The Importance of Mortality Risk Assessment: Validation of the Pediatric Index of Mortality 3 Score

Objective: To evaluate the performance of the newest version of the Pediatric Index of Mortality 3 score and compare it with the Pediatric Index of Mortality 2 in a multicenter national cohort of children admitted to PICU. Design: Retrospective, prospective cohort study. Setting: Seventeen Italian PICUs. Patients: All children 0 to 15 years old admitted in PICU from January 2010 to October 2014. Interventions: None. Measurement and main results: Eleven thousand one hundred nine children were enrolled in the study. The mean Pediatric Index of Mortality 2 and 3 values of 4.9 and 3.9, respectively, differed significantly (p < 0.05). Overall mortality rate was 3.9%, and the standardized mortality ratio was 0.80 for Pediatric Index of Mortality 2 and 0.98 for Pediatric Index of Mortality 3 (p < 0.05). The area under the curve of the receiver operating characteristic curves was similar for Pediatric Index of Mortality 2 and Pediatric Index of Mortality 3. The Hosmer-Lemeshow test was not significant for Pediatric Index of Mortality 3 (p = 0.21) but was highly significant for Pediatric Index of Mortality 2 (p < 0.001), which overestimated death mainly in high-risk categories. Conclusions: Mortality indices require validation in each country where it is used. The new Pediatric Index of Mortality 3 score performed well in an Italian population. Both calibration and discrimination were appropriate, and the score more accurately predicted the mortality risk than Pediatric Index of Mortality 2

OVERCOMING DORMANCY IN CITRUS ROOTSTOCK SEEDS

Citrus is a fruit of great importance in Brazil, mainly in the socio-economic issue as it generates employment and income due to the production and export of concentrated orange juice, as well as other products. In view of the above, this work aimed to evaluate the dormancy overcoming of citrus seeds of the cultivars: Flying Dragon, San Diego, Índio, Cravo Santa Cruz, Riverside, BRS Sunki Tropical, Volkamerian, as well as the species Poncirus trifoliata. The seeds from Embrapa (Brazilian Agricultural Research Corporation) Clima Temperado, located in Pelotas-RS, as well as from Embrapa Cassava e Fruticultura, located in Cruz das Almas-BA, were submitted to the germination test as written in the Seed Analysis Rules and a germination test in which a small cut was made in the seed coat on the side of the embryo, around 0.1 mm with the help of a stylet, which was used 200 seeds (4 samples of 50 seeds per repetition) on germitest® paper, moistened with distilled water in an amount equivalent to 2.5 times its weight and kept inside a germinator at a constant temperature of 25°C, photoperiod of 12 hours. The evaluations were carried out at the end of the 21 days after the installation of the test, providing data that were expressed in percentage of normal and abnormal seedlings and non-germinated seeds (hard, dormant or dead). of citrus seedlings at the end of the tests and the data obtained were submitted to analysis of variance and the means were compared by the Tukey test at a 5% significance level (p≤0.05), with the aid of the R- bio. It is concluded that, when evaluating germination and shoot and root length of seedlings cultivars Flying Dragon, Índio, Cravo Santa Cruz, BRS Sunki Tropical, Riverside and Volkameriano, San Diego and the species Poncirus trifoliata, were satisfactory when submitted in the dormancy breaking process, but further studies are needed.Os citros é uma frutífera de grande importância no Brasil, principalmente na questão sócio econômico pois gera emprego e renda por conta da produção e exportação de suco concentrado de laranja, bem como outros produtos. Diante do exposto este trabalho teve como objetivo avaliar a superação de dormência de sementes de citros das cultivares: Flying Dragon, San Diego, Índio, Cravo Santa Cruz, Riverside, BRS Sunki Tropical, Volkameriano, bem como a espécie Poncirus trifoliata. As sementes oriundas Embrapa (Empresa Brasileira de Pesquisa Agropecuária) Clima Temperado, localizada em Pelotas-RS, bem como da Embrapa Mandioca e Fruticultura, localizada em Cruz das Almas-BA, foram submetidas ao teste de germinação como escrito nas Regras de Análise de Sementes e a um teste de germinação na qual foi feito  um pequeno corte no tegumento da semente do lado do embrião, em torno de 0,1 mm com ajuda de um estilete, a qual foi utilizada 200 sementes (4 amostras de 50 sementes por repetição) em   papel germitest®, umedecido com água destilada em quantidade equivalente a 2,5 vezes o seu peso e mantidos no interior de um germinador à temperatura constante de 25°C, fotoperíodo de 12 horas. As avaliações, foram realizada ao final dos 21 dias após a instalação do teste, fornecendo dados que foram expressos em porcentagem de plântulas normais, anormais e     sementes não germinadas (duras, dormentes ou mortas).Além de ser realizado o comprimento da parte aérea e raiz das plântulas de citros no final dos testes e os dados obtidos foram submetidos à análise de variância e as médias, comparadas pelo teste Tukey ao nível de 5% de significância (p≤0,05), com o auxílio do pacote estatístico R-bio. Conclui-se, que ao avaliar a germinação e o comprimento da parte aérea e raiz das plântulas cultivares Flying Dragon, Índio, Cravo Santa Cruz, BRS Sunki Tropical, Riverside e Volkameriano, San Diego e a espécie Poncirus trifoliata, foram satisfatórios, quando submetidos no processo de quebra de dormência, porém se faz necessário mais estudos a respeito

