An analysis of protocols and publications suggested that most discontinuations of clinical trials were not based on preplanned interim analyses or stopping rules.

OBJECTIVES: To investigate the frequency of interim analyses, stopping rules, and data safety and monitoring boards (DSMBs) in protocols of randomized controlled trials (RCTs); to examine these features across different reasons for trial discontinuation; and to identify discrepancies in reporting between protocols and publications. STUDY DESIGN AND SETTING: We used data from a cohort of RCT protocols approved between 2000 and 2003 by six research ethics committees in Switzerland, Germany, and Canada. RESULTS: Of 894 RCT protocols, 289 prespecified interim analyses (32.3%), 153 stopping rules (17.1%), and 257 DSMBs (28.7%). Overall, 249 of 894 RCTs (27.9%) were prematurely discontinued; mostly due to reasons such as poor recruitment, administrative reasons, or unexpected harm. Forty-six of 249 RCTs (18.4%) were discontinued due to early benefit or futility; of those, 37 (80.4%) were stopped outside a formal interim analysis or stopping rule. Of 515 published RCTs, there were discrepancies between protocols and publications for interim analyses (21.1%), stopping rules (14.4%), and DSMBs (19.6%). CONCLUSION: Two-thirds of RCT protocols did not consider interim analyses, stopping rules, or DSMBs. Most RCTs discontinued for early benefit or futility were stopped without a prespecified mechanism. When assessing trial manuscripts, journals should require access to the protocol.

Managing Risk in a Culture of Rights: Providing Support and Treatment in Community-Based Settings for Persons with Intellectual Disabilities who Sexually Offend

People with intellectual disability who sexually offend commonly live in community-based settings since the closing of all institutions across the province of Ontario. Nine (n=9) front line staff who provide support to these individuals in three different settings (treatment setting, transitional setting, residential setting) were interviewed. Participants responded to 47 questions to explore how sex offenders with intellectual disability can be supported in the community to prevent re-offenses. Questions encompassed variables that included staff attitudes, various factors impacting support, structural components of the setting, quality of life and the good life, staff training, staff perspectives on treatment, and understanding of risk management. Three overlapping models that have been supported in the literature were used collectively for the basis of this research: The Good Lives Model (Ward & Gannon, 2006; Ward et al., 2007), the quality of life model (Felce & Perry, 1995), and variables associated with risk management. Results of this research showed how this population is being supported in the community with an emphasis on the following elements: positive and objective staff attitude, teamwork, clear rules and protocols, ongoing supervision, consistency, highly trained staff, and environments that promote quality of life. New concepts arose which suggested that all settings display an unequal balance of upholding human rights and managing risks when supporting this high-risk population. This highlights the need for comprehensive assessments in order to match the offender to the proper setting and supports, using an integration of a Risk, Need, Responsivity model and the Good Lives model for offender rehabilitation and to reduce the likelihood of re-offenses.

Impact of type of drug insurance on adherence, persistence and costs of antidepressant drugs : a Quebec population-based study

Contexte: À date, il existe peu de données sur l’adhésion, la persistance et les coûts associés aux antidépresseurs selon le type d’assurance médicament (privé ou public). Objectif: Comparer selon le régime d’assurance médicament (privé ou public), l'adhésion, la persistance et les coûts des antidépresseurs. Méthodes de recherche: Une étude de cohorte appariée a été réalisée en utilisant des bases de données du Québec. Sujets: Nous avons sélectionné 194 patients assurés par un régime privé et 1923 patients assurés par le régime public de la Régie de l’assurance maladie du Québec (RAMQ) (18-64 ans) qui ont rempli au moins une ordonnance pour un antidépresseur entre décembre 2007 et septembre 2009. Mesures: L’adhésion, mesurée sur une période d’un an, a été estimée en utilisant le proportion of prescribed days covered (PPDC). Un modèle de régression linéaire a été utilisé afin d’estimer la différence moyenne en PPDC entre les patients assurés par un régime privé et ceux assurés par le régime public de la RAMQ. La persistance a été comparé entre ces deux groupes avec un modèle de régression de survie Cox, et le coût mensuel d'antidépresseurs ($ CAN) a été comparé entre ces deux groupes en utilisant un modèle de régression linéaire. Résultats: Le PPDC parmi les patients assurés par un régime privé était de 86,4% (intervalle de confiance (IC) 95%: 83,3%-89,5%) versus 81,3% (IC 95%: 80,1%-82,5%) pour les patients assurés par le régime public de la RAMQ, pour une différence moyenne ajustée de 6,7% (IC 95%: 3,0%-10,4%). La persistance après un an parmi les patients assurés par un régime privé était de 49,5% versus 18,9% pour les patients assurés par le régime public de la RAMQ (p <0,001), et le rapport de risque ajusté était de 0,48 (IC 95%: 0,30-0,76). Comparativement aux patients assurés par le régime public de la RAMQ, les patients ayant une assurance privée ont payé 14,94 $ CAD (95% CI: $12,30-$17,58) de plus par mois en moyenne pour leurs antidépresseurs. Conclusion: Les patients assurés par un régime privé avaient une meilleure adhésion, persistance, mais avaient aussi un plus haut coût pour leurs antidépresseurs que ceux assurés par le régime public de la RAMQ. Cette différence de coûts peut être due aux différentes exigences de paiement en pharmacie entre les deux régimes ainsi qu’aux limites des honoraires des pharmaciens imposés par le régime public.

Genetic association study of plasma creatine kinase levels in the Montreal Heart Institute Hospital Cohort

Il a déjà été démontré que les statines (ou inhibiteurs de la HMG-CoA réductase) sont efficaces pour réduire le LDL-cholestérol et elles se sont depuis établies comme étant le pilier dans le traitement de la dyslipidémie. Toutefois, environ 10 pourcent des utilisateurs de statines souffrent d'effets indésirables, généralement sous forme de myopathie qui est souvent accompagnée d’un taux élevé de la créatine kinase (CK) plasmatique. Il est fréquent que les patients doivent arrêter les statines à cause d’un taux de CK dépassant un seuil de référence. Nous avons examiné le taux de CK de près de 6000 participants de la biobanque de l’ICM, qui ont récemment été génotypés à l'aide de la micropuce d'ADN ExomChip d'Illumina. Des études antérieures ont démontré une association significative entre le taux de CK plasmatique et des polymorphismes génétiques et nous avons cherché à répliquer ces résultats par association génétique et à l'aide du test SKAT pour les polymorphismes rares. Nous avons répliqué les résultats dans le gène CKM (rs11559024, p=1.59x10-23) et le gène LILRB5 (rs12975366, p=1.44x10-26) dans le chromosome 19. Nous espérons que ces résultats seront éventuellement utilisés en clinique pour la prédiction des taux de référence de CK personnalisés selon le profil génétique des patients utilisateurs de statines.

A heuristic algorithm for the Capacitated Vehicle Routing Problem with Synchronized Pick-ups and Drop-offs : a case study for medications delivery and supervision in DR Congo

Dans des contextes de post-urgence tels que le vit la partie occidentale de la République Démocratique du Congo (RDC), l’un des défis cruciaux auxquels font face les hôpitaux ruraux est de maintenir un niveau de médicaments essentiels dans la pharmacie. Sans ces médicaments pour traiter les maladies graves, l’impact sur la santé de la population est significatif. Les hôpitaux encourent également des pertes financières dues à la péremption lorsque trop de médicaments sont commandés. De plus, les coûts du transport des médicaments ainsi que du superviseur sont très élevés pour les hôpitaux isolés ; les coûts du transport peuvent à eux seuls dépasser ceux des médicaments. En utilisant la province du Bandundu, RDC pour une étude de cas, notre recherche tente de déterminer la faisabilité (en termes et de la complexité du problème et des économies potentielles) d’un problème de routage synchronisé pour la livraison de médicaments et pour les visites de supervision. Nous proposons une formulation du problème de tournées de véhicules avec capacité limitée qui gère plusieurs exigences nouvelles, soit la synchronisation des activités, la préséance et deux fréquences d’activités. Nous mettons en œuvre une heuristique « cluster first, route second » avec une base de données géospatiales qui permet de résoudre le problème. Nous présentons également un outil Internet qui permet de visualiser les solutions sur des cartes. Les résultats préliminaires de notre étude suggèrent qu’une solution synchronisée pourrait offrir la possibilité aux hôpitaux ruraux d’augmenter l’accessibilité des services médicaux aux populations rurales avec une augmentation modique du coût de transport actuel.

