Respiratory Paradoxical Adverse Drug Reactions Associated with Acetylcysteine and Carbocysteine Systemic Use in Paediatric Patients: A National Survey

OBJECTIVE: To report pediatric cases of paradoxical respiratory adverse drug reactions (ADRs) after exposure to oral mucolytic drugs (carbocysteine, acetylcysteine) that led to the withdrawal of licenses for these drugs for infants in France and then Italy. DESIGN: The study followed the recommendations of the European guidelines of pharmacovigilance for medicines used in the paediatric population. SETTING: Cases voluntarily reported by physicians from 1989 to 2008 were identified in the national French pharmacovigilance public database and in drug company databases. PATIENTS: The definition of paradoxical respiratory ADRs was based on the literature. Exposure to mucolytic drugs was arbitrarily defined as having received mucolytic drugs for at least 2 days (>200 mg) and at least until the day before the first signs of the suspected ADR. RESULTS: The non-exclusive paradoxical respiratory ADRs reported in 59 paediatric patients (median age 5 months, range 3 weeks to 34 months, 98% younger than 2 years old) were increased bronchorrhea or mucus vomiting (n = 27), worsening of respiratory distress during respiratory tract infection (n = 35), dyspnoea (n = 18), cough aggravation or prolongation (n = 11), and bronchospasm (n = 1). Fifty-one (86%) children required hospitalization or extended hospitalization because of the ADR; one patient died of pulmonary oedema after mucus vomiting. CONCLUSION: Parents, physicians, pharmacists, and drug regulatory agencies should know that the benefit risk ratio of mucolytic drugs is at least null and most probably negative in infants according to available evidence

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Evidence synthesis to inform model-based cost-effectiveness evaluations of diagnostic tests: a methodological systematic review of health technology assessments

Background: Evaluations of diagnostic tests are challenging because of the indirect nature of their impact on patient outcomes. Model-based health economic evaluations of tests allow different types of evidence from various sources to be incorporated and enable cost-effectiveness estimates to be made beyond the duration of available study data. To parameterize a health-economic model fully, all the ways a test impacts on patient health must be quantified, including but not limited to diagnostic test accuracy. Methods: We assessed all UK NIHR HTA reports published May 2009-July 2015. Reports were included if they evaluated a diagnostic test, included a model-based health economic evaluation and included a systematic review and meta-analysis of test accuracy. From each eligible report we extracted information on the following topics: 1) what evidence aside from test accuracy was searched for and synthesised, 2) which methods were used to synthesise test accuracy evidence and how did the results inform the economic model, 3) how/whether threshold effects were explored, 4) how the potential dependency between multiple tests in a pathway was accounted for, and 5) for evaluations of tests targeted at the primary care setting, how evidence from differing healthcare settings was incorporated. Results: The bivariate or HSROC model was implemented in 20/22 reports that met all inclusion criteria. Test accuracy data for health economic modelling was obtained from meta-analyses completely in four reports, partially in fourteen reports and not at all in four reports. Only 2/7 reports that used a quantitative test gave clear threshold recommendations. All 22 reports explored the effect of uncertainty in accuracy parameters but most of those that used multiple tests did not allow for dependence between test results. 7/22 tests were potentially suitable for primary care but the majority found limited evidence on test accuracy in primary care settings. Conclusions: The uptake of appropriate meta-analysis methods for synthesising evidence on diagnostic test accuracy in UK NIHR HTAs has improved in recent years. Future research should focus on other evidence requirements for cost-effectiveness assessment, threshold effects for quantitative tests and the impact of multiple diagnostic tests

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Troubles bipolaires du sujet âgé : spécificités cliniques et thérapeutiques, aspects cognitifs, question des liens avec les démences

Contexte, hypothèses et objectifs : la maladie bipolaire du sujet âgé peut être associée à des difficultés diagnostiques et thérapeutiques, notamment du fait d’une évolution démentielle. Face à cette association, plusieurs interrogations surviennent. Existe-t-il des spécificités sémiologiques ou de prise en charge en population gériatrique ? Comment définir la bipolarité d’apparition tardive ? Quels sont les mécanismes de l’involution cognitive ? Quels sont les liens ou situations d’errances diagnostiques entre bipolarité et démences ? Méthodologie : nous avons décrit trois cas cliniques complexes, réalisé une revue de la littérature ainsi qu’une étude épidémiologique, descriptive, multicentrique et transversale afin d’évaluer les connaissances et les pratiques de différentes populations de médecins. Résultats : la maladie bipolaire du sujet âgé apparaît moins fréquente, mais est sans doute sous-diagnostiquée du fait de l’atypicité clinique. On distingue les patients diagnostiqués à l’âge adulte qui vieillissent, et des formes d’apparition tardives (LOBD : Late Onset Bipolar Disorder), pour lesquelles des spécificités épidémiologiques et cliniques semblent se dégager. Le trouble bipolaire est caractérisé par une dysrégulation émotionnelle, mais des anomalies cognitives et de neuro-imagerie ont également été identifiées. A l’âge gériatrique, ces troubles peuvent constituer d’authentiques syndromes démentiels aboutissant à une atteinte sous-cortico-frontale, rejoignant en quelque sorte l’ancien concept de « démence vésanique ». L’hypothèse étiopathogénique retient une toxicité neurologique cumulative des épisodes thymiques, associée à celle des comorbidités et de certains psychotropes, mais le rôle d’autres facteurs reste à éclaircir. Des comorbidités neurologiques restent possibles, d’autant que la maladie bipolaire est associée à des facteurs de risque de démence. Des liens sont parfois suspectés et il semble exister des situations d’errances diagnostiques avec certaines maladies neurologiques. Notre étude a mis en évidence un intérêt pour ces questions, ainsi que des différences de connaissances et de pratiques entres psychiatres généraux et psychiatres du sujet âgé, neurologues, gériatres et médecins généralistes. Discussion, conclusion : le nombre de diagnostics de trouble bipolaire en population gériatrique risque d’augmenter dans les années à venir (vieillissement des patients et émergences de LOBD). Chez le sujet âgé, surtout en cas d’atypicité et/ou de premier épisode thymique tardif, l’exclusion d’une cause somatique et d’une confusion est primordiale. Il existe de nombreux facteurs confondants pour l’involution cognitive, et les études sont la plupart du temps rétrospectives à partir d’échantillons réduits. Il existe une hétérogénéité dans la définition des LOBD, faisant suspecter plusieurs hypothèses étiopathogéniques. La prévention des troubles cognitifs repose sur leur dépistage précoce, la prise en charge des comorbidités et une utilisation optimale des traitements. A un stade de démence, ces préconisations sont à poursuivre, et la prise en charge sociale doit être centrale et adaptée. Notre étude semble confirmer des difficultés diagnostiques et thérapeutiques dans le champ de la maladie bipolaire du sujet âgé, mais laisse également entrevoir une possible complémentarité entre différentes spécialités

Effets indésirables des fluidifiants bronchiques chez le nourrisson (étude nationale de pharmacovigilance)

PARIS-BIUP (751062107) / SudocSudocFranceF

I can’t get it off my mind: Attentional bias in former and current cocaine addiction

International audienceBackground: Cocaine addiction is a global health issue with limited therapeutic options and a high relapse rate. Attentional bias towards substance-related cues may be an important factor for relapse. However, it has never been compared in former and current cocaine-dependent patients.Methods: Attentional bias towards cocaine-related words was assessed using an emotional Stroop task in cocaine-dependent patients (N = 40), long-term abstinent former cocaine-dependent patients (N = 24; mean abstinence: 2 years) and control subjects (N = 28). Participants had to name the colour of cocaine-related words, neutral words and colour names. We assessed response times using an automatic voice-onset detection method we developed and we measured attentional bias as the difference in response times between cocaine-related and neutral conditions.Results: There was an overall group effect on attentional bias towards cocaine, but no group effect on the colour Stroop effect. Two-by-two comparison showed a difference in attentional bias between cocaine-dependent patients and controls, whereas long-term abstinent former cocaine-dependent patients were not different from either. Although cocaine-dependent patients showed a significant attentional bias, consistent with the literature, neither long-term abstinent former cocaine-dependent patients nor controls showed a significant attentional bias towards cocaine-related words. We found no link between attentional bias size and either addiction severity or craving.Conclusions: Cocaine abstinence was associated with an absence of significant attentional bias towards cocaine-related words, which may be interpreted either as an absence of attentional bias predicting success in maintaining abstinence, or as attentional bias being able to disappear with long-term cocaine abstinence. Further research is needed to distinguish the role of attentional bias in maintaining abstinence

Individualized immunological data for precise classification of OCD patients

Obsessive⁻compulsive disorder (OCD) affects about 2% of the general population, for which several etiological factors were identified. Important among these is immunological dysfunction. This review aims to show how immunology can inform specific etiological factors, and how distinguishing between these etiologies is important from a personalized treatment perspective. We found discrepancies concerning cytokines, raising the hypothesis of specific immunological etiological factors. Antibody studies support the existence of a potential autoimmune etiological factor. Infections may also provoke OCD symptoms, and therefore, could be considered as specific etiological factors with specific immunological impairments. Finally, we underline the importance of distinguishing between different etiological factors since some specific treatments already exist in the context of immunological factors for the improvement of classic treatments

3D Marine Sedimentary Reservoir Stochastic Simulation Accounting for High Resolution Sequence Stratigraphy and Sedimentological Rules

International audienceQuantifying the proportions and distribution of rock types is a key step in modeling sedimentary formations, since it greatly determines the quality of petrophysical and dynamic flow models. While forward stratigraphic models well reproduce deposition processes, they rely on inversion for data conditioning, which critically raises the empty space problem. Therefore, several stochastic methods have been suggested to simulate proportions and distribution of rock types in reservoirs respecting the observation data while reproducing realistic spatial patterns. However, these methods are always limited by the stationarity decision. We propose a method to generate 3D facies probability cubes which account for well and seismic data, stratigraphic interpretation, sedimentological rules describing the spatial distribution of rock types, and sequence stratigraphy principles. Different probability cubes are computed by integrating various information controlling the lithofacies occurrence, for instance the stratigraphic control of the shoreline migration, by defining linear or inequality constraints at the spatial estimation stage. The generated P-field cubes can then be combined considering the redundancy of the data they express such as the tau model. This methodology is demonstrated on typical synthetic data sets and on a North Sea reservoir