The role of advanced glycation end-products (AGEs) in patients with chronic heart failure with or without diabetes mellitus

Background: Both Diabetes Mellitus (DM) and heart failure (HF) are becoming diseases of epidemic proportions. In patients with DM and HF, symptoms seem to be more severe compared to similar HF patients without DM. There are several possible explanations for this. In recent years, the accumulation of AGEs is recognized as an important factor in the development and progression of chronic HF. Amongst several other properties, AGEs stimulate collagen crosslink formation. This crosslink formation might induce stiffening of the myocardium, leading to diastolic HF. In the vascular smooth muscle cells, collagen crosslink formation might contribute to vascular stiffening, leading to decreased vascular compliance, and therefore increased afterload. Previous studies show that AGE levels are increased in patients with DM. However, the relation between AGE levels, quality of life, diastolic function and vascular elasticity in patients with chronic HF with or without DM is unknown. We hypothesize that patients with high AGE levels have more often DM, have more severe symptoms which can impair quality of life, and have a more impaired diastolic cardiac function and vascular elasticity. Methods: We collected clinical and laboratory data, non-invasive pulse wave measurements and echocardiographic parameters for diastolic function of 42 patients with chronic HF, of whom 21 also had DM type II. Patients performed a cardiopulmonary exercise test (VO2max) and fill in a Minnesota Living with Heart Failure Questionnaire (MLHFQ), a questionnaire that reflects quality of life in patients with heart failure. Results: Patients with high AGE levels had more often DM (70% vs. 30%, p=0.01). Age and gender were similar. No association was found between AGE levels, diastolic function and vascular elasticity. However, MLHFQ and peak VO2 were associated with AGE levels (r=0.49; p=0.001 and r=-0.44; p=0.006, respectively). Univariate regression analysis showed that AGE levels were associated with age (p=0.04), DM (p=0.05), smoking (p=0.02) and MLHFQ (p=0.001). For MLHFQ and smoking, this relation continued after correcting for confounding variables (p= 0.001 and p=0.01, respectively). Conclusion: Chronic HF patients with high AGE levels have more often DM and have a more impaired quality of life and than similar patients with low AGE levels. No relation was found between AGE levels and diastolic and vascular function.

Overview of the GANIL Control Systems for the Different Projects Around the Facility

TUPHA016, Poster SessionInternational audienceThe GANIL facility is drastically extending its possibilities with new projects, soincreasing its capabilities in nuclear physics. The most significant one is the Spiral2installation based on a linear accelerator, then to be associated with the S3, NFSand DESIR new experimental rooms. Beside of the legacy home made controlsystem handling the original installation, Epics was chosen as the basic frameworkfor these projects. First, some control system components were used during preliminarybeam tests. In parallel, the whole architecture was designed while theorganization for future operation started to be considered; also, more structuredand sophisticated tools were developed and the first high level applications for thewhole machine tuning started to be tested, jointly with the current onsite beamcommissioning. Progression of the control system development is presented, fromthe first beam tests up to the whole Spiral2 commissioning. Then, according tothe new projects to cope with, some highlights are given concerning the relatedorganization as well as specific items and developments to be considered, takingbenefit from the Spiral2 control system feedback experience

Familial Occurrence of Adult Granulosa Cell Tumors: Analysis of Whole-Genome Germline Variants

Simple SummaryAlthough granulosa cell tumors can occur in rare syndromes and one familial case of a granulosa cell tumor has been described, a genetic predisposition for granulosa cell tumors has not been identified. Through our collaborations with patients, we identified four families in which two women of each family were diagnosed with an adult granulosa cell tumor. Although predicted deleterious variants in PIK3C2G, BMP5, and LRP2 were found, we could not identify an overlapping genetic variant or affected locus that may explain a genetic predisposition for granulosa cell tumors. The age of onset in the familial patients was significantly lower (median 38 years, range from 17 to 60) than in sporadic patients (median between 50 and 55 years). Furthermore, breast cancer, polycystic ovary syndrome, and subfertility were seen in these families.Adult granulosa cell tumor (AGCT) is a rare ovarian cancer subtype, with a peak incidence around 50-55 years. Although AGCT can occur in specific syndromes, a genetic predisposition for AGCT has not been identified. The aim of this study is to identify a genetic variant in families with AGCT patients, potentially contributing to tumor evolution. We identified four families, each including two women diagnosed with AGCT. Whole-genome sequencing was performed to identify overlapping germline variants or affected genes. Familial relationship was evaluated using genealogy and genomic analyses. Patient characteristics, medical (family) history, and pedigrees were collected. Findings were compared to a reference group of 33 unrelated AGCT patients. Mean age at diagnosis was 38 years (range from 17 to 60) versus 51 years in the reference group, and seven of eight patients were premenopausal. In two families, three first degree relatives were diagnosed with breast cancer. Furthermore, polycystic ovary syndrome (PCOS) and subfertility was reported in three families. Predicted deleterious variants in PIK3C2G, BMP5, and LRP2 were identified. In conclusion, AGCTs occur in families and could potentially be hereditary. In these families, the age of AGCT diagnosis is lower and cases of breast cancer, PCOS, and subfertility are present. We could not identify an overlapping genetic variant or affected locus that may explain a genetic predisposition for AGCT.Cervix cance

