Xenogeneic, extracorporeal liver perfusion in primates improves the ratio of branched-chain amino acids to aromatic amino acids (Fischer's ratio)

In fulminant hepatic failure (FHF), the development of hepatic encephalopathy is associated with grossly abnormal concentrations of plasma amino acids (PAA). Normalization of the ratio of branched-chain amino acids to aromatic amino acids (Fischer's ratio) correlates with clinical improvement. This study evaluated changes in PAA metabolism during 4 h of isolated, normothermic extracorporeal liver perfusion using a newly designed system containing human blood and a rhesus monkey liver. Bile and urea production were within the physiological range. Release of the transaminases AST, ALT and LDH were minimal. The ratio of branched (valine, leucine, isoleucine) to aromatic (tyrosine, phenylalanine) amino acids increased significantly. These results indicate that a xenogeneic extracorporeal liver perfusion system is capable of significantly increasing Fischer's ratio and may play a role in treating and bridging patients in FHF in the future

Conditional Intensity and Gibbsianness of Determinantal Point Processes

The Papangelou intensities of determinantal (or fermion) point processes are investigated. These exhibit a monotonicity property expressing the repulsive nature of the interaction, and satisfy a bound implying stochastic domination by a Poisson point process. We also show that determinantal point processes satisfy the so-called condition $(\Sigma_{\lambda})$ which is a general form of Gibbsianness. Under a continuity assumption, the Gibbsian conditional probabilities can be identified explicitly.Comment: revised and extende

Large-eddy simulation of two-dimensional dunes in a steady, unidirectional flow

We performed large-eddy simulations of the flow over a typical two-dimensional dune geometry at laboratory scale (the Reynolds number based on the average channel height andmean velocity is 18,900) using the Lagrangian dynamic eddy-viscosity subgrid-scale model. The results are validated by comparison with simulations and experiments in the literature. The flowseparates at the dune crest, generating a shear layer that plays a crucial role in the transport of momentum and energy, and the generation of coherent structures. The turbulent kinetic energy budgets show the importance of the turbulent transport and mean-flow advection in the bulk flow above the shear layer. In the recirculation zone and in the attached boundary layers production and dissipation are the most important terms. Large, coherent structures of various types can be observed. Spanwise vortices are generated in the separated shear layer due to the Kelvin-Helmholtz instability; as they are advected, they undergo lateral instabilities and develop into horseshoe-like structures, are tilted downward, and finally reach the surface. The ejection that occurs between the legs of the vortex creates the upwelling and downdrafting events on the free surface known as "boils." Near-wall turbulence, after the reattachment point, is affected by large streamwise Taylor-Görtler vortices generated on the concave part of the stoss side, which affect the distribution of the near-wall streaks

Uncertainty quantification for kinetic models in socio-economic and life sciences

Kinetic equations play a major rule in modeling large systems of interacting particles. Recently the legacy of classical kinetic theory found novel applications in socio-economic and life sciences, where processes characterized by large groups of agents exhibit spontaneous emergence of social structures. Well-known examples are the formation of clusters in opinion dynamics, the appearance of inequalities in wealth distributions, flocking and milling behaviors in swarming models, synchronization phenomena in biological systems and lane formation in pedestrian traffic. The construction of kinetic models describing the above processes, however, has to face the difficulty of the lack of fundamental principles since physical forces are replaced by empirical social forces. These empirical forces are typically constructed with the aim to reproduce qualitatively the observed system behaviors, like the emergence of social structures, and are at best known in terms of statistical information of the modeling parameters. For this reason the presence of random inputs characterizing the parameters uncertainty should be considered as an essential feature in the modeling process. In this survey we introduce several examples of such kinetic models, that are mathematically described by nonlinear Vlasov and Fokker--Planck equations, and present different numerical approaches for uncertainty quantification which preserve the main features of the kinetic solution.Comment: To appear in "Uncertainty Quantification for Hyperbolic and Kinetic Equations

Exploring the decision-making process in model development: focus on the Arctic snowpack

The Arctic poses many challenges to Earth System and snow physics models, which are unable to simulate crucial Arctic snowpack processes, such as vapour gradients and rain-on-snow-induced ice layers. These limitations raise concerns about the current understanding of Arctic warming and its impact on biodiversity, livelihoods, permafrost and the global carbon budget. Recognizing that models are shaped by human choices, eighteen Arctic researchers were interviewed to delve into the decision-making process behind model construction. Although data availability, issues of scale, internal model consistency, and historical and numerical model legacies were cited as obstacles to developing an Arctic snowpack model, no opinion was unanimous. Divergences were not merely scientific disagreements about the Arctic snowpack, but reflected the broader research context. Inadequate and insufficient resources partly driven by short-term priorities dominating research landscapes, impeded progress. Nevertheless, modellers were found to be both adaptable to shifting strategic research priorities – an adaptability demonstrated by the fact that interdisciplinary collaborations were the key motivation for model development – and anchored in the past. This anchoring led to diverging opinions about whether existing models are “good enough” and whether investing time and effort to build a new model was a useful strategy when addressing pressing research challenges. Moving forward, we recommend that both stakeholders and modellers be involved in future snow model intercomparison projects in order to drive developments that address snow model limitations that currently impede progress in various disciplines. We also argue for more transparency about the contextual factors that shape research decisions. Otherwise, the reality of our scientific process will remain hidden, limiting the changes necessary to our research practice

Inhibition of the MID1 protein complex: a novel approach targeting APP protein synthesis

Alzheimer's disease (AD) is characterized by two neuropathological hallmarks: senile plaques, which are composed of amyloid-β (Aβ) peptides, and neurofibrillary tangles, which are composed of hyperphosphorylated tau protein. Aβ peptides are derived from sequential proteolytic cleavage of the amyloid precursor protein (APP). In this study, we identified a so far unknown mode of regulation of APP protein synthesis involving the MID1 protein complex: MID1 binds to and regulates the translation of APP mRNA. The underlying mode of action of MID1 involves the mTOR pathway. Thus, inhibition of the MID1 complex reduces the APP protein level in cultures of primary neurons. Based on this, we used one compound that we discovered previously to interfere with the MID1 complex, metformin, for in vivo experiments. Indeed, long-term treatment with metformin decreased APP protein expression levels and consequently Aβ in an AD mouse model. Importantly, we have initiated the metformin treatment late in life, at a time-point where mice were in an already progressed state of the disease, and could observe an improved behavioral phenotype. These findings together with our previous observation, showing that inhibition of the MID1 complex by metformin also decreases tau phosphorylation, make the MID1 complex a particularly interesting drug target for treating AD

Tenosynovial giant cell tumors as accidental findings after episodes of distortion of the ankle: two case reports

<p>Abstract</p> <p>Introduction</p> <p>Tenosynovial giant cell tumors are benign tumors of uncertain pathogenesis. They occur in the joints, tendons and synovial bursas. Due to a high recurrence rate of up to 50%, some authors call a giant cell tumor a semimalignant tumor. To date, less than 10 cases of tenosynovial giant cell tumor of the ankle have been published in the international medical literature.</p> <p>Case presentation</p> <p>In this case report, we present two patients with localized tumors that were detected accidentally after the occurrence of ankle sprains with persisting pain in the joint. The tumors were resected by open marginal surgery and regular follow-up examinations were carried out.</p> <p>Conclusions</p> <p>We present an unusual occurrence of a tumor along with a possible follow-up strategy, which has not been previously discussed in the international literature.</p

Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial

Background Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. The aim of this large randomised controlled trial was to collect data to enhance the validity and applicability of the evidence from previous trials to inform practice. Methods In this randomised placebo-controlled trial, we recruited very preterm infants born before 32 weeks' gestation in 37 UK hospitals and younger than 72 h at randomisation. Exclusion criteria were presence of a severe congenital anomaly, anticipated enteral fasting for longer than 14 days, or no realistic prospect of survival. Eligible infants were randomly assigned (1:1) to receive either enteral bovine lactoferrin (150 mg/kg per day; maximum 300 mg/day; lactoferrin group) or sucrose (same dose; control group) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers, and outcome assessors were unaware of group assignment. The primary outcome was microbiologically confirmed or clinically suspected late-onset infection (occurring >72 h after birth), which was assessed in all participants for whom primary outcome data was available by calculating the relative risk ratio with 95% CI between the two groups. The trial is registered with the International Standard Randomised Controlled Trial Number 88261002. Findings We recruited 2203 participants between May 7, 2014, and Sept 28, 2017, of whom 1099 were assigned to the lactoferrin group and 1104 to the control group. Four infants had consent withdrawn or unconfirmed, leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants (1093 [99·5%] of 1098 in the lactoferrin group and 1089 [99·0] of 1101 in the control group) were available for inclusion in the modified intention-to-treat analyses. 316 (29%) of 1093 infants in the intervention group acquired a late-onset infection versus 334 (31%) of 1089 in the control group. The risk ratio adjusted for minimisation factors was 0·95 (95% CI 0·86–1·04; p=0·233). During the trial there were 16 serious adverse events for infants in the lactoferrin group and 10 for infants in the control group. Two events in the lactoferrin group (one case of blood in stool and one death after intestinal perforation) were assessed as being possibly related to the trial intervention. Interpretation Enteral supplementation with bovine lactoferrin does not reduce the risk of late-onset infection in very preterm infants. These data do not support its routine use to prevent late-onset infection and associated morbidity or mortality in very preterm infants. Funding UK National Institute for Health Research Health Technology Assessment programme (10/57/49)

Enteral lactoferrin supplementation for very preterm infants: a randomised placebo-controlled trial

Background Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. The aim of this large randomised controlled trial was to collect data to enhance the validity and applicability of the evidence from previous trials to inform practice. Methods In this randomised placebo-controlled trial, we recruited very preterm infants born before 32 weeks' gestation in 37 UK hospitals and younger than 72 h at randomisation. Exclusion criteria were presence of a severe congenital anomaly, anticipated enteral fasting for longer than 14 days, or no realistic prospect of survival. Eligible infants were randomly assigned (1:1) to receive either enteral bovine lactoferrin (150 mg/kg per day; maximum 300 mg/day; lactoferrin group) or sucrose (same dose; control group) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers, and outcome assessors were unaware of group assignment. The primary outcome was microbiologically confirmed or clinically suspected late-onset infection (occurring >72 h after birth), which was assessed in all participants for whom primary outcome data was available by calculating the relative risk ratio with 95% CI between the two groups. The trial is registered with the International Standard Randomised Controlled Trial Number 88261002. Findings We recruited 2203 participants between May 7, 2014, and Sept 28, 2017, of whom 1099 were assigned to the lactoferrin group and 1104 to the control group. Four infants had consent withdrawn or unconfirmed, leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants (1093 [99·5%] of 1098 in the lactoferrin group and 1089 [99·0] of 1101 in the control group) were available for inclusion in the modified intention-to-treat analyses. 316 (29%) of 1093 infants in the intervention group acquired a late-onset infection versus 334 (31%) of 1089 in the control group. The risk ratio adjusted for minimisation factors was 0·95 (95% CI 0·86–1·04; p=0·233). During the trial there were 16 serious adverse events for infants in the lactoferrin group and 10 for infants in the control group. Two events in the lactoferrin group (one case of blood in stool and one death after intestinal perforation) were assessed as being possibly related to the trial intervention. Interpretation Enteral supplementation with bovine lactoferrin does not reduce the risk of late-onset infection in very preterm infants. These data do not support its routine use to prevent late-onset infection and associated morbidity or mortality in very preterm infants. Funding UK National Institute for Health Research Health Technology Assessment programme (10/57/49)