Is regulatory innovation fit for purpose? A case study of adaptive regulation for advanced biotherapeutics

The need to better balance the promotion of scientific and technological innovation with risk management for consumer protection has inspired several recent reforms attempting to make regulations more flexible and adaptive. The pharmaceutical sector has a long, established regulatory tradition, as well as a long history of controversies around how to balance incentives for needed therapeutic innovations and protecting patient safety. The emergence of disruptive biotechnologies has provided the occasion for regulatory innovation in this sector. This article investigates the regulation of advanced biotherapeutics in the European Union and shows that it presents several defining features of an adaptive regulation regime, notably institutionalized processes of planned adaptation that allow regulators to gather, generate, and mobilize new scientific and risk evidence about innovative products. However, our in-depth case analysis highlights that more attention needs to be paid to the consequences of the introduction of adaptive regulations, especially for critical stakeholders involved in this new regulatory ecosystem, the capacity and resource requirements placed on them to adapt, and the new tradeoffs they face. In addition, our analysis highlights a deficit in how we currently evaluate the performance and public value proposition of adaptive regulations vis-à-vis their stated goals and objectives

Liquid-liquid coexistence in the phase diagram of a fluid confined in fractal porous materials

Multicanonical ensemble sampling simulations have been performed to calculate the phase diagram of a Lennard-Jones fluid embedded in a fractal random matrix generated through diffusion limited cluster aggregation. The study of the system at increasing size and constant porosity shows that the results are independent from the matrix realization but not from the size effects. A gas-liquid transition shifted with respect to bulk is found. On growing the size of the system on the high density side of the gas-liquid coexistence curve it appears a second coexistence region between two liquid phases. These two phases are characterized by a different behaviour of the local density inside the interconnected porous structure at the same temperature and chemical potential.Comment: 5 pages, 4 figures. To be published in Europhys. Letter

Introduction—Grand Challenges and small steps

This collection addresses two different audiences: 1) historians and philosophers of the life sciences reflecting on collaborations across disciplines, especially as regards defining and addressing Grand Challenges; 2) researchers and other stakeholders involved in cross-disciplinary collaborations aimed at tackling Grand Challenges in the life and medical sciences. The essays collected here offer ideas and resources both for the study and for the practice of goal-driven cross-disciplinary research in the life and medical sciences. We organise this introduction in three sections. The first section provides some background and context. The second motivates our take on this topic and then outlines the central ideas of each paper. The third section highlights the specificity and significance of this approach by considering: a) how this collection departs from existing literature on inter- and transdisciplinarity, b) what is characteristic about this approach, and c) what role this suggests for the history and philosophy of the life sciences in addressing Grand Challenges

Modelling Magnetar Behaviour with 3D Magnetothermal Simulations

The observational properties of isolated NSs are shaped by their magnetic field and surface temperature. They evolve in a strongly coupled fashion, and modelling them is key in understanding the emission properties of NSs. Much effort was put in tackling this problem in the past but only recently a suitable 3D numerical framework was developed. We present a set of 3D simulations addressing both the long-Term evolution (≈ 104-106 yrs) and short-lived outbursts (â 1 yr). Not only a 3D approach allows one to test complex field geometries, but it is absolutely key to model magnetar outbursts, which observations associate to the appearance of small, inherently asymmetric hot regions. Even though the mechanism that triggers these phenomena is not completely understood, following the evolution of a localised heat injection in the crust serves as a model to study the unfolding of the event

Three-dimensional Modeling of the Magnetothermal Evolution of Neutron Stars: Method and Test Cases

Neutron stars harbor extremely strong magnetic fields within their solid outer crust. The topology of this field strongly influences the surface temperature distribution and, hence, the star's observational properties. In this work, we present the first realistic simulations of the coupled crustal magnetothermal evolution of isolated neutron stars in three dimensions accounting for neutrino emission, obtained with the pseudo-spectral code parody. We investigate both the secular evolution, especially in connection with the onset of instabilities during the Hall phase, and the short-term evolution following episodes of localized energy injection. Simulations show that a resistive tearing instability develops in about a Hall time if the initial toroidal field exceeds $\approx {10}^{15}$ G. This leads to crustal failures because of the huge magnetic stresses coupled with the local temperature enhancement produced by dissipation. Localized heat deposition in the crust results in the appearance of hot spots on the star surface, which can exhibit a variety of patterns. Because the transport properties are strongly influenced by the magnetic field, the hot regions tend to drift away and get deformed following the magnetic field lines while cooling. The shapes obtained with our simulations are reminiscent of those recently derived from NICER X-ray observations of the millisecond pulsar PSR J0030+0451

Calidad de vida en niños con antecedentes de desnutrición

Estudio observacional, prospectivo, transversal y correlacional dirigido a estimar las prevalencias de condiciones físicas, psicológicas y sociales en diferentes circunstancias de salud o enfermedad. Se investiga la relación de un atributo específico (condición social o de salud) y parámetros desarrollados para medir la calidad de vida.Fil: Armelini, Pedro Alberto. Universidad Católica de Córdoba. Facultad de Ciencias de la Salud; ArgentinaFil: Apaz, María Teresa. Universidad Católica de Córdoba. Facultad de Ciencia Política y Relaciones Internacionales; Argentin

The laminar organization of the motor cortex in monodactylous mammals: a comparative assessment based on horse, chimpanzee, and macaque

The architecture of the neocortex classically consists of six layers, based on cytological criteria and on the layout of intra/interlaminar connections. Yet, the comparison of cortical cytoarchitectonic features across different species proves overwhelmingly difficult, due to the lack of a reliable model to analyze the connection patterns of neuronal ensembles forming the different layers. We first defined a set of suitable morphometric cell features, obtained in digitized Nissl-stained sections of the motor cortex of the horse, chimpanzee, and crab-eating macaque. We then modeled them using a quite general non-parametric data representation model, showing that the assessment of neuronal cell complexity (i.e., how a given cell differs from its neighbors) can be performed using a suitable measure of statistical dispersion such as the mean absolute deviation\u2014mean absolute deviation (MAD). Along with the non-parametric combination and permutation methodology, application of MAD allowed not only to estimate, but also to compare and rank the motor cortical complexity across different species. As to the instances presented in this paper, we show that the pyramidal layers of the motor cortex of the horse are far more irregular than those of primates. This feature could be related to the different organizations of the motor system in monodactylous mammals

Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification.

Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by a combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on brain imaging. To date, mutations in five genes have been linked to PFBC. However, more than 50% of individuals affected by PFBC have no molecular diagnosis. We report four unrelated families presenting with initial learning difficulties and seizures and later psychiatric symptoms, cerebellar ataxia, extrapyramidal signs, and extensive calcifications on brain imaging. Through a combination of homozygosity mapping and exome sequencing, we mapped this phenotype to chromosome 21q21.3 and identified bi-allelic variants in JAM2. JAM2 encodes for the junctional-adhesion-molecule-2, a key tight-junction protein in blood-brain-barrier permeability. We show that JAM2 variants lead to reduction of JAM2 mRNA expression and absence of JAM2 protein in patient's fibroblasts, consistent with a loss-of-function mechanism. We show that the human phenotype is replicated in the jam2 complete knockout mouse (jam2 KO). Furthermore, neuropathology of jam2 KO mouse showed prominent vacuolation in the cerebral cortex, thalamus, and cerebellum and particularly widespread vacuolation in the midbrain with reactive astrogliosis and neuronal density reduction. The regions of the human brain affected on neuroimaging are similar to the affected brain areas in the myorg PFBC null mouse. Along with JAM3 and OCLN, JAM2 is the third tight-junction gene in which bi-allelic variants are associated with brain calcification, suggesting that defective cell-to-cell adhesion and dysfunction of the movement of solutes through the paracellular spaces in the neurovascular unit is a key mechanism in CNS calcification