Auswahl der wissenschaftlichen Literatur zum Thema „Variant à risque“

Introduction. La vaccination contre la COVID-19 est une mesure efficace pour réduire le risque de formes graves chez l’adulte. Cependant, l’apparition d’un risque de myocardite post-vaccinale chez les adolescents est à considérer dans l’évaluation de la balance/bénéfice risque de la vaccination généralisée de ces sujets. Objectif. Synthétiser les données d’efficacité et de tolérance de la vaccination anti-COVID chez l’adolescent. Méthode. Revue narrative de la littérature. Résultats. Le risque de myocardite et d’hospitalisation lors d’une infection à COVID-19 est respectivement de 122/100 000 et 64/100 000 sujets. La vaccination des adolescents réduit de quasiment 100 % le risque d’infection symptomatique et divise par 10 leur risque d’hospitalisation. Les données françaises, américaines et israéliennes de pharmacovigilance ont estimé le risque de myocardite post-vaccinale variant selon le genre entre 1 à 14 cas pour 100 000 adolescents vaccinés et d’hospitalisation post-vaccinale de 10/100 000. Conclusion. La vaccination systématique des adolescents semble réduire le risque d’hospitalisation au prix de rares myocardites légères à modérées. Les mesures barrières habituelles sont toujours recommandées compte tenu de la prévalence très majoritaire du variant Delta en France.

La neutropénie fébrile (NF) est une situation fréquemment rencontrée aux urgences avec un taux de mortalité non négligeable variant de 5 à 40 %. Cette variabilité importante met en avant l’importance de stratifier le risque afin de permettre un traitement ambulatoire per os de certains patients à faible risque. En plus du MASCC (The Multinational Association for Supportive Care in Cancer) score, d’autres outils permettent d’évaluer ce risque ou sont à l’étude dans ce but, tels que le dosage de la CRP, la procalcitonine ou encore le score CISNE. Après une prise en charge rapide aux urgences incluant l’administration sans délai d’un traitement adéquat, la poursuite de l’antibiothérapie per os à domicile est envisageable chez les patients à faible risque. La combinaison amoxicilline–acide clavulanique et ciprofloxacine est le plus souvent recommandée, mais la moxifloxacine ou la lévofloxacine en monothérapie peuvent également être utilisées pour les patients traités à domicile. Le retour à domicile permet de réduire fortement les coûts engendrés par l’hospitalisation, de diminuer le risque d’infection nosocomiale et d’améliorer la qualité de vie des patients avec NF à faible risque. Dans cette optique, plusieurs critères doivent être remplis, et une discussion avec le patient reste primordiale à la prise de décision. Parmi ceux-ci, nous retiendrons notamment un score MASCC supérieur à 21, une durée attendue de neutropénie inférieure à sept jours, l’accord du patient et de son entourage ainsi que la proximité entre le domicile et un service de soin adapté.

Le stress (psychologique) est de plus en plus considéré comme un facteur de risque important et potentiellement modifiable de maladies cardiovasculaires. Le stress peut intervenir à différentes étapes du processus de développement de ces maladies : de l’exposition aux facteurs de risque cardiovasculaires (sédentarité, hypertension, tabagisme, etc.) à la manifestation préclinique et à l’issue de la maladie (récurrence d’évènements et mortalité) en passant par le développement à long terme de l’athérosclérose. Le concept de stress a beaucoup évolué au cours du XXe siècle et il est généralement admis aujourd’hui qu’un état de stress survient « lorsqu’il y a déséquilibre entre la perception qu’une personne a des contraintes que lui impose son environnement et la perception qu’elle a de ses propres ressources pour y faire face ». Même si plusieurs travaux ont montré que des situations de stress aigu (catastrophes naturelles par exemple) peuvent agir comme un déclencheur d’évènements cardiaques chez des personnes atteintes d’athérosclérose, c’est sur l’impact du stress chronique sur ce risque que se concentre l’essentiel de la recherche de type épidémiologique. Le stress au travail, qui a fait l’objet de plusieurs conceptualisations (modèles de Karasek et de Siegrist), constitue l’un des modèles de stress chronique le plus étudié, avec la mise en évidence d’augmentation du risque de maladie coronarienne variant de 30 à 60 % chez les personnes exposées à ce stress. Parmi les mécanismes pathophysiologiques privilégiés pour expliquer l’effet de stress sur le risque cardiovasculaire figurent les dysfonctionnements du système nerveux autonome (p.ex. hausse de la presse artérielle, baisse de la variabilité du rythme cardiaque), endocrinien (p.ex. sécrétion importante de cortisol) et immunitaire (p.ex. sécrétion importante de cytokines). Bien que l’importance de la prise en charge du stress ait été soulignée dans les directives européennes en matière de prévention des maladies cardiovasculaires, son application en clinique semble assez limitée.

Le trouble bipolaire (TB) est une maladie psychiatrique multifactorielle à hérédité complexe faisant intervenir des facteurs de risque génétiques et environnementaux [1]. Parmi ces facteurs de risque, des anomalies des rythmes circadiens et du sommeil ont été mises en évidence dans les TB et témoignent de l’implication d’anomalies de l’horloge circadienne dans la physiopathologie du TB [2]. En effet, Il existe une littérature importante sur les anomalies circadiennes observées dans le TB (sommeil, rythmes veille/sommeil, chronotypes, perturbations circadiennes biologiques et comportementales, etc.). Ces anomalies sont présentes, non seulement en phase aiguë, mais aussi au cours des phases de stabilité de l’humeur (ou euthymiques) constituant ainsi des anomalies « trait » du TB [2]. Ainsi, l’exploration du sommeil et des rythmes circadiens chez des patients euthymiques avec TB par des mesures objectives (actigraphie) et subjectives (questionnaires) démontre que les patients présentent un sommeil plus long, de moins bonne qualité, avec retard important à l’endormissement, plus de réveils nocturnes et un retentissement diurne plus important que des témoins sains [3]. Par ailleurs, certains variants de gènes circadiens associés au TB peuvent s’associer chez les patients à des modifications particulières de ces rythmes circadiens. Ainsi, dans une étude pilote, il a été observé qu’un variant commun associé au TB du gène ASMT (codant pour l’une des deux enzymes de synthèse de la mélatonine) était associé à une modification des rythmes circadiens marquée par une période de sommeil allongée, une plus grande activité nocturne et une plus grande stabilité des rythmes [4]. Ces résultats intéressants soulignent l’intérêt de l’exploration des anomalies circadiennes du TB dans un but étiopathogénique et diagnostique, mais aussi possiblement thérapeutique.

Cette étude vise à établir une carte du risque inondation sur la plaine côtière de Saïdia située sur le littoral méditerranéen du Nord Est du Maroc. Cette plaine est limitée au Sud par les plateaux des Ouled Mansour aux formes vigoureuses et incisés par des ravins dont les eaux temporaires se jettent directement dans la plaine. Elle est enserrée entre deux oueds : la Moulouya à l'Ouest et le Kiss à l'Est. Ce littoral est caractérisé par un climat méditerranéen semi-aride à saisons contrastées où les pluies torrentielles engendrent d'importantes inondations accentuées par la faible profondeur de la nappe phréatique. Ce contexte géomorphologique et climatique couplé aux aménagements actuels a aggravé le risque d'inondations. Dans cette étude, la méthodologie adoptée est fondée sur la structuration dans un système d'information géographique (SIG) des données de la télédétection spatiale, des produits dérivés d'un modèle numérique d'altitude (MNA) et des données exogènes (lithologie, niveau piézométrique de la nappe phréatique, etc.). L'approche analytique comporte 1) une phase de traitement numérique d'une image satellitaire GeoEye-1 pour cartographier l'occupation des sols; 2) une phase d'extraction des attributs topographiques et la morphométrie du terrain, représentés par le modèle numérique d'altitude (MNA) et 3) une phase de structuration de l'information par analyse spatiale dans un SIG. Ces informations ont permis la réalisation de deux cartes : la carte de l'aléa inondation et la carte de vulnérabilité. La carte de l'aléa inondation montre que les zones de fort à très fort aléa, représentent 57% du site. Elles sont caractérisées par de faibles altitudes (0-4m) et des profondeurs de la nappe variant entre 0 et 4m. La carte de vulnérabilité fait référence aux différentes classes d'occupation de sol. La superposition de ces deux cartes a permis d'établir la carte du risque inondation. Cette carte thématique montre que les niveaux de risque fort affectent 43\% de l'ensemble du territoire étudié, et correspondent aux abords de Oued Moulouya, et en grande partie à une vaste surface occupée par la nouvelle station balnéaire "Mediterranea--Saïdia".

La violence constitue une problématique importante dans notre système de soins. Cette violence est un phénomène complexe qui résulte de l’intrication de plusieurs facteurs étiologiques, variant selon le type de violence rencontré. L’objectif de ce travail était d’identifier des facteurs en lien avec la survenue d’évènements violents dans les soins hospitaliers, le vécu des soignants et leurs impacts. La méthode comportait une enquête transversale, multicentrique (CHU de Toulouse et Poitiers), multi-sites (urgences psychiatriques et somatiques, services fermés de psychiatrie) auprès des personnels volontaires infirmiers et aides soignants. L’auto-questionnaire comportait les caractéristiques individuelles des soignants, dont l’échelle MBI (évaluation de l’épuisement professionnel), les variables d’organisation du travail (score de Pression Temporelle, score d’Incertitude validés par Presst-Next), la partie interactionnelle dont l’échelle IRI d’empathie. L’analyse descriptive et comparative des données selon le niveau de violence précédait une régression logistique du risque de violence déclarée en fonction des variables indépendantes retenues. Le taux de réponse était de 58,1 %, 150 questionnaires furent validés et traités. Les résultats révèlent que la fréquence de confrontation à la violence et le sentiment d’insécurité au travail sont élevés chez les soignants interrogés. L’épuisement professionnel, la pression temporelle, les horaires de travail sont associés à une violence élevée. La dimension cognitive PT (Prise de perspective) de l’empathie est associée à une réduction du risque de violence déclarée. Ces résultats révèlent ainsi que l’empathie dans les soins prévient la survenue d’évènements de violence. En revanche, la pression au travail, l’épuisement professionnel et la sympathie semblent constituer des facteurs de risque par l’altération de la relation soignants-soignés.ConclusionCes résultats suggèrent la nécessité d’améliorer les conditions de travail, de prévenir l’apparition d’un épuisement professionnel et de préserver l’empathie clinique chez les soignants. Ces actions pourraient contribuer à prévenir la violence interactionnelle dans les soins par l’amélioration de la relation thérapeutique.