Interacting software-agents to support a kind of expert supervision systems

Expert supervision systems are software applications specially designed to automate process monitoring. The goal is to reduce the dependency on human operators to assure the correct operation of a process including faulty situations. Construction of this kind of application involves an important task of design and development in order to represent and to manipulate process data and behaviour at different degrees of abstraction for interfacing with data acquisition systems connected to the process. This is an open problem that becomes more complex with the number of variables, parameters and relations to account for the complexity of the process. Multiple specialised modules tuned to solve simpler tasks that operate under a co-ordination provide a solution. A modular architecture based on concepts of software agents, taking advantage of the integration of diverse knowledge-based techniques, is proposed for this purpose. The components (software agents, communication mechanisms and perception/action mechanisms) are based on ICa (Intelligent Control architecture), software middleware supporting the build-up of applications with software agent features

Clinical experience of clobazam as add-on treatment in a cohort of adults with epilepsy

Objective: Epilepsy is a common neurologic disorder affecting 1% of the world population with one-third of these patients failing to have seizure control for more than one year. Clobazam is a long-acting benzodiazepine used worldwide for the treatment of epilepsy. This antiepileptic drug has demonstrated great clinical benefits with mild side effects. The objective of this study was to better understand the efficacy of clobazam treatment on adult patients with refractory epilepsy. Design: A retrospective review of 44 adult patients with diagnosis of epilepsy that were seen at our Epilepsy Clinic between January 2014 and May 2015. Setting: An outpatient epilepsy clinic at the Hospital Universitario Fundación Santa Fe de Bogota, Colombia. Participants: 44 adult patients with diagnosis of epilepsy. Measurements: Seizure frequency, adverse effects and the use of concomitant AEDs were reviewed in each of the patient´s clinical charts. Results: The responder rate of patients with clobazam was 52% at 3 months, 50% at 6 months and 55% at 12 month. Seizure freedom rates at 3, 6 and 12 months were 18%, 25% and 25% respectively. Clobazam related adverse events occurred only in four patients (9%) at the end of the twelve months with somnolence being the most common. Conclusion: These findings suggest that clobazam treatment in adult patients with focal or generalized epilepsy is effective and safe. Its use should be considered early when first-line agents fail to provide seizure control.

DAI-DEPUR: an integrated and distributed architecture for wastewater treatment plants supervision

The activated sludge process - the main biological technology usually applied to wastewater treatment plants (WWTP) - directly depends on live beings (microorganisms), and therefore on unforeseen changes produced by them. It could be possible to get a good plant operation if the supervisory control system is able to react to the changes and deviations in the system and can take the necessary actions to restore the system’s performance. These decisions are often based both on physical, chemical, microbiological principles (suitable to be modelled by conventional control algorithms) and on some knowledge (suitable to be modelled by knowledge-based systems). But one of the key problems in knowledge-based control systems design is the development of an architecture able to manage efficiently the different elements of the process (integrated architecture), to learn from previous cases (spec@c experimental knowledge) and to acquire the domain knowledge (general expert knowledge). These problems increase when the process belongs to an ill-structured domain and is composed of several complex operational units. Therefore, an integrated and distributed AI architecture seems to be a good choice. This paper proposes an integrated and distributed supervisory multi-level architecture for the supervision of WWTP, that overcomes some of the main troubles of classical control techniques and those of knowledge-based systems applied to real world systems

Bayesian decision procedures for dose-escalation based on evidence of undesirable events and therapeutic benefit.

In this paper, Bayesian decision procedures are developed for dose-escalation studies based on bivariate observations of undesirable events and signs of therapeutic benefit. The methods generalize earlier approaches taking into account only the undesirable outcomes. Logistic regression models are used to model the two responses, which are both assumed to take a binary form. A prior distribution for the unknown model parameters is suggested and an optional safety constraint can be included. Gain functions to be maximized are formulated in terms of accurate estimation of the limits of a therapeutic window or optimal treatment of the next cohort of subjects, although the approach could be applied to achieve any of a wide variety of objectives. The designs introduced are illustrated through simulation and retrospective implementation to a completed dose-escalation study. Copyright © 2006 John Wiley & Sons, Ltd.