Multidisciplinary Perspectives on Signalling Text Organisation

Coordination éditoriale du numéro : Shirley Carter-Thomas & Frédéric Landragi

Integrated clinical and omics approach to rare diseases: novel genes and oligogenic inheritance in holoprosencephaly

Kim et al. identify novel genes and disease pathways in the forebrain developmental disorder holoprosencephaly, and show that many cases involve oligogenic inheritance. The findings underline the roles of Sonic Hedgehog and primary cilia in forebrain development, and show that integrating clinical phenotyping into genetic studies can uncover relevant mutations.Holoprosencephaly is a pathology of forebrain development characterized by high phenotypic heterogeneity. The disease presents with various clinical manifestations at the cerebral or facial levels. Several genes have been implicated in holoprosencephaly but its genetic basis remains unclear: different transmission patterns have been described including autosomal dominant, recessive and digenic inheritance. Conventional molecular testing approaches result in a very low diagnostic yield and most cases remain unsolved. In our study, we address the possibility that genetically unsolved cases of holoprosencephaly present an oligogenic origin and result from combined inherited mutations in several genes. Twenty-six unrelated families, for whom no genetic cause of holoprosencephaly could be identified in clinical settings [whole exome sequencing and comparative genomic hybridization (CGH)-array analyses], were reanalysed under the hypothesis of oligogenic inheritance. Standard variant analysis was improved with a gene prioritization strategy based on clinical ontologies and gene co-expression networks. Clinical phenotyping and exploration of cross-species similarities were further performed on a family-by-family basis. Statistical validation was performed on 248 ancestrally similar control trios provided by the Genome of the Netherlands project and on 574 ancestrally matched controls provided by the French Exome Project. Variants of clinical interest were identified in 180 genes significantly associated with key pathways of forebrain development including sonic hedgehog (SHH) and primary cilia. Oligogenic events were observed in 10 families and involved both known and novel holoprosencephaly genes including recurrently mutated FAT1, NDST1, COL2A1 and SCUBE2. The incidence of oligogenic combinations was significantly higher in holoprosencephaly patients compared to two control populations (P < 10(9)). We also show that depending on the affected genes, patients present with particular clinical features. This study reports novel disease genes and supports oligogenicity as clinically relevant model in holoprosencephaly. It also highlights key roles of SHH signalling and primary cilia in forebrain development. We hypothesize that distinction between different clinical manifestations of holoprosencephaly lies in the degree of overall functional impact on SHH signalling. Finally, we underline that integrating clinical phenotyping in genetic studies is a powerful tool to specify the clinical relevance of certain mutations.Molecular Technology and Informatics for Personalised Medicine and Healt

At-admission prediction of mortality and pulmonary embolism in an international cohort of hospitalised patients with COVID-19 using statistical and machine learning methods

By September 2022, more than 600 million cases of SARS-CoV-2 infection have been reported globally, resulting in over 6.5 million deaths. COVID-19 mortality risk estimators are often, however, developed with small unrepresentative samples and with methodological limitations. It is highly important to develop predictive tools for pulmonary embolism (PE) in COVID-19 patients as one of the most severe preventable complications of COVID-19. Early recognition can help provide life-saving targeted anti-coagulation therapy right at admission. Using a dataset of more than 800,000 COVID-19 patients from an international cohort, we propose a cost-sensitive gradient-boosted machine learning model that predicts occurrence of PE and death at admission. Logistic regression, Cox proportional hazards models, and Shapley values were used to identify key predictors for PE and death. Our prediction model had a test AUROC of 75.9% and 74.2%, and sensitivities of 67.5% and 72.7% for PE and all-cause mortality respectively on a highly diverse and held-out test set. The PE prediction model was also evaluated on patients in UK and Spain separately with test results of 74.5% AUROC, 63.5% sensitivity and 78.9% AUROC, 95.7% sensitivity. Age, sex, region of admission, comorbidities (chronic cardiac and pulmonary disease, dementia, diabetes, hypertension, cancer, obesity, smoking), and symptoms (any, confusion, chest pain, fatigue, headache, fever, muscle or joint pain, shortness of breath) were the most important clinical predictors at admission. Age, overall presence of symptoms, shortness of breath, and hypertension were found to be key predictors for PE using our extreme gradient boosted model. This analysis based on the, until now, largest global dataset for this set of problems can inform hospital prioritisation policy and guide long term clinical research and decision-making for COVID-19 patients globally. Our machine learning model developed from an international cohort can serve to better regulate hospital risk prioritisation of at-risk patients. © The Author(s) 2024