Un couple consulte son médecin généraliste. L’entrée en matière est directe : « Docteur, mon épouse ne veut pas se faire vacciner… Moi, je vais me faire vacciner, surtout pour elle, elle est à risque. Dites-lui, docteur… » Cette patiente de 79 ans est traitée par une trithérapie pour une hypertension. Elle a changé ses habitudes de vie depuis plusieurs années afin d’équilibrer son diabète. « Dites-lui, docteur, qu’ils vont l’intuber si elle l’attrape… » Il a douze ans de moins qu’elle et n’a qu’une monothérapie, pour son hypertension… Après avoir rappelé les facteurs associés à la gravité de la COVID-19, le médecin demande à la patiente ce qui la fait hésiter. La patiente répond de manière laconique : « rien en particulier, mais les vaccins… ». Une reformulation simple en écho obtient : « ils ont été développés rapidement… ». Le médecin rappelle brièvement pourquoi et comment la production de ces vaccins a été accélérée1. Le mari demande alors au médecin : « vous les faites, les vaccins ? ». Le médecin explique qu’il disposait jusqu’à présent de dix doses du vaccin ChAdOx1 par semaine. Il explique que d’autres vaccins sont et seront disponibles dans les jours et semaines à venir. Il explique aussi que les pharmaciens vont pouvoir désormais vacciner. Il demande aussi à ce couple ce qu’ils savent de ce vaccin. Le mari explique que ce vaccin est « moins bon » que celui à ARN, et son épouse ose : « il y a beaucoup d’effets indésirables ». Le médecin présente alors la balance bénéfice/risque de ce vaccin de manière complète, en laissant la porte ouverte aux questions2. Il rappelle que, même si la comparaison est tentante, en l’absence de comparaison directe, il n’est pas possible d’affirmer qu’un vaccin est supérieur à l’autre2. La question des variants surgit alors, et cette fois elle est posée par le couple. Le mari : « de toute façon, avec les variants… » ; l’épouse : « les vaccins marchent encore moins ». Le médecin explique alors que pour le moment le variant d’intérêt majoritaire en France est le variant dit anglais. Il explique que des signaux écossais issus d’une étude de cohorte prospective en temps réel portant sur 5,4 millions de personnes laissent à penser que les vaccins sont efficaces sur ce variant3. Lors des consultations conjointes, le médecin généraliste réalise trois consultations : celles de chacun des deux protagonistes et celle du couple. L’approche phénoménologique de Camia et Bénédini permet de comprendre la dynamique des couples4. Ces auteurs nous expliquent que le « je » devient « nous ». La retraite agit comme une rupture d’un habitus social, et cette reconstruction autour de la maladie chronique explique la crainte de la mort de l’autre. L’hésitation vaccinale demande des compétences communicationnelles mais aussi de disposer de données autour de la vaccination. Par exemple, savoir que l’analyse globale de la tolérance du ChAdOx1 est rendue difficile par la multiplicité des placebos (vaccin antiméningococcique, soluté physiologique, ou succession des deux). L’article de Pouchain et al. exprime les résultats en termes de nombre de sujets à vacciner afin d’éviter les présentations réductrices (95 % pour le Cominarty et 60 % pour le ChAdOx1) et une comparaison scientifiquement incorrecte2. La revue exercer permet de comprendre et de répondre aux questions des patients. La rédaction d’exercer remercie tous les auteurs et relecteurs qui nous ont permis de répondre aux questions générées par la COVID-19 depuis une année. Parmi ces auteurs, la rédaction remercie affectueusement Denis Pouchain, ancien rédacteur en chef de la revue.

La maladie rénale chronique est une pathologie complexe aux nombreuses étiologies et susceptible de conduire à une insuffisance chronique terminale (IRCT), c’est-à-dire une incapacité des reins à filtrer le sang, une fonction essentielle au fonctionnement de l’organisme humain. La transplantation rénale constitue le meilleur traitement de l’IRCT. Si les taux de survie du greffon rénal à court terme sont désormais satisfaisants (plus de 90% à 1 an en France), la survie à moyen et long terme n’est pas encore optimale (autour de 60% à 5 ans en France). Bien que la compatibilité HLA ait été associée à une moins survie greffon, les mécanismes impliqués dans la perte du greffon rénal ne sont pas encore totalement connus. Ces travaux ont pour but d’identifier des variants génétiques en dehors du HLA associés au rejet et à la survie du greffon rénal. Ils s’appuient sur l’analyse de données génétiques de patients transplantés exclusivement à Nantes (N=1969 paires).La combinaison des génomes du donneur et du receveur a permis la découverte d’une nouvelle incompatibilité en amont du gène TOM1L1 associée avec la perte du greffon rénal. Ce signal a été validé dans trois cohortes indépendantes. Grâce à une granularité phénotypique inédite dans la littérature de la génétique de la transplantation rénale, un premier profil génétique de l’inflammation microvasculaire isolée (IMVi) a été établi. En plus de montrer l’influence de la survenue de l’IMVi sur la survie du greffon rénal, nous avons identifié de nombreux gènes associés à ce phénotype encore peu décrit. Nous avons montré que son fond génétique se distingue de celui du rejet humoral et d’autres sous-types de l’IMV
Chronic kidney disease is a complex multifactorial pathology leading to end-stage renal disease (ESRD), which is characterized by an inability of the kidneys to filter blood. Kidney transplant is currently the best treatment of ESRD both in terms of quality of life and patient survival. Despite satisfying short term survival rates (above 90% in France), mid and long-term survival are not optimal (around 60% at 5 years in France). Even if donor-recipient HLA compatibility was shown to have adverse effects on survival, kidney graft loss underlying mechanisms are not fully understood. This work aims at identifying variants outside of the HLA region associated with kidney graft loss and rejection. It relies on the analysis of genetic data of patients exclusively transplanted in Nantes (n=x). Combining donor and recipient genomes enabled the discovery a new donor-recipient genetic mismatch upstream the TOM1L1 gene associated with kidney graft loss. This signal was replicated in three independent cohorts. Thanks to an unprecedented phenotypic granularity in kidney transplant genetics literature, we described the first genetic profile of isolated microvascular inflammation (iMVI), a poorly defined phenotype, and highlighted a different genetic background from humoral rejection. We also showed that iMVI confers a higher risk of kidney graft loss and reported several genes associated with iMVI, hence contributing to better characterize this outcome

La mort subite cardiaque est initiée par une tachycardie ventriculaire - ou une extrasystole ventriculaire - dégénérant en fibrillation ventriculaire. Les morts subites sont le plus souvent associées à des anomalies structurales du cœur ou d’origine ischémique. Cependant, certaines arythmies ventriculaires surviennent dans un contexte de cœur structurellement normal avec un ECG basal normal telles que les tachycardies ventriculaires polymorphes catécholaminergiques (CPVT) ou les torsades de pointes à couplage court (TdPcc). Le premier objectif de ma thèse a été d’étudier l’origine génétique des TdPcc grâce au séquençage d’exome de 20 patients. Cette étude nous a permis de démontrer l’hétérogénéité génétique de cette pathologie, mais aussi d’identifier une forte proportion de variants impliqués dans la régulation calcique du cœur. Nous avons analysé un variant perte de fonction CACNA1C induisant une perte de densité du courant calcique de type lent et une augmentation de l’inactivation dépendante du potentiel. Ce variant, fréquent dans la population africaine, est possiblement un facteur de vulnérabilité aux arythmies ventriculaires. Les études fonctionnelles de variants dans le gène RYR2 ont également été au centre de cette thèse avec l’identification de 3 variants RyR2 gain de fonction chez des patients atteints de TdPcc et d’un variant perte de fonction présent, pour la première fois, à l’état homozygote et hétérozygote chez deux familles atteintes de CPVT. Ce travail de thèse aura donc permis de mieux comprendre l’origine génétique des TdPcc et de montrer l’implication dans les TdPcc de deux gènes déjà bien connus dans les arythmies ventriculaires, CACNA1C et RYR2
Cardiac sudden death is due to ventricular tachycardia (VT) degenerating into ventricular fibrillation and asystole. Life-threatening arrhythmias are mostly associated with structural heart abnormalities or ischemia. In contrast, there are patients with no ECG abnormalities at basal level, such as catecholaminergic polymorphic ventricular tachycardia (CPVT) or short-coupled torsades de pointes (scTdP). The first aim of my thesis was to study the genetic origin of scTdP through exome sequencing of 20 patients. This study allowed us to show the genetic heterogeneity of this pathology, but also to identify a large proportion of variants involved in the cardiac calcium regulation. Among all identified variants, we analyzed a CACNA1C loss-of-function variant inducing a reduction in current density of the L-type calcium current and an increase of its voltage-dependent inactivation. This variant, present in 0.8% of the African population, is a new risk factor for ventricular arrhythmias. Functional studies were focused on 3 RYR2 variants leading to channel hyperactivity in patients with TdPcc and the identification of a loss-of-function variant present, for the first time, at the homozygous and the heterozygous states in two families with CPVT. This last variant lead to a blunted response to adrenergic stimulation. This work provided a better understanding of the genetics of scTdP and allowed us to show the involvement in scTdP of two genes already implicated in ventricular arrhythmias, CACNA1C and RYR2. The present studies confirm that RYR2 variants are responsible for several phenotypes associated with cardiac arrhythmias leading to sudden death

L'objectif de cette these est d'analyser le risque bancaire dans l'environnement reglementaire des annees 80. Le modele de portefeuille a deux parametres (esperance et variance) est applique a la firme bancaire et les regles prudentielles y sont introduites. Il est montre a la fois d'un point de vue theorique qu'empirique que les regles prudentielles, meme les plus sophistiquees (radio cooke), sont incapables a elles seules de maitriser le risque de defaillance bancaire. Il est suggere qu'un controle individualise des banques par les autorites soit egalement necessaire tant que les problemes d'imperfection de l'information et d'alea de moralite ne sont pas resolus
The aim of this thesis is the analysis of bank risk in the regulatory environment fo the 80's. The two parameter portfolio model (mean-variance) is applied to the banking firm and prudential rules are introduced as well. It is shown on the theoretical as well as empirical level that prudential rules are not sufficient to contain the risk of failure of banks. It is suggested that close monitoring of banks by the authorities may be a necessity as long as imperfect information and moral hazard problems are not solved

Le cancer du sein est la néoplasie la plus fréquente chez la femme. Un ensemble de facteurs génétiques et environnementaux sont impliqués dans cette maladie complexe. Dans le cadre de mes études doctorales, je me suis intéressée à la composante génétique associée au risque de cancer du sein chez les femmes dans la population générale ainsi qu’à la modification du risque pour ce cancer chez des porteuses de mutations des gènes BRCA1 et BRCA2. Actuellement, environ la moitié de cette composante génétique est expliquée par une combinaison d'allèles à pénétrance faible, moyenne ou élevée. En outre, de récentes études ont démontré l'implication majeure de certains facteurs génétiques dans la modification du risque de cancer du sein chez des porteuses de mutations de BRCA1 et BRCA2. Dans le cadre de ce projet, nous avons étudié l’impact potentiel de certains variants génétiques dans les régions régulatrices de différents gènes et évalué leurs associations avec le risque de cancer du sein. Le projet a été divisé en deux parties : tout d'abord, nous avons évalué l'association directe entre les variants associés avec l’expression allélique différentielle et le risque de cancer du sein, afin d'identifier de nouveaux locus de susceptibilité à ce cancer. En second lieu, nous avons évalué l'impact sur l’expression génique de variants caractérisés au sein des régions promotrices de certains gènes sélectionnés, pour ensuite évaluer l’impact de ces variants sur l’expression génique. En résumé, la première partie de ce projet a conduit à l'identification d'un nouveau locus de faible pénétrance associés au risque de cancer du sein sur le locus 4q21 (rs11099601, odds ratio=1.05, p = 6.4 x 10-6), et deux nouveaux locus (11q22.3 et BRCA1- rs16942) associés avec la modification du risque de cancer du sein chez les porteuses de mutations du gène BRCA1. La seconde partie du projet a permis l'identification de nouveaux variants fonctionnels situés dans les régions promotrices des gènes ESR1, ESR2, FOXA1, RAP80, NBN et CDC7. D’autres études d’association dans de plus large cohorte ainsi que d’autres analyses fonctionnelles seront nécessaires pour confimer ces résultats, ce qui permettra de les inclure dans les nouveaux outils de prédiction de risque et ainsi assurer une estimation plus précise du risque de cancer du sein.
Breast cancer is the most common malignancy in women. A set of environmental and genetic factors are involved in this complex disease. This project focused on the genetic components of breast cancer susceptibility and breast cancer risk modification in BRCA1 and BRCA2 mutation carriers. Currently, about half of the inherited susceptibility to breast cancer can be imputed to a combination of high-, intermediate-, and low-risk alleles. Thus, many as yet unknown susceptibility loci remain to be identified. Moreover, recent studies have provided evidence for the involvement of genetic risk factors that might considerably modify the risk of developing breast cancer in BRCA1 and BRCA2 mutation carriers. Furthermore, genome-wide association studies have shown that several genetic variants within non-coding gene regions are associated with breast cancer risk. In this project, we focused on regulatory gene variants and their association with breast cancer risk. The project was divided in two parts. In the first section, we evaluated the direct association between single-nucleotide polymorphisms associated with differential allelic expression and breast cancer risk in order to identify new loci of breast cancer susceptibility. In the second part, we evaluated the functional impact on gene expression of variants identified within the promoter regions of selected candidate genes and then, characterize the functional impact of these variants. In summary, the first part of this project has led to the identification of a new low-penetrance locus associated with breast cancer risk on the 4q21 locus (rs11099601; odds ratio=1.05, p= 6.4 x 10-6), and two new modifiers of breast cancer risk in BRCA1 mutations carriers (11q22.3 locus and the wild type allele of BRCA1). The second part of the project allowed us to describe new functional variants within the promoters of the selected breast cancer gene candidates. Other association studies in larger cohorts and further functional analysis will be required to confirm these results, which will allow their inclusion in breast cancer risk prediction tools and thus ensure a more accurate estimation of breast cancer risk.

Le premier chapitre examine les caractéristiques statistiques à long terme des rendements financiers en France et aux USA. Les propriétés des différents actifs font apparaître qu’à long terme les actions procurent un risque sensiblement moins élevé. En outre, les propriétés de retour à la moyenne des actions justifient qu’elles soient utilisées dans une stratégie de cycle de vie comme « option par défaut » de plans d’épargne retraite. Le chapitre deux fournit une explication au débat sur l'hypothèse d’efficience des marchés. La cause du débat est souvent attribuée à la petite taille des échantillons et à la faible puissance des tests statistiques dédiés. Afin de contourner ce problème, nous utilisons l'approche développée par Campbell et Viceira (2005) qui utilisent une méthode VAR pour mettre en évidence l’existence de retour vers la moyenne dans le cours des actifs risqués.Le troisième chapitre évalue la vitesse de convergence des cours des actions. Un moyen classique pour caractériser la vitesse de retour vers la moyenne est la « demi-vie ». En comparant les indices boursiers de quatre pays développés (États-Unis, Royaume-Uni, France et Japon) sur la période 1950-2014, nous établissons une vitesse de convergence significative, avec une demi-vie entre 4,0 et 5,8 ans.Le dernier chapitre présente les résultats d'un modèle conçu pour étudier les interactions entre la démographie et les régimes de retraite. Afin d’étudier les risques inhérents à l’utilisation des revenus du capital pour financer les retraites, nous utilisons un « Trending OU process » au lieu d’un MBG classique pour modéliser les rendements. Pour un épargnant averse au risque le marché pourrait concurrencer les régimes par répartition
Chapter one examines the long run statistical characteristics of financial returns in France and the USA for selected assets. This study clearly shows that the returns’ distributions diverge from the Gaussian strategy as regards longholding periods. Thereafter we analyze the consequences of the non-Gaussian nature of stock returns on default-option retirement plans.Chapter two provides a reasonable explanation to the strong debate on the Efficient Market Hypothesis. The cause of the debate is often attributed to small sample sizes in combination with statistical tests for mean reversion that lackpower. In order to bypass this problem, we use the approach developed by Campbell and Viceira (2005) who have settled a vectorial autoregressive methodology (VAR) to measure the mean reversion of asset returns.The third chapter evaluates the speed of convergence of stock prices. A convenient way to characterize the speed of mean reversion is the half-life. Comparing the stock indexes of four developed countries (US, UK, France and Japan) during the period 1950-2014, we establish significant mean reversion, with a half-life lying between 4,0 and 5,8 years.The final chapter provides some results from a model built in order to study the linked impacts of demography and economy on the French pension scheme. In order to reveal the risks that are contained in pension fund investment, we use a Trending Ornstein-Uhlenbeck process instead of the typical GBM for modeling stock returns. We find that funded scheme returns, net of management fees, are slightly lower thanthe PAYG internal rate of return

La présente thèse s'est inscrite dans une perspective d'améliorer les outils de mesure du risque de marché en proposant des solutions capables de reproduire certaines caractéristiques empiriques d'évolution des marchés financiers. A travers une étude empirique sur des données réelles, nous montrons que la réalité des marchés financiers possède certaines caractéristiques empiriques connues et résumées sous le nom "faits stylisés", qui rendent les mesures usuelles du risque de marché incapables de reproduire ces caractéristiques. Nous proposons des nouvelles méthodes de mesure de la Value-at-Risk (VaR), en fonction de la volatilité passée et des corrélations existant entre les actifs composant un portefeuille, dans le cadre de deux grandes approches de mesure du risque : une approche de mesure du risque global (ou risque univarié) et une approche de mesure du risque multiple (ou risque multivarié), tout en testant leur qualité prédictive au moyen des procédures de backtesting. Les résultats obtenus montrent une grande capacité des différentes mesures utilisées à capturer les faits stylisés caractérisant l'évolution des marchés financiers étudiés avec une nette surperformance des méthodes de mesure de la VaR estimées dans le cadre du risque multivarié par rapport à celles du risque univarié
This thesis has object to improve the methods for estimating market risk by offering solutions capable to replicate some empirical properties of asset returns. Through an empirical study on real data, we show that the reality of financial markets has some empirical characteristics known and summarized as "stylized facts" that render the conventional market risk measurement unable to reproduce. We propose a Value-at-Risk (VaR) measures, based on modeling portfolio volatility and correlations between assets classes, using two risk measurement approaches: an univariate risk measurement approach and multivariate risk measurement approach, and testing their quality predictive using backtesting procedures. The results obtained show a great ability of different used risk measurement to capture the stylized facts characterizing financial markets, with a clear outperformance of the multivariate VaR measures than the univariate VaR measures

Ce travail de thèse a pour thème l'étude des formulations multivariées à hétéroscedasticité conditionnelle, à travers une application aux taux de change du système monétaire européen. Dans une première section, il est procédé à une évaluation empirique de la qualité des ajustements procurés par des modèles récents : l'aspect univarié est tout d'abord envisagé, puis dans une deuxième étape une extension au cas de plusieurs variables permet un examen approfondi des modèles à facteurs et de leurs différentes méthodes d'estimation. La deuxième section a fait l'objet d'un article "Forecasting foreign exchange risk" présenté au congrès mondial de la société d'économétrie à Tokyo en août 1995. Il s'y trouve introduit en un nouveau concept de "volatilité stochastique de forme inconnue", lequel permet notamment d'apporter une interprétation possible de l'excès de kurtosis pour les distributions marginales des séries étudiées en termes de comportement aléatoire de leur variance conditionnelle. On s'intéresse ensuite au problème de l'estimation des paramètres de moyenne conditionnelle dans le cas d'un modèle multivarié autorégressif dont les erreurs suivent un processus sv : des estimateurs de type moments généralisés permettant d'obtenir des estimations plus précises que par la méthode des moindres carrés ordinaires sont alors proposés et testés à l'aide de simulations de type Monte Carlo. Des formules de prévision de la volatilité à l'horizon k sont ensuite établies pour ce même type de modèle, ce qui permet finalement une application au problème de l'allocation d'actifs pour un portefeuille constitué de devises étrangères
The object of this work is to deal with the multivariate formulations of conditional heteroskedastic models, through an application to the European monetary system. In a first section we made an empirical evaluation of the fitness of recent models when applicated to ems exchanges rates against French franc: at first we made a survey of the univariate case, then in a second step, by extending to the case of several variables, we made a particular investigation upon dynamic factors models and the different ways to estimate them. The second section permitted the presentation (7th econometric society world congress, Tokyo august 1996) of a working paper "forecasting foreign exchange risk". We introduced a new concept of stochastic volatility of unknown form, which allows particularly giving a possible interpretation of the leptokurtosis for the marginal distribution in terms of stochastic features of conditional variance. Then we considered the problem of conditional mean parameters estimation in the case of a multivariate ar model with s. V. Errors: we presented a class of gmm estimators which are more efficient than ols one ; these estimators were tested using Monte Carlo experiments. In an other hand, formulas for k-ahead forecasting volatility were built up for such multivariate models. All these results were finally applied to the problem of asset allocation

Cette thèse, basée sur des articles, propose des solutions aux investisseurs pour construire et gérer des portefeuilles en tenant compte de la fréquence des crises. Le premier chapitre explique la motivation de ces articles. Le deuxième chapitre propose une solution pour construire une allocation robuste aux risques de moyen terme alors que les trois et quatrièmes chapitres proposent des solutions pour gérer les risques de court terme. En utilisant des formulations différentes de la "robust optimization" de portefeuille, quadratique et absolue, je montre que, (a) dans la limite d'une faible incertitude sur les rendements attendus, l'allocation obtenue converge vers le portefeuille Moyenne-Variance, et que (b) dans la limite d'une grande incertitude sur les rendements attendus l'allocation obtenue converge vers une allocation "risk based" selon la forme d'incertitude définie sur les rendements. La stratégie "Inter-temporal risk parity" rééquilibre en effet un portefeuille entre un actif risqué et un actif monétaire afin de viser un risque constant au fil du temps. Lorsque la stratégie est appliquée aux actions par rapport à un portefeuille "Buy-and-Hold", il est bien connu qu'elle améliore le ratio de Sharpe et réduit les pertes maximum. J'utilise des simulations Monte-Carlo basées sur des modèles de séries temporelles de la famille GARCH afin d'analyser les effets qui expliquent ces avantages. Je décline également la stratégie aux facteurs d'investissements communément appelés "value" et "momentum", appliqués aux actions, obligations et taux de changes
This thesis, based on articles, propose solutions to investors to build and manage portfolios taking into account the frequency of crisis. The first chapter explains the motivation of these articles. The second chapter proposes a solution to build robust mid-term asset allocation whereas the chapter three and four offer solutions to manage short term risk. For a number of different formulations of robust portfolio optimization, quadratic and absolute, I show that (a) in the limit of low uncertainty in estimated asset mean returns the robust portfolio converges towards the mean-variance portfolio obtained with the same inputs, and (b) in the limit of high uncertainty the robust portfolio converges towards a risk-based portfolio, which is a function of how the uncertainty in estimated asset mean returns is defined. Inter-temporal risk parity is a strategy which rebalances between a risky asset and cash in order to target a constant level of risk over time. When applied to equities and compared to a buy and hold strategy it is known to improve the Sharpe ratio and reduce drawdowns. I used Monte Carlo simulations based on a number of time-series parametric models from the GARCH family in order to analyze the relative importance of a number of effects in explaining those benefits. I also apply these strategies to factor investing, namely value and momentum investing in equities, government bonds and foreign exchange. Value and momentum factors generate a premium which is traditionally captured by dollar-neutral long-short portfolios rebalanced every month to take into account changes in stock, bond or foreign exchange factor exposures and keep leverage constant

Les affections cardiovasculaires sont des pathologies complexes résultant des interconnexions d'un grand nombre de facteurs de risque. Si l'étiologie génétique de ces affections a largement été étudiée, les variants fonctionnels à l'origine de la large héritabilité génétique des facteurs de risque cardiovasculaire et les mécanismes d'interactions gène-gène-environnement masquant ou modulant l'effet de la génétique restent à élucider.Ce mémoire présente l'étude de la génétique de facteurs de risque des pathologies cardiovasculaires : les lipides, la pression artérielle, l'haptoglobine et le facteur de croissance de l'endothélium vasculaire.Nous avons réalisé des études d'association pangénomique sur 631 enfants non apparentés issus de la cohorte STANISLAS et avons répliqué nos résultats sur près de 9 000 enfants appartenant à quatre cohortes pédiatriques et 13 300 adultes provenant de trois cohortes distinctes.Nous avons ainsi pu démontrer que certaines associations génétiques mises en évidence chez l'adulte avaient un effet observable dès l'enfance et avons discuté des outils bioinformatiques, biostatistiques et méthodologiques manquants encore aujourd'hui à l'approche pangénomique ; notamment l'intérêt des approches transcriptomiques en validation.En conclusion, lors de notre thèse, nous avons eu à la fois une démarche épidémiologique et une démarche de proposition de designs intégrés permettant de mener plus avant les investigations sur l'étiologie génétique des pathologies cardiovasculaires
Complex synergies of multiple risk factors are at the origin of cardiovascular pathologies. Their genetic etiology has been extensively investigated but many questions remain on the identification of functional variants explaining the large genetic heritability of cardiovascular risk factors and gene-gene-environment interactions hiding or modulating genetics underpinning cardiovascular physiopathology.Herein we describe our study of the genetics of cardiovascular risk factors: lipids, blood pressure, haptoglobin and vascular endothelial growth factor.We performed Genome-Wide Scan Association Studies (GWAS) on a subsample of 631 unrelated children selected in the STANISLAS cohort and replicated our results in 9,000 children from four pediatric cohorts and 13,300 adults from three different cohorts.We demonstrated that genetic associations highlighted in adults were observable in childhood and addressed the tools missing in bioinformatics, biostatistics and methodologies used in GWAS approaches, notably concerning trasncriptomic validations.In summary, during our thesis, we followed an epidemiologic approach and proposed integrated designs in order to upgrade the investigations on genetic epidemiology of cardiovascular diseases

Cette thèse s’intéresse à différents problèmes de contrôle et d’optimisation dont il n’existe à ce jour que des solutions approchées. D’une part nous nous intéressons à des techniques visant à réduire ou supprimer les approximations pour obtenir des solutions plus précises voire exactes. D’autre part nous développons de nouvelles méthodes d’approximation pour traiter plus rapidement des problèmes à plus grande échelle. Nous étudions des méthodes numériques de simulation d’équation différentielle stochastique et d’amélioration de calculs d’espérance. Nous mettons en œuvre des techniques de type quantification pour la construction de variables de contrôle ainsi que la méthode de gradient stochastique pour la résolution de problèmes de contrôle stochastique. Nous nous intéressons aussi aux méthodes de clustering liées à la quantification, ainsi qu’à la compression d’information par réseaux neuronaux. Les problèmes étudiés sont issus non seulement de motivations financières, comme le contrôle stochastique pour la couverture d’option en marché incomplet mais aussi du traitement des grandes bases de données de médias communément appelé Big data dans le chapitre 5. Théoriquement, nous proposons différentes majorations de la convergence des méthodes numériques d’une part pour la recherche d’une stratégie optimale de couverture en marché incomplet dans le chapitre 3, d’autre part pour l’extension la technique de Beskos-Roberts de simulation d’équation différentielle dans le chapitre 4. Nous présentons une utilisation originale de la décomposition de Karhunen-Loève pour une réduction de variance de l’estimateur d’espérance dans le chapitre 2
This thesis proposes different problems of stochastic control and optimization that can be solved only thanks approximation. On one hand, we develop methodology aiming to reduce or suppress approximations to obtain more accurate solutions or something exact ones. On another hand we develop new approximation methodology in order to solve quicker larger scale problems. We study numerical methodology to simulated differential equations and enhancement of computation of expectations. We develop quantization methodology to build control variate and gradient stochastic methods to solve stochastic control problems. We are also interested in clustering methods linked to quantization, and principal composant analysis or compression of data thanks neural networks. We study problems motivated by mathematical finance, like stochastic control for the hedging of derivatives in incomplete market but also to manage huge databases of media commonly known as big Data in chapter 5. Theoretically we propose some upper bound for convergence of the numerical method used. This is the case of optimal hedging in incomplete market in chapter 3 but also an extension of Beskos-Roberts methods of exact simulation of stochastic differential equations in chapter 4. We present an original application of karhunen-Loève decomposition for a control variate of computation of expectation in chapter 2

The passage or translatio between bodies of knowledge and geographic terrains prompted the transformation of the choreomania concept from mildly quaint to dangerously exotic, in a context of rising anti-colonial revolt. This chapter introduces part II of the book, which emphasizes the transformation of ‘choreomania’ on colonial shores. Considering the rise in comparative literature and medical geography, as well as performative reconstructions of ancient Greek attitudes, this chapter shows how travellers, translators, and anthropologists contributed to expanding the archival repertoire of choreomanias with cases and marginalia emphasizing the exotic South and East. Tarantellas, in particular, imagined as gateways to Greece and Africa via Sicily, appeared to reach back not only to medieval and ancient Europe but also across to present-day Abyssinia. The tigretier, an African ‘variant’, and further apparent variants in Nigeria, made of the ‘dancing disease’ a feminine and soon, too, a typically colonial figure of duplicity and deceit.