Depression in men in the postnatal period and later child psychopathology: a population cohort study

Objective: Postnatal depression in women is associated with adverse effects on both maternal health and children's development. It is unclear whether depression in men at this time poses comparable risks. The present study set out to assess the association between depression in men in the postnatal period and later psychiatric disorders in their children and to investigate predisposing factors for depression in men following childbirth. Method: A population-based cohort of 10,975 fathers and their children from the Avon Longitudinal Study of Parents and Children (ALSPAC) was recruited in the prenatal period and followed for 7 years. Paternal depressive symptoms were assessed with the Edinburgh Postnatal Depression Scale and later child psychiatric disorder (DSM-IV) with the Development and Well-Being Assessment. Results: Depression in fathers in the postnatal period was significantly associated with psychiatric disorder in their children 7 years later (adjusted OR 1.72, 95% CI 1.07-2.77), most notably oppositional defiant/conduct disorders (adjusted OR 1.94, 95% CI 1.04-3.61), after adjusting for maternal depression and paternal educational level. A history of severe depression and high prenatal symptom scores for depression and anxiety were the strongest predictors of paternal depression in the postnatal period. Conclusions: Depression in fathers in the postnatal period is associated with later psychiatric disorders in their children, independently of maternal postnatal depression. Further research into the risks associated with paternal psychopathology is required because this could represent an important opportunity for public health intervention.

Antioxidant enzymes, inflammatory indices and lifestyle factors in older men: a cohort analysis

We examined the relationship between blood antioxidant enzyme activities, indices of inflammatory status and a number of lifestyle factors in the Caerphilly prospective cohort study of ischaemic heart disease. The study began in 1979 and is based on a representative male population sample. Initially 2512 men were seen in phase I, and followed-up every 5 years in phases II and III; they have recently been seen in phase IV. Data on social class, smoking habit, alcohol consumption were obtained by questionnaire, and body mass index was measured. Antioxidant enzyme activities and indices of inflammatory status were estimated by standard techniques. Significant associations were observed for: age with α-1-antichymotrypsin (p<0.0001) and with caeruloplasmin, both protein and oxidase (p<0.0001); smoking habit with α-1-antichymotrypsin (p<0.0001), with caeruloplasmin, both protein and oxidase (p<0.0001) and with glutathione peroxidose (GPX) (p<0.0001); social class with α-1-antichymotrypsin (p<0.0001), with caeruloplasmin both protein (p<0.001) and oxidase (p<0.01) and with GPX (p<0.0001); body mass index with α-1-antichymotrypsin (p<0.0001) and with caeruloplasmin protein (p<0.001). There was no significant association between alcohol consumption and any of the blood enzymes measured. Factor analysis produced a three-factor model (explaining 65.9% of the variation in the data set) which appeared to indicate close inter-relationships among antioxidants.

Trajectories of maternal depression and offspring psychopathology at 6 years: 2004 Pelotas cohort study

BACKGROUND: Few studies have addressed the course and severity of maternal depression and its effects on child psychiatric disorders from a longitudinal perspective. This study aimed to identify longitudinal patterns of maternal depression and to evaluate whether distinct depression trajectories predict particular psychiatric disorders in offspring. METHODS: Cohort of 4231 births followed-up in the city of Pelotas, Brazil. Maternal depressive symptoms were assessed with the Edinburgh Postnatal Depression Scale (EPDS) at 3, 12, 24 and 48 months and 6 years after delivery. Psychiatric disorders in 6-year-old children were evaluated through the development and well-being assessment (DAWBA) instrument. Trajectories of maternal depression were calculated using a group-based modelling approach. RESULTS: We identified five trajectories of maternal depressive symptoms: a "low" trajectory (34.8%), a "moderate low" (40.9%), a "increasing" (9.0%), a "decreasing" (9.9%), and a "high-chronic" trajectory (5.4%). The probability of children having any psychiatric disorder, as well as both internalizing and externalizing problems, increased as we moved from the "low" to the "high-chronic" trajectory. These differences were not explained by maternal and child characteristics examined in multivariate analyses. LIMITATIONS: Data on maternal depression at 3-months was available on only a sub-sample. In addition, we had to rely on maternal report of child's behavior alone. CONCLUSIONS: The study revealed an additive effect on child outcome of maternal depression over time. We identified a group of mothers with chronic and severe symptoms of depression throughout the first six years of the child life and for this group child psychiatric outcome was particularly compromised.

Effects of a web-based personalized intervention on physical activity in European adults: a randomized controlled trial

Background: The high prevalence of physical inactivity worldwide calls for innovative and more effective ways to promote physical activity (PA). There are limited objective data on the effectiveness of Web-based personalized feedback on increasing PA in adults. Objective: It is hypothesized that providing personalized advice based on PA measured objectively alongside diet, phenotype, or genotype information would lead to larger and more sustained changes in PA, compared with nonpersonalized advice. Methods: A total of 1607 adults in seven European countries were randomized to either a control group (nonpersonalized advice, Level 0, L0) or to one of three personalized groups receiving personalized advice via the Internet based on current PA plus diet (Level 1, L1), PA plus diet and phenotype (Level 2, L2), or PA plus diet, phenotype, and genotype (Level 3, L3). PA was measured for 6 months using triaxial accelerometers, and self-reported using the Baecke questionnaire. Outcomes were objective and self-reported PA after 3 and 6 months. Results: While 1270 participants (85.81% of 1480 actual starters) completed the 6-month trial, 1233 (83.31%) self-reported PA at both baseline and month 6, but only 730 (49.32%) had sufficient objective PA data at both time points. For the total cohort after 6 months, a greater improvement in self-reported total PA (P=.02) and PA during leisure (nonsport) (P=.03) was observed in personalized groups compared with the control group. For individuals advised to increase PA, we also observed greater improvements in those two self-reported indices (P=.006 and P=.008, respectively) with increased personalization of the advice (L2 and L3 vs L1). However, there were no significant differences in accelerometer results between personalized and control groups, and no significant effect of adding phenotypic or genotypic information to the tailored feedback at month 3 or 6. After 6 months, there were small but significant improvements in the objectively measured physical activity level (P<.05), moderate PA (P<.01), and sedentary time (P<.001) for individuals advised to increase PA, but these changes were similar across all groups. Conclusions: Different levels of personalization produced similar small changes in objective PA. We found no evidence that personalized advice is more effective than conventional “one size fits all” guidelines to promote changes in PA in our Web-based intervention when PA was measured objectively. Based on self-reports, PA increased to a greater extent with more personalized advice. Thus, it is crucial to measure PA objectively in any PA intervention study.

Interactions between uncoupling protein 2 gene polymorphisms, obesity and alcohol intake on liver function: a large meta-analysed population-based study

BACKGROUND AND OBJECTIVE: Given the role of uncoupling protein 2 (UCP2) in the accumulation of fat in the hepatocytes and in the enhancement of protective mechanisms in acute ethanol intake, we hypothesised that UCP2 polymorphisms are likely to cause liver disease through their interactions with obesity and alcohol intake. To test this hypothesis, we investigated the interaction between tagging polymorphisms in the UCP2 gene (rs2306819, rs599277 and rs659366), alcohol intake and obesity traits such as BMI and waist circumference (WC) on alanine aminotransferase (ALT) and gamma glutamyl transferase (GGT) in a large meta-analysis of data sets from three populations (n=20 242). DESIGN AND METHODS: The study populations included the Northern Finland Birth Cohort 1966 (n=4996), Netherlands Study of Depression and Anxiety (n=1883) and LifeLines Cohort Study (n=13 363). Interactions between the polymorphisms and obesity and alcohol intake on dichotomised ALT and GGT levels were assessed using logistic regression and the likelihood ratio test. RESULTS: In the meta-analysis of the three cohorts, none of the three UCP2 polymorphisms were associated with GGT or ALT levels. There was no evidence for interaction between the polymorphisms and alcohol intake on GGT and ALT levels. In contrast, the association of WC and BMI with GGT levels varied by rs659366 genotype (Pinteraction=0.03 and 0.007, respectively; adjusted for age, gender, high alcohol intake, diabetes, hypertension and serum lipid concentrations). CONCLUSION: In conclusion, our findings in 20 242 individuals suggest that UCP2 gene polymorphisms may cause liver dysfunction through the interaction with body fat rather than alcohol intake.

Using problem-based learning in a chemistry practical class for pharmacy students and engaging them with feedback

Objective: To introduce a new approach to problem based learning (PBL) used in the context of medicinal chemistry practical class teaching pharmacy students. Design: The described chemistry practical is based on independent studies by small groups of undergraduate students (4-5), who design their own practical work taking relevant professional standards into account. Students are carefully guided by feedback and acquire a set of skills important to their future profession as healthcare professionals. This model has been tailored to the application of PBL in a chemistry practical class setting for a large student cohort (150 students). Assessment: The achievement of learning outcomes is based on the submission of relevant documentation including a certificate of analysis, in addition to peer assessment. Some of the learning outcomes are also assessed in the final written examination at the end of the academic year. Conclusion: The described design of a novel PBL chemistry laboratory course for pharmacy students has been found to be successful. Self-reflective learning and engagement with feedback were encouraged, and students enjoyed the challenging learning experience. Skills that are highly essential for the students’ future careers as healthcare professionals are promoted.