Micro-based evidence of EU competitiveness: The CompNet Database. National Bank of Belgium Working Paper No. 253, March 2014

Drawing from confidential firm-level balance sheets in 11 European countries, the paper presents a novel sectoral database of comparable productivity indicators built by members of the Competitiveness Research Network (CompNet) using a newly developed research infrastructure. Beyond aggregate information available from industry statistics of Eurostat or EU KLEMS, the paper provides information on the distribution of firms across several dimensions related to competitiveness, e.g. productivity and size. The database comprises so far 11 countries, with information for 58 sectors over the period 1995-2011. The paper documents the development of the new research infrastructure, the construction of the database, and shows some preliminary results. Among them, it shows that there is large heterogeneity in terms of firm productivity or size within narrowly defined industries in all countries. Productivity, and above all, size distribution are very skewed across countries, with a thick left-tail of low productive firms. Moreover, firms at both ends of the distribution show very different dynamics in terms of productivity and unit labour costs. Within-sector heterogeneity and productivity dispersion are positively correlated to aggregate productivity given the possibility of reallocating resources from less to more productive firms. To this extent, we show how allocative efficiency varies across countries, and more interestingly, over different periods of time. Finally, we apply the new database to illustrate the importance of productivity dispersion to explain aggregate trade results

An explainable model of host genetic interactions linked to COVID-19 severity

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as "Respiratory or thoracic disease", supporting their link with COVID-19 severity outcome.A multifaceted computational strategy identifies 16 genetic variants contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing dataset of a cohort of Italian patients

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor

A history of invasion: COI phylogeny of Manila clam Ruditapes philippinarum in Europe

The Manila clam Ruditapes philippinarum – synonym Venerupis philippinarum (Adams and Reeve, 1850) is now one of the top 5 most commercially valuable bivalve species worldwide. Originally from the Indo-Pacific region, it has been introduced in many countries for fisheries and aquaculture, including estuarine environments along Atlantic and Mediterranean European coasts. Yet despite its commercial value and widespread distribution, the precise origins of stocks remain speculative and the genetic diversity of introduced populations is poorly known. Thus, the aim of this work was to collect mtDNA COI (Cytochrome oxidase I) gene sequences from 5 European countries with Manila clam stocks and compare them with native Asian populations to evaluate their genetic diversity and identify possible routes of invasion. The COI gene sequencing supported a strong founder effect in the European populations with 3 main haplotypes occurring at high frequencies, derived from Japan. However, high haplotype diversity was also observed due to the occurrence of 10 rare haplotypes. This supports hypotheses (i) there have been additional, previous unrecorded, introductions as previously hypothesized by analysis of 16S rDNA, and (ii) there has been a limited loss of genetic diversity in introduced populations, as previously suggested by microsatellite data. This is the first genetic comparison of Manila clam populations introduced in to Europe with native clams. Genetic data herein presented are fundamentally important for the traceability of clam products and stock management programmes and will also inform discussion on the potential resilience of exploited Manila clam populations

Peri-operative red blood cell transfusion in neonates and infants: NEonate and Children audiT of Anaesthesia pRactice IN Europe: A prospective European multicentre observational study

BACKGROUND: Little is known about current clinical practice concerning peri-operative red blood cell transfusion in neonates and small infants. Guidelines suggest transfusions based on haemoglobin thresholds ranging from 8.5 to 12 g dl-1, distinguishing between children from birth to day 7 (week 1), from day 8 to day 14 (week 2) or from day 15 (≥week 3) onwards. OBJECTIVE: To observe peri-operative red blood cell transfusion practice according to guidelines in relation to patient outcome. DESIGN: A multicentre observational study. SETTING: The NEonate-Children sTudy of Anaesthesia pRactice IN Europe (NECTARINE) trial recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. PATIENTS: The data included 5609 patients undergoing 6542 procedures. Inclusion criteria was a peri-operative red blood cell transfusion. MAIN OUTCOME MEASURES: The primary endpoint was the haemoglobin level triggering a transfusion for neonates in week 1, week 2 and week 3. Secondary endpoints were transfusion volumes, 'delta haemoglobin' (preprocedure - transfusion-triggering) and 30-day and 90-day morbidity and mortality. RESULTS: Peri-operative red blood cell transfusions were recorded during 447 procedures (6.9%). The median haemoglobin levels triggering a transfusion were 9.6 [IQR 8.7 to 10.9] g dl-1 for neonates in week 1, 9.6 [7.7 to 10.4] g dl-1 in week 2 and 8.0 [7.3 to 9.0] g dl-1 in week 3. The median transfusion volume was 17.1 [11.1 to 26.4] ml kg-1 with a median delta haemoglobin of 1.8 [0.0 to 3.6] g dl-1. Thirty-day morbidity was 47.8% with an overall mortality of 11.3%. CONCLUSIONS: Results indicate lower transfusion-triggering haemoglobin thresholds in clinical practice than suggested by current guidelines. The high morbidity and mortality of this NECTARINE sub-cohort calls for investigative action and evidence-based guidelines addressing peri-operative red blood cell transfusions strategies. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02350348

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types