Assessment of the Impact of a Head-mounted Augmented Reality Low Vision Aid on Vision and Quality of Life in Children and Young People with Visual Impairment.

Introduction: Electronic head-mounted low vision aids (LVAs) can help children and young people (CYP) to access schoolwork and leisure activities which they would otherwise struggle to be able to do with traditional optical or hand held LVAs. SightPlus uses a smartphone mounted in a virtual reality headset controlled using a Bluetooth joystick. It offers users 0.7-24.3× magnification alongside enhanced modes to maximise vision. Methods: Eighteen participants aged 8-16 years with reduced vision were given SightPlus to use at home for four weeks. Visual acuity was assessed with and without SightPlus along with reading performance, contrast sensitivity, functional vision and quality of life questionnaires. Results: Clinically significant improvements in distance vision (0.633logMAR SD ± 0.359), near vision (0.411logMAR SD ± 0.368), reading acuity (0.454LlogMAR SD ± 0.406) and critical print size (0.285logMAR ± 0.360) were seen when testing with SightPlus.However, there was a mean decrease in contrast sensitivity and reading speed when using SightPlus. Despite this, nine out of the 14 patients included for analysis indicated a preference to continue to use SightPlus. Of note, younger participants were more likely to show a preference for using SightPlus. All seven CYP aged 10 or under wanted to continue to use SightPlus; in contrast, only two of the seven participants aged 11 or over wanted to continue. Conclusions: Like the results in adult populations, SightPlus has been found to improve CYP visual functions. Older participants were less likely to want to continue to use SightPlus, potentially suggesting they have found other methods for managing sight loss.

Risk factors for early-onset pancreatic ductal adenocarcinoma: A systematic literature review.

BACKGROUND: Emerging cancer trends suggest an increase in pancreatic cancer incidence in individuals younger than its typical age of onset, potentially reflecting changes in population exposures and lifestyles. PATIENTS AND METHODS: We conducted a PRISMA-standard systematic literature review to identify non-heritable risk factors for early-onset pancreatic ductal adenocarcinoma (PDAC) (PROSPERO number: CRD42022299397). Systematic searches of MEDLINE and Embase bibliographic databases were performed (January 2022), and publications were screened against predetermined eligibility criteria; data were extracted using standardised data fields. The STROBE checklist was used to assess the completeness of reporting as a proxy for publication quality. Data were categorised by risk factor and analysed descriptively. RESULTS: In total, 24 publications were included. All publications reported observational study data; thresholds for age group comparisons ranged between 40 and 65 years. Lifestyle factors investigated included smoking, alcohol consumption, obesity, physical inactivity, meat intake, socioeconomic status and geographical residence. Clinical factors investigated included pancreatitis, diabetes/insulin resistance, prior cancer and cancer stage at diagnosis, hepatitis B infection, metabolic syndrome and long-term proton pump inhibitor exposure. Publication STROBE scores were 6-21 (maximum, 22). Eight studies reported results adjusted for confounders. Potential non-heritable risk factors for early-onset PDAC that warrant further investigation included smoking, alcohol consumption, pancreatitis and hepatitis B infection. CONCLUSION: Evidence for non-heritable risk factors for early-onset PDAC is heterogeneous, but four factors were identified that might aid the identification of at-risk individuals who may benefit from screening and risk reduction strategies.

Palbociclib releases the latent differentiation capacity of neuroblastoma cells.

Neuroblastoma is the most common extracranial solid tumor in infants, arising from developmentally stalled neural crest-derived cells. Driving tumor differentiation is a promising therapeutic approach for this devastating disease. Here, we show that the CDK4/6 inhibitor palbociclib not only inhibits proliferation but induces extensive neuronal differentiation of adrenergic neuroblastoma cells. Palbociclib-mediated differentiation is manifested by extensive phenotypic and transcriptional changes accompanied by the establishment of an epigenetic program driving expression of mature neuronal features. In vivo palbociclib significantly inhibits tumor growth in mouse neuroblastoma models. Furthermore, dual treatment with retinoic acid resets the oncogenic adrenergic core regulatory circuit of neuroblastoma cells, further suppresses proliferation, and can enhance differentiation, altering gene expression in ways that significantly correlate with improved patient survival. We therefore identify palbociclib as a therapeutic approach to dramatically enhance neuroblastoma differentiation efficacy that could be used in combination with retinoic acid to improve patient outcomes.

Evolutionary ecology of microbial populations inhabiting deep sea sediments associated with cold seeps.

Deep sea cold seep sediments host abundant and diverse microbial populations that significantly influence biogeochemical cycles. While numerous studies have revealed their community structure and functional capabilities, little is known about genetic heterogeneity within species. Here, we examine intraspecies diversity patterns of 39 abundant species identified in sediment layers down to 430 cm below the sea floor across six cold seep sites. These populations are grouped as aerobic methane-oxidizing bacteria, anaerobic methanotrophic archaea and sulfate-reducing bacteria. Different evolutionary trajectories are observed at the genomic level among these physiologically and phylogenetically diverse populations, with generally low rates of homologous recombination and strong purifying selection. Functional genes related to methane (pmoA and mcrA) and sulfate (dsrA) metabolisms are under strong purifying selection in most species investigated. These genes differ in evolutionary trajectories across phylogenetic clades but are functionally conserved across sites. Intrapopulation diversification of genomes and their mcrA and dsrA genes is depth-dependent and subject to different selection pressure throughout the sediment column redox zones at different sites. These results highlight the interplay between ecological processes and the evolution of key bacteria and archaea in deep sea cold seep extreme environments, shedding light on microbial adaptation in the subseafloor biosphere.

Horizontal Gene Transfer, Fitness Costs and Mobility Shape the Spread of Antibiotic Resistance Genes into Experimental Populations of Acinetobacter Baylyi.

Horizontal gene transfer (HGT) is important for microbial evolution, but how evolutionary forces shape the frequencies of horizontally transferred genetic variants in the absence of strong selection remains an open question. In this study, we evolve laboratory populations of Acinetobacter baylyi (ADP1) with HGT from two clinically relevant strains of multidrug-resistant Acinetobacter baumannii (AB5075 and A9844). We find that DNA can cross the species barrier, even without strong selection, and despite substantial DNA sequence divergence between the two species. Our results confirm previous findings that HGT can drive the spread of antibiotic resistance genes (ARGs) without selection for that antibiotic, but not for all of the resistance genes present in the donor genome. We quantify the costs and benefits of horizontally transferred variants and use whole population sequencing to track the spread of ARGs from HGT donors into antibiotic-sensitive recipients. We find that even though most ARGs are taken up by populations of A. baylyi, the long-term fate of an individual gene depends both on its fitness cost and on the type of genetic element that carries the gene. Interestingly, we also found that an integron, but not its host plasmid, is able to spread in A. baylyi populations despite its strong deleterious effect. Altogether, our results show how HGT provides an evolutionary advantage to evolving populations by facilitating the spread of non-selected genetic variation including costly ARGs.

The proneural transcription factor ASCL1 regulates cell proliferation and primes for differentiation in neuroblastoma.

