Scale-free bursting in human cortex following hypoxia at birth

The human brain is fragile in the face of oxygen deprivation. Even a briefinterruption of metabolic supply at birth challenges an otherwise healthy neonatal cortex, leading to a cascade of homeostatic responses. During recovery from hypoxia, cortical activity exhibits a period of highly irregular electrical fluctuations known as burst suppression. Here we show that these bursts have fractal properties, with power-law scaling of burst sizes across a remarkable 5 orders of magnitude and a scale-free relationship between burst sizes and durations. Although burst waveforms vary greatly, their average shape converges to a simple form that is asymmetric at long time scales. Using a simple computational model, we argue that this asymmetry reflects activity-dependent changes in the excitatory-inhibitory balance of cortical neurons. Bursts become more symmetric following the resumption of normal activity, with a corresponding reorganization of burst scaling relationships. These findings place burst suppression in the broad class of scale-free physical processes termed crackling noise and suggest that the resumption of healthy activity reflects a fundamental reorganization in the relationship between neuronal activity and its underlying metabolic constraints

On Measuring Net Ecosystem Carbon Exchange over Tall Vegetation on Complex Terrain

To assess annual budgets of CO2 exchange between the biosphere and atmosphere over representative ecosystems, long-term measurements must be made over ecosystems that do not exist on ideal terrain. How to interpret eddy covariance measurements correctly remains a major task. At present, net ecosystem CO2 exchange is assessed, by members of the micrometeorological community, as the sum of eddy covariance measurements and the storage of CO2 in the underlying air. This approach, however, seems unsatisfactory as numerous investigators are reporting that it may be causing nocturnal respiration flux densities to be underestimated. A new theory was recently published by Lee (1998, Agricultural and Forest Meteorology 91: 39– 50) for assessing net ecosystem-atmosphere CO2 exchange (Ne) over non-ideal terrain. It includes a vertical advection term. We apply this equation over a temperate broadleaved forest growing in undulating terrain. Inclusion of the vertical advection term yields hourly, daily and annual sums of net ecosystem CO2 exchange that are more ecologically correct during the growing season. During the winter dormant period, on the other hand, corrected CO2 flux density measurements of an actively respiring forest were near zero. This observation is unrealistic compared to chamber measurements and model calculations. Only during midday, when the atmosphere is well-mixed, do measurements of Ne match estimates based on model calculations and chamber measurements. On an annual basis, sums of Ne without the advection correction were 40% too large, as compared with computations derived from a validated and process-based model. With the inclusion of the advection correction term, we observe convergence between measured and calculated values of Ne on hourly, daily and yearly time scales. We cannot, however, conclude that inclusion of a one-dimensional, vertical advection term into the continuity equation is sufficient for evaluating CO2 exchange over tall forests in complex terrain. There is an indication that the neglected term, u(c/x), is non-zero and that CO2 may be leaking from the sides of the control volume during the winter. In this circumstance, forest floor CO2 efflux densities exceed effluxes measured above the canopy

Subdivision surfaces with creases and truncated multiple knot lines

We deal with subdivision schemes based on arbitrary degree B-splines. We focus on extraordinary knots which exhibit various levels of complexity in terms of both valency and multiplicity of knot lines emanating from such knots. The purpose of truncated multiple knot lines is to model creases which fair out. Our construction supports any degree and any knot line multiplicity and provides a modelling framework familiar to users used to B-splines and NURBS systems

Design of Phase 3 Studies Evaluating Vixotrigine for Treatment of Trigeminal Neuralgia

Purpose: Vixotrigine (BIIB074) is a voltage- and use-dependent sodium channel blocker. These studies will evaluate the efficacy and safety of vixotrigine in treating pain experienced by patients with trigeminal neuralgia (TN) using enriched enrollment randomized withdrawal trial designs. Patients and Methods: Two double-blind randomized withdrawal studies are planned to evaluate the efficacy and safety of vixotrigine compared with placebo in participants with TN (NCT03070132 and NCT03637387). Participant criteria include ≥ 18 years old who have classical, purely paroxysmal TN diagnosed ≥ 3 months prior to study entry, who experience ≥ 3 paroxysms of pain/day. The two studies will include a screening period, 7-day run-in period, a 4- or 6-week single-dose-blind dose-optimization period (Study 1) or 4-week open-label period (Study 2), and 14-week double-blind period. Participants will receive vixotrigine 150 mg orally three times daily in the dose-optimization and open-label periods. The primary endpoint of both studies is the proportion of participants classified as responders at Week 12 of the double-blind period. Secondary endpoints include safety measures, quality of life, and evaluation of vixotrigine population pharmacokinetics. Conclusion: There is a need for an effective, well-tolerated, noninvasive treatment for the neuropathic pain associated with TN. The proposed studies will evaluate the efficacy and safety of vixotrigine in treating pain experienced by patients with TN

Efficacy and tolerability of an endogenous metabolic modulator (AXA1125) in fatigue-predominant long COVID: a single-centre, double-blind, randomised controlled phase 2a pilot study

Background: ‘Long COVID’ describes persistent symptoms, commonly fatigue, lasting beyond 12 weeks following SARS-CoV-2 infection. Potential causes include reduced mitochondrial function and cellular bioenergetics. AXA1125 has previously increased β-oxidation and improved bioenergetics in preclinical models along with certain clinical conditions, and therefore may reduce fatigue associated with Long COVID. We aimed to assess the efficacy, safety and tolerability of AXA1125 in Long COVID. / Methods: Patients with fatigue dominant Long COVID were recruited in this single-centre, double-blind, randomised controlled phase 2a pilot study completed in the UK. Patients were randomly assigned (1:1) using an Interactive Response Technology to receive either AXA1125 or matching placebo in a clinical based setting. Each dose (33.9 g) of AXA1125 or placebo was administered orally in a liquid suspension twice daily for four weeks with a two week follow-up period. The primary endpoint was the mean change from baseline to day 28 in the phosphocreatine (PCr) recovery rate following moderate exercise, assessed by 31P-magnetic resonance spectroscopy (MRS). All patients were included in the intention to treat analysis. This trial was registered at ClinicalTrials.gov, NCT05152849. / Findings: Between December 15th 2021, and May 23th 2022, 60 participants were screened and 41 participants were randomised and included in the final analysis. Changes in skeletal muscle phosphocreatine recovery time constant (τPCr) and 6-min walk test (6MWT) did not significantly differ between treatment (n = 21) and placebo group (n = 20). However, treatment with AXA1125 was associated with significantly reduced day 28 Chalder Fatigue Questionnaire [CFQ-11] fatigue score when compared with placebo (least squares mean difference [LSMD] −4.30, 95% confidence interval (95% CI) −7.14, −1.47; P = 0.0039). Eleven (52.4%, AXA1125) and four (20.0%, placebo) patients reported treatment-emergent adverse events; none were serious, or led to treatment discontinuation. / Interpretation: Although treatment with AXA1125 did not improve the primary endpoint (τPCr-measure of mitochondrial respiration), when compared to placebo, there was a significant improvement in fatigue-based symptoms among patients living with Long COVID following a four week treatment period. Further multicentre studies are needed to validate our findings in a larger cohort of patients with fatigue-dominant Long COVID. / Funding: Axcella Therapeutics

Novel features of early burst suppression predict outcome after birth asphyxia

Peer reviewe

Laboratory investigation of lateral dispersion within dense arrays of randomly distributed cylinders at transitional Reynolds number

Published versio

Energy- and flux-budget turbulence closure model for stably stratified flows. Part II: the role of internal gravity waves

We advance our prior energy- and flux-budget turbulence closure model (Zilitinkevich et al., 2007, 2008) for the stably stratified atmospheric flows and extend it accounting for additional vertical flux of momentum and additional productions of turbulent kinetic energy, turbulent potential energy (TPE) and turbulent flux of potential temperature due to large-scale internal gravity waves (IGW). Main effects of IGW are following: the maximal value of the flux Richardson number (universal constant 0.2-0.25 in the no-IGW regime) becomes strongly variable. In the vertically homogeneous stratification, it increases with increasing wave energy and can even exceed 1. In the heterogeneous stratification, when IGW propagate towards stronger stratification, the maximal flux Richardson number decreases with increasing wave energy, reaches zero and then becomes negative. In other words, the vertical flux of potential temperature becomes counter-gradient. IGW also reduce anisotropy of turbulence and increase the share of TPE in the turbulent total energy. Depending on the direction (downward or upward), IGW either strengthen or weaken the total vertical flux of momentum. Predictions from the proposed model are consistent with available data from atmospheric and laboratory experiments, direct numerical simulations and large-eddy simulations.Comment: 37 pages, 5 figures, revised versio