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The relationship between a performer’s conscious involvement or investment in movement control and monitoring and the ability to inhibit the movement is still unclear. We conducted three experiments to investigate whether a higher inclination for conscious movement investment benefits the inhibition of a simple keypress response. In all experiments, the inclination for conscious movement investment was measured with the Movement-Specific Reinvestment Scale. In Experiment 1, participants performed the go/no-go task and conscious investment was manipulated by directing conscious attention either to the finger movement (i.e., internal focus) or to the resulting motion of the key (i.e., external focus). The results showed that neither the participants’ inclination for conscious movement investment, nor the direction of conscious attention affected inhibition performance. In Experiment 2, participants performed the stop-signal task, which is more attention demanding than the go/no-go task. The results showed that participants with a high or low inclination for conscious movement investment did not differ in inhibition performance. In Experiment 3 an ego-depletion procedure was included that limits resources for conscious movement investment. Before and after this ego-depletion procedure, participants performed the stop-signal task. The results showed that participants with a high inclination for conscious movement investment slowed down inhibition when they felt mentally depleted, while no slowing down of inhibition was found among participants who felt less depleted and/or had a low inclination for conscious movement investment. Together, the study provides evidence that increased conscious movement investment is beneficial for movement inhibition. Yet, these effects only emerge against the dynamic background of interacting individual (e.g., inclination for conscious movement investment, available attentional resources) and task constraints (e.g., task difficulty).

ObjectivePiperacillin/tazobactam (PIP/TAZ) is used for the treatment of lower respiratory tract bacterial infections in children. This study was performed to evaluate if the current dosing regimen results in therapeutic drug concentrations.Patients and methodsPatients suspected or proven to have lower respiratory tract bacterial infection and administrated PIP/TAZ intravenously for a duration of no less than 0.5 h, q6h–q12h daily, were enrolled. Blood samples were collected, and PIP concentrations were determined by high-performance liquid chromatography. The individual predicted concentration of PIP was evaluated using the individual empirical Bayesian estimate method. The evaluated PK/PD targets included (1) 70% time when the predicted free drug concentration exceeds the minimum inhibitory concentration (fT > MIC) and (2) 50% fT > 4× MIC. Probability of target attainment (PTA) was assessed by the proportion of patients who reached the PK/PD targets. The PIP concentrations between different groups of patients were compared.ResultsA total of 57 samples were collected from 57 patients with a median age of 2.26 years (0.17–12.58). For the PK/PD targets of 70% fT > MIC and 50% fT > 4× MIC for Pseudomonas aeruginosa and Klebsiella pneumoniae, the PTA was all 0. The median Cmin of PIP was significantly higher in infants than in children, and the median Cmin after administration in q8h was significantly higher than that after administration in q12h.ConclusionThe current dose regimen of PIP/TAZ leads to extremely low plasma concentrations in most children with lower respiratory tract bacterial infections. More optimized dosing regimens or better alternative therapies need to be further explored.

Systemic sclerosis (SSc) is a rare and heterogeneous disease with no relevant environmental trigger or significant responsible gene. It has been and will continue to be difficult to identify large enough patients to conduct classic population-based epidemiologic exposure/non-exposure studies with adequate power to ascertain environmental and genetic risk factors for these entities. The complexity of pathogenesis and heterogeneity are likely to require personalized/precision medicine for SSc. Since several potential drugs are currently available for specific patients if not whole SSc, classification of SSc seems to form the foundation for a better therapeutic strategy. To date, SSc has been classified based on the extent/severity of the affected area as well as some disease markers, including the autoantibody profile. However, such an analysis should also lead to improvements in the design of appropriately stratified clinical trials to determine the effects and prediction of targeted therapies. An approach based on drug response preclinically conducted using patients’ own fibroblasts in vitro, can provide a precise disease marker/therapeutic selection for clinical practice. Because scleroderma dermal fibroblasts have a persistent hyper-productive phenotype occurring not only in person, but also in cell culture conditions. Thus, an accumulating approach based on disease markers ensures progression and de-escalation to re-establish a better life with a personally optimized drug environment after the onset of SSc.

Soils are increasingly acknowledged as complex systems, with potential non-linear behaviors having important implications for ecosystem and Earth system dynamics, but soil models could improve adoption of analytical tools from the broader interdisciplinary field of complex systems. First- and new-generation soil models formulate many soil pools using first-order decomposition, which tends to generate simpler yet numerous parameters. Systems or complexity theory, developed across various scientific and social fields, may help improve robustness of soil models, by offering consistent assumptions about system openness, potential dynamic instability and distance from commonly assumed stable equilibria, as well as new analytical tools for formulating more generalized model structures that reduce parameter space and yield a wider array of possible model outcomes, such as quickly shrinking carbon stocks with pulsing or lagged respiration. This paper builds on recent perspectives of soil modeling to ask how various soil functions can be better understood by applying a complex systems lens. We synthesized previous literature reviews with concepts from non-linear dynamical systems in theoretical ecology and soil sciences more broadly to identify areas for further study that may help improve the robustness of soil models under the uncertainty of human activities and management. Three broad dynamical concepts were highlighted: soil variable memory or state-dependence, oscillations, and tipping points with hysteresis. These themes represent possible dynamics resulting from existing observations, such as reversibility of organo-mineral associations, dynamic aggregate- and pore hierarchies, persistent wet-dry cycles, higher-order microbial community and predator-prey interactions, cumulative legacy land use history, and social management interactions and/or cooperation. We discuss how these aspects may contribute useful analytical tools, metrics, and frameworks that help integrate the uncertainties in future soil states, ranging from micro-to regional scales. Overall, this study highlights the potential benefits of incorporating spatial heterogeneity and dynamic instabilities into future model representations of whole soil processes, and contributes to the field as a modern synthetic review that connects existing similar ideas across disciplines and highlights their implications for future work and potential findings. Additionally, it advocates for transdisciplinary collaborations between natural and social scientists, extending research into anthropedology and biogeosociochemistry.

BackgroundIt is desirable that (more) children continue swimming after having completed their swimming lessons to preserve their swimming skills and water safety, and as part of an active, healthy lifestyle. This may be encouraged by stirring children's intrinsic motivation for swimming during swimming lessons. However, it is currently unknown how intrinsically motivating swimming lessons are in Western countries.PurposeThis study examined to what extent swimming instructors in the Netherlands cater to the basic needs of autonomy, competence, and relatedness, which, according to Self-Determination Theory (SDT), promote intrinsic motivation. Additionally, it examined whether an SDT-based teaching program prompts instructors to better meet these needs, and to what extent the teaching program, the education and experience of the instructor, and the group size predict the employment of SDT in swimming lessons.MethodsA total of 128 swimming lessons given by equally many instructors were observed in the Netherlands and rated on a modified version of the SDT teaching style scale to assess autonomy, competence, and relatedness support. The swimming lessons referred to four teaching programs, one of which was explicitly based on SDT.ResultsInstructors exhibited autonomy-thwarting, weakly competence-supportive, and relatedness-supportive behaviors. The SDT-based teaching program scored higher on the provision of autonomy, competence, and relatedness in lessons. This finding was significant for autonomy. Teaching program was the only significant predictor of SDT employment by instructors.ConclusionFurther improvement is desirable in catering to the basic needs, particularly autonomy, which can be achieved by deliberately implementing the principles of SDT into teaching programs for swimming.

In studying circularity in the construction and demolition industry (CDI) in the EU, five projects in selected EU countries were compared to assess how the application of circularity achieved balance in the environment, social and economic dimensions of sustainability. The selected projects using secondary data based on a web search of these projects involved different stages of the circularity ladder, used diverse design principles, and focused on different stages of the construction life cycle, making them interesting comparators for applying circularity in CDI. For strong sustainability to exist, there should be a balance between the sustainability triptych covering environment, social and economic dimensions which is often overlooked in many circular and sustainability projects with an overemphasis on one dimension and disregard for another. Selected indicators for the three dimensions included those found in environmental impact and life cycle assessments for environmental criteria, social impact assessments for social criteria and economic feasibility, and project appraisal and evaluation reports for economic criteria. In weighting criteria, several methods exist comprising subjective, objective, and integrated techniques. The robustness of objective vs. subjective weights is rather debatable. The objective of the research is to test different weighting techniques using subjective and objective methods to determine if differences in project rankings exist in terms of sustainability balance. The ranking of projects and conclusions about best practices in the CDI circular economy could be influenced by the weighting techniques used. As the weighting of criteria could influence project outcomes, objectivity in weighting is often advised. However, in this study, computational comparisons indicated that subjective methods do not significantly differ from objective ones that use mathematical and statistical rigor. As such, subjective weighting methods still conveniently capture credible and consistent results. Nonetheless, this should not detract from efforts to objectify weighting methods that lend more credence and justification to scoring and ranking results.

Background and objective: Causes for nasal airway obstruction (NAO) are many but septum deviation is the most prevalent etiology. A deviated septum affects the airflow dynamics in the human nasal cavity, which in turn affects the physiological functions of the nasal cavity like heating, humidification, and filtration capabilities. The present study investigates and compares the airflow patterns in a healthy nasal cavity to a septal deviated nasal cavity.Methods: Two nasal airway models are considered and compared in this study. One with a septal deviation and the second with a healthy patent nasal cavity. Airflow analysis is carried out by developing the CT scans into 3D models using Materialise MIMICS (Materialise, Ann Arbor, MI), and then using the FLUENT solver of ANSYS 2020R2. The simulations are carried out for airflows ranging in laminar and turbulent flows using the SST k-ω turbulence model. Polyhedral meshes are used and the mesh check using Grid Convergence Index studies is adopted.Results: The pressure and velocity profiles are assessed for a wide range of mass flow rates. The results indicate a turbulent flow pattern for mass flow rates over 15 LPM. The velocity profiles show aberrated flow profiles in a septal deviated nasal cavity where the peak velocity is observed at the mid-nasal region rather than the nasal valve region. There was a 38% to 55% higher nasal resistance in the septal deviated nasal cavity as compared to a normal and healthy nasal cavity. The pressure drop in the septal deviated nasal cavity is higher by 60%–120% when compared to a healthy nasal cavity.Conclusion: The septal deviated nasal cavity greatly affects the nasal airflow distribution resulting in higher velocities in the mid-nasal region, increased pressure drop and higher nasal resistance. Hence the NAO with septal deviation has to be rectified with proper surgical procedures.

Plants produce the volatile hormone ethylene to regulate many developmental processes and to deal with (a)biotic stressors. In seed plants, ethylene is synthesized from 1-aminocyclopropane-1-carboxylic acid (ACC) by the dedicated enzyme ACC oxidase (ACO). Ethylene biosynthesis is tightly regulated at the level of ACC through ACC synthesis, conjugation and transport. ACC is a non-proteinogenic amino acid, which also has signaling roles independent from ethylene. In this work, we investigated the biological function of an uncharacterized ACC dipeptide. The custom-synthesized di-ACC molecule can be taken up by Arabidopsis in a similar way as ACC, in part via Lysine Histidine Transporters (e.g., LHT1). Using Nano-Particle Assisted Laser Desoprtion/Ionization (Nano-PALDI) mass-spectrometry imaging, we revealed that externally fed di-ACC predominantly localizes to the vasculature tissue, despite it not being detectable in control hypocotyl segments. Once taken up, the ACC dimer can evoke a triple response phenotype in dark-grown seedlings, reminiscent of ethylene responses induced by ACC itself, albeit less efficiently compared to ACC. Di-ACC does not act via ACC-signaling, but operates via the known ethylene signaling pathway. In vitro ACO activity and molecular docking showed that di-ACC can be used as an alternative substrate by ACO to form ethylene. The promiscuous nature of ACO for the ACC dimer also explains the higher ethylene production rates observed in planta, although this reaction occurred less efficiently compared to ACC. Overall, the ACC dipeptide seems to be transported and converted into ethylene in a similar way as ACC, and is able to augment ethylene production levels and induce subsequent ethylene responses in Arabidopsis.

Objective: The perspective of real-world study is especially relevant to newborns, enabling dosage regimen optimization and regulatory approval of medications for use in newborns. The aim of the present study was to conduct a pharmacokinetic analysis of cefotaxime and evaluate the dosage used in newborns with early-onset sepsis (EOS) using real-world data in order to support the rational use in the clinical practice.Methods: This prospective, open-label study was performed in newborns with EOS. A developmental pharmacokinetic-pharmacodynamic model of cefotaxime in EOS patients was established based on an opportunistic sampling method. Then, clinical evaluation of cefotaxime was conducted in newborns with EOS using real-world data.Results: A one-compartment model with first-order elimination was developed, using 101 cefotaxime concentrations derived from 51 neonates (30.1–41.3°C weeks postmenstrual age), combining current weight and postnatal age. The pharmacokinetic-pharmacodynamic target was defined as the free cefotaxime concentration above MIC during 70% of the dosing interval (70% fT > MIC), and 100% of neonates receiving the dose of 50 mg/kg, BID attained the target evaluated using the model. Additionally, only two newborns had adverse reactions possibly related to cefotaxime treatment, including diarrhea and feeding intolerance.Conclusion: This prospective real-world study demonstrated that cefotaxime (50 mg/kg, BID) had a favorable efficacy and an accepted safety profile for neonates with EOS.

Background: There is emphasis on timely administration of thrombolysis and clot retrieval but not antithrombotic therapy within 48 h for ischemic stroke (frequency of 64% in Australia and 97% in North America). We planned to assess the time metrics and variables associated with delaying antithrombotics (antiplatelet and anticoagulant therapy) administration.Methods: This was a retrospective study at Monash Health over 12 months in 2015. We plotted the cumulative event and mapped the key drivers (dimensionless variable Shapley value/SV) of antithrombotics.Results: There were 42 patients with transient ischemic attack/TIA and 483 with ischemic stroke [mean age was 71.8 ± 15.4; 56.0% male; nil by mouth (NBM) 74.5 and 49.3% of patients received “stat” (immediate and one off) dose antithrombotics]. The median time to imaging for the patients who did not have stroke code activated was 2.3 h (IQR 1.4–3.7), from imaging to dysphagia screen was 14.6 h (IQR 6.2–20.3), and from stopping NBM to antithrombotics was 1.7 h (IQR 0–16.5). TIA patients received antithrombotics earlier than those with ischemic stroke (90.5 vs. 86.5%, p = 0.01). Significant variables in regression analysis for time to antithrombotics were time to dysphagia screen (β 0.20 ± 0.03, SV = 3.2), nasogastric tube (β 19.8 ± 5.9, SV = −0.20), Alteplase (β 8.6 ± 3.6, SV = −1.9), stat dose antithrombotic (β −18.9 ± 2.9, SV = −10.8) and stroke code (β −5.9 ± 2.5, SV = 2.8). The partial correlation network showed that the time to antithrombotics increased with delay in dysphagia screen (coefficient = 0.33) and decreased if “stat” dose of antithrombotics was given (coefficient = −0.32).Conclusion: The proportion of patients receiving antithrombotics within 48 h was higher than previously reported in Australia but remained lower than the standard achieved in North American hospitals. Our process map and network analysis show avenues to shorten the time to antithrombotic.

Cross-education is the phenomenon in which repeated practice of a unilateral motor task does not only result in performance improvement of the trained limb, but also in the untrained contralateral limb. The aim of this study was to test whether cross-education or positive transfer of learning is also achieved for tasks in which both limbs contribute in different ways by using modified equipment that switches the limbs’ role. To this end, a reverse field hockey stick was used that requires a mirroring of arm and hand use and dominance (i.e., right hand on top of the hockey stick instead of the left hand). Two groups of young skilled female field hockey players participated in a crossover-design, in which participants received four training sessions with a reverse hockey stick followed by four training sessions with a regular hockey stick, or vice versa. In a pre-test, intermediate test (following the first intervention period), a post-test (after the second intervention period) and a retention test, participants’ performance on a field hockey skill test with a regular hockey stick was measured. The results revealed that training with the reversed hockey stick led to significantly increased improvements compared to training with a regular hockey stick. We conclude that modified equipment can be used to exploit positive transfer of learning by switching the limbs’ roles. The findings are discussed by referring to the symmetry preservation principle in dynamic systems theory and have clear practical relevance for field hockey trainers and players seeking to further improve field hockey skills.

Research in penalty kicking has primarily focused on spatial decision making, while temporal decision making has largely been neglected, even though it is as critical for success. Temporal decision making concerns goalkeepers choosing when to initiate their jump to the ball during the penalty taker's run-up (i.e., jump early or wait long), and penalty takers deciding where to kick the ball, either prior to the run-up or after the goalkeeper has committed to one side. We analyzed penalty takers' and goalkeepers' behavior during penalty shoot-outs at FIFA World Cups and UEFA European Championships to scrutinize if temporal aspects of decision making have an impact on penalty kick success. Results indicate that the likelihood of a penalty kick being scored depends on the combination of penalty takers' and goalkeepers' temporal decision-making strategies. Hence, moving early more often seems fruitful for goalkeepers, while penalty takers should consider varying penalty kick strategy between attempts.

Objectives: Augmented renal clearance (ARC) of primarily renally eliminated antibacterial agents may result in subtherapeutic antibiotic concentrations and, as a consequence, worse clinical outcomes. Cefathiamidine is frequently used as empirical antimicrobial therapy in children with ARC, but pharmacokinetic studies in infants are lacking. This population pharmacokinetic study in infants with ARC was conducted to determine optimal dosing regimens of cefathiamidine.Methods: The population pharmacokinetics was conducted in 20 infants treated with cefathiamidine. Plasma samples of cefathiamidine were collected using opportunistic sampling, and the concentrations were detected by UPLC-MS/MS. Data analysis was performed to determine pharmacokinetic parameters and to characterize pharmacokinetic variability of cefathiamidine using nonlinear mixed effects modelling (NONMEM) software program.Results: The data (n = 36) from 20 infants (age range, 0.35–1.86 years) with ARC were fitted best with a 1-compartment model. Allometrically scaled weight and age as significant covariates influenced cefathiamidine pharmacokinetics. The median (range) values of estimated clearance and the volume of distribution were 0.22 (0.09–0.29) L/h/kg and 0.34 (0.24–0.41) L/kg, respectively. Monte Carlo simulations showed that the cefathiamidine doses of 100 mg/kg/day q12 h, 50 mg/kg/day q8 h and 75 mg/kg/day q6 h were chosen for bacteria with MIC 0.25, 0.5 and 2 mg/L, respectively.Conclusion: The population pharmacokinetic model of cefathiamidine for infants with ARC was developed. The PTA - based dosing regimens were recommended based on the final model.

Purpose: Serum creatinine (SCr) is used as a marker of kidney function to guide dosing of renally eliminated drugs. Serum Cystatin C (S-CysC) has been suggested as a more reliable kidney marker than SCr in adults and children. Purpose of this study was to investigate S-CysC as alternative renal marker to SCr for estimating vancomycin clearance in neonates undergoing intensive care.Methods: Vancomycin pharmacokinetics (PK), SCr and S-CysC data were collected in patients undergoing vancomycin treatment in the neonatal intensive care unit of Robert Debré Hospital - Paris. A population PK analysis was performed utilizing routine therapeutic drug monitoring samples. S-CysC and SCr were compared as covariates on vancomycin clearance using stepwise covariate modeling (forward inclusion [p < 0.05] and backward elimination [p < 0.01]). Model performance was evaluated by graphical and statistical criteria.Results: A total of 108 vancomycin concentrations from 66 patients (postmenstrual age [PMA] of 26–46 weeks) were modeled with an allometric one-compartment model. The median (range) values for SCr and S-CysC were 41 (12–153) µmol/l and 1.43 (0.95–2.83) mg/l, respectively. Following stepwise covariate model building, SCr was retained as single marker of kidney function (after accounting for weight and PMA) in the final model. Compared to the final model based on SCr, the alternative model based on S-CysC showed very similar performance (e.g. BIC of 578.3 vs. 576.4) but included one additional covariate: impact of mechanical ventilation on vancomycin clearance, in addition to the effects of size and maturation.Conclusion: ill neonates. However, if using S-CysC for this purpose mechanical ventilation needs to be taken into account.

Background: Recognizing a change in serum creatinine concentrations is useful to detect a renal adverse drug reaction signal. Assessing and characterizing the nephrotoxic side-effects of drugs in extremely low birth weight (ELBW, ≤1000 g) neonates remain challenging due to the high variability in creatinine in this population. This study aims to investigate and quantify the impact of ibuprofen treatment on kidney function, reflected by serum creatinine.Method: A recently developed dynamical model for serum creatinine was used to simulate creatinine profiles for typical, reference ELBW neonates with varying gestational and postnatal ages whilst being exposed to ibuprofen treatment.Results: The increase of serum creatinine concentrations due to ibuprofen treatment is most apparent during the first week of life. The difference in serum creatinine values between ibuprofen-exposed vs. non-exposed neonates decreases with increasing postnatal age, independent of gestational age.Conclusion: The difference in serum creatinine concentrations between ibuprofen-exposed vs. non-exposed neonates decreases with postnatal age, indicating an increased clearing capacity and resulting in a weak ibuprofen-related adverse drug reaction signal beyond early neonatal life.

The complement system comprises the frontline of the innate immune system. Triggered by pathogenic surface patterns in different pathways, the cascade concludes with the formation of a membrane attack complex (MAC; complement components C5b to C9) and C5a, a potent anaphylatoxin that elicits various inflammatory signals through binding to C5a receptor 1 (C5aR1). Despite its important role in pathogen elimination, priming and recruitment of myeloid cells from the immune system, as well as crosstalk with other physiological systems, inadvertent activation of the complement system can result in self-attack and overreaction in autoinflammatory diseases. Consequently, it constitutes an interesting target for specialized therapies. The paradigm of safe and efficacious terminal complement pathway inhibition has been demonstrated by the approval of eculizumab in paroxysmal nocturnal hematuria. In addition, complement contribution in rare kidney diseases, such as lupus nephritis, IgA nephropathy, atypical hemolytic uremic syndrome, C3 glomerulopathy, or antineutrophil cytoplasmic antibody-associated vasculitis has been demonstrated. This review summarizes the involvement of the terminal effector agents of the complement system in these diseases and provides an overview of inhibitors for complement components C5, C5a, C5aR1, and MAC that are currently in clinical development. Furthermore, a link between increased complement activity and lung damage in severe COVID-19 patients is discussed and the potential for use of complement inhibitors in COVID-19 is presented.

The use of additives in food products has become an important public health concern. In recent reports, dietary emulsifiers have been shown to affect the gut microbiota, contributing to a pro-inflammatory phenotype and metabolic syndrome. So far, it is not yet known whether similar microbiome shifts are observable for a more diverse set of emulsifier types and to what extent these effects vary with the unique features of an individual’s microbiome. To bridge this gap, we investigated the effect of five dietary emulsifiers on the fecal microbiota from 10 human individuals upon a 48 h exposure. Community structure was assessed with quantitative microbial profiling, functionality was evaluated by measuring fermentation metabolites, and pro-inflammatory properties were assessed with the phylogenetic prediction algorithm PICRUSt, together with a TLR5 reporter cell assay for flagellin. A comparison was made between two mainstream chemical emulsifiers (carboxymethylcellulose and P80), a natural extract (soy lecithin), and biotechnological emulsifiers (sophorolipids and rhamnolipids). While fecal microbiota responded in a donor-dependent manner to the different emulsifiers, profound differences between emulsifiers were observed. Rhamnolipids, sophorolipids, and soy lecithin eliminated 91 ± 0, 89 ± 1, and 87 ± 1% of the viable bacterial population after 48 h, yet they all selectively increased the proportional abundance of putative pathogens. Moreover, profound shifts in butyrate (−96 ± 6, −73 ± 24, and −34 ± 25%) and propionate (+13 ± 24, +88 ± 50, and +29 ± 16%) production were observed for these emulsifiers. Phylogenetic prediction indicated higher motility, which was, however, not confirmed by increased flagellin levels using the TLR5 reporter cell assay. We conclude that dietary emulsifiers can severely impact the gut microbiota, and this seems to be proportional to their emulsifying strength, rather than emulsifier type or origin. As biotechnological emulsifiers were especially more impactful than chemical emulsifiers, caution is warranted when considering them as more natural alternatives for clean label strategies.

Esters are important flavor and fragrance compounds that are present in many food and beverage products. Many of these esters are produced by yeasts and bacteria during fermentation. While ester production in yeasts through the alcohol acyl transferase reaction has been thoroughly investigated, ester production through alcoholysis has been completely neglected. Here, we further analyze the catalytic capacity of the yeast Eat1 enzyme and demonstrate that it also has alcoholysis and thiolysis activities. Eat1 can perform alcoholysis in an aqueous environment in vitro, accepting a wide range of alcohols (C2–C10) but only a small range of acyl donors (C2–C4). We show that alcoholysis occurs in vivo in several Crabtree negative yeast species but also in engineered Saccharomyces cerevisiae strains that overexpress Eat1 homologs. The alcoholysis activity of Eat1 was also used to upgrade ethyl esters to butyl esters in vivo by overexpressing Eat1 in Clostridium beijerinckii. Approximately 17 mM of butyl acetate and 0.3 mM of butyl butyrate could be produced following our approach. Remarkably, the in vitro alcoholysis activity is 445 times higher than the previously described alcohol acyl transferase activity. Thus, alcoholysis is likely to affect the ester generation, both quantitatively and qualitatively, in food and beverage production processes. Moreover, mastering the alcoholysis activity of Eat1 may give rise to the production of novel food and beverage products.

Carbapenem-resistant enterobacteriaceae (CRE) bloodstream infections have been rapidly spreading worldwide with a high mortality and pose a challenge to therapeutic decision-making, especially in premature neonates because insufficient empirical antimicrobial therapy is independently associated with high mortality. This case reported that a premature infant with CRE bloodstream infection was treated successfully with high-dose meropenem treatment with model-based therapeutic drug monitoring (TDM). In clinical settings, treatment target attainment of meropenem can be improved by increasing the frequency of administration, prolonging the infusion time, and using a high dose. This case report shows a successful regimen for CRE infection in a premature neonate and emphasizes the utility of model-based TDM of high-dose meropenem treatment. The adequate antimicrobial benefit provided by innovative techniques could ensure the efficacy and safety of high-dose meropenem therapy for CRE infection.

SpoIIE is a phosphatase involved in the activation of the first sigma factor of the forespore, σF, during sporulation. A ΔspoIIE mutant of Clostridium beijerinckii NCIMB 8052, previously generated by CRISPR-Cas9, did not sporulate but still produced granulose and solvents. Microscopy analysis also showed that the cells of the ΔspoIIE mutant are elongated with the presence of multiple septa. This observation suggests that in C. beijerinckii, SpoIIE is necessary for the completion of the sporulation process, as seen in Bacillus and Clostridium acetobutylicum. Moreover, when grown in reactors, the spoIIE mutant produced higher levels of solvents than the wild type strain. The impact of the spoIIE inactivation on gene transcription was assessed by comparative transcriptome analysis at three time points (4 h, 11 h and 23 h). Approximately 5% of the genes were differentially expressed in the mutant compared to the wild type strain at all time points. Out of those only 12% were known sporulation genes. As expected, the genes belonging to the regulon of the sporulation specific transcription factors (σF, σE, σG, σK) were strongly down-regulated in the mutant. Inactivation of spoIIE also caused differential expression of genes involved in various cell processes at each time point. Moreover, at 23 h, genes involved in butanol formation and tolerance, as well as in cell motility, were up-regulated in the mutant. In contrast, several genes involved in cell wall composition, oxidative stress and amino acid transport were down-regulated. These results indicate an intricate interdependence of sporulation and stationary phase cellular events in C. beijerinckii.

There are two interrelated issues that seem to be emerging as central to the understanding of ecological systems more generally, particularly relevant to agroecosystems. First is the key insights of Alan Turing in which spatial pattern emerges from a system in which there is a reaction between two objects, both of which are diffusing in space, a pest and its natural enemy, for example. Secondly, as small-scale farmers make complex decisions about their farm's ecosystem management, they are forced to contemplate market forces as much as the background ecology. This necessity automatically involves a time lag in that remuneration for produce is realized substantially after the decision to plant is made. Here, behavioral economics intersects with non-linear ecological dynamics to produce an expectation of chaotic patterns. It is suggested that these two core ideas, spatial dynamics (e.g., Turing's dynamic instability in space) and chaos (e.g., Simon's constrained rationality in farm decisions) form a qualitative theoretical foundation for understanding the ecology of agroecosystems.

Renal precision medicine in neonates is useful to support decision making on pharmacotherapy, signal detection of adverse (drug) events, and individual prediction of short- and long-term prognosis. To estimate kidney function or glomerular filtration rate (GFR), the most commonly measured and readily accessible biomarker is serum creatinine (Scr). However, there is extensive variability in Scr observations and GFR estimates within the neonatal population, because of developmental physiology and superimposed pathology. Furthermore, assay related differences still matter for Scr, but also exist for Cystatin C. Observations in extreme low birth weight (ELBW) and term asphyxiated neonates will illustrate how renal precision medicine contributes to neonatal precision medicine. When the Kidney Disease Improving Global Outcome (KDIGO) definition of acute kidney injury (AKI) is used, this results in an incidence up to 50% in ELBW neonates, associated with increased mortality and morbidity. However, urine output criteria needed adaptations to broader time intervals or weight trends, while Scr and its trends do not provide sufficient detail on kidney function between ELBW neonates. Instead, we suggest to use assay-specific centile Scr values to better describe postnatal trends and have illustrated its relevance by quantifying an adverse drug event (ibuprofen) and by explaining individual amikacin clearance. Term asphyxiated neonates also commonly display AKI. While oliguria is a specific AKI indicator, the majority of term asphyxiated cases are non-oliguric. Asphyxia results in a clinical significant—commonly transient—mean GFR decrease (−50%) with a lower renal drug elimination. But there is still major (unexplained) inter-individual variability in GFR and subsequent renal drug elimination between these asphyxiated neonates. Recently, the Baby-NINJA (nephrotoxic injury negated by just-in-time action) study provided evidence on the concept that a focus on nephrotoxic injury negation has a significant impact on AKI incidence and severity. It is hereby important to realize that follow-up should not be discontinued at discharge, as there are concerns about long-term renal outcome. These illustrations suggest that integration of renal (patho)physiology into neonatal precision medicine are an important tool to improve contemporary neonatal care, not only for the short-term but also with a positive health impact throughout life.

The structure of terrestrial landscapes is commonly viewed as a problem of statistical description defined by the number, size and distance between habitat patches. Yet, for organisms living in that landscape, structure may be perceived very differently depending on the dispersal capacity of the organism of concern—large animals may perceive a highly fragmented forest as a single patch if adjacent forest patches are sufficiently close, while small animals may be less likely to disperse across degraded habitat and therefore experience a much different patch structure. This is particularly relevant for fragmented landscapes like cities. Urban gardens are reputed to support a diversity of native and non-native urban species found in urban landscapes. Yet we know little about the long-term persistence of organisms associated with urban gardens. Here we utilize Taylor's law, a universal scaling law denoting a power law relationship between population size and variance to indicate the synchrony of arthropod populations sampled across time in a fragmented urban landscape. Our results indicate that the utility of urban gardens as habitat is strongly dependent on sampling month, spatial scale and taxon. Constrained dispersal across the landscape may limit the potential of urban gardens to conserve natural enemies including ladybird beetles and parasitoid wasps. In contrast, aphid pests are moving much more freely in the landscape as exhibited through synchrony in abundances sampled across local and landscape scales. We find that regardless of the fragmentation pattern existing in the landscape, short-ranged arthropods are isolated to small, independent garden habitat patches (metapopulation-like) with abundances that oscillate out of sync, while long-ranged species traverse greater distances, synchronizing abundances across large, shared spaces (source sink-like). These results suggest an inherent link between Taylor's temporal law and metapopulation theory, providing a potential mechanism to explain species-specific slopes of Taylor's law as arising from the ability of organisms to differentially experience fragmented space along the continuum between metapopulation and source-sink.

In mainstream or strong university education, the teacher selects and transmits knowledge and skills that students are to acquire and reproduce. Many researchers of radical embodied cognitive science still adhere to this way of teaching, even though this prescriptive pedagogy deeply contrasts with the theoretical underpinnings of their science. In this paper, we search for alternative ways of teaching that are more aligned with the central non-prescriptive and non-representational tenets of radical embodied cognitive science. To this end, we discuss recent views on education by Tim Ingold and Gert Biesta, which are based on Dewey’s philosophy of pragmatism and Gibsons’ ecological approach. The paper starts by introducing radical embodied cognitive science, particularly as it relates to motor skill learning, one of our prime interests in research and teaching. Next, we provide a synopsis and critique of the still dominant prescriptive and explicating pedagogy of strong education. Following Ingold and Biesta, we search for a weak alternative through a careful consideration of the education of attention and the participating teacher. To illustrate our arguments, we use examples of the first author’s teaching about/of motor skill learning. The paper is concluded by briefly considering the implications of weak education for a radical embodied science of motor skill learning.

This study addressed the question whether coaches better allow athletes to self-control their decisions when under pressure or whether to impose a decision upon them. To this end, an experiment was conducted that manipulated the soccer kickers’ degree of control in decision-making. Two groups of elite under-19 soccer players (n = 18) took penalty kicks in a self-controlled (i.e., kickers themselves decided to which side to direct the ball) and an externally controlled condition (i.e., the decision to which side to direct the ball was imposed upon the kickers). One group performed the penalty kick under psychological pressure (i.e., the present coaching staff assessed their performance), while the second group performed without pressure. Just before and after performing the kicks, CSAI-2 was used to measure cognitive and somatic anxiety and self-confidence. Further, the number of goals scored, ball placement and speed, and the duration of preparatory and performatory behaviors were determined. The results verified increased levels of cognitive and somatic anxiety after performing the kicks in the pressured group compared to the no-pressure group. In addition, degree of self-control affected the participants’ performance, particularly in the pressured group. They scored more goals and placed the kicks higher in the self-controlled than in the externally-controlled condition. Participants also took more time preparing and performing the run-up in the self-controlled condition. Findings indicate that increased self-control helps coping with the debilitating effects of pressure and can counter performance deteriorations. The findings are discussed within the framework of self-control theories, and recommendations for practitioners and athletes are made.

Esters are essential for the flavor and aroma of fermented products, and are mainly produced by alcohol acyl transferases (AATs). A recently discovered AAT family named Eat (Ethanol acetyltransferase) contributes to ethyl acetate synthesis in yeast. However, its effect on the synthesis of other esters is unknown. In this study, the role of the Eat family in ester synthesis was compared to that of other Saccharomyces cerevisiae AATs (Atf1p, Atf2p, Eht1p, and Eeb1p) in silico and in vivo. A genomic study in a collection of industrial S. cerevisiae strains showed that variation of the primary sequence of the AATs did not correlate with ester production. Fifteen members of the EAT family from nine yeast species were overexpressed in S. cerevisiae CEN.PK2-1D and were able to increase the production of acetate and propanoate esters. The role of Eat1p was then studied in more detail in S. cerevisiae CEN.PK2-1D by deleting EAT1 in various combinations with other known S. cerevisiae AATs. Between 6 and 11 esters were produced under three cultivation conditions. Contrary to our expectations, a strain where all known AATs were disrupted could still produce, e.g., ethyl acetate and isoamyl acetate. This study has expanded our understanding of ester synthesis in yeast but also showed that some unknown ester-producing mechanisms still exist.

Systemic sclerosis (SSc) is a poorly understood heterogeneous condition with progressive multi-organ fibrosis. Recent genetic and genomic evidence suggest a pathogenic role for dysregulated innate immunity and toll-like receptor (TLR) activity in SSc. Levels of both TLR4, as well as certain endogenous TLR ligands, are elevated in skin and lung tissues from patients with SSc and correlate with clinical disease parameters. Conversely, genetic targeting of TLR4 or its endogenous “damage-associated” ligands ameliorates progressive tissue fibrosis. Targeting TLR4 signaling therefore represents a pharmacological strategy to prevent intractable fibrosis. We examined the effect of TAK242, a small molecule TLR4 inhibitor, in preclinical fibrosis models and in SSc fibroblasts. TAK242 treatment prevented, promoted regression of, bleomycin-induced dermal and pulmonary fibrosis, and reduced the expression of several pro-fibrotic mediators. Furthermore, TAK242 ameliorated peritoneal fibrosis and reduced spontaneous hypodermal thickness in TSK/+ mice. Importantly, TAK242 abrogated collagen synthesis and myofibroblasts differentiation in explanted constitutively active SSc fibroblast. Altogether, these findings identify TAK242 as an anti-fibrotic agent in preclinical models of organ fibrosis. TAK242 might potentially represent a novel strategy for the treatment of SSc and other fibrotic diseases.

Sepsis in neonates and infants remains a major cause of death despite a decline in child mortality and morbidity over the last decades. A key factor in further reducing poor clinical outcomes is the optimal use of antibiotics in sepsis management. Developmental changes such as maturation of organ function and capacity of drug metabolizing enzymes can affect the pharmacokinetic profile and therefore the antibiotic exposure and response in neonates and infants. Optimal antibiotic treatment of sepsis in neonates and young infants is dependent on several key components such as the determination of treatment phase, the administered dose and the resulted drug exposure and microbiological response. During the initial phase of suspected sepsis, the primary focus of empirical treatment is to assure efficacy. Once bacterial infection as the cause of sepsis is confirmed the focus shifts toward a targeted treatment, ensuring an optimal balance between efficacy and safety. Interpretation of antibiotic exposure and microbiological response in neonates and infants is multifaceted. The response or treatment effect can be determined by the microbiological parameters (MIC) together with the characteristics of the pathogen (time- or concentration dependent). The antibiotic response is influenced by the properties of the causative pathogen and the unique characteristics of the vulnerable patient population such as reduced humoral response or reduced skin barrier function. Therapeutic drug monitoring (TDM) of antibiotics may be used to increase effectiveness while maximizing safety and minimizing the toxicity, but requires expertise in different fields and requires collaborations between physicians, lab technicians, and quantitative clinical pharmacologists. Understanding these clinical, pharmacological, and microbiological components and their underlying relationship can provide a scientific basic for proper antibiotic use and reduction of antibiotic resistance in neonates and infants. This highlights the necessity of a close multidisciplinary collaboration between physicians, pharmacists, clinical pharmacologists and microbiologist to assure the optimal utilization of antibiotics in neonates and young infants.

In cognitive science, creative ideas are defined as original and feasible solutions in response to problems. A common proposal is that creative ideas are generated across dedicated cognitive pathways. Only after creative ideas have emerged, they can be enacted to solve the problem. We present an alternative viewpoint, based upon the dynamic systems approach to perception and action, that creative solutions emerge in the act rather than before. Creative actions, thus, are as much a product of individual constraints as they are of the task and environment constraints. Accordingly, we understand creative motor actions as functional movement patterns that are new to the individual and/or group and adapted to satisfy the constraints on the motor problem at hand. We argue that creative motor actions are promoted by practice interventions that promote exploration by manipulating constraints. Exploration enhances variability of functional movement patterns in terms of either coordination or control solutions. At both levels, creative motor actions can emerge from finding new and degenerate adaptive motor solutions. Generally speaking, we anticipate that in most cases, when exposed to variation in constraints, people are not looking for creative motor actions, but discover them while doing an effort to satisfy constraints. For future research, this paper achieves two important aspects: it delineates how adaptive (movement) variability is at the heart of (motor) creativity, and it sets out methodologies toward stimulating adaptive variability.

Scope: Theobromine is a major active compound in cocoa with allegedly beneficial effect on high-density-lipoprotein-cholesterol (HDL-CH). We have investigated the effect of theobromine (TB) consumption on the concentrations of triglyceride (TG) and cholesterol (CH) in various lipoprotein (LP) subclasses.Methods: In a randomized, double-blind, placebo-controlled, cross-over study, 44 apparently healthy women and men (age: 60 ± 6 years, BMI: 29 ± 3 kg/m2) with low baseline HDL-CH concentrations consumed a drink supplemented with 500 mg/d theobromine for 4 weeks. TG and CH concentrations in 15 LP subclasses were predicted from diffusion-edited 1H NMR spectra of fasting serum.Results: The LP phenotype of the subjects was characterized by low CH concentrations in the large HDL particles and high TG concentrations in large VLDL and chylomicron (CM) particles, which clearly differed from a LP phenotype of subjects with normal HDL-CH. TB only reduced CH concentrations in the LDL particles by 3.64 and 6.79%, but had no effect on TG and CH in any of the HDL, VLDL and CM subclasses.Conclusion: TB was not effective on HDL-CH in subjects with a LP phenotype characterized by low HDL-CH and high TG in VLDL.

Background and aimThe availability and access of hospital administrative data [coding for Charlson comorbidity index (CCI)] in large data form has resulted in a surge of interest in using this information to predict mortality from stroke. The aims of this study were to determine the minimum clinical data set to be included in models for predicting disability after ischemic stroke adjusting for CCI and clinical variables and to evaluate the impact of CCI on prediction of outcome.MethodWe leverage anonymized clinical trial data in the Virtual International Stroke Trials Archive. This repository contains prospective data on stroke severity and outcome. The inclusion criteria were patients with available stroke severity score such as National Institutes of Health Stroke Scale (NIHSS), imaging data, and outcome disability score such as 90-day Rankin Scale. We calculate CCI based on comorbidity data in this data set. For logistic regression, we used these calibration statistics: Nagelkerke generalised R2 and Brier score; and for discrimination we used: area under the receiver operating characteristics curve (AUC) and integrated discrimination improvement (IDI). The IDI was used to evaluate improvement in disability prediction above baseline model containing age, sex, and CCI.ResultsThe clinical data among 5,206 patients (55% males) were as follows: mean age 69 ± 13 years, CCI 4.2 ± 0.8, and median NIHSS of 12 (IQR 8, 17) on admission and 9 (IQR 5, 15) at 24 h. In Model 2, adding admission NIHSS to the baseline model improved AUC from 0.67 (95% CI 0.65–0.68) to 0.79 (95% CI 0.78–0.81). In Model 3, adding 24-h NIHSS to the baseline model resulted in substantial improvement in AUC to 0.90 (95% CI 0.89–0.91) and increased IDI by 0.23 (95% CI 0.22–0.24). Adding the variable recombinant tissue plasminogen activator did not result in a further change in AUC or IDI to this regression model. In Model 3, the variable NIHSS at 24 h explains 87.3% of the variance of Model 3, follow by age (8.5%), comorbidity (3.7%), and male sex (0.5%).ConclusionOur results suggest that prediction of disability after ischemic stroke should at least include 24-h NIHSS and age. The variable CCI is less important for prediction of disability in this data set.

There is a long-standing proposal for the existence of two neuroanatomically and functionally separate visual systems; one supported by the dorsal pathway to control action and the second supported by the ventral pathway to handle explicit perceptual judgments. The dorsal pathway requires fast access to egocentric information, while the ventral pathway primarily requires allocentric information. Despite the evidence for functionally distinct systems, researchers have posited important interactions. This paper examines evidence to what degree the interaction becomes more important when target-identity, the perception of which is supported by the ventral stream, is verbalized during the execution of a target-directed far-aiming movement. In the experiment reported here participants hit balls toward distant targets while concurrently making explicit perceptual judgments of target properties. The endpoint of a shaft served as the target, with conditions including illusory arrow fins at the endpoint. Participants verbalized the location of the target by comparing it to a reference line and calling out “closer” or “further” while propelling the ball to the target. The impact velocity at ball contact was compared for hits toward three shafts of lengths, 94, 100, and 106 cm, with and without verbalizations and delays. It was observed that the meaning of the expressed words modulated movement execution when the verbalizations were consistent with the action characteristics. This effect of semantic content was evident regardless of target visibility during movement execution, demonstrating it was not restricted to movements that rely on visual memory. In addition to a direct effect of semantic content we anticipated an indirect effect of verbalization to result in action shifting toward the use of context-dependent allocentric information. This would result in an illusion bias on the impact velocity when the target is embedded in a Müller-Lyer configuration. We observed an ubiquitous effect of illusory context on movement execution, and not only when verbalizations were made. We suggest that the current experimental design with a far-aiming task where most conditions required reporting or retaining spatial characteristics of targets for action over time may have elicited a strong reliance on allocentric information to guide action.

Large-archives of neuroimaging data present many opportunities for re-analysis and mining that can lead to new findings of use in basic research or in the characterization of clinical syndromes. However, interaction with such archives tends to be driven textually, based on subject or image volume meta-data, not the actual neuroanatomical morphology itself, for which the imaging was performed to measure. What is needed is a content-driven approach for examining not only the image content itself but to explore brains that are anatomically similar, and identifying patterns embedded within entire sets of neuroimaging data. With the aim of visual navigation of large- scale neurodatabases, we introduce the concept of brain meta-spaces. The meta-space encodes pair-wise dissimilarities between all individuals in a population and shows the relationships between brains as a navigable framework for exploration. We employ multidimensional scaling (MDS) to implement meta-space processing for a new coordinate system that distributes all data points (brain surfaces) in a common frame of reference, with anatomically similar brain data located near each other. To navigate within this derived meta-space, we have developed a fully interactive 3D visualization environment that allows users to examine hundreds of brains simultaneously, visualize clusters of brains with similar characteristics, zoom in on particular instances, and examine the surface topology of an individual brain's surface in detail. The visualization environment not only displays the dissimilarities between brains, but also renders complete surface representations of individual brain structures, allowing an instant 3D view of the anatomies, as well as their differences.

The LONI Pipeline is a graphical environment for construction, validation and execution of advanced neuroimaging data analysis protocols [1]. It enables automated data format conversion, allows Grid utilization, facilitates data provenance, and provides a significant library of computational tools. There are two main advantages of the LONI Pipeline over other graphical analysis workflow architectures. It is built as a distributed Grid computing environment and permits efficient tool integration, protocol validation and broad resource distribution. To integrate existing data and computational tools within the LONI Pipeline environment, no modification of the resources themselves is required. The LONI Pipeline provides several types of process submissions based on the underlying server hardware infrastructure. Only workflow instructions and references to data, executable scripts and binary instructions are stored within the LONI Pipeline environment. This makes it portable, computationally efficient, distributed and independent of the individual binary processes involved in pipeline data-analysis workflows. We have expanded the LONI Pipeline (V.4.2) to include server-to-server (peer-to-peer) communication and a 3-tier failover infrastructure (Grid hardware, Sun Grid Engine/Distributed Resource Management Application API middleware, and the Pipeline server). Additionally, the LONI Pipeline provides 3 layers of background-server executions for all users/sites/systems. These new LONI Pipeline features facilitate resource-interoperability, decentralized computing, construction and validation of efficient and robust neuroimaging data-analysis workflows. Using brain imaging data from the Alzheimer’s Disease Neuroimaging Initiative [2], we demonstrate integration of disparate resources, graphical construction of complex neuroimaging analysis protocols and distributed parallel computing. The LONI Pipeline, its features, specifications, documentation and usage are available o