CompCert - A Formally Verified Optimizing Compiler

International audienceCompCert is the first commercially available optimizing compiler that is formally verified, using machine-assisted mathematical proofs, to be exempt from mis-compilation. The executable code it produces is proved to behave exactly as specified by the semantics of the source C program. This article gives an overview of the design of CompCert and its proof concept and then focuses on aspects relevant for industrial application. We briefly summarize practical experience and give an overview of recent CompCert development aiming at industrial usage. CompCert's intended use is the compilation of life-critical and mission-critical software meeting high levels of assurance. In this context tool qualification is of paramount importance. We summarize the confidence argument of CompCert and give an overview of relevant qualification strategies

CompCert: Practical Experience on Integrating and Qualifying a Formally Verified Optimizing Compiler

International audienceCompCert is the first commercially available optimizing compiler that is formally verified, using machine-assisted mathematical proofs, to be exempt from mis-compilation. The executable code it produces is proved to behave exactly as specified by the semantics of the source C program. This article gives an overview of the use of CompCert to gain certification credits for a highly safety-critical industry application, certified according to IEC 60880. We will briefly introduce the target application, illustrate the process of changing the existing compiler infrastructure to CompCert, and discuss performance characteristics. The main part focuses on the tool qualification strategy, in particular on how to take advantage of the formal correctness proof in the certification process

Overall Survival by Response to First-line Induction Treatment with Atezolizumab plus Platinum-based Chemotherapy or Placebo plus Platinum-based Chemotherapy for Metastatic Urothelial Carcinoma

Standard-of-care first-line treatment for metastatic urothelial carcinoma (mUC) is platinum-based chemotherapy (CTx). Maintenance immunotherapy is a treatment option for patients without progressive disease (PD) after induction CTx. IMvigor130 was a randomised, phase 3 study evaluating atezolizumab plus platinum-based CTx (arm A), atezolizumab monotherapy (arm B), or placebo plus platinum-based CTx (arm C) as first-line treatment for mUC. The primary progression-free survival (PFS) analysis showed a statistically significant PFS benefit favouring arm A versus arm C, which did not translate into overall survival (OS) benefit at the final OS analysis. We report exploratory analyses based on response to combination induction treatment (arm A vs arm C) using final OS data. Post-induction OS was analysed for patients without PD during induction (4-6 CTx cycles) who received at least one dose of single-agent atezolizumab/placebo maintenance treatment. Post-progression OS was analysed for patients with PD during induction CTx. Addition of atezolizumab to CTx did not impact OS outcomes, regardless of response to induction CTx, with hazard ratios of 0.84 (95% confidence interval [CI] 0.63-1.10) for patients without PD and 0.75 (95% CI 0.54-1.05) for those with PD during induction CTx. Treatment effects appeared to be greatest for patients treated with cisplatin and for those with PD-L1-high tumours. Patient summary: The IMvigor130 trial showed that addition of atezolizumab to chemotherapy (CTx) did not improve survival over CTx alone in patients with bladder cancer. Overall, patients whose cancer did not progress during initial treatment tended to live longer than patients whose cancer did progress, but addition of atezolizumab to CTx did not help either group live longer in comparison to CTx alone. However, the results suggest that patients who received a certain CTx drug (cisplatin) or who had high levels of a marker called PD-L1 in their tumour may get the most improvement from addition of atezolizumab to CTx. The IMvigor130 trial is registered on ClinicalTrials.gov as NCT02807636. (c) 2023 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Nuclear receptor coregulator SNP discovery and impact on breast cancer risk

<p>Abstract</p> <p>Background</p> <p>Coregulator proteins are "master regulators", directing transcriptional and posttranscriptional regulation of many target genes, and are critical in many normal physiological processes, but also in hormone driven diseases, such as breast cancer. Little is known on how genetic changes in these genes impact disease development and progression. Thus, we set out to identify novel single nucleotide polymorphisms (SNPs) within SRC-1 (NCoA1), SRC-3 (NCoA3, AIB1), NCoR (NCoR1), and SMRT (NCoR2), and test the most promising SNPs for associations with breast cancer risk.</p> <p>Methods</p> <p>The identification of novel SNPs was accomplished by sequencing the coding regions of these genes in 96 apparently normal individuals (48 Caucasian Americans, 48 African Americans). To assess their association with breast cancer risk, five SNPs were genotyped in 1218 familial BRCA1/2-mutation negative breast cancer cases and 1509 controls (rs1804645, rs6094752, rs2230782, rs2076546, rs2229840).</p> <p>Results</p> <p>Through our resequencing effort, we identified 74 novel SNPs (30 in NCoR, 32 in SMRT, 10 in SRC-3, and 2 in SRC-1). Of these, 8 were found with minor allele frequency (MAF) >5% illustrating the large amount of genetic diversity yet to be discovered. The previously shown protective effect of rs2230782 in SRC-3 was strengthened (OR = 0.45 [0.21-0.98], p = 0.04). No significant associations were found with the other SNPs genotyped.</p> <p>Conclusions</p> <p>This data illustrates the importance of coregulators, especially SRC-3, in breast cancer development and suggests that more focused studies, including functional analyses, should be conducted.</p

