Factors which influence penetrance in Familial Pancreatic Cancer

Introduction Pancreatic cancer (PDAC) confers a high mortality rate as it often presents at an advanced stage. Screening could improve early detection and survival. However, the prevalence of the disease and absence of specific screening tools mean that screening of the general population would result in many false positive tests. This may mean unnecessary overtreatment including surgery with considerable morbidity. Current screening techniques have associated risks including exposure to radiation and induction of pancreatitis. It is therefore essential to identify high risk screening populations and improve both specificity and safety of the screening modality. The European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC) was established to identify individuals with a genetic predisposition for PDAC to offer secondary screening. Thesis Aims The aims of this thesis were to identify subpopulations of high risk families who are at the greatest risk of pancreatic cancer in order to undertake targeted screening. Furthermore, to minimise the risks and complications to individuals participating in the EUROPAC secondary screening study for early PDAC. Materials and Methods Familial Pancreatic Cancer (FPC) was defined as autosomal dominant predisposition for PDAC. Hereditary Pancreatitis (HP) is an autosomal dominant predisposition for pancreatitis associated with an approximately 40% life time risk of PDAC. Families with other recognised cancer syndromes conferring a predisposition to PDAC were also recruited. At recruitment, blood samples for DNA storage and cell lines were obtained for the analysis of potential candidate genes implicated in FPC. Individual and familial demographic, lifestyle and disease related data were collected to facilitate analysis of possible risk factors which could influence penetrance in these high risk groups. On confirmation of a familial predisposition, eligible individuals were invited to participate in the EUROPAC secondary screening study for early pancreatic cancer. The screening protocol comprised blood tests and imaging techniques along with analysis of molecular markers in pancreatic juice. Results 273 potential FPC kindreds were identified and recruited; 89 had 3 or more affected family members. In FPC, age is a major risk factor but the pattern of age related risk is the same as in the general population. However, this is consistently 100 fold greater in FPC. No evidence was found for earlier age of onset in FPC contrary to other reports. Selection bias based on proband is proposed as an explanation for the apparent differences seen in the literature. Reporting bias could also explain the relationship of smoking and PDAC in FPC kindreds. No further causative mutations were found during the preparation of this thesis but a PALB2 mutation was found in three families (possibly associated with breast cancer). A model for risk was proposed, but in this thesis only secondary screening based on previous estimates is described. The methodology involved Endoscopic Retrograde Cholangiopancreatography (ERCP) and 7 cases of pancreatitis resulted. Consequently, stenting and use of diclofenac was introduced resulting in a significant reduction in ERCP associated pancreatitis (3 of 31 screens). Use of secretin to allow sampling of pancreatic juice from the duodenum was also piloted to further improve safety. This thesis provides data to support risk stratification in FPC and an improved screening modality. A total of 212 HP kindreds were identified. A variable clinical picture and cancer risk was found in the HP families with p.R122H, p.N29I and p.A16V all conferring a significantly increased lifetime risk for the development of pancreatic cancer, in addition to the earlier age of onset of exocrine and endocrine failure. Cancer risk was shown to be increased with smoking and diabetes. Risk of PDAC increases with age equally for HP and the general population but was 28 fold higher in each age group with HP. Conclusion My thesis has identified specific lifestyle and disease derived risk factors which may influence risk for the development of PDAC in high risk groups. As a direct result of this thesis, amendments made to the screening protocol have improved safety and minimised harm to those individuals undertaking screening for early pancreatic cancer under the auspices of EUROPAC

Dioxin Toxicity In Vivo Results from an Increase in the Dioxin-Independent Transcriptional Activity of the Aryl Hydrocarbon Receptor

The Aryl hydrocarbon receptor (Ahr) is the nuclear receptor mediating the toxicity of dioxins -widespread and persistent pollutants whose toxic effects include tumor promotion, teratogenesis, wasting syndrome and chloracne. Elimination of Ahr in mice eliminates dioxin toxicity but also produces adverse effects, some seemingly unrelated to dioxin. Thus the relationship between the toxic and dioxin-independent functions of Ahr is not clear, which hampers understanding and treatment of dioxin toxicity. Here we develop a Drosophila model to show that dioxin actually increases the in vivo dioxin-independent activity of Ahr. This hyperactivation resembles the effects caused by an increase in the amount of its dimerisation partner Ahr nuclear translocator (Arnt) and entails an increased transcriptional potency of Ahr, in addition to the previously described effect on nuclear translocation. Thus the two apparently different functions of Ahr, dioxin-mediated and dioxin-independent, are in fact two different levels (hyperactivated and basal, respectively) of a single function

The challenge of antimicrobial resistance: What economics can contribute

BACKGROUND: Antimicrobial resistance (AMR) is increasing, driven by widespread antibiotic use. The wide availability of effective antibiotics is under threat, jeopardizing modern health care. Forecasts of the economic costs are similar to those of a 2°C rise in global average surface temperature, above preindustrial levels. AMR is becoming an urgent priority for policy-makers, and pressure is mounting to secure international commitments to tackle the problem. // ADVANCES: Estimating the value of interventions to reduce antibiotic use requires predictions of future levels of antibiotic resistance. However, modeling the trajectory of antibiotic resistance, and how marginal changes in antibiotic consumption contribute to resistance, is complex. The challenge of estimating the resulting impact on health and the economy is similarly daunting. As with the cost of climate change, estimates of total AMR costs are fraught with uncertainty and may be far too low. Much of the uncertainty arises from the complexity of estimating the cost of changes in overall resistance levels. This cost depends on various factors: which drug and pathogen are involved, the mechanism of antibiotic resistance, the prevalence of that pathogen, the types of infections it causes and their level of transmissibility, the health burden of those infections, and whether alternative treatments are available. Effective new antibiotics are urgently needed. However, without government intervention, R&D for antibiotics is rarely profitable, and most major pharmaceutical companies have left the field. New ways are needed to make antibiotic development profitable, decoupling profits from volumes sold. // OUTLOOK: Analogies can be drawn between climate change and AMR, both of which have been described as a global “tragedy of the commons.” There is some consensus that we should treat carbon emissions reduction as an insurance policy against the possibility of a catastrophic climate outcome—and avoid waiting for a definitive optimum-abatement policy. A similar paradigm shift is needed to incentivize both the introduction and valuation of interventions to reduce antibiotic use and R&D of new antibiotics. Rather than taxing the price and letting the market dictate the quantity of antibiotics supplied, an alternative may be to establish a regulatory body that issues prescribers tradable permits and to allow the market to determine the price. Such an approach could create a predictable revenue stream through more-foreseeable licensing fees for important antibiotics by decoupling the return on investment from the volume used. Approaches such as this could incentivize industry to develop new antibiotics for which there would otherwise be too small a market to provide a sufficient return on investment. Reducing inappropriate antibiotic use while expanding essential access is a difficult challenge, especially in low- and middle-income countries. However, policy-makers and philanthropists are alert to the importance of AMR and increasingly are making substantial research funds available, with much of these funds devoted to the social sciences. We need economists, across many different fields, to engage with this pressing global problem

A cross-national study on the antecedents of work–life balance from the fit and balance perspective

Drawing on the perceived work–family fit and balance perspective, this study investigates demands and resources as antecedents of work–life balance (WLB) across four countries (New Zealand, France, Italy and Spain), so as to provide empirical cross-national evidence. Using structural equation modelling analysis on a sample of 870 full time employees, we found that work demands, hours worked and family demands were negatively related to WLB, while job autonomy and supervisor support were positively related to WLB. We also found evidence that resources (job autonomy and supervisor support) moderated the relationships between demands and work–life balance, with high resources consistently buffering any detrimental influence of demands on WLB. Furthermore, our study identified additional predictors of WLB that were unique to some national contexts. For example, in France and Italy, overtime hours worked were negatively associated with WLB, while parental status was positively associated with WLB. Overall, the implications for theory and practice are discussed.Peer ReviewedPostprint (author's final draft

French database of children and adolescents with Prader-Willi syndrome

<p>Abstract</p> <p>Background</p> <p>Prader-Willi syndrome (PWS) is a rare multisystem genetic disease leading to severe complications mainly related to obesity. We strongly lack information on the natural history of this complex disease and on what factors are involved in its evolution and its outcome. One of the objectives of the French reference centre for Prader-Willi syndrome set-up in 2004 was to set-up a database in order to make the inventory of Prader-Willi syndrome cases and initiate a national cohort study in the area covered by the centre.</p> <p>Description</p> <p>the database includes medical data of children and adolescents with Prader-Willi syndrome, details about their management, socio-demographic data on their families, psychological data and quality of life of the parents. The tools and organisation used to ensure data collection and data quality in respect of good clinical practice procedures are discussed, and main characteristics of our Prader-Willi population at inclusion are presented.</p> <p>Conclusion</p> <p>this database covering all the aspects of PWS clinical, psychological and social profiles, including familial psychological and quality of life will be a powerful tool for retrospective studies concerning this complex and multi factorial disease and could be a basis for the design of future prospective multicentric studies. The complete database and the Stata.do files are available to any researcher wishing to use them for non-commercial purposes and can be provided upon request to the corresponding author.</p

Awareness of appropriate antibiotic use in primary care for influenza-like illness: Evidence of improvement from UK population-based surveys

Supplementary Materials: The following are available online at https://www.mdpi.com/2079-6382/9/10/690/s1, Figure S1: Changes from Survey 1 (red) to Survey 3 (blue) in the percentage of individuals who would go to the GP with ILI by population subgroup; Figure S2. Changes from Survey 1 (red) to Survey 3 (blue) in the percentage of individuals would ask for antibiotics by population subgroup; Figure S3. Changes from Survey 1 (red) to Survey 3 (blue) in the percentage of individuals that have taken antibiotics for ILI in the past 12 months by population subgroup; Figure S4. Changes from Survey 1 (red) to Survey 3 (blue) in the percentage of individuals that would go to GP with a child with ILI by population subgroup; Figure S5. Changes from Survey 1 (red) to Survey 3 (blue) in the percentage of individuals that would ask for antibiotics for a child with ILI by population subgroup; Figure S6. Changes from Survey 1 (red) to Survey 3 (blue) in the percentage of individuals that think antibiotics would help for a child with ILI by population subgroup; Figure S7. Changes from Survey 1 (red) to Survey 3 (blue) in the percentage of individuals for which child has taken an antibiotic for ILI in the past 12 months by population subgroup; Figure S8. Changes from Survey 1 (red) to Survey 3 (blue) in the percentage of individuals for which AMR information was surprising/new by population subgroup.Copyright © 2020 by the authors. Influenza-like illnesses (ILI) account for a significant portion of inappropriate antibiotic use. Patient expectations for antibiotics for ILI are likely to play a substantial role in ‘unnecessary’ antibiotic consumption. This study aimed to investigate trends in awareness of appropriate antibiotic use and antimicrobial resistance (AMR). Three sequential online surveys of independent representative samples of adults in the United Kingdom investigated expectations for, and consumption of, antibiotics for ILI (May/June 2015 (n = 2064); Oct/Nov 2016 (n = 4000); Mar 2017 (n = 4000)). Respondents were asked whether they thought antibiotics were effective for ILI and about their antibiotic use. Proportions and 95% confidence intervals (CI) were calculated for each question and interactions with respondent characteristics were tested using logistic regression. Over the three surveys, the proportion of respondents who believed antibiotics would “definitely/probably” help an ILI fell from 37% (95% CI 35–39%) to 28% (95% CI 26–29%). Those who would “definitely/probably” visit a doctor in this situation fell from 48% (95% CI 46–50%) to 36% (95% CI 34–37%), while those who would request antibiotics during a consultation fell from 39% (95% CI 37–41%) to 30% (95% CI 29–32%). The percentage of respondents who found the information we provided about AMR “new/surprising” fell from 34% (95% CI 32–36%) to 28% (95% CI 26–31%). Awareness improved more among black, Asian and minority ethnic (BAME) than white people, with little other evidence of differences in improvements between subgroups. Whilst a degree of selection bias is unavoidable in online survey samples, the results suggest that awareness of AMR and appropriate antibiotic use has recently significantly improved in the United Kingdom, according to a wide range of indicators.The research was funded by the National Institute for Health Research (NIHR) Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance at the University of Oxford in partnership with Public Health England (PHE) [grant numbers HPRU-2012-10041 and NIHR200915], and the NIHR HPRU in Evaluation of Interventions at the University of Bristol, also in partnership with PHE [grant number HPRU-2012-10026]. Michele Peters is an Associate Professor supported by the NIHR funded Policy Research Unit on Quality, Safety and Outcomes (QSO), a collaboration between the Universities of Kent and Oxford, the London School of Hygiene and Tropical Medicine, the Hull-York Medical School and the Picker Institute. Laurence S. J. Roope, James Buchanan, Derrick W. Crook, Tim Peto, A. Sarah Walker and Sarah Wordsworth are partly funded by the Oxford NIHR Biomedical Research Centre. Tim Peto, Christopher C. Butler and A. Sarah Walker are NIHR Senior Investigators. Enrique Castro-Sánchez is affiliated with the NIHR HPRU in Healthcare Associated Infection and Antimicrobial Resistance at Imperial College London in partnership with Public Health England [grant number HPRU-2012-10047], is a National Institute for Health Research Senior Nurse and Midwife Research Leader and acknowledges the support of the BRC. The views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research (NIHR), the Department of Health, or Public Health England (PHE)

