Association of hepatitis C virus NS5B variants with resistance to new antiviral drugs among untreated patients

Mutations located in the 109-amino acid fragment of NS5B are typically associated with resistance to interferon (IFN) and ribavirin (RIB) and to new antiviral drugs. The prevalence of these mutations was examined in 69 drug-naïve individuals with hepatitis C virus (HCV) infections in Rio de Janeiro, Brazil. Mutations related to non-response to IFN/RIB were observed in all subtypes studied (1a, 1b, 2b, 3a and 4). The most common mutation was Q309R, present in all subtypes, except subtype 2b with frequency above 20%. D244N was detected only in subtype 3a and A333E was detected only in subtype 2b. We did not detect the S282T, S326G or T329I mutations in any of the samples analysed. Of note, the C316N mutation, previously related to a new non-nucleoside compound (HCV796 and AG-021541), was observed in only eight of 33 (24%) samples from subtype 1b. Site 316 was under positive selection in this HCV variant. Our data highlight the presence of previously described resistance mutations in HCV genotypes from drug-naïve patients.

A serological, parasitological and clinical evaluation of untreated Chagas disease patients and those treated with benznidazole before and thirteen years after intervention

The etiological treatment of Chagas disease is recommended for all patients with acute or recent chronic infection, but controversies remain regarding the benefit of chemotherapy and interpretations of the parasitological cure after etiological treatment. This study compares the laboratory and clinical evaluations of Chagas disease patients who were diagnosed 13 years earlier. Fifty-eight Chagas disease patients (29 treated with benznidazole and 29 untreated) were matched at the time of treatment based on several variables. Conventional serology revealed the absence of seroconversion in all patients. However, lower serological titres were verified in the treated group, primarily among patients who had the indeterminate form of the disease. Haemoculture performed 13 years after the intervention was positive for 6.9% and 27.6% of the treated and untreated patients, respectively. Polymerase chain reaction tests were positive for 44.8% and 13.8% of the treated and untreated patients, respectively. Patients who presented with the indeterminate form of the disease at the beginning of the study exhibited less clinical progression (17.4%) compared with the untreated group (56.5%). Therefore, this global analysis revealed that etiological treatment with benznidazole may benefit patients with respect to the clinical progression of Chagas disease and the prognosis, particularly when administered to patients with the indeterminate form of the disease.

Using petri nets to specify and execute missions for autonomous underwater vehicles

This paper presents the design and implementation of a mission control system (MCS) for an autonomous underwater vehicle (AUV) based on Petri nets. In the proposed approach the Petri nets are used to specify as well as to execute the desired autonomous vehicle mission. The mission is easily described using an imperative programming language called mission control language (MCL) that formally describes the mission execution thread. A mission control language compiler (MCL-C) able to automatically translate the MCL into a Petri net is described and a real-time Petri net player that allows to execute the resulting Petri net onboard an AUV are also presented

Duration of untreated psychosis: a proposition regarding treatment definition.

Aim: Duration of untreated psychosis (DUP) refers to the time elapsing between psychosis onset and treatment initiation. Despite a certain degree of consensus regarding the definition of psychosis onset, the definition of treatment commencement varies greatly between studies and DUP may be underestimated due to lack of agreement. In the present study, three sets of criteria to define the end of the untreated period were applied in a first-episode psychosis cohort to assess the impact of the choice of definition on DUP estimation. Methods: The DUP of 117 patients admitted in the Treatment and Early Intervention in Psychosis Program Psychosis in Lausanne was measured using the following sets of criteria to define treatment onset: (i) initiation of antipsychotic medication; (ii) entry into a specialized programme; and (iii) entry into a specialized programme and adequate medication with a good compliance. Results: DUP varied greatly according to definitions, the most restrictive criteria leading to the longest DUP (median DUP1 = 2.2 months, DUP2 = 7.4 months and DUP3 = 13.6 months). A percentage of 19.7 of the patients who did not meet these restrictive criteria had poorer premorbid functioning and were more likely to use cannabis. Longer DUP3 was associated with poorer premorbid functioning and with younger age at onset of psychosis. Conclusion: These results underline the need for a unique and standardized definition of the end of DUP. We suggest that the most restrictive definition of treatment should be used when using the DUP concept in future research.

Perineuronal nets protect fast-spiking interneurons against oxidative stress.

A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks. The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress. Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress. These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults. We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display. Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress. In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets. Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress. The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets. Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia.

Prognostic effect of epithelial cell adhesion molecule overexpression in untreated node-negative breast cancer.

PURPOSE: Epithelial cell adhesion molecule (Ep-CAM) recently received increased attention not only as a prognostic factor in breast cancer but also as a potential target for immunotherapy. We examined Ep-CAM expression in 402 consecutive node-negative breast cancer patients with long-term follow-up not treated in the adjuvant setting. EXPERIMENTAL DESIGN: Ep-CAM expression was evaluated by immunostaining. Its prognostic effect was estimated relative to overexpression/amplification of HER-2, histologic grade, tumor size, age, and hormone receptor expression. RESULTS: Ep-CAM status was positive in 106 (26.4%) patients. In multivariate analysis, Ep-CAM status was associated with disease-free survival independent of age, pT stage, histologic grade, estrogen receptor (ER), progesterone receptor (PR), as well as HER2 status (P = 0.028; hazard ratio, 1.60; 95% confidence interval, 1.05-2.44). Recently, so-called triple-negative (HER-2, ER, and PR) breast cancer has received increased attention. We noticed a similar association of Ep-CAM with disease-free survival in the triple-negative group as for the entire cohort. CONCLUSION: In this study of untreated breast cancer patients, Ep-CAM overexpression was associated with poor survival in the entire cohort and in the subgroup of triple-negative breast cancer. This suggests that Ep-CAM may be a well-suited target for specific therapies particularly in HER-2-, ER-, and PR-negative tumors.

A non-interventional phase IV Belgian survey to assess the antiviral effectiveness of pegylated interferon-alpha-2b and ribavirin treatment according to the stage of liver fibrosis in previously untreated patients with genotype 1/4/5/6 chronic hepatitis C (PRACTICE).

BACKGROUND AND STUDY AIMS: This was an observational, non-interventional, multicenter, phase IV study, in patients with genotype 1/4/5/6 chronic hepatitis C (CHC). The primary objectives were to evaluate SVR in patients with no or minimal fibrosis (METAVIR F0-F1) versus well established fibrosis (F2-F4), and to estimate response on Weeks 12, 24 and 48 on treatment in previously untreated patients with genotypes 1/4/5/6 CHC. PATIENTS AND METHODS: 538 patients treated with pegylated interferon alfa 2b 1.5 mcg/kg in combination with ribavirin 800-1200 mg/day were enrolled in 55 sites in Belgium and Luxembourg, 505 being considered for the analysis. 40% of the patients were female and 60% male, the average age was 47.5 years, 10.5% were 65 or older. RESULTS: SVR was observed in 35% of the patients, EVR in 68%, of which pEVR in 33% and cEVR in 35%. SVR was observed in 43% of the low fibrosis group (F0, F1) and 30% of the high fibrosis group (F2, F3, F4) (p = 0.005). SVR rates were 34% for genotype 1, 37% for genotype 4, and 47% for genotype 5 (NS). Multivariate analysis showed that EVR and baseline METAVIR score are independent prognostic factors for SVR. CONCLUSIONS: This trial confirms that fibrosis stage and early viral response are the most important key-factors to predict sustained response, suggesting that the earlier patients are treated, the better the outcome. Non-invasive techniques enable us to closely monitor progression of fibrosis, allowing a better selection of patients for antiviral treatment in the DAA-era.

Transfers, social safety nets and economic growth

The role of social safety nets in the form of redistributional transfersand wage subsidies is analyzed using a simple model of criminal behavior. Itis argued that public welfare programs act as a crime--preventing ordisruption--preventing devices because they tend to increase the opportunitycost of engaging in crime or disruptive activities. It is shown that, in thepresence of a leisure choice, wage subsidies may be better than pure transfers. Using a simple growth model, it is shown that it is not optimal for the governmentto try to fully eliminate crime. The optimal size of the public welfare programis found and it is argued that public welfare should be financed with income(not lump--sum) taxes, despite the fact that income taxes are distortionary.The intuition for this result is that income taxes act as a user fee oncongested public goods and transfers can be thought of as {\it productive}public goods {\it subject to congestion}. Finally, using a cross-section of 75 countries, the partial correlation betweentransfers and growth is shown to be significantly positive.

