Cost-Effectiveness of Bosutinib for the Treatment of Adult Patients with Chronic Phase Chronic Myeloid Leukemia in the Second-Line Setting

Background A recently conducted matching-adjusted indirect comparison demonstrated that bosutinib improved progression-free survival, and delayed progression to advanced disease compared with dasatinib and nilotinib in patients with second line (2L) chronic-phase chronic myeloid leukemia (CP-CML). However, the long-term clinical and economic impact of using bosutinib versus dasatinib and nilotinib has not been evaluated. The objective was to determine the cost-effectiveness of bosutinib compared with dasatinib and bosutinib compared with nilotinib from a US payer perspective. Methods A cost-effectiveness model was developed using partition survival methods and three health states: progression-free, progression, and death. Trial data (individual patient-level and aggregate-level data) informed the progression-free and overall survival estimates. Costs included drugs and medical resource use. Utility values were obtained from literature. Sensitivity analyses (SAs) included one-way and probabilistic sensitivity analyses (PSAs). Results Comparing bosutinib versus dasatinib resulted in a gain of 0.4 discounted life years, 1.5 quality-adjusted life years (QALYs), and incremental costs of $28,459 (values in 2020 US dollars), for an incremental cost-effectiveness ratio (ICER) of$19,811/QALY gained. Comparing bosutinib versus nilotinib resulted in a gain of 0.8 discounted life-years, 1.8 QALYs, and incremental costs of $76,563, for an ICER of$41,932/QALY gained. Drug costs and extrapolation distribution type were the main drivers of the model in the one-way SAs. In the PSAs, bosutinib had >90% and >80% probabilities of being cost-effective at a willingness-to-pay threshold of $100,000/QALY versus dasatinib and nilotinib, respectively. Conclusions Our results suggest that compared with dasatinib and nilotinib, bosutinib may represent good value for money for treating 2L CP-CML patients

Wet-dry-wet drug screen leads to the synthesis of TS1, a novel compound reversing lung fibrosis through inhibition of myofibroblast differentiation

Therapies halting the progression of fibrosis are ineffective and limited. Activated myofibroblasts are emerging as important targets in the progression of fibrotic diseases. Previously, we performed a high-throughput screen on lung fibroblasts and subsequently demonstrated that the inhibition of myofibroblast activation is able to prevent lung fibrosis in bleomycin-treated mice. High-throughput screens are an ideal method of repurposing drugs, yet they contain an intrinsic limitation, which is the size of the library itself. Here, we exploited the data from our “wet” screen and used “dry” machine learning analysis to virtually screen millions of compounds, identifying novel anti-fibrotic hits which target myofibroblast differentiation, many of which were structurally related to dopamine. We synthesized and validated several compounds ex vivo (“wet”) and confirmed that both dopamine and its derivative TS1 are powerful inhibitors of myofibroblast activation. We further used RNAi-mediated knock-down and demonstrated that both molecules act through the dopamine receptor 3 and exert their anti-fibrotic effect by inhibiting the canonical transforming growth factor β pathway. Furthermore, molecular modelling confirmed the capability of TS1 to bind both human and mouse dopamine receptor 3. The anti-fibrotic effect on human cells was confirmed using primary fibroblasts from idiopathic pulmonary fibrosis patients. Finally, TS1 prevented and reversed disease progression in a murine model of lung fibrosis. Both our interdisciplinary approach and our novel compound TS1 are promising tools for understanding and combating lung fibrosis

Linking formal child care characteristics to children's socioemotional well-being: A comparative perspective

Most research on formal child care and children’s outcomes has focused on single countries. We, however, contend that policy context may moderate the association between formal child care characteristics and children’s socioemotional well-being. We examined this by comparing the Netherlands, Finland and the UK; three countries that differ regarding family policies. Of these three countries, Finland was recently ranked highest (ranked 1st) with regards to quality of child care in a recent analysis by the Economist ,followed by the UK (ranked 3rd) and then the Netherlands (ranked 7th) .We hypothesized that children who attend child - care settings in countries with higher- uality formal child- are provision would generally show better socioemotional outcomes. Data from the comparative ‘F amilies 24/7’ survey were used, including 990 parents with children aged 0–12. We distinguished between two age groups in our analysis. Results indicated that, compared to the UK, longer hours in formal care were less beneficial in the Netherlands. Furthermore, spen ding time in formal care during nonstandard hours was more harmful for children in Finland compared to the UK. Lastly, receiving care from multiple caregivers was more disruptive for British children than for Dutch children. No differences were found between Finland and the Netherlands

The reliability of side to side measurements of upper extremity activity levels in healthy subjects

<p>Abstract</p> <p>Background</p> <p>In both clinical and occupational settings, ambulatory sensors are becoming common for assessing all day measurements of arm motion. In order for the motion of a healthy, contralateral side to be used as a control for the involved side, the inherent side to side differences in arm usage must be minimal. The goal of the present study was to determine the reliability of side to side measurements of upper extremity activity levels in healthy subjects.</p> <p>Methods</p> <p>Thirty two subjects with no upper extremity pathologies were studied. Each subject wore a triaxial accelerometer on both arms for three and a half hours. Motion was assessed using parameters previously reported in the literature. Side to side differences were compared with the intraclass correlation coefficient, standard error of the mean, minimal detectable change scores and a projected sample size analysis.</p> <p>Results</p> <p>The variables were ranked based on their percentage of minimal detectable change scores and sample sizes needed for paired t-tests. The order of these rankings was found to be identical and the top ranked parameters were activity counts per hour (MDC% = 9.5, n = 5), jerk time (MDC% = 15.8, n = 8) and percent time above 30 degrees (MDC% = 34.7, n = 9).</p> <p>Conclusions</p> <p>In general, the mean activity levels during daily activities were very similar between dominant and non-dominant arms. Specifically, activity counts per hour, jerk time, and percent time above 30 degrees were found to be the variables most likely to reveal significant difference or changes in both individuals and groups of subjects. The use of ambulatory measurements of upper extremity activity has very broad uses for occupational assessments, musculoskeletal injuries of the shoulder, elbow, wrist and hand as well as neurological pathologies.</p

Competences of Mathematics Teachers in Diagnosing Teaching Situations and Offering Feedback to Students:Specificity, Consistency and Reification of Pedagogical and Mathematical Discourses

In the study we report in this chapter, we investigate the competences of mathematics pre- and in-service teachers in diagnosing situations pertaining to mathematics teaching and in offering feedback to the students at the heart of said situations. To this aim we deploy a research design that involves engaging teachers with situation-specific tasks in which we invite participants to: solve a mathematical problem; examine a (fictional yet research-informed) solution proposed by a student in class and a (fictional yet research-informed) teacher response to the student; and, describe the approach they themselves would adopt in this classroom situation. Participants were 23 mathematics graduates enrolled in a post-graduate mathematics education programme, many already in-service teachers. They responded to a task that involved debating the identification of a tangent line at an inflection point of a cubic function through resorting to the formal definition of tangency or the function graph. Analysis of their written responses to the task revealed a great variation in the participants’ diagnosing and addressing of teaching issues – in this case involving the role of visualisation in mathematical reasoning. We describe this variation in terms of a typology of four interrelated characteristics that emerged from the data analysis: consistency between stated beliefs/knowledge and intended practice, specificity of the response to the given classroom situation, reification of pedagogical discourses, and reification of mathematical discourses. We propose that deploying the theoretical construct of these characteristics in tandem with our situation-specific task design can contribute towards the identification – as well as reflection upon and development – of mathematics teachers’ diagnostic competences in teacher education and professional development programmes