Risk of Pregnancy in Women with Cardiovascular Disease

Leading a ‘normal’ life is important to young women with heart disease, just as it is for their healthy peers, and pregnancy is one important aspect of that normal life. This thesis investigated the risk of pregnancy in women with several types of cardiac and aortic disease. Apart from some high risk groups, women with cardiac disease tolerate pregnancy reasonably well in the current era. The majority of young girls and women with heart disease can be reassured about these improving prospects, provided that we accurately search for the ones with a substantial higher risk. We are still at the beginning of elucidating this interesting research area. By shedding a light on these issues, young women with heart disease will have a chance to lead a life as close to normal

Pregnancy in congenital heart disease: Risk prediction and counselling

Risk prediction and counselling are the key to limit risks of complications during pregnancy in women with congenital heart disease. The WHO classification and clinical risk tools will guide the physician to the best available risk estimate, but an individualised approach and expert opinion remains paramount in counselling women with congenital heart disease with a pregnancy wish. In women with an estimated low-risk or intermediate-risk pregnancy, planned follow-up and a delivery plan made by a multidisciplinary team provides the best chance of an uncomplicated pregnancy. While the majority do well, there is a small group of women that need an explicit advice not to embark pregnancy, to prevent devastating situations

Managing cardiac emergencies in pregnancy

A multidisciplinary, high-risk team should evaluate all pregnant women presenting with an acute cardiac event. Such events are potentially devastating if not recognised early and treated by experienced specialists. Management decisions are determined by the severity of the maternal condition and fetal viability. The management of most cardiac complications is similar in pregnant and non-pregnant women. There are n

Peripartum Cardiomyopathy: Euro Observational Research Program

Peripartum cardiomyopathy is a rare but potentially life-threatening form of heart failure affecting women late in pregnancy or in the first months after delivery. Peripartum cardiomyopathy is difficult to diagnose and its onset and progression are variable between individuals. The pathophysiology remains poorly understood, hence treatment options are limited and possibly harmful to the foetus. Furthermore, geographical incidence varies greatly and little is known about the incidence in Western countries. To gain further understanding of the pathophysiology and incidence of peripartum cardiomyopathy, the European Society of Cardiology initiated a study group to implement a registry. This review provides an overview of current insights into peripartum cardiomyopathy, highlights the need for such a registry and provides information about this Euro Observational Research Program

Enginyeria de tràfic en xarxes de transport òptiques per a entorns d'àrea metropolitana (RPR) i de gran abast (ASON)

La arquitectura de las redes de transporte actuales está basada en la tecnología de transporte SDH (Synchronous Digital Hierarchy). Las redes SDH se han diseñado y están optimizadas básicamente para el transporte del tráfico de voz. Actualmente, se está experimentando un crecimiento exponencial del volumen de tráfico de datos. Este crecimiento se debe a que el protocolo IP se está consolidando como capa de integración para servicios múltiples, algunos de ellos con requerimientos de Calidad de Servicio (QoS) y también a la introducción de tecnología de acceso de alta velocidad. Las características estadísticas del tráfico de datos son diferentes respecto a las del tráfico telefónico. De hecho, el tráfico IP se caracteriza no solo por su asimetría sino por su naturaleza dinámica, ya que presenta fluctuaciones o picos difíciles de predecir a priori.Como consecuencia, ha surgido la necesidad de emigrar desde las actuales redes hacia una estructura más flexible y dinámica, optimizada para el transporte de tráfico de datos.La evolución de las actuales redes de transporte incluye trasladar todas las funcionalidades de SDH (conmutación, monitorización de la calidad de la señal, protección frente a fallos) a nivel óptico. El resultado consistirá en una red de transporte óptica (Optical Transport Network, OTN) basada en tecnología DWDM, con Optical Cross Connects (OXC) para encaminar canales ópticos de forma permanente o conmutada (Automatic Switched Optical Network, ASON).Uno de los principales problemas a solucionar por las operadoras de red es la eficiente gestión de la capacidad disponible, y así evitar por un lado la necesidad de sobredimensionar la red de transporte y por el otro optimizar la utilización de los recursos mediante la definición de estrategias de ingeniería de tráfico.La introducción de las redes de transporte a conmutación automática (ASON), capaces de proporcionar conexiones ópticas bajo demanda, es considerada como la solución de red que puede proporcionar el rápido y flexible aprovisionamiento de ancho de banda. Tal funcionalidad, posible gracias a la definición de un plano de control basado en el paradigma GMPLS, puede ser usada para gestionar de manera dinámica los recursos disponibles, tanto a nivel SDH como a nivel óptico, respondiendo de forma eficiente a las fluctuaciones del tráfico generado por la red cliente. Sin embargo, el problema que surge es el diseño de un mecanismo para disparar automáticamente las peticiones de establecimiento de circuitos SDH/canales ópticos conmutados.En este sentido, la primera contribución de esta Tesis es el diseño de un mecanismo de disparo de peticiones de circuitos SDH/canales ópticos basado en la monitorización y predicción del tráfico de la red cliente (IP). Además, el mecanismo diseñado incluye la definición de políticas de ingeniería de tráfico para la optimización de la utilización del elevado ancho de banda proporcionado por las conexiones ópticas. Concretamente, el mecanismo diseñado se caracteriza por la interoperabilidad entre la capa cliente y la capa de transporte.La Tesis incluye también una contribución sobre el diseño de una metodología para el dimensionado de la redes ASON, basada en la caracterización del tráfico de llegadas de peticiones de establecimiento de conexiones, mediante su valor medio y el factor de peakedness.Por otro lado, la optimización de los recursos disponibles es muy crítica cuando se produce un fallo en la infraestructura de red debido a la necesidad de encontrar rutas alternativas para el tráfico afectado. Debido al gran volumen de tráfico a transportar, un fallo en la infraestructura de red puede tener graves consecuencias económicas. Por ejemplo, un corte de una única fibra óptica produce el fallo de todas las longitudes de onda que transporta; de esta manera la pérdida de cada longitud de onda operante a 2.5 Gbps o 10 Gbps puede resultar en el corte de un enorme número de conexiones en curso. Por lo tanto, a mayor capacidad, mayor es la importancia de la rapidez y rendimiento de los mecanismos de protección y recuperación.Las estrategias de protección frente a fallos deben ser simples, minimizar las pérdidas de tráfico y deben utilizar eficientemente los recursos disponibles.La recién estandardizada tecnología para redes de entornos metropolitanos, Resilient Packet Ring (RPR) se caracteriza por mecanismos de protección optimizados para minimizar el tiempo de recuperación en caso de fallos. Además, tales mecanismos no requieren la asignación a priori de recursos de red a utilizar solamente en caso de fallos.Por lo que respecta a los mecanismos de recuperación, se puede optar por una estrategia de recuperación en una sola capa (single layer recovery) o alternativamente por una estrategia de recuperación en múltiples capas (multi-layer recovery), donde en la recuperación intervienen diferentes capas de la estructura de red. El esquema de recuperación multi-capas más fácil de implementar es el consistente en ejecutar los mecanismos de protección/recuperación de los distintos niveles de manera paralela e independiente. Esta estrategia no es, sin embargo, la más eficiente. La interoperabilidad entre los mecanismos de protección de las diferentes capas permite reaccionar más rápidamente a los fallos que se pueden producir.La segunda contribución de esta Tesis es el diseño de una política de coordinación entre los mecanismos de protección proporcionados por RPR y los mecanismos de protección definidos por la capa óptica. Concretamente, la estrategia diseñada se basa en la interoperabilidad entre la capa RPR y la capa de transporte (OTN) para redes de entornos metropolitanos. La estrategia diseñada permite, además, la optimización de los recursos de red.The main objective of the traffic engineering (TE) strategies is the efficient mapping of the actual traffic onto the available network resources. Legacy Time Division Multiplexing-based networking architecture was basically designed to transport symmetric voice traffic. However, the volume of data traffic is increasing at explosive rate and already dominates the voice traffic. This is due to a progressive migration of many applications and services over the Internet Protocol (IP) and also to a deeper and deeper introduction of high-speed access technologies. Also there is the convergence towards the IP of real-time applications (i.e. multimedia applications) which have very strict QoS requirements. The statistical characteristics of the data traffic are rather different from those of telephone traffic. Specifically, IP traffic is highly dynamic showing predictable and unpredictable traffic surges/peaks. Such surges are caused by unexpected events such as user' behaviours, weather conditions, accidents, fault, etc. This can cause significant fluctuations of the aggregated data traffic to be carried by the transport networks. The current SONET/SDH transport networks (but also the incoming Optical Transport Networks) tend to be static, which means that connections (SONET/SDH circuits and light paths) are provided manually through the Network Management System. The manual configuration is time consuming, which means that weeks or even months are needed to provide high bandwidth connections.The highly dynamic IP traffic pattern does not match with the static provisioning of capacity of the optical transport networks, leading to non-optimal utilization of the resources (i.e. network congestion or under-utilization of resources).Thus, the problem that arises for Network Operators is how to efficiently manage the network resources in the transport network to efficiently respond to the changes in the traffic demands reaching, in such a way, traffic engineering objectives. The introduction of the Automatic Switched Optical Networks (ASON), which is able to provide dynamically switched connections on demand, is recognized as the enabling solution to meet the requirement of fast and flexible end-to-end bandwidth provisioning. The automatic set up and tear down of optical connections can be used for the dynamic management of the transport network resources to track significant variations in the volume of the network client traffic. In such a context, a mechanism that triggers demands to set up/tear down light paths as a function of the variation of the client traffic to be transported is required. The design of a multi-layer traffic engineering (MTE) strategy for IP/MPLS over ASON/GMPLS networks to face with the dynamic traffic demands is the first contribution of this Ph.D. Thesis. It has to be underlined that the policies for the set up of the light paths are out of the scope of this work. In fact, it is assumed that the set up/tear down of the switched connections is in charge of the ASON control plane, namely the GMPLS-based routing and signalling protocols.As a second contribution, it is presented a practical approach for ASON networks dimensioning purposes based on the approximate characterization of the traffic arrival process, through its mean and the peakedness factor. On the other hand, the optimization of the utilization of network resources is very critical when failures occur in the network as a consequence of the need of rerouting the affected traffic. The increase of the capacity and number of wavelengths that can be multiplexed onto the same fibre, each one carrying 2.5 or 10 Gbps client signals, implies that outages of the network infrastructure can have serious economical and social consequences. Network recovery/resilience, i.e., the capability of the networks to efficiently recover from failures, has become of vital importance. Thus, optical transport networks need to be very robust to face failures. The protection mechanisms should be designed basically with the aim to be simple, to minimize the traffic losses and to optimize the utilization of the network resources.Survivability strategies in current transport networks are based on the pre-allocation of network resources to be used only to switch (route) the affected traffic in case of failures. In legacy multi-layer networks, each layer (e.g. IP, SDH) has its own protection mechanism built in, independent from the other layers. Network recovery basically relies on the SONET/SDH network layer. Indeed, different mechanisms, based on the protection approach, have been proposed that allow fast recovery within the target of 50 ms. Nevertheless, SONET/SDH protection is mainly limited to ring topologies and it is not able to distinguish between different priorities of traffic and it has not vision of higher layer failures.The emerging packet-based Resilient Packet Ring (RPR) technology for metropolitan networks provides powerful protection mechanisms that minimize the time needed to restore the traffic without the pre-allocation of resources.To face to failures, the resilience single-layer strategy (a single layer has the responsibility for the recovery) is very simple from the implementation point of view. However it may not be able to efficiently recover the network from all kind of failures that can occur. Therefore, multi-layer resilience (various network layers can participate to the recovery actions) provides better performance not only in terms of protection but also in terms of resources optimization. Multi-layer resilience strategies require coordinating the recovery mechanisms provided by each layer. In such a context, another contribution of this Ph.D. Thesis is the design and evaluation of a multi-layer resilience mechanism to be used in the IP over RPR over intelligent optical transport network for metropolitan environment to efficiently face with a wide range of network outages, while optimizing the utilization of the network resources. Its novelty relies on the interworking required between the RPR and the optical transport layer. Finally, the fourth contribution of the Thesis deals with the optimization of the bandwidth utlization of the RPR rings taking benefits from the automatic switching of optical connections capabilities of the underlying ASON/GMPLS networks.Postprint (published version

Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: A multi-ethnic meta-analysis of 45,891 individuals

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8- 1.2 ×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10−4). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10−3, n = 22,044), increased triglycerides (p = 2.6×10−14, n = 93,440), increased waist-to-hip ratio (p = 1.8×10−5, n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10−3, n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL- cholesterol concentrations (p = 4.5×10−13, n = 96,748) and decreased BMI (p = 1.4×10−4, n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance

Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index

The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single-nucleotide polymorphisms (SNPs) with the lowest P-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI-related loci was performed in the AN GWAMA. We detected significant associations (P-values <5 × 10-5, Bonferroni-corrected P<0.05) for nine SNP alleles at three independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; Poverall: 2.47 × 10-06/Pfemales: 3.45 × 10-07/Pmales: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet-induced obese (DIO) mice as compared with age-matched lean controls. We observed no evidence for associations for the look-up of BMI-related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the association with obesity was primarily driven by females. In addition, the detected altered hypothalamic expression patterns of Ctbp2 and Nbeal1 as a result of fasting and DIO implicate these genes in weight regulation

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes

OBJECTIVE - Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired b-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS - We have conducted a meta-analysis of genome-wide association tests of ;2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS - Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10-8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/ C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 3 10-4), improved b-cell function (P = 1.1 × 10-5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10-6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS - We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis