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.

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.

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.

REPRODUCTIVE AGEING: Altered histone modification landscapes underpin defects in uterine stromal cell decidualization in aging females.

In Brief: Advanced maternal age is associated with a higher rate of pregnancy complications that are unrelated to karyotypic abnormalities of the oocyte. This study shows that the murine uterine stroma undergoes profound epigenetic changes affecting active and repressive histone modification profiles that are associated with impaired endometrial functionality and underpin the decline in reproductive performance of aged females. Abstract: Decidualization describes the transformation of the uterine stroma in response to an implanting embryo, a process critical for supporting the development of the early embryo, for ensuring normal placentation and ultimately for a healthy reproductive outcome. Maternal age has been found to impede the progression of decidualization, heightening the risk of reproductive problems. Here, we set out to comprehensively characterize this deficit by pursuing transcriptomic and epigenomic profiling approaches specifically in the uterine stromal cell (UtSC) compartment of young and aged female mice. We find that UtSCs from aged females are globally far less responsive to the decidualization stimulus triggered by exposure to the steroid hormones estrogen and progesterone. Despite an overall transcriptional hyperactivation of genes that are differentially expressed as a function of maternal age, the hormonally regulated genes specifically fail to be activated in aged UtSCs. Moreover, even in their unstimulated 'ground' state, UtSCs from aged females are epigenetically distinct, as determined by genomic enrichment profiling for the active and repressive histone marks H3K4me3 and H3K9me3, respectively. We find that many hormone-inducible genes exhibit a profound lack of promoter-associated H3K4me3 in aged UtSCs, implying that a significant enrichment of active histone marks prior to gene stimulation is required to enable the elicitation of a rapid transcriptional response. With this combination of criteria, our data highlight specific deficits in epigenetic marking and gene expression of ion channels and vascular markers. These results point to fundamental defects in muscle-related and perivascular niche functions of the uterine stroma with advanced maternal age.

Epigenetic changes occur at decidualisation genes as a function of reproductive ageing in mice.

Reproductive decline in older female mice can be attributed to a failure of the uterus to decidualise in response to steroid hormones. Here, we show that normal decidualisation is associated with significant epigenetic changes. Notably, we identify a cohort of differentially methylated regions (DMRs), most of which gain DNA methylation between the early and late stages of decidualisation. These DMRs are enriched at progesterone-responsive gene loci that are essential for reproductive function. In female mice nearing the end of their reproductive lifespan, DNA methylation fidelity is lost at a number of CpG islands (CGIs) resulting in CGI hypermethylation at key decidualisation genes. Importantly, this hypermethylated state correlates with the failure of the corresponding genes to become transcriptionally upregulated during the implantation window. Thus, age-associated DNA methylation changes may underlie the decidualisation defects that are a common occurrence in older females. Alterations to the epigenome of uterine cells may therefore contribute significantly to the reproductive decline associated with advanced maternal age.

Horizontal gene transfer potentiates adaptation by reducing selective constraints on the spread of genetic variation.

Horizontal gene transfer (HGT) confers the rapid acquisition of novel traits and is pervasive throughout microbial evolution. Despite the central role of HGT, the evolutionary forces that drive the dynamics of HGT alleles in evolving populations are poorly understood. Here, we show that HGT alters the evolutionary dynamics of genetic variation, so that deleterious genetic variants, including antibiotic resistance genes, can establish in populations without selection. We evolve antibiotic-sensitive populations of the human pathogen Helicobacter pylori in an environment without antibiotic but with HGT from an antibiotic-resistant isolate of H. pylori We find that HGT increases the rate of adaptation, with most horizontally transferred genetic variants establishing at a low frequency in the population. When challenged with antibiotic, this low-level variation potentiates adaptation, with HGT populations flourishing in conditions where nonpotentiated populations go extinct. By extending previous models of evolution under HGT, we evaluated the conditions for the establishment and spread of HGT-acquired alleles into recipient populations. We then used our model to estimate parameters of HGT and selection from our experimental evolution data. Together, our findings show how HGT can act as an evolutionary force that facilitates the spread of nonselected genetic variation and expands the adaptive potential of microbial populations.

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.

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.

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.

Causal Effects of Alcohol Intoxication on Sexual Risk Intentions and Condom Negotiation Skills Among High-Risk Men Who Have Sex with Men (MSM).

Alcohol use is a key risk factor for HIV infection among MSM, in part because intoxication may interfere with the use of prevention methods like condoms. However, few studies have examined whether this is due to alcohol's pharmacological or expectancy effects or explored the specific aspects of sexual decision-making that may be affected. In this study, high-risk, heavy drinking MSM (N = 121) were randomly assigned to receive either (1) alcohol beverages, (2) placebo beverages, or (3) control beverages, before navigating a video-based sexual risk scenario that assessed several aspects of sexual decision-making. Results showed that condom use intentions and negotiation behaviors were lower among alcohol and placebo participants compared with controls, but that few significant differences emerged between the alcohol and placebo groups. These findings contrast with similar past studies, and suggest that alcohol's expectancy effects may play a role in sexual decision-making.

