Paediatric primary care in Europe: Variation between countries

in Archives of Disease in Childhood (2010), 95(10), 791-795

Background: Although it is known that differences in paediatric primary care (PPC) are found throughout Europe, little information exists as to where, how and who delivers this care. The aim of this study ... [more ▼]

Background: Although it is known that differences in paediatric primary care (PPC) are found throughout Europe, little information exists as to where, how and who delivers this care. The aim of this study was to collect information on the current existing situation of PPC in Europe. Methods: A survey, in the form of a questionnaire, was distributed to the primary or secondary care delegates of 31 European countries asking for information concerning their primary paediatric care system, demographic data, professionals involved in primary care and details of their training. All of them were active paediatricians with a broad knowledge on how PPC is organised in their countries. Results: Responses were received from 29 countries. Twelve countries (41%) have a family doctor/general practitioner (GP/FD) system, seven (24%) a paediatrician-based system and 10 (35%) a combined system. The total number of paediatricians in the 29 countries is 82 078 with 33 195 (40.4%) working in primary care. In only 15 countries (51.7%), paediatric age at the primary care level is defined as 0-18 years. Training in paediatrics is 5 years or more in 20 of the 29 countries. In nine countries, training is less than 5 years. The median training time of GPs/FDs in paediatrics is 4 months (IQR 3-6), with some countries having no formal paediatric training at all. The care of adolescents and involvement in school health programmes is undertaken by different health professionals (school doctors, GPs/FDs, nurses and paediatricians) depending on the country. Conclusions: Systems and organisations of PPC in Europe are heterogeneous. The same is true for paediatric training, school healthcare involvement and adolescent care. More research is needed to study specific healthcare indicators in order to evaluate the efficacy of different systems of PPC. [less ▲]

Paediatric screening for hypercholesterolaemia in Europe

in Archives of Disease in Childhood (2012), 97(3), 272-276

Different screening strategies are currently recommended to identify children with (familial) hypercholesterolaemia in order to initiate early lipid management. However, these strategies are characterised ... [more ▼]

Different screening strategies are currently recommended to identify children with (familial) hypercholesterolaemia in order to initiate early lipid management. However, these strategies are characterised to date by low adherence by the medical community and limited compliance by parents and children. In a literature review, the authors assess which children should undergo screening and which children are in effect identifi ed through the currently recommended strategies. Furthermore, the authors discuss the different screening tools and strategies currently used in Europe and what is known about the negative aspects of screening. The authors conclude that currently recommended selective screening strategies, which are mainly based on family history, lack precision and that a large percentage of affected children who are at increased risk of future coronary artery disease are not being identifi ed. The authors propose universal screening of children between 1 and 9 years of age, a strategy likely to be most effective in terms of sensitivity and specificity for the identification of children with familial hypercholesterolaemia. However, this concept has yet to be proven in clinical practice. [less ▲]

THE PARKINSON’S DISEASE ASSOCIATED PINK1-PARKIN PATHWAY IN PATHOLOGY AND DEVELOPMENT

Doctoral thesis (2018)

Parkinson’s disease (PD) has an aetiology not completely understood. One of the hypothesis in the field is that many neurodegenerative diseases are influenced by developmental disorders. The underlying ... [more ▼]

Parkinson’s disease (PD) has an aetiology not completely understood. One of the hypothesis in the field is that many neurodegenerative diseases are influenced by developmental disorders. The underlying concept is that already during brain development some processes are deregulated producing a higher degree of susceptibility for neurodegeneration during aging. Two hereditary early onset forms of PD are caused by recessive mutations in PTEN-induced putative kinase 1 (PINK1) and Parkin genes that regulate mitochondrial function and morphology, quarantining damaged mitochondria before their degradation as well as triggering the process of mitophagy. Our hypothesis is that alterations of the Pink1-Parkin pathway have an impact in mitochondrial physiology tempering the differentiation ability of neuroepithelial stem cells into dopaminergic neurons. For evaluating this hypothesis we reprogramed patients’ fibroblasts carrying PINK1 mutations, as well as from healthy individuals, to human induced pluripotent stem cells. We developed a streamlined technique of gene editing (FACE) by using the CRISPR/Cas9 system combined with a composite of fluorescent proteins in the donor template for biallelic gene targeting. Isogenic controls were generated using this technique that allowed us to analyze the contribution of corrected patients’ mutations in the cellular defects observed. Human iPSCs were differentiated into a neuroepithelial stem cell state (NESC) from where the cells were further differentiated into neurons. We established different algorithms for pattern recognition and applied them for image analysis of different features such as mitochondrial morphology, proliferation capacity, apoptosis and differentiation. Patient’s derived cells presented an impaired differentiation efficiency into dopaminergic neurons as well as an imbalanced cell renewal that can be linked to the mitochondrial differences. Using 3D cultures, such as microfluidics and organoids, we were able to recapitulate this differentiation impairment in a system that mimics better the context of an in vivo environment. We evaluated the energetic capabilities of the NESCs and the firing activity of differentiated neurons, which also showed a dysregulation in patient cells. We introduced a new system for large-scale analysis of the autophagy and mitophagy pathways by the combination of stably integrated Rosella constructs in different patients’ lines and an image analysis script for classification of the different subcellular structures involved in these pathways activities. This revealed that the basal activity as well as the response against stressors of these pathways are altered in cells derived from patients having different mutations causative of PD. We performed a screen of repurposed drugs as well as of novel compounds to evaluate their impact in this altered developmental transition identifying a potential candidate to be further analysed in an in vivo context. [less ▲]

Parkinson’s disease-associated alterations of the gut microbiome predict diseaserelevant changes in metabolic functions

in BMC Biology (2020)

Background: Parkinson’s disease (PD) is a systemic disease clinically defined by the degeneration of dopaminergic neurons in the brain. While alterations in the gut microbiome composition have been ... [more ▼]

Background: Parkinson’s disease (PD) is a systemic disease clinically defined by the degeneration of dopaminergic neurons in the brain. While alterations in the gut microbiome composition have been reported in PD, their functional consequences remain unclear. Herein, we addressed this question by an analysis of stool samples from the Luxembourg Parkinson’s Study (n = 147 typical PD cases, n = 162 controls). Results: All individuals underwent detailed clinical assessment, including neurological examinations and neuropsychological tests followed by self-reporting questionnaires. Stool samples from these individuals were first analysed by 16S rRNA gene sequencing. Second, we predicted the potential secretion for 129 microbial metabolites through personalised metabolic modelling using the microbiome data and genome-scale metabolic reconstructions of human gut microbes. Our key results include the following. Eight genera and seven species changed significantly in their relative abundances between PD patients and healthy controls. PD-associated microbial patterns statistically depended on sex, age, BMI, and constipation. Particularly, the relative abundances of Bilophila and Paraprevotella were significantly associated with the Hoehn and Yahr staging after controlling for the disease duration. Furthermore, personalised metabolic modelling of the gut microbiomes revealed PD-associated metabolic patterns in the predicted secretion potential of nine microbial metabolites in PD, including increased methionine and cysteinylglycine. The predicted microbial pantothenic acid production potential was linked to the presence of specific non-motor symptoms. Conclusion: Our results suggest that PD-associated alterations of the gut microbiome can translate into substantial functional differences affecting host metabolism and disease phenotype. [less ▲]

PATHOGENIC ROLE OF PARKINSON’S DISEASE-ASSOCIATED MIRO1 MUTATIONS IN THE MITOCHONDRIAL-ENDOPLASMIC RETICULUM INTERPLAY

Doctoral thesis (2019)

Parkinson´s disease (PD) is a chronic neurodegenerative disorder, in which only 5-10% of the cases are caused by genetic mutations. One of the main pathological hallmarks of PD is the loss of midbrain ... [more ▼]

Parkinson´s disease (PD) is a chronic neurodegenerative disorder, in which only 5-10% of the cases are caused by genetic mutations. One of the main pathological hallmarks of PD is the loss of midbrain dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) of diseased brains. These DA neurons require large amounts of energy for the maintenance of their pace-making activity and their complex dendritic and axonal arborizations, features that force them to rely on a fully functional mitochondrial network. In this regard, mitochondrial dyshomeostasis is a central factor in PD pathophysiology. Mitochondria are considered the powerhouse of the cells, and they are extremely dynamic organelles that are distributed throughout the entire neuronal body to meet the cellular energy demands. The maintenance of mitochondrial function requires their interaction with other cellular organelles, in particular, the endoplasmic reticulum (ER). Overwhelming evidence indicates that the mitochondrial-ER interface is a potential target of growing importance for the investigation of PD. Several PD-related proteins were found to be involved in the structural maintenance and signaling regulation of mitochondrial-ER contact sites (MERCs). In recent years, myriad studies have identified the mitochondrial GTPase Miro1 as a crucial player in PD pathology. Miro1 protein is not only an adaptor for mitochondrial transport, but also acts as a cytosolic calcium sensor and as an ubiquitination target for the mitochondrial quality control machinery. Moreover, Miro1 can localize to MERCs, where it functions as a regulator of the calcium exchange between both organelles. To date, no genetic link between Miro1 and PD has been identified, and the influence of Miro1 in the regulation of MERCs within the context of neurodegeneration is still underestimated. This current study explored the damaging effect of novel PD-associated heterozygous mutations in RHOT1, the gene encoding Miro1 protein, in a diseased genetic background. We first obtained skin fibroblasts from the affected PD patients harboring Miro1 mutations, which we further differentiated into iPSC-derived neurons. The characterization of the mutations in both patient-derived cellular models unveiled important impairments in mitochondrial calcium homeostasis and sensitivity to calcium stress, associated with alterations in the abundance and functionality of the MERCs. Consequently, downstream pathways to these mechanisms were affected, such as autophagy flux and mitochondrial clearance. From our results, we can conclude that PD-associated mutant Miro1 leads to crucial alterations in MERCs, consequently affecting downstream mechanisms such as calcium homeostasis and mitophagy. These dysregulations might lead to an increased sensitivity to stress and finally cell death. Our findings strongly support the key role of MERCs in the progress of neurodegeneration and establish RHOT1 as a rare genetic risk factor in PD. [less ▲]

“Patient participation” and related concepts: A scoping review on their dimensional

in Patient Education and Counseling (2019)

Several concepts on collaboration between patients and healthcare systems have emerged in the literature but there is little consensus on their meanings and differences. In this study, “patient ... [more ▼]

Several concepts on collaboration between patients and healthcare systems have emerged in the literature but there is little consensus on their meanings and differences. In this study, “patient participation” and related concepts were studied by focusing on the dimensions that compose them. This review follows two objectives: (1) to produce a detailed and comprehensive overview of the “patient participation” dimensions; (2) to identify differences and similarities between the related concepts. Methods; A scoping review was performed to synthesize knowledge into a conceptual framework. An electronic protocol driven search was conducted in two bibliographic databases and a thematic analysis was used to analyse the data. Results. The search process returned 39 articles after exclusion for full data extraction and analysis. Through the thematic analysis, the dimensions, influencing factors and expected outcomes of “patient participation” were determined. Finally, differences between the included concepts were identified. Conclusion. This global vision of “patient participation” allows us to go beyond the distinctions between the existing concepts and reveals their common goal to include the patient in the healthcare system. Practice implications. This scoping review provides useful information to propose a conceptual model of “patient participation”, which could impact clinical practice and medical training programs. [less ▲]

A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson's disease.

in Science translational medicine (2020), 12(560),

Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder with monogenic forms representing prototypes of the underlying molecular pathology and reproducing to variable degrees the sporadic ... [more ▼]

Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder with monogenic forms representing prototypes of the underlying molecular pathology and reproducing to variable degrees the sporadic forms of the disease. Using a patient-based in vitro model of PARK7-linked PD, we identified a U1-dependent splicing defect causing a drastic reduction in DJ-1 protein and, consequently, mitochondrial dysfunction. Targeting defective exon skipping with genetically engineered U1-snRNA recovered DJ-1 protein expression in neuronal precursor cells and differentiated neurons. After prioritization of candidate drugs, we identified and validated a combinatorial treatment with the small-molecule compounds rectifier of aberrant splicing (RECTAS) and phenylbutyric acid, which restored DJ-1 protein and mitochondrial dysfunction in patient-derived fibroblasts as well as dopaminergic neuronal cell loss in mutant midbrain organoids. Our analysis of a large number of exomes revealed that U1 splice-site mutations were enriched in sporadic PD patients. Therefore, our study suggests an alternative strategy to restore cellular abnormalities in in vitro models of PD and provides a proof of concept for neuroprotection based on precision medicine strategies in PD. [less ▲]

Patient-derived colon cancer stem cell-like spheroid cultures-characterization and effect of hypoxia

Doctoral thesis (2015)

Patients Treated for Central Airway Stenosis After Lung Transplantation Have Persistent Airflow Limitation

in Annals of Transplantation: Quarterly of the Polish Transplantation Society (2019)

BACKGROUND: Although central airway stenosis (CAS) is a common complication after lung transplantation, its consequences have been poorly evaluated. The objective of our study was to evaluate the impact ... [more ▼]

BACKGROUND: Although central airway stenosis (CAS) is a common complication after lung transplantation, its consequences have been poorly evaluated. The objective of our study was to evaluate the impact of CAS on lung function after lung transplantation. MATERIAL AND METHODS: All lung transplant recipients from June 2009 to August 2014 in a single center (Strasbourg, France) were retrospectively reviewed. RESULTS: A total of 191 lung transplantations were performed: 175 bilateral, 15 single, and 1 heart-lung transplantation. Of the 161 bilateral lung-transplanted patients who survived >3 months, 22 (13.6%) developed CAS requiring endobronchial treatment. All these patients were treated by endoscopic balloon dilatation, and 9 additionally needed endobronchial stents. Respiratory function tests demonstrated persistent obstructive ventilatory pattern despite endoscopic treatment in recipients with CAS compared to those without CAS at 6, 12, and 18 months post-transplant. At 18 months, CAS patients had significantly lower post-transplant FEV1 (1.96±0.60 L versus 2.57±0.76 L, p=0.001) and FEV1/FVC (61±14% versus 81±13%, p<0.001). The percentage of patients hospitalized for respiratory infections and number of hospital days were significantly increased in recipients with CAS (20 [91%] versus 92 [66%] p=0.036, and 144±110 days versus 103±83 days p=0.042, respectively). Survival in transplant recipients did not significantly differ between those with CAS and those without. CONCLUSIONS: CAS after lung transplantation was not associated with worse survival, but it did have a significant and persistent effect on lung function, and was associated with increased rate of respiratory infection. [less ▲]

The patients’ perspective on access to and use of Personal Health Records

Scientific Conference (2020, October 29)

We present the patients' perspective regarding the use of Personal Health Records, and give insights on patients' characteristics, such as socioeconomic and behavioural factors, that are associated with ... [more ▼]

We present the patients' perspective regarding the use of Personal Health Records, and give insights on patients' characteristics, such as socioeconomic and behavioural factors, that are associated with the access to and use of Personal Health Records. The findings come from the INTERREG APPS project that investigated preferences for and intention to use Personal Health Records in four cross-border regions, in Lorraine/France, Luxembourg, Rhineland-Palatinate and Saarland/Germany, and Wallonia/Belgium. [less ▲]