A comparison between early presentation of dementia with Lewy Bodies, Alzheimer's disease and Parkinson's disease: evidence from routine primary care and UK Biobank data

OBJECTIVE: To simultaneously contrast prediagnostic clinical characteristics of individuals with a final diagnosis of dementia with Lewy Bodies, Parkinson's disease, Alzheimer's disease compared to controls without neurodegenerative disorders. METHODS: Using the longitudinal THIN database in the UK, we tested the association of each neurodegenerative disorder with a selected list of symptoms and broad families of treatments, and compared the associations between disorders to detect disease-specific effects. We replicated the main findings in the UK Biobank. RESULTS: We used data of 28,222 patients with PD, 20,214 with AD, 4,682 with DLB and 20,214 controls. All neurodegenerative disorders were significantly associated with the presence of multiple clinical characteristics before their diagnosis including sleep disorders, falls, psychiatric symptoms and autonomic dysfunctions. When comparing DLB patients with patients with PD and AD patients, falls, psychiatric symptoms and autonomic dysfunction were all more strongly associated with DLB in the five years preceding the first neurodegenerative diagnosis. The use of statins was lower in patients who developed PD and higher in patients who developed DLB compared to AD. In PD patients, the use of statins was associated with the development of dementia in the five years following PD diagnosis. INTERPRETATION: Prediagnostic presentations of falls, psychiatric symptoms and autonomic dysfunctions were more strongly associated with DLB than PD and AD. This study also suggests that whilst several associations with medications are similar in neurodegenerative disorders, statin usage is negatively associated with Parkinson's Disease but positively with DLB and AD as well as development of dementia in PD

Determinants of the access to remote specialised services provided by national sarcoma reference centres

BACKGROUND: Spatial inequalities in cancer management have been evidenced by studies reporting lower quality of care or/and lower survival for patients living in remote or socially deprived areas. NETSARC+ is a national reference network implemented to improve the outcome of sarcoma patients in France since 2010, providing remote access to specialized diagnosis and Multidisciplinary Tumour Board (MTB). The IGéAS research program aims to assess the potential of this innovative organization, with remote management of cancers including rare tumours, to go through geographical barriers usually impeding the optimal management of cancer patients. METHODS: Using the nationwide NETSARC+ databases, the individual, clinical and geographical determinants of the access to sarcoma-specialized diagnosis and MTB were analysed. The IGéAS cohort (n = 20,590) includes all patients living in France with first sarcoma diagnosis between 2011 and 2014. Early access was defined as specialised review performed before 30 days of sampling and as first sarcoma MTB discussion performed before the first surgery. RESULTS: Some clinical populations are at highest risk of initial management without access to sarcoma specialized services, such as patients with non-GIST visceral sarcoma for diagnosis [OR 1.96, 95% CI 1.78 to 2.15] and MTB discussion [OR 3.56, 95% CI 3.16 to 4.01]. Social deprivation of the municipality is not associated with early access on NETSARC+ remote services. The quintile of patients furthest away from reference centres have lower chances of early access to specialized diagnosis [OR 1.18, 95% CI 1.06 to 1.31] and MTB discussion [OR 1.24, 95% CI 1.10 to 1.40] but this influence of the distance is slight in comparison with clinical factors and previous studies on the access to cancer-specialized facilities. CONCLUSIONS: In the context of national organization driven by reference network, distance to reference centres slightly alters the early access to sarcoma specialized services and social deprivation has no impact on it. The reference networks' organization, designed to improve the access to specialized services and the quality of cancer management, can be considered as an interesting device to reduce social and spatial inequalities in cancer management. The potential of this organization must be confirmed by further studies, including survival analysis

Persistance du génome d'entérovirus et des bactériophages de Bacteroides fragilis dans les eaux : intérêt de ces marqueurs en tant qu'indicateurs de contamination virale

Non disponible / Not availableAu début des années 1990, quelques voix se sont élevées dans la communauté scientifique, en particulier parmi les spécialistes de biologie moléculaire préconisant l'utilisation de la PCR pour le diagnostic virologique du milieu hydrique. Certains postulaient que la détection du génome viral dans une eau, une boue ou un coquillage pouvait apporter la preuve que ce milieu était contaminé par le virus infectieux correspondant. D'autres affirmaient au contraire qu'une «PCR positive» ne pouvait en aucun cas indiquer la présence de virus infectieux, tout au plus pouvait-elle servir de témoin de contamination virale. La présence de génome viral est-elle le témoin d'une présence de virus infectieux ou simplement un témoin d'une contamination virale plus ou moins ancienne ? L'objectif de ce travail est d'apporter des éléments de réponses à cette interrogation et dans ce cadre, nous avons considéré qu'il était fondamental de comparer le comportement du génome et du virus infectieux. dans le milieu hydrique. En effet, pour que la présence de génome puisse témoigner de celle de virus infectieux, il semble nécessaire que la capacité de survie de ces 2 entités soit identique. La première partie réalisée en milieu hydrique artificiellement contaminé par du coxsackievirus B3 et du bactériophage de Bacteroides fragilis montre que : - une incubation à forte température (> 55°C) se traduit par l'inactivation rapide du virus infectieux, alors que le génome reste présent jusqu'à des températures de 95°C ; - en milieu PBS à 25°C, la survie du génome est deux fois supérieure à celle du virus infectieux et du phage de Bacteroides fragilis. La présence de Na-montmorillonite augmente la persistance du génome d'un facteur 2, alors qu'elle n'augmente celle du virus infectieux que de quelques jours ; - en eau d'adduction (chlore résiduel 0,08 rng.L-1), la persistance du génome est là encore supérieure d'un facteur 2 à celle du virus infectieux, mais est comparable à celle du phage de Bacteroides fragilis. Cependant contrairement au phage, le génome et le virus infectieux sont sensibles aux faibles doses de chlore résiduel ; - en eau de forage, la persistance du génome est équivalente à celle du virus infectieux, alors que le phage survit 2 fois plus longtemps. En milieu PBS et en eau d'adduction, le génome ne constitue qu'un indicateur de contamination virale au même titre que le phage de Bacteroides fragilis. Cependant, il semble qu'en eau de forage la détection de génome peut témoigner de la présence de virus infectieux. La deuxième partie consiste à rechercher le génome d' entérovirus, les phages de Bacteroides fragilis et les coliphages somatiques comparativement aux entérovirus infectieux dans des eaux usées traitées de qualité différente. Les résultats montrent que : - la détection d'entérovirus infectieux, de génome d'entérovirus et de phage de Bacteroides fragilis doit s'effectuer après concentration des eaux usées traitées ; - la densité en coliphage somatique est suffisante pour l'analyse directe des eaux ; - la détection de génome entéroviral ne constitue qu'un indicateur de contamination virale ; - les phages de Bacteroides fragilis semblent constituer le meilleur indicateur de présence d'entérovirus contrairement aux coliphages qui ne sont que des indicateurs d'efficacité de traitement. Le génome entéroviral qui présente une fréquence de détection analogue à celle des phages des Bacteroides fragilis semble lui aussi constituer un bon indicateur de contamination entérovirale

Le thème « Territoires ruraux et ressources en eau »

National audienc

Intoxications alimentaires liées à la consommation de coquillages contaminés par des dinoflagelles toxiques

NANCY1-SCD Pharmacie-Odontologie (543952101) / SudocSudocFranceF

Development of real-time RT-PCR methods for specific detection of F-specific RNA bacteriophage genogroups: Application to urban raw wastewater

International audienceF-specific RNA bacteriophages have been classified into four genogroups (GI, GII, GIII and GIV). It was suggested that two of these genogroups are more frequent in human excreta (GII and GIII) and the two other (GI and GIV) are specific for animal excreta. Real-time RT-PCR methods using TaqMan MGB probe were developed to detect the four genogroups. Primers and probes of each specific RT-PCR were designed to target all sequenced bacteriophages belonging to one genogroup, without cross-reactivity with other genogroups. These four methods showed detection limits ranging between 0.01 and 10 PFU/mL and PCR efficiencies ranging between 87 and 95%. The newly methods were tested in urban raw wastewater. Genogroups I and II were detected in all samples (n = 7); GIII in six samples and GIV was never detected. GI was predominant in one sample, in which the quantity of Cryptosporidium and Giardia was, respectively, three and eight times higher than the mean values. Because GI is mainly observed in animals, it was hypothesized that this increase was due to an animal input. The use of F-specific RNA phage genotyping to estimate the origin of faecal pollution requires appropriate validation. In this context, real-time RT-PCR will undoubtedly be useful

Adhesion-Aggregation and Inactivation of Poliovirus 1 in Groundwater Stored in a Hydrophobic Container

Viral inactivation and adhesion-aggregation in water are often studied as separate phenomena. When the focus is placed on viral adhesion-aggregation, inactivation is neglected because the phenomena under investigation occur over a short period measured in days. When viral inactivation is studied, adhesion-aggregation phenomena are considered to be negligible because viral survival is traced over several days or months. In the present work, we took a global approach, examining the relative contributions of each of these processes in a complex system composed of groundwater, Poliovirus 1, and a hydrophobic container (polypropylene) maintained in a dark environment at 20°C. We demonstrated that infectious viral load fell off 2.8 log(10) during the first 20 days. During this time, adhesion was far from negligible because it accounted for most of the decline, 1.5 log(10). Adhesion was undoubtedly favored by the presence of divalent ions in the groundwater. After 20 days, aggregation may also have been the cause of 0.66 to 0.92 log(10) of viral loss. Finally, viral inactivation was quantitatively the lowest phenomena because it only explained 0.38 to 0.64 log(10) of the viral loss. This study thus clearly demonstrated that estimates of viral survival in a given system must always take into account adhesion-aggregation phenomena which may be responsible for the majority of viral loss in the aqueous phase. Adhesion and aggregation are reversible processes which may lead to an underestimation of viral load in certain studies

Inactivation of Poliovirus 1 and F-Specific RNA Phages and Degradation of Their Genomes by UV Irradiation at 254 Nanometers

Several models (animal caliciviruses, poliovirus 1 [PV1], and F-specific RNA bacteriophages) are usually used to predict inactivation of nonculturable viruses. For the same UV fluence, viral inactivation observed in the literature varies from 0 to 5 logs according to the models and the methods (infectivity versus molecular biology). The lack of knowledge concerning the mechanisms of inactivation due to UV prevents us from selecting the best model. In this context, determining if viral genome degradation may explain the loss of infectivity under UV radiation becomes essential. Thus, four virus models (PV1 and three F-specific RNA phages: MS2, GA, and Qβ) were exposed to UV radiation from 0 to 150 mJ · cm(−2). PV1 is the least-resistant virus, while MS2 and GA phages are the most resistant, with phage Qβ having an intermediate sensitivity; respectively, 6-log, 2.3-log, 2.5-log, and 4-log decreases for 50 mJ · cm(−2). In parallel, analysis of RNA degradation demonstrated that this phenomenon depends on the fragment size for PV1 as well as for MS2. Long fragments (above 2,000 bases) for PV1 and MS2 fell rapidly to the background level (>1.3-log decrease) for 20 mJ · cm(−2) and 60 mJ · cm(− 2), respectively. Nevertheless, the size of the viral RNA is not the only factor affecting UV-induced RNA degradation, since viral RNA was more rapidly degraded in PV1 than in the MS2 phage with a similar size. Finally, extrapolation of inactivation and UV-induced RNA degradation kinetics highlights that genome degradation could fully explain UV-induced viral inactivation

Intérêt du génotypage des phages ARN F-spécifiques pour estimer la pollution fécale et virale des eaux

Les bactériophages ARN F-spécifiques sont des virus qui infectent Escherichia coli et possèdent une structure et une taille comparables à celles des principaux virus entériques pathogènes. Ils sont proposés comme indicateurs de pollution fécale du milieu hydrique, comme modèles du comportement des virus pathogènes dans l environnement et comme outil de discrimination de l origine de la pollution fécale. En effet, dans les eaux usées, il a été rapporté que les génogroupes II et III avaient principalement une origine humaine alors que les génogroupes I et IV avaient, quant à eux, plutôt une origine animale. Paradoxalement, peu de données existent quant à la répartition des différents génogroupes dans les eaux naturelles. L objectif de ce travail a, par conséquent, été de préciser les relations existantes entre les différents génogroupes des phages ARN F-spécifiques et la pollution fécale et virale des eaux naturelles. Tout d abord, nous avons développé les premiers systèmes de RT-PCR en temps réel capables d identifier les quatre génogroupes dans les eaux environnementales. La sensibilité, la spécificité et la rapidité de détection constituent les avantages majeurs de cette approche. Par rapport aux outils existants, cette méthode permet de s affranchir de l étape de culture et donc de minimiser les problèmes engendrés par des taux d inactivation importants des particules virales infectieuses, en réponse aux stress environnementaux. En effet, les études de persistance, réalisées aussi bien dans l eau usée que dans l eau souterraine, démontrent que, selon les conditions expérimentales, le génome phagique est de 3 à 20 fois plus résistant que les phages infectieux. Dans un second temps, l analyse d échantillons d eaux usées urbaines nous a permis de vérifier que, malgré le changement de référentiel de mesure (génome versus particule infectieuse) inhérent à notre méthode de détection, les bactériophages ARN F-spécifiques pouvaient donner des informations intéressantes quant à la caractérisation de la pollution fécale. Dans ce type de milieu, les génogroupes II et III sont majoritairement retrouvés à des concentrations relativement stables au cours du temps. De manière ponctuelle, la présence du génogroupe I a pu, à la fois, être mise en relation avec les précipitations et avec la présence de pathogènes à caractère zoonotique (Cryptosporidium et Giardia), suggérant un apport de pollution animale par des phénomènes de ruissellement. Ceci a conforté l idée que le génotypage pourrait constituer un outil intéressant de discrimination de l origine de la pollution fécale. En revanche, la comparaison des résultats de génotypage aux concentrations en virus pathogènes montre que ces phages ne sont pas adaptés à la prédiction de la présence de norovirus et d entérovirus, en raison d un caractère saisonnier de ces derniers. Les deux études de cas consacrées aux eaux naturelles constituent l étape majeure de notre étude. Dans un contexte de pollution principalement anthropique, il est démontré qu au niveau de l eau de rivière, le génogroupe II est très majoritairement observé. Les variations de concentration de ce génogroupe ont pu être corrélées positivement avec les indicateurs bactériens (E. coli, entérocoques) et avec les adénovirus humains attestant de son origine fécale humaine. Le génogroupe I est également très souvent représenté mais avec de plus amples variations de concentration. Ce génogroupe n a été corrélé ni aux indicateurs bactériens, ni au génogroupe II, ni aux adénovirus humains, étayant l hypothèse d une autre origine de ce génogroupe. La corrélation positive avec les valeurs de turbidité de l eau laisse supposer un apport de ces phages suite à des événements de ruissellement. Ainsi, dans l eau de rivière, les génogroupes I et II semblent apporter des informations intéressantes quant à l origine de la pollution fécale. Dans ce cadre, nous proposons l utilisation d un ratio de concentrations des génogroupes I et II pour caractériser la pollution fécale. A titre d exemple, pour une concentration en E. coli de 3,6 log10 NPP/100mL, la valeur du log10 (GGII/GGI) peut être aussi bien de 3,8 que de -1,7. Avec la turbidité de l eau, ce ratio a été le seul paramètre permettant de distinguer une modification dans la nature de la pollution fécale. Le génome des phages ARN F-spécifiques n a pas été mis en évidence dans les prélèvements d eaux souterraines protégées de la pollution fécale. Par contre, du génome d adénovirus humains a été identifié dans 7 échantillons sur 60. Ainsi, des marqueurs plus persistants que le génome des phages ARN F-spécifiques peuvent être détectés. Au cours de l étude de persistance menée dans ce milieu, aucune dégradation de l ADN n a été observée sur les 200 jours de l expérience, supportant l idée que l ADN est un marqueur de pollution fécale extrêmement conservateur. Finalement, les méthodes nouvellement développées au cours de cette thèse ont abouti à une meilleure connaissance de la distribution des différents génogroupes au sein des eaux naturelles. Le génotypage des phages ARN F-spécifiques apporte des informations originales par rapport aux indicateurs bactériens, mais ne constitue pas, à lui seul, l indicateur universel de pollution fécale ou virale des eaux.F-specific RNA phages, which are non pathogenic viruses with similar size and structure to human enteric viruses, have been proposed like faecal pollution indicators, like models for pathogenic viruses in environment and like tools for microbial source tracking. The key trait on which the F-specific RNA phage approach of source tracking is based is that genogroups I and IV are predominantly isolated from non human faeces, while genogroups II and III are predominantly isolated from human faeces and sewage. Paradoxically, few data are available as for the genogroups distribution in environmental waters. So, the topic of this study was to provide additional information about the relationships between the genogroups of F-specific RNA phages and the level of faecal and viral pollution to environmental waters. First, the methodological work undertaken at the beginning of this project made it possible to develop the first real-time RT-PCR assays able to typing the F-specific RNA phages. The major advantages of this approach are a good sensitivity, a quick detection and a great specificity. Compared with the current tools, this method allows to avoid the phage cultivation and thus to play down the biases associated with the survival characteristics of infectious F-specific RNA phages in the environmental waters. Indeed, survival studies, realized in urban wastewater and also in ground water, have shown that the inactivation rates of infectious particles are always more important that this of viral RNA, whatever the experimental design was. Secondly, the analysis of urban wastewater samples enabled to check that F-specific RNA phages could give interesting information as for the characterization of faecal pollution in spite of the change of reference frame of measurement inherent in our detection method (genome versus infectious particle). In these kinds of samples, the majority of phages isolated belonged to the genogroups II and III, and they exhibited steady concentrations. In several particular samples, the high concentration of genogroup I phages has been associated with rainfall events and with the presence of zoonotic pathogens (Cryptosporidium and Giardia). This observation suggests the presence of an animal pollution after streaming phenomena. All the results obtained with urban wastewaters strengthen the use of F-specific RNA phages like reliable source identification tool. On the other hand, the comparison between the pathogenic virus concentrations and the results of genotyping has shown that phage genogroups are not relevant indicators for the presence of enteric viruses. For instance, norovirus and enterovirus concentrations in wastewater displayed a seasonal distribution while human genogroups exhibited steady concentrations over the time. Thirdly, two particular case studies devoted to natural waters constitute the major aspect of our work. In river water principally influenced by human wastes, genotyping results show that genogroup II is very largely isolated. For the first time, positive correlations between the concentrations of genogroup II phages, bacterial indicators (E. coli, enterococci) and human adenoviruses was observed, which attests the human faecal origin of this genogroup. Genogroup I was also often isolated but it appeared irregularly distributed. The correlation analysis has shown that genogroup I was linked neither with the concentration of genogroup II nor with that of bacterial or viral faecal indicators. The absence of a link between the concentrations of these two genogroups supports the assumption of another faecal origin. Conversely, a relationship was shown between genogroup I and the water turbidity observed at the sampling. This suggests that the origin of this genogroup could be related to streaming phenomena following precipitations. Thus, in river water the genogroup I and II would be the two most interesting genogroups in order to characterize faecal pollution. As a consequence, genogroup II/genogroup I ratio may be an interesting tool for faecal source tracking. Indeed, depending on the sign of the ratio, it seems possible to determine the main source of pollution at a given point. For example, for an E. coli concentration of 3.6log10 MPN/100mL, log-ratio values could as well be 3.8 as -1.7. With the water turbidity, this log-ratio was the only parameter enabled to highlight a change of faecal pollution nature. In ground waters protected from faecal pollution, genome of F-specific RNA phages was not observed while genome of adenoviruses was isolated in 7 samples on the 60 analyzed. This observation suggests that more persistent markers than RNA of phages could be detected in ground waters. More over, in persistence study, no degradation of adenoviral DNA was observed during all the time (200 days) of the experiment. Finally, the typing method newly developed during this study led to a better knowledge of the distribution of different the genogroups within environmental waters. F-specific RNA phage typing provides original information compared to the bacterial indicators, but does not constitute alone the universal indicator of faecal or viral pollution of waters.NANCY1-Bib. numérique (543959902) / SudocSudocFranceF