Timeline: A web application for assessing the timing and details of health behaviors.

BACKGROUND: Timeline Followback (TLFB) interview methods are used to assess a variety of health behaviors, including alcohol use, drug use, and sexual behavior. While several online TLFBs have been developed, most focus on single behaviors, and few studies have explored their validity in assessing multiple risk behaviors using a single online TLFB. OBJECTIVE: To examine the validity of a customizable web application (Timeline) for assessing alcohol use, drug use, and sexual behavior among high-risk men who have sex with men. METHODS: Participants (N = 15 men) completed standardized survey instruments before undergoing a 30-day daily diary procedure where they submitted daily reports of health risk behaviors via smartphone. They then completed a Timeline at the end of the 30-day period covering the same time interval. RESULTS: Comparing a baseline administration of Timeline with popular surveys of health risk behaviors supported Timeline's validity (r = 0.41-0.59 for alcohol use, r = 0.83 for drug use, and r = 0.34-0.52) for sexual behaviors. While participants reported similar amounts of each behavior via daily diary as they did on a follow-up Timeline (r = 0.55-0.88 for alcohol use, r = 0.69 for drug use, and r = 0.87-0.92 for sexual behaviors), results provided evidence of underreporting on the Timeline. Timing of behaviors also frequently disagreed across these methods. CONCLUSIONS: Timeline is valid for assessing overall engagement in alcohol use, drug use, and sexual behavior over a 30-day window. However, researchers interested in the specific timing of behaviors within assessment intervals should use smaller follow-up intervals (e.g., 7 days, 14 days) or more intensive reporting methods (e.g., daily diary).

HIV Testing Among Men Who Have Sex with Men in the Northeastern United States.

Men who have sex with men (MSM) continue to be at especially high risk for HIV in the United States. Past studies have shown that rates of HIV testing differ across a number of demographic and behavioral factors, and this research may be helpful for targeting efforts to increase testing among certain subgroups of MSM. In this study, MSM were recruited from several online sources to complete a questionnaire on HIV testing. Generalized ordered logit models suggested that the odds of having tested within the last 12 months were higher among racial/ethnic minority MSM, those with a college degree, and those who engaged in more recent HIV-risk behavior. The odds of having tested within the last 12 months were also higher among those who reported having sex with a partner they met online in the last 12 months. Conversely, the odds of having tested in the last 12 months were lower among those who reported drinking alcohol heavily, when compared with more moderate drinkers, highlighting yet another potential impact of alcohol on HIV outcomes.

Life tables for global surveillance of cancer survival (the CONCORD programme): data sources and methods.

BACKGROUND: We set out to estimate net survival trends for 10 common cancers in 279 cancer registry populations in 67 countries around the world, as part of the CONCORD-2 study. Net survival can be interpreted as the proportion of cancer patients who survive up to a given time, after eliminating the impact of mortality from other causes (background mortality). Background mortality varies widely between populations and over time. It was therefore necessary to construct robust life tables that accurately reflected the background mortality in each of the registry populations. METHODS: Life tables of all-cause mortality rates by single year of age and sex were constructed by calendar year for each population and, when possible, by racial or ethnic sub-groups. We used three different approaches, based on the type of mortality data available from each registry. With death and population counts, we adopted a flexible multivariable modelling approach. With unsmoothed mortality rates, we used the Ewbank relational method. Where no data were available from the registry or a national statistical office, we used the abridged UN Population Division life tables and interpolated these using the Elandt-Johnson method. We also investigated the impact of using state- and race-specific life tables versus national race-specific life tables on estimates of net survival from four adult cancers in the United States (US). RESULTS: We constructed 6,514 life tables covering 327 populations. Wide variations in life expectancy at birth and mortality by age were observed, even within countries. During 1995-99, life expectancy was lowest in Nigeria and highest in Japan, ranging from 47 to 84 years among females and 46 to 78 years among males. During 2005-09, life expectancy was lowest in Lesotho and again highest in Japan, ranging from 45 to 86 years among females and 45 to 80 years among males. For the US, estimates of net survival differed by up to 4% if background mortality was fully controlled with state- and race-specific life tables, rather than with national race-specific life tables. CONCLUSIONS: Background mortality varies worldwide. This emphasises the importance of using population-specific life tables for geographic and international comparisons of net survival.

Synthesis and Biological Evaluation of 7-Deoxy-Epothilone Analogues.

The synthesis of two deoxygenated analogues of potent epothilones is reported in an effort to analyze the relative importance of molecular conformation and ligand-target interactions to biological activity. 7-deoxy-epothilone D and 7-deoxy-(S)-14-methoxy-epothilone D were prepared through total synthesis and shown to maintain the conformational preferences of their biologically active parent congeners through computer modeling and nuclear magnetic resonance (NMR) studies. The significant decrease in observed potency for each compound suggests that a hydrogen bond between the C7-hydroxyl group and the tubulin binding site plays a critical role in the energetics of binding in the epothilone class of polyketides.