Through an in-depth analysis of bestselling “how-to-succeed” books along with popular television shows and well-trafficked “mommy” blogs, The Rise of Neoliberal Feminism demonstrates how the notion of a happy work-family balance has not only been incorporated into the popular imagination as a progressive feminist ideal but also lies at the heart of a new variant of feminism. Embraced by high-powered women, from Facebook executive Sheryl Sandberg to Ivanka Trump, this variant of feminism abandons key terms, such as equal rights and liberation, advocating, instead, for a life of balance and happiness. What we are ultimately witnessing, Catherine Rottenberg argues, is the emergence of a neoliberal feminism that abandons the struggle to undo the unjust gendered distribution of labor and that helps to ensure that all responsibility for reproduction and care work falls squarely on the shoulders of individual women. Moreover, this increasingly dominant form of feminism simultaneously splits women into two distinct groups: worthy capital-enhancing women and the “unworthy” disposable female “other” who performs much of the domestic and care work. This split, not surprisingly, transpires along racial, class, and citizen-immigrant lines. The Rise of Neoliberal Feminism thus underscores the ways in which neoliberal feminism forsakes the vast majority of women, while it facilitates new and intensified forms of racialized and class-stratified gender exploitation. Given our frightening neoliberal reality, the monumental challenge, then, is how we can successfully reorient and reclaim feminism as a social justice movement.

Seeking to consolidate the state socialist framework of government, individual regimes developed, in dialogue with social scientific research, peculiar disciplines of state socialist governance and authoritarian socio-technics. With the help of political economy, socialist jurisprudence, political sociology, or “prognostics,” late socialist regimes tried hard to stabilize their rule. At the same time, knowledge production catalyzed from above gave rise to a critical potential that caused a majority of the experts to endorse wholeheartedly first perestroika and glasnost coming from the Soviet Union and later also the radical break with the state socialist political system. Another effort to boost the failing legitimacy of the regime was a reconfiguration of national communism. Whereas the earlier, “liberalizing” variant was turning to the liberal nationalist tradition for inspiration, linking the cause of individual and national liberty, the later, “homogenizing” version drew more on the romantic nationalist identification of the ethnic Other as the oppressor.

As one of the few resources to thoroughly examine the critical problem of over-diagnosis in psychiatry today, this title covers how over-diagnosis in psychiatric practice may lead to over-treatment. It considers the complications of the DSM-5 classification system, with particular reference to major depression, bipolar disorder, Post-traumatic Stress Disorder (PTSD), and Attention-Deficit Hyperactivity Disorder (ADHD). While each of these conditions have given rise to diagnostic fads and epidemics, the classification of mental disorders remains provisional without any biomarkers for mental disorders. It then covers the importance of conservative diagnoses, recognizing that normal variants are not necessarily disorder, and that in many cases, under-, rather than over-diagnosing may be best practice.

In this chapter, we deal with polaritons as a “quantum fluid of light”, described by variants of the Gross–Pitaevskii equation. We discuss how interactions between flowing polaritons and a defect allow to study their superfluid regime and generate topological defects. Including spin gives rise to an effective magnetic field (polariton spin-orbit coupling) that acts on the topological defects—half-solitons and half-vortices—behaving as effective magnetic monopoles. We describe various techniques to create periodic potentials, that can lead to the formation of polaritonic bands and gaps with a unique flexibility. Special focus is given to topologically nontrivial bands, leading to a polariton topological insulator, based on a polariton graphene analog.

The monograph is a study of main trends of emergence and evolution of the national historical writing in Western Europe in the XVIIth century. Based on a complex analysis of several phenomena which defined the development of the Early Modern historical writing, it provides a comparative analysis of the regional schools of historical writing (particularly those of the English antiquaries and French érudits) in the process of their respective growth and formation accomplished by the end of XVIIth century with the advent of the national historiography. The conceptual unity of the book is verified within the context of the rise of the national states in England and France, which stipulated a consistent demand for reinforcing the nationally orientated discourses not only in a historical writing but also in legal and political thought. The perception of England as an empire, entrenched in the insular historical and legal consciousness, recurring during the reigns of the Stuarts and extending to the whole British archipelago, determined the establishment of chorography as a prevalent form characteristic of the English historiography. Chorographic structure of the narrative unfolding the space of the territorial “empire” to the reader corresponded to the method of “intellectual appropriation” of the British Isles by the English antiquarians which could be defined as “cultural-historical”. A considerable role was devoted to reactualization of ethnogenetic myths at different levels: while some of them (primarily – the Galfridian myth) were regarded as relevant to the pan-British cultural and historical past, others emphasized autonomous dimensions of the past and present of distinct composites (Scotland, Ireland, Wales) The continental French variant of proto-national historiography also utilized the idea of empire but in a different mode defined by the formula “rex in regno suo imperator est”. The emerging school of érudits modelled principles of its narratives on patrimonial structures rooted in the feudal medieval society (dynasty; royal family; aristocratic lineages; seigneurial rights and vassal obligations; the system of offices created by the monarch stemming from the royal household etc.). The unity of the subjects of the French kingdom was ensured not by the shared territorial commonality but by their loyalty to the king. Therefore, the French variant of “intellectual appropriation” was developed in a socio-political direction in contrast to the territorial.

Non-Hodgkin lymphomas (NHL) are a heterogeneous group of malignancies originating from B- or T-lymphocytes and engaging lymphoid tissue. Clinically, NHL subtypes range from chronic indolent to aggressive life-threatening diseases. The incidence of NHL overall increased dramatically worldwide during the latter half of the twentieth century but has now leveled off in many countries. Although some etiologic factors have been identified, most newly diagnosed cases of NHL as well as the previous rise in incidence remain largely unexplained. Well-established risk factors include severe immune suppression following HIV/AIDS and organ transplantation, autoimmune and inflammatory disorders, some infectious agents, and family history. More recently, lifestyle factors have also been linked with certain subtypes of NHL. Through the work of the international InterLymph consortium, several subtype-specific genetic susceptibility variants have also been revealed, promising to shed further light on mechanisms of lymphomagenesis.

Using a variety of old and new archival sources to examine the emergence of the Soviet system (1917-1937), this combined approach offers chronologically coherent and original construction of some crucial stages and problems in Soviet history. The past two centuries have produced an extraordinary number of new states—more than 30 in 20th-century Europe alone. It is within this turbulent context that one must analyze the rise of the Soviet state, an entity that would prove fragile in the long run despite its all-powerful facade. An examination of the extreme features and peculiarities of the Soviet variant offers revealing insights into this exceptional historical process and contributes to a wider understanding of the European Forty Year War (1912-1953). Graziosi devotes particular attention to Soviet solutions to the peasant and nationality problems, as well as to the pre-eminent role of ideology, the rise of personal despotism, and the unusual degree of penetration between state and economy. Using a variety of interpretations, he applies concepts from political, economic, and social history to the Soviet phenomenon without losing sight of its connections with more general European developments. The life of a Bolshevik leader is used to provide an overview of the whole period from six points of view: psychology, ideology, despotism, nationality, relations with the West, and economic building. Also, an analysis of industrialization based on the accounts of foreign workers who often met a tragic fate in the great purges contributes significantly to an assessment of the role that myth building played in the Stalinist repression of the Soviet working class.

AbstractLifted (family-based) static analysis by abstract interpretation is capable of analyzing all variants of a program family simultaneously, in a single run without generating any of the variants explicitly. The elements of the underlying lifted analysis domain are tuples, which maintain one property per variant. Still, explicit property enumeration in tuples, one by one for all variants, immediately yields combinatorial explosion. This is particularly apparent in the case of program families that, apart from Boolean features, contain also numerical features with large domains, thus giving rise to astronomical configuration spaces.The key for an efficient lifted analysis is a proper handling of variability-specific constructs of the language (e.g., feature-based runtime tests and $$\texttt {\#if}$$ # if directives). In this work, we introduce a new symbolic representation of the lifted abstract domain that can efficiently analyze program families with numerical features. This makes sharing between property elements corresponding to different variants explicitly possible. The elements of the new lifted domain are constraint-based decision trees, where decision nodes are labeled with linear constraints defined over numerical features and the leaf nodes belong to an existing single-program analysis domain. To illustrate the potential of this representation, we have implemented an experimental lifted static analyzer, called SPLNum$$^2$$ 2 Analyzer, for inferring invariants of C programs. An empirical evaluation on BusyBox and on benchmarks from SV-COMP yields promising preliminary results indicating that our decision trees-based approach is effective and outperforms the baseline tuple-based approach.

Research on Spanish future-time expression has revealed a diachronic rise for the periphrastic future. However, future-in-the-past expression remains understudied. Two common variants are the periphrastic future in the imperfect (e.g., iba a bailar ‘I was going to dance’) and the conditional (e.g., bailaría ‘I would dance’). Our study is unique in assessing future-in-the-past expression through a controlled task able to elicit greater token counts and its consideration of data beyond Spain. In this exploratory study, we analyzed residents of Seville, Spain and Caracas, Venezuela via a written contextualized task, examining linguistic predictors (temporal distance, polarity, and verb type). Results echo research on future-time expression: the periphrastic form has gained traction and has developed through analogous predictors. Moreover, findings reveal notable cross-variety similarity.

