Epidemiological patterns of asbestos exposure and spatial clusters of incident cases of malignant mesothelioma from the Italian national registry

Abstract BACKGROUND: Previous ecological spatial studies of malignant mesothelioma cases, mostly based on mortality data, lack reliable data on individual exposure to asbestos, thus failing to assess the contribution of different occupational and environmental sources in the determination of risk excess in specific areas. This study aims to identify territorial clusters of malignant mesothelioma through a Bayesian spatial analysis and to characterize them by the integrated use of asbestos exposure information retrieved from the Italian national mesothelioma registry (ReNaM). METHODS: In the period 1993 to 2008, 15,322 incident cases of all-site malignant mesothelioma were recorded and 11,852 occupational, residential and familial histories were obtained by individual interviews. Observed cases were assigned to the municipality of residence at the time of diagnosis and compared to those expected based on the age-specific rates of the respective geographical area. A spatial cluster analysis was performed for each area applying a Bayesian hierarchical model. Information about modalities and economic sectors of asbestos exposure was analyzed for each cluster. RESULTS: Thirty-two clusters of malignant mesothelioma were identified and characterized using the exposure data. Asbestos cement manufacturing industries and shipbuilding and repair facilities represented the main sources of asbestos exposure, but a major contribution to asbestos exposure was also provided by sectors with no direct use of asbestos, such as non-asbestos textile industries, metal engineering and construction. A high proportion of cases with environmental exposure was found in clusters where asbestos cement plants were located or a natural source of asbestos (or asbestos-like) fibers was identifiable. Differences in type and sources of exposure can also explain the varying percentage of cases occurring in women among clusters. CONCLUSIONS: Our study demonstrates shared exposure patterns in territorial clusters of malignant mesothelioma due to single or multiple industrial sources, with major implications for public health policies, health surveillance, compensation procedures and site remediation programs

Transcriptional Regulation of N-Acetylglutamate Synthase

The urea cycle converts toxic ammonia to urea within the liver of mammals. At least 6 enzymes are required for ureagenesis, which correlates with dietary protein intake. The transcription of urea cycle genes is, at least in part, regulated by glucocorticoid and glucagon hormone signaling pathways. N-acetylglutamate synthase (NAGS) produces a unique cofactor, N-acetylglutamate (NAG), that is essential for the catalytic function of the first and rate-limiting enzyme of ureagenesis, carbamyl phosphate synthetase 1 (CPS1). However, despite the important role of NAGS in ammonia removal, little is known about the mechanisms of its regulation. We identified two regions of high conservation upstream of the translation start of the NAGS gene. Reporter assays confirmed that these regions represent promoter and enhancer and that the enhancer is tissue specific. Within the promoter, we identified multiple transcription start sites that differed between liver and small intestine. Several transcription factor binding motifs were conserved within the promoter and enhancer regions while a TATA-box motif was absent. DNA-protein pull-down assays and chromatin immunoprecipitation confirmed binding of Sp1 and CREB, but not C/EBP in the promoter and HNF-1 and NF-Y, but not SMAD3 or AP-2 in the enhancer. The functional importance of these motifs was demonstrated by decreased transcription of reporter constructs following mutagenesis of each motif. The presented data strongly suggest that Sp1, CREB, HNF-1, and NF-Y, that are known to be responsive to hormones and diet, regulate NAGS transcription. This provides molecular mechanism of regulation of ureagenesis in response to hormonal and dietary changes

Evaluation of a quality improvement intervention to reduce anastomotic leak following right colectomy (EAGLE): pragmatic, batched stepped-wedge, cluster-randomized trial in 64 countries

Background: Anastomotic leak affects 8 per cent of patients after right colectomy with a 10-fold increased risk of postoperative death. The EAGLE study aimed to develop and test whether an international, standardized quality improvement intervention could reduce anastomotic leaks. Methods: The internationally intended protocol, iteratively co-developed by a multistage Delphi process, comprised an online educational module introducing risk stratification, an intraoperative checklist, and harmonized surgical techniques. Clusters (hospital teams) were randomized to one of three arms with varied sequences of intervention/data collection by a derived stepped-wedge batch design (at least 18 hospital teams per batch). Patients were blinded to the study allocation. Low- and middle-income country enrolment was encouraged. The primary outcome (assessed by intention to treat) was anastomotic leak rate, and subgroup analyses by module completion (at least 80 per cent of surgeons, high engagement; less than 50 per cent, low engagement) were preplanned. Results: A total 355 hospital teams registered, with 332 from 64 countries (39.2 per cent low and middle income) included in the final analysis. The online modules were completed by half of the surgeons (2143 of 4411). The primary analysis included 3039 of the 3268 patients recruited (206 patients had no anastomosis and 23 were lost to follow-up), with anastomotic leaks arising before and after the intervention in 10.1 and 9.6 per cent respectively (adjusted OR 0.87, 95 per cent c.i. 0.59 to 1.30; P = 0.498). The proportion of surgeons completing the educational modules was an influence: the leak rate decreased from 12.2 per cent (61 of 500) before intervention to 5.1 per cent (24 of 473) after intervention in high-engagement centres (adjusted OR 0.36, 0.20 to 0.64; P < 0.001), but this was not observed in low-engagement hospitals (8.3 per cent (59 of 714) and 13.8 per cent (61 of 443) respectively; adjusted OR 2.09, 1.31 to 3.31). Conclusion: Completion of globally available digital training by engaged teams can alter anastomotic leak rates. Registration number: NCT04270721 (http://www.clinicaltrials.gov)

What are large-scale archaeometric programmes for?: Bell Beaker pottery and societies from the 3rd millennium BC in Western Europe

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ONFOODS: New and re-emerging risks in the food system and sustainable mitigation strategies

Agri-food product quality and safety could greatly be compromised by fungi able to produce toxic metabolites as well as by the residues of the conventional means used for their control. Several pathogenic fungi can produce different metabolites of a given mycotoxin, and in some cases more than one chemical type is produced. Moreover, climate change and food-processing systems contributed increasing the occurrence of toxigenic genera. Therefore, reducing the biological/chemical risk and guarantee food safety is of paramount importance, as well as finding novel sustainable control strategies that might fit the postharvest handling and transformation phases. Within this framework, ONFOODS aims at applying omics techniques to greatly strengthen the knowledge and better understand the possible hazards of eating food contaminated by well-known toxigenic genera (Aspergillus or Penicillium), still poorly studied genera (Alternaria), or not yet recognized genera (Monilinia). Nextgeneration sequencing methods and metabolomic approaches will be used to generate data to develop assays to detect specific outbreak strains or new/ emerging pathogens and metabolites, and to understand clearly/better the mechanisms underlying the production/accumulation of different mycotoxins. Multiple mitigation solutions will be investigated and applied during the postharvest and retailing phase offering new strategies/approaches according to the “multiple-hurdle” concept

Molecular basis of differential 3' splice site sensitivity to anti-tumor drugs targeting U2 snRNP

Several splicing-modulating compounds, including Sudemycins and Spliceostatin A, display anti-tumor properties. Combining transcriptome, bioinformatic and mutagenesis analyses, we delineate sequence determinants of the differential sensitivity of 3' splice sites to these drugs. Sequences 5' from the branch point (BP) region strongly influence drug sensitivity, with additional functional BPs reducing, and BP-like sequences allowing, drug responses. Drug-induced retained introns are typically shorter, displaying higher GC content and weaker polypyrimidine-tracts and BPs. Drug-induced exon skipping preferentially affects shorter alternatively spliced regions with weaker BPs. Remarkably, structurally similar drugs display both common and differential effects on splicing regulation, SSA generally displaying stronger effects on intron retention, and Sudemycins more acute effects on exon skipping. Collectively, our results illustrate how splicing modulation is exquisitely sensitive to the sequence context of 3' splice sites and to small structural differences between drugs

Prediction of morbidity and mortality after early cholecystectomy for acute calculous cholecystitis: results of the S.P.Ri.M.A.C.C. study

BackgroundLess invasive alternatives than early cholecystectomy (EC) for acute calculous cholecystitis (ACC) treatment have been spreading in recent years. We still lack a reliable tool to select high-risk patients who could benefit from these alternatives. Our study aimed to prospectively validate the Chole-risk score in predicting postoperative complications in patients undergoing EC for ACC compared with other preoperative risk prediction models.MethodThe S.P.Ri.M.A.C.C. study is a World Society of Emergency Surgery prospective multicenter observational study. From 1st September 2021 to 1st September 2022, 1253 consecutive patients admitted in 79 centers were included. The inclusion criteria were a diagnosis of ACC and to be a candidate for EC. A Cochran-Armitage test of the trend was run to determine whether a linear correlation existed between the Chole-risk score and a complicated postoperative course. To assess the accuracy of the analyzed prediction models-POSSUM Physiological Score (PS), modified Frailty Index, Charlson Comorbidity Index, American Society of Anesthesiologist score (ASA), APACHE II score, and ACC severity grade-receiver operating characteristic (ROC) curves were generated. The area under the ROC curve (AUC) was used to compare the diagnostic abilities.ResultsA 30-day major morbidity of 6.6% and 30-day mortality of 1.1% were found. Chole-risk was validated, but POSSUM PS was the best risk prediction model for a complicated course after EC for ACC (in-hospital mortality: AUC 0.94, p < 0.001; 30-day mortality: AUC 0.94, p < 0.001; in-hospital major morbidity: AUC 0.73, p < 0.001; 30-day major morbidity: AUC 0.70, p < 0.001). POSSUM PS with a cutoff of 25 (defined in our study as a 'Chole-POSSUM' score) was then validated in a separate cohort of patients. It showed a 100% sensitivity and a 100% negative predictive value for mortality and a 96-97% negative predictive value for major complications.ConclusionsThe Chole-risk score was externally validated, but the CHOLE-POSSUM stands as a more accurate prediction model. CHOLE-POSSUM is a reliable tool to stratify patients with ACC into a low-risk group that may represent a safe EC candidate, and a high-risk group, where new minimally invasive endoscopic techniques may find the most useful field of action.Trial Registration: ClinicalTrial.gov NCT04995380