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Supplementary Table S2. TL quartiles and OS association analysis (Crude Cox regression).

Supplementary Figure S1. Kaplan-Meier OS curves of bladder cancer patients stratified for TL quartiles. OS, overall survival; TL, telomere length.

Background: Shorter telomere length (TL) has been reported to be associated with increased risk of early death in elder individuals. Telomere shortening has been also related to chromosomal instability, which may possibly contribute to the development of several types of digestive or urogenital system cancers and smoking-related tumors. Therefore, we investigated the impact of TL on bladder cancer survival.Methods: TL was measured in leukocyte DNA from whole peripheral blood using quantitative real-time PCR in 463 patients with bladder cancer from a total 726 cases who were followed for up to 18 years.Results: Patients with muscle-invasive tumor/any grade had shorter telomere than patients with non–muscle-invasive tumor/high-grade and with non–muscle-invasive tumor/non–high-grade (TL reference 0.7 ± 0.2; vs. respectively, 0.8 ± 0.2, P = 3.4 × 10−2 and 0.8 ± 0.2, P = 3.6 × 10−2). Moreover, patients in the lowest quartiles of TL were associated with decreased survival after diagnosis (log-rank test, P = 3.9 × 10−4). A Cox regression adjusted by age, cancer aggressiveness, Bacillus Calmette-Guérin, radical cystectomy, radiotherapy, and chemotherapy showed an independent effect of TL on bladder cancer survival (HR, 3.9; 95% confidence interval, 1.7–9.1; P = 1.2 × 10−3).Conclusions: Our results suggest that leukocyte TL is only partly related to tumor aggressiveness and that shorter telomeres act as independent prognostic predictor of survival in patients with bladder cancer. TL information may allow to better select therapeutic approaches in patients with the same stage and grade.Impact: Blood leukocyte TL levels could provide an additional noninvasive prognostic marker to better predict survival and personalize therapies in patients with bladder cancer. Cancer Epidemiol Biomarkers Prev; 23(11); 2439–46. ©2014 AACR.

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer mainly caused by asbestos exposure. Specific and sensitive non-invasive biomarkers may facilitate and enhance screening programs for the early detection of cancer. We investigated DNA methylation (DNAm) profiles in MPM pre-diagnostic blood samples in a case-control study nested in the European Prospective Investigation into Cancer and nutrition (EPIC) cohort, aiming to characterise DNAm biomarkers associated with MPM. From the EPIC cohort, we included samples from 135 participants who developed MPM during 20 years of follow up and from 135 matched, cancer-free, controls. For the discovery phase we selected EPIC participants who developed MPM within five years from enrolment (n=36) with matched controls. We identified nine differentially methylated CpGs, selected by 10-fold cross-validation and correlation analyses: cg25755428 (MRI1), cg20389709 (KLF11), cg23870316, cg13862711 (LHX6), cg06417478 (HOOK2), cg00667948, cg01879420 (AMD1), cg25317025 (RPL17) and cg06205333 (RAP1A). Receiver operating characteristic (ROC) analysis showed that the model including baseline characteristics (age, sex, PC1wbc) along with the nine MPM-related CpGs has a better predictive value for MPM occurrence than the baseline model alone, maintaining some performance also at more than five years before diagnosis [AUC (area under the curve) 10 years=0.75; baseline AUC range=0.63-0.67)]. DNAm changes as non-invasive biomarkers in pre-diagnostic blood samples of MPM cases were investigated for the first time. Their application can improve the identification of asbestos-exposed individuals at higher MPM risk in order to possibly adopt more intensive monitoring for early disease identification.

To reconstruct the phenotypical and clinical implications of the Italian genetic structure, we thoroughly analyzed a whole-exome sequencing data set comprised of 1686 healthy Italian individuals. We found six previously unreported variants with remarkable frequency differences between Northern and Southern Italy in the HERC2, OR52R1, ADH1B, and THBS4 genes. We reported 36 clinically relevant variants (submitted as pathogenic, risk factors, or drug response in ClinVar) with significant frequency differences between Italy and Europe. We then explored putatively pathogenic variants in the Italian exome. On average, our Italian individuals carried 16.6 protein-truncating variants (PTVs), with 2.5% of the population having a PTV in one of the 59 American College of Medical Genetics (ACMG) actionable genes. Lastly, we looked for PTVs that are likely to cause Mendelian diseases. We found four heterozygous PTVs in haploinsufficient genes (KAT6A, PTCH1, and STXBP1) and three homozygous PTVs in genes causing recessive diseases (DPYD, FLG, and PYGM). Comparing frequencies from our data set to other public databases, like gnomAD, we showed the importance of population-specific databases for a more accurate assessment of variant pathogenicity. For this reason, we made aggregated frequencies from our data set publicly available as a tool for both clinicians and researchers (http://nigdb.cineca.it; NIG-ExIT).

This paper studies the effect of preregistration laws on government spending in the U.S. Preregistration allows young citizens to register before being eligible to vote and has been introduced in different states in different years. Employing a difference-in-differences regression design, we first establish that preregistration shifts state-level government spending toward expenditure on higher education. The magnitude of the increase is larger when political competition is weaker and inequality is higher. Second, we document a positive effect of preregistration on state-provided student aid and its number of recipients by comparing higher education institutions within border-county pairs. Lastly, using individual-level data on voting records, we show that preregistration promotes a de facto youth enfranchisement episode. Consistent with a political economy model of distributive politics,the results collectively suggest strong political responsiveness to the needs of the newly-enfranchised constituent group.

Current guidelines for preterm newborns recommend high energy nutrition soon after birth in order to limit growth retardation. However, long-term effects of this nutritional approach are still debated, and it has been demonstrated that cerebral growth depends on protein intake in early life. A negative impact of early high energy intake by parenteral nutrition (PN) has been reported for patients in critically ill conditions, observed in intensive care unit. We aimed at evaluating the impact of energy intake on cerebral growth in preterm neonates early in life. We included preterm newborns with gestational age p r = − 0.243*) and a positive correlation between total energy intake and transverse cerebellum diameter (r = 0.254*). Multivariate analysis showed that energy intake administered by enteral nutrition (EN), independently increased growth of left caudate head (β = 0.227*) and height cerebellar vermis (β = 0.415*), while PN independently affected growth of both right and left caudate head (β = − 0.164* and β = − 0.228*, respectively) and cerebellum transverse diameter (β = − 0.849*). The route of energy administration may exert different effects on cerebral growth in early life. High energy intake administered through EN seems to be positively correlated to cerebral growth; conversely, PN energy intake results in a poorer cerebral growth evaluated with cUS.

Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasm. Patients are usually diagnosed when current treatments have limited benefits, highlighting the need for noninvasive tests aimed at an MPM risk assessment tool that might improve life expectancy. Three hundred asbestos-exposed subjects (163 MPM cases and 137 cancer-free controls), from the same geographical region in Italy, were recruited. The evaluation of asbestos exposure was conducted considering the frequency, the duration and the intensity of occupational, environmental and domestic exposure. A genome-wide methylation array was performed to identify novel blood DNA methylation (DNAm) markers of MPM. Multiple regression analyses adjusting for potential confounding factors and interaction between asbestos exposure and DNAm on the MPM odds ratio were applied. Epigenome-wide analysis (EWAS) revealed 12 single-CpGs associated with the disease. Two of these showed high statistical power (99%) and effect size (&gt, 0.05) after false discovery rate (FDR) multiple comparison corrections: (i) cg03546163 in FKBP5, significantly hypomethylated in cases (Mean Difference in beta values (MD) = −0.09, 95% CI = −0.12|−0.06, p = 1.2 × 10−7), and (ii) cg06633438 in MLLT1, statistically hypermethylated in cases (MD = 0.07, 95% CI = 0.04|0.10, p = 1.0 × 10−6). Based on the interaction analysis, asbestos exposure and epigenetic profile together may improve MPM risk assessment. Above-median asbestos exposure and hypomethylation of cg03546163 in FKBP5 (OR = 20.84, 95% CI = 8.71|53.96, p = 5.5 × 10−11) and hypermethylation of cg06633438 in MLLT1 (OR = 11.71, 95% CI = 4.97|29.64, p = 5.9 × 10−8) genes compared to below-median asbestos exposure and hyper/hypomethylation of single-CpG DNAm, respectively. Receiver Operation Characteristics (ROC) for Case-Control Discrimination showed a significant increase in MPM discrimination when DNAm information was added in the model (baseline model, BM: asbestos exposure, age, gender and white blood cells), area under the curve, AUC = 0.75, BM + cg03546163 at FKBP5. AUC = 0.89, 2.1 × 10−7, BM + cg06633438 at MLLT1. AUC = 0.89, 6.3 × 10−8. Validation and replication procedures, considering independent sample size and a different DNAm analysis technique, confirmed the observed associations. Our results suggest the potential application of DNAm profiles in blood to develop noninvasive tests for MPM risk assessment in asbestos-exposed subjects.

