Sulfonylative Hiyama Cross-Coupling: Development and Mechanistic Insights

International audienceDue to distinctive structural and electronic features, sulfones have attracted a particular attention over the pa st few decades, ma king it a widespread functional group.[1] Present in many contemporary pharmaceuticals and agrochemicals, they are also used as essential intermediates in organic synthesis. Therefore, numérous methodologies have been developed for their preparation. [1] However, the most common methods suffer from significant limitations with harsh reaction conditions or regioselectivity issues. Recently, the insertion of a molecule of sulfur dioxide between two partners was investigated and reactions involving organomagnesium,[2a] organozind2b] and organoboron[2c] compounds were reported. Herein we report a direct single-step palladium-catalyzed synthesis of sulfones involving organosilanes, sulfur dioxide and organohalides. Different mechanistic pathways were envisaged and discussed both from an experimental and theoretical stand point

Guidance in author instructions of hematology and oncology journals: A cross sectional and longitudinal study.

The debate about the value of biomedical publications led to recommendations for improving reporting quality. It is unclear to what extent these recommendations have been endorsed by journals. We analyzed whether specific recommendations were included in author instructions, which journal characteristics were associated with their endorsement, how endorsement of the domains changed and whether endorsement was associated with change of impact factor between 2010 and 2015. We considered two study samples consisting of "Hematology" and "Oncology" journals of the Journal Citation Report 2008 and 2014, respectively. We extracted information regarding endorsement of the (1) recommendations of the International Committee of Medical Journal Editors, of (2) reporting guidelines, (3) requirement for trial registration and (4) disclosure of conflicts of interest. Data extraction was done by reading the author instructions before conducting a text search with keywords. We calculated a global generalized linear mixed effects model for endorsement of each of the four domains followed by separate multivariable logistic regression models and a longitudinal analysis. We defined endorsement as the author instructions saying that they approve the use of the recommendations. In 2015, the ICMJE recommendations were mentioned in author instructions of 156 journals (67.5%). CONSORT was referred to by 77 journals (33.3%); MOOSE, PRISMA, STARD and STROBE were referred to by less than 15% of journals. There were 99 journals (42.9%) that recommended or required trial registration, 211 (91.3%) required authors to disclose conflicts of interest. Journal impact factor, journal start year and geographical region were positively associated with endorsement of any of the four domains. The overall endorsement of all domains increased between 2010 and 2015. The endorsement of any domain in 2010 seemed to be associated with an increased impact factor in 2014. Hematology and oncology journals endorse major recommendations to various degrees. Endorsement is increasing slowly over time and might be positively associated with the journals' impact factor

Intrauterine instillation of diluted seminal plasma at oocyte pick-up does not increase the IVF pregnancy rate: a double-blind, placebo controlled, randomized study

STUDY QUESTION Does intrauterine application of diluted seminal plasma (SP) at the time of ovum pick-up improve the pregnancy rate by ≥14% in IVF treatment? SUMMARY ANSWER Intrauterine instillation of diluted SP at the time of ovum pick-up is unlikely to increase the pregnancy rate by ≥14% in IVF. WHAT IS KNOWN ALREADY SP modulates endometrial function, and sexual intercourse around the time of embryo transfer has been suggested to increase the likelihood of pregnancy. A previous randomized double-blind pilot study demonstrated a strong trend towards increased pregnancy rates following the intracervical application of undiluted SP. As this study was not conclusive and as the finding could have been confounded by sexual intercourse, the intrauterine application of diluted SP was investigated in the present trial. STUDY DESIGN, SIZE, DURATION A single-centre, prospective, double-blind, placebo-controlled, randomized, superiority trial on women undergoing IVF was conducted from April 2007 until February 2012 at the University Department of Gynaecological Endocrinology and Reproductive Medicine, Heidelberg, Germany. PARTICIPANTS/MATERIALS, SETTING, METHODS The study was powered to detect an 14% increase in the clinical pregnancy rate and two sequential tests were planned using the Pocock spending function. At the first interim analysis, 279 women had been randomly assigned to intrauterine diluted SP (20% SP in saline from the patients' partner) (n = 138) or placebo (n = 141) at the time of ovum pick-up. MAIN RESULTS AND THE ROLE OF CHANCE The clinical pregnancy rate per randomized patient was 37/138 (26.8%) in the SP group and 41/141 (29.1%) in the placebo group (difference: −2.3%, 95% confidence interval of the difference: −12.7 to +8.2%; P = 0.69). The live birth rate per randomized patient was 28/138 (20.3%) in the SP group and 33/141 (23.4%) in the placebo group (difference: −3.1%, 95% confidence interval of the difference: −12.7 to +6.6%; P = 0.56). It was decided to terminate the trial due to futility at the first interim analysis, at a conditional power of 62%. LIMITATIONS, REASONS FOR CAUTION The confidence interval of the difference remains wide, thus clinically relevant differences cannot reliably be excluded based on this single study. WIDER IMPLICATIONS OF THE FINDINGS The results of this study cast doubt on the validity of the concept that SP increases endometrial receptivity and thus implantation in humans. STUDY FUNDING/COMPETING INTEREST(S) Funding was provided by the department's own research facilities. TRIAL REGISTRATION NUMBER DRKS0000461