Neuroblastoma is believed to arise from sympathetic neuroblast precursors that fail to engage the neuronal differentiation programme, but instead become locked in a pro-proliferative developmental state. Achaete-scute homolog 1 (ASCL1) is a proneural master regulator of transcription which modulates both proliferation and differentiation of sympathetic neuroblast precursor cells during development, while its expression has been implicated in the maintenance of an oncogenic programme in MYCN-amplified neuroblastoma. However, the role of ASCL1 expression in neuroblastoma is not clear, especially as its levels vary considerably in different neuroblastoma cell lines. Here, we have investigated the role of ASCL1 in maintaining proliferation and controlling differentiation in both MYCN amplified and Anaplastic Lymphoma Kinase (ALK)-driven neuroblastoma cells. Using CRISPR deletion, we generated neuroblastoma cell lines lacking ASCL1 expression, and these grew more slowly than parental cells, indicating that ASCL1 contributes to rapid proliferation of MYCN amplified and non-amplified neuroblastoma cells. Genome-wide analysis after ASCL1 deletion revealed reduced expression of genes associated with neuronal differentiation, while chromatin accessibility at regulatory regions associated with differentiation genes was also attenuated by ASCL1 knock-out. In neuroblastoma, ASCL1 has been described as part of a core regulatory circuit of developmental regulators whose high expression is maintained by mutual cross-activation of a network of super enhancers and is further augmented by the activity of MYC/MYCN. Surprisingly, ASCL1 deletion had little effect on the transcription of CRC gene transcripts in these neuroblastoma cell lines, but the ability of MYC/MYCN and CRC component proteins, PHOX2B and GATA3, to bind to chromatin was compromised. Taken together, our results demonstrate several roles for endogenous ASCL1 in neuroblastoma cells: maintaining a highly proliferative phenotype, regulating DNA binding of the core regulatory circuit genes to chromatin, while also controlling accessibility and transcription of differentiation targets. Thus, we propose a model where ASCL1, a key developmental regulator of sympathetic neurogenesis, plays a pivotal role in maintaining proliferation while simultaneously priming cells for differentiation in neuroblastoma.

Super-enhancer associated core regulatory circuits mediate susceptibility to retinoic acid in neuroblastoma cells.

Neuroblastoma is a pediatric tumour that accounts for more than 15% of cancer-related deaths in children. High-risk tumours are often difficult to treat, and patients' survival chances are less than 50%. Retinoic acid treatment is part of the maintenance therapy given to neuroblastoma patients; however, not all tumours differentiate in response to retinoic acid. Within neuroblastoma tumors, two phenotypically distinct cell types have been identified based on their super-enhancer landscape and transcriptional core regulatory circuitries: adrenergic (ADRN) and mesenchymal (MES). We hypothesized that the distinct super-enhancers in these different tumour cells mediate differential response to retinoic acid. To this end, three different neuroblastoma cell lines, ADRN (MYCN amplified and non-amplified) and MES cells, were treated with retinoic acid, and changes in the super-enhancer landscape upon treatment and after subsequent removal of retinoic acid was studied. Using ChIP-seq for the active histone mark H3K27ac, paired with RNA-seq, we compared the super-enhancer landscape in cells that undergo neuronal differentiation in response to retinoic acid versus those that fail to differentiate and identified unique super-enhancers associated with neuronal differentiation. Among the ADRN cells that respond to treatment, MYCN-amplified cells remain differentiated upon removal of retinoic acid, whereas MYCN non-amplified cells revert to an undifferentiated state, allowing for the identification of super-enhancers responsible for maintaining differentiation. This study identifies key super-enhancers that are crucial for retinoic acid-mediated differentiation.

Are deprivation-specific cancer survival patterns similar according to individual-based and area-based measures? A cohort study of patients diagnosed with five malignancies in England and Wales, 2008-2016.

OBJECTIVE: To investigate if measured inequalities in cancer survival differ when using individual-based ('person') compared with area-based ('place') measures of deprivation for three socioeconomic dimensions: income, deprivation and occupation. DESIGN: Cohort study. SETTING: Data from the Office for National Statistics Longitudinal Study of England and Wales, UK, linked to the National Cancer Registration Database. PARTICIPANTS: Patients diagnosed with cancers of the colorectum, breast, prostate, bladder or with non-Hodgkin's lymphoma during the period 2008-2016. PRIMARY AND SECONDARY OUTCOME MEASURES: Differentials in net survival between groups defined by individual wage, occupation and education compared with those obtained from corresponding area-level metrics using the English and Welsh Indices of Multiple Deprivation. RESULTS: Survival was negatively associated with area-based deprivation irrespective of the type analysed, although a trend from least to most deprived was not always observed. Socioeconomic differences were present according to individually-measured socioeconomic groups although there was an absence of a consistent 'gradient' in survival. The magnitude of differentials was similar for area-based and individually-derived measures of deprivation, which was unexpected. CONCLUSION: These unique data suggest that the socioeconomic influence of 'person' is different to that of 'place' with respect to cancer outcomes. This has implications for health policy aimed at reducing inequalities. Further research could consider the separate and additional influence of area-based deprivation over individual-level characteristics (contextual effects) as well as investigate the geographic, socioeconomic and healthcare-related characteristics of areas with poor outcomes in order to inform policy intervention.

Multiple imputation to minimise bias from missing stage information in estimates of early cancer diagnosis in England: a population-based study.

INTRODUCTION: Monitoring early diagnosis is a priority of cancer policy in England. Information on stage has not always been available for a large proportion of patients, however, which may bias temporal comparisons. We previously estimated that early-stage diagnosis of colorectal cancer rose from 32% to 44% during 2008-2013, using multiple imputation. Here we examine the underlying assumptions of multiple imputation for missing stage using the same dataset. METHODS: Individually-linked cancer registration, Hospital Episode Statistics (HES), and audit data were examined. Six imputation models including different interaction terms, post-diagnosis treatment, and survival information were assessed, and comparisons drawn with the a priori optimal model. Models were further tested by setting stage values to missing for some patients under one plausible mechanism, then comparing actual and imputed stage distributions for these patients. Finally, a pattern-mixture sensitivity analysis was conducted. RESULTS: Data from 196,511 colorectal patients were analysed, with 39.2% missing stage. Inclusion of survival time increased the accuracy of imputation: the odds ratio for change in early-stage diagnosis during 2008-2013 was 1.7 (95% CI: 1.6, 1.7) with survival to 1 year included, compared to 1.9 (95% CI 1.9-2.0) with no survival information. Imputation estimates of stage were accurate in one plausible simulation. Pattern-mixture analyses indicated our previous analysis conclusions would only change materially if stage were misclassified for 20% of the patients who had it categorised as late. INTERPRETATION: Multiple imputation models can substantially reduce bias from missing stage, but data on patient's one-year survival should be included for highest accuracy.

Bacteriophages evolve enhanced persistence to a mucosal surface.

The majority of viruses within the gut are obligate bacterial viruses known as bacteriophages (phages). Their bacteriotropism underscores the study of phage ecology in the gut, where they modulate and coevolve with gut bacterial communities. Traditionally, these ecological and evolutionary questions were investigated empirically via in vitro experimental evolution and, more recently, in vivo models were adopted to account for physiologically relevant conditions of the gut. Here, we probed beyond conventional phage-bacteria coevolution to investigate potential tripartite evolutionary interactions between phages, their bacterial hosts, and the mammalian gut mucosa. To capture the role of the mammalian gut, we recapitulated a life-like gut mucosal layer using in vitro lab-on-a-chip devices (to wit, the gut-on-a-chip) and showed that the mucosal environment supports stable phage-bacteria coexistence. Next, we experimentally coevolved lytic phage populations within the gut-on-a-chip devices alongside their bacterial hosts. We found that while phages adapt to the mucosal environment via de novo mutations, genetic recombination was the key evolutionary force in driving mutational fitness. A single mutation in the phage capsid protein Hoc-known to facilitate phage adherence to mucus-caused altered phage binding to fucosylated mucin glycans. We demonstrated that the altered glycan-binding phenotype provided the evolved mutant phage a competitive fitness advantage over its ancestral wild-type phage in the gut-on-a-chip mucosal environment. Collectively, our findings revealed that phages-in addition to their evolutionary relationship with bacteria-are able to evolve in response to a mammalian-derived mucosal environment.

Elevated ASCL1 activity creates de novo regulatory elements associated with neuronal differentiation.

