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This article investigates the factors that contributed to the proliferation of online COVID skepticism on Twitter across Italian municipalities in 2020. We demonstrate that sociodemographic factors were likely to mitigate the emergence of skepticism, whereas populist political leanings were more likely to foster it. Furthermore, pre-COVID anti-vaccine sentiment, represented by "old truthers" on Twitter, amplified online COVID skepticism in local communities. Additionally, exploiting the spatial variation in restrictive economic policies with severe implications for suspended workers in nonessential economic sectors, we find that COVID skepticism spreads more in municipalities significantly affected by the economic lockdown. Finally, the diffusion of COVID skepticism is positively associated with COVID vaccine hesitancy., (Copyright © 2024 The Authors.)

Purpose: To evaluate the prevalence of chronic comorbidities according to BMI classes and assess the interplay between excess body weight and blood glucose abnormalities in increasing the risk of major chronic diseases., Methods: The study is based on data from the Health Search/IQVIA Health LPD Longitudinal Patient Database, an Italian general practice registry, with data obtained from electronic clinical records of 800 general practitioners throughout Italy. Data relative to the year 2018 were analyzed. The study population was classified according to BMI (normal weight, overweight, and obesity classes 1, 2 and 3) and glucose metabolism status (normoglycemia-NGT; impaired fasting glucose-IFG; diabetes mellitus-DM). Comorbidities were identified through ICD-9 CM codes., Results: Data relative to 991,917 adults were analyzed. The prevalence of overweight was 39.4%, while the prevalence of obesity was 11.1% (class 1: 7.9%, class 2: 2.3%, class 3: 0.9%). In the whole population, the prevalence of DM and IFG was 8.9% and 4.2%, respectively. Both overweight and obesity were associated with an increasing prevalence of glucose metabolism alterations and a large array of different chronic conditions, including cardio-cerebrovascular diseases, heart failure, chronic kidney disease, osteoarticular diseases, depression, sleep apnea, and neoplasms of the gastrointestinal tract. Within each BMI class, the presence of IFG, and to a greater extent DM, identified subgroups of individuals with a marked increase in the risk of concomitant chronic conditions., Conclusion: Addressing the double burden of excess weight and hyperglycemia represents an important challenge and a healthcare priority., (© 2024. The Author(s).)

We use longitudinal electronic clinical data on a large representative sample of the Italian population to estimate the lifetime profile costs of different BMI classes - normal weight, overweight, and obese (I, II, and III) - in a primary care setting. Our research reveals that obese patients generate the highest cost differential throughout their lives compared to normal weight patients. Moreover, we show that overweight individuals spend less than those with normal weight, primarily due to reduced expenditures beginning in early middle age. Our estimates could serve as a vital benchmark for policymakers looking to prioritize public interventions that address the obesity pandemic while considering the increasing obesity rates projected by the OECD until 2030., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Genome-wide association studies (GWAS) are a powerful tool for detecting variants associated with complex traits and can help risk stratification and prevention strategies against pancreatic ductal adenocarcinoma (PDAC). However, the strict significance threshold commonly used makes it likely that many true risk loci are missed. Functional annotation of GWAS polymorphisms is a proven strategy to identify additional risk loci. We aimed to investigate single-nucleotide polymorphisms (SNP) in regulatory regions [transcription factor binding sites (TFBSs) and enhancers] that could change the expression profile of multiple genes they act upon and thereby modify PDAC risk. We analyzed a total of 12,636 PDAC cases and 43,443 controls from PanScan/PanC4 and the East Asian GWAS (discovery populations), and the PANDoRA consortium (replication population). We identified four associations that reached study-wide statistical significance in the overall meta-analysis: rs2472632(A) (enhancer variant, OR 1.10, 95%CI 1.06,1.13, p = 5.5 × 10 -8 ), rs17358295(G) (enhancer variant, OR 1.16, 95%CI 1.10,1.22, p = 6.1 × 10 -7 ), rs2232079(T) (TFBS variant, OR 0.88, 95%CI 0.83,0.93, p = 6.4 × 10 -6 ) and rs10025845(A) (TFBS variant, OR 1.88, 95%CI 1.50,1.12, p = 1.32 × 10 -5 ). The SNP with the most significant association, rs2472632, is located in an enhancer predicted to target the coiled-coil domain containing 34 oncogene. Our results provide new insights into genetic risk factors for PDAC by a focused analysis of polymorphisms in regulatory regions and demonstrating the usefulness of functional prioritization to identify loci associated with PDAC risk., (© 2024. The Author(s).)

Coding sequence variants comprise a small fraction of the germline genetic variability of the human genome. However, they often cause deleterious change in protein function and are therefore associated with pathogenic phenotypes. To identify novel pancreatic ductal adenocarcinoma (PDAC) risk loci, we carried out a complete scan of all common missense and synonymous SNPs and analysed them in a case-control study comprising four different populations, for a total of 14 538 PDAC cases and 190 657 controls. We observed a statistically significant association between 13q12.2-rs9581957-T and PDAC risk (P = 2.46 × 10-9), that is in linkage disequilibrium (LD) with a deleterious missense variant (rs9579139) of the URAD gene. Recent findings suggest that this gene is active in peroxisomes. Considering that peroxisomes have a key role as molecular scavengers, especially in eliminating reactive oxygen species, a malfunctioning URAD protein might expose the cell to a higher load of potentially DNA damaging molecules and therefore increase PDAC risk. The association was observed in individuals of European and Asian ethnicity. We also observed the association of the missense variant 15q24.1-rs2277598-T, that belongs to BBS4 gene, with increased PDAC risk (P = 1.53 × 10-6). rs2277598 is associated with body mass index and is in LD with diabetes susceptibility loci. In conclusion, we identified two missense variants associated with the risk of developing PDAC independently from the ethnicity highlighting the importance of conducting reanalysis of genome-wide association studies (GWASs) in light of functional data., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Genes carrying high-penetrance germline mutations may also be associated with cancer susceptibility through common low-penetrance genetic variants. To increase the knowledge on genetic pancreatic ductal adenocarcinoma (PDAC) aetiology, the common genetic variability of PDAC familial genes was analysed in our study. We conducted a multiphase study analysing 7745 single nucleotide polymorphisms (SNPs) from 29 genes reported to harbour a high-penetrance PDAC-associated mutation in at least one published study. To assess the effect of the SNPs on PDAC risk, a total of 14 666 PDAC cases and 221 897 controls across five different studies were analysed. The T allele of the rs1412832 polymorphism, that is situated in the CDKN2B-AS1/ANRIL, showed a genome-wide significant association with increased risk of developing PDAC (OR = 1.11, 95% CI = 1.07-1.15, P = 5.25 × 10 -9 ). CDKN2B-AS1/ANRIL is a long noncoding RNA, situated in 9p21.3, and regulates many target genes, among which CDKN2A (p16) that frequently shows deleterious somatic and germline mutations and deregulation in PDAC. Our results strongly support the role of the genetic variability of the 9p21.3 region in PDAC aetiopathogenesis and highlight the importance of secondary analysis as a tool for discovering new risk loci in complex human diseases., (© 2022 UICC.)

Background: To evaluate outpatient healthcare expenditure associated with different levels of BMI and glucose metabolism alterations., Methods: The study is based on a representative national sample of adults, with data obtained from electronic clinical records of 900 Italian general practitioners. Data relative to the year 2018 were analyzed. The study population was classified according to BMI (normal weight, overweight, and obesity classes 1, 2, and 3) and glucose metabolism status (normoglycemia - NGT; impaired fasting glucose - IFG; diabetes mellitus - DM). Outpatient health expenditures include diagnostic tests, specialist visits, and drugs., Results: Data relative to 991,917 adults were analyzed. Annual per capita expenditure rose from 252.2 Euro among individuals with normal weight to 752.9 Euro among those with class 3 obesity. The presence of obesity determined an excess cost, particularly among younger individuals. Within each BMI class, the presence of IFG or DM2 identified subgroups of individuals with substantially higher healthcare expenditures., Conclusions: Outpatient healthcare costs markedly increased with increasing BMI in all age categories, particularly among individuals below 65. Addressing the double burden of excess weight and hyperglycemia represents a significant challenge and a healthcare priority., (© 2023. The Author(s).)

Pancreatic cancer has an incidence that almost matches its mortality. Only a small number of risk factors and 33 susceptibility loci have been identified. so Moreover, the relative rarity of pancreatic cancer poses significant hurdles for research aimed at increasing our knowledge of the genetic mechanisms contributing to the disease. Additionally, the inability to adequately power research questions prevents small monocentric studies from being successful. Several consortia have been established to pursue a better understanding of the genetic architecture of pancreatic cancers. The Pancreatic disease research (PANDoRA) consortium is the largest in Europe. PANDoRA is spread across 12 European countries, Brazil and Japan, bringing together 29 basic and clinical research groups. In the last ten years, PANDoRA has contributed to the discovery of 25 susceptibility loci, a feat that will be instrumental in stratifying the population by risk and optimizing preventive strategies., Competing Interests: Declaration of Competing Interest MFB has received research funding from Celgene, Frame Therapeutics, and Lead Pharma, and has acted as a consultant to Servier., (Copyright © 2023. Published by Elsevier B.V.)

Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults worldwide. Although genome-wide association studies (GWAS) have uncovered the germline genetic component underlying CLL susceptibility, the potential use of GWAS-identified risk variants to predict disease progression and patient survival remains unexplored. Here, we evaluated whether 41 GWAS-identified risk variants for CLL could influence overall survival (OS) and disease progression, defined as time to first treatment (TTFT) in a cohort of 1039 CLL cases ascertained through the CRuCIAL consortium. Although this is the largest study assessing the effect of GWAS-identified susceptibility variants for CLL on OS, we only found a weak association of ten single nucleotide polymorphisms (SNPs) with OS ( p < 0.05) that did not remain significant after correction for multiple testing. In line with these results, polygenic risk scores (PRSs) built with these SNPs in the CRuCIAL cohort showed a modest association with OS and a low capacity to predict patient survival, with an area under the receiver operating characteristic curve (AUROC) of 0.57. Similarly, seven SNPs were associated with TTFT ( p < 0.05); however, these did not reach the multiple testing significance threshold, and the meta-analysis with previous published data did not confirm any of the associations. As expected, PRSs built with these SNPs showed reduced accuracy in prediction of disease progression (AUROC = 0.62). These results suggest that susceptibility variants for CLL do not impact overall survival and disease progression in CLL patients.

Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome-wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10 -8 ) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4-rs34517439-A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13-1.32, P = 4.81 × 10 -7 ). rs34517439-A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA-binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4-rs34517439 as a potentially novel MM risk locus., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Intraductal papillary mucinous neoplasms (IPMNs) are nonobligatory precursor lesions of pancreatic ductal adenocarcinoma (PDAC). The identification of molecular biomarkers able to predict the risk of progression of IPMNs toward malignancy is largely lacking and sorely needed. Telomere length (TL) is associated with the susceptibility of developing cancers, including PDAC. Moreover, several PDAC risk factors have been shown to be associated with IPMN transition to malignancy. TL is genetically determined, and the aim of this study was to use 11 SNPs, alone or combined in a score (teloscore), to estimate the causal relation between genetically determined TL and IPMNs progression. For this purpose, 173 IPMN patients under surveillance were investigated. The teloscore did not show any correlation, however, we observed an association between PXK-rs6772228-A and an increased risk of IPMN transition to malignancy (HR = 3.17; 95%CI 1.47-6.84; P = 3.24 × 10-3). This effect was also observed in a validation cohort of 142 IPMNs even though the association was not statistically significant. The combined analysis was consistent showing an association between PXK-rs6772228-A and increased risk of progression. The A allele of this SNP is strongly associated with shorter LTL that in turn have been reported to be associated with increased risk of developing PDAC. These results clearly highlight the importance of looking for genetic variants as potential biomarkers in this setting in order to further our understanding the etiopathogenesis of PDAC and suggest that genetically determined TL might be an additional marker of IPMN prognosis., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Gastric cancer is worldwide the fourth more common cancer type by incidence, and the third by mortality. We analyzed three missense variants of TAS2R38 gene: rs713598 (A49P), rs1726866 (V262A), and rs10246939 (I296V). These variants and their combination in haplotypes (proline, alanine and valine/tasters or alanine, valine and isoleucine/nontasters) and diplotypes are responsible for individual differences in bitter perception. The single-nucleotide polymorphisms and the related phenotypes are known to be associated with susceptibility to Gram-negative bacterial infections, such as Helicobacter pylori , and with risk of various cancer types. An association between intermediate tasters (as defined by TAS2R38 diplotypes) and increased risk of gastric cancer was reported in a Korean population., Methods: We analyzed 2616 individuals of Latin American origin, representing the whole spectrum of lesions from gastritis to gastric cancer., Results: Comparing cancer cases vs. noncancers we observed a decrease in risk associated with heterozygous carriers of rs10246939 ( P  = 0.006) and rs1726866 ( P  = 0.003) when compared with homozygotes of the more common allele. Also, the analysis of diplotypes/phenotypes reflected the same association, with super-tasters showing a borderline increased risk of developing gastric cancer compared to medium-tasters [odds ratio (OR) = 1.63; 95% confidence interval (CI), 1.04-2.56; P  = 0.033]. Also, nontasters showed an increased risk when compared to medium-tasters although not reaching statistical significance (OR = 1.58; 95% CI, 0.80-2.87; P  = 0.203). We also tested the interactions between the TAS2R38 genotypes and H. pylori cagA status in a subset of samples and found no interaction., Conclusion: In conclusion, our results suggest only a modest contribution of TAS2R38 gene genetic variability in gastric cancer etiology., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Mitochondrial DNA copy number (mtDNAcn) variation has been associated with increased risk of several human diseases in epidemiological studies. The quantification of mtDNAcn performed with real-time PCR is currently considered the de facto standard among several techniques. However, the heterogeneity of the laboratory methods (DNA extraction, storage, processing) used could give rise to results that are difficult to compare and reproduce across different studies. Several lines of evidence suggest that mtDNAcn is influenced by nuclear and mitochondrial genetic variability, however this relation is largely unexplored. The aim of this work was to elucidate the genetic basis of mtDNAcn variation. We performed a genome-wide association study (GWAS) of mtDNAcn in 6836 subjects from the ESTHER prospective cohort, and included, as replication set, the summary statistics of a GWAS that used 295 150 participants from the UK Biobank. We observed two novel associations with mtDNAcn variation on chromosome 19 (rs117176661), and 12 (rs7136238) that reached statistical significance at the genome-wide level. A polygenic score that we called mitoscore including all known single nucleotide polymorphisms explained 1.11% of the variation of mtDNAcn (p = 5.93 × 10-7). In conclusion, we performed a GWAS on mtDNAcn, adding to the evidence of the genetic background of this trait., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

In the last decades the association of leukocyte telomere length (LTL) and mitochondrial copy number (mtDNAcn) with cancer risk has been the focus of many reports, however the relation is not yet completely understood. A meta-analysis of 112 studies including 64,184 cancer cases and 278,641 controls that analysed LTL and mtDNAcn in relation to cancer risk has been conducted to further our understanding of the topic. Stratified analyses for tumor type were also performed. Overall, no association was observed for all cancer combined neither for LTL nor mtDNAcn. Significant associations were detected for these biomarkers and specific cancer type; however, a large degree of heterogeneity was present, even within the same tumor type. Alternatives approaches based on polymorphic variants, such as polygenic risk scores and mendelian randomization, could be adopted to unravel the causal correlation of telomere length and mitochondrial copy number with cancer risk., (Copyright © 2021 Elsevier B.V. All rights reserved.)

We investigate the heterogeneous effects of particle pollution on Italian daily hospitalizations and their costs by exploiting public transportation strikes as plausibly-exogenous shocks in pollution exposure. We find that a one standard deviation increase in PM 10 causes additional 0.79 hospitalizations per 100,000 residents, and the effect is stronger for the elderly, low educated individuals and migrants. Furthermore, we find that young individuals, an arguably healthy age group, exhibit economically meaningful responses to air pollution with an effect ranging between 0.45 and 1.04. Our results imply a large role of avoidance behavior driving heterogeneous marginal health effects. Total daily costs of a one standard deviation increase in PM 10 represent 0.5% of the total daily health expenditure, and 85% of this additional spending comes from more patients hospitalized, while the remaining 15% can be attributable to more costly, and likely more complex, hospitalizations., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second cancer-related cause of death by 2030. Identifying novel risk factors, including genetic risk loci, could be instrumental in risk stratification and implementation of prevention strategies. Long noncoding RNAs (lncRNAs) are involved in regulation of key biological processes, and the possible role of their genetic variability has been unexplored so far. Combining genome wide association studies and functional data, we investigated the genetic variability in all lncRNAs. We analyzed 9893 PDAC cases and 9969 controls and identified a genome-wide significant association between the rs7046076 SNP and risk of developing PDAC (P = 9.73 × 10 -9 ). This SNP is located in the NONHSAG053086.2 (lnc-SMC2-1) gene and the risk allele is predicted to disrupt the binding of the lncRNA with the micro-RNA (miRNA) hsa-mir-1256 that regulates several genes involved in cell cycle, such as CDKN2B. The CDKN2B region is pleiotropic and its genetic variants have been associated with several human diseases, possibly though an imperfect interaction between lncRNA and miRNA. We present a novel PDAC risk locus, supported by a genome-wide statistical significance and a plausible biological mechanism., (© 2021 UICC.)

