Randomized controlled trial of interventions for young people at ultra-high risk of psychosis: study design and baseline characteristics.

OBJECTIVE: Intervention during the pre-psychotic period of illness holds the potential of delaying or even preventing the onset of a full-threshold disorder, or at least of reducing the impact of such a disorder if it does develop. The first step in realizing this aim was achieved more than 10 years ago with the development and validation of criteria for the identification of young people at ultra-high risk (UHR) of psychosis. Results of three clinical trials have been published that provide mixed support for the effectiveness of psychological and pharmacological interventions in preventing the onset of psychotic disorder. METHOD: The present paper describes a fourth study that has now been undertaken in which young people who met UHR criteria were randomized to one of three treatment groups: cognitive therapy plus risperidone (CogTher + Risp: n = 43); cognitive therapy plus placebo (CogTher + Placebo: n = 44); and supportive counselling + placebo (Supp + Placebo; n = 28). A fourth group of young people who did not agree to randomization were also followed up (monitoring: n = 78). Baseline characteristics of participants are provided. RESULTS AND CONCLUSION: The present study improves on the previous studies because treatment was provided for 12 months and the independent contributions of psychological and pharmacological treatments in preventing transition to psychosis in the UHR cohort and on levels of psychopathology and functioning can be directly compared. Issues associated with recruitment and randomization are discussed.

Duloxetine inhibits effects of MDMA ("ecstasy") in vitro and in humans in a randomized placebo-controlled laboratory study.

This study assessed the effects of the serotonin (5-HT) and norepinephrine (NE) transporter inhibitor duloxetine on the effects of 3,4-methylenedioxy-methamphetamine (MDMA, ecstasy) in vitro and in 16 healthy subjects. The clinical study used a double-blind, randomized, placebo-controlled, four-session, crossover design. In vitro, duloxetine blocked the release of both 5-HT and NE by MDMA or by its metabolite 3,4-methylenedioxyamphetamine from transmitter-loaded human cells expressing the 5-HT or NE transporter. In humans, duloxetine inhibited the effects of MDMA including elevations in circulating NE, increases in blood pressure and heart rate, and the subjective drug effects. Duloxetine inhibited the pharmacodynamic response to MDMA despite an increase in duloxetine-associated elevations in plasma MDMA levels. The findings confirm the important role of MDMA-induced 5-HT and NE release in the psychotropic effects of MDMA. Duloxetine may be useful in the treatment of psychostimulant dependence. TRIAL REGISTRATION: Clinicaltrials.gov NCT00990067.

Use of nicotine substitute prescribed at hourly plus ad libitum intake or ad libitum for heavy smokers willing to quit : a randomized controlled trial

Rapport de synthèse : l .Objectif Evaluer l'effet qu'ont les consignes d'utilisation régulière d'un spray nasal à la nicotine sur leur véritable utilisation durant les 3 premières semaines d'un sevrage tabagique. Un objectif secondaire est d'évaluer l'effet des consignes d'utilisation régulière du spray durant les premières semaines de sevrage tabagique sur le taux de succès à 6 mois par rapport à un groupe pouvant utiliser le spray « ad libitum ». 2. Méthode II s'agit d'une étude ouverte, randomisée contrôlée, incluant 50 patients présentant une dépendance nicotinique forte, se trouvant en phase de préparation selon le modèle transthéorique du changement de Prochaska et Di Clemente, recrutés au sein de la consultation «stop tabac » de la Policlinique Médicale Universitaire de Lausanne. Dans le groupe «contrôle », les patients ont été instruits à utiliser le spray « ad libitum », soit dès qu'apparaissaient des envies irrésistibles de fumer, tandis que le groupe «intervention » a reçu pour consigne d'utiliser le spray au moins 1 fois par heure dès le lever, voire plus en cas d'envie de fumer. L'utilisation du spray nasal a été enregistrée par un dispositif électronique fixé sur le spray (MDILogTM) durant les 3 premières semaines d'utilisation. Durant le suivi, l'abstinence tabagique a été vérifiée par une mesure du taux de CO expiré par un appareil spécifique (Bedfont Smokerlyzer). L'abstinence tabagique a été considérée comme un succès si le taux de CO était s 10 ppm (particules par million). 3. Résultats Un patient a été perdu durant le suivi. Au moment de la randomisation, le groupe «intervention » comprenait plus de femmes, des patients ayant un nombre plus grand de précédentes tentatives d'arrêt du tabagisme, plus de co-morbidités psychiatriques, mais moins de co-morbidités somatiques que le groupe «contrôle ». Dans les 2 groupes, les participants ont utilisé le spray nasal plus de 8 fois par jour (minimum demandé dans le groupe intervention). L'utilisation moyenne du spray était de 13,6 doses/jour pour le groupe «intervention » et de 1 l,l doses/jour pour le groupe contrôle. Ajusté aux différences entre les 2 groupes, la différence entre les doses plus importantes utilisées dans le groupe «intervention »par rapport à celles du groupe « ad libitum »reste non significative durant la première (0.8 ; CI 95% -5.1 ; 6,7), la deuxième (4.0 ; CI 95% -1.9 ; 9.9) et la troisième semaine (3.0 ; CI 95% -2.5 ; 8.5). De même, le fait d'instruire le patient à utiliser chaque heure le spray nasal durant les premières semaines n'a pas eu d'impact sur le taux de succès à 6 mois (RR = 0.69 ; CI 95% 0.34 ; 1.39). 4. Conclusions Cette étude négative montre que les différences d'utilisation du spray nasal nicotinique sont plus dépendantes des caractéristiques individuelles du patient que des recommandations d'utilisation du thérapeute. Les patients présentant un syndrome de dépendance à la nicotine forte utilisent spontanément de manière importante le spray nasal nicotinique, indépendamment des recommandations données. Pour les patients présentant un syndrome de dépendance à la nicotine forte, les recommandations par le thérapeute d'utiliser le spray nasal dès l'apparition d'envies de fumer semblent être la manière de faire la plus adéquate.

