Validity-Guided Synthesis of Reactive Systems from Assume-Guarantee Contracts

Automated synthesis of reactive systems from specifications has been a topic of research for decades. Recently, a variety of approaches have been proposed to extend synthesis of reactive systems from proposi- tional specifications towards specifications over rich theories. We propose a novel, completely automated approach to program synthesis which reduces the problem to deciding the validity of a set of forall-exists formulas. In spirit of IC3 / PDR, our problem space is recursively refined by blocking out regions of unsafe states, aiming to discover a fixpoint that describes safe reactions. If such a fixpoint is found, we construct a witness that is directly translated into an implementation. We implemented the algorithm on top of the JKind model checker, and exercised it against contracts written using the Lustre specification language. Experimental results show how the new algorithm outperforms JKinds already existing synthesis procedure based on k-induction and addresses soundness issues in the k-inductive approach with respect to unrealizable results.Comment: 18 pages, 5 figures, 2 table

The creation of Wing Tsun: a German case study

Ip Man’s immigration to Hong Kong in 1949, followed by Bruce Lee’s sudden fame as a martial arts superstar after 1971, ensured that wing chun kung fu, a previously obscure hand combat style from Guangdong Province, would become one of the most globally popular Chinese martial arts. Yet this success has not been evenly distributed. Despite its cultural and geographic distance from Hong Kong, Germany now boasts a number of wing chun practitioners that is second only to China. The following article draws on the prior work of Judkins and Nielson [2015], as well as on systems theory, to understand possible reasons for why this is the case. Drawing on both local historical sources and various theoretical approaches, we outline which constellations, structures, and semantic strategies proved decisive

Preliminary definitions for the sonographic features of synovitis in children

Objectives Musculoskeletal ultrasonography (US) has the potential to be an important tool in the assessment of disease activity in childhood arthritides. To assess pathology, clear definitions for synovitis need to be developed first. The aim of this study was to develop and validate these definitions through an international consensus process. Methods The decision on which US techniques to use, the components to be included in the definitions as well as the final wording were developed by 31 ultrasound experts in a consensus process. A Likert scale of 1-5 with 1 indicating complete disagreement and 5 complete agreement was used. A minimum of 80% of the experts scoring 4 or 5 was required for final approval. The definitions were then validated on 120 standardized US images of the wrist, MCP and tibiotalar joints displaying various degrees of synovitis at various ages. Results B-Mode and Doppler should be used for assessing synovitis in children. A US definition of the various components (i.e. synovial hypertrophy, effusion and Doppler signal within the synovium) was developed. The definition was validated on still images with a median of 89% (range 80-100) of participants scoring it as 4 or 5 on a Likert scale. Conclusions US definitions of synovitis and its elementary components covering the entire pediatric age range were successfully developed through a Delphi process and validated in a web-based still images exercise. These results provide the basis for the standardized US assessment of synovitis in clinical practice and research

IGF1 and insulin receptor single nucleotide variants associated with response in HER2-negative breast cancer patients treated with neoadjuvant chemotherapy with or without a fasting mimicking diet (BOOG 2013-04 DIRECT trial)

Simple Summary: Insulin and insulin-like growth factor 1 (IGF1) are metabolic hormones, which are often upregulated to stimulate proliferation in breast cancer. A fasting mimicking diet (FMD) targets insulin signaling pathway downregulation to hamper tumor growth. Genes encoding for the insulin receptors on the cell's surface contain genetic variation between patients, which can affect insulin receptor function and cellular response. Therefore, a group of 113 patients with HER2-negative breast cancer receiving neoadjuvant chemotherapy with or without a fasting mimicking diet were investigated. We found that two IGF1 receptor variants were associated with worse pathological response compared to the reference alleles, out of the 17 interrogated common variants. Additionally, two IGF1 receptor variants could interact negatively within the FMD group regarding radiological response. These results emphasize that genetic variation harbors predictive clinical relevance to optimize and personalize cancer therapy. Aim: We aimed to investigate associations between IGF1R and INSR single nucleotide variants (SNVs) and clinical response in patients with breast cancer treated with neoadjuvant chemotherapy with or without a fasting mimicking diet (FMD) from the DIRECT trial (NCT02126449), since insulin-like growth factor 1 (IGF1) and the insulin pathway are heavily involved in tumor growth and progression. Methods: Germline DNA from 113 patients was tested for 17 systematically selected candidate SNVs in IGF1R and INSR with pathological and radiological response. Results: IGF1R variants A > G (rs3743259) and G > A (rs3743258) are associated with worse pathological response compared to reference alleles p = 0.002, OR = 0.42 (95%CI: 0.24; 0.73); p = 0.0016; OR = 0.40 (95%CI: 0.23; 0.70). INSR T > C (rs1051690) may be associated with worse radiological response p = 0.02, OR = 2.92 (95%CI: 1.16; 7.36), although not significant after Bonferroni correction. Exploratory interaction analysis suggests that IGF1R SNVs rs2684787 and rs2654980 interact negatively with the FMD group regarding radiological response p = 0.036, OR = 5.13 (95%CI: 1.12; 23.63); p = 0.024, OR = 5.71 (95%CI: 1.26; 25.85). Conclusions: The IGF1R variants rs3743259 and rs3743258 are negatively associated with pathological response in this cohort, suggesting potential relevance as a predictive biomarker. Further research is needed to validate these findings and elucidate the underlying mechanisms and interaction with FMD.Metabolic health: pathophysiological trajectories and therap

How does a cadaver model work for testing ultrasound diagnostic capability for rheumatic-like tendon damage?

To establish whether a cadaver model can serve as an effective surrogate for the detection of tendon damage characteristic of rheumatoid arthritis (RA). In addition, we evaluated intraobserver and interobserver agreement in the grading of RA-like tendon tears shown by US, as well as the concordance between the US findings and the surgically induced lesions in the cadaver model. RA-like tendon damage was surgically induced in the tibialis anterior tendon (TAT) and tibialis posterior tendon (TPT) of ten ankle/foot fresh-frozen cadaveric specimens. Of the 20 tendons examined, six were randomly assigned a surgically induced partial tear; six a complete tear; and eight left undamaged. Three rheumatologists, experts in musculoskeletal US, assessed from 1 to 5 the quality of US imaging of the cadaveric models on a Likert scale. Tendons were then categorized as having either no damage, (0); partial tear, (1); or complete tear (2). All 20 tendons were blindly and independently evaluated twice, over two rounds, by each of the three observers. Overall, technical performance was satisfactory for all items in the two rounds (all values over 2.9 in a Likert scale 1-5). Intraobserver and interobserver agreement for US grading of tendon damage was good (mean κ values 0.62 and 0.71, respectively), with greater reliability found in the TAT than the TPT. Concordance between US findings and experimental tendon lesions was acceptable (70-100 %), again greater for the TAT than for the TPT. A cadaver model with surgically created tendon damage can be useful in evaluating US metric properties of RA tendon lesions

Reliability testing of tendon disease using two different scanning methods in patients with rheumatoid arthritis

Objective. To assess the intra- and interobserver reliability of musculoskeletal ultrasonography (US) in detecting inflammatory and destructive tendon abnormalities in patients with RA using two different scanning methods.Methods. Thirteen observers examined nine patients with RA and one healthy individual in two rounds independently and blindly of each other. Each round consisted of two consecutive examinations, an anatomy-based examination and a free examination according to personal preferences. The following tendons were evaluated: wrist extensor compartments 2, 4 and 6, finger flexor tendons 3 and 4 at MCP level, tibialis posterior tendon and both peronei tendons. Overall, positive and negative agreements and \u3ba-values for greyscale (GS) tenosynovitis, peritendinous power Doppler (PPD) signal, intratendinous power Doppler (IPD) signal and GS tendon damage were calculated.Results. Intraobserver \u3ba-value ranges were 0.53-0.55 (P < 0.0005) for GS tenosynovitis, 0.61-0.64 (P < 0.0005) for PPD signal, 0.65-0.66 (P < 0.0005) for IPD signal and 0.44-0.53 (P < 0.0005) for GS tendon damage. For interobserver reliability, substantial overall agreement ranged from 80 to 89% for GS tenosynovitis, 97 to 100% for PPD signal, 97 to 100% for IPD signal and 97 to 100% for GS tendon damage. Results were independent of scanning technique.Conclusion. Intraobserver reliability for tenosynovitis and tendon damage varied from moderate for GS to good for PD. Overall interobserver reliability for tenosynovitis and tendon damage was excellent both for GS and PD. This qualitative scoring system may serve as the first step to a semi-quantitative score for tendon pathology. \ua9 The Author 2012. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved

Atomic-scale confinement of optical fields

In the presence of matter there is no fundamental limit preventing confinement of visible light even down to atomic scales. Achieving such confinement and the corresponding intensity enhancement inevitably requires simultaneous control over atomic-scale details of material structures and over the optical modes that such structures support. By means of self-assembly we have obtained side-by-side aligned gold nanorod dimers with robust atomically-defined gaps reaching below 0.5 nm. The existence of atomically-confined light fields in these gaps is demonstrated by observing extreme Coulomb splitting of corresponding symmetric and anti-symmetric dimer eigenmodes of more than 800 meV in white-light scattering experiments. Our results open new perspectives for atomically-resolved spectroscopic imaging, deeply nonlinear optics, ultra-sensing, cavity optomechanics as well as for the realization of novel quantum-optical devices

Reliability testing of tendon disease using two different scanning methods in patients with rheumatoid arthritis

Objective. To assess the intra- and interobserver reliability of musculoskeletal ultrasonography (US) in detecting inflammatory and destructive tendon abnormalities in patients with RA using two different scanning methods.Methods. Thirteen observers examined nine patients with RA and one healthy individual in two rounds independently and blindly of each other. Each round consisted of two consecutive examinations, an anatomy-based examination and a free examination according to personal preferences. The following tendons were evaluated: wrist extensor compartments 2, 4 and 6, finger flexor tendons 3 and 4 at MCP level, tibialis posterior tendon and both peronei tendons. Overall, positive and negative agreements and κ-values for greyscale (GS) tenosynovitis, peritendinous power Doppler (PPD) signal, intratendinous power Doppler (IPD) signal and GS tendon damage were calculated.Results. Intraobserver κ-value ranges were 0.53-0.55 (P < 0.0005) for GS tenosynovitis, 0.61-0.64 (P < 0.0005) for PPD signal, 0.65-0.66 (P < 0.0005) for IPD signal and 0.44-0.53 (P < 0.0005) for GS tendon damage. For interobserver reliability, substantial overall agreement ranged from 80 to 89% for GS tenosynovitis, 97 to 100% for PPD signal, 97 to 100% for IPD signal and 97 to 100% for GS tendon damage. Results were independent of scanning technique.Conclusion. Intraobserver reliability for tenosynovitis and tendon damage varied from moderate for GS to good for PD. Overall interobserver reliability for tenosynovitis and tendon damage was excellent both for GS and PD. This qualitative scoring system may serve as the first step to a semi-quantitative score for tendon pathology. © The Author 2012. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved

Influence of pharmacogenetic variability on the pharmacokinetics and toxicity of the aurora kinase inhibitor danusertib

Objectives Danusertib is a serine/threonine kinase inhibitor of multiple kinases, including aurora-A, B, and C. This explorative study aims to identify possible relationships between single nucleotide polymorphisms in genes coding for drug metabolizing enzymes and transporter proteins and clearance of danusertib, to clarify the interpatient variability in exposure. In addition, this study explores the relationship between target receptor polymorphisms and toxicity of danusertib. Methods For associations with clearance, 48 cancer patients treated in a phase I study were analyzed for ABCB1, ABCG2 and FMO3 polymorphisms. Association analyses between neutropenia and drug target receptors, including KDR, RET, FLT3, FLT4, AURKB and AURKA, were performed in 30 patients treated at recommended phase II dose-levels in three danusertib phase I or phase II trials. Results No relationships between danusertib clearance and drug metabolizing enzymes and transporter protein polymorphisms were found. Only, for the one patient with FMO3 18281AA polymorphism, a significantly higher clearance was noticed, compared to patients carrying at least 1 wild type allele. No effect of target receptor genotypes or haplotypes on neutropenia was observed. Conclusions As we did not find any major correlations between pharmacogenetic variability in the studied enzymes and transporters and pharmacokinetics nor toxicity, it is unlikely that danusertib is highly susceptible for pharmacogenetic variation. Therefore, no dosing alterations of danusertib are expected in the future, based on the polymorphisms studied. However, the relationship between FMO3 polymorphisms and clearance of danusertib warrants further research, as we could study only a small group of patients