Genome of the Avirulent Human-Infective Trypanosome—Trypanosoma rangeli

Background: Trypanosoma rangeli is a hemoflagellate protozoan parasite infecting humans and other wild and domestic mammals across Central and South America. It does not cause human disease, but it can be mistaken for the etiologic agent of Chagas disease, Trypanosoma cruzi. We have sequenced the T. rangeli genome to provide new tools for elucidating the distinct and intriguing biology of this species and the key pathways related to interaction with its arthropod and mammalian hosts.  Methodology/Principal Findings: The T. rangeli haploid genome is ,24 Mb in length, and is the smallest and least repetitive trypanosomatid genome sequenced thus far. This parasite genome has shorter subtelomeric sequences compared to those of T. cruzi and T. brucei; displays intraspecific karyotype variability and lacks minichromosomes. Of the predicted 7,613 protein coding sequences, functional annotations could be determined for 2,415, while 5,043 are hypothetical proteins, some with evidence of protein expression. 7,101 genes (93%) are shared with other trypanosomatids that infect humans. An ortholog of the dcl2 gene involved in the T. brucei RNAi pathway was found in T. rangeli, but the RNAi machinery is non-functional since the other genes in this pathway are pseudogenized. T. rangeli is highly susceptible to oxidative stress, a phenotype that may be explained by a smaller number of anti-oxidant defense enzymes and heatshock proteins.  Conclusions/Significance: Phylogenetic comparison of nuclear and mitochondrial genes indicates that T. rangeli and T. cruzi are equidistant from T. brucei. In addition to revealing new aspects of trypanosome co-evolution within the vertebrate and invertebrate hosts, comparative genomic analysis with pathogenic trypanosomatids provides valuable new information that can be further explored with the aim of developing better diagnostic tools and/or therapeutic targets

Genomic Analysis of wig-1 Pathways

Background: Wig-1 is a transcription factor regulated by p53 that can interact with hnRNP A2/B1, RNA Helicase A, and dsRNAs, which plays an important role in RNA and protein stabilization. in vitro studies have shown that wig-1 binds p53 mRNA and stabilizes it by protecting it from deadenylation. Furthermore, p53 has been implicated as a causal factor in neurodegenerative diseases based in part on its selective regulatory function on gene expression, including genes which, in turn, also possess regulatory functions on gene expression. In this study we focused on the wig-1 transcription factor as a downstream p53 regulated gene and characterized the effects of wig-1 down regulation on gene expression in mouse liver and brain. Methods and Results: Antisense oligonucleotides (ASOs) were identified that specifically target mouse wig-1 mRNA and produce a dose-dependent reduction in wig-1 mRNA levels in cell culture. These wig-1 ASOs produced marked reductions in wig-1 levels in liver following intraperitoneal administration and in brain tissue following ASO administration through a single striatal bolus injection in FVB and BACHD mice. Wig-1 suppression was well tolerated and resulted in the reduction of mutant Htt protein levels in BACHD mouse brain but had no effect on normal Htt protein levels nor p53 mRNA or protein levels. Expression microarray analysis was employed to determine the effects of wig-1 suppression on genome-wide expression in mouse liver and brain. Reduction of wig-1 caused both down regulation and up regulation of several genes