Gradients of O-information highlight synergy and redundancy in physiological applications

The study of high order dependencies in complex systems has recently led to the introduction of statistical synergy, a novel quantity corresponding to a form of emergence in which patterns at large scales are not traceable from lower scales. As a consequence, several works in the last years dealt with the synergy and its counterpart, the redundancy. In particular, the O-information is a signed metric that measures the balance between redundant and synergistic statistical dependencies. In spite of its growing use, this metric does not provide insight about the role played by low-order scales in the formation of high order effects. To fill this gap, the framework for the computation of the O-information has been recently expanded introducing the so-called gradients of this metric, which measure the irreducible contribution of a variable (or a group of variables) to the high order informational circuits of a system. Here, we review the theory behind the O-information and its gradients and present the potential of these concepts in the field of network physiology, showing two new applications relevant to brain functional connectivity probed via functional resonance imaging and physiological interactions among the variability of heart rate, arterial pressure, respiration and cerebral blood flow

Prone position ameliorates lung elastance and increases functional residual capacity independently from lung recruitment

BACKGROUND: Prone position is used to recruit collapsed dependent lung regions during severe acute respiratory distress syndrome, improving lung elastance and lung gas content. We hypothesised that, in the absence of recruitment, prone position would not result in any improvement in lung mechanical properties or gas content compared to supine position. METHODS: Ten healthy pigs under general anaesthesia and paralysis underwent a pressure-volume curve of the respiratory system, chest wall and lung in supine and prone positions; the respective elastances were measured. A lung computed tomography (CT) scan was performed in the two positions to compute gas content (i.e. functional residual capacity (FRC)) and the distribution of aeration. Recruitment was defined as a percentage change in non-aerated lung tissue compared to the total lung weight. RESULTS: Non-aerated (recruitable) lung tissue was a small percentage of the total lung tissue weight in both positions (4\u2009\ub1\u20093 vs 1\u2009\ub1\u20091 %, supine vs prone, p\u2009=\u20090.004). Lung elastance decreased (20.5\u2009\ub1\u20091.8 vs 15.5\u2009\ub1\u20091.6 cmH2O/l, supine vs prone, p\u2009<\u20090.001) and functional residual capacity increased (380\u2009\ub1\u200982 vs 459\u2009\ub1\u200960 ml, supine vs prone, p\u2009=\u20090.025) in prone position; specific lung elastance did not change (7.0\u2009\ub1\u20090.5 vs 6.5\u2009\ub1\u20090.5 cmH2O, supine vs prone, p\u2009=\u20090.24). Lung recruitment was low (3\u2009\ub1\u20092 %) and was not correlated to increases in functional residual capacity (R (2) 0.2, p\u2009=\u20090.19). A higher amount of well-aerated and a lower amount of poorly aerated lung tissue were found in prone position. CONCLUSIONS: In healthy pigs, prone position ameliorates lung mechanical properties and increases functional residual capacity independently from lung recruitment, through a redistribution of lung aeration

The use of a physiologically based pharmacokinetic model to evaluate deconvolution measurements of systemic absorption

BACKGROUND: An unknown input function can be determined by deconvolution using the systemic bolus input function (r) determined using an experimental input of duration ranging from a few seconds to many minutes. The quantitative relation between the duration of the input and the accuracy of r is unknown. Although a large number of deconvolution procedures have been described, these routines are not available in a convenient software package. METHODS: Four deconvolution methods are implemented in a new, user-friendly software program (PKQuest, ). Three of these methods are characterized by input parameters that are adjusted by the user to provide the "best" fit. A new approach is used to determine these parameters, based on the assumption that the input can be approximated by a gamma distribution. Deconvolution methodologies are evaluated using data generated from a physiologically based pharmacokinetic model (PBPK). RESULTS AND CONCLUSIONS: The 11-compartment PBPK model is accurately described by either a 2 or 3-exponential function, depending on whether or not there is significant tissue binding. For an accurate estimate of r the first venous sample should be at or before the end of the constant infusion and a long (10 minute) constant infusion is preferable to a bolus injection. For noisy data, a gamma distribution deconvolution provides the best result if the input has the form of a gamma distribution. For other input functions, good results are obtained using deconvolution methods based on modeling the input with either a B-spline or uniform dense set of time points

Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial.

BACKGROUND: Mycophenolate mofetil has replaced azathioprine in immunosuppression regimens worldwide to prevent graft rejection. However, evidence that its antirejection activity is better than that of azathioprine has been provided only by registration trials with an old formulation of ciclosporin and steroid. We aimed to compare the antirejection activity of these two drugs with a new formulation of ciclosporin. METHODS: The mycophenolate steroids sparing multicentre, prospective, randomised, parallel-group trial compared acute rejections and adverse events in recipients of cadaver-kidney transplants over 6-month treatment with mycophenolate mofetil or azathioprine along with ciclosporin microemulsion (Neoral) and steroids (phase A), and over 15 more months without steroids (phase B). The primary endpoint was occurrence of acute rejection episodes. Analysis was by intention to treat. FINDINGS: 168 patients per group entered phase A. 56 (34%) assigned mycophenolate mofetil and 58 (35%) assigned azathioprine had clinical rejections (risk reduction [RR] on mycophenolate mofetil compared with azathioprine 13.7% [95% CI -25.7% to 40.7%], p=0.44). 88 patients in the mycophenolate mofetil group and 89 in the azathioprine group entered phase B. 14 (16%) taking mycophenolate mofetil and 11 (12%) taking azathioprine had clinical rejections (RR -16.2%, [-157.5% to 47.5%], p=0.71). Average per-patient costs of mycophenolate mofetil treatment greatly exceeded those of azathioprine (phase A 2665 Euros [SD 586] vs Euros 184 [62]; phase B 5095 Euros [2658] vs 322 Euros [170], p<0.0001 for both). INTERPRETATION: In recipients of cadaver kidney-transplants given ciclosporin microemulsion, mycophenolate mofetil offers no advantages over azathioprine in preventing acute rejections and is about 15 times more expensive. Standard immunosuppression regimens for transplantation should perhaps include azathioprine rather than mycophenolate mofetil, at least for kidney graft

Geodynamics, geophysical and geochemical observations, and the role of CO2 degassing in the Apennines

An accurate survey of old and new datasets allowed us to probe the nature and role of fluids in the seismogenic processes of the Apennines mountain range in Italy. New datasets include the 1985–2021 instrumented seismicity catalog, the computed seismogenic thickness, and geodetic velocities and strains, whereas data from the literature comprise focal mechanism solutions, CO2 release, Moho depth, tomographic seismic velocities, heat flow and Bouguer gravity anomalies. Most of the inspected datasets highlight differences between the western and eastern domains of the Apennines, while the transition zone is marked by high geodetic strain, prevailing uplift at the surface and high seismic release, and spatially corresponds with the overlapping Tyrrhenian and Adriatic Mohos. Published tomographic models suggest the presence of a large hot asthenospheric mantle wedge which intrudes beneath the western side of the Apennines and disappears at the southern tip of the southern Apennines. This wedge modulates the thermal structure and rheology of the overlying crust as well as the melting of carbonate-rich sediments of the subducting Adriatic lithosphere. As a result, CO2-rich fluids of mantle-origin have been recognized in association with the occurrence of destructive seismic sequences in the Apennines. The stretched western domain of the Apennines is characterized by a broad pattern of emissions from CO2-rich fluids that vanishes beneath the axial belt of the chain, where fluids are instead trapped within crustal overpressurized reservoirs, favoring their involvement in the evolution of destructive seismic sequences in that region. In the Apennines, areas with high mantle He are associated with different degrees of metasomatism of the mantle wedge from north to south. Beneath the chain, the thickness and permeability of the crust control the formation of overpressurized fluid zones at depth and the seismicity is favored by extensional faults that act as high permeability pathways. This multidisciplinary study aims to contribute to our understanding of the fluid-related mechanisms of earthquake preparation, nucleation and evolution encouraging a multiparametric monitoring system of different geophysical and geochemical observables that could lead the creation of a data-constrained and reliable conceptual model of the role of fluids in the preparatory phase of earthquakes in the Apennines

Personalizing Cancer Pain Therapy: Insights from the Rational Use of Analgesics (RUA) Group

Introduction: A previous Delphi survey from the Rational Use of Analgesics (RUA) project involving Italian palliative care specialists revealed some discrepancies between current guidelines and clinical practice with a lack of consensus on items regarding the use of strong opioids in treating cancer pain. Those results represented the basis for a new Delphi study addressing a better approach to pain treatment in patients with cancer. Methods: The study consisted of a two-round multidisciplinary Delphi study. Specialists rated their agreement with a set of 17 statements using a 5-point Likert scale (0 = totally disagree and 4 = totally agree). Consensus on a statement was achieved if the median consensus score (MCS) (expressed as value at which at least 50% of participants agreed) was at least 4 and the interquartile range (IQR) was 3–4. Results: This survey included input from 186 palliative care specialists representing all Italian territory. Consensus was reached on seven statements. More than 70% of participants agreed with the use of low dose of strong opioids in moderate pain treatment and valued transdermal route as an effective option when the oral route is not available. There was strong consensus on the importance of knowing opioid pharmacokinetics for therapy personalization and on identifying immediate-release opioids as key for tailoring therapy to patients’ needs. Limited agreement was reached on items regarding breakthrough pain and the management of opioid-induced bowel dysfunction. Conclusion: These findings may assist clinicians in applying clinical evidence to routine care settings and call for a reappraisal of current pain treatment recommendations with the final aim of optimizing the clinical use of strong opioids in patients with cancer