Glutathione precursor N-acetyl-cysteine modulates EEG synchronization in schizophrenia patients: a double-blind, randomized, placebo-controlled trial.

Glutathione (GSH) dysregulation at the gene, protein, and functional levels has been observed in schizophrenia patients. Together with disease-like anomalies in GSH deficit experimental models, it suggests that such redox dysregulation can play a critical role in altering neural connectivity and synchronization, and thus possibly causing schizophrenia symptoms. To determine whether increased GSH levels would modulate EEG synchronization, N-acetyl-cysteine (NAC), a glutathione precursor, was administered to patients in a randomized, double-blind, crossover protocol for 60 days, followed by placebo for another 60 days (or vice versa). We analyzed whole-head topography of the multivariate phase synchronization (MPS) for 128-channel resting-state EEGs that were recorded at the onset, at the point of crossover, and at the end of the protocol. In this proof of concept study, the treatment with NAC significantly increased MPS compared to placebo over the left parieto-temporal, the right temporal, and the bilateral prefrontal regions. These changes were robust both at the group and at the individual level. Although MPS increase was observed in the absence of clinical improvement at a group level, it correlated with individual change estimated by Liddle's disorganization scale. Therefore, significant changes in EEG synchronization induced by NAC administration may precede clinically detectable improvement, highlighting its possible utility as a biomarker of treatment efficacy. TRIAL REGISTRATION: ClinicalTrials.gov NCT01506765.

Sustained antipsychotic effect of metacognitive training in psychosis: a randomized-controlled study.

Persistent psychotic symptoms represent a major challenge for psychiatric care. Basic research has shown that psychotic symptoms are associated with cognitive biases. Metacognitive training (MCT) aims at helping patients to become aware of these biases and to improve problem-solving. Fifty-two participants fulfilling diagnostic criteria of schizophrenia or schizoaffective disorders and persistent delusions and stabilized antipsychotic medication were enrolled in this study. Following baseline assessment patients were randomized either to treatment as usual (TAU) conditions or TAU+MCT. The intervention consisted of eight weekly 1-hour sessions (maximum: 8 hours). Participants were assessed at 8 weeks and 6-months later by blind assessors. Participants were assessed with the Psychotic Symptoms Rating Scales (PSYRATS) and the positive subscale of the PANSS. Between-group differences in post- and pre-test values were significant at a medium effect size in favor of the MCT for the PSYRATS delusion scale and the positive scale of the PANSS both at post and follow-up. The results of this study indicate that MCT training has a surplus antipsychotic effect for patients suffering from schizophrenia-related disorders who demonstrate only a partial response to antipsychotic treatment and that the effect of the intervention persists for at least 6 months after the intervention.

eVOC: a controlled vocabulary for unifying gene expression data.

Expression data contribute significantly to the biological value of the sequenced human genome, providing extensive information about gene structure and the pattern of gene expression. ESTs, together with SAGE libraries and microarray experiment information, provide a broad and rich view of the transcriptome. However, it is difficult to perform large-scale expression mining of the data generated by these diverse experimental approaches. Not only is the data stored in disparate locations, but there is frequent ambiguity in the meaning of terms used to describe the source of the material used in the experiment. Untangling semantic differences between the data provided by different resources is therefore largely reliant on the domain knowledge of a human expert. We present here eVOC, a system which associates labelled target cDNAs for microarray experiments, or cDNA libraries and their associated transcripts with controlled terms in a set of hierarchical vocabularies. eVOC consists of four orthogonal controlled vocabularies suitable for describing the domains of human gene expression data including Anatomical System, Cell Type, Pathology and Developmental Stage. We have curated and annotated 7016 cDNA libraries represented in dbEST, as well as 104 SAGE libraries,with expression information,and provide this as an integrated, public resource that allows the linking of transcripts and libraries with expression terms. Both the vocabularies and the vocabulary-annotated libraries can be retrieved from http://www.sanbi.ac.za/evoc/. Several groups are involved in developing this resource with the aim of unifying transcript expression information.

Effect of a governmentally-led physical activity program on motor skills in young children attending child care centers: a cluster randomized controlled trial.

OBJECTIVE: To assess the effect of a governmentally-led center based child care physical activity program (Youp'la Bouge) on child motor skills.Patients and methods: We conducted a single blinded cluster randomized controlled trial in 58 Swiss child care centers. Centers were randomly selected and 1:1 assigned to a control or intervention group. The intervention lasted from September 2009 to June 2010 and included training of the educators, adaptation of the child care built environment, parental involvement and daily physical activity. Motor skill was the primary outcome and body mass index (BMI), physical activity and quality of life secondary outcomes. The intervention implementation was also assessed. RESULTS: At baseline, 648 children present on the motor test day were included (age 3.3 +/- 0.6, BMI 16.3 +/- 1.3 kg/m2, 13.2% overweight, 49% girls) and 313 received the intervention. Relative to children in the control group (n = 201), children in the intervention group (n = 187) showed no significant increase in motor skills (delta of mean change (95% confidence interval: -0.2 (-0.8 to 0.3), p = 0.43) or in any of the secondary outcomes. Not all child care centers implemented all the intervention components. Within the intervention group, several predictors were positively associated with trial outcomes: 1) free-access to a movement space and parental information session for motor skills 2) highly motivated and trained educators for BMI 3) free-access to a movement space and purchase of mobile equipment for physical activity (all p < 0.05). CONCLUSION: This "real-life" physical activity program in child care centers confirms the complexity of implementing an intervention outside a study setting and identified potentially relevant predictors that could improve future programs.Trial registration: Trial registration number: clinical trials.gov NCT00967460 http://clinicaltrials.gov/ct2/show/NCT00967460.

Ethanol among randomly controlled drivers

Objectives: Ethanol is well-known to impair driving ability. The major aim of this study was to evaluate the number of drivers driving under the influence of ethanol in a population of randomly controlled drivers. Methods: 1016 drivers were randomly controlled at 27 different locations in Western Switzerland from October 2006 to April 2008. Drivers were controlled for alcohol consumption with a breathalyzer according to the Swiss Road traffic law. If the result was equal or higher than an equivalent of a blood alcohol concentration of 0.8 g/kg, a blood sample was taken; otherwise, a saliva sample was obtained. Blood and saliva were analysed for ethanol by Head-space gas chromatography coupled with a FID detector. Results: Among the controlled drivers, men (69%) predominated over female (31%). The mean age was 41 (range: 16 90). For 968 drivers (95.3%) ethanol was not detected in blood or saliva. These drivers were not under the influence of ethanol. Ethanol was detected in saliva or blood of 48 drivers (4.7%). Among these drivers, blood alcohol concentration (BAC) was above the legal limit of 0.8 g/kg (serious offence) in 14 cases (1.4% of the total population). BAC were in the range of 0.91 to 2.43 g/kg (mean: 1.32 g/kg, median: 1.11 g/kg). Among these 14 cases, men (13 cases, 93%) were over represented. No ethanol was found in the population of truck drivers (17 cases). 986 drivers were car drivers and 46 of them have drunk ethanol (5%). 13 bikers were controlled and 2 of them have drunk ethanol (15%). Conclusion: Driving under the influence of ethanol concerned about 5% of a population of randomly controlled drivers, and 1,4% of the drivers had a blood alcohol concentration higer than 0.8 g/kg (legale limit for a serious offence).

Automatic selection of tidal volume, respiratory frequency and minute ventilation in intubated ICU patients as start up procedure for closed-loop controlled ventilation.