Zero-variance principle for Monte Carlo algorithms

We present a general approach to greatly increase at little cost the efficiency of Monte Carlo algorithms. To each observable to be computed we associate a renormalized observable (improved estimator) having the same average but a different variance. By writing down the zero-variance condition a fundamental equation determining the optimal choice for the renormalized observable is derived (zero-variance principle for each observable separately). We show, with several examples including classical and quantum Monte Carlo calculations, that the method can be very powerful.Comment: 9 pages, Latex, to appear in Phys. Rev. Let

Cluster update and recognition

We present a fast and robust cluster update algorithm that is especially efficient in implementing the task of image segmentation using the method of superparamagnetic clustering. We apply it to a Potts model with spin interactions that are are defined by gray-scale differences within the image. Motivated by biological systems, we introduce the concept of neural inhibition to the Potts model realization of the segmentation problem. Including the inhibition term in the Hamiltonian results in enhanced contrast and thereby significantly improves segmentation quality. As a second benefit we can - after equilibration - directly identify the image segments as the clusters formed by the clustering algorithm. To construct a new spin configuration the algorithm performs the standard steps of (1) forming clusters and of (2) updating the spins in a cluster simultaneously. As opposed to standard algorithms, however, we share the interaction energy between the two steps. Thus the update probabilities are not independent of the interaction energies. As a consequence, we observe an acceleration of the relaxation by a factor of 10 compared to the Swendson and Wang procedure.Comment: 4 pages, 2 figure

Infrared behavior of the gluon propagator in lattice Landau gauge: the three-dimensional case

We evaluate numerically the three-momentum-space gluon propagator in the lattice Landau gauge, for three-dimensional pure-SU(2) lattice gauge theory with periodic boundary conditions. Simulations are done for nine different values of the coupling $\beta$, from $\beta = 0$ (strong coupling) to $\beta = 6.0$ (in the scaling region), and for lattice sizes up to $V = 64^3$. In the limit of large lattice volume we observe, in all cases, a gluon propagator decreasing for momenta smaller than a constant value $p_{dec}$. From our data we estimate $p_{dec} \approx 350$ MeV. The result of a gluon propagator decreasing in the infrared limit has a straightforward interpretation as resulting from the proximity of the so-called first Gribov horizon in the infrared directions.Comment: 14 pages, BI-TP 99/03 preprint, correction in the Acknowledgments section. To appear in Phys.Rev.

Model-Driven Chatbot Development

Esta versión del artículo ha sido aceptada para su publicación, después de la revisión por pares (cuando corresponda) y está sujeta a los términos de uso de AM de Springer Nature, pero no es la Versión de Registro y no refleja mejoras posteriores a la aceptación, ni ninguna corrección. La versión del registro está disponible en línea en: https://doi.org/10.1007/978-3-030-62522-1_15Chatbots are software services accessed via conversation in natural language. They are increasingly used to help in all kinds of procedures like booking flights, querying visa information or assigning tasks to developers. They can be embedded in webs and social networks, and be used from mobile devices without installing dedicated apps. While many frameworks and platforms have emerged for their development, identifying the most appropriate one for building a particular chatbot requires a high investment of time. Moreover, some of them are closed – resulting in customer lock-in – or require deep technical knowledge. To tackle these issues, we propose a model-driven engineering approach to chatbot development. It comprises a neutral meta-model and a domainspecific language (DSL) for chatbot description; code generators and parsers for several chatbot platforms; and a platform recommender. Our approach supports forward and reverse engineering, and model-based analysis. We demonstrate its feasibility presenting a prototype tool and an evaluation based on migrating third party Dialogflow bots to RasaWork funded by the Spanish Ministry of Science (RTI2018095255-B-I00) and the R&D programme of Madrid (P2018/TCS-4314

Psychology as a natural science in the eighteenth century

Psychology considered as a natural science began as Aristotelian "physics" or "natural philosophy" of the soul. C. Wolff placed psychology under metaphysics, coordinate with cosmology. Scottish thinkers placed it within moral philosophy, but distinguished its "physical" laws from properly moral laws (for guiding conduct). Several Germans sought to establish an autonomous empirical psychology as a branch of natural science. British and French visual theorists developed mathematically precise theories of size and distance perception; they created instruments to test these theories and to measure visual phenomena such as the duration of visual impressions. These investigators typically were dualists who included mental phenomena within nature

HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer

Introduction: Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1). Therefore, we investigated HER2 and ESR1 mRNA levels in core biopsies of HER2-positive breast carcinomas from patients treated within the neoadjuvant GeparQuattro trial. Methods: HER2 levels were centrally analyzed by immunohistochemistry (IHC), silver in-situ hybridization (SISH) and qRT-PCR in 217 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) core biopsies. All tumors had been HER2-positive by local pathology and had been treated with neoadjuvant trastuzumab/ chemotherapy in GeparQuattro. Results: Only 73% of the tumors (158 of 217) were centrally HER2-positive (cHER2-positive) by IHC/SISH, with cHER2-positive tumors showing a significantly higher pCR rate (46.8% vs. 20.3%, p<0.0005). HER2 status by qRT-PCR showed a concordance of 88.5% with the central IHC/SISH status, with a low pCR rate in those tumors that were HER2-negative by mRNA analysis (21.1% vs. 49.6%, p<0.0005). The level of HER2 mRNA expression was linked to response rate in ESR1-positive tumors, but not in ESR1-negative tumors. HER2 mRNA expression was significantly associated with pCR in the HER2-positive/ESR1-positive tumors (p=0.004), but not in HER2-positive/ESR1-negative tumors. Conclusions: Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy. In patients with cHER2-negative tumors the pCR rate is comparable to the pCR rate in the non-trastuzumab treated HER-negative population. Response to trastuzumab is correlated to HER2 mRNA levels only in ESR1-positive tumors. This study adds further evidence to the different biology of both subsets within the HER2-positive group

Comparison of CT, MRI, and F-18 FDG PET/CT for initial N-staging of oral squamous cell carcinoma: a cost-effectiveness analysis.

BACKGROUND AND PURPOSE Treatment of oral squamous cell carcinoma (OSCC) is based on clinical exam, biopsy, and a precise imaging-based TNM-evaluation. A high sensitivity and specificity for magnetic resonance imaging (MRI) and F-18 FDG PET/CT are reported for N-staging. Nevertheless, staging of oral squamous cell carcinoma is most often based on computed tomography (CT) scans. This study aims to evaluate cost-effectiveness of MRI and PET/CT compared to standard of care imaging in initial staging of OSCC within the US Healthcare System. METHODS A decision model was constructed using quality-adjusted life years (QALYs) and overall costs of different imaging strategies including a CT of the head, neck, and the thorax, MRI of the neck with CT of the thorax, and whole body F-18 FDG PET/CT using Markov transition simulations for different disease states. Input parameters were derived from literature and willingness to pay (WTP) was set to US $100,000/QALY. Deterministic sensitivity analysis of diagnostic parameters and costs was performed. Monte Carlo modeling was used for probabilistic sensitivity analysis. RESULTS In the base-case scenario, total costs were at US$239,628 for CT, US $240,001 for MRI, and US$239,131 for F-18 FDG PET/CT whereas the model yielded an effectiveness of 5.29 QALYs for CT, 5.30 QALYs for MRI, and 5.32 QALYs for F-18 FDG PET/CT respectively. F-18 FDG PET/CT was the most cost-effective strategy over MRI as well as CT, and MRI was the cost-effective strategy over CT. Deterministic and probabilistic sensitivity analysis showed high robustness of the model with incremental cost effectiveness ratio remaining below US $100,000/QALY for a wide range of variability of input parameters. CONCLUSION F-18 FDG PET/CT is the most cost-effective strategy in the initial N-staging of OSCC when compared to MRI and CT. Despite less routine use, both whole body PET/CT and MRI are cost-effective modalities in the N-staging of OSCC. Based on these findings, the implementation of PET/CT for initial staging could be suggested to help reduce costs while increasing effectiveness in OSCC