DUCAT (Dutch inventory of invasive Coronary Atherosclerosis Treatments)

Het DUCAT (Dutch inventory of invasive Coronary Atherosclerosis Treatments) project had tot doel te bepalen hoe passend behandelbeslissingen (beleidsbeslissingen) zijn bij patiënten met vernauwing van een of meer kransslagaders rond het hart (coronairlijden). DUCAT bestond uit drie delen: a) bepaling van de passendheid van behandelindicaties door een panel van deskundigen, uitgaande van drie behandelvormen: coronaire-omleidingsoperatie (CABG), 'dotteren' (PTCA), en medicamenteuze of andere niet-invasieve therapie (conservatieve behandeling); b) toetsing van de beleidsbeslissingen in tien hartcentra in Nederland aan de paneloordelen; c) het volgen van de lotgevallen van patiënten met passende en niet-passende beleidsbeslissingen. Dat laatste is beperkt gebleven tot een periode van een jaar. Hoe kan men vaststellen of een indicatie voor een ingreep passend is of niet? Ideaal zou zijn als de wetenschappelijke literatuur geen twijfel toelaat over wat de beste benadering is, maar dat is niet zo. De literatuur biedt voor vele toepassingen van CABG en vooral PTCA onvoldoende zekerheid. Er moet daarom ook een beroep worden gedaan op de ervaring van deskundigen die de indicaties in de praktijk stellen. Een aanpak - maar zeker niet de enige - om die ervaring te laten meetellen is ontwikkeld door het Amerikaanse instituut RAND in samenwerking met de Universiteit van California in Los Angeles (UCLA). De RAND/UCLA methode houdt in dat vele modelpatiënten, en bijpassende indicaties voor behandeling, worden onderscheiden op basis van combinaties van klinische kenmerken. Deskundige leden van een panel geven, op grond van de literatuur en aanvullende medische inzichten, voor elk van die modelpatiënten aan of een behandelindicatie passend, onzeker of niet-passend is. DUCAT is het eerste onderzoek in Nederland waarin deze methode is toegepast. DUCAT kende een theorie- en een praktijkdeel. In het theoriedeel kwamen twee vragen aan de orde. Hoe passend waren volgens het DUCAT-panel de vele indicaties voor behandeling bij coronairlijden en welke klinische en niet-klinische factoren hadden invloed op de oordelen van het panel? Het panel koos bij bijna de helft van de modelpatiënten voor invasieve behandeling en bij ruim een op de vijf voor conservatieve therapie, terwijl het in de rest van de gevallen geen voorkeur had voor de ene of andere benadering. Het panel vond CABG-indicaties vaker passend dan PTCA-indicaties. Het baseerde zich daarbij vooral op medische overwegingen, zoals het actuele klinische beeld en vooral de ernst van de anatomische afwijkingen. Anatomische kenmerken wogen in de oordeelsvorming zwaarder dan andere karakteristieken, zoals medicatie en de uitslag van een inspanningsproef. DUCAT richtte zich op patiënten die in het hartcentrum werden besproken op initiatief van een verwijzend cardioloog waarbij de bespreking leidde tot een beleidsbeslissing. Onze primaire belangstelling ging uit naar 3647 mensen met anatomisch gedefinieerd significant coronairlijden. De desbetreffende DUCAT-populatie bestond in doorsnee uit niet al te jonge mannen en vrouwen van wie velen zich presenteerden met een uitgebreide geschiedenis of actuele uiting van risicofactoren, ziekteverschijnselen, vatafwijkingen en behandelingen, dus met ernstige pathologie. Dat gold niet over de hele linie. Opvallend was het grote aantal mensen met eenvatslijden. Bij verreweg de meeste patiënten met significant coronairlijden opteerden de interventieartsen voor invasieve behandeling (CABG of PTCA); bij 13 procent viel de keus op conservatieve therapie. CABG kr

Impaired Social Behavior in 5-HT3A Receptor Knockout Mice

The 5-HT3 receptor is a ligand-gated ion channel expressed on interneurons throughout the brain. So far, analysis of the 5-HT3A knockout mouse revealed changes in nociceptive processing and a reduction in anxiety related behavior. Recently, it was shown that the 5-HT3 receptor is also expressed on Cajal-Retzius cells which play a key role in cortical development and that knockout mice lacking this receptor showed aberrant growth of the dendritic tree of cortical layer II/III pyramidal neurons. Other mouse models in which serotonergic signaling was disrupted during development showed