Impact of deprivation on breast cancer survival among women eligible for mammographic screening in the West Midlands (UK) and New South Wales (Australia): Women diagnosed 1997-2006.

Women diagnosed with breast cancer in the UK display marked differences in survival between categories defined by socio-economic deprivation. Timeliness of diagnosis is one of the possible explanations for these patterns. Women whose cancer is screen-detected are more likely to be diagnosed at an earlier stage. We examined deprivation and screening-specific survival in order to evaluate the role of early diagnosis upon deprivation-specific survival differences in the West Midlands (UK) and New South Wales (Australia). We estimated net survival for women aged 50-65 years at diagnosis and whom had been continuously eligible for screening from the age of 50. Records for 5,628 women in West Midlands (98.5% of those eligible, mean age at diagnosis 53.7 years) and 6,396 women in New South Wales (99.9% of those eligible, mean age at diagnosis 53.8 years). In New South Wales, survival was similar amongst affluent and deprived women, regardless of whether their cancer was screen-detected or not. In the West Midlands, there were large and persistent differences in survival between affluent and deprived women. Deprivation differences were similar between the screen-detected and non-screen detected groups. These differences are unlikely to be solely explained by artefact, or by patient or tumour factors. Further investigations into the timeliness and appropriateness of the treatments received by women with breast cancer across the social spectrum in the UK are warranted.

Are international differences in breast cancer survival between Australia and the UK present amongst both screen-detected women and non-screen-detected women? survival estimates for women diagnosed in West Midlands and New South Wales 1997-2006.

We examined survival in screened-detected and non-screen-detected women diagnosed in the West Midlands (UK) and New South Wales (Australia) in order to evaluate whether international differences in survival are related to early diagnosis, or to other factors relating to the healthcare women receive. Data for women aged 50 - 65 years who had been eligible for screening from 50 years were examined. Data for 5,628 women in West Midlands and 6,396 women in New South Wales were linked to screening service records (mean age at diagnosis 53.7 years). We estimated net survival and modelled the excess hazard ratio of breast cancer death by screening status. Survival was lower for women in the West Midlands than in New South Wales (5-year net survival 90.9% [95% CI 89.9%-91.7%] compared with 93.4% [95% CI 92.6%-94.1%], respectively). The difference was greater between the two populations of non-screen-detected women (4.9%) compared to between screen-detected women, (1.8% after adjustment for lead-time and over-diagnosis). The adjusted excess hazard ratio of breast cancer death for West Midlands compared with New South Wales was greater in the non-screen-detected group (EHR 2.00, 95% CI 1.70 - 2.31) but not significantly different to that for women whose cancer had been screen-detected (EHR 1.72, 95% CI 0.87 - 2.56). In this study more than one in three breast cancer deaths in the West Midlands would have been avoided if survival had been the same as in New South Wales. The possibility that women in the UK receive poorer treatment is an important potential explanation which should be examined with care.

Multivariable flexible modelling for estimating complete, smoothed life tables for sub-national populations.

BACKGROUND: The methods currently available to estimate age- and sex-specific mortality rates for sub-populations are subject to a number of important limitations. We propose two alternative multivariable approaches: a relational model and a Poisson model both using restricted cubic splines. METHODS: We evaluated a flexible Poisson and flexible relational model against the Elandt-Johnson approach in a simulation study using 100 random samples of population and death counts, with different sampling proportions and data arrangements. Estimated rates were compared to the original mortality rates using goodness-of-fit measures and life expectancy. We further investigated an approach for determining optimal knot locations in the Poisson model. RESULTS: The flexible Poisson model outperformed the flexible relational and Elandt-Johnson methods with the smallest sample of data (1%). With the largest sample of data (20%), the flexible Poisson and flexible relational models performed comparably, though the flexible Poisson model displayed a slight advantage. Both approaches tended to underestimate infant mortality and thereby overestimate life expectancy at birth. The flexible Poisson model performed much better at young ages when knots were fixed a priori. For ages 30 and above, results were similar to the model with no fixed knots. CONCLUSIONS: The flexible Poisson model is recommended because it derives robust and unbiased estimates for sub-populations without making strong assumptions about age-specific mortality profiles. Fixing knots a priori in the final model greatly improves fit at the young ages.

Cancer incidence, survival and mortality: explaining the concepts.

Cancer incidence, survival and mortality are essential population-based indicators for public health and cancer control. Confusion and misunderstanding still surround the estimation and interpretation of these indicators. Recurring controversies over the use and misuse of population-based cancer statistics in health policy suggests the need for further clarification. In our article, we describe the concepts that underlie the measures of incidence, survival and mortality, and illustrate the synergy between these measures of the cancer burden. We demonstrate the relationships between trends in incidence, survival and mortality, using real data for cancers of the lung and breast from England and Sweden. Finally, we discuss the importance of using all three measures in combination when interpreting overall progress in cancer control, and we offer some recommendations for their use.

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.