Nets: Network estimation for time series

This work proposes novel network analysis techniques for multivariate time series.We define the network of a multivariate time series as a graph where verticesdenote the components of the process and edges denote non zero long run partialcorrelations. We then introduce a two step LASSO procedure, called NETS, toestimate high dimensional sparse Long Run Partial Correlation networks. This approachis based on a VAR approximation of the process and allows to decomposethe long run linkages into the contribution of the dynamic and contemporaneousdependence relations of the system. The large sample properties of the estimatorare analysed and we establish conditions for consistent selection and estimation ofthe non zero long run partial correlations. The methodology is illustrated with anapplication to a panel of U.S. bluechips.

CD4(+) T cell count decreases by ethnicity among untreated patients with HIV infection in South Africa and Switzerland.

BACKGROUND: Estimates of the decrease in CD4(+) cell counts in untreated patients with human immunodeficiency virus (HIV) infection are important for patient care and public health. We analyzed CD4(+) cell count decreases in the Cape Town AIDS Cohort and the Swiss HIV Cohort Study. METHODS: We used mixed-effects models and joint models that allowed for the correlation between CD4(+) cell count decreases and survival and stratified analyses by the initial cell count (50-199, 200-349, 350-499, and 500-750 cells/microL). Results are presented as the mean decrease in CD4(+) cell count with 95% confidence intervals (CIs) during the first year after the initial CD4(+) cell count. RESULTS: A total of 784 South African (629 nonwhite) and 2030 Swiss (218 nonwhite) patients with HIV infection contributed 13,388 CD4(+) cell counts. Decreases in CD4(+) cell count were steeper in white patients, patients with higher initial CD4(+) cell counts, and older patients. Decreases ranged from a mean of 38 cells/microL (95% CI, 24-54 cells/microL) in nonwhite patients from the Swiss HIV Cohort Study 15-39 years of age with an initial CD4(+) cell count of 200-349 cells/microL to a mean of 210 cells/microL (95% CI, 143-268 cells/microL) in white patients in the Cape Town AIDS Cohort > or =40 years of age with an initial CD4(+) cell count of 500-750 cells/microL. CONCLUSIONS: Among both patients from Switzerland and patients from South Africa, CD4(+) cell count decreases were greater in white patients with HIV infection than they were in nonwhite patients with HIV infection.

Using graphical probability analysis (Bayes Nets) to evaluate a conditional DNA inclusion

This paper discusses the analysis of cases in which the inclusion or exclusion of a particular suspect, as a possible contributor to a DNA mixture, depends on the value of a variable (the number of contributors) that cannot be determined with certainty. It offers alternative ways to deal with such cases, including sensitivity analysis and object-oriented Bayesian networks, that separate uncertainty about the inclusion of the suspect from uncertainty about other variables. The paper presents a case study in which the value of DNA evidence varies radically depending on the number of contributors to a DNA mixture: if there are two contributors, the suspect is excluded; if there are three or more, the suspect is included; but the number of contributors cannot be determined with certainty. It shows how an object-oriented Bayesian network can accommodate and integrate varying perspectives on the unknown variable and how it can reduce the potential for bias by directing attention to relevant considerations and distinguishing different sources of uncertainty. It also discusses the challenge of presenting such evidence to lay audiences.

Indicators of therapeutic effect in FIT-06, a Phase II trial of a DNA vaccine, GTU(®)-Multi-HIVB, in untreated HIV-1 infected subjects.

BACKGROUND: Combination highly active antiretroviral therapy (HAART) has significantly decreased HIV-1 related morbidity and mortality globally transforming HIV into a controllable condition. HAART has a number of limitations though, including limited access in resource constrained countries, which have driven the search for simpler, affordable HIV-1 treatment modalities. Therapeutic HIV-1 vaccines aim to provide immunological support to slow disease progression and decrease transmission. We evaluated the safety, immunogenicity and clinical effect of a novel recombinant plasmid DNA therapeutic HIV-1 vaccine, GTU(®)-multi-HIVB, containing 6 different genes derived from an HIV-1 subtype B isolate. METHODS: 63 untreated, healthy, HIV-1 infected, adults between 18 and 40 years were enrolled in a single-blinded, placebo-controlled Phase II trial in South Africa. Subjects were HIV-1 subtype C infected, had never received antiretrovirals, with CD4 ≥ 350 cells/mm(3) and pHIV-RNA ≥ 50 copies/mL at screening. Subjects were allocated to vaccine or placebo groups in a 2:1 ratio either administered intradermally (ID) (0.5mg/dose) or intramuscularly (IM) (1mg/dose) at 0, 4 and 12 weeks boosted at 76 and 80 weeks with 1mg/dose (ID) and 2mg/dose (IM), respectively. Safety was assessed by adverse event monitoring and immunogenicity by HIV-1-specific CD4+ and CD8+ T-cells using intracellular cytokine staining (ICS), pHIV-RNA and CD4 counts. RESULTS: Vaccine was safe and well tolerated with no vaccine related serious adverse events. Significant declines in log pHIV-RNA (p=0.012) and increases in CD4+ T cell counts (p=0.066) were observed in the vaccine group compared to placebo, more pronounced after IM administration and in some HLA haplotypes (B*5703) maintained for 17 months after the final immunisation. CONCLUSIONS: The GTU(®)-multi-HIVB plasmid recombinant DNA therapeutic HIV-1 vaccine is safe, well tolerated and favourably affects pHIV-RNA and CD4 counts in untreated HIV-1 infected individuals after IM administration in subjects with HLA B*57, B*8101 and B*5801 haplotypes.

Duration of untreated psychosis : a proposition regarding treatment definition

La durée de psychose non traitée (Duration of Untreated Psychosis, DUP) est définie par le temps écoulé entre l'émergence d'un trouble psychotique et le début de son traitement. La réduction de la DUP est un des objectifs principaux des programmes spécialisés dans le traitement de la psychose émergente, de nombreux travaux de recherche suggérant qu'une DUP longue est associée à une évolution défavorable de la maladie. Ces résultats restent cependant controversés, certaines études ne démontrant pas une telle association. Cette contradiction dans les résultats pourrait être la conséquence d'un manque d'uniformité dans les définitions appliquées pour mesurer la DUP, plus particulièrement en ce qui concerne la définition de ce que l'on considère être « début » du traitement. En effet, si l'étude de la phase d'émergence de la pathologie psychotique a été le focus d'une attention considérable qui a conduit à un certain degré de consensus quant à sa définition, le concept de début du traitement n'est clairement pas défini de manière aussi homogène. Compte tenu de l'importance des enjeux relatifs à l'intervention précoce dans les troubles psychotiques, il nous a semblé utile d'explorer cette question de manière plus approfondie, considérant qu'un manque de consensus dans la définition de la DUP contribue certainement à troubler les résultats des études qui visent à évaluer son impact sur l'évolution de ces maladies. En conséquence, l'objectif premier de ce travail est d'explorer l'impact de l'application de diverses définitions de début de traitement sur l'estimation de la DUP. Dans un premier article, publié dans Acta Neuropsychiatrica en 2009 (Duration of untreated psychosis : What are we talking about ?), le focus a été placé sur une revue de littérature concernant les définitions utilisées pour caractériser la fin de la DUP ainsi que sur les conséquences possibles d'un manque de précision dans cette définition sur l'évaluation de l'impact d'un retard de traitement dans la psychose débutante. Ce travail nous a permis d'identifier trois groupes principaux de définition de fin de DUP (End of DUP ; E-DUP) parmi les multiples critères utilisés dans les études publiées. E-DUP-1 est définie par la mise en route d'un traitement antipsychotique, le plus souvent sans tenir compte ni du dosage prescrit, ni de l'adhérence au traitement. E-DUP-2 est définie par l'entrée dans un programme de traitement spécialisé, et E-DUP-3 enfin est définie par la conjonction de la prescription d'un traitement antipsychotique adapté, de l'adhérence à ce traitement, et de la mise en route d'une prise en charge dans un programme spécialisé. En conclusion, nous relevions que cette grande variété dans les définitions appliquées pour l'évaluation de la DUP avait probablement contribué à l'aspect contradictoire des résultats des études de son impact sur l'évolution des psychoses et qu'il était donc temps de proposer une définition de consensus. La deuxième étude a été conduite dans le cadre d'un suivi de cohorte mis en place dans le programme de Traitement et Intervention Précoce dans les troubles Psychotiques (TIPP) établi dans le Département de Psychiatrie du CHUV à Lausanne depuis 2004. Les objectifs de cette seconde étude étaient au nombre de trois: (1) Exploration des variations de la DUP en fonction de l'application de trois principales définitions de fin de DUP (E-DUP) identifiées dans la littérature ; (2) Evaluation de la proportion de patients remplissant au moins une fois au cours des 18 mois de traitement la définition de E-DUP la plus compatible avec les directives de traitement proposées par l'International Early Psychosis Association (patient est à la fois engagé dans le traitement et se montre compliant à la médication, E-DUP-3); (3) Enfin, identification desfacteurs qui caractérisent les patients qui ne remplissent jamais les critères de cette dernière définition. L'exploration de différentes durées de DUP en utilisant les trois définitions d'E-DUP a donné les résultats suivants : La DUP1 médiane (2.2 mois) était significativement plus courte que la DUP2 (7.4 mois), et la DUP3 (13.6 mois) était significativement la plus longue des trois. De plus, 19.7% des patients n'avaient jamais rempli les critères de E-DUP-3 ; on peut donc considérer que près de 20% des patients traités dans ce programme spécialisé ne recevaient pas un traitement adéquat selon les directives intrernationales actuellement reconnues. Sur la base de ces chiffres, il apparaît clairement que, dans les études de l'impact de la DUP sur l'évolution de la psychose débutante, bon nombre des patients pour lesquels on considère que la DUP est terminée ne sont en fait pas adéquatement traités. Il est en conséquence très probable que ceci ait faussé les résultats de ces études, et qu'une définition plus restrictive permettrait de répondre de manière plus précise à cette question. Les patients qui ne remplissaient pas les critères E-DUP3 au cours des 18 premiers mois de traitement étaient caractérisés par un moins bon niveau de fonctionnement au cours de leur vie (« lower lifetime SOFAS » ; p=0.017) et ils étaient plus susceptibles de consommer du cannabis à l'entrée du programme ???? (?2 (1, n=49)=4.241, p=0.039). Pour ceux qui avaient rempli les critères E-DUP-3 au cours des 18 mois, une longue DUP3 était associée avec un jeune âge au début des symptômes psychotiques (rs =-0.573, p<0.001), et avec un faible niveau de fonctionnement pré-morbide (score de PAS élevés (rs =0.373, p=0.001), niveau maximal au cours de la vie bas pour le GAF(rs =-0.367, p<0.001) et pour le SOFAS (rs =-0.314, p=0.003)). En conclusion, ce travail a permis de mettre en évidence une grande variabilité dans la définition de la fin de la DUP parmi les études publiées jusque à ce jour, et l'impact important que le choix d'une ou l'autre de ces définitions peut avoir sur l'estimation de la DUP. De plus, nous avons observé que malgré la mise en place d'un programme spécialisé, près de 20% des patients ne remplissent pas les critères d'exposition à un traitement adéquat au cours des 18 premiers mois de prise en charge. Il est donc probable que l'estimation de l'impact de la DUP ait été faussé par cette variabilité, et il semble important que la communauté scientifique s'accorde sur une définition plus rigoureuse de cette variable. Enfin, certaines caractéristiques permettent d'identifier les patients qui sont à risque de ne pas remplir les critères de traitement adéquat a cours des 18 premiers mois de prise en charge ; il est possible qu'une identification précoce de ceux-ci permette la mise en place de stratégies mieux adaptées pour les aider à s'engager dans les soins. Le futur développement de ce travail sera d'évaluer l'impact de la DUP sur l'évolution des patients au cours des 36 mois de traitement proposés dans le programme TIPP, en appliquant les divers critères E-DUP, afin de voir si notre hypothèse que la variation des définitions a effectivement faussé les résultats de telles études. Nous devons pour cela attendre qu'un nombre suffisant de patients ait complété les 36 mois de traitement, de manière à avoir une puissance statistique suffisante pour répondre clairement à cette question.