The Remains of the Day: The International Economic Order in the Era of Disintegration

The last two decades of the XX century have been marked by a vigorous acceleration of international economic integration both at a global and regional level. States accepted pervasive constraints on their national decision-making in the hope that stability and predictability would favor economic growth. This model of international economic integration, however, has recently shown worrying signs of ‘disintegration’. Disintegration manifests itself both as disintegration of the international legal regimes which compose the international economic order; and disintegration through law, namely the social, economic and environmental disintegration phenomena,triggered or at leastfacilitated by these regimes. Relying on the paradox integration/disintegration as an analytical framework, this article draws a blueprint of the various disintegration phenomena, which are further analyzed in the individual contributions to this Special Issue. It seeks to identify a relationship betweenthetwo dimensions of disintegration and detect possible correlation patterns. Last, after engaging with the different normative alternatives put forward by the contributors, it concludes by calling for a rethinking of the traditional approach to international economic integration. This reconceptualization should be premised on the full realization that the current model entails a great deal of environmental and social ‘hidden costs’

The remains of the day: The international economic order in the era of disintegration

The last two decades of the XX century have been marked by a vigorous acceleration of international economic integration both at a global and regional level. States accepted pervasive constraints on their national decision-making in the hope that stability and predictability would favor economic growth. This model of international economic integration, however, has recently shown worrying signs of 'disintegration'. Disintegration manifests itself both as disintegration of the international legal regimes which compose the international economic order; and disintegration through law, namely the social, economic and environmental disintegration phenomena, triggered or at least facilitated by these regimes. Relying on the paradox integration/disintegration as an analytical framework, this article draws a blueprint of the various disintegration phenomena, which are further analyzed in the individual contributions to this Special Issue. It seeks to identify a relationship between the two dimensions of disintegration and detect possible correlation patterns. Last, after engaging with the different normative alternatives put forward by the contributors, it concludes by calling for a rethinking of the traditional approach to international economic integration. This reconceptualization should be premised on the full realization that the current model entails a great deal of environmental and social 'hidden costs'

Justice for All? Protecting the Public Interest in Investment Treaties

Investment arbitration has come increasingly under fire because of its design flaws. There is an emerging consensus that investment treaty arbitration not only falls short of ensuring a sufficient degree of transparency of arbitral proceedings and impartiality of arbitrators, but also that its institutional architecture is unjustifiably asymmetric, entrusting foreign investors with significant rights while no protection is afforded to the host states’ constituencies. In response to these criticisms, several states have attempted in recent years to reform the rules governing investor-state arbitration. A perusal of recently concluded international investment agreements, however, reveals that the reform efforts so far have focused on the first two shortcomings. Very little, instead, has been done with regard to the asymmetric character of the system. This Essay seeks to specifically address this flaw, by placing the rights of investment-affected people on par with those of investors. To do this, we seek to display the viable alternatives to the currently predominant—and flawed—model of investment dispute settlement. We start by outlining the features of the investor-state dispute settlement system that lie at the root of the system’s legitimacy crisis. In particular, relying on a burgeoning body of scholarship, we expose the inadequacy of private order dispute settlement mechanisms in dealing with mainly public law disputes. Bearing this in mind, we contend that future reform efforts should reckon with the rights and interests of the individuals and groups of individuals who are likely to be affected by the investment operations. In other words, States can only remove the asymmetric character of the system by endowing this category of individuals with substantive and procedural rights. We also argue that international investment agreements should go beyond their traditional protective function by aiming to keep investors’ conduct in check. We opine that such agreements should also clearly establish investors’ obligations to safeguard the wide range of noninvestment interests implicated in investment operations. This Essay envisages three innovative models for the solution of investment disputes and presents a comparative analysis of alternative scenarios. The first suggests the abandonment of investment arbitration in favor of soft-law grievance mechanisms. The second envisages arbitration for both investors and investment-affected parties. The third proposal is a networked system where arbitration is coupled with grievance mechanisms for investment-affected individuals. In short, we submit that future treaties should either completely ditch the ISDS system or undertake a major overhaul of the system. Each proposal has its limits and promises. We conclude that, in spite of their limits, any of these proposals would offer a superior alternative to the dramatic deficiencies of the current system and future research should be directed to further articulate the contours of our proposals

Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1-TGF-β-OTX2-SNAIL via PTEN inhibition.

Genetic modifications during development of paediatric groups 3 and 4 medulloblastoma are responsible for their highly metastatic properties and poor patient survival rates. PRUNE1 is highly expressed in metastatic medulloblastoma group 3, which is characterized by TGF-β signalling activation, c-MYC amplification, and OTX2 expression. We describe the process of activation of the PRUNE1 signalling pathway that includes its binding to NME1, TGF-β activation, OTX2 upregulation, SNAIL (SNAI1) upregulation, and PTEN inhibition. The newly identified small molecule pyrimido-pyrimidine derivative AA7.1 enhances PRUNE1 degradation, inhibits this activation network, and augments PTEN expression. Both AA7.1 and a competitive permeable peptide that impairs PRUNE1/NME1 complex formation, impair tumour growth and metastatic dissemination in orthotopic xenograft models with a metastatic medulloblastoma group 3 cell line (D425-Med cells). Using whole exome sequencing technology in metastatic medulloblastoma primary tumour cells, we also define 23 common 'non-synonymous homozygous' deleterious gene variants as part of the protein molecular network of relevance for metastatic processes. This PRUNE1/TGF-β/OTX2/PTEN axis, together with the medulloblastoma-driver mutations, is of relevance for future rational and targeted therapies for metastatic medulloblastoma group 3

The acute phase management of spinal cord injury affecting polytrauma patients : the ASAP study

Publisher Copyright: © 2022, The Author(s).Background: Few data on the management of acute phase of traumatic spinal cord injury (tSCI) in patients suffering polytrauma are available. As the therapeutic choices in the first hours may have a deep impact on outcome of tSCI patients, we conducted an international survey investigating this topic. Methods: The survey was composed of 29 items. The main endpoints of the survey were to examine: (1) the hemodynamic and respiratory management, (2) the coagulation management, (3) the timing of magnetic resonance imaging (MRI) and spinal surgery, (4) the use of corticosteroid therapy, (5) the role of intraspinal pressure (ISP)/spinal cord perfusion pressure (SCPP) monitoring and (6) the utilization of therapeutic hypothermia. Results: There were 171 respondents from 139 centers worldwide. A target mean arterial pressure (MAP) target of 80–90 mmHg was chosen in almost half of the cases [n = 84 (49.1%)]. A temporary reduction in the target MAP, for the time strictly necessary to achieve bleeding control in polytrauma, was accepted by most respondents [n = 100 (58.5%)]. Sixty-one respondents (35.7%) considered acceptable a hemoglobin (Hb) level of 7 g/dl in tSCI polytraumatized patients. An arterial partial pressure of oxygen (PaO2) of 80–100 mmHg [n = 94 (55%)] and an arterial partial pressure of carbon dioxide (PaCO2) of 35–40 mmHg [n = 130 (76%)] were chosen in most cases. A little more than half of respondents considered safe a platelet (PLT) count > 100.000/mm3 [n = 99 (57.9%)] and prothrombin time (PT)/activated partial thromboplastin time (aPTT) < 1.5 times the normal control [n = 85 (49.7%)] in patients needing spinal surgery. MRI [n = 160 (93.6%)] and spinal surgery [n = 158 (92.4%)] should be performed after intracranial, hemodynamic, and respiratory stabilization by most respondents. Corticosteroids [n = 103 (60.2%)], ISP/SCPP monitoring [n = 148 (86.5%)], and therapeutic hypothermia [n = 137 (80%)] were not utilized by most respondents. Conclusions: Our survey has shown a great worldwide variability in clinical practices for acute phase management of tSCI patients with polytrauma. These findings can be helpful to define future research in order to optimize the care of patients suffering tSCI.Peer reviewe

On Nontrival Equilibria in Finitely Repeated Games

Background: Data on the effect of oral bisphosphonates (BPs) on risk of upper gastrointestinal complications (UGIC) are conflicting. We conducted a large population-based study from a network of Italian healthcare utilization databases aimed to assess the UGIC risk associated with use of BPs in the setting of secondary prevention of osteoporotic fractures.Methods: A nested case-control study was carried out within a cohort of 68,970 patients aged 45 years or older, who have been hospitalized for osteoporotic fracture from 2003 until 2005. Cases were the 804 patients who experienced hospitalization for UGIC until 2007. Up to 20 controls were randomly selected for each case. Conditional logistic regression model was used to estimate odds ratio (OR) associated with current and past use of BPs (i.e. for drug dispensation within 30 days and over 31 days prior the outcome onset, respectively) after adjusting for several covariates.Results: Compared with patients who did not use BPs, current and past users had OR (and 95% confidence interval) of 0.86 (0.60 to 1.22) and 1.07 (0.80 to 1.44) respectively. There was no difference in the ORs estimated according with BPs type (alendronate or risedronate) and regimen (daily or weekly), nor with co-therapies and comorbidities.Conclusions: Further evidence that BPs dispensed for secondary prevention of osteoporotic fractures are not associated with increased risk of severe gastrointestinal complications is supplied from this study. Further research is required to clarify the role BPs and other drugs of co-medication in inducing UGI

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Use of Functional Magnetic Resonance Imaging (fMRI) for the investigation of the Human Olfactory System

In vivo fMRI study of the human olfactory system is difficult not only because the devoted areas in human cortex are much less extended than those of the other sensory systems, but also for the presence of a high magnetic susceptibility around the olfactory stations. This work presents the results obtained in the attempt of developing a robust and reproducible fMRI technique to evaluate the human olfactory system in healthy subjects

Cellular and molecular features of COVID-19 associated ARDS: therapeutic relevance

The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection can be asymptomatic or cause a disease (COVID-19) characterized by different levels of severity. The main cause of severe COVID-19 and death is represented by acute (or acute on chronic) respiratory failure and acute respiratory distress syndrome (ARDS), often requiring hospital admission and ventilator support. The molecular pathogenesis of COVID-19-related ARDS (by now termed c-ARDS) is still poorly understood. In this review we will discuss the genetic susceptibility to COVID-19, the pathogenesis and the local and systemic biomarkers correlated with c-ARDS and the therapeutic options that target the cell signalling pathways of c-ARDS