbiotic microorganisms living in association with animals contribute to odor profiles used in chemical communication and that variation in these chemical signals reflects variation in the microbial community. Here we examine the fermentation hypothesis by characterizing volatile organic compounds (VOC) and bacteria isolated from anal sac secretions collected from a male Bengal cat (Felis catus × Prionailurus bengalensis), a cross between the domestic cat and the leopard cat. Both left and right anal sacs of a male Bengal cat were manually expressed (emptied) and collected. Half of the material was used to culture bacteria or to extract bacterial DNA and the other half was used for VOC analysis. DNA was extracted from the anal sac secretions and used for a 16S rRNA gene PCR amplification and sequencing based characterization of the microbial community. Additionally, some of the material was plated out in order to isolate bacterial colonies. Three taxa (Bacteroides fragilis, Tessaracoccus, and Finegoldia magna) were relatively abundant in the 16S rRNA gene sequence data and also isolated by culturing. Using Solid Phase Microextraction (SPME) gas chromatography-mass spectrometry (GC-MS), we tentatively identified 52 compounds from the Bengal cat anal sac secretions and 67 compounds from cultures of the three bacterial isolates chosen for further analysis. Among 67 compounds tentatively identified from bacterial isolates, 51 were also found in the anal sac secretion. We show that the bacterial community in the anal sac consists primarily of only a few abundant taxa and that isolates of these taxa produce numerous volatiles that are found in the combined anal sac volatile profile. Several of these volatiles are found in anal sac secretions from other carnivorans, and are also associated with known bacterial biosynthesis pathways. This is consistent with the fermentation hypothesis and the possibility that the anal sac is maintained at least in part to house bacteria that produce volatiles for the host.

Kernel morphology characteristics of wheat are complex and quantitatively inherited. A doubled haploid (DH) population of the cross RL4452/'AC Domain' was used to study the genetic basis of seed shape. Quantitative trait loci (QTL) analyses were conducted on a total of 18 traits: 14 grain shape traits, flour yield (Fyd), and three agronomic traits (Plant height [Plht], 1000 Grain weight [Gwt], Test weight [Twt]), using data from trial locations at Glenlea, Brandon, and Morden in Manitoba, Canada, between 1999 and 2004. Kernel shape was studied through digital image analysis with an Acurum® grain analyzer. Plht, Gwt, Twt, Fyd, and grain shape QTL were correlated with each other and QTL analysis revealed that QTL for these traits often mapped to the same genetic locations. The most significant QTL for the grain shape traits were located on chromosomes 4B and 4D, each accounting for up to 24.4% and 53.3% of the total phenotypic variation, respectively. In addition, the most significant QTL for Plht, Gwt, and Twt were all detected on chromosome 4D at the Rht-D1 locus. Rht-D1b decreased Plht, Gwt, Twt, and kernel width relative to the Rht-D1a allele. A narrow genetic interval on chromosome 4B contained significant QTL for grain shape, Gwt, and Plht. The 'AC Domain' allele reduced Plht, Gwt, kernel length and width traits, but had no detectable effect on Twt. The data indicated that this variation was inconsistent with segregation at Rht-B1. Numerous QTL were identified that control these traits in this population.