The Glasgow consensus on the delineation between pesticide emission inventory and impact assessment for LCA

Purpose: Pesticides are applied to agricultural fields in order to optimise crop yield and their global use is substantial. Their consideration in Life cycle assessment (LCA) is currently affected by important inconsistencies between the emission inventory and impact assessment phases of LCA. A clear definition of the delineation between the product system model (life cycle inventory, technosphere) and the natural environment (life cycle impact assessment, ecosphere) is currently missing and could be established via consensus building. Methods: A workshop held on the 11 May 2013, in Glasgow, UK, back to back with the 23rd SETAC Europe meeting had the goal of establishing consensus and creating clear guidelines where the boundary between the emission inventory and the impact characterisation model should be set in all three spatial dimensions and time when considering application of substances to an open agricultural field or in greenhouses, and consequent emissions to the natural environment and their potential impacts. More than 30 specialists in agrifood LCI, LCIA, risk assessment, and ecotoxicology, representing industry, government, and academia from 15 countries and four continents met to discuss and reach consensus. The resulting guidelines target LCA practitioners, data (base) and characterisation method developers, and decision makers. Results and discussion: Although, the initial goal was to define recommendations concerning boundaries between technosphere and ecosphere, it became clear that these strongly depend on goal and scope of an LCA study. Instead, the focus was on defining a clear interface between LCI and LCIA, capable of supporting any goal and scope requirements while avoiding double counting or exclusion of important emission flows and their potential impacts. Consensus was reached accordingly on distinct sets of recommendations for LCI and LCIA respectively, recommending for example that buffer zones should be considered as part of the crop production system and the change in yield per ha be considered. While the spatial dimensions of the field were not fixed, the temporal boundary between dynamic LCI fate modelling and steady-state LCIA fate modelling needs to be defined. Conclusions and recommendations: For pesticides application, the inventory should report: pesticide identification, crop, mass applied of each active ingredient, application method or formulation type, presence of buffer zones (y/n), location/country, application time in days before harvest and crop growth stage during application, adherence with Good Agricultural Practice (GAP), and whether the field is considered part of the technosphere or the ecosphere. Additionally, emission fractions to defined environmental media on-field and off-field should be reported. For LCIA, the directly concerned impact categories were identified as well as a list of relevant fate and exposure processes. Next steps and future work were identified: 1) establishing default emission fractions to environmental media for integration into LCI databases, and 2) interaction among impact model developers to extend current methods with new elements/processes mentioned in the recommendations, including targeted technical workshops on “how to” model specific processes.JRC.H.8-Sustainability Assessmen

Identification of a DMBT1 polymorphism associated with increased breast cancer risk and decreased promoter activity

According to present estimations, the unfavorable combination of alleles with low penetrance but high prevalence in the population might account for the major part of hereditary breast cancer risk. Deleted in Malignant Brain Tumors 1 (DMBT1) has been proposed as a tumor suppressor for breast cancer and other cancer types. Genomewide mapping in mice further identified Dmbt1 as a potential modulator of breast cancer risk. Here, we report the association of two frequent and linked single-nucleotide polymorphisms (SNPs) with increased breast cancer risk in women above the age of 60 years: DMBT1 c.-93C>T, rs2981745, located in the DMBT1 promoter; and DMBT1 c.124A>C, p.Thr42Pro, rs11523871(odds ratio [OR]=1.66, 95% confidence interval [CI]=1.21-2.29, P=0.0017; and OR=1.66; 95% CI=1.21-2.28, P=0.0016, respectively), based on 1,195 BRCA1/2 mutation-negative German breast cancer families and 1,466 unrelated German controls. Promoter studies in breast cancer cells demonstrate that the risk-increasing DMBT1 -93T allele displays significantly decreased promoter activity compared to the DMBT1 -93C allele, resulting in a loss of promoter activity. The data suggest that DMBT1 polymorphisms in the 5'-region are associated with increased breast cancer risk. In accordance with previous results, these data link decreased DMBT1 levels to breast cancer risk

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Дослідження структури порушених відкритою розробкою земель й пошук шляхів вдосконалення рекультивації залишкових виробок кар'єрів

Стаття присвячена дослідженням структури порушених земель, на ділянках з видобутку корисних копалин відкритим способом. Наведено площі порушень земель при розробці основних видів корисних копалин. Проаналізовано ризики, що виникають із несвоєчасною рекультивацією земель гірничого відводу, а також від покинутих гірничих виробок старих кар'єрів. Паралельно розглянуті обсяги відходів гірничого виробництва та їх повторне використання в якості заповнювача для залишкових вироблених просторів кар'єрів.The article is devoted to the research of land violation indicators at the extraction of minerals by surface mining method. Data gives about the land violations area at the mining key minerals. Ana-lyzed the risks from the not-on-time reclamation of the mining clam and abandoned excavations of the old quarries. In parallel considered the volumes of mining wastes and their reuse as aggregate for filling residual spaces of surface mines.Статья посвящена исследованиям площадей нарушения земель, связанных с добычей полезных ископаемых открытым способом. Приведены площади нарушений земель при разработке основных видов полезных ископаемых. Проанализированы риски, представляемые несвоевременной рекультивацией земель горного отвода, а также заброшенными горными выработками старых карьеров. Параллельно рассмотрены объемы отходов горного производства и их повторное использование в качестве заполнителя для остаточных выработанных пространств карьеров

A gain-of-function variant in <i>DIAPH1 </i>causes dominant macrothrombocytopenia and hearing loss

Macrothrombocytopenia (MTP) is a heterogeneous group of disorders characterized by enlarged and reduced numbers of circulating platelets, sometimes resulting in abnormal bleeding. In most MTP, this phenotype arises because of altered regulation of platelet formation from megakaryocytes (MK). We report the identification of DIAPH1, which encodes the Rho-effector diaphanous-related formin 1 (DIAPH1), as a candidate gene for MTP using exome sequencing, ontological phenotyping and similarity regression. We describe two unrelated pedigrees with MTP and sensorineural hearing loss that segregate with a DIAPH1 p.R1213* variant predicting partial truncation of the DIAPH1 diaphanous autoregulatory domain. The R1213* variant was associated with reduced proplatelet formation from cultured MKs, cell clustering and abnormal cortical filamentous actin. Similarly, in platelets there was increased filamentous actin and stable microtubules, indicating constitutive activation of DIAPH1. Over-expression of DIAPH1 R1213* in cells reproduced the cytoskeletal alterations found in platelets. Our description of a novel disorder of platelet formation and hearing loss extends the repertoire of DIAPH1-related disease and provides new insights into the autoregulation of DIAPH1 activity

Integrative Annotation of 21,037 Human Genes Validated by Full-Length cDNA Clones

The human genome sequence defines our inherent biological potential; the realization of the biology encoded therein requires knowledge of the function of each gene. Currently, our knowledge in this area is still limited. Several lines of investigation have been used to elucidate the structure and function of the genes in the human genome. Even so, gene prediction remains a difficult task, as the varieties of transcripts of a gene may vary to a great extent. We thus performed an exhaustive integrative characterization of 41,118 full-length cDNAs that capture the gene transcripts as complete functional cassettes, providing an unequivocal report of structural and functional diversity at the gene level. Our international collaboration has validated 21,037 human gene candidates by analysis of high-quality full-length cDNA clones through curation using unified criteria. This led to the identification of 5,155 new gene candidates. It also manifested the most reliable way to control the quality of the cDNA clones. We have developed a human gene database, called the H-Invitational Database (H-InvDB; http://www.h-invitational.jp/). It provides the following: integrative annotation of human genes, description of gene structures, details of novel alternative splicing isoforms, non-protein-coding RNAs, functional domains, subcellular localizations, metabolic pathways, predictions of protein three-dimensional structure, mapping of known single nucleotide polymorphisms (SNPs), identification of polymorphic microsatellite repeats within human genes, and comparative results with mouse full-length cDNAs. The H-InvDB analysis has shown that up to 4% of the human genome sequence (National Center for Biotechnology Information build 34 assembly) may contain misassembled or missing regions. We found that 6.5% of the human gene candidates (1,377 loci) did not have a good protein-coding open reading frame, of which 296 loci are strong candidates for non-protein-coding RNA genes. In addition, among 72,027 uniquely mapped SNPs and insertions/deletions localized within human genes, 13,215 nonsynonymous SNPs, 315 nonsense SNPs, and 452 indels occurred in coding regions. Together with 25 polymorphic microsatellite repeats present in coding regions, they may alter protein structure, causing phenotypic effects or resulting in disease. The H-InvDB platform represents a substantial contribution to resources needed for the exploration of human biology and pathology