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A subgroup of CHDs can only be treated palliatively through a Fontan circulation. In case of a failing Fontan situation, serum proteins are lost unspecifically and can also lead to a loss of vaccine antibodies. In a failing Fontan situation, heart transplantation may be the only feasible option. We describe a 17-year-old patient born with a hypoplastic left heart complex, who underwent Fontan completion at the age of 4 years and developed a failing Fontan physiology. Therefore, a Fontan takedown with creation of a reverse 1½-circulation was performed. Multiple exacerbations of protein losing enteropathy occurred with a hypoproteinaemia, hypalbuminaemia, and hypogammaglobulinaemia. The patient was hospitalised several times and treated with intravenous application of immunoglobulins and albumin for symptom control. Before one of this substitutions, the immunoglobulin G against measles, mumps, and rubella was determined: the patient's serum demonstrated a positive measles and rubella, but mumps was negative. After administration of the iv-therapy, the lacking antibodies were replenished, and there was a positive test for mumps. Serum samples were analysed by neutralisation test and enzyme-linked immunosorbent assay (ELISA). Although the patient had been vaccinated according to national guidelines, we saw an intermittent immune deficiency for mumps, but not for rubella and measles. For patient with a failing Fontan circulation, we recommend to test to vaccine antibodies for mumps, measles, and rubella with an ELISA an if its negative with a neutralisation test, especially in view of a possible heart transplantation to find a possible immune deficiency.

Accurate measurement of transcutaneous oxygen saturation is important for the assessment of cyanosis in CHD. Aim of this study was the evaluation of a supplementary transcutaneous oxygen saturation measurement with an Apple watch® in children with cyanotic heart disease. During a six-minute walk test, measurement of transcutaneous oxygen saturation was performed simultaneously with an Oximeter (Nellcor, Medtronic, USA) and an Apple watch® Series 7 (Apple inc, USA) in 36 children with cyanotic heart disease. Median age was 9.2 (IQR 5.7-13.8) years. Transcutaneous oxygen saturation measurement with the Apple watch® was possible in 35/36 and 34/36 subjects before and after six-minute walk test. Children, in whom Apple watch® measurement was not possible, had a transcutaneous oxygen saturation < 85% on oximeter. Before six-minute walk test, median transcutaneous oxygen saturation was 93 (IQR 91-97) % measured by oximeter and 95 (IQR 93-96) % by the Apple watch®. After a median walking distance of 437 (IQR 360-487) m, transcutaneous oxygen saturation dropped to 92 (IQR 88-95, p < 0.001) % by oximeter and to 94 (IQR 90-96, p = 0.013) % measured with the Apple watch®. In children with mild cyanosis measurement of transcutaneous oxygen saturation with an Apple watch® showed only valid results if transcutaneous oxygen saturation was > 85%, with higher values being measured with the smart watch. In children with moderate or severe cyanosis transcutaneous oxygen saturation measurement with the Apple watch® was not reliable and cannot be recommended to monitor oxygen saturation at home.

Sportomics is a subject-centered holistic method similar to metabolomics focusing on sports as the metabolic challenge. Dried blood spot is emerging as a technique due to its simplicity and reproducibility. In addition, mass spectrometry and integrative computational biology enhance our ability to understand exercise-induced modifications. We studied inflammatory blood proteins (Alpha-1-acid glycoprotein—A1AG1; Albumin; Cystatin C; C-reactive protein—CRP; Hemoglobin—HBA; Haptoglobin—HPT; Insulin-like growth factor 1; Lipopolysaccharide binding protein—LBP; Mannose-binding lectin—MBL2; Myeloperoxidase—PERM and Serum amyloid A1—SAA1), in 687 samples from 97 World-class and Olympic athletes across 16 sports in nine states. Data were analyzed with Spearman's rank-order correlation. Major correlations with CRP, LBP; MBL2; A1AG1, and SAA1 were found. The pairs CRP-SAA1 and CRP-LBP appeared with a robust positive correlation. Other pairs, LBP-SAA1; A1AG1-CRP; A1AG1-SAA1; A1AG1-MBL, and A1AG1-LBP, showed a broader correlation across the sports. The protein–protein interaction map revealed 1500 interactions with 44 core proteins, 30 of them linked to immune system processing. We propose that the inflammation follow-up in exercise can provide knowledge for internal cargo management in training, competition, recovery, doping control, and a deeper understanding of health and disease.

Background Cryopreservation of ovarian tissue is a fertility-preservation option for women before gonadotoxic treatments. However, cryopreserved ovarian tissue transplantation must be performed with caution in women with malignancies that may metastasize to the ovaries. For this purpose, detecting minimal residual disease (MRD) in the ovarian cortex using sensitive methods is a crucial step. We developed an automated ovarian tissue dissociation method to obtain ovarian cell suspensions. Results We assessed MRD by multicolor flow cytometry (MFC) in cryopreserved ovarian cortex of 15 leukemia patients: 6 with B-cell acute lymphoblastic leukemia (B-ALL), 2 with T-cell acute lymphoblastic leukemia (T-ALL) and 7 with acute myeloid leukemia (AML). Ovarian MRD was positive in 5 of the 15 leukemia patients (one T-ALL and 4 AML). No B-ALL patient was positive by MFC. Quantitative reverse-transcribed polymerase chain reaction was performed when a molecular marker was available, and confirmed the MFC results for 3 patients tested. Xenografts into immunodeficient mice were also performed with ovarian cortical tissue from 10 leukemia patients, with no evidence of leukemic cells after the 6-month grafting period. Conclusions In conclusion, this is the first study using MFC to detect MRD in ovarian cortical tissue from acute leukemia patients. MFC has been accepted in clinical practice for its ease of use, the large number of parameters available simultaneously, and high throughput analysis. We demonstrate here that MFC is a reliable method to detect MRD in cryopreserved ovarian tissue, with a view to controlling the oncological risk before ovarian tissue transplantation in leukemia patients.

Background: Exercise can be used as a model to understand immunometabolism. Biological data on elite athletes are limited, especially for female athletes, including relevant data on acute-phase proteins and amino acid metabolism. Methods: We analyzed acute-phase proteins and amino acids collected at South American, Pan-American, and Olympic Games for 16 Olympic sports. We compared female and male elite athletes (447 vs. 990 samples) across four states (fasting, pre-exercise, post-exercise, and resting) to understand sex-specific immunometabolic responses in elite athletes. Results: Considering all states and sports, we found that elite female athletes exhibited higher concentrations of C-reactive protein, lipopolysaccharide-binding protein, myeloperoxidase, haptoglobin, and IGF1, with ratios ranging from 1.2 to 2.0 (p < 0.001). Women exhibited lower concentrations of most amino acids, except for glutamate and alanine. Although almost 30% lower in women, branched-chain amino acids (BCAAs) showed a similar pattern in all states (ρ ≥ 0.9; p < 0.001), while aromatic amino acids (AAAs) showed higher consumption during exercise in women. Conclusion: We established sex dimorphism in elite athletes’ metabolic and inflammatory responses during training and competition. Our data suggest that female athletes present a lower amino acid response towards central fatigue development than male athletes. Understanding these differences can lead to insights into sex-related immuno-metabolic responses in sports or other inflammatory conditions.

De novo mutations in chromatin modifier genes can lead to a variety of complex developmental syndromes that can have severe consequences for affected patients and their families. In this dissertation we will develop a computational framework for investigating the etiology of this diverse class of disorders, with the underlying motivation being that a deeper and more thorough understanding of the mechanisms underlying these disorders is essential to supporting the development of therapeutics that can improve the quality of life for those affected. In Chapter 1 we will provide background information essential for understanding the work developed in this dissertation. We will begin this chapter with a rather broad overview of the basic biology that grounds our direction of investigation into chromatin modifier syndromes and provide some definitions for key concepts. In Chapter 2 we will then cover in some detail the methods in molecular biology that form the state of the art employed for studying chromatin modifier syndromes. In particular we will look at the various functional genomics assays that are used to measure the transcriptomic and epigenomic effects caused by mutations in chromatin modifier genes. Here we will also give a survey of existing computational methods for the analysis of data generated by these molecular biology assays. In this survey we will highlight several critical gaps that exist in current methods of analysis and note how these hinder investigations into the etiology of chromatin modifier syndromes. This will lead us into the subsequent chapters of the dissertation where we develop methods that address these gaps.In Chapter 3, we will look at the gap that exists in our ability to use existing methods to identify the scale of changes over the genome and develop a method for the analysis of differential DNA methylation that addresses this problem. In Chapter 4 we will look at the limitations of current methods for integrating analysis with the wealth of existing knowledge on the structure of and relationships between biological entities. This limitation we address in our development of a method to weight measures of gene expression specificity based on the similarity structure of the biological entities that compose the underlying sample set. The novel methods that we develop in Chapter 3 and Chapter 4 provide a framework for building a more systems level understanding of the molecular pathology of chromatin modifier syndromes that we believe will be essential in the pursuit of effective treatments and therapies for these diverse and complex disorders. To conclude in Chapter 5, we will summarize our main results and take a brief prospective look at the direction of the field of research into chromatin modifier syndromes making note of promising directions for future research to expand on the work developed here.

Background Heart failure (HF) with preserved ejection fraction (HFpEF) is increasingly prevalent worldwide due to aging and comorbidities. Epicardial adipose tissue (EAT), favored by diabetes and obesity, was shown to contribute to HFpEF pathophysiology and is an emerging therapeutic target. This study explored the relationship between ventricular EAT measured by cardiovascular magnetic resonance (CMR), metabolic factors, and imaging characteristics in controls, pre-HF patients, and HFpEF patients. Methods Patients from a Belgian cohort enrolled from December 2015 to June 2017 were categorized by HF stage: pre-HF (n = 16), HFpEF (n = 104) and compared to matched controls (n = 26) and to pre-HF (n = 191) from the Beta3-LVH cohort. Biventricular EAT volume was measured in end-diastolic short-axis cine stacks. In the Belgian cohort, associations between EAT, HF stage, and various biological and imaging markers were explored. The clinical endpoint was a composite of mortality or first HF hospitalization in the HFpEF group. Results EAT significantly differed between groups, with higher values in HFpEF patients compared to pre-HF and controls (72.4 ± 20.8ml/m 2 vs. 55.0 ± 11.8ml/m 2 and 48 ± 8.9ml/m 2 , p < 0.001) from the Belgian cohort and to pre-HF (52.0 ± 15.0 ml/m 2 , p < 0.001) from the Beta3-LVH cohort. Subsequent analyses focused on the Belgian cohort. In contrast to atrial fibrillation, diabetes prevalence and body mass index (BMI) did not differ between pre-HF and HFpEF patients. Multivariable logistic regression and random forest classification identified EAT, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and H 2 FPEF score as strong markers of HFpEF status. EAT was significantly correlated with H 2 FPEF score (r = 0.41, p = 0.003), BMI (r = 0.30, p < 0.001), high‐sensitive troponin T (r = 0.41, p < 0.001), NT-proBNP (r = 0.37, p < 0.001), soluble suppression of tumorigenicity-2 (sST2) (r = 0.30, p < 0.001), E/e’ ratio (r = 0.33, p < 0.001), and left ventricular global longitudinal strain (r = 0.35, p < 0.001). In HFpEF patients, diabetes, ischemic cardiomyopathy, and elevated sST2 were independently associated with elevated EAT. In contrast with diabetes and BMI, increased EAT was not associated with prognosis. Conclusions EAT assessed by CMR was significantly higher in HFpEF patients compared to controls and pre-HF patients, irrespective of diabetes and BMI. EAT was moderately associated with HFpEF status. HFpEF patients with elevated EAT exhibited a marked diabetic, ischemic, and inflammatory profile, highlighting the potential role of drugs targeting EAT. Trial registration Characterization of Heart Failure With Preserved Ejection Fraction; Assessment of Efficacy of Mirabegron, a New beta3-adrenergic Receptor in the Prevention of Heart Failure (Beta3_LVH). Trial registration number ClinicalTrials.gov. Identifier: NCT03197350; NCT02599480. Graphical abstract

Background Morphological aspect of polycystic ovaries (PCO) is a very common finding in an IVF center population: this includes PCOS patients identified in 18–25% of the couples presenting with infertility and so called “sonographic PCO only” the prevalence of which has been estimated as high as 33% in asymptomatic patients. Finding the optimal first intention IVF protocol for polycystic ovaries patients is still challenging in order to improve the controlled ovarian hyperstimulation (COH) outcome while avoiding ovarian hyperstimulation syndrome (OHSS). It has been suggested that women with PCO would benefit from a longer period of pituitary down-regulation. The purpose of this study was to compare an extended duration of OCP pretreatment with a classic GnRH agonist protocol. Methods A single center prospective non-randomized study was performed from January 2009 to December 2010 in the Lille University Hospital including 113 women diagnosed with PCO(S) according to the Rotterdam ultrasonographic criteria and undergoing their first IVF attempt. Comprehensive hormonal and ultra-sonographic assessments were collected during COH in these patients. LH and androgen suppression and dynamics of follicular growth were compared between the two protocols as well as the COH outcome in terms of oocyte/embryo number and quality, implantation and pregnancy rates. Results No significant difference was observed between the two groups concerning dynamics of follicular growth and hormonal values. Clinical and ongoing pregnancy rates were significantly lower in the OCP group despite same oocyte and embryo quality. Nevertheless, the cumulative pregnancy rate did not differ between the two groups. The incidence of OHSS was not statistically significant. Conclusions Extended duration of OCP pretreatment, as a first intention IVF protocol for PCO patients, does not improve the pattern of follicular growth nor the oocyte and embryo quality.

As a thinker, mystic and social critic, Simone Weil is one of the most extraordinary figures of the 20th century. She was a Marxist who experienced the relations of power between producing and ruling classes first hand as a field and factory worker. She was an internationalist who felt that the fall of Paris was a 'great day for Indo-China', and yet she wanted to fight for France. Camus called her social writings 'more penetrating and more prophetic than anything since Marx.' What comes through strongly in this book are Weil's power of analysis and criticism, her love of truth and hunger for justice, her commitment to non-violence, and, most of all, her regard for everyone and everything marginalized or excluded by orthodoxies and establishments, whether colonized people or heresy.