Brain energy metabolism is optimized to minimize the cost of enzyme synthesis and transport.

The energy metabolism of the brain is poorly understood partly due to the complex morphology of neurons and fluctuations in ATP demand over time. To investigate this, we used metabolic models that estimate enzyme usage per pathway, enzyme utilization over time, and enzyme transportation to evaluate how these parameters and processes affect ATP costs for enzyme synthesis and transportation. Our models show that the total enzyme maintenance energy expenditure of the human body depends on how glycolysis and mitochondrial respiration are distributed both across and within cell types in the brain. We suggest that brain metabolism is optimized to minimize the ATP maintenance cost by distributing the different ATP generation pathways in an advantageous way across cell types and potentially also across synapses within the same cell. Our models support this hypothesis by predicting export of lactate from both neurons and astrocytes during peak ATP demand, reproducing results from experimental measurements reported in the literature. Furthermore, our models provide potential explanation for parts of the astrocyte-neuron lactate shuttle theory, which is recapitulated under some conditions in the brain, while contradicting other aspects of the theory. We conclude that enzyme usage per pathway, enzyme utilization over time, and enzyme transportation are important factors for defining the optimal distribution of ATP production pathways, opening a broad avenue to explore in brain metabolism.

Economic analyses in cardiac electrophysiology: from clinical efficacy to cost utility.

Cardiac electrophysiology is an evolving field that relies heavily on costly device- and catheter-based technologies. An increasing number of patients with heart rhythm disorders are becoming eligible for cardiac interventions, not least due to the rising prevalence of atrial fibrillation and increased longevity in the population. Meanwhile, the expansive costs of healthcare face finite societal resources, and a cost-conscious approach to new technologies is critical. Cost-effectiveness analyses support rational decision-making in healthcare by evaluating the ratio of healthcare costs to health benefits for competing therapies. They may, however, be subject to significant uncertainty and bias. This paper aims to introduce the basic concepts, framework, and limitations of cost-effectiveness analyses to clinicians including recent examples from clinical electrophysiology and device therapy.

Easy and reliable assessment of the prevalence of porcine post-weaning diarrhoea.

Post-weaning diarrhoea is a condition of increasing importance due to recent restrictions and bans on the preventive use of antimicrobials and medicinal zinc oxide. For various purposes, it is valuable to monitor the occurrence of post-weaning diarrhoea. The aim of this paper was to propose a protocol for easy and reliable assessment of the prevalence of post-weaning diarrhoea within a section of pigs as an alternative to clinical examination of a random sample of pigs. Two datasets were collected in two different observational field investigations, including more than 4000 individual clinical examinations of newly weaned pigs. First we identified a clinical marker for post-weaning diarrhoea. Second, we drew samples by simulation from our two dataset using different simplified sampling strategies and compared these to conventional random sampling strategies. The prediction error for estimates of the diarrhoea prevalence within a section was compared for the different sampling strategies. The study showed that pigs with diarrhoea had an increased risk of displaying diarrheic soiling of the hind part as well as dull, long, and bristly hair coat, and possibly also hollow flanks and a suboptimal body condition score. Diarrheic soiling of the hind part was the best clinical predictor of diarrhoea; our best estimate of the diagnostic sensitivity was 76.1% (95% credible interval: 72.0, 79.8), and the specificity was 97.1% (95% credible interval: 96.5 0.97.7). Diarrheic soiling of the hind is only a valid clinical predictor of diarrhoea for the first 14 days after insertion into the nursery unit. The precision and accuracy of prevalence estimates were similar for haphazard sampling compared to random sampling of the pigs. Likewise, sampling from a restricted number of pens produced prediction errors similar to sampling across all pens. Yet, the study had limitations regarding sample sizes, and furthermore it is difficult to provide certainty for absence of effects. We recommend sampling pigs haphazardly within at least three randomly selected pens for post-weaning diarrhoea prevalence surveys in order to easily obtain a reliable prevalence estimate. Based on our findings, we conclude the paper by proposing a simple four-step protocol for surveys of the within-section prevalence of post-weaning diarrhoea.

Cost-effectiveness of an antibacterial envelope for infection prevention in patients undergoing cardiac resynchronization therapy reoperations in Denmark.

AIMS: Use of an absorbable antibacterial envelope during implantation prevents cardiac implantable electronic device infections in patients with a moderate-to-high infection risk. Previous studies demonstrated that an envelope is cost-effective in high-risk patients within German, Italian, and English healthcare systems, but these analyses were based on limited data and may not be generalizable to other healthcare settings. METHODS AND RESULTS: A previously published decision-tree-based cost-effectiveness model was used to compare the costs per quality-adjusted life year (QALY) associated with adjunctive use of an antibacterial envelope for infection prevention compared to standard-of-care intravenous antibiotics. The model was adapted using data from a Danish observational two-centre cohort study that investigated infection-risk patients undergoing cardiac resynchronization therapy (CRT) reoperations with and without an antibacterial envelope (n = 1943). We assumed a cost-effectiveness threshold of €34 125/QALY gained, based on the upper threshold used by the National Institute for Health and Care Excellence (£30 000). An antibacterial envelope was associated with an incremental cost-effectiveness ratio (ICER) of €12 022 per QALY in patients undergoing CRT reoperations, thus indicating that the envelope is cost-effective when compared with standard of care. A separate analysis stratified by device type showed ICERS of €6227 (CRT defibrillator) and €29 177 (CRT pacemaker) per QALY gained. CONCLUSIONS: Cost-effectiveness ratios were favourable for patients undergoing CRT reoperations in the Danish healthcare system, and thus are in line with previous studies. Results from this study can contribute to making the technology available to Danish patients and align preventive efforts in the pacemaker and ICD area.

Yeast has evolved to minimize protein resource cost for synthesizing amino acids.

Proteins, as essential biomolecules, account for a large fraction of cell mass, and thus the synthesis of the complete set of proteins (i.e., the proteome) represents a substantial part of the cellular resource budget. Therefore, cells might be under selective pressures to optimize the resource costs for protein synthesis, particularly the biosynthesis of the 20 proteinogenic amino acids. Previous studies showed that less energetically costly amino acids are more abundant in the proteomes of bacteria that survive under energy-limited conditions, but the energy cost of synthesizing amino acids was reported to be weakly associated with the amino acid usage in Saccharomyces cerevisiae Here we present a modeling framework to estimate the protein cost of synthesizing each amino acid (i.e., the protein mass required for supporting one unit of amino acid biosynthetic flux) and the glucose cost (i.e., the glucose consumed per amino acid synthesized). We show that the logarithms of the relative abundances of amino acids in S. cerevisiae's proteome correlate well with the protein costs of synthesizing amino acids (Pearson's r = -0.89), which is better than that with the glucose costs (Pearson's r = -0.5). Therefore, we demonstrate that S. cerevisiae tends to minimize protein resource, rather than glucose or energy, for synthesizing amino acids.

Quantitative MRI and Clinical Assessment of Muscle Function in Adults With Cerebral Palsy.

Aim: To relate quantitative magnetic resonance imaging (MRI) of ankle plantar flexor muscles to clinical functional tests in adults with cerebral palsy (CP) and neurologically intact (NI) adults. Methods: Eleven adults with CP (aged 41 ± 12, GMFCS level I-II) and 11 NI adults (aged 35 ± 10) participated in this case-control study. We used MRI to assess muscle volume and composition of the triceps surae muscles. We quantified muscle function as maximal voluntary plantarflexion (MVC) torque and countermovement jump (CMJ) height. Results: Compared to NI adults, the MRI intramuscular fat fraction estimate was significantly higher and MRI muscle volume and functional abilities (MVC and CMJ) significantly lower in adults with CP. In NI adults, but not adults with CP, MRI muscle volume correlated significantly with MVC and CMJ. In adults with CP, the estimate of intramuscular fat levels correlated significantly with jump height in a CMJ. Discussion: This study shows reduced muscle volume and altered muscle composition in adults with CP. Muscle composition appears to provide a better marker than muscle volume of reduced muscle function and impaired performance in this population. Measurements of muscle composition could be used in the assessment of neuromuscular impairments and in the determination of rehabilitation protocols in individuals with neurological disorders.

COpenhagen Neuroplastic TRaining Against Contractures in Toddlers (CONTRACT): protocol of an open-label randomised clinical trial with blinded assessment for prevention of contractures in infants with high risk of cerebral palsy.

INTRODUCTION: Contractures are frequent causes of reduced mobility in children with cerebral palsy (CP) already at the age of 2-3 years. Reduced muscle use and muscle growth have been suggested as key factors in the development of contractures, suggesting that effective early prevention may have to involve stimuli that can facilitate muscle growth before the age of 1 year. The present study protocol was developed to assess the effectiveness of an early multicomponent intervention, CONTRACT, involving family-oriented and supervised home-based training, diet and electrical muscle stimulation directed at facilitating muscle growth and thus reduce the risk of contractures in children at high risk of CP compared with standard care. METHODS AND ANALYSIS: A two-group, parallel, open-label randomised clinical trial with blinded assessment (n=50) will be conducted. Infants diagnosed with CP or designated at high risk of CP based on abnormal neuroimaging or absent fidgety movement determined as part of General Movement Assessment, age 9-17 weeks corrected age (CA) will be recruited. A balanced 1:1 randomisation will be made by a computer. The intervention will last for 6 months aiming to support parents in providing daily individualised, goal-directed activities and primarily in lower legs that may stimulate their child to move more and increase muscle growth. Guidance and education of the parents regarding the nutritional benefits of docosahexaenic acid (DHA) and vitamin D for the developing brain and muscle growth will be provided. Infants will receive DHA drops as nutritional supplements and neuromuscular stimulation to facilitate muscle growth. The control group will receive standard care as offered by their local hospital or community. Outcome measures will be taken at 9, 12, 18, 24, 36 and 48 months CA. Primary and secondary outcome measure will be lower leg muscle volume and stiffness of the triceps surae musculotendinous unit together with infant motor profile, respectively. ETHICS AND DISSEMINATION: Full approval from the local ethics committee, Danish Committee System on Health Research Ethics, Region H (H-19041562). Experimental procedures conform with the Declaration of Helsinki. TRIAL REGISTRATION NUMBER: NCT04250454. EXPECTED RECRUITMENT PERIOD: 1 January 2021-1 January 2025.

Risk of Cardiac Implantable Electronic Device Malfunctioning During Pencil Beam Proton Scanning in an In Vitro Setting.

PURPOSE: Cardiac implantable electronic devices (CIED) are sensitive to scattered secondary neutrons from proton beam irradiation. This experimental in vitro study investigated risk of CIED errors during pencil beam proton therapy. METHODS AND MATERIALS: We used 62 explanted CIEDs from 4 manufacturers; 49 CIEDs were subjected to a simulated clinical protocol with daily 2 Gy relative biological effectiveness fractions prescribed to the phantom. Devices were located at 3 different lateral distances from the spread-out Bragg peak to investigate the risk of permanent or temporary device errors. Additionally, 13 devices with leads connected were monitored live during consecutive irradiations to investigate the risk of noise, over- or undersense, pace inhibition, and inappropriate shock therapy. RESULTS: We detected 61 reset errors in 1728 fractions, and all except 1 CIED were reprogrammed to normal function. All, except 1 reset, occurred in devices from the same manufacturer. These were successfully reprogrammed to normal function. The 1 remaining CIED was locked in permanent safety mode. Secondary neutron dose, as estimated by Monte Carlo simulations, was found to significantly increase the odds of CIED resets by 55% per mSv. Clinically significant battery depletion was observed in 5 devices. We observed no noise, over- or undersense, pace inhibition, or inappropriate shock therapy during 362 fractions of live monitoring. CONCLUSIONS: Reprogrammable CIED reset was the most commonly observed malfunction during proton therapy, and reset risk depended on secondary neutron exposure. The benefits of proton therapy are expected to outweigh the risk of CIED malfunctioning for most patients.

A Caching Scheme To Accelerate Kinetic Monte Carlo Simulations of Catalytic Reactions.

Kinetic Monte Carlo (KMC) simulations have been instrumental in advancing our fundamental understanding of heterogeneously catalyzed reactions, with particular emphasis on structure sensitivity, ensemble effects, and the interplay between adlayer structure and adsorbate-adsorbate lateral interactions in shaping the observed kinetics. Yet, the computational cost of KMC remains high, thereby motivating the development of acceleration schemes that would improve the simulation efficiency. We present an exact such scheme, which implements a caching algorithm along with shared-memory parallelization to improve the computational performance of simulations incorporating long-range adsorbate-adsorbate lateral interactions. This scheme is based on caching information about the energetic interaction patterns associated with the products of each possible lattice process (adsorption, desorption, reaction etc.). Thus, every time a reaction occurs ("ongoing reaction"), it enables fast updates of the rate constants of "affected reactions", i.e., possible reactions in the region of influence of the "ongoing reaction". Benchmarks on KMC simulations of NOx oxidation/reduction, yielded acceleration factors of up to 20, when comparing single-thread runs without caching to runs on 16 threads with caching, for simulations with a cluster expansion Hamiltonian that incorporates up to 8th-nearest-neighbor interactions.

Genome-scale reconstructions of the mammalian secretory pathway predict metabolic costs and limitations of protein secretion.

In mammalian cells, >25% of synthesized proteins are exported through the secretory pathway. The pathway complexity, however, obfuscates its impact on the secretion of different proteins. Unraveling its impact on diverse proteins is particularly important for biopharmaceutical production. Here we delineate the core secretory pathway functions and integrate them with genome-scale metabolic reconstructions of human, mouse, and Chinese hamster ovary cells. The resulting reconstructions enable the computation of energetic costs and machinery demands of each secreted protein. By integrating additional omics data, we find that highly secretory cells have adapted to reduce expression and secretion of other expensive host cell proteins. Furthermore, we predict metabolic costs and maximum productivities of biotherapeutic proteins and identify protein features that most significantly impact protein secretion. Finally, the model successfully predicts the increase in secretion of a monoclonal antibody after silencing a highly expressed selection marker. This work represents a knowledgebase of the mammalian secretory pathway that serves as a novel tool for systems biotechnology.

Data for long-term marginal abatement cost curves of non-CO2 greenhouse gases.

This dataset represents long-term marginal abatement cost (MAC) curves of all major emission sources of non-CO2 greenhouse gases (GHGs); methane (CH4), nitrous oxide (N2O) and fluorinated gases (HFCs, PFCs and SF6). The work is based on existing short-term MAC curve datasets and recent literature on individual mitigation measures. The data represent a comprehensive set of MAC curves, covering all major non-CO2 emission sources for 26 aggregated world regions. They are suitable for long-term global mitigation scenario development, as dynamical elements (technological progress, removal of implementation barriers) are included. The data is related to the research article: "Long-term marginal abatement cost curves of non-CO 2 greenhouse gases" [1].

Harnessing xylose pathways for biofuels production.

Energy security, environmental pollution, and economic development drive the development of alternatives to fossil fuels as an urgent global priority. Lignocellulosic biomass has the potential to contribute to meeting the demand for biofuel production via hydrolysis and fermentation of released sugars, such as glucose, xylose, and arabinose. Construction of robust cell factories requires introducing and rewiring of their metabolism to efficiently use all these sugars. Here, we review recent advances in re-constructing pathways for metabolism of pentoses, with special focus on xylose metabolism in the most widely used cell factories Saccharomyces cerevisiae and Escherichia coli. We also highlight engineering advanced biofuels-synthesis pathways and describes progress toward overcoming the challenges facing adoption of large-scale biofuel production.

Effect of ecological momentary assessment, goal-setting and personalized phone-calls on adherence to interval walking training using the InterWalk application among patients with type 2 diabetes-A pilot randomized controlled trial.

OBJECTIVES: The objective was to investigate the feasibility and usability of electronic momentary assessment, goal-setting and personalized phone-calls on adherence to a 12-week self-conducted interval walking training (IWT) program, delivered by the InterWalk smartphone among patients with type 2 diabetes (T2D). METHODS: In a two-arm pilot randomized controlled trial (Denmark, March 2014 to February 2015), patients with T2D (18-80 years with a Body Mass Index of 18 and 40 kg/m2) were randomly allocated to 12 weeks of IWT with (experimental) or without additional support (control). The primary outcome was the difference between groups in accumulated time of interval walking training across 12 weeks. All patients were encouraged to use the InterWalk application to perform IWT for ≥90 minute/week. Patients in the experimental group made individual goals regarding lifestyle change. Once a week inquiries about exercise adherence was made using an ecological momentary assessment (EMA). In case of consistent self-reported non-adherence, the patients would receive a phone-call inquiring about the reason for non-adherence. The control group did not receive additional support. Information about training adherence was assessed objectively. Usability of the EMA was assessed based on response rates and self-reported satisfaction after 12-weeks. RESULTS: Thirty-seven patients with T2D (66 years, 65% female, hemoglobin 1Ac 50.3 mmol/mol) where included (n = 18 and n = 19 in experimental and control group, respectively). The retention rate was 83%. The experimental group accumulated [95%CI] 345 [-7, 698] minutes of IWT more than the control group. The response rate for the text-messages was 83% (68% for males and 90% for females). Forty-one percent of the experimental and 25% of the control group were very satisfied with their participation. CONCLUSION: The combination inquiry about adherence using EMA, goal-setting with the possibility of follow-up phone calls are considered feasible interventions to attain training adherence when using the InterWalk app during a 12-week period in patients with T2D. Some uncertainty about the effect size of adherence remains. TRIAL REGISTRATION: Clinicaltrials.gov NCT02089477.