AbstractRealism is generally seen as one of the most influential theories of international politics. Military and foreign policy officials adhere to the apparent timeless insights of realism. They stress the importance of power, especially military power, and the need to ensure the survival and security of the state. Ontologically, realism depicts a hostile world of power-seeking states. Some realists explain this in terms of human nature while others emphasize the anarchical structure of international politics. The chapter begins with a brief overview of the development of realist theory from Thucydides, who was an Athenian military official, to the present day. The next section explains the various epistemological, methodological, and ontological positions that realists hold. Next, the common elements that comprise the essence of realism will be identified: rationality, statism, survival, and self-help (the three S’s). In the third section, the differences between two variants of realist theory, classical and structural realism, are explained. In the conclusion the timeless wisdom of realism is revisited by considering the rise of China and the implications this has for international order.

AbstractGiven the versatility of timed automata a huge body of work has evolved that considers extensions of timed automata. One extension that has received a lot of interest is timed automata with a, possibly unbounded, stack, also called pushdown timed automata (PDTA). While different algorithms have been given for reachability in different variants of this model, most of these results are purely theoretical and do not give rise to efficient implementations. One main reason for this is that none of these algorithms (and the implementations that exist) use the so-called zone-based abstraction, but rely either on the region-abstraction or other approaches, which are significantly harder to implement.In this paper, we show that a naive extension, using simulations, of the zone based reachability algorithm for the control state reachability problem of timed automata is not sound in the presence of a stack. To understand this better we give an inductive rule based view of the zone reachability algorithm for timed automata. This alternate view allows us to analyze and adapt the rules to also work for pushdown timed automata. We obtain the first zone-based algorithm for PDTA which is terminating, sound and complete. We implement our algorithm in the tool TChecker and perform experiments to show its efficacy, thus leading the way for more practical approaches to the verification of timed pushdown systems.

Genome-wide association studies (GWAS) are designed to find associations between genomic variants and a phenotype, usually a complex multifactorial disease. The idea for association studies in a large cohort was floated after linkage analysis, which proved extremely successful in the identification of causative genes for rare disorders, but it did not come up to expectations in the case of common complex disorders where causative alleles are less frequently aggregated in families. Ever since their advent in 2005, GWAS have transformed gene identification ventures in complex disease genetics over the past fifteen years, giving rise to several powerful associations for complex traits and disorders. Association studies are based on the “common disease common variant” hypothesis which assumes that genomic variation with low penetrance and high population frequency are involved in the causation of common complex disorders. Although GWAS, complemented with the downstream functional assessment of the variants, have been successful in identifying novel disease-causing genes and biological mechanisms, the field has also received intense criticism over the years, especially its failure in tracing the so-called ‘missing heritability’. Therefore, further functional studies are mandatory to precisely establish a link between risk alleles and a phenotype. This chapter broadly covers an introduction of GWAS, their successes and limitations, and various important factors affecting the design and results, followed by challenges in the post-GWAS era.

The increased demand for product variety has implied that many manufacturing companies are struggling with managing product complexity. This article suggests a framework for combined modeling of product variants and the process flow in production and assembly for customized products. The aim of the framework is to create a visual model that illustrates the product variety relative to the process flow and provides transparency of product variety in the different process steps. Literature has suggested various methods and techniques. These provide means for reducing complexity based on analysis of the end product, but do not pay much attention to understanding where in the production and assembly processes, this variance occurs. The suggested models form a basis for analyzing and reducing product complexity based on a visual model of the product variety in each process step. The models gave rise to a reduction of the SKUs with 33% without losing product variety offered to the end customer. The initial test of the framework and models in the case company showed that the models can provide new insight into the product variety, which forms a solid basis for making decisions on reducing product portfolio variety and adjusting the order decoupling point.

Abstract Over the last decade a number of authors, including ourselves, have attempted to understand human cultural variation using Darwinian methods. This work is unified by the idea that culture is a system of inheritance: individuals vary in their skills, habits, beliefs, values, and attitudes, and these variations are transmitted to others through time by teaching, imitation, and other forms of social learning. To understand cultural change, we must account for the microevolutionary processes that increase the numbers of some cultural variants and reduce the numbers of others.

Abstract Obstructive sleep apnea (OSA) is a primary respiratory disorder, to which obese persons are more susceptible than those who are lean. It gives rise to nocturnal hypertension and, in a proportion of subjects, also to daytime hypertension. In this chapter, some of the features of OSA and its clinical physiology are considered briefly, followed by a discussion of the mechanisms that contribute to the autonomic cardiovascular changes. The responses have features of the diving response of marine mammals and to arterial hypoxia of some terrestrial species. Both conserve O2 and represent distinctive variants of the defense response from the “ready-for-action” variants of exercise and mental stress. The daytime rise in BP depends on repeated nocturnal arousals with unpleasant associations, not unlike the response to mental stress. However, the rise in BP is smaller than in stress-related EH, and the synaptic strengthening also appears to be of a different kind. Moreover, the diurnal elevation of BP affects both lean and obese people, whose BP may be normal or raised.

Two of the most central algorithmic paradigms implemented in practical solvers for maximum satisfiability (MaxSAT) and other related declarative paradigms for NP-hard combinatorial optimization are the core-guided (CG) and implicit hitting set (IHS) approaches. We develop a general unifying algorithmic framework, based on the recent notion of abstract cores, that captures both CG and IHS computations. The framework offers a unified way of establishing the correctness of variants of the approaches, and can be instantiated in novel ways giving rise to new algorithmic variants of the core-guided and IHS approaches. We illustrate the latter aspect by developing a prototype implementation of an algorithm variant for MaxSAT based on the framework.

In this paper are presented comparisons of SPH variants on academic test cases classically used to validate numerical fluid dynamics software. These comparisons are extracted from NextMuSE FP7 project activities which will be published more extensively in the near future. One of the goals of this project was to better understand the SPH method and to leave the path to its establishment within CFD methods. An important work load was thus dedicated to benchmark SPH variants on selected test cases. A number of results and conclusions of this comparative study are presented in this paper. The studied variants are: standard weekly-compressible SPH, δ-SPH, Riemann-SPH, incompressible SPH, and FVPM. The majority of the test cases also present a reference solution, either experimental or computed using a mesh-based solver. Test cases include: wave propagation, flow past a cylinder, jet impact, floating body, bubble rise, dam break on obstacle, floating body dynamics, etc. Conclusions may help SPH practitioners to choose one variant or another and shall give detailed understanding necessary to derive further improvements of the method.

Under conditions of East Siberia, the positive effect of sainfoin on the fertility of gray forest soil and the introduction of this crop into fodder five-course rotations have been studied. In Siberia the Hungarian sainfoin (Onobrychis arenaria) is well-spread. As a control variant the crop rotation without perennial legume crops (sainfoin-free) was taken. Our research on the introduction of a new legume crop — sainfoin has shown that the content of mobile phosphorus, on the average in crop rotations, varies from 15.3 to 17.1 mg per 100 g of soil, the value of the nitrate nitrogen indicator — from 21.5 to 25.3 mg/kg. The intake of organic matter into the soil, due to a green manure — sainfoin — increases the humus content to 4.8–4.9 %. The rise in the yield of cultivated grain-forage crops after perennial legumes has been proved. Thus, the yield of pea-oats amounted 2.0–2.4 t/ha feed units. Among the crops harvested for green mass corn was more productive. It provided 1.8–2.2 t/ha of feed units. Pea-oats gave less productivity — from 1.5 t/ha of feed units in a control variant to 1.8 t/ha of feed units in the variants with sainfoin. The yielding capacity of sainfoin was 2.1–2.2 t/ha of feed units. The average yield for crop rotations with sainfoin was higher than the control by 16.6 %. Taking the obtained data into account, it may be concluded that all three five-course crop rotations are productive, the best, according to all criteria, is the variant with two fields of sainfoin providing the decline in cost price up to 3529.9 rub. one feed unit, the high level of pure income 11848 rub./ha and the biggest coefficient of energy efficiency — 3.0

Background & Objective: The SARS-COV-2 virus has mutated frequently, giving rise to multiple variants with more threatening characteristics. Our study aims to assess knowledge and attitude among university students regarding the emergent variants. Method: A descriptive, cross-sectional design was utilized in this study where knowledge, attitude, and worry towards the emergent variants were tested using an online self-administered questionnaire distributed among 417 Jordanian public university students on an interactive social media platform. Results: 60% of participants believed that new COVID-19 strains can be potentially dangerous and should be dealt with, while 16% of participants believed that they weren’t an important threat. Knowledge scores among participants were low as the mean score out of 18 was x̄ = 9.14/18 (SD = ± 5.22). Worry scores among participants were moderate, as the mean score out of 35 was x̄ = 22.6 (SD = ± 5,53). Finally, we found a significant and positive correlation between knowledge and worry. (r = 0.218, p < 0.001). Conclusion: The relatively low knowledge and moderately worry scores found among a Jordanian public university students regarding COVID-19 variants shows the urgency of implementing educational programs aimed at enriching awareness in this regard. Keywords: COVID-19; Public Health; Knowledge; Worry

A coherently illuminated diffuse scatterer (object) gives rise to ensemble field statistics at spatial locations in the Fraunhofer plane of the object modeled by circularly complex Gaussian random variables [ref 1]. The joint probability density function for the phase is used to determine the ensemble phase correlation function at two arbitrary spatial locations in the object’s Fraunhofer plane (the entrance pupil plane of a telescope imaging the object). The phase correlation function is used in conjunction with a minimum variance technique to obtain an optimum solution matrix mapping phase difference measurements to phase estimates at arbitrary points in the pupil. Expressions for the expected mean squared phase error are developed for the minimum variance technique and compared with conventional Least Mean Squared reconstructors. Phase estimates using the minimum variance technique and known amplitudes are used to reconstruct the image for simple targets.