Simple Summary Our study is the first one to investigate DNA methylation changes in white blood cells (WBCs) from easily accessible peripheral blood as malignant pleural mesothelioma (MPM) survival biomarker. The Cox proportional hazards regression model highlighted that the methylation status of the CpG dinucleotide cg03546163 is an independent marker of prognosis in MPM patients with a better performance than traditional inflammation-based scores such as lymphocyte-to-monocyte ratio (LMR). Biological validation and replication showed that epigenetic changes at the FKBP5 gene were robustly associated with overall survival (OS) in MPM cases. The identification of simple and valuable prognostic markers for MPM will enable clinicians to select patients who are most likely to benefit from aggressive therapies and avoid subjecting non-responder patients to ineffective treatment. Abstract Malignant pleural mesothelioma (MPM) is an aggressive tumor with median survival of 12 months and limited effective treatments. The scope of this study was to study the relationship between blood DNA methylation (DNAm) and overall survival (OS) aiming at a noninvasive prognostic test. We investigated a cohort of 159 incident asbestos exposed MPM cases enrolled in an Italian area with high incidence of mesothelioma. Considering 12 months as a cut-off for OS, epigenome-wide association study (EWAS) revealed statistically significant (p value = 7.7 × 10−9) OS-related differential methylation of a single-CpG (cg03546163), located in the 5′UTR region of the FKBP5 gene. This is an independent marker of prognosis in MPM patients with a better performance than traditional inflammation-based scores such as lymphocyte-to-monocyte ratio (LMR). Cases with DNAm < 0.45 at the cg03546163 had significantly poor survival compared with those showing DNAm ≥ 0.45 (mean: 243 versus 534 days; p value< 0.001). Epigenetic changes at the FKBP5 gene were robustly associated with OS in MPM cases. Our results showed that blood DNA methylation levels could be promising and dynamic prognostic biomarkers in MPM.

Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.

We study the role of media reporting of alleged adverse effects of influenza vaccination on adults' (aged 50 or more) decisions to vaccinate against the flu. We exploit the diffusion of news linking suspected deaths to the vaccine, during the 2014 vaccination campaign in Italy. Using daily variation in news items across the 2014 campaign and the previous year campaign, unaffected by media cases, we show that media reporting decreases flu vaccination by about 2.5 % (78 fewer vaccinations per day). The effect, however, is short-lived, as it fades away after approximately 10 days from the news outbreak.

Introduction: To limit extrauterine growth restriction, recent guidelines on nutrition of preterm neonates recommended high protein intake since the first day of life (DOL). The impact of this nutritional strategy on the brain is still controversial. We aimed to evaluate the effects of protein intake on early cerebral growth in very low birth weight newborns. Materials and Methods: We performed serial cranial ultrasound (cUS) scans at 3-7 DOL and at 28 DOL in very low birth weight newborns consecutively observed in the neonatal intensive care unit. We analyzed the relation between protein intake and cerebral measurements at 28 DOL performed by cUS. Results: We enrolled 100 newborns (gestational age 29 ± 2 weeks, birth weight 1,274 ± 363 g). A significant (p < 0.05) positive correlation between enteral protein intake and biparietal diameter (r = 0.490**), occipital-frontal diameter (r = 0.608**), corpus callosum (length r = 0.293*, genu r = 0.301*), caudate head (right r = 0.528**, left r = 0.364**), and cerebellum (transverse diameter r = 0.440**, vermis height r = 0.356**, vermis width r = 0.377**) was observed at 28 DOL. Conversely, we found a significant negative correlation of protein intake given by parenteral nutrition (PN) with biparietal diameter (r = -0.524**), occipital-frontal diameter (r = -0.568**), body of corpus callosum (r = -0.276*), caudate head (right r = -0.613**, left r = -0.444**), and cerebellum (transverse diameter r = -0.403**, vermis height r = -0.274*, vermis width r = -0.462**) at 28 DOL. Multivariate regression analysis showed that measurements of occipital-frontal diameter, caudate head, and cerebellar vermis at 28 DOL depend positively on protein enteral intake (r = 0.402*, r = 0.305*, and r = 0.271*) and negatively by protein parenteral intake (r = -0.278*, r = -0.488*, and r = -0.342*). Conclusion: Brain development in neonatal life depends on early protein intake. High protein intake affects cerebral structures' measurements of preterm newborn when administered by PN. Positive impact on brain development encourages the administration of recommended protein intake mainly by enteral nutrition.

Valutazione delle abilità neurocognitive in bambini affetti da sindrome delle apnee ostruttive in sonno prima e dopo adenotonsillectomia.La Sindrome delle Apnee Ostruttive del Sonno (OSAS, Obstructive Sleep Apnea Syndrome) è la forma più severa di Disturbo Respiratorio Sonno-correlato (SRDB, Sleep-related Disordered Breathing) ed è caratterizzata da russamento, apnee, e/o ipopnee associate a ipossia, ipercapnia, o ripetuti risvegli dal sonno (arousals). L’OSAS include tre categorie di morbidità: neurocomportamentali, cardiovascolari, disturbi della crescita somatica. Il gold standard per la diagnosi oggettiva di severità del SRDB ostruttivo è rappresentato dalla polisonnografia (PSG). L’indicazione al trattamento chirurgico nei bambini è la diagnosi di OSAS moderata-severa (indice di apnea-ipopnea5/h) e di OSAS lieve (indice di apnea-ipopnea 2-5/h) se sono presenti complicanze o comorbidità. Lo spettro intero di SRDB definiti mediante PSG (dal Russamento Primario all’OSAS severa) potrebbe correlare con deficit comportamentali, attentive e delle funzioni esecutive dovuti all’ipossia ed alla frammentazione del sonno: in alcuni casi, queste alterazioni possono mimare il Disturbo da deficit di Attenzione con Iperattività (ADHD, Attention Deficit Hyperactivity Disorder). Lo scopo di questa ricerca è stato quello di valutare le abilità visuopercettive e costruttive, i punteggi al Pediatric Sleep Questionnaire ed alla PSG prima e dopo l’intervento di adenotonsillectomia fornendo informazoni oggettive e soggettive. Abbiamo incluso in questo studio 59 bambini sottoposti a valutazione clinica otorinolaringoiatrica e neuropsichiatrica e poi al test di Beery-Buktenica Developmental Test of Visual-Motor Integration (VMI) ed ai genitori veniva chiesto di compilare il Pediaric Sleep Questionnaire (PSQ); ogni bambino veniva sottoposto a PSG. Dopo 6 mesi dall’intervento di adeotonsillectomia sono state ripetute tutte le valutazioni come al tempo 0. L’analisi statistica evidenzia risultati significativi al PSQ, VMI standard e visivo ed ai parametri polisonnografici se confrontati prima e dopo l’intervento chirurgico di adenotonsillectomia nei bambini affetti da OSAS moderata-severa. Questi risultati hanno mostrato il raggiungimento dei vantaggi terapeutici attraverso il miglioramento della qualità della vita dei bambini e dei loro genitori.Obstructive sleep apnoea syndrome (OSAS) is the most severe form of sleep-related disordered breathing (SRDB) and is characterised by snoring, apnoeas, and/or hypopnoeas associated to hypoxia, hypercarbia, or repeated arousals from sleep. OSAS has three major categories of morbidities: neurobehavioural, cardiovascular and somatic growth failure. The gold standard for objective diagnosis of obstructive-SRDB severity is polysomnography (PSG). The indication for surgical treatment in children is moderate-severe OSAS (AHI, apnoea hypopnoea index5/h) and in mild OSAS (AHI 2-5/h) with complications or morbidity. The entire spectrum of PSG-defined SRDB (ranging from Primary Snoring to severe OSAS) may correlate with behavioural, attentional and executive function deficits relating to hypoxia and sleep disruption: in some cases, these alterations may mimic attention deficit hyperactivity disorder (ADHD). The aim of this research was to evaluate visuoperceptual and constructional abilities, paediatric sleep questionnaire and polysomnographic scores before and 6 months after adenotonsillectomy with objective and subjective information. We included 59 children who underwent neuropsychiatric and otolaryngologist clinical evaluation and the Beery-Buktenica Developmental Test of Visual-Motor Integration (VMI); children parents were asked to fill in the Paediatric Sleep Questionnaire (PSQ); each child underwent PSG. At 6 months after adenotonsillectomy, all patients were evaluated again. There is a significant difference in PSQ parameters, VMI standard, visual tests scores and PSG parameters before and after adenotonsillectomy in children affected by OSAS. These results showed the achievement of therapeutic benefits with improvement of the quality of life for both children and their parents.

Umbilical cord care can be a stressful practice for parents. Complications of cord care can increase neonatal morbidity and mortality. The extracts of Arnica montana (AM) have been reported to possess antibacterial, anti-inflammatory, antifungal, and immunomodulatory activities. We aim to demonstrate the efficacy of AM on cord detachment and parents’ stress level induced by cord medication in healthy full-term newborns. We enrolled full-term infants with a birth weight ≥ 2500 g in healthy conditions. Cord stumps of infants in the PRE-group were cleaned and dried, while cord stumps of infants in the POST-group were cleaned, dried, and medicated with a natural topic dermo-protective powder containing AM. After discharge, we interviewed parents on the stump status during follow-up visits in a pediatric office at 7 and 14 days of life, or by phone calls after follow-up visits. Long-rank test showed that time of cord separation of newborns in the PRE-group was significantly higher compared to that in the POST-group (p < 0.001). Parents of newborns in the PRE-group were significantly more stressed during cord medication compared to parents in the POST-group (2.0 (1.2 to 2.1) vs 1.0 (0.8 to 1.3), p = 0.011). Multivariate analysis showed a significantly linear relation with group assignment for cord separation (p < 0.001) and parents’ stress during the medication (p = 0.033).Conclusion: The use of a natural topic dermo-protective powder containing AM reduces the time of cord separation, improves parents’ stress level, and reduces the risk of complications. What is Known:• Cord stump care can be a stressful practice for parents.• Antiseptic treatment recommended for cord care could be associated with side effects such as burning and sensitization. What is New:• The medication of cord stump with a natural topic dermo-protective powder containing Arnica montana reduces time of cord detachment and of complication such as redness’, bleeding, or secretions.• The use of Arnica montana for cord medication may have a positive impact on the family, reducing parents’ stress, and the use of other medications.

Intervista a Henry Giroux, tradotta in italiano., Iperstoria, No 5 (2015): Teaching English for Specific Purposes in Higher Education

Modified from the protocol of Baptiste Mayjonade, Jérome Gouzy, Cécile Donnadieu, Nicolas Pouilly, William Marande, Caroline Callot, Nicolas Langlade and Stéphane Munos, High molecular weight gDNA extraction, Bio Techniques, Vol. 61, No. 4, October 2016, pp. 203-205. BioTechniques 61:203-205 (October 2016) doi 10.2144/000114460 https://www.future-science.com/doi/10.2144/000114460 The original protocol failed to extract High Molecular Weight genomic DNA from orchids samples (poor yield and low purity). Therefore modifications (mainly/mostly BME addition during the lysis step and a Phenol:Chloroform purification step) were made to create a new version of this protocol. This new version allowed to successfully extract DNA from orchid samples. This DNA was then sequenced on a Nanopore PromethION platform and good results in term of total yield and read length were obtained. This protocol was also successfully applied to a wide range of plant species (See attached document/excel sheet). ACKNOWLEDGEMENT Sequencing of the Arabidopsis thaliana samples listed in the attached reports was performed in collaboration with the GeT core facility, Toulouse, France (http://get.genotoul.fr), and was supported by France Génomique National infrastructure, funded as part of “Investissement d’avenir” program managed by Agence Nationale pour la Recherche (contract ANR-10-INBS-09). We particularly want to thank Lisa Gil and Céline Lopez-Roques for the sequencing part and Roxane Boyer for the data processing. Sampling and DNA Extraction for the Ophrys sphegodes samples were financially supported by the University of Zürich Research Priority Programme URPP "Evolution in Action" (PMS/AR). Sequencing was performed by Daniel Frei in the Department of Molecular Diagnostics, Genomics and Bioinformatics, Agroscope Wädenswil, Switzerland. We are thankful to Jürg E. Frey, Agroscope, for financial support. We are grateful to Philipp M. Schlüter and Ueli Grossniklaus for support and helpful discussion. Sequencing of Lolium multiflorium was performed in Agroscope by Daniel Frei. We thank Daniel, Jürg E. Frei, Dario Copetti and Bruno Studer, Department of Environmental Systems Science, ETH Zürich, for sharing the sequencing results. Sequencing of Brassica incana was performed at FGCZ Zürich. We are thankful to Léa Frachon, Department of Systematic and Evolutionary Botany, UZH Zürich, to share the data. DNA extraction of Gorteria diffusa was performed by Roman T. Kellenberger, Department of Plant Sciences, University of Cambridge. We wish to thank him for sharing his sequencing results.

This paper studies how organizations seek to promote cooperation between their members when individual contributions to an organization’s output are imperfectly observable. It considers an overlapping-generations game in which members with conflicting interests expend effort in pursuing activities outside the organization, in addition to the effort they devote to increasing the organization’s output. We show that cooperation is easier to enforce when organizations link rewards and punishments to effort in outside activities. In the best public perfect equilibrium, effort in outside activities is distorted in order to signal a member’s willingness to cooperate inside the organization.

This paper analyzes a game in which countries repeatedly make emission and technology investment decisions. We derive the best equilibrium, i.e., the Paretooptimal subgame-perfect equilibrium, when countries are insufficiently patient for folk theorems to be relevant. Relative to the first best, the best equilibrium requires countries to overinvest in technologies that are green, i.e., strategic substitutes for polluting, but to underinvest in adaptation and brown technologies, i.e., strategic complements to polluting. Under uncertainty, strategic investments reduce the need for a long and costly punishment phase or the probability that it will be triggered. Technological transffers and spillovers might discourage investments but can be necessary to motivate compliance when countries are heterogeneous.

Malignant pleural mesothelioma (MPM) is an aggressive tumor with median survival of 12 months and limited effective treatments. The scope of this study was to study the relationship between blood DNA methylation (DNAm) and overall survival (OS) aiming at a noninvasive prognostic test. We investigated a cohort of 159 incident asbestos exposed MPM cases enrolled in an Italian area with high incidence of mesothelioma. Considering 12 months as a cut-off for OS, epigenome-wide association study (EWAS) revealed statistically significant (p value = 7.7 &times, 10&minus, 9) OS-related differential methylation of a single-CpG (cg03546163), located in the 5&prime, UTR region of the FKBP5 gene. This is an independent marker of prognosis in MPM patients with a better performance than traditional inflammation-based scores such as lymphocyte-to-monocyte ratio (LMR). Cases with DNAm &lt, 0.45 at the cg03546163 had significantly poor survival compared with those showing DNAm &ge, 0.45 (mean: 243 versus 534 days, p value&lt, 0.001). Epigenetic changes at the FKBP5 gene were robustly associated with OS in MPM cases. Our results showed that blood DNA methylation levels could be promising and dynamic prognostic biomarkers in MPM.

A dynamic political economy theory of scal policy is presented to explain the simultaneous existence of public education and pensions in modern democracies. The driving force of the model is the intergenerational conict over the allocation of the public budget. Successive generations of voters choose scal policies through repeated elections. The political power of elderly voters creates the motive for adults to support public investment in the human capital of future generations since it expands future pension possibilities. We characterize the Markov perfect equilibrium of the voting game in a small open economy. The equilibrium reproduces salient features of intergenerational

Bladder cancer (BC) has a typical aetiology characterized by a multistep carcinogenesis due to environmental exposures, genetic susceptibility, and their interaction. Several lines of evidence suggest that DNA repair plays a role in the development and progression of BC. In particular, the study of individual susceptibility to DNA double strand breaks (DSBs) may provide valuable information on BC risk, and help to identify those patients at high-risk of either recurrence or progression of the disease, possibly personalizing both surveillance and treatment. Among the different DSB markers, the most well characterized is phosphorylation of the histone H2AX (γ-H2AX). We assessed any potential role of γ-H2AX as a molecular biomarker in a case-control study (146 cases and 146 controls) to identify individuals with increased BC risk and at high-risk of disease recurrence or progression. We investigated γ-H2AX levels in peripheral blood mononuclear cells before and after their exposure to ionizing radiation (IR). We did not find any significant difference among cases and controls. However, we observed a significant association between γ-H2AX basal levels and risk of disease recurrence or progression. In particular, both BC patients as a whole and the subgroup of non-muscle invasive BC (NMIBC) with high basal H2AX phosphorylation levels had a decreased risk of recurrence or progression (for all BC HR 0.70, 95%CI 0.52-0.94, P = 0.02; for NMIBC HR 0.68, 95%CI 0.50-0.92, P = 0.01), suggesting a protective effect of basal DSB signaling. Our data suggest that γ-H2AX can be considered as a potential molecular biomarker to identify patients with a higher risk of BC recurrence. © 2015 Wiley Periodicals, Inc.

Background: Shorter telomere length (TL) has been reported to be associated with increased risk of early death in elder individuals. Telomere shortening has been also related to chromosomal instability, which may possibly contribute to the development of several types of digestive or urogenital system cancers and smoking-related tumors. Therefore, we investigated the impact of TL on bladder cancer survival. Methods: TL was measured in leukocyte DNA from whole peripheral blood using quantitative real-time PCR in 463 patients with bladder cancer from a total 726 cases who were followed for up to 18 years. Results: Patients with muscle-invasive tumor/any grade had shorter telomere than patients with non–muscle-invasive tumor/high-grade and with non–muscle-invasive tumor/non–high-grade (TL reference 0.7 ± 0.2; vs. respectively, 0.8 ± 0.2, P = 3.4 × 10−2 and 0.8 ± 0.2, P = 3.6 × 10−2). Moreover, patients in the lowest quartiles of TL were associated with decreased survival after diagnosis (log-rank test, P = 3.9 × 10−4). A Cox regression adjusted by age, cancer aggressiveness, Bacillus Calmette-Guérin, radical cystectomy, radiotherapy, and chemotherapy showed an independent effect of TL on bladder cancer survival (HR, 3.9; 95% confidence interval, 1.7–9.1; P = 1.2 × 10−3). Conclusions: Our results suggest that leukocyte TL is only partly related to tumor aggressiveness and that shorter telomeres act as independent prognostic predictor of survival in patients with bladder cancer. TL information may allow to better select therapeutic approaches in patients with the same stage and grade. Impact: Blood leukocyte TL levels could provide an additional noninvasive prognostic marker to better predict survival and personalize therapies in patients with bladder cancer. Cancer Epidemiol Biomarkers Prev; 23(11); 2439–46. ©2014 AACR.

We analyze a repeated game in which countries are polluting as well as investing in technologies. While folk theorems point out that the first best can be sustained as a subgame-perfect equilibrium when the players are sufficiently patient, we derive the second best equilibrium when they are not. This equilibrium is distorted in that countries over-invest in technologies that are “green” (i.e., strategic substitutes for polluting) but under-invest in adaptation and “brown” technologies (i.e., strategic complements to polluting). It is in particular countries which are small or benefit little from cooperation that will be required to strategically invest in this way. With imperfect monitoring or uncertainty, such strategic investments reduce the need for a long, costly punishment phase and the probability that punishment will be triggered.

Recent epidemiological investigations have reported on the association between telomere length (TL) and a number of malignancies, including B-cell lymphoma (BCL). The reported results for BCLs are however inconsistent. We carried out a nested case-control study to determine whether TL is associated with future risk of BCL. Using quantitative polymerase chain reaction, the relative TL (i.e. the ratio of telomere repeat copy number to single gene copy number) was measured in mononuclear cell DNA of prediagnostic peripheral blood samples of 464 lymphoma cases and 464 matched controls (median time between blood collection and diagnosis, 4.6 years). Conditional logistic regression was used to analyze the association between TL and the risk of developing lymphoma and histologic subtypes. TL was significantly longer in cases compared to controls (p 5 0.01). Multivariable models showed a significantly increased risk of BCL [odds ratio (OR) = 1.66, 1.80 and 3.20 for quartiles 2-4, respectively, p-trend = 0.001], diffuse large B-cell lymphoma (DLBCL) (OR = 1.20, 2.48 and 2.36 for quartiles 2-4, respectively, p-trend = 0.03) and follicular lymphoma (FL) (OR = 1.39, 1.90 and 2.69 for quartiles 2-4, respectively, p-trend = 0.02) with increasing TL. This study suggests an association between longer leucocyte TL and increased risk of BCL which was most pronounced for DLBCL and FL.