BACKGROUND:Cause-specific mortality trends are routinely reported for Scotland. However, ill-defined deaths are not routinely redistributed to more precise and internationally comparable categories nor is the mortality reported in terms of years of life lost to facilitate the calculation of the burden of disease. This study describes trends in Years of Life Lost (YLL) for specific causes of death in Scotland from 2000 to 2015. METHODS:We obtained records of all deaths in Scotland by age, sex, area and underlying cause of death between 2000 and 2015. We redistributed Ill-Defined Deaths (IDDs) to more exact and meaningful causes using internationally accepted methods. Years of Life Lost (YLL) using remaining life expectancy by sex and single year of age from the 2013 Scottish life table were calculated for each death. These data were then used to calculate the crude and age-standardised trends in YLL by age, sex, cause, health board area, and area deprivation decile. RESULTS:Between 2000 and 2015, the annual percentage of deaths that were ill-defined varied between 10% and 12%. The proportion of deaths that were IDDs increased over time and were more common: in women; amongst those aged 1-4 years, 25-34 years and >80 years; in more deprived areas; and in the island health boards. The total YLL fell from around 17,800 years per 100,000 population in 2000 to around 13,500 years by 2015. The largest individual contributors to YLL were Ischaemic Heart Disease (IHD), respiratory cancers, Chronic Obstructive Pulmonary Disease (COPD), cerebrovascular disease and Alzheimer's/dementia. The proportion of total YLL due to IHD and stroke declined over time, but increased for Alzheimer's/dementia and drug use disorders. There were marked absolute inequalities in YLL by area deprivation, with a mean Slope Index of Inequality (SII) for all causes of 15,344 YLL between 2001 and 2015, with IHD and COPD the greatest contributors. The Relative Index of Inequality (RII) for YLL was highest for self-harm and lower respiratory infections. CONCLUSION:The total YLL per 100,000 population in Scotland has declined over time. The YLL in Scotland is predominantly due to a wide range of chronic diseases, substance misuse, self-harm and increasingly Alzheimer's disease and dementia. Inequalities in YLL, in both relative and absolute terms, are stark.

Although substantial attention has focused on efforts by the new Administration to block environmental policies, climate politics have been contentious in the US since well before the election of Donald Trump. In this paper, we extend previous work on empirical examinations of echo chambers in US climate politics using new data collected on the federal climate policy network in summer 2016. We test for the similarity and differences at two points in time in homophily and echo chambers using Exponential Random Graph Models (ERGM) to compare new findings from 2016 to previous work on data from 2010. We show that echo chambers continue to play a significant role in the network of information exchange among policy elites working on the issue of climate change. In contrast to previous findings where echo chambers centered on a binding international commitment to emission reductions, we find that the pre-existing echo chambers have almost completely disappeared and new structures have formed around one of the main components of the Obama Administration's national climate policy: the Clean Power Plan. These results provide empirical evidence that science communication and policymaking at the elite level shift in relation to the policy instruments under consideration.

BackgroundReducing health inequalities is an important policy objective but there is limited quantitative information about the impact of specific interventions.ObjectivesTo provide estimates of the impact of a range of interventions on health and health inequalities.Materials and methodsLiterature reviews were conducted to identify the best evidence linking interventions to mortality and hospital admissions. We examined interventions across the determinants of health: a 'living wage'; changes to benefits, taxation and employment; active travel; tobacco taxation; smoking cessation, alcohol brief interventions, and weight management services. A model was developed to estimate mortality and years of life lost (YLL) in intervention and comparison populations over a 20-year time period following interventions delivered only in the first year. We estimated changes in inequalities using the relative index of inequality (RII).ResultsIntroduction of a 'living wage' generated the largest beneficial health impact, with modest reductions in health inequalities. Benefits increases had modest positive impacts on health and health inequalities. Income tax increases had negative impacts on population health but reduced inequalities, while council tax increases worsened both health and health inequalities. Active travel increases had minimally positive effects on population health but widened health inequalities. Increases in employment reduced inequalities only when targeted to the most deprived groups. Tobacco taxation had modestly positive impacts on health but little impact on health inequalities. Alcohol brief interventions had modestly positive impacts on health and health inequalities only when strongly socially targeted, while smoking cessation and weight-reduction programmes had minimal impacts on health and health inequalities even when socially targeted.ConclusionsInterventions have markedly different effects on mortality, hospitalisations and inequalities. The most effective (and likely cost-effective) interventions for reducing inequalities were regulatory and tax options. Interventions focused on individual agency were much less likely to impact on inequalities, even when targeted at the most deprived communities.

Stem rust, caused by Puccinia graminis (Pgt), is a damaging disease of wheat that can be controlled by utilizing effective stem rust resistance genes. 'Thatcher' wheat carries complex resistance to stem rust that is enhanced in the presence of the resistance gene Lr34. The purpose of this study was to examine APR in 'Thatcher' and look for genetic interactions with Lr34. A RIL population was tested for stem rust resistance in field nurseries in Canada, USA, and Kenya. BSA was used to find SNP markers associated with reduced stem rust severity. A major QTL was identified on chromosome 3BL near the centromere in all environments. Seedling testing showed that Sr12 mapped to the same region as the QTL for APR. The SNP markers were physically mapped and the region carrying the resistance was searched for sequences with homology to members of the NB-LRR resistance gene family. SNP marker from one NB-LRR-like sequence, NB-LRR3 co-segregated with Sr12. Two additional populations, including one that lacked Lr34, were tested in field nurseries. NB-LRR3 mapped near the maximum LOD for reduction in stem rust severity in both populations. Lines from a population that segregated for Sr12 and Lr34 were tested for seedling Pgt biomass and infection type, as well as APR to field stem rust which showed an interaction between the genes. We concluded that Sr12, or a gene closely linked to Sr12, was responsible for 'Thatcher'-derived APR in several environments and this resistance was enhanced in the presence of Lr34.

Studies assessing the costs of alcoholic liver disease are lacking. We aimed to calculate the costs of hospitalisations before and after diagnosis compared to population controls matched by age, sex and socio-economic deprivation. We aimed to use population level data to identify a cohort of individuals hospitalised for the first time with alcoholic liver disease in Scotland between 1991 and 2011.Incident cases were classified by disease severity, sex, age group, socio-economic deprivation and year of index admission. 5 matched controls for every incident case were identified from the Scottish population level primary care database. Hospital costs were calculated for both cases and controls using length of stay from morbidity records and hospital-specific daily rates by specialty. Remaining lifetime costs were estimated using parametric survival models and predicted annual costs. 35,208 incident alcoholic liver disease hospitalisations were identified. Mean annual hospital costs for cases were 2.3 times that of controls pre diagnosis (£804 higher) and 10.2 times (£12,774 higher) post diagnosis. Mean incident admission cost was £6,663. Remaining lifetime cost for a male, 50-59 years old, living in the most deprived area diagnosed with acoholic liver disease was estimated to be £65,999 higher than the matched controls (£12,474 for 7.43 years remaining life compared to £1,224 for 21.8 years). In Scotland, alcoholic liver disease diagnosis is associated with significant increases in admissions to hospital both before and after diagnosis. Our results provide robust population level estimates of costs of alcoholic liver disease for the purposes of health-care delivery, planning and future cost-effectiveness analyses.

BACKGROUND:Fusarium head blight (FHB) caused by Fusarium graminearum not only causes severe losses in yield, but also reduces quality of wheat grain by accumulating mycotoxins. Breeding for host plant resistance is considered as the best strategy to manage FHB. Resistance in wheat to FHB is quantitative in nature, involving cumulative effects of many genes governing resistance. The poor understanding of genetics and lack of precise phenotyping has hindered the development of FHB resistant cultivars. Though more than 100 QTLs imparting FHB resistance have been reported, none discovered the specific genes localized within the QTL region, nor the underlying mechanisms of resistance. FINDINGS:In our study recombinant inbred lines (RILs) carrying resistant (R-RIL) and susceptible (S-RIL) alleles of QTL-Fhb2 were subjected to metabolome and transcriptome profiling to discover the candidate genes. Metabolome profiling detected a higher abundance of metabolites belonging to phenylpropanoid, lignin, glycerophospholipid, flavonoid, fatty acid, and terpenoid biosynthetic pathways in R-RIL than in S-RIL. Transcriptome analysis revealed up-regulation of several receptor kinases, transcription factors, signaling, mycotoxin detoxification and resistance related genes. The dissection of QTL-Fhb2 using flanking marker sequences, integrating metabolomic and transcriptomic datasets, identified 4-Coumarate: CoA ligase (4CL), callose synthase (CS), basic Helix Loop Helix (bHLH041) transcription factor, glutathione S-transferase (GST), ABC transporter-4 (ABC4) and cinnamyl alcohol dehydrogenase (CAD) as putative resistance genes localized within the QTL-Fhb2 region. CONCLUSION:Some of the identified genes within the QTL region are associated with structural resistance through cell wall reinforcement, reducing the spread of pathogen through rachis within a spike and few other genes that detoxify DON, the virulence factor, thus eventually reducing disease severity. In conclusion, we report that the wheat resistance QTL-Fhb2 is associated with high rachis resistance through additive resistance effects of genes, based on cell wall enforcement and detoxification of DON. Following further functional characterization and validation, these resistance genes can be used to replace the genes in susceptible commercial cultivars, if nonfunctional, based on genome editing to improve FHB resistance.

A sample of caecal effluent was obtained from a female patient who had undergone a routine colonoscopic examination. Bacteria were isolated anaerobically from the sample, and screened against the remaining filtered caecal effluent in an attempt to isolate bacteriophages (phages). A lytic phage, named KLPN1, was isolated on a strain identified as Klebsiella pneumoniae subsp. pneumoniae (capsular type K2, rmpA+). This Siphoviridae phage presents a rosette-like tail tip and exhibits depolymerase activity, as demonstrated by the formation of plaque-surrounding haloes that increased in size over the course of incubation. When screened against a panel of clinical isolates of K. pneumoniae subsp. pneumoniae, phage KLPN1 was shown to infect and lyse capsular type K2 strains, though it did not exhibit depolymerase activity on such hosts. The genome of KLPN1 was determined to be 49,037 bp (50.53 %GC) in length, encompassing 73 predicted ORFs, of which 23 represented genes associated with structure, host recognition, packaging, DNA replication and cell lysis. On the basis of sequence analyses, phages KLPN1 (GenBank: KR262148) and 1513 (a member of the family Siphoviridae, GenBank: KP658157) were found to be two new members of the genus “Kp36likevirus.”

Epidemic strains of Pseudomonas aeruginosa have been found worldwide among the cystic fibrosis (CF) patient population. Using pulse-field gel electrophoresis, the Prairie Epidemic Strain (PES) has recently been found in one-third of patients attending the Calgary Adult CF Clinic in Canada. Using multi-locus sequence typing, PES isolates from unrelated patients were found to consistently have ST192. Though most patients acquired PES prior to enrolling in the clinic, some patients were observed to experience strain replacement upon transitioning to the clinic whereby local non-epidemic P. aeruginosa isolates were displaced by PES. Here we genotypically and phenotypically compared PES to other P. aeruginosa epidemic strains (OES) found around the world as well as local non-epidemic CF P. aeruginosa isolates in order to characterize PES. Since some epidemic strains are associated with worse clinical outcomes, we assessed the pathogenic potential of PES to determine if these isolates are virulent, shared properties with OES, and if its phenotypic properties may offer a competitive advantage in displacing local non-epidemic isolates during strain replacement. As such, we conducted a comparative analysis using fourteen phenotypic traits, including virulence factor production, biofilm formation, planktonic growth, mucoidy, and antibiotic susceptibility to characterize PES, OES, and local non-epidemic isolates. We observed that PES and OES could be differentiated from local non-epidemic isolates based on biofilm growth with PES isolates being more mucoid. Pairwise comparisons indicated that PES produced significantly higher levels of proteases and formed better biofilms than OES but were more susceptible to antibiotic treatment. Amongst five patients experiencing strain replacement, we found that super-infecting PES produced lower levels of proteases and elastases but were more resistant to antibiotics compared to the displaced non-epidemic isolates. This comparative analysis is the first to be completed on a large scale between groups of epidemic and non-epidemic CF P. aeruginosa isolates.

We present a case of a 21 year old male patient diagnosed with a 2.2 cm prolactin-secreting adenoma in contact with the optic chiasm. The patient was treated with up to 6mg/week of cabergoline (total cumulative dose 814 mg) and developed mild valvulopathy. Valvulopathy was subsequently reversed after discontinuation of cabergoline therapy.

