Clinical and Genetic Studies in Inherited Cardiovascular Malformations

Cardiovascular malformations comprise a broad spectrum of anomalies of the heart and blood vessels, including congenital heart malformations (CHM) and aortic aneurysms, the two main topics of this thesis. These conditions lead to significant morbidity and mortality both in infancy and adulthood. A substantial proportion of cardiovascular malformations have a genetic background, including large chromosomal abnormalities, submicroscopic chromosome deletions or duplications, and single gene mutations. However, the majority of cardiovascular malformations is thought to be due to multifactorial inheritance, involving a multitude of mutations in susceptibility genes superposed on unfavorable environmental and life style factors. In the past decade, great progress has been made in the unravelling of genes involved in cardiovascular malformations. This made it possible to understand the genetic pathways and underlying pathophysiologic mechanisms, and develop therapeutic and preventive measures. It also led to the need for multidisciplinary cardiogenetic clinics in order to improve diagnosis and treatment of cardiovascular diseases. Such a multidisciplinary cardiogenetic clinic has been established in the (Paediatric) Cardiology Department of the Erasmus Medical Center in Rotterdam. In this setting most patients described in this thesis were studied. With the enthusiastic participation of these patients, their families and physicians, scientific studies were initiated to understand the genetic cause of cardiovascular malformations

Patient participation in decision making about Disease Modifying Anti-Rheumatic Drugs:perceived and preferred roles of patients

Purpose: This study explores what role patients with rheumatic diseases perceive and prefer to have in decisions about Disease-Modifying Anti-Rheumatic Drugs (DMARDs) and what the concordance between preferred and perceived role in these decisions is. Method: Patients (n = 519) diagnosed with Rheumatoid Arthritis, Arthritis Psoriatica or Ankylosis Spondylitis from 2 hospitals in the Netherlands filled out a questionnaire. Questions included perceived and preferred role in medical decision making in general, and in 4 specific decision-categories: starting to use traditional DMARDs, starting to inject a DMARD, starting to use biological DMARDs and decrease or stop using DMARDs. Result: Most respondents perceived that, in current practice, treatment decisions in general were made by the doctor (43%) or by the doctor and patient together (55%). However, the perceived roles varied per decision category: e.g., most patients (72%) felt that the decision to start using a traditional DMARD was made by the doctor, whereas the decision to decrease or stop using DMARD’s was more often perceived as being made by the patients themselves (24%) or by doctor and patient together (38%). The preferred roles were, contrary to the perceived roles, consistent across the decision-categories. Most respondents (59%-63%) preferred to share decisions with their doctor. By using a paired sample t test the concordance between the perceived and preferred role was evaluated. Table 1 shows that there was a significant difference in 4 of 5 decision categories. Only the decision to decrease or stop using DMARDs had no significant difference between perceived and preferred role. For a considerable group, the perceived and preferred participation for decision making in general matched (61%); about one third (29%) perceived less participation than preferred and a minority perceived more participation than preferred. Again, the concordance varied across the decision categories. Especially for the decision to start with a traditional DMARD, many respondents had experienced less participation than they preferred (54%). Conclusion: Although patients seem consistent in their preference for participation in various DMARD decisions, the amount of perceived participation varied across the different decisions. Patients should especially be more involved in decisions about starting to use a traditional DMARD. Patient Decision aids might be helpful tools to increase patient participation

Health-related quality of life in sarcoidosis

Purpose of review: The review presents an overview of the scientific publications in the field of health-related quality of life (HRQL) in sarcoidosis. Recent findings: Literature on HRQL in sarcoidosis is limited. HRQL was mainly used as a primary or secondary endpoint in intervention studies. Moreover, most studies have measured HRQL in sarcoidosis by means of the generic questionnaire 36-Item Short-Form Health Survey. Sarcoidosis-specific questionnaires and computer-adapted testing are innovative approaches to the field. Summary: HRQL as a primary or secondary outcome in sarcoidosis studies is still scarce. In addition to the proper definition of the concept, the mode of measurement of HRQL remains a matter of debate. Because health-economical evaluations require data on gained quality of life, future studies on sarcoidosis should include HRQL as the study endpoin

