Model Reduction on the Wnt Pathway Leads to Biological Adaptation

Complex systems are an unavoidable problem in the field of biology. One of the ways that scientists have tried to overcome this problem is by building mathematical models—manageable representations designed to look at specific physical phenomena. The Wnt Signaling Pathway is a complex system known to regulate cell-to-cell interactions, play a crucial role in Embryonic Development, and has been implicated in the study of cancer. Typically, the Wnt signal is observed through the behavior of a protein called beta-Catenin (β-Catenin). In 2003, Lee et al. built a model of the Wnt pathway which caused β-Catenin to increase over time. However, in 2010, Jensen et al. built a different model of the Wnt pathway which caused β-Catenin to oscillate over time. This project called for model reduction on the Jensen et al. model to identify the phenomenological parameter combinations that determined features of the Wnt oscillations. The method used to reduce the model is called the Manifold Boundary Approximation Method, which is a geometric, parameter-independent method of reducing the model one parameter at a time. Reduction of the model showed that there were 5 variables and 8 parameters which drove the oscillating behavior of the system. After comparing our results to the Lee et al. reduced model of the Wnt pathway done by student Dane Bjork, a minimal model was constructed which predicted a novel class behavior of the Wnt system: biological adaptation

Societal preferences for standard health insurance coverage in the Netherlands: a cross-sectional study

INTRODUCTION: Cost-effectiveness is an important criterion in the decision to cover interventions in health insurance packages. One of the outcome measures, the quality-adjusted life year, has been criticised on its assumptions and implications concerning life expectancy and quality of life. Several studies have been conducted that measured societal preferences concerning healthcare rationing decisions. These studies mainly focused on one attribute. To adjust quality-adjusted life year maximisation in accordance with societal preferences, the relative importance of attributes should be studied. The present study aims to measure the relative importance of age, gender, socioeconomic status, pre-intervention health state, treatment effect, chance of treatment success and number of people in need of the intervention. A secondary objective is to compare the validity of the willingness to pay method with the validity of a relatively new preference elicitation method, best-worst scaling. METHODS AND ANALYSIS: A representative sample of 2000 Dutch citizens, over 18 years of age, are recruited to complete a web-based survey containing treatment scenarios. The scenarios present different levels of attributes. Respondents are asked to select one of the four scenarios that they prefer to be covered by the Dutch standard health insurance package and one that they prefer not to be covered. They are also asked to indicate how much they are willing to pay for each treatment scenario. At the end of the survey, respondents are asked to rate every attribute on a 1-10 scale. Two versions of the questionnaire are developed which differ on the framing, that is, treatments can be added to or removed from the insurance package. The data will be analysed by means of sequential conditional logit analysis (best-worst scaling) and analysis of variance (willingness to pay). ETHICS AND DISSEMINATION: The protocol is reviewed and approved by the medical ethical committee of the University Medical Center Leiden.Medical Decision MakingAnalysis and support of clinical decision makin

Окрема думка судді в кримінальному процесі

З’ясовується змістове наповнення правових засад, на підставі яких суддя може викласти окрему думку. Досліджується поняття «окремої думки судді» в різних країнах та правових системах. Висвітлюється механізм реалізації окремої думки судді в порівнянні з правом зарубіжних держав та вносить пропозиції щодо запозичення та ведення аналогічних механізмів реалізації окремої думки судді в Україні.Раскрывается содержание правовых принципов, на основании которых судья может изложить особое мнение. Исследуется понятие «особого мнения судьи » в разных странах и правовых системах. Освещается механизм реализации особого мнения судьи в сравнении с правом зарубежных государств и вносит предложение относительно заимствования и ведения аналогичных механизмов реализации особого мнения судьи в Украине.This article investigated the legal principles on which the judge may express the separate opinion; the existence of the notion of «the separate opinion of judge» in different countries and legal systems is conducted. The author analyzed the mechanism of realization of the separate opinion of judge in comparison with the law of foreign countries and made proposals for borrowing and introduction of the similar mechanisms for realization the dissenting the separate opinion of judge in Ukraine

Old age mortality and macroeconomic cycles

Background As mortality is more and more concentrated at old age, it becomes critical to identify the determinants of old age mortality. It has counterintuitively been found that mortality rates at all ages are higher during short-term increases in economic growth. Work-stress is found to be a contributing factor to this association, but cannot explain the association for the older, retired population. Methods Historical figures of gross domestic product (Angus Maddison) were compared with mortality rates (Human Mortality Database) of middle aged (40– 44 years) and older people (70–74 years) in 19 developed countries for the period 1950–2008. Regressions were performed on the de-trended data, accounting for autocorrelation and aggregated using random effects models. Results Most countries show pro-cyclical associations between the economy and mortality, especially with regard to male mortality rates. On average, for every 1% increase in gross domestic product, mortality increases with 0.36% for 70-year-old to 74-year-old men (p<0.001) and 0.38% for 40-year-old to 44-year-old men ( p<0.001). The effect for women is 0.18% for 70-year-olds to 74-year-olds ( p=0.012) and 0.15% for 40-year-olds to 44-year-olds ( p=0.118). Conclusions In developed countries, mortality rates increase during upward cycles in the economy, and decrease during downward cycles. This effect is similar for the older and middle-aged population. Traditional explanations as work-stress and traffic accidents cannot explain our findings. Lower levels of social support and informal care by the working population during good economic times can play an important role, but this remains to be formally investigated.Wetensch. publicati

Survival and Cost-Effectiveness of Trabectedin Compared to Ifosfamide Monotherapy in Advanced Soft Tissue Sarcoma Patients

Contains fulltext : 208922.pdf (publisher's version ) (Open Access)Trabectedin and ifosfamide are among the few cytostatic agents active in advanced soft tissue sarcomas (STSs). Trabectedin is most potent against so-called L-sarcomas (leiomyosarcoma and liposarcoma). The survival gain and cost-effectiveness of these agents in a second-line setting were analysed in the setting of advanced STS after failure of anthracyclines. A prospective observational trial had previously been performed to assess the use of trabectedin in a Dutch real-world setting. Data on ifosfamide monotherapy were acquired from previous studies, and an indirect comparison of survival was made. A state-transition economic model was constructed, in which patients could be in mutually exclusive states of being preprogression, postprogression, or deceased. The costs and quality-adjusted life years (QALYs) for both treatments were assessed from a Dutch health-care perspective. Separate analyses for the group of L-sarcomas and non-L-sarcomas were performed. Trabectedin treatment resulted in a median progression-free survival of 5.2 months for L-sarcoma patients, 2.0 months for non-L-sarcoma patients, and a median overall survival of 11.8 and 6.0 months, respectively. For L-sarcoma patients, trabectedin offered an increase of 0.368 life years and 0.251 QALYs compared to ifosfamide and euro20,082 in additional costs, for an incremental cost-effectiveness ratio (ICER) of euro80,000 per QALY gained. In the non-L-sarcoma patients, trabectedin resulted in 0.413 less life years and 0.266 less QALYs, at the increased cost of euro4,698. The difference in survival between drugs and the acquisition costs of trabectedin were the main influences in these models. Trabectedin was shown to have antitumour efficacy in advanced L-sarcoma. From a health economics perspective, the costs per QALY gained compared to ifosfamide monotherapy that may be acceptable, considering what is currently regarded as acceptable in the Netherlands

Facial-muscle weakness, speech disorders and dysphagia are common in patients with classic infantile Pompe disease treated with enzyme therapy

Classic infantile Pompe disease is an inherited generalized glycogen storage disorder caused by deficiency of lysosomal acid α-glucosidase. If left untreated, patients die before one year of age. Although enzyme-replacement therapy (ERT) has significantly prolonged lifespan, it has also revealed new aspects of the disease. For up to 11 years, we investigated the frequency and consequences of facial-muscle weakness, speech disorders and dysphagia in long-term survivors. Sequential photographs were used to determine the timing and severity of facial-muscle weakness. Using standardized articulation tests and fibreoptic endoscopic evaluation of swallowing, we investigated speech and swallowing function in a subset of patients. This study included 11 patients with classic infantile Pompe disease. Median age at the start of ERT was 2.4 months (range 0.1-8.3 months), and median age at the end of the study was 4.3 years (range 7.7 months −12.2 years). All patients developed facial-muscle weakness before the age of 15 months. Speech was studied in four patients. Articulation was disordered, with hypernasal resonance and reduced speech intelligibility in all four. Swallowing function was studied in six patients, the most important findings being ineffective swallowing with residues of food (5/6), penetration or aspiration (3/6), and reduced pharyngeal and/or laryngeal sensibility (2/6). We conclude that facial-muscle weakness, speech disorders and dysphagia are common in long-term survivors receiving ERT for classic infantile Pompe disease. To improve speech and reduce the risk for aspiration, early treatment by a speech therapist and regular swallowing assessments are recommended

Influence of low back pain and prognostic value of MRI in sciatica patients in relation to back pain

Background: Patients with sciatica frequently complain about associated back pain. It is not known whether there are prognostic relevant differences in Magnetic Resonance Imaging (MRI) findings between sciatica patients with and without disabling back pain. Methods: The study population contained patients with sciatica who underwent a baseline MRI to assess eligibility for a randomized trial designed to compare the efficacy of early surgery with prolonged conservative care for sciatica. Two neuroradiologists and one neurosurgeon independently evaluated all MR images. The MRI readers were blinded to symptom status. The MRI findings were compared between sciatica patients with and without disabling back pain. The presence of disabling back pain at baseline was correlated with perceived recovery at one year. Results: Of 379 included sciatica patients, 158 (42%) had disabling back pain. Of the patients with both sciatica and disabling back pain 68% did reveal a herniated disc with nerve root compression on MRI, compared to 88% of patients with predominantly sciatica (P,0.001). The existence of disabling back pain in sciatica at baseline was negatively associated with perceived recovery at one year (Odds ratio [OR] 0.32, 95% Confidence Interval 0.18-0.56, P,0.001). Sciatica patients with disabling back pain in absence of nerve root compression on MRI at baseline reported less perceived recovery at one year compared to those with predominantly sciatica and nerve root compression on MRI (50% vs 91%, P,0.001). Conclusion: Sciatica patients with disabling low back pain reported an unfavorable outcome at one-year follow-up compared to those with predominantly sciatica. If additionally a clear herniated disc with nerve root compression on MRI was absent, the results were even worse. Copyright