The extant snake fauna has its roots in faunal upheaval occurring across the Paleogene-Neogene transition. On northern continents, this turnover is well established by the late early Miocene. However, this transition is poorly documented on southern landmasses, particularly on continental Africa, where no late Paleogene terrestrial snake assemblages are documented south of the equator. Here we describe a newly discovered snake fauna from the Late Oligocene Nsungwe Formation in the Rukwa Rift Basin of Tanzania. The fauna is small but diverse with eight identifiable morphotypes, comprised of three booids and five colubroids. This fauna includes Rukwanyoka holmani gen. et sp. nov., the oldest boid known from mainland Africa. It also provides the oldest fossil evidence for the African colubroid clade Elapidae. Colubroids dominate the fauna, comprising more than 75% of the recovered material. This is likely tied to local aridification and/or seasonality and mirrors the pattern of overturn in later snake faunas inhabiting the emerging grassland environments of Europe and North America. The early emergence of colubroid dominance in the Rukwa Rift Basin relative to northern continents suggests that the pattern of overturn that resulted in extant faunas happened in a more complex fashion on continental Africa than was previously realized, with African colubroids becoming at least locally important in the late Paleogene, either ahead of or as a consequence of the invasion of colubrids. The early occurrence of elapid snakes in the latest Oligocene of Africa suggests the clade rapidly spread from Asia to Africa, or arose in Africa, before invading Europe.

Reproductive isolation at the gamete stage has become a focus of speciation research because of its potential to evolve rapidly between closely related species. Conspecific sperm precedence (CSP), a type of gametic isolation, has been demonstrated in a number of taxa, both marine and terrestrial, with the potential to play an important role in speciation. Free-spawning marine invertebrates are ideal subjects for the study of CSP because of a likely central role for gametic barriers in reproductive isolation. The western Atlantic Mytilus blue mussel hybrid zone, ranging from the Atlantic Canada to eastern Maine, exhibits characteristics conducive to the study of CSP. Previous studies have shown that gametic incompatibility is incomplete, variable in strength and the genotype distribution is bimodal-dominated by the parental species, with a low frequency of hybrids. We conducted gamete crossing experiments using M. trossulus and M. edulis individuals collected from natural populations during the spring spawning season in order to detect the presence or absence of CSP within this hybrid zone. We detected CSP, defined here as a reduction in heterospecific offspring from competitive fertilizations in vitro compared to that seen in non-competitive fertilizations, in five of the twelve crosses in which conspecific crosses were detectable. This is the first finding of CSP in a naturally hybridizing population of a free-spawning marine invertebrate. Our findings support earlier predictions that CSP can promote assortative fertilization in bimodal hybrid zones, further advancing their hypothesized progression towards full speciation. Despite strong CSP numerous heterospecific fertilizations remain, reinforcing the hypothesis that compatible females are a source of hybrid offspring in mixed natural spawns.

There has been increasing pressure on farmers in Europe to reduce the emissions of ammonia from their land. Due to the current financial climate in which farmers have to operate, it is important to identify ammonia control measures that can be adopted with minimum cost. The planting of trees around farmland and buildings has been identified as a potentially effective and low-cost measure to enhance ammonia recapture at a farm level and reduce long-range atmospheric transport. This work assesses experimentally what fraction of ammonia farm woodlands could potentially remove from the atmosphere. We constructed an experimental facility in southern Scotland to simulate a woodland shelterbelt planted in proximity to a small poultry unit. By measuring horizontal and vertical ammonia concentration profiles within the woodland, and comparing this to the concentration of an inert tracer (SF6) we estimate the depletion of ammonia due to dry deposition to the woodland canopy. Together with measurements of mean ammonia concentrations and throughfall fluxes of nitrogen, this information is used to provide a first estimate of the fraction of emitted ammonia that is recaptured by the woodland canopy. Analysis of these data give a lower limit of recapture of emitted ammonia, at the experimental facility, of 3%. By careful design of shelterbelt woodlands this figure could be significantly higher.