European reference network for rare vascular diseases (VASCERN) consensus statement for the screening and management of patients with pathogenic ACTA2 variants

Malaltia aòrtica; Dissecció; Aneurisma aòrtic toràcicEnfermedad aórtica; Disección; Aneurisma de aorta torácicaAortic disease; Dissection; Thoracic aortic aneurysmThe ACTA2 gene encodes for smooth muscle specific α-actin, a critical component of the contractile apparatus of the vascular smooth muscle cell. Pathogenic variants in the ACTA2 gene are the most frequently encountered genetic cause of non-syndromic hereditary thoracic aortic disease (HTAD). Although thoracic aortic aneurysm and/or dissection is the main clinical manifestation, a variety of occlusive vascular disease and extravascular manifestations occur in ACTA2-related vasculopathy. Current data suggest possible mutation-specific manifestations of vascular and extra-aortic traits. Despite its relatively high prevalence, comprehensive recommendations on the care of patients and families with pathogenic variants in ACTA2 have not yet been established. We aimed to develop a consensus document to provide medical guidance for health care professionals involved in the diagnosis and treatment of patients and relatives with pathogenic variants in ACTA2. The HTAD Working Group of the European Reference Network for Rare Vascular Diseases (VASCERN) convened to review current literature and discuss expert opinions on clinical management of ACTA2 related vasculopathy. This consensus statement summarizes our recommendations on diagnosis, monitoring, treatment, pregnancy, genetic counselling and testing in patients with ACTA2-related vasculopathy. However, there is a clear need for additional prospective multicenter studies to further define proper guidelines.This work was supported by the Dutch Heart Foundation (2014 T007) and by an Erasmus University Rotterdam Fellowship (I.M.B.H. van de Laar)

MEAN-pinolla tehdyn järjestelmän yksikkötestaaminen

Tämä opinnäytetyö on laadittu tilaajayritys Mekiwi Oy:n tarpeisiin ja siinä tutkitaan yksikkötestejä sekä niiden merkitystä ja hyötyjä MEAN-pinolla tehdyssä järjestelmässä. Tarve opinnäytetyölle ilmeni, kun sen kohteena olevan järjestelmän testausta haluttiin helpottaa ja automatisoida. Tavoitteena oli tuottaa yritykselle tietoa yksikkötestauksesta ja yksikkötestien rakentamisesta sekä suunnitella ja toteuttaa yksikkötestit kattamaan järjestelmän koko lähdekoodi. Alusta asti oli selvää, että tutkimusta tarvittaisiin varsin vähän, sillä työn painopiste on toiminnallisuudessa. Lähteiden sisältö onkin suurimmaksi osaksi teoriapohjaa, jolla avataan tarvittavat käsitteet ja teknologiat itse toteutusosaa varten. Käytetyistä lähteistä suurin osa on kunkin käsiteltävän asian kotisivuja. Opinnäytetyön tuloksena on kaksi sarjaa yksikkötestejä, jotka testaavat järjestelmän asiakassovelluksen käyttäjiä koskevia tietokantatoimintoja ja HTTP-rajapintoja. Lisäksi sen tuloksena saatiin tietoa tarvittavista toimenpiteistä yksikkötestien tekemisestä kattamaan koko järjestelmän koodi. Pelkkä testien kirjoittaminen ei tule riittämään, sillä sekä järjestelmän palvelin- että asiakassovelluksessa on koodia, jonka yksikkötestaaminen ilman koodimuutoksia on vähintäänkin epäluotettavaa ellei jopa mahdotonta.This thesis was made for a company called Mekiwi Oy. The subject is to examine the purpose and benefits of unit tests in a software built with the MEAN stack. The need for this thesis arose when the company wanted to improve the testing of a software and to make it more automatic. The goal was to provide information to the company about unit testing and to design and produce unit tests to cover the whole of the software’s codebase. It was clear right from the start that the need for research would be limited because the main focus would be on the functional side. The majority of the source material used is information about the concepts and technologies described either in the theory section or in the implementation section. The vast majority of the references are links to a homepage of the subject in question. The end result was two sets of unit tests: one testing the database functionalities regarding users and one testing the HTTP application programming interfaces regarding users. Information on creating unit tests to cover the entire codebase was also uncovered. Mere writing the unit testing will not be sufficient because both the client and the server have code that will need refactoring to make unit testing it possible

Genomic SNP array as a gold standard for prenatal diagnosis of foetal ultrasound abnormalities

Background: We have investigated whether replacing conventional karyotyping by SNP array analysis in cases of foetal ultrasound abnormalities would increase the diagnostic yield and speed of prenatal diagnosis in clinical practice. Findings/results. From May 2009 till June 2011 we performed HumanCytoSNP-12 array (HCS) (http://www.Illumina.com) analysis in 207 cases of foetal structural abnormalities. HCS allows detecting unbalanced genomic abnormalities with a resolution of about 150/200 kb. All cases were selected by a clinical geneticist after excluding the most common aneuploidies by RAD (rapid aneuploidy detection). Pre-test genetic counselling was offered in all cases. In 24/207 (11,6%) foetuses a clinically relevant genetic abnormality was detected. Only 8/24 abnormalities would have been detected if only routine karyotyping was performed. Submicroscopic abnormalities were found in 16/207 (7,7%) cases. The array results were achieved within 1-2 weeks after amniocentesis. Conclusions: Prenatal SNP array testing is faster than karyotyping and allows detecting much smaller aberrations (∼0.15 Mb) in addition to the microscopic unbalanced chromosome abnormalities detectable with karyotyping (∼ > 5 Mb). Since karyotyping would have missed 66% (16/24) of genomic abnormalities in our cohort, we propose to perform genomic high resolution array testing assisted by pre-test counselling as a primary prenatal diagnostic test in cases of foetal ultrasound abnormalities

Abnormal aortic wall properties in women with Turner syndrome

Background Turner syndrome (TS) is associated with aortic dilatation and dissection, but the underlying process is unclear. The aim of this study was to investigate the elastic properties and composition of the aortic wall in women with TS. Methods In this cross-sectional study, 52 women with TS aged 35 ± 13 years (50% monosomy, 12 with bicuspid aortic valve [BAV] and 4 with coarctation) were investigated using carotid-femoral pulse wave velocity (CF-PWV) by echocardiography and ascending aortic distensibility (AAD) and aortic arch pulse wave velocity (AA-PWV) by magnetic resonance imaging (MRI). As control group, 13 women with BAV without TS and 48 healthy patients were included. Results Women with TS showed a higher AA-PWV (β = 1.08, confidence interval [CI]: 0.54–1.62) after correcting for age and comorbidities compared with controls. We found no significant difference in AAD and CF-PWV. In women with TS, the presence of BAV, coarctation of the aorta, or monosomy (45, X) was not associated with aortic stiffness. In addition, aortic tissue samples were investigated with routine and immunohistochemical stains in five additional women with TS who were operated. The tissue showed more compact smooth muscle cell layers with abnormal deposition and structure of elastin and diminished or absent expression of contractile proteins desmin, actin, and caldesmon, as well as the progesterone receptor. Conclusion Both aortic arch stiffness measurements on MRI and histomorphological changes point toward an inherent abnormal thoracic aortic wall in women with TS

Eficacia de dexketoprofeno versus tramadol como analgesia preventiva en Anestesia General Balanceada

El dolor postoperatorio los pacientes lo aceptaban como una experiencia desagradable e inevitable, uno de los peor tratados, el control del mismo es primordial para los pacientes sometidos a cirugías abdominales. Su principio es simple y consiste en administrar un analgésico preoperatoriamente antes de la incisión quirúrgica ya que puede prevenir o reducir la hipersensibilidad de las neuronas del asta dorsal para reducir o eliminar el dolor subsiguiente. Este mal control del dolor post operatorio está asociado a una variedad de consecuencias negativas, que incluyen alteraciones cardíacas e incremento del riesgo de isquemia o infarto al miocardio, complicaciones tromboembólicas y pulmonares, alteraciones inmunes, deprivación del sueño y trastornos psicológicos como ansiedad y depresión, incrementa el riesgo de dolor postoperatorio persistente, necesidad de rehabilitación, incrementa la estancia hospitalaria o reingreso y disminuye la calidad de vida de quien la padec