Identification of cancer predisposition variants in apparently healthy individuals using a next-generation sequencing-based family genomics approach

Cancer, like many common disorders, has a complex etiology, often with a strong genetic component and with multiple environmental factors contributing to susceptibility. A considerable number of genomic variants have been previously reported to be causative of, or associated with, an increased risk for various types of cancer. Here, we adopted a next-generation sequencing approach in 11 members of two families of Greek descent to identify all genomic variants with the potential to predispose family members to cancer. Cross-comparison with data from the Human Gene Mutation Database identified a total of 571 variants, from which 47 % were disease-associated polymorphisms, 26 % disease-associated polymorphisms with additional supporting functional evidence, 19 % functional polymorphisms with in vitro/laboratory or in vivo supporting evidence but no known disease association, 4 % putative disease-causing mutations but with some residual doubt as to their pathological significance, and 3 % disease-causing mutations. Subsequent analysis, focused on the latter variant class most likely to be involved in cancer predisposition, revealed two variants of prime interest, namely MSH2 c.2732T>A (p.L911R) and BRCA1 c.2955delC, the first of which is novel. KMT2D c.13895delC and c.1940C>A variants are additionally reported as incidental findings. The next-generation sequencing-based family genomics approach described herein has the potential to be applied to other types of complex genetic disorder in order to identify variants of potential pathological significance

Expanded national database collection and data coverage in the FINDbase worldwide database for clinically relevant genomic variation allele frequencies

FINDbase (http://www.findbase.org) is a comprehensive data repository that records the prevalence of clinically relevant genomic variants in various populations worldwide, such as pathogenic variants leading mostly to monogenic disorders and pharmacogenomics biomarkers. The database also records the incidence of rare genetic diseases in various populations, all in well-distinct data modules. Here, we report extensive data content updates in all data modules, with direct implications to clinical pharmacogenomics. Also, we report significant new developments in FINDbase, namely (i) the release of a new version of the ETHNOS software that catalyzes development curation of national/ethnic genetic databases, (ii) the migration of all FINDbase data content into 90 distinct national/ethnic mutation databases, all built around Microsoft’s PivotViewer (http://www.getpivot.com) software (iii) new data visualization tools and (iv) the interrelation of FINDbase with DruGeVar database with direct implications in clinical pharmacogenomics. The above mentioned updates further enhance the impact of FINDbase, as a key resource for Genomic Medicine applications

CryoSat Ice Baseline-D validation and evolutions

The ESA Earth Explorer CryoSat-2 was launched on 8 April 2010 to monitor the precise changes in the thickness of terrestrial ice sheets and marine floating ice. To do that, CryoSat orbits the planet at an altitude of around 720 km with a retrograde orbit inclination of 92∘ and a quasi repeat cycle of 369 d (30 d subcycle). To reach the mission goals, the CryoSat products have to meet the highest quality standards to date, achieved through continual improvements of the operational processing chains. The new CryoSat Ice Baseline-D, in operation since 27 May 2019, represents a major processor upgrade with respect to the previous Ice Baseline-C. Over land ice the new Baseline-D provides better results with respect to the previous baseline when comparing the data to a reference elevation model over the Austfonna ice cap region, improving the ascending and descending crossover statistics from 1.9 to 0.1 m. The improved processing of the star tracker measurements implemented in Baseline-D has led to a reduction in the standard deviation of the point-to-point comparison with the previous star tracker processing method implemented in Baseline-C from 3.8 to 3.7 m. Over sea ice, Baseline-D improves the quality of the retrieved heights inside and at the boundaries of the synthetic aperture radar interferometric (SARIn or SIN) acquisition mask, removing the negative freeboard pattern which is beneficial not only for freeboard retrieval but also for any application that exploits the phase information from SARIn Level 1B (L1B) products. In addition, scatter comparisons with the Beaufort Gyre Exploration Project (BGEP; https://www.whoi.edu/beaufortgyre, last access: October 2019) and Operation IceBridge (OIB; Kurtz et al., 2013) in situ measurements confirm the improvements in the Baseline-D freeboard product quality. Relative to OIB, the Baseline-D freeboard mean bias is reduced by about 8 cm, which roughly corresponds to a 60 % decrease with respect to Baseline-C. The BGEP data indicate a similar tendency with a mean draft bias lowered from 0.85 to −0.14 m. For the two in situ datasets, the root mean square deviation (RMSD) is also well reduced from 14 to 11 cm for OIB and by a factor of 2 for the BGEP. Observations over inland waters show a slight increase in the percentage of good observations in Baseline-D, generally around 5 %–10 % for most lakes. This paper provides an overview of the new Level 1 and Level 2 (L2) CryoSat Ice Baseline-D evolutions and related data quality assessment, based on results obtained from analyzing the 6-month Baseline-D test dataset released to CryoSat expert users prior to the final transfer to operations

Social difference, cultural arbitrary and identity : an analysis of a new national curriculum document in a non-secular environment

This article focuses on the idea of the Curriculum as a 'selection from the cultures of society' and as a site of contestation for legitimacy and identity affirmation. The purpose is to shed some light on the nature of curricular reform being advocated in a specific context - Malta. Throughout the past four years, there has been a revamping of the National Minimum Curriculum (NMC) document in Malta, established in 1988. The 'old' National Minimum Curriculum was subject to criticism focusing on a variety of issues (echoing criticisms levelled at similar National Curricula elsewhere), including issues concerning difference and identity. The first part of the article deals briefly with the issues concerning difference raised in this criticism, focusing on the issues of class, race/ethnicity, gender and disability. The second part focuses on the long and gradual build up towards the development of the new National Curriculum document. The process centres around two documents, the preliminary Tomorrow's Schoolsdocument and the draft NMC document. The issues of equity and the affirmation of social difference, as well as the move towards de-streaming, are discussed. It is argued that this process of reform benefited from the criticism of the earlier NMC document. The process of reform involved an attempt at widespread participation by various stakeholders - parents, teachers, students, unions, women's organisations, disabled person's organisations etc. The final section focuses on the final new NMC document. In this section, the authors explore the compromises, which have been made in reaction to the draft document, indicating the interests at play. Whose cultural arbitrary is reflected in the final document? The article concludes with a discussion centring around lessons to be drawn from a process of curricular reform, involving issues related to identity and difference, carried out in a country characterised by a non-secular environment.peer-reviewe

Correction: A european spectrum of pharmacogenomic biomarkers: Implications for clinical pharmacogenomics (PLoS ONE (2016) 11:9 (e0162866) DOI: 10.1371/journal.pone.0162866)

The thirty-Third author's name is spelled incorrectly. The correct name is: Jadranka Sertić

The Libyan civil conflict: selected case series of orthopaedic trauma managed in Malta in 2014

AIM: The purpose of this series of cases was to analyse our management of orthopaedic trauma casualties in the Libyan civil war crisis in the European summer of 2014. We looked at both damage control orthopaedics and for case variety of war trauma at a civilian hospital. Due to our geographical proximity to Libya, Malta was the closest European tertiary referral centre. Having only one Level 1 trauma care hospital in our country, our Trauma and Orthopaedics department played a pivotal role in the management of Libyan battlefield injuries. Our aims were to assess acute outcomes and short term mortality of surgery within the perspective of a damage control orthopaedic strategy whereby aggressive wound management, early fixation using relative stability principles, antibiotic cover with adequate soft tissue cover are paramount. We also aim to describe the variety of war injuries we came across, with a goal for future improvement in regards to service providing. METHODS: Prospective collection of six interesting cases with severe limb and spinal injuries sustained in Libya during the Libyan civil war between June and November 2014. CONCLUSIONS: We applied current trends in the treatment of war injuries, specifically in damage control orthopaedic strategy and converting to definitive treatment where permissible. The majority of our cases were classified as most severe (Type IIIB/C) according to the Gustilo-Anderson classification of open fractures. The injuries treated reflected the type of standard and improved weaponry available in modern warfare affecting both militants and civilians alike with increasing severity and extent of damage. Due to this fact, multidisciplinary team approach to patient centred care was utilised with an ultimate aim of swift recovery and early mobilisation. It also highlighted the difficulties and complex issues required on a hospital management level as a neighbouring country to war zone countries in transforming care of civil trauma to military trauma

A European spectrum of pharmacogenomic biomarkers: Implications for clinical pharmacogenomics

Pharmacogenomics aims to correlate inter-individual differences of drug efficacy and/or toxicity with the underlying genetic composition, particularly in genes encoding for protein factors and enzymes involved in drug metabolism and transport. In several European populations, particularly in countries with lower income, information related to the prevalence of pharmacogenomic biomarkers is incomplete or lacking. Here, we have implemented the microattribution approach to assess the pharmacogenomic biomarkers allelic spectrum in 18 European populations, mostly from developing European countries, by analyzing 1,931 pharmacogenomics biomarkers in 231 genes. Our data show significant interpopulation pharmacogenomic biomarker allele frequency differences, particularly in 7 clinically actionable pharmacogenomic biomarkers in 7 European populations, affecting drug efficacy and/or toxicity of 51 medication treatment modalities. These data also reflect on the differences observed in the prevalence of high-risk genotypes in these populations, as far as common markers in the CYP2C9, CYP2C19, CYP3A5, VKORC1, SLCO1B1 and TPMT pharmacogenes are concerned. Also, our data demonstrate notable differences in predicted genotype-based warfarin dosing among these populations. Our findings can be exploited not only to develop guidelines for medical prioritization, but most importantly to facilitate integration of pharmacogenomics and to support pre-emptive pharmacogenomic testing. This may subsequently contribute towards significant cost-savings in the overall healthcare expenditure in the participating countries, where pharmacogenomics implementation proves to be cost-effective

A genomic catalog of Earth’s microbiomes

The reconstruction of bacterial and archaeal genomes from shotgun metagenomes has enabled insights into the ecology and evolution of environmental and host-associated microbiomes. Here we applied this approach to >10,000 metagenomes collected from diverse habitats covering all of Earth’s continents and oceans, including metagenomes from human and animal hosts, engineered environments, and natural and agricultural soils, to capture extant microbial, metabolic and functional potential. This comprehensive catalog includes 52,515 metagenome-assembled genomes representing 12,556 novel candidate species-level operational taxonomic units spanning 135 phyla. The catalog expands the known phylogenetic diversity of bacteria and archaea by 44% and is broadly available for streamlined comparative analyses, interactive exploration, metabolic modeling and bulk download. We demonstrate the utility of this collection for understanding secondary-metabolite biosynthetic potential and for resolving thousands of new host linkages to uncultivated viruses. This resource underscores the value of genome-centric approaches for revealing genomic properties of uncultivated microorganisms that affect ecosystem processes