Telomeres are involved in processes like cellular growth, chromosomal stability, and proper segregation to daughter cells. Telomere length measured in leukocytes (LTL) has been investigated in different cancer types, including multiple myeloma (MM). However, LTL measurement is prone to heterogeneity due to sample handling and study design (retrospective vs. prospective). LTL is genetically determined; genome-wide association studies identified 11 SNPs that, combined in a score, can be used as a genetic instrument to measure LTL and evaluate its association with MM risk. This approach has been already successfully attempted in various cancer types but never in MM. We tested the "teloscore" in 2407 MM patients and 1741 controls from the International Multiple Myeloma rESEarch (IMMeNSE) consortium. We observed an increased risk for longer genetically determined telomere length (gdTL) (OR = 1.69; 95% CI 1.36-2.11; P = 2.97 × 10 -6 for highest vs. lowest quintile of the score). Furthermore, in a subset of 1376 MM patients we tested the relationship between the teloscore and MM patients survival, observing a better prognosis for longer gdTL compared with shorter gdTL (HR = 0.93; 95% CI 0.86-0.99; P = 0.049). In conclusion, we report convincing evidence that longer gdTL is a risk marker for MM risk, and that it is potentially involved in increasing MM survival.

Myeloproliferative neoplasms (MPNs) are a group of diseases that cause myeloid hematopoietic cells to overproliferate. Epidemiological and familial studies suggest that genetic factors contribute to the risk of developing MPN, but the genetic susceptibility of MPN is still not well known. Indeed, only few loci are known to have a clear role in the predisposition to this disease. Some studies reported a diagnosis of MPNs and multiple myeloma (MM) in the same patients, but the biological causes are still unclear. We tested the hypothesis that the two diseases share at least partly the same genetic risk loci. In the context of a European multicenter study with 460 cases and 880 controls, we analyzed the effect of the known MM risk loci, individually and in a polygenic risk score (PRS). The most significant result was obtained among patients with chronic myeloid leukemia (CML) for PS0RS1C1-rs2285803, which showed to be associated with an increased risk (OR = 3.28, 95% CI 1.79-6.02, P = .00012, P = .00276 when taking into account multiple testing). Additionally, the PRS showed an association with MPN risk when comparing the last with the first quartile of the PRS (OR = 2.39, 95% CI 1.64-3.48, P = 5.98 × 10 -6 ). In conclusion, our results suggest a potential common genetic background between MPN and MM, which needs to be further investigated., (© 2020 UICC.)

Telomere length measured in leukocyte (LTL) has been found to be associated with the risk of developing several cancer types, including myeloproliferative neoplasms (MPNs). LTL is genetically determined by, at least, 11 SNPs previously shown to influence LTL. Their combination in a score has been used as a genetic instrument to measure LTL and evaluate the causative association between LTL and the risk of several cancer types. We tested, for the first time, the "teloscore" in 480 MPN patients and 909 healthy controls in a European multi-center case-control study. We found an increased risk to develop MPNs with longer genetically determined telomeres (OR = 1.82, 95% CI 1.24-2.68, P = 2.21 × 10 -3 , comparing the highest with the lowest quintile of the teloscore distribution). Analyzing the SNPs individually we confirm the association between TERT-rs2736100-C allele and increased risk of developing MPNs and we report a novel association of the OBFC1-rs9420907-C variant with higher MPN risk (OR allelic  = 1.43; 95% CI 1.15-1.77; P = 1.35 × 10 -3 ). Consistently with the results obtained with the teloscore, both risk alleles are also associated with longer LTL. In conclusion, our results suggest that genetically determined longer telomeres could be a risk marker for MPN development.