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Many types of data are often incompletely observed. How incompletely is typically randomly determined. Heitjan and Rubin (Annals of Statistics, 1991) proposed a condition, "coarsened at random" or CAR, ensuring ignorability of this randomness in discrete sample spaces. In general sample spaces CAR comes in two flavors according to whether it is defined in terms of probabilities or densities. In this paper, CAR defined in terms of densities, called relative CAR, is discussed as a condition for ignorability in a statistical model allowing for partial observation of random elements determining the degree of incompleteness in the observation of the data.

PurposeThe existence of CD8+cells with pro‐inflammatory properties referred to as Tc17 cells has recently been acknowledged. While it is evident that CD4+pro‐inflammatory IL‐17‐producing Th17 cells are important in the regulation of chronic viral infections, the role of Tc17 cells is largely unknown. Tc17 cells are characterized by expression of high levels of CD161 (CD161high). We hypothesized that Tc17 cells are involved in immune regulation in HIV‐ infection.Methods67 HIV‐infected patients were included in a cross‐sectional study. All patients had nadir CD4 counts<200 cells/µL, fully suppressed viral loads, and had been on cART for at least 2 years. Three groups were defined: Immunological Non Responders (INR, CD4 counts<200 cells/µL), Intermediate Responders (IR, CD4 counts 200–500 cells/µL), and Responders (RES, CD4 counts>500 cells/µL). Percentages of CD8+cells expressing CD3+CD8+CD161high were evaluated using flow cytometry. Additionally, Production of IL‐17 in phytohaemagglutinin(PHA)‐stimulated peripheral blood was determined by Luminex. For statistics Kruskall Wallis test followed by Mann‐Whitney U test was used. Data are given as medians.Summary of resultsINR had lower levels of Tc17 cells compared to IR, RES and controls (0.4%, 1.0%, 2.1%, 6.1%, p values<0.05). All HIV‐infected patients had lower levels than controls (p values<0.0001). Furthermore, all HIV‐infected patients displayed lower production of IL‐17 in peripheral blood compared to controls (p values<0.001).
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PurposeMost HIV‐infected patients develop immunodeficiency without treatment. However, Long‐Term Non Progressors (LTNP) and Viremic Controllers (VC) maintain normal CD4 counts and do not progress in the absence of treatment. While VC are able to control viral replication LTNP are not. Thus, lack of viral replication cannot explain non‐progression in LTNP. Therefore we hypothesized that the immunological mechanism responsible for preserved CD4 counts in LTNP is different from that in VC.Methods69 treatment naïve HIV‐infected patients were included in a cross‐sectional study. A total of 14 LTNP (viral load, VL>5000 copies/ml, CD4+ cell count>350 cells/ul, infected>10 years), 30 VC (VL<5000 copies/ml, CD4 count>350 cells/ul), and 25 progressors (PR) (VL>5.000 copies/ml, CD4 count>350 cells/ul) were included. Immune activation (CD4+ and CD8+cells co‐expressing CD38+HLA‐DR+), apoptosis (CD8+CD28‐CD95+), Th17 cells (CD4+CD161+), and regulatory T cells (Tregs, CD4+CD25+CD127lowFoxP3+) were evaluated using flow cytometry. For statistics Kruskal‐Wallis test followed by Mann‐Whitney U test were used. Data are given as medians.Summary of resultsLTNP had higher frequency of activated CD4+ and CD8+cells compared to VC (3.4% vs. 1.6%, P=0.007, 21.7% vs. 12.0%, P=0.051) and similar levels to PR (4.2%, 22.4%, P>0.05). Likewise, LTNP had higher frequency of apoptotic cells compared to VC (63.7% vs. 48.6%, P=0.0408) and similar levels to PR (63.8%, P>0.05). Interestingly, borderline significant trends towards lower Th17/Treg ratio in LTNP compared to VC were found (3.8 vs. 5.5, P=0.068) while ratios in LTNP and PR were similar (4.0, P>0.05).ConclusionLTNP displayed high levels of immune activation, apoptotic cells and reduced Th17/Treg ratio compared to VC, while LTNP were similar to PR. Thus, the immunological mechanism responsible for preserved CD4 counts in LTNP is still unclear but seems to be different from that in VC.
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Naloxone is a well-established essential medicine for the treatment of life-threatening heroin/opioid overdose in emergency medicine. Over two decades, the concept of 'take-home naloxone' has evolved, comprising pre-provision of an emergency supply to laypersons likely to witness an opioid overdose (e.g. peers and family members of people who use opioids as well as non-medical personnel), with the recommendation to administer the naloxone to the overdose victim as interim care while awaiting an ambulance. There is an urgent need for more widespread naloxone access considering the growing problem of opioid overdose deaths, accounting for more than 100,000 deaths worldwide annually. Rises in mortality are particularly sharp in North America, where the ongoing prescription opioid problem is now overlaid with a rapid growth in overdose deaths from heroin and illicit fentanyl. Using opioids alone is dangerous, and the mortality risk is clustered at certain times and contexts, including on prison release and discharge from hospital and residential care. The provision of take-home naloxone has required the introduction of new legislation and new naloxone products. These include pre-filled syringes and auto-injectors and, crucially, new concentrated nasal sprays (four formulations recently approved in different countries) with speed of onset comparable to intramuscular naloxone and relative bioavailability of approximately 40–50%. Choosing the right naloxone dose in the fentanyl era is a matter of ongoing debate, but the safety margin of the approved nasal sprays is superior to improvised nasal kits. New legislation in different countries permits over-the-counter sales or other prescription-free methods of provision. However, access remains uneven with take-home naloxone still not provided in many countries and communities, and with ongoing barriers contributing to implementation inertia. Take-home naloxone is an important component of the response to the global overdose problem, but greater commitment to implementation will be essential, alongside improved affordable products, if a greater impact is to be achieved.

Reporting and design standards are key indicators of the quality of diagnostic accuracy (validation) studies but, with the exception of aquatic animal diseases and paratuberculosis in ruminants, there is limited guidance for designing these studies in animals. There is, therefore, a need for generic guidelines that are based on disease characteristics, such as mode of transmission, latent period and pathogenesis. Comprehensive, clear and transparent reporting of primary test accuracy studies for diseases listed by the World Organisation for Animal Health (OIE) has value for the end users of diagnostic tests and, ultimately, for decision-makers, who require systematic reviews and meta-analysis of multiple tests for specified diseases and testing purposes. The recent publication of reporting standards for Bayesian latent class models, to analyse test-accuracy data from naturally occurring disease events, fills an important gap as these methods are being increasingly used for OIE-listed diseases. Adherence to design and reporting standards, as well as to guidelines, helps to ensure that research funding for test validation studies is used appropriately and that the strengths and limitations of single tests or test combinations are made clear to test users. The authors provide a review of key points that are often overlooked or misinterpreted in test validation studies, as well as two concrete examples of good practice for use as a reference point for future studies. ; Les normes de notification et de conception sont des indicateurs essentiels de la qualité des études de validation des tests destinées à déterminer leur exactitude diagnostique ; or, en dehors des maladies des animaux aquatiques et de la paratuberculose chez les ruminants, il n'existe guère de lignes directrices pour concevoir ce type d'études pour les tests utilisés en santé animale. À la connaissance des auteurs, il n'existe pas non plus de normes de conception applicables aux études de validation en santé humaine. Par conséquent, il conviendrait de disposer de lignes directrices génériques fondées sur les caractéristiques des maladies telles que leurs modalités de transmission, leur période de latence et leur pathogénie. Une notification complète, claire et transparente des études d'exactitude des tests primaires pour les maladies listées par l'Organisation mondiale de la santé animale (OIE) serait une aide précieuse pour les utilisateurs finaux des tests de diagnostic, mais aussi pour les responsables de l'élaboration des politiques, dont les décisions reposent sur des examens et des méta-analyses systématiques couvrant un grand nombre de tests pour certaines maladies ou pour certains usages d'un test. La publication récente des normes de notification applicables aux modèles bayésiens à classe latente pour analyser les données de performance d'un test à partir de foyers naturels de maladie comble une lacune importante dans la mesure où ces méthodes sont de plus en plus utilisées pour les maladies listées par l'OIE. L'adhésion à des normes de conception et de notification ainsi qu'à des lignes directrices en la matière permettra de garantir que les fonds alloués aux études de validation des tests sont bien utilisés et que les atouts et les limitations de certains tests individuels ou associations de tests sont clairement perçus par les utilisateurs. Les auteurs passent en revue certains points essentiels qui sont souvent ignorés ou mal interprétés lors des études de validation des tests et proposent deux exemples concrets de bonnes pratiques qui pourront servir de références pour les études à venir.

The modern understanding of sleep is based on the classification of sleep into stages defined by their electroencephalography (EEG) signatures, but the underlying brain dynamics remain unclear. Here we aimed to move significantly beyond the current state-of-the-art description of sleep, and in particular to characterise the spatiotemporal complexity of whole-brain networks and state transitions during sleep. In order to obtain the most unbiased estimate of how whole-brain network states evolve through the human sleep cycle, we used a Markovian data-driven analysis of continuous neuroimaging data from 57 healthy participants falling asleep during simultaneous functional magnetic resonance imaging (fMRI) and EEG. This Hidden Markov Model (HMM) facilitated discovery of the dynamic choreography between different whole-brain networks across the wake-non-REM sleep cycle. Notably, our results reveal key trajectories to switch within and between EEG-based sleep stages, while highlighting the heterogeneities of stage N1 sleep and wakefulness before and after sleep. ; Spanish Research Project PSI2016-75688-P (AEI/FEDER) and by the European Union's Horizon 2020 research and innovation programme under Grant agreement no. 720270 (HBP SGA1). M.L.K. was supported by the ERC Consolidator Grant CAREGIVING (615539) and the Center for Music in the Brain, funded by the Danish National Research Foundation Grant DNRF117. J.C. was supported under the project ...

BACKGROUND: Norovirus is often transmitted from person-to-person. Transmission may also be food-borne, but only few norovirus outbreak investigations have identified food items as likely vehicles of norovirus transmission through an analytical epidemiological study.During 7-9 January, 2009, 36 persons at a military base in Germany fell ill with acute gastroenteritis. Food from the military base's canteen was suspected as vehicle of infection, norovirus as the pathogen causing the illnesses. An investigation was initiated to describe the outbreak's extent, to verify the pathogen, and to identify modes of transmission and source of infection to prevent further cases. METHODS: For descriptive analysis, ill persons were defined as members of the military base with acute onset of diarrhoea or vomiting between 24 December 2008, and 3 February 2009, without detection of a pathogen other than norovirus in stools. We conducted a retrospective cohort study within the headquarters company. Cases were military base members with onset of diarrhoea or vomiting during 5-9 January. We collected information on demographics, food items eaten at the canteen and contact to ill persons or vomit, using a self-administered questionnaire. We compared attack rates (AR) in exposed and unexposed persons, using bivariable and multivariable logistic regression modelling. Stool specimens of ill persons and canteen employees, canteen food served during 5-7 January and environmental swabs were investigated by laboratory analysis. RESULTS: Overall, 101/815 (AR 12.4%) persons fell ill between 24 December 2008 and 3 February 2009. None were canteen employees. Most persons (n = 49) had disease onset during 7-9 January. Ill persons were a median of 22 years old, 92.9% were male. The response for the cohort study was 178/274 (72.1%). Of 27 cases (AR 15.2%), 25 had eaten at the canteen and 21 had consumed salad. Salad consumption on 6 January (aOR: 8.1; 95%CI: 1.5-45.4) and 7 January (aOR: 15.7; 95%CI: 2.2-74.1) were independently associated with increased risk of disease.Norovirus was detected in 8/28 ill persons' and 4/25 canteen employees' stools, 6/55 environmental swabs and 0/33 food items. Sequences were identical in environmental and stool samples (subtype II.4 2006b), except for those of canteen employees. Control measures comprised cohort isolation of symptomatic persons, exclusion of norovirus-positive canteen employees from work and disinfection of the canteen's kitchen. CONCLUSIONS: Our investigation indicated that consumption of norovirus-contaminated salad caused the peak of the outbreak on 7-9 January. Strict personal hygiene and proper disinfection of environmental surfaces remain crucial to prevent norovirus transmission

Rift Valley fever (RVF) is a vector‐borne disease transmitted by a broad spectrum of mosquito species, especially Aedes and Culex genus, to animals (domestic and wild ruminants and camels) and humans. Rift Valley fever is endemic in sub‐Saharan Africa and in the Arabian Peninsula, with periodic epidemics characterised by 5–15 years of inter‐epizootic periods. In the last two decades, RVF was notified in new African regions (e.g. Sahel), RVF epidemics occurred more frequently and low‐level enzootic virus circulation has been demonstrated in livestock in various areas. Recent outbreaks in a French overseas department and some seropositive cases detected in Turkey, Tunisia and Libya raised the attention of the EU for a possible incursion into neighbouring countries. The movement of live animals is the most important pathway for RVF spread from the African endemic areas to North Africa and the Middle East. The movement of infected animals and infected vectors when shipped by flights, containers or road transport is considered as other plausible pathways of introduction into Europe. The overall risk of introduction of RVF into EU through the movement of infected animals is very low in all the EU regions and in all MSs (less than one epidemic every 500 years), given the strict EU animal import policy. The same level of risk of introduction in all the EU regions was estimated also considering the movement of infected vectors, with the highest level for Belgium, Greece, Malta, the Netherlands (one epidemic every 228–700 years), mainly linked to the number of connections by air and sea transports with African RVF infected countries. Although the EU territory does not seem to be directly exposed to an imminent risk of RVFV introduction, the risk of further spread into countries neighbouring the EU and the risks of possible introduction of infected vectors, suggest that EU authorities need to strengthen their surveillance and response capacities, as well as the collaboration with North African and Middle Eastern countries.

13 páginas, 5 figuras, 3 tablas. ; The COST action "Standardising output-based surveillance to control non-regulated diseases of cattle in the European Union (SOUND control)," aims to harmonise the results of surveillance and control programmes (CPs) for non-EU regulated cattle diseases to facilitate safe trade and improve overall control of cattle infectious diseases. In this paper we aimed to provide an overview on the diversity of control for these diseases in Europe. A non-EU regulated cattle disease was defined as an infectious disease of cattle with no or limited control at EU level, which is not included in the European Union Animal health law Categories A or B under Commission Implementing Regulation (EU) 2020/2002. A CP was defined as surveillance and/or intervention strategies designed to lower the incidence, prevalence, mortality or prove freedom from a specific disease in a region or country. Passive surveillance, and active surveillance of breeding bulls under Council Directive 88/407/EEC were not considered as CPs. A questionnaire was designed to obtain country-specific information about CPs for each disease. Animal health experts from 33 European countries completed the questionnaire. Overall, there are 23 diseases for which a CP exists in one or more of the countries studied. The diseases for which CPs exist in the highest number of countries are enzootic bovine leukosis, bluetongue, infectious bovine rhinotracheitis, bovine viral diarrhoea and anthrax (CPs reported by between 16 and 31 countries). Every participating country has on average, 6 CPs (min–max: 1–13) in place. Most programmes are implemented at a national level (86%) and are applied to both dairy and non-dairy cattle (75%). Approximately one-third of the CPs are voluntary, and the funding structure is divided between government and private resources. Countries that have eradicated diseases like enzootic bovine leukosis, bluetongue, infectious bovine rhinotracheitis and bovine viral diarrhoea have implemented CPs for other diseases to further improve the health status of cattle in their country. The control of non-EU regulated cattle diseases is very heterogenous in Europe. Therefore, the standardising of the outputs of these programmes to enable comparison represents a challenge. ; Peer reviewed