Ceftolozane/tazobactam for the treatment of serious Pseudomonas aeruginosa infections: a multicentre nationwide clinical experience

This study describes the largest clinical experience using ceftolozane/tazobactam (C/T) for different Pseudomonas aeruginosa infections. A retrospective study was performed at 22 hospitals in Italy (June 2016\u2013March 2018). All adult patients treated with 654 days of C/T were enrolled. Successful clinical outcome was defined as complete resolution of clinical signs/symptoms related to P. aeruginosa infection and lack of microbiological evidence of infection. C/T treatment was documented in 101 patients with diverse infections, including nosocomial pneumonia (31.7%), acute bacterial skin and skin-structure infection (20.8%), complicated UTI (13.9%), complicated IAI (12.9%), bone infection (8.9%) and primary bacteraemia (5.9%). Over one-half of P. aeruginosa strains were XDR (50.5%), with 78.2% of isolates resistant to at least one carbapenem. C/T was used as first-line therapy in 39 patients (38.6%). When used as second-line or later, the most common reasons for discontinuation of previous antibiotics were in vitro resistance of P. aeruginosa and clinical failure of previous therapy. Concomitant antibiotics were reported in 35.6% of patients. C/T doses were 1.5 g q8h in 70 patients (69.3%) and 3 g q8h in 31 patients (30.7%); median duration of C/T therapy was 14 days. Overall clinical success was 83.2%. Significant lower success rates were observed in patients with sepsis or receiving continuous renal replacement therapy (CRRT). Mild adverse events were reported in only three patients. C/T demonstrated a favourable safety and tolerability profile regardless of the infection type. Clinicians should be aware of the risk of clinical failure with C/T therapy in septic patients receiving CRRT

Insights into mantle composition and mantle melting beneath mid-ocean ridges from postspreading volcanism on the fossil Galapagos Rise

New major and trace element and Sr, Nd, and Pb isotope data, together with 39Ar-40Ar ages for lavas from the extinct Galapagos Rise spreading center in the eastern Pacific reveal the evolution in magma compositions erupted during slowdown and after the end of active spreading at a mid-ocean ridge. Lavas erupted at 9.2 Ma, immediately prior to the end of spreading are incompatible element depleted mid-ocean ridge tholeiitic basalts, whereas progressively younger (7.5 to 5.7 Ma) postspreading lavas are increasingly alkalic, have higher concentrations of incompatible elements, higher La/Yb, K/Ti, 87Sr/86Sr, and lower 143Nd/144Nd ratios and were produced by smaller degrees of mantle melting. The large, correlated variations in trace element and isotope compositions can only be explained by melting of heterogenous mantle, in which incompatible trace element enriched lithologies preferentially contribute to smaller degree mantle melts. The effects of variable degrees of melting of heterogeneous mantle on lava compositions must be taken into account when using mid-ocean ridge basalt (MORB) to infer the conditions of melting beneath active spreading ridges. For example, the stronger “garnet signature” inferred from Sm/Nd and 143Nd/144Nd ratios for postspreading lavas from the Galapagos Rise results from a larger contribution from enriched lithologies with high La/Yb and Sm/Yb, rather than from a greater proportion of melting in the stability field of garnet peridotite. Correlations between ridge depth and Sm/Yb and fractionation-corrected Na concentrations in MORB worldwide could result from variations in mantle fertility and/or variations in the average degree of melting, rather than from large variations in mantle temperature. If more fertile mantle lithologies are preferentially melted beneath active spreading ridges, then the upper mantle may be significantly more “depleted” than is generally inferred from the compositions of MORB

The Genomic and Evolutionary Landscapes of Anaplastic Thyroid Carcinoma

Anaplastic thyroid carcinoma is arguably the most lethal human malignancy. It often co-occurs with differentiated thyroid cancers, yet the molecular origins of its aggressivity are unknown. We sequenced tumor DNA from 329 regions of thyroid cancer, including 213 from patients with primary anaplastic thyroid carcinomas. We also whole genome sequenced 9 patients using multi-region sequencing of both differentiated and anaplastic thyroid cancer components. Using these data, we demonstrate thatanaplastic thyroid carcinomas have a higher burden of mutations than other thyroid cancers, with distinct mutational signatures and molecular subtypes. Further, different cancer driver genes are mutated in anaplastic and differentiated thyroid carcinomas, even those arising in a single patient. Finally, we unambiguously demonstrate that anaplastic thyroid carcinomas share a genomic origin with co-occurring differentiated carcinomas and emerge from a common malignant field through acquisition of characteristic clonal driver mutations

The Monarch Initiative in 2019: an integrative data and analytic platform connecting phenotypes to genotypes across species.

In biology and biomedicine, relating phenotypic outcomes with genetic variation and environmental factors remains a challenge: patient phenotypes may not match known diseases, candidate variants may be in genes that haven\u27t been characterized, research organisms may not recapitulate human or veterinary diseases, environmental factors affecting disease outcomes are unknown or undocumented, and many resources must be queried to find potentially significant phenotypic associations. The Monarch Initiative (https://monarchinitiative.org) integrates information on genes, variants, genotypes, phenotypes and diseases in a variety of species, and allows powerful ontology-based search. We develop many widely adopted ontologies that together enable sophisticated computational analysis, mechanistic discovery and diagnostics of Mendelian diseases. Our algorithms and tools are widely used to identify animal models of human disease through phenotypic similarity, for differential diagnostics and to facilitate translational research. Launched in 2015, Monarch has grown with regards to data (new organisms, more sources, better modeling); new API and standards; ontologies (new Mondo unified disease ontology, improvements to ontologies such as HPO and uPheno); user interface (a redesigned website); and community development. Monarch data, algorithms and tools are being used and extended by resources such as GA4GH and NCATS Translator, among others, to aid mechanistic discovery and diagnostics

Expansion of the Human Phenotype Ontology (HPO) knowledge base and resources.

The Human Phenotype Ontology (HPO)-a standardized vocabulary of phenotypic abnormalities associated with 7000+ diseases-is used by thousands of researchers, clinicians, informaticians and electronic health record systems around the world. Its detailed descriptions of clinical abnormalities and computable disease definitions have made HPO the de facto standard for deep phenotyping in the field of rare disease. The HPO\u27s interoperability with other ontologies has enabled it to be used to improve diagnostic accuracy by incorporating model organism data. It also plays a key role in the popular Exomiser tool, which identifies potential disease-causing variants from whole-exome or whole-genome sequencing data. Since the HPO was first introduced in 2008, its users have become both more numerous and more diverse. To meet these emerging needs, the project has added new content, language translations, mappings and computational tooling, as well as integrations with external community data. The HPO continues to collaborate with clinical adopters to improve specific areas of the ontology and extend standardized disease descriptions. The newly redesigned HPO website (www.human-phenotype-ontology.org) simplifies browsing terms and exploring clinical features, diseases, and human genes

Potential for a Circular Autopoietic Economy on Canavese Territory

The aim of this gigamap is to describe and summarize a student work carried out during the semester course Open Systems Design at Politecnico Torino. The map is one of the outputs from an analysis of the Canavese, Piedmont region and subsequently an in-depth study of the relationships and “flows” with certain “currencies” between some selected economic and public actors. Canavese is a historical-geographical area located in the province of Turin, Italy; it’s full of great natural and geological spots, with a strong enogastronomic identity, historical re-enactments, a well-known manufacture sector like the ceramic of Castellamonte, as well as the leading high-tech branch like Arduino. Through the approach deriving from systemic design, it was possible to identify some strategies for the creation of new networks aimed at transforming the economy and production processes from linear to circular approach. Five types of “circular flows” were assessed and “designed into” the current linear system, thus proposing an improved economy based on circularity: flows of matter (energy/CO2, water, materials), economic flows, and social flows. The Gigamap will be presented to stakeholders in a public hearing and supposedly be used to illustrate and incubate a circular economy that is more resilient and more regenerative. Reading the map The reading should start at the top left, where the abstract is located, next, there is an outline that shows the connections between the five topics investigated. Subsequently, there is a timeline with some fundamental events in the history of the Canavese. In the center there is the circularity map with the main cities, focusing on new opportunities of circular flows between the 15 analysed economic actors. At the bottom, some general data and on the right a brief description of the role and territorial qualities of the companies. Lastly, there is a summary of the emerging properties

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis