Health and social care workers experiences of coping while working in the frontline during the COVID-19 pandemic: One year on

BACKGROUND: The unprecedented pressure of working on the frontline during the Covid-19 pandemic had a demonstrable impact on the mental health and wellbeing of health and social care workers in the early stages of the pandemic, however, less research has focused on workers' experiences over the longer course of the pandemic. AIMS: We set out to develop an explanatory model of the processes that helped and hindered the coping of HSCWs working over the course of the Covid-19 pandemic. METHOD: Twenty HSCWs based in the UK took part in the study. They completed semi-structured interviews 12-18 months after the peak of the first wave in the UK. Interviews were transcribed and analysed using grounded theory methodology. RESULTS: The analysis identified eleven theoretical codes: personal context, organisational resources, organisational response, management, colleagues, decision-making and responsibilities, internal impacts, external impactors, safety, barriers to accessing support and temporal factors. The findings suggest that factors related to the individual themselves, their personal context, the organisation they work in, their managers, the support structures around them and their sense of safety impacted on HSCWs; ability to cope. Some factors changed over time throughout the first year of the pandemic, such as workload and staff illness, which further impacted HSCWs' coping. There were many barriers to accessing support that also impacted coping, including availability, awareness and time. The relationship between the factors that impacted coping are represented in an explanatory model. CONCLUSIONS: The findings extend previous studies on the mental health impact on frontline HSCWs working during Covid-19, providing novel insight by developing an explanatory model illustrating the underlying factors that impacted their coping experiences over the course of the pandemic in the UK. The findings from this study may assist in the development of improved and more effective support for HSCWs going forwards

The livelihood impacts of cash transfers in sub-Saharan Africa: beneficiary perspectives from six countries

Cash transfers (CTs) are a social protection mechanism to reduce the poorest households’ vulnerability to shocks and build human capital by smoothing consumption and sustaining expenditure on education and social welfare. Our study examines whether and how CTs go beyond welfare objectives to promote livelihoods. Presenting a cross-case analysis using original qualitative data on beneficiary perspectives from six African countries - Kenya, Ethiopia, Malawi, Lesotho, Zimbabwe and Ghana – we explore CT livelihood impacts within household economies and social networks, paying attention to gender issues. We find that a small but predictable flow of cash improves strategic livelihood choices and stimulates productive investments, including through positive effects on beneficiary entry into risk-sharing arrangements and networks for economic collaboration. Levels of household vulnerability and labour constraint nevertheless significantly mediate the ability of CTs to consolidate present livelihood outcomes. The varying availability of economic opportunities and effective programme implementation also shape livelihood impact. Incorporating beneficiary perspectives brings to the fore the multi-dimensionality of CT effects on experiences of poverty and deprivation, including gender dynamics and intangibles such as dignity and respect; they add powerful realism to the influence of the CT on both immediate survival and livelihood choices. Beyond this, they confirm wider knowledge on productive impact and bring nuance to the conditions under which, and mechanisms by which beneficiaries’ use CTs to build productive capability and assets and to make strategic livelihood choices

Assessment of carbon capture and storage in natural systems within the English North Sea (Including within Marine Protected Areas)

This report was commissioned by the North Sea Wildlife Trusts, Blue Marine Foundation, WWF and the RSPB to assess the extent, scale, distribution, and potential of the current blue carbon sinks in the English North Sea (i.e. seabed sediments, saltmarsh, kelp forests, seagrass beds and biogenic reefs). The focus was to i) review the current extent and distribution of each blue carbon habitat, ii) estimate the quantity of carbon currently stored within these habitats, iii) establish the average net sequestration rate (i.e. gC m-2 yr-1), and iv) estimate the potential net total sequestration (i.e. gC yr-1) of each blue carbon habitat. This analysis synthesises and reviews the most up-to-date scientific literature on fixation, processing, and storage of carbon in the English North Sea, including within Marine Protected Areas (MPAs). Carbon stock densities and rates of production and storage are combined with measures of habitat area to give estimates of total carbon stored in blue carbon habitats and their associated sediment stores. The results are intended to inform management decisions and identify opportunities to enhance the seabed and their carbon sequestration potential. Evidence of this nature will contribute to explore the potential of the English North Sea Marine Protected Area (MPA) network to help mitigate against the effects of climate change. Extents of blue carbon habitats for the North Sea region were derived from available sources. These include the EUNIS level 3 combined map from JNCC, Natural England Marine Habitats and Species Open Data, and recently published estimates of organic carbon (OC) and inorganic carbon (IC) stocks in surface sediments (Smeaton et al., 2021). Where maps of coastal habitats based on surveys were not available, including kelp and seagrass, extents of these habitats were estimated from models. Limitations of the estimates produced here link primarily to poorly constrained spatial extents of blue carbon habitats at the scales required for this report. For some habitats (intertidal and subtidal sediments), confidence in observational understanding of long-term sequestration is very low, as is that for transport and fate of carbon from macroalgae. Kelp forests in the region, for example, have received little attention compared to the rest of the United Kingdom. Furthermore, the science of understanding the effects of physical disturbance (including trawling) and climate change on these systems is very much in its infancy and new developments will allow a much better-informed outlook for the fate of these stocks and accumulation rates in a changing world and under varying management scenarios. Direct comparison between these North Sea carbon stores and those in terrestrial vegetation and soils are fraught with difficulty. Carbon stock sizes (MtC) and density per unit area (t/km2) are assessed differently, over different areas of habitats, and different timescales for storage of reported stocks. Carbon in living material may persist for years or decades, while that buried in soils and marine sediments may last for 100s to 1000s of years. Such lack of comparability renders straight numerical comparisons nearly meaningless. This is even more of a problem when comparing marine and terrestrial stocks, where soils and sediments and the nature of vegetated habitats are so radically different from each other. Depths of soils considered are a vital consideration. Here we consider marine sediments to a depth of only 10cm, while carbon in terrestrial soils is often reported to depths, typically 30cm to a metre or more. Given these caveats, conclusions that the total carbon reported for the area is 19% of that in UK forests (101 Mt vs 529 Mt) should be treated with extreme caution.Publisher PD

Assessment of carbon capture and storage in natural systems within the English North Sea (Including within Marine Protected Areas)

This report was commissioned by the North Sea Wildlife Trusts, Blue Marine Foundation, WWF and the RSPB to assess the extent, scale, distribution, and potential of the current blue carbon sinks in the English North Sea (i.e. seabed sediments, saltmarsh, kelp forests, seagrass beds and biogenic reefs). The focus was to i) review the current extent and distribution of each blue carbon habitat, ii) estimate the quantity of carbon currently stored within these habitats, iii) establish the average net sequestration rate (i.e. gC m-2 yr-1), and iv) estimate the potential net total sequestration (i.e. gC yr-1) of each blue carbon habitat. This analysis synthesises and reviews the most up-to-date scientific literature on fixation, processing, and storage of carbon in the English North Sea, including within Marine Protected Areas (MPAs). Carbon stock densities and rates of production and storage are combined with measures of habitat area to give estimates of total carbon stored in blue carbon habitats and their associated sediment stores. The results are intended to inform management decisions and identify opportunities to enhance the seabed and their carbon sequestration potential. Evidence of this nature will contribute to explore the potential of the English North Sea Marine Protected Area (MPA) network to help mitigate against the effects of climate change. Extents of blue carbon habitats for the North Sea region were derived from available sources. These include the EUNIS level 3 combined map from JNCC, Natural England Marine Habitats and Species Open Data, and recently published estimates of organic carbon (OC) and inorganic carbon (IC) stocks in surface sediments (Smeaton et al., 2021). Where maps of coastal habitats based on surveys were not available, including kelp and seagrass, extents of these habitats were estimated from models. Limitations of the estimates produced here link primarily to poorly constrained spatial extents of blue carbon habitats at the scales required for this report. For some habitats (intertidal and subtidal sediments), confidence in observational understanding of long-term sequestration is very low, as is that for transport and fate of carbon from macroalgae. Kelp forests in the region, for example, have received little attention compared to the rest of the United Kingdom. Furthermore, the science of understanding the effects of physical disturbance (including trawling) and climate change on these systems is very much in its infancy and new developments will allow a much better-informed outlook for the fate of these stocks and accumulation rates in a changing world and under varying management scenarios. Direct comparison between these North Sea carbon stores and those in terrestrial vegetation and soils are fraught with difficulty. Carbon stock sizes (MtC) and density per unit area (t/km2) are assessed differently, over different areas of habitats, and different timescales for storage of reported stocks. Carbon in living material may persist for years or decades, while that buried in soils and marine sediments may last for 100s to 1000s of years. Such lack of comparability renders straight numerical comparisons nearly meaningless. This is even more of a problem when comparing marine and terrestrial stocks, where soils and sediments and the nature of vegetated habitats are so radically different from each other. Depths of soils considered are a vital consideration. Here we consider marine sediments to a depth of only 10cm, while carbon in terrestrial soils is often reported to depths, typically 30cm to a metre or more. Given these caveats, conclusions that the total carbon reported for the area is 19% of that in UK forests (101 Mt vs 529 Mt) should be treated with extreme caution.Publisher PD

Themis2/ICB1 Is a Signaling Scaffold That Selectively Regulates Macrophage Toll-Like Receptor Signaling and Cytokine Production

BACKGROUND: Thymocyte expressed molecule involved in selection 1 (Themis1, SwissProt accession number Q8BGW0) is the recently characterised founder member of a novel family of proteins. A second member of this family, Themis2 (Q91YX0), also known as ICB1 (Induced on contact with basement membrane 1), remains unreported at the protein level despite microarray and EST databases reporting Themis2 mRNA expression in B cells and macrophages. METHODOLOGY/PRINCIPAL FINDINGS: Here we characterise Themis2 protein for the first time and show that it acts as a macrophage signalling scaffold, exerting a receptor-, mediator- and signalling pathway-specific effect on TLR responses in RAW 264.7 macrophages. Themis2 over-expression enhanced the LPS-induced production of TNF but not IL-6 or Cox-2, nor TNF production induced by ligands for TLR2 (PAM3) or TLR3 (poly IratioC). Moreover, LPS-induced activation of the MAP kinases ERK and p38 was enhanced in cells over-expressing Themis2 whereas the activation of JNK, IRF3 or NF-kappaB p65, was unaffected. Depletion of Themis2 protein by RNA inteference inhibited LPS-induced TNF production in primary human macrophages demonstrating a requirement for Themis2 in this event. Themis2 was inducibly tyrosine phosphorylated upon LPS challenge and interacted with Lyn kinase (P25911), the Rho guanine nucleotide exchange factor, Vav (P27870), and the adaptor protein Grb2 (Q60631). Mutation of either tyrosine 660 or a proline-rich sequence (PPPRPPK) simultaneously interrupted this complex and reduced by approximately 50% the capacity of Themis2 to promote LPS-induced TNF production. Finally, Themis2 protein expression was induced during macrophage development from murine bone marrow precursors and was regulated by inflammatory stimuli both in vitro and in vivo. CONCLUSIONS/SIGNIFICANCE: We hypothesise that Themis2 may constitute a novel, physiological control point in macrophage inflammatory responses

A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study.

Funder: Victorian Cancer AgencyFunder: NIHR Manchester Biomedical Research CentreFunder: Cancer Research UKFunder: Cancer Council TasmaniaFunder: Instituto de Salud Carlos IIIFunder: Cancer AustraliaFunder: NIHR Oxford Biomedical Research CentreFunder: Fundación Científica de la Asociación Española Contra el CáncerFunder: Cancer Council South AustraliaFunder: Swedish Cancer SocietyFunder: NIHR Cambridge Biomedical Research CentreFunder: Institut Català de la SalutFunder: Cancer Council VictoriaFunder: Prostate Cancer Foundation of AustraliaFunder: National Institutes of HealthBACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHODS: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual. FINDINGS: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0). INTERPRETATION: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings. FUNDING: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer

Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10−15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62–4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead