Validation d’un fixateur extramédullaire pour l’ostéogenèse par distraction chez les patients pédiatriques

La distraction osseuse est une procédure chirurgicale employée pour corriger l’asymétrie de patients atteints d’une inégalité de longueur des membres inférieurs. Cette technique consiste en l’espacement graduel de segments osseux, suite à une corticotomie de l’os à allonger. La distraction de l’os et sa stabilisation sont contrôlées par un fixateur extensible. Entre autres, le fixateur externe de type Iizarov est le plus utilisé en orthopédie pédiatrique. Cependant, il est encombrant et son aspect percutané entraîne des infections et des cicatrisations excessives. L’utilisation de fixateur intramédullaire remédie à ce type de problème, mais seulement chez l’adulte. En effet, son utilisation chez les enfants n’est pas possible car son installation endommagerait les plaques épiphysaires, ce qui altérerait le processus de croissance de l’enfant. Il n’existe actuellement pas de solution commercialisée optimale pour les patients pédiatriques souffrant d’une inégalité de longueur des membres inférieurs. Pour répondre à ce besoin, un fixateur interne extramédullaire composé de plaques télescopiques a été conçu dans le laboratoire de Prof. Isabelle Villemure. Totalement implantable grâce à son mécanisme activé magnétiquement à distance, ce dispositif préserve les plaques épiphysaires et le périoste par son système de fixation à l’aide de vis de verrouillage sur la surface externe de l’os. Son fonctionnement repose sur les mouvements relatifs de trois groupes cinématiquement liés, soit la translation du bloc piston le long du bloc canon grâce à la rotation des pièces standards. Par le biais d’un test de distraction, simulant les forces de résistance des tissus, la première version du dispositif, dite de Polytechnique, a pu générer une force de distraction jusqu’à 735N, ce qui est supérieur à la force maximale de résistance des tissus pour les allongements osseux pédiatriques (673N). Cependant, cette version n’est pas adaptée pour une étude in vivo à cause de sa taille, de la présence de colle non biocompatible et de la présence d’interstices fragilisant le dispositif face à une potentielle infiltration de liquide. L’objectif de ce projet était de concevoir une nouvelle version adaptée pour une étude in vivo. Une version améliorée du fixateur, dite E-kut, a donc été conçue en réduisant en longueur la taille du dispositif pour être en adéquation avec les dimensions d’un fémur de mouton mature, en retirant les interstices et en ajoutant un joint en silicone pour gagner en étanchéité et en affinant la manufacture des pièces par la méthode d’électroérosion proposée par Electro-Kut. La distraction maximale possible est donc réduite et passe de 5cm à 2cm pour la version Polytechnique et celle de E-Kut, respectivement. Trois prototypes de cette version ont été manufacturés. Le premier dispositif (D1) a été irradié au rayon gamma par Nordion et sa stérilité a été testée par Neopharm Labs. Bien que certifié stérile, une présence de résidu et de liquide a été observée après l’ouverture du dispositif. Une analyse du dispositif a déterminé que la cause de cette non-étanchéité était le serrage trop faible entre le canon et son tube. Le deuxième dispositif (D2) a été utilisé pour des tests de distraction classique. Il s’est avéré ne pas pouvoir générer de force de distraction supérieure à 196N, niveau de charge auquel le serrage entre le canon et son tube a cédé. De plus, le bris du réducteur a permis d’identifier un mauvais transfert des charges, qui devrait s’effectuer entre l’accouplement mécanique et le roulement à billes axial, mais qui se faisait entre les axes du réducteur et de la tige filetée. Le troisième dispositif (D3), bénéficiant d’une manufacture plus rigoureuse, a été utilisé pour poursuivre les tests de distraction. Il a été à nouveau impossible de générer des forces de distraction supérieur à 196N, à cause de frottement trop élevé entre le bloc piston et le tube du canon. Afin de continuer les tests sur la version E-kut et déceler de potentiels autres disfonctionnements, un quatrième dispositif (D4) a été confectionné à partir des pièces fonctionnelles des trois autres, tout en éloignant les axes du réducteur et de la tige filetée, afin de corriger le problème de transfert de charge. D4 a subi des tests de distraction classique et s’est avéré ne pas pouvoir générer de force de distraction supérieure à 222N. L’interruption du test a été provoquée par la rupture des serrages entre le piston et son bouchon, et entre le canon et son tube. De plus, un effet ressort non négligeable, i.e. une variation maximum de 1.4mm, a été observé à la pose et au retrait des poids. Les tests sur ces quatre dispositifs ont permis d’identifier trois principaux problèmes nuisant au bon fonctionnement de la version E-kut du dispositif, soient l’effet ressort de l’accouplement mécanique, la liaison encastrement inadéquate entre le canon et son tube et la liaison encastrement inadéquate entre le piston et son bouchon. La version E-kut a donc été modifiée par, premièrement, le renforcement des liaisons encastrement, et donc de l’étanchéité, en ajoutant des soudures entre le canon et son tube et au niveau des bouchons et en implémentant des goupilles au niveau des bouchons (D4+ et D5) et par, secondement, la suppression de l’effet ressort en remplaçant l’accouplement mécanique flexible et la tige filetée par un bloc monolithique (D5). Deux dispositifs (D4+, D5) ont alors été assemblés en combinant de nouvelles pièces fabriquées et des pièces restantes des autres dispositifs. D4+ et D5 ont pu générer une force de distraction jusqu’à 814N, sans signe de défaillance mécanique et avec une vitesse de distraction constante (de 0.1430 ± 0.0049mm/s pour D4+ et 0.1427 ± 0.0047mm/s pour D5) indépendamment de l’augmentation de poids. De plus, aucun effet ressort ne fut observé sur D5 qui possédait le bloc monolithique. La version E-Kut modifiée a donc été démontrée valide mécaniquement. En parallèle à ces travaux, la méthode du test de distraction a été perfectionnée. En effet, l’une des étapes préalables au test de distraction est l’installation de l’os synthétique dans le banc expérimental. Or, le positionnement, qui se faisait visuellement, n’était pas reproductible. C’est pourquoi des socles contenant un moule de la partie proximale de l’os et dont le plan de la base est normal à l’axe souhaité (anatomique ou mécanique) ont été conçus. Pour ce faire, le modèle 3D du fémur artificiel utilisé pour les expériences a été obtenu par rétro-ingénierie. Les modèles des socles ont été créés en conséquence tout en ayant défini préalablement les axes sur CATIA. Ils ont ensuite été imprimés en 3D. Ils assureront un positionnement immédiat de l’os artificiel selon l’axe souhaité pour les futurs tests de distraction. Bien que la version E-Kut améliorée (D5) ait été démontrée valide mécaniquement, des modifications de design supplémentaires sont requises. En effet, l’incorporation d’une butée et d’un embrayage serait nécessaire pour limiter la distraction maximale du dispositif et, par conséquent empêcher le désengagement de la tige filetée du tube du piston. Une réduction en longueur est aussi requise pour pouvoir réaliser un test in vivo sur un mouton pédiatrique (vs adulte), de même qu’une réduction en diamètre est recommandée pour se rapprocher des dimensions des dispositifs sur le marché. Il reste aussi l’ajout du joint en silicone entre la version Polytechnique et E-Kut qui n’a pas pu être validé. Un test d’étanchéité est donc à prévoir. Enfin, pour continuer la validation mécanique du dispositif, sa stabilité biomécanique devra être évaluée à partir de tests de résistance mécanique. Les tests de distraction devront aussi être poursuivis en les réalisant selon l’axe mécanique d’un os artificiel, similairement à l’utilisation clinique prévue. Ainsi l’objectif général a été complété puisqu’une version adaptée pour une étude in vivo a été conçue et validée mécaniquement sous distraction avec chargement. La méthode de stérilisation par irradiation gamma resterait cependant à revalider afin de s’assurer qu’aucun liquide ne s’infiltre à l’intérieur du dispositif D5. Un test préliminaire in vivo sur un mouton adulte permettra de vérifier si la génération du cal osseux se fait sans encombre pendant une distraction avec ce fixateur. Les travaux futurs comprennent également l’amélioration de la manette pour contrôler le dispositif en contexte in vivo.----------ABSTRACT Distraction osteogenesis is a surgical procedure used to treat limb length discrepancies. This technique is based on a bone corticotomy, followed by progressive separation of the resultant bone segments. Extensible fixators are used to distract and stabilize bone segments. The Iizarov type external fixator is the most widely used in pediatric orthopedics. However, it is bulky and increases risk of pin tract infections and scarring. Intramedullary fixators overcome these issues but only for adults’ patients. In fact, these fixators are not implantable in children since the growth plates would be damaged upon implantation, hence impeding the child’s normal musculoskeletal development. There is currently no optimal commercially available solution for pediatric patients with limb length discrepancies. To meet this need, an internal extramedullary fixator was designed in the laboratory of Prof. Isabelle Villemure. Fully implantable thanks to its remotely magnetic controlled mechanism, this device composed of two telescopic bodies preserves the epiphyseal plates, as well as the periosteum by its fixation system using locking screws on the external surface of the bone. Its operation consists in relative movements of three kinematically linked groups, i.e. the translation of the piston block along the barrel block in response to the rotation of standard parts. A distraction test, simulating tissue resistance forces, was designed and the first version of the device, named Polytechnique, was shown to generate distraction forces up to 735N, which exceeds the value of soft tissue resistance forces in pediatric limb lengthening (673N). Nevertheless, this version is not adapted for an in vivo animal study because of its size, the presence of non-biocompatible glue and the presence of interstices that weaken the device against potential liquid infiltration. Therefore, the goal of this project was to design a new version of the device suitable for in vivo tests. An improved version, named E-Kut, was created by reducing the length of the device to match the dimensions of a mature sheep's femur, removing the interstices and adding a silicone gasket to improve sealing and by refining the manufacture of the parts using the electrical discharge machining proposed by Electro-Kut. The maximum possible distraction is therefore reduced from 5cm to 2cm for the Polytechnique and E-Kut versions, respectively. Three prototypes of this version were manufactured. The first protoptype (D1) was gamma irradiated by Nordion and its sterility was tested by Neopharm Labs. Although certified sterile, some residue and liquid were observed after the device was opened. An analysis of the device determined that the cause of this non-sealing was the insufficient fit between the barrel and its tube. The second device (D2) was used for conventional distraction testing. It was found to be unable to generate a distraction force greater than 196N, the load level at which the fit between the barrel and its tube broke. In addition, the failure of the gearbox identified a wrong load transfer, which should have occurred between the coupling and the axial bearing but was between the shafts of the gearbox and the leadscrew. The third device (D3), benefiting from a more rigorous manufacturing process, was used to proceed the distraction tests. It was again impossible to generate distraction forces greater than 196N, due to excessive friction between the piston block and the barrel tube. In order to continue the tests on the E-kut version and to detect other potential defects, a fourth device (D4) was made from the functional parts of the other three, while taking care to distance the shafts of the gearbox and the leadscrew from each other, in order to correct the load transfer problem. D4 underwent conventional distraction tests and was found to be unable to generate a distraction force greater than 222N. The interruption of the test was caused by the rupture of the fit between the piston and its cap, and between the barrel and its tube. Moreover, a non-negligible spring effect, i.e. a maximum variation of 1.4mm, was observed at the installation and removal of the weights. These tests on four devices allowed us to identify three main problems affecting the correct operation of the E-kut version of the device, i.e. the spring effect of the coupling, the inadequate fit connection between the barrel and its tube, and the inadequate fit connection between the piston and its cap. The E-Kut version was therefore modified to improve further the previous version. Firstly, the fit and the sealing were reinforced by adding welds between the barrel, its tube, and at the caps and also by implementing pins at the caps (D4+ and D5). Secondly, the spring effect was eliminated by replacing the flexible coupling and the leadscrew with a monolithic block (D5). Two devices (D4+, D5) were then assembled by combining new manufactured parts and remaining parts from the other devices. D4+ and D5 could generate a distraction force of up to 814N, without any sign of mechanical failure and with a constant distraction rate (0.1430 ± 0.0049mm/s for D4+ and 0.1427 ± 0.0047mm/s for D5) regardless of the weight increase. Moreover, no spring effect was observed on D5 which had been improved with the monolithic block. The modified E-Kut version was therefore shown to be mechanically valid. In parallel with this work, the distraction test method was improved. In fact, one of the steps prior to the distraction test is the installation of the synthetic bone in the experimental bench However, its placement, which was done visually, was not reproducible. For this reason, supports containing a mold of the proximal part of the bone were designed in such a way that their base plane is normal to the desired axis (anatomical or mechanical). To do this, the 3D model of the artificial femur used for the experiments was obtained by reverse engineering. The models of the supports were created accordingly while having previously defined the axis (anatomical or mechanical) on CATIA. They were then printed in 3D. They will ensure immediate placement of the artificial bone along the desired axis for future distraction tests. Although the improved E-Kut version (D5) has been shown to be mechanically valid, additional design modifications are still required. Indeed, the incorporation of an abutment and a clutch would be necessary to limit the maximum distraction of the device and therefore prevent the disengagement of the leadscrew from the piston tube. A reduction in length is also required to perform an in vivo test on a pediatric (vs adult) sheep femur, and a reduction in diameter is recommended to approach the dimensions of devices on the market. There is also the addition of the silicone gasket between the Polytechnique and E-Kut versions which could not be validated. A tightness test is therefore to be planned. Finally, in order to proceed the mechanical validation of the device, its biomechanical stability will have to be evaluated using resistance tests. Distraction tests will also have to be proceeded by performing them along the mechanical axis of an artificial bone, similarly to the intended clinical use. In summary, the general objective of this project was completed since an adapted version for an in vivo study was designed and mechanically validated under distraction with loading. However, the sterilization by gamma irradiation method would still need to be revalidated to ensure that no liquid infiltrates into the D5 device. A preliminary in vivo test on an adult sheep will allowed us to verify that the generation of the bone callus can be safely achieved during distraction with this fixator. Future work also includes improving the controller to control the device in an in vivo context

Implementation of tiled vector services: a case study

Abstract. Vector tiling aims at cutting vector data into smaller entities. It offers several opportunities, especially for the development of web-mapping systems, such as the possibilities to apply different styles, to access attributes or to render 3D data. Today no open and widely adopted standard exists for the implementation of web services involving vector tiles. In this paper we investigate several important parameters that need to be considered for the implementation of vector tile services. We then present a case-study where several tiled vector services are implemented. The results of this case study are useful for further implementations of tiled vector services and discussions regarding standardization

Peristrut microhemorrhages: a possible cause of in-stent neoatherosclerosis?

AbstractBackgroundIn-stent neoatherosclerosis is characterized by the delayed appearance of markers of atheroma in the subintima, but the pathophysiology underlying this new disease entity remains unclear.Methods and resultsWe collected 20 human coronary artery stents by removal from explanted hearts. The mean duration of stent implantation was 34 months. In all samples, neoatherosclerosis was detected, particularly in peristrut areas. It consisted of foam cells and cholesterol clefts, with or without calcification, associated with neovascularization. Iron and glycophorin-A were present in peristrut areas, as well as autofluorescent ceroids. Moreover, in response to neoatherosclerosis, tertiary lymphoid organs (tissue lymphoid clusters) often developed in the adventitia. Some of these features could be reproduced in an experimental carotid stenting model in rabbits fed a high-cholesterol diet. Foam cells were present in all samples, and peristrut red blood cells (RBCs) were also detected, as shown by iron deposits and Bandeiraea simplicifiola isolectin-B4 staining of RBC membranes. Finally, in silico models were used to evaluate the compliance mismatch between the rigid struts and the distensible arterial wall using finite element analysis. They show that stenting approximately doubles the local von Mises stress in the intimal layer.ConclusionsWe show here that stent implantation both in human and in rabbit arteries is characterized by local peristrut microhemorrhages and finally by both cholesterol accumulation and oxidation, triggering together in-stent neoatherosclerosis. Our data indicate that these processes are likely initiated by an increased mechanical stress due to the compliance mismatch between the rigid stent and the soft wall

Drug-induced eRF1 degradation promotes readthrough and reveals a new branch of ribosome quality control.

Suppression of premature termination codons (PTCs) by translational readthrough is a promising strategy to treat a wide variety of severe genetic diseases caused by nonsense mutations. Here, we present two potent readthrough promoters-NVS1.1 and NVS2.1-that restore substantial levels of functional full-length CFTR and IDUA proteins in disease models for cystic fibrosis and Hurler syndrome, respectively. In contrast to other readthrough promoters that affect stop codon decoding, the NVS compounds stimulate PTC suppression by triggering rapid proteasomal degradation of the translation termination factor eRF1. Our results show that this occurs by trapping eRF1 in the terminating ribosome, causing ribosome stalls and subsequent ribosome collisions, and activating a branch of the ribosome-associated quality control network, which involves the translational stress sensor GCN1 and the catalytic activity of the E3 ubiquitin ligases RNF14 and RNF25

Models of quintessence coupled to the electromagnetic field and the cosmological evolution of alpha

We study the change of the effective fine structure constant in the cosmological models of a scalar field with a non-vanishing coupling to the electromagnetic field. Combining cosmological data and terrestrial observations we place empirical constraints on the size of the possible coupling and explore a large class of models that exhibit tracking behavior. The change of the fine structure constant implied by the quasar absorption spectra together with the requirement of tracking behavior impose a lower bound of the size of this coupling. Furthermore, the transition to the quintessence regime implies a narrow window for this coupling around $10^{-5}$ in units of the inverse Planck mass. We also propose a non-minimal coupling between electromagnetism and quintessence which has the effect of leading only to changes of alpha determined from atomic physics phenomena, but leaving no observable consequences through nuclear physics effects. In doing so we are able to reconcile the claimed cosmological evidence for a changing fine structure constant with the tight constraints emerging from the Oklo natural nuclear reactor.Comment: 13 pages, 10 figures, RevTex, new references adde

Global carbon budget 2022

Accurate assessment of anthropogenic carbon dioxide (CO2) emissions and their redistribution among the atmosphere, ocean, and terrestrial biosphere in a changing climate is critical to better understand the global carbon cycle, support the development of climate policies, and project future climate change. Here we describe and synthesize data sets and methodologies to quantify the five major components of the global carbon budget and their uncertainties. Fossil CO2 emissions (EFOS) are based on energy statistics and cement production data, while emissions from land-use change (ELUC), mainly deforestation, are based on land use and land-use change data and bookkeeping models. Atmospheric CO2 concentration is measured directly, and its growth rate (GATM) is computed from the annual changes in concentration. The ocean CO2 sink (SOCEAN) is estimated with global ocean biogeochemistry models and observation-based data products. The terrestrial CO2 sink (SLAND) is estimated with dynamic global vegetation models. The resulting carbon budget imbalance (BIM), the difference between the estimated total emissions and the estimated changes in the atmosphere, ocean, and terrestrial biosphere, is a measure of imperfect data and understanding of the contemporary carbon cycle. All uncertainties are reported as ±1σ. For the year 2021, EFOS increased by 5.1% relative to 2020, with fossil emissions at 10.1±0.5GtCyr-1 (9.9±0.5GtCyr-1 when the cement carbonation sink is included), and ELUC was 1.1±0.7GtCyr-1, for a total anthropogenic CO2 emission (including the cement carbonation sink) of 10.9±0.8GtCyr-1 (40.0±2.9GtCO2). Also, for 2021, GATM was 5.2±0.2GtCyr-1 (2.5±0.1ppmyr-1), SOCEAN was 2.9 ±0.4GtCyr-1, and SLAND was 3.5±0.9GtCyr-1, with a BIM of -0.6GtCyr-1 (i.e. the total estimated sources were too low or sinks were too high). The global atmospheric CO2 concentration averaged over 2021 reached 414.71±0.1ppm. Preliminary data for 2022 suggest an increase in EFOS relative to 2021 of +1.0% (0.1% to 1.9%) globally and atmospheric CO2 concentration reaching 417.2ppm, more than 50% above pre-industrial levels (around 278ppm). Overall, the mean and trend in the components of the global carbon budget are consistently estimated over the period 1959-2021, but discrepancies of up to 1GtCyr-1 persist for the representation of annual to semi-decadal variability in CO2 fluxes. Comparison of estimates from multiple approaches and observations shows (1) a persistent large uncertainty in the estimate of land-use change emissions, (2) a low agreement between the different methods on the magnitude of the land CO2 flux in the northern extratropics, and (3) a discrepancy between the different methods on the strength of the ocean sink over the last decade. This living data update documents changes in the methods and data sets used in this new global carbon budget and the progress in understanding of the global carbon cycle compared with previous publications of this data set. The data presented in this work are available at 10.18160/GCP-2022 (Friedlingstein et al., 2022b)

Stability and moduli spaces of syzygy bundles

It is a longstanding problem in Algebraic Geometry to determine whether a syzygy bundle on the projective space defined as the kernel of a general epimorphism given by homogeneous forms is (semi)stable. In this thesis, attention is restricted to the case of syzygy bundles associated to n generic forms of the same degree d

Global Carbon Budget 2022

Accurate assessment of anthropogenic carbon dioxide (CO$_2$) emissions and their redistribution among the atmosphere, ocean, and terrestrial biosphere in a changing climate is critical to better understand the global carbon cycle, support the development of climate policies, and project future climate change. Here we describe and synthesize data sets and methodologies to quantify the five major components of the global carbon budget and their uncertainties. Fossil CO$_2$ emissions (E$_{FOS}$) are based on energy statistics and cement production data, while emissions from land-use change (E$_{LUC}$), mainly deforestation, are based on land use and land-use change data and bookkeeping models. Atmospheric CO$_2$ concentration is measured directly, and its growth rate (G$_{ATM}$) is computed from the annual changes in concentration. The ocean CO$_2$ sink (S$_{OCEAN}$) is estimated with global ocean biogeochemistry models and observation-based data products. The terrestrial CO$_2$ sink (S$_{LAND}$) is estimated with dynamic global vegetation models. The resulting carbon budget imbalance (B$_{IM}$), the difference between the estimated total emissions and the estimated changes in the atmosphere, ocean, and terrestrial biosphere, is a measure of imperfect data and understanding of the contemporary carbon cycle. All uncertainties are reported as ±1σ. For the year 2021, E$_{FOS}$ increased by 5.1 % relative to 2020, with fossil emissions at 10.1 ± 0.5 GtC yr$^{−1}$ (9.9 ± 0.5 GtC yr$^{−1}$ when the cement carbonation sink is included), and E$_{LUC}$ was 1.1 ± 0.7 GtC yr$^{−1}$, for a total anthropogenic CO$_2$ emission (including the cement carbonation sink) of 10.9 ± 0.8 GtC yr$^{−1}$ (40.0 ± 2.9 GtCO$_2$). Also, for 2021, G$_{ATM}$ was 5.2 ± 0.2 GtC yr$^{−1}$ (2.5 ± 0.1 ppm yr$^{−1}$), S$_{OCEAN}$ was 2.9  ± 0.4 GtC yr$^{−1}$, and S$_{LAND}$ was 3.5 ± 0.9 GtC yr$^{−1}$, with a B$_{IM}$ of −0.6 GtC yr$^{−1}$ (i.e. the total estimated sources were too low or sinks were too high). The global atmospheric CO$_2$ concentration averaged over 2021 reached 414.71 ± 0.1 ppm. Preliminary data for 2022 suggest an increase in E$_{FOS}$ relative to 2021 of +1.0 % (0.1 % to 1.9 %) globally and atmospheric CO$_2$ concentration reaching 417.2 ppm, more than 50 % above pre-industrial levels (around 278 ppm). Overall, the mean and trend in the components of the global carbon budget are consistently estimated over the period 1959–2021, but discrepancies of up to 1 GtC yr$^{−1}$ persist for the representation of annual to semi-decadal variability in CO$_2$ fluxes. Comparison of estimates from multiple approaches and observations shows (1) a persistent large uncertainty in the estimate of land-use change emissions, (2) a low agreement between the different methods on the magnitude of the land CO$_2$ flux in the northern extratropics, and (3) a discrepancy between the different methods on the strength of the ocean sink over the last decade. This living data update documents changes in the methods and data sets used in this new global carbon budget and the progress in understanding of the global carbon cycle compared with previous publications of this data set. The data presented in this work are available at https://doi.org/10.18160/GCP-2022 (Friedlingstein et al., 2022b)

Varying constants, Gravitation and Cosmology

Fundamental constants are a cornerstone of our physical laws. Any constant varying in space and/or time would reflect the existence of an almost massless field that couples to matter. This will induce a violation of the universality of free fall. It is thus of utmost importance for our understanding of gravity and of the domain of validity of general relativity to test for their constancy. We thus detail the relations between the constants, the tests of the local position invariance and of the universality of free fall. We then review the main experimental and observational constraints that have been obtained from atomic clocks, the Oklo phenomenon, Solar system observations, meteorites dating, quasar absorption spectra, stellar physics, pulsar timing, the cosmic microwave background and big bang nucleosynthesis. At each step we describe the basics of each system, its dependence with respect to the constants, the known systematic effects and the most recent constraints that have been obtained. We then describe the main theoretical frameworks in which the low-energy constants may actually be varying and we focus on the unification mechanisms and the relations between the variation of different constants. To finish, we discuss the more speculative possibility of understanding their numerical values and the apparent fine-tuning that they confront us with.Comment: 145 pages, 10 figures, Review for Living Reviews in Relativit

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders