Effects of EU harmonization policies on national public supervision of clinical trials: A dynamic cycle of institutional change and institutional work.
The EU Clinical Trials Directive (EUCTD) and the EU Clinical Trials Regulation aim to harmonize good clinical practice (GCP) of clinical trials across Member States. Using the Netherlands as a case study, this paper analyzes how endeavours to implement the EUCTD set in motion a dynamic process of institutional change and institutional work. This process lead to substantial differences between policy and actual practice; therefore, it is important to learn more about the implementation of harmonization policies. Relevant documents, such as legal texts and previous research, were analyzed. Interviews were conducted with stakeholders in clinical trials and inspectors from (inter)national supervisory bodies (n=33), and Dutch Health Care Inspectorate inspections were observed (n=4). Dutch legislators' efforts to implement the EUCTD created a new level of governance in an already multilevel legislative framework. Institutional layering caused a complex and fragmented organizational structure in public supervision, leading to difficulties in achieving GCP. This instigated institutional work by actors, which set in motion further incremental institutional change, principally drift and conversion. Harmonization processes can create dynamic cycles between institutional change and institutional work, leading to significant divergence from the intended effects of legislation. If legislation intended to strengthen harmonization is not carefully implemented, it can become counterproductive to its aims.


Intravenous Acetaminophen For the Management of Pain During Vaso-occlusive Crises in Pediatric Patients.
Children with sickle cell disease experience vaso-occlusive crises (VOC) that requires opioid pharmacotherapy. Multimodal analgesic therapy may reduce pain and opioid-induced adverse effects. The primary objective was to examine the effectiveness of intravenous (IV) acetaminophen in children presenting with pain from VOC. Secondary objectives were to document the safety and opioid-sparing effects of IV acetaminophen during VOC in pediatric patients. Children's Medical Center, NYU-Winthrop Hospital. This retrospective study had two groups of patients, those who received opioids alone (group O) and those who received acetaminophen with opioids (group OA). Children two to 19 years of age who were admitted to the children's medical center for VOC were eligible for inclusion. A reduction in pain by at least 1 out of 10. With every analgesic dose, we documented pain scales and pain scores before and after each dose, the number of doses administered per day, and mg/kg/day. Data were analyzed using the mixed effect model. All opioids administered to patients were converted to morphine equivalents. We documented length of stay and adverse events. We had a total of 46 children: 28 in group O and 18 in group OA. Acetaminophen reduced the pain from VOC by 2.3/10. There were trends in different assessments of opioid-sparing effects, in reducing opioid dosage (-0.5 mg/kg morphine equivalent; P = 0.45), reducing overall morphine equivalent doses (-18.5 mg; P = 0.066), and opioid-related adverse effects. This is the first study to demonstrate the effectiveness of IV acetaminophen in treating VOC pain in children, supporting multimodal analgesic therapy in this setting. Opioid-sparing effects were also encouraging.


[Pathophysiology of involuntary movements in adults].
Inhibitory control of basal ganglia output to thalamocortical projection plays an important role in normal cortical activity in the current model of the basal ganglia motor circuit. Hypokinetic and hyperkinetic movement disorders of basal ganglia origin can be explained by excess or collapse of the basal ganglia output. An abundance of evidence indicates that parkinsonian akinesia results from hyperactivity of the basal ganglia output. Reversal of akinesia by lesions of the internal division of the globus pallidus (GPi) or its excitatory source, the subthalamic nucleus, agrees with this pathological schema. Ballism associated with subthalamic lesions, and dopa-induced dyskinesia are regarded as hyperkinetic disorders resulting from suppressed subthalamopallidal projection. Decreased firing rate in GPi was reported in both disorders. However, pallidotomy has recently been postulated to abolish both ballism and dopa-induced dyskinesia. A possible mechanism for the effect of GPi destruction in these hyperkinetic disorders may be blockade of the generation or conduction of phasic neuronal activities driving choreic movements. Symptomatologically, dystonia has aspects of both hypokinetic and hyperkinetic disorders. Overactivity of the premotor cortices, which receive projections from the basal ganglia via the ventral thalamus, was found both at rest and on movement in idiopathic dystonia. This abnormal cortical activity may arise from underactivity of basal ganglia output; however, the amelioration of dystonia with pallidotomy suggests a complex pathomechanism of the pallidothalamic system in dystonia.


Multiple cognitive control effects of error likelihood and conflict.
Recent work on cognitive control has suggested a variety of performance monitoring functions of the anterior cingulate cortex such as errors, conflict, error likelihood, and others. Given the variety of monitoring effects, a corresponding variety of control effects on behavior might be expected. This paper explores whether conflict and error likelihood produce distinct cognitive control effects on behavior, as measured by response time. A Change signal task (Brown & Braver, Science 307:1118-1121, 2005) was modified to include conditions of likely errors due to tardy as well as premature responses in conditions with and without conflict. The results discriminate between competing hypotheses of independent versus interacting conflict and error likelihood control effects. Specifically, the results suggest that the likelihood of premature versus tardy response errors can lead to multiple distinct control effects, which are independent of cognitive control effects driven by response conflict. As a whole, the results point to the existence of multiple distinct cognitive control mechanisms and challenge existing models of cognitive control that incorporate only a single control signal.


Metabolomics and Biomarkers for Drug Discovery.
Metabolomics and biomarkers are increasingly used in drug discovery and development, and are applied to personalized medicine. Progress in these research areas has increased our understanding of disease pathology and improved therapeutic strategies for many diseases with unmet challenges. Further advances will ultimately result in the development of better drugs and breakthrough therapies, which will benefit millions of patients suffering from chronic and life-threatening diseases worldwide.


CMGRN: a web server for constructing multilevel gene regulatory networks using ChIP-seq and gene expression data.
ChIP-seq technology provides an accurate characterization of transcription or epigenetic factors binding on genomic sequences. With integration of such ChIP-based and other high-throughput information, it would be dedicated to dissecting cross-interactions among multilevel regulators, genes and biological functions. Here, we devised an integrative web server CMGRN (constructing multilevel gene regulatory networks), to unravel hierarchical interactive networks at different regulatory levels. The newly developed method used the Bayesian network modeling to infer causal interrelationships among transcription factors or epigenetic modifications by using ChIP-seq data. Moreover, it used Bayesian hierarchical model with Gibbs sampling to incorporate binding signals of these regulators and gene expression profile together for reconstructing gene regulatory networks. The example applications indicate that CMGRN provides an effective web-based framework that is able to integrate heterogeneous high-throughput data and to reveal hierarchical 'regulome' and the associated gene expression programs. http://bioinfo.icts.hkbu.edu.hk/cmgrn; http://www.byanbioinfo.org/cmgrn CONTACT: email@example.com or firstname.lastname@example.com Supplementary Information: Supplementary data are available at Bioinformatics online.