BACKGROUND: The pro-neural transcription factor ASCL1 is a master regulator of neurogenesis and a key factor necessary for the reprogramming of permissive cell types to neurons. Endogenously, ASCL1 expression is often associated with neuroblast stem-ness. Moreover, ASCL1-mediated reprogramming of fibroblasts to differentiated neurons is commonly achieved using artificially high levels of ASCL1 protein, where ASCL1 acts as an "on-target" pioneer factor. However, the genome-wide effects of enhancing ASCL1 activity in a permissive neurogenic environment has not been thoroughly investigated. Here, we overexpressed ASCL1 in the neuronally-permissive context of neuroblastoma (NB) cells where modest endogenous ASCL1 supports the neuroblast programme. RESULTS: Increasing ASCL1 in neuroblastoma cells both enhances binding at existing ASCL1 sites and also leads to creation of numerous additional, lower affinity binding sites. These extensive genome-wide changes in ASCL1 binding result in significant reprogramming of the NB transcriptome, redirecting it from a proliferative neuroblastic state towards one favouring neuronal differentiation. Mechanistically, ASCL1-mediated cell cycle exit and differentiation can be increased further by preventing its multi-site phosphorylation, which is associated with additional changes in genome-wide binding and gene activation profiles. CONCLUSIONS: Our findings show that enhancing ASCL1 activity in a neurogenic environment both increases binding at endogenous ASCL1 sites and also results in additional binding to new low affinity sites that favours neuronal differentiation over the proliferating neuroblast programme supported by the endogenous protein. These findings have important implications for controlling processes of neurogenesis in cancer and cellular reprogramming.

Recombination resolves the cost of horizontal gene transfer in experimental populations of Helicobacter pylori.

Horizontal gene transfer (HGT) is important for microbial evolution, yet we know little about the fitness effects and dynamics of horizontally transferred genetic variants. In this study, we evolve laboratory populations of Helicobacter pylori, which take up DNA from their environment by natural transformation, and measure the fitness effects of thousands of transferred genetic variants. We find that natural transformation increases the rate of adaptation but comes at the cost of significant genetic load. We show that this cost is circumvented by recombination, which increases the efficiency of selection by decoupling deleterious and beneficial genetic variants. Our results show that adaptation with HGT, pervasive in natural microbial populations, is shaped by a combination of selection, recombination, and genetic drift not accounted for in existing models of evolution.

Species interactions constrain adaptation and preserve ecological stability in an experimental microbial community.

Species loss within a microbial community can increase resource availability and spur adaptive evolution. Environmental shifts that cause species loss or fluctuations in community composition are expected to become more common, so it is important to understand the evolutionary forces that shape the stability and function of the emergent community. Here we study experimental cultures of a simple, ecologically stable community of Saccharomyces cerevisiae and Lactobacillus plantarum, in order to understand how the presence or absence of a species impacts coexistence over evolutionary timescales. We found that evolution in coculture led to drastically altered evolutionary outcomes for L. plantarum, but not S. cerevisiae. Both monoculture- and co-culture-evolved L. plantarum evolved dozens of mutations over 925 generations of evolution, but only L. plantarum that had evolved in isolation from S. cerevisiae lost the capacity to coexist with S. cerevisiae. We find that the evolutionary loss of ecological stability corresponds with fitness differences between monoculture-evolved L. plantarum and S. cerevisiae and genetic changes that repeatedly evolve across the replicate populations of L. plantarum. This work shows how coevolution within a community can prevent destabilising evolution in individual species, thereby preserving ecological diversity and stability, despite rapid adaptation.

An investigation of cancer survival inequalities associated with individual-level socio-economic status, area-level deprivation, and contextual effects, in a cancer patient cohort in England and Wales.

BACKGROUND: People living in more deprived areas of high-income countries have lower cancer survival than those in less deprived areas. However, associations between individual-level socio-economic circumstances and cancer survival are relatively poorly understood. Moreover, few studies have addressed contextual effects, where associations between individual-level socio-economic status and cancer survival vary depending on area-based deprivation. METHODS: Using 9276 individual-level observations from a longitudinal study in England and Wales, we examined the association with cancer survival of area-level deprivation and individual-level occupation, education, and income, for colorectal, prostate and breast cancer patients aged 20-99 at diagnosis. With flexible parametric excess hazard models, we estimated excess mortality across individual-level and area-level socio-economic variables and investigated contextual effects. RESULTS: For colorectal cancers, we found evidence of an association between education and cancer survival in men with Excess Hazard Ratio (EHR) = 0.80, 95% Confidence Interval (CI) = 0.60;1.08 comparing "degree-level qualification and higher" to "no qualification" and EHR = 0.74 [0.56;0.97] comparing "apprenticeships and vocational qualification" to "no qualification", adjusted on occupation and income; and between occupation and cancer survival for women with EHR = 0.77 [0.54;1.10] comparing "managerial/professional occupations" to "manual/technical," and EHR = 0.81 [0.63;1.06] comparing "intermediate" to "manual/technical", adjusted on education and income. For breast cancer in women, we found evidence of an association with income (EHR = 0.52 [0.29;0.95] for the highest income quintile compared to the lowest, adjusted on education and occupation), while for prostate cancer, all three individual-level socio-economic variables were associated to some extent with cancer survival. We found contextual effects of area-level deprivation on survival inequalities between occupation types for breast and prostate cancers, suggesting wider individual-level inequalities in more deprived areas compared to least deprived areas. Individual-level income inequalities for breast cancer were more evident than an area-level differential, suggesting that area-level deprivation might not be the most effective measure of inequality for this cancer. For colorectal cancer in both sexes, we found evidence suggesting area- and individual-level inequalities, but no evidence of contextual effects. CONCLUSIONS: Findings highlight that both individual and contextual effects contribute to inequalities in cancer outcomes. These insights provide potential avenues for more effective policy and practice.

Can we screen for pancreatic cancer? Identifying a sub-population of patients at high risk of subsequent diagnosis using machine learning techniques applied to primary care data.

BACKGROUND: Pancreatic cancer (PC) represents a substantial public health burden. Pancreatic cancer patients have very low survival due to the difficulty of identifying cancers early when the tumour is localised to the site of origin and treatable. Recent progress has been made in identifying biomarkers for PC in the blood and urine, but these cannot be used for population-based screening as this would be prohibitively expensive and potentially harmful. METHODS: We conducted a case-control study using prospectively-collected electronic health records from primary care individually-linked to cancer registrations. Our cases were comprised of 1,139 patients, aged 15-99 years, diagnosed with pancreatic cancer between January 1, 2005 and June 30, 2009. Each case was age-, sex- and diagnosis time-matched to four non-pancreatic (cancer patient) controls. Disease and prescription codes for the 24 months prior to diagnosis were used to identify 57 individual symptoms. Using a machine learning approach, we trained a logistic regression model on 75% of the data to predict patients who later developed PC and tested the model's performance on the remaining 25%. RESULTS: We were able to identify 41.3% of patients < = 60 years at 'high risk' of developing pancreatic cancer up to 20 months prior to diagnosis with 72.5% sensitivity, 59% specificity and, 66% AUC. 43.2% of patients >60 years were similarly identified at 17 months, with 65% sensitivity, 57% specificity and, 61% AUC. We estimate that combining our algorithm with currently available biomarker tests could result in 30 older and 400 younger patients per cancer being identified as 'potential patients', and the earlier diagnosis of around 60% of tumours. CONCLUSION: After further work this approach could be applied in the primary care setting and has the potential to be used alongside a non-invasive biomarker test to increase earlier diagnosis. This would result in a greater number of patients surviving this devastating disease.

Describing socio-economic variation in life expectancy according to an individual's education, occupation and wage in England and Wales: An analysis of the ONS Longitudinal Study.

People who live in more deprived areas have poorer health outcomes, and this inequality is a major driver of health and social policy. Many interventions targeting these disparities implicitly assume that poorer health is predominantly associated with area-level factors, and that these inequalities are the same for men and women. However, health differentials due to individual socio-economic status (SES) of men and women are less well documented. We used census data linked to the ONS Longitudinal Study to derive individual-level SES in terms of occupation, education and estimated wage, and examined differences in adult mortality and life expectancy. We modelled age-, sex- and SES-specific mortality using Poisson regression, and summarised mortality differences using life expectancy at age 20. We compared the results to those calculated using area-level deprivation metrics. Wide inequalities in life expectancy between SES groups were observed, although differences across SES groups were smaller for women than for men. The widest inequalities were found across men's education (7.2-year (95% CI: 3.0-10.1) difference in life expectancy between groups) and wage (7.0-year (95% CI: 3.5-9.8) difference), and women's education (5.4-year (95% CI: 2.2-8.1) difference). Men with no qualifications had the lowest life expectancy of all groups. In terms of the number of years' difference in life expectancy, the inequalities measured here with individual-level data were of a similar magnitude to inequalities identified previously using area-level deprivation metrics. These data show that health inequalities are as strongly related to individual SES as to area-level deprivation, highlighting the complementary usefulness of these different metrics. Indeed, poor outcomes are likely to be a product of both community and individual influences. Current policy which bases health spending decisions on evidence of inequalities between geographical areas may overlook individual-level SES inequalities for those living in affluent areas, as well as missing important sex differences.

Are socio-economic inequalities in breast cancer survival explained by peri-diagnostic factors?

BACKGROUND: Patients living in more deprived localities have lower cancer survival in England, but the role of individual health status at diagnosis and the utilisation of primary health care in explaining these differentials has not been widely considered. We set out to evaluate whether pre-existing individual health status at diagnosis and primary care consultation history (peri-diagnostic factors) could explain socio-economic differentials in survival amongst women diagnosed with breast cancer. METHODS: We conducted a retrospective cohort study of women aged 15-99 years diagnosed in England using linked routine data. Ecologically-derived measures of income deprivation were combined with individually-linked data from the English National Cancer Registry, Clinical Practice Research Datalink (CPRD) and Hospital Episodes Statistics (HES) databases. Smoking status, alcohol consumption, BMI, comorbidity, and consultation histories were derived for all patients. Time to breast surgery was derived for women diagnosed after 2005. We estimated net survival and modelled the excess hazard ratio of breast cancer death using flexible parametric models. We accounted for missing data using multiple imputation. RESULTS: Net survival was lower amongst more deprived women, with a single unit increase in deprivation quintile inferring a 4.4% (95% CI 1.4-8.8) increase in excess mortality. Peri-diagnostic co-variables varied by deprivation but did not explain the differentials in multivariable analyses. CONCLUSIONS: These data show that socio-economic inequalities in survival cannot be explained by consultation history or by pre-existing individual health status, as measured in primary care. Differentials in the effectiveness of treatment, beyond those measuring the inclusion of breast surgery and the timing of surgery, should be considered as part of the wider effort to reduce inequalities in premature mortality.

Host diversity slows bacteriophage adaptation by selecting generalists over specialists.

Most viruses can infect multiple hosts, yet the selective mechanisms that maintain multi-host generalists over single-host specialists remain an open question. Here we propagate populations of the newly identified bacteriophage øJB01 in coculture with many host genotypes and find that while phage can adapt to infect any of the new hosts, increasing the number of hosts slows the rate of adaptation. We quantify trade-offs in the capacity for individual phage to infect different hosts and find that phage from evolved populations with more hosts are more likely to be generalists. Sequencing of evolved phage reveals strong selection and the genetic basis of adaptation, supporting a model that shows how the addition of more potential hosts to a community can select for low-fitness generalists over high-fitness specialists. Our results show how evolution with multiple hosts alters the rate of viral adaptation and provides empirical support for an evolutionary mechanism that promotes generalists over specialists.

The evolution of coexistence from competition in experimental co-cultures of Escherichia coli and Saccharomyces cerevisiae.

Microbial communities are comprised of many species that coexist on small spatial scales. This is difficult to explain because many interspecies interactions are competitive, and ecological theory predicts that one species will drive the extinction of another species that competes for the same resource. Conversely, evolutionary theory proposes that natural selection can lead to coexistence by driving competing species to use non-overlapping resources. However, evolutionary escape from extinction may be slow compared to the rate of competitive exclusion. Here, we use experimental co-cultures of Escherichia coli and Saccharomyces cerevisiae to study the evolution of coexistence in species that compete for resources. We find that while E. coli usually outcompetes S. cerevisiae in co-culture, a few populations evolved stable coexistence after ~1000 generations of coevolution. We sequenced S. cerevisiae and E. coli populations, identified multi-hit genes, and engineered alleles from these genes into several genetic backgrounds, finding that some mutations modified interactions between E. coli and S. cerevisiae. Together, our data demonstrate that coexistence can evolve, de novo, from intense competition between two species with no history of coevolution.