<p>The studies of building structures accounting construction stages considered the optimization of embedded materials both at the design stage and at the construction stage. Axial shortening of the vertical load-bearing elements under the effect of gravitational loads and due to the characteristics of the building materials is an important point of structural analysis of tall buildings that should be considered. The present study analyzes the influence of the floor structure stiffness and the vertical load-bearing element / floor structure connection over the axial shortening of walls and columns which affects the distribution of normal forces in them. A computational model of a building structure with simplified geometry and loads is considered to emphasize the impact of the stiffness of the floor structure. The results of the solution of several variants of calculation models are compared. Generalized conclusions are given in the end.</p>

<p>The studies of building structures accounting construction stages considered the optimization of embedded materials both at the design stage and at the construction stage. Axial shortening of the vertical load-bearing elements under the effect of gravitational loads and due to the characteristics of the building materials is an important point of structural analysis of tall buildings that should be considered. The present study analyzes the influence of the floor structure stiffness and the vertical load-bearing element / floor structure connection over the axial shortening of walls and columns which affects the distribution of normal forces in them. A computational model of a building structure with simplified geometry and loads is considered to emphasize the impact of the stiffness of the floor structure. The results of the solution of several variants of calculation models are compared. Generalized conclusions are given in the end.</p>

Microstructural engineering to obtain 100% shear area in DWTT at low temperature requires target parameters to suppress brittle fracture. In-depth characterization of benchmarked steels has confirmed that %age shear area is decreased by high number density of ultra-fine precipitates (<10nm) that contribute to precipitation strengthening, high intensity of rotated cube texture and coarse brittle constituents like M/A or carbides. The control of these parameters by nano-scale precipitate engineering of TiN-NbC was covered in a previous presentation in IPC 2016 [1]. The present paper focuses on crystallographic variants selection that controls the density and dispersion of high angle boundaries, which arrest microcracks to suppress brittle fracture, thereby increasing %age shear area in DWTT at low temperature. Studies on crystallographic variants selection in single undeformed austenite grain have clarified crystallographic variants configuration which gives rise to high angle boundaries is influenced by hardenability parameters, i.e., alloying, cooling rate and austenite grain size. The profound effect of carbon and solute niobium on density and dispersion of high angle boundaries in CGHAZ is demonstrated by analyzing EBSD data to reconstruct the shear transformation of undeformed austenite using K-S relationship. Moreover, pancaking of austenite influences crystallographic variants through Sv factor and dislocation density. Experimental results on nano-scale TiN-NbC composite precipitate engineered steel confirm that adequate solute niobium (>0.03wt%) is retained in the matrix, which is aided by the suppression of delayed strain induced precipitation of ultra-fine precipitates of NbC. The hardenability from solute niobium is found to be adequate to give high density of high angle boundaries to give about 95% shear area in DWTT at −40°C in 32 mm gage K-60 plate and 100% shear area in 16.3 mm X-90 strip. Both steels were processed by nano-scale precipitate engineering of TiN-NbC composite to control size and uniformity of distribution of austenite grains before pancaking.

In this paper, we present the design, fabrication and characterization of fully soft pneumatic artificial muscles (PAMs) with low threshold pressures that are intended for direct cardiac compression (DCC). McKibben type PAMs typically have a threshold pressure of at least 100 kPa and require rigid end fittings which may damage soft tissue and cause local stress concentrations, and thus failure points in the actuator. The actuator design we present is a variant on the McKibben PAM with the following key differences: the nylon mesh is embedded in the elastomeric tube, and closure of the end of the tube is achieved without rigid ends. The actuators were tested to investigate the effects of mesh geometry and elastomer material on force output, contraction, and rise time. Lower initial mean braid angles and softer elastomer materials provided the best force, contraction, and rise times; Up to 50 N of force, 24% contraction, and response times of 0.05 s were achieved at 100 kPa. The actuators exhibited low threshold pressures (<5 kPa) and high rupture pressures (138 kPa – 720 kPa) which suggest safe operation for the DCC application. These results demonstrate that the actuators can achieve forces, displacements, and rise times suitable to assist with cardiac function.

Human fibrinogen has repeatedly been shown to occur in a great number of different molecular forms. Some types of heterogeneity are evident already from variations in solubility properties and in ion-exchange-chromatographic as well as gel-electrophoretic behaviour of the total molecule and of its peptide chain components. The reason for these variations are partly known.Thus, degradation of the C-terminal parts and phosphorylation of two serine residues gives rise to heterogeneity in the Aα-chain. Differences in the sialylation of the carbohydrate side chain causes heterogeneity both in the Bβ- and the γ-chain. Differences in chain length at the C-terminus of the γ-chain are responsible for additional variation. All these variants are expected to exist in each human being. An other category of human fibrinogen variants may be due to genetic polymorphism within the population, i.e. the presence of inherited, common, normal variants. Seven sites of microheterogeneity have so far been tentatively identified, mainly by disagreements between protein and DNA sequence analyses. Three of the sites are located in the Aα-chain (positions 47, 296 and 312), three in the Bβ-chain (positions 162, 296 and 44-8) and one in the γ-chain (position 88). The aim of the present study was to identify these sites on the proteinchemical level in pooled plasma as well as in plasma from single individuals, especially various members of the same family. For this purpose suitable fibrinogen fragments containing the tentatively microheterogeneous sites were isolated after cleavage of fibrinogen with cyanogen bromide, trypsin and/or chymotrypsin by repeated fractionations by means of conventional and reversed-phase high-performance liquid chromatography and counter-current distribution. The components were characterized by N-terminal sequence and amino acid composition. Polymorphism in human fibrinogen has previously only once been identified by restriction fragment length analysis in a non-transcribed region of the Aα-chain locus but never in the transcribed regions, i.e. the peptide chains.The present investigation will allow the estimation of the number of peptide chain haplotypes and their possible correlation to other genetic variants of fibrinogen.

El Niño peut être considéré comme un phénomène climatique à risques multiples, et les considérations relatives aux besoins en matière d’information varient selon les populations et les risques, y compris les risques directs liés aux conditions météorologiques, la réduction de la production agricole, une insécurité alimentaire et une malnutrition plus importantes, une transmission accrue des maladies infectieuses et des conséquences sur l’accès aux soins de santé. Les communications d’avertissement de danger à long et à court terme sont susceptibles de devoir contenir différents appels à l’action, et il y aura probablement différents niveaux d’urgence à ces appels. Cette synthèse des considérations clés décrit les implications d’El Niño dans la région Afrique de l’Est et Afrique australe (ESAR) pour les initiatives de Communication des Risques et d’Engagement Communautaire (CREC), basées sur des événements météorologiques comparables antérieurs. Les enseignements tirés proviennent principalement de la littérature sur la communication des prévisions et des informations météorologiques, mais ont des implications pour la riposte CREC à risques multiples. Certains enseignements sont également tirés au-delà de l’Afrique de l’Est et de l’Afrique australe, mais sont pris en considération dans le cadre des effets anticipés d’El Niño dans la région ESAR en particulier. La première section de la note stratégique porte sur les besoins en matière d’information, la deuxième section porte sur la façon de garantir et de renforcer la confiance dans l’information, et la dernière section porte sur les stratégies de communication et d’engagement communautaire. Cette note stratégique a été commandée par le Service Collectif en tant que ressource destinée aux organisations travaillant sur la stratégie de CREC liée à El Niño dans la région ESAR.

This article explores how China’s rise as a ‘civilization state’ encourages some European states to challenge US political dominance. While countries like Russia and Turkey have also employed civilizational populist rhetoric in domestic and foreign policy issues, this article focuses on Xi Jinping’s recent visits to France, Hungary, and Serbia and examines how European leaders like Emmanuel Macron, Viktor Orbán, and Aleksandar Vučić find inspiration in China’s civilizational model. Further research is needed on the growing civilizational competition between these states and the West, particularly in Africa, where China, Russia, and Turkey project all variants (soft, smart, sharp and hard) of power to assert influence and challenge Western dominance in international relations and global politics.

“Are private schools better than public schools?” This ubiquitous debate in low- and middle-income countries is the wrong one to have. The foreword and three essays collected in this Forum each explore how to move past the stuck “public vs. private” binary. Jason Silberstein is a Research Fellow at RISE. His foreword is titled “A Shift in Perspective: Zooming Out from School Type and Bringing Neighborhood Education Systems into Focus.” It summarizes the current state of the “public vs. private” debate, outlines an alternative approach focused on neighborhood education systems, and then synthesizes key findings from the other essays. Jishnu Das has conducted decades of research on school systems in low-income countries, including in Zambia, India, and Pakistan. His essay is titled “The Emergence and Consequence of Schooling Markets.” It describes exactly what schooling markets look like in Pakistan, including the incredible variance in school quality in both public and private schools within the same village. Das then reviews the evidence on how to engineer local education markets to improve learning in all schools, including polices that have underdelivered (e.g., vouchers) and more promising policies (e.g., finance and information structured to take advantage of inter-school competition, and a focus on the lowest performing public schools). Das’ research on Pakistan is available through leaps.hks.harvard.edu, which also houses the data and documentation for the project. Lant Pritchett writes from a global lens grounded in his work on systems thinking in education. His essay is titled “Schooling Ain’t Just Learning: Controlling the Means of Producing Citizens.” It observes that governments supply, and families demand, education for many reasons. The academic emphasis on one of these reasons, producing student learning, has underweighted the critical importance of other features of education, in particular the socialization function of schooling, which more persuasively explain patterns of provision of both public school and different kinds of private schools. With this key fact in mind, Pritchett argues that there is a strong liberty case for allowing private schools, but that calls for governments to fund them are either uncompelling or “aggressively missing the point”. Joanna Härmä has done mixed-methods research on private schools across many cities and rural areas in sub-Saharan Africa and India, and has also founded a heavily-subsidized private school in Uttar Pradesh, India. Her essay responds to both Das and Pritchett and is titled “Why We Need to Stop Worrying About People’s Coping Mechanism for the ‘Global Learning Crisis’—Their Preference for Low-Fee Private Schools”. It outlines the different forces behind the rise of low-fee private schools and asserts that both the international development sector and governments have failed to usefully respond. Policy toward these private schools is sometimes overzealous, as seen in regulatory regimes that in practice are mostly used to extract bribes, and at other times overly solicitous, as seen in government subsidies that would usually be better spent improving the worst government schools. Perhaps, Härmä concludes, “we should leave well enough alone.”

Macroeconomic summary Several factors contributed to an increase in projected inflation on the forecast horizon, keeping it above the target rate. These included inflation in December that surpassed expectations (5.62%), indexation to higher inflation rates for various baskets in the consumer price index (CPI), a significant real increase in the legal minimum wage, persistent external and domestic inflationary supply shocks, and heightened exchange rate pressures. The CPI for foods was affected by the persistence of external and domestic supply shocks and was the most significant contributor to unexpectedly high inflation in the fourth quarter. Price adjustments for fuels and certain utilities can explain the acceleration in inflation for regulated items, which was more significant than anticipated. Prices in the CPI for goods excluding food and regulated items also rose more than expected. This was partly due to a smaller effect on prices from the national government’s VAT-free day than anticipated by the technical staff and more persistent external pressures, including via peso depreciation. By contrast, the CPI for services excluding food and regulated items accelerated less than expected, partly reflecting strong competition in the communications sector. This was the only major CPI basket for which prices increased below the target inflation rate. The technical staff revised its inflation forecast upward in response to certain external shocks (prices, costs, and depreciation) and domestic shocks (e.g., on meat products) that were stronger and more persistent than anticipated in the previous report. Observed inflation and a real increase in the legal minimum wage also exceeded expectations, which would boost inflation by affecting price indexation, labor costs, and inflation expectations. The technical staff now expects year-end headline inflation of 4.3% in 2022 and 3.4% in 2023; core inflation is projected to be 4.5% and 3.6%, respectively. These forecasts consider the lapse of certain price relief measures associated with the COVID-19 health emergency, which would contribute to temporarily keeping inflation above the target on the forecast horizon. It is important to note that these estimates continue to contain a significant degree of uncertainty, mainly related to the development of external and domestic supply shocks and their ultimate effects on prices. Other contributing factors include high price volatility and measurement uncertainty related to the extension of Colombia’s health emergency and tax relief measures (such as the VAT-free days) associated with the Social Investment Law (Ley de Inversión Social). The as-yet uncertain magnitude of the effects of a recent real increase in the legal minimum wage (that was high by historical standards) and high observed and expected inflation, are additional factors weighing on the overall uncertainty of the estimates in this report. The size of excess productive capacity remaining in the economy and the degree to which it is closing are also uncertain, as the evolution of the pandemic continues to represent a significant forecast risk. margin, could be less dynamic than expected. And the normalization of monetary policy in the United States could come more quickly than projected in this report, which could negatively affect international financing costs. Finally, there remains a significant degree of uncertainty related to the duration of supply chocks and the degree to which macroeconomic and political conditions could negatively affect the recovery in investment. The technical staff revised its GDP growth projection for 2022 from 4.7% to 4.3% (Graph 1.3). This revision accounts for the likelihood that a larger portion of the recent positive dynamic in private consumption would be transitory than previously expected. This estimate also contemplates less dynamic investment behavior than forecast in the previous report amid less favorable financial conditions and a highly uncertain investment environment. Third-quarter GDP growth (12.9%), which was similar to projections from the October report, and the fourth-quarter growth forecast (8.7%) reflect a positive consumption trend, which has been revised upward. This dynamic has been driven by both public and private spending. Investment growth, meanwhile, has been weaker than forecast. Available fourth-quarter data suggest that consumption spending for the period would have exceeded estimates from October, thanks to three consecutive months that included VAT-free days, a relatively low COVID-19 caseload, and mobility indicators similar to their pre-pandemic levels. By contrast, the most recently available figures on new housing developments and machinery and equipment imports suggest that investment, while continuing to rise, is growing at a slower rate than anticipated in the previous report. The trade deficit is expected to have widened, as imports would have grown at a high level and outpaced exports. Given the above, the technical staff now expects fourth-quarter economic growth of 8.7%, with overall growth for 2021 of 9.9%. Several factors should continue to contribute to output recovery in 2022, though some of these may be less significant than previously forecast. International financial conditions are expected to be less favorable, though external demand should continue to recover and terms of trade continue to increase amid higher projected oil prices. Lower unemployment rates and subsequent positive effects on household income, despite increased inflation, would also boost output recovery, as would progress in the national vaccination campaign. The technical staff expects that the conditions that have favored recent high levels of consumption would be, in large part, transitory. Consumption spending is expected to grow at a slower rate in 2022. Gross fixed capital formation (GFCF) would continue to recover, approaching its pre-pandemic level, though at a slower rate than anticipated in the previous report. This would be due to lower observed GFCF levels and the potential impact of political and fiscal uncertainty. Meanwhile, the policy interest rate would be less expansionary as the process of monetary policy normalization continues. Given the above, growth in 2022 is forecast to decelerate to 4.3% (previously 4.7%). In 2023, that figure (3.1%) is projected to converge to levels closer to the potential growth rate. In this case, excess productive capacity would be expected to tighten at a similar rate as projected in the previous report. The trade deficit would tighten more than previously projected on the forecast horizon, due to expectations of an improved export dynamic and moderation in imports. The growth forecast for 2022 considers a low basis of comparison from the first half of 2021. However, there remain significant downside risks to this forecast. The current projection does not, for example, account for any additional effects on economic activity resulting from further waves of COVID-19. High private consumption levels, which have already surpassed pre-pandemic levels by a large margin, could be less dynamic than expected. And the normalization of monetary policy in the United States could come more quickly than projected in this report, which could negatively affect international financing costs. Finally, there remains a significant degree of uncertainty related to the duration of supply chocks and the degree to which macroeconomic and political conditions could negatively affect the recovery in investment. External demand for Colombian goods and services should continue to recover amid significant global inflation pressures, high oil prices, and less favorable international financial conditions than those estimated in October. Economic activity among Colombia’s major trade partners recovered in 2021 amid countries reopening and ample international liquidity. However, that growth has been somewhat restricted by global supply chain disruptions and new outbreaks of COVID-19. The technical staff has revised its growth forecast for Colombia’s main trade partners from 6.3% to 6.9% for 2021, and from 3.4% to 3.3% for 2022; trade partner economies are expected to grow 2.6% in 2023. Colombia’s annual terms of trade increased in 2021, largely on higher oil, coffee, and coal prices. This improvement came despite increased prices for goods and services imports. The expected oil price trajectory has been revised upward, partly to supply restrictions and lagging investment in the sector that would offset reduced growth forecasts in some major economies. Elevated freight and raw materials costs and supply chain disruptions continue to affect global goods production, and have led to increases in global prices. Coupled with the recovery in global demand, this has put upward pressure on external inflation. Several emerging market economies have continued to normalize monetary policy in this context. Meanwhile, in the United States, the Federal Reserve has anticipated an end to its asset buying program. U.S. inflation in December (7.0%) was again surprisingly high and market average inflation forecasts for 2022 have increased. The Fed is expected to increase its policy rate during the first quarter of 2022, with quarterly increases anticipated over the rest of the year. For its part, Colombia’s sovereign risk premium has increased and is forecast to remain on a higher path, to levels above the 15-year-average, on the forecast horizon. This would be partly due to the effects of a less expansionary monetary policy in the United States and the accumulation of macroeconomic imbalances in Colombia. Given the above, international financial conditions are projected to be less favorable than anticipated in the October report. The increase in Colombia’s external financing costs could be more significant if upward pressures on inflation in the United States persist and monetary policy is normalized more quickly than contemplated in this report. As detailed in Section 2.3, uncertainty surrounding international financial conditions continues to be unusually high. Along with other considerations, recent concerns over the potential effects of new COVID-19 variants, the persistence of global supply chain disruptions, energy crises in certain countries, growing geopolitical tensions, and a more significant deceleration in China are all factors underlying this uncertainty. The changing macroeconomic environment toward greater inflation and unanchoring risks on inflation expectations imply a reduction in the space available for monetary policy stimulus. Recovery in domestic demand and a reduction in excess productive capacity have come in line with the technical staff’s expectations from the October report. Some upside risks to inflation have materialized, while medium-term inflation expectations have increased and are above the 3% target. Monetary policy remains expansionary. Significant global inflationary pressures and the unexpected increase in the CPI in December point to more persistent effects from recent supply shocks. Core inflation is trending upward, but remains below the 3% target. Headline and core inflation projections have increased on the forecast horizon and are above the target rate through the end of 2023. Meanwhile, the expected dynamism of domestic demand would be in line with low levels of excess productive capacity. An accumulation of macroeconomic imbalances in Colombia and the increased likelihood of a faster normalization of monetary policy in the United States would put upward pressure on sovereign risk perceptions in a more persistent manner, with implications for the exchange rate and the natural rate of interest. Persistent disruptions to international supply chains, a high real increase in the legal minimum wage, and the indexation of various baskets in the CPI to higher inflation rates could affect price expectations and push inflation above the target more persistently. These factors suggest that the space to maintain monetary stimulus has continued to diminish, though monetary policy remains expansionary. 1.2 Monetary policy decision Banco de la República’s board of directors (BDBR) in its meetings in December 2021 and January 2022 voted to continue normalizing monetary policy. The BDBR voted by a majority in these two meetings to increase the benchmark interest rate by 50 and 100 basis points, respectively, bringing the policy rate to 4.0%.