Poly-pathway model approach: Simulation of multiple metabolic states

Animal cell lines have a complex and flexible metabolism and can display varied metabolic behavior depending on the culture conditions. A model that simulate and predict these variations would be a precious tool in the development of media, feeds or processes. However, in order to function as a predictive tool such a model has to describe the multiple metabolic states that can occur for a variety of conditions. This leads to the challenge of identifying a flexible model structure of relevant metabolic pathways and kinetics. To address this challenge, we have introduced the poly-pathway model approach aiming at capturing multiple metabolic states in one single model. The approach assumes that the cells modulate their metabolism by using metabolic pathways in different combinations in response to external stimuli, e.g., to compensate for nutrient depletion or by-product accumulation. Each pathway is represented by a macro-reaction obtained via elementary flux mode (EFM) analysis of a metabolic network, and modeled by a kinetic equation e.g., Michaelis-Menten type kinetic equations. The model is identified using rich information, e.g., experimental data obtained from parallel cultures of a CHO cell line subjected to depletion and abundance of amino acids. The measurements are limited to cell and extracellular metabolite concentrations obtained by analytical techniques achievable in most laboratories. For simplified networks, all possible EFMs can be found by enumeration. Such a priori simplifications may however exclude relevant macro-reactions from the set. Meanwhile, enumeration becomes prohibitive with increasing network complexity. To solve this issue, we have developed new mathematical algorithms that identify reduced sets of macro-reactions relevant to experimental data [1]. For the present work, we applied these algorithms to derive macro-reactions from complex metabolic networks for which complete enumeration is prohibitive. We also extended the kinetic equations to account for saturation and inhibition effects imposed by medium components and by-products. By using macro-reactions from a combination of complex networks together with the extended kinetics, the poly-pathway model achieved an excellent fit between simulated and experimental data and could accurately simulate the variations in growth and metabolic uptake/secretion rates for different metabolic states

The Cost Effectiveness of Levodopa-Carbidopa Intestinal Gel in the Treatment of Advanced Parkinson’s Disease in England

Background: Parkinson’s disease is a progressive neurodegenerative disease, which significantly impacts patients’ quality of life and is associated with high treatment and direct healthcare costs. In England, levodopa/carbidopa intestinal gel (LCIG) is indicated for the treatment of levodopa-responsive advanced Parkinson’s disease with troublesome motor fluctuations when available combinations of medicinal products are unsatisfactory. Objective: We aimed to determine the cost effectiveness of LCIG compared to the standard of care for patients with advanced Parkinson’s disease in England, using real-world data. Methods: A Markov model was adapted from previous published studies, using the perspective of the English National Health System and Personal and Social Services to evaluate the cost effectiveness of LCIG compared to standard of care in patients with advanced Parkinson’s disease over a 20-year time horizon. The model comprised 25 health states, defined by a combination of the Hoehn and Yahr scale, and waking time spent in OFF-time. The base case considered an initial cohort of patients with an Hoehn and Yahr score of ≥ 3, and > 4 h OFF-time. Standard of care comprised standard oral therapies, and a proportion of patients were assumed to be treated with subcutaneous apomorphine infusion or injection in addition to oral therapies. Efficacy inputs were based on LCIG clinical trials where possible. Resource use and utility values were based on results of a large-scale observational study, and costs were derived from the latest published UK data, valued at 2017 prices. The EuroQol five-dimensions-3-level (EQ-5D-3L) instrument was used to measure utilities. Costs and quality-adjusted life-years were discounted at 3.5%. Both deterministic and probabilistic sensitivity analyses were conducted. Results: Total costs and quality-adjusted life-years gained for LCIG vs standard of care were £586,832 vs £554,022, and 2.82 vs 1.43, respectively. The incremental cost-effectiveness ratio for LCIG compared to standard of care was £23,649/quality-adjusted life-year. Results were sensitive to the healthcare resource utilisation based on real-world data, and long-term efficacy of LCIG. Conclusions: The base-case incremental cost-effectiveness ratio was estimated to be within the acceptable thresholds for cost effectiveness considered for England

Soil carbon loss in warmed subarctic grasslands is rapid and restricted to topsoil

Global warming may lead to carbon transfers from soils to the atmosphere, yet this positive feedback to the climate system remains highly uncertain, especially in subsoils (Ilyina and Friedlingstein, 2016; Shi et al., 2018). Using natural geothermal soil warming gradients of up to +6.4 degrees C in subarctic grasslands (Sigurdsson et al., 2016), we show that soil organic carbon (SOC) stocks decline strongly and linearly with warming (-2.8 t ha(-1) degrees C-1). Comparison of SOC stock changes following medium-term (5 and 10 years) and long-term (> 50 years) warming revealed that all SOC stock reduction occurred within the first 5 years of warming, after which continued warming no longer reduced SOC stocks. This rapid equilibration of SOC observed in Andosol suggests a critical role for ecosystem adaptations to warming and could imply short-lived soil carbon-climate feedbacks. Our data further revealed that the soil C loss occurred in all aggregate size fractions and that SOC stock reduction was only visible in topsoil (0-10 cm). SOC stocks in subsoil (10-30 cm), where plant roots were absent, showed apparent conservation after > 50 years of warming. The observed depth-dependent warming responses indicate that explicit vertical resolution is a prerequisite for global models to accurately project future SOC stocks for this soil type and should be investigated for soils with other mineralogies

Supply Chain Resilience in Finnish Grocery Industry during COVID-19

The COVID-19 outbreak subjected grocery supply chains to exceptional disruptions with consumer panic buying, demand shift to online channels, logistic bottlenecks, and supply shortages. Despite these simultaneous shocks, grocery supply chains were able to swiftly recover their balance and performance by activating various response strategies. These resilience-increasing strategies have been documented in qualitative research. This research uses system dynamics modeling to quantitively assess these response strategies in light of multiple real-life demand scenarios. The most impactful response actions are outlined and linked to corresponding supply chain disruption. The optimal combination of strategies is also discussed. The simulation results indicate that the optimal response strategy depends on the demand scenario. For supply chains experiencing a severe drop in demand, preventing destocking and increasing information sharing leads to the highest resilience. For supply chains experiencing demand increase, the combination of increased information sharing and the ability to increase production capacity derives the most resilient outcome. Finally, managerial implications are discussed, and a design for a pandemic resilient supply chain is proposed

Laparoscopic management of achalasia

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldCardiomyotomy for achalasia is one of the ideal procedures for the video endoscopic approach. Magnification of the operative field during laparoscopic surgery allows precise division of the muscle fibers with excellent results. The number of reports on cardiomyotomy performed with laparoscopic (and thoracoscopic) access is growing. They all show the same excellent results as for conventional (open) myotomy, with minimal morbidity, short hospital stay, and early return to routine activity

Selfoss Declaration Achievements Report

This report reflects on the achievements of the Selfoss Declaration on sustainable forestry in the Nordic region, made in 2008 by the Ministers of Forestry in the Nordic countries and the following reccommendations on how to implement the intention of the declaration. The question is, did the forestry sector focus on the resolution acknowledged by the forestry ministers in the Declaration, and furthermore, how did it affect the forestry sector in the Nordic countries. The Selfoss Declaration initiated a lot of activities, financed with funds from the Nordic Council of Ministers and incisive actions in organizing the forest research cooperation across national boundaries within the Nordic neighbouring countries. Based on this experience, it seems important that the forestry ministers continue to take an active part in visualizing where Nordic cooperation should head in the future