OBJECTIVE: Before a patient can be connected to a mechanical ventilator, the controls of the apparatus need to be set up appropriately. Today, this is done by the intensive care professional. With the advent of closed loop controlled mechanical ventilation, methods will be needed to select appropriate start up settings automatically. The objective of our study was to test such a computerized method which could eventually be used as a start-up procedure (first 5-10 minutes of ventilation) for closed-loop controlled ventilation. DESIGN: Prospective Study. SETTINGS: ICU's in two adult and one children's hospital. PATIENTS: 25 critically ill adult patients (age > or = 15 y) and 17 critically ill children selected at random were studied. INTERVENTIONS: To stimulate 'initial connection', the patients were disconnected from their ventilator and transiently connected to a modified Hamilton AMADEUS ventilator for maximally one minute. During that time they were ventilated with a fixed and standardized breath pattern (Test Breaths) based on pressure controlled synchronized intermittent mandatory ventilation (PCSIMV). MEASUREMENTS AND MAIN RESULTS: Measurements of airway flow, airway pressure and instantaneous CO2 concentration using a mainstream CO2 analyzer were made at the mouth during application of the Test-Breaths. Test-Breaths were analyzed in terms of tidal volume, expiratory time constant and series dead space. Using this data an initial ventilation pattern consisting of respiratory frequency and tidal volume was calculated. This ventilation pattern was compared to the one measured prior to the onset of the study using a two-tailed paired t-test. Additionally, it was compared to a conventional method for setting up ventilators. The computer-proposed ventilation pattern did not differ significantly from the actual pattern (p > 0.05), while the conventional method did. However the scatter was large and in 6 cases deviations in the minute ventilation of more than 50% were observed. CONCLUSIONS: The analysis of standardized Test Breaths allows automatic determination of an initial ventilation pattern for intubated ICU patients. While this pattern does not seem to be superior to the one chosen by the conventional method, it is derived fully automatically and without need for manual patient data entry such as weight or height. This makes the method potentially useful as a start up procedure for closed-loop controlled ventilation.

Sequence homologies within the 5' end region of the estrogen-controlled vitellogenin gene in Xenopus and chicken.

In oviparous vertebrates vitellogenin, the precursor of the major yolk proteins, is synthesized in the liver of mature females under the control of estrogen. We have established the organization and primary structure of the 5' end region of the Xenopus laevis vitellogenin A2 gene and of the major chicken vitellogenin gene. The first three homologous exons have exactly the same length in both species, namely 53, 21 and 152 nucleotides, and present an overall sequence homology of 60%. In both species, the 5'-non-coding region of the vitellogenin mRNA measures only 13 nucleotides, nine of which are conserved. In contrast, the corresponding introns of the Xenopus and the chicken vitellogenin gene show no significant sequence homology. Within the 500 nucleotides preceding the 5' end of the genes, at least six blocks with sequence homologies of greater than 70% were detected. It remains to be demonstrated which of these conserved sequences, if any, are involved in the hormone-regulated expression of the vitellogenin genes.

Does altering inclination alter effectiveness of treadmill training for gait impairment after stroke? A randomized controlled trial.

Objective: To assess whether a downhill walking training programme is more effective than the same amount of training applied uphill in chronic stroke survivors. Design: Randomized, single-blind study. Setting: Outpatient rehabilitation service. Methods: Thirty-eight adults with hemiplegia from stroke lasting more than three months were randomly allocated to one of the two groups: 'UP' - 45 minutes of physical therapy + 30 minutes of treadmill with 5% ascending slope; and 'DOWN' - 45 minutes of physical therapy + 30 minutes of treadmill with 5% descending slope. Both groups were treated 5 times a week for six weeks. Patients were evaluated before treatment, at the end of treatment and after three months. Outcome measures: Primary outcome measure was the number of patients showing an improvement in 6-minute walking test (6MWT) greater than 50 m. Secondary outcome measures were: (1) number of patients showing a clinically relevant improvement of gait speed during 10-m walking test (10mWT); (2) number of patients showing an improvement in timed up and go (TUG) greater than minimal detectable change. Results: Both groups had a significant improvement after treatment and at follow-up. At the end of treatment, compared to UP group, more patients in the DOWN group showed clinically significant improvements in primary and secondary outcomes (16/19 patients for 6MWT, 11/19 patients for 10mWT and 9/19 patients for TUG compared with 3/19, 4/19 and 2/19 patients, respectively, P < 0.01). At follow-up, results were similar except for 10mWT. Conclusions: In chronic stroke patients, downhill treadmill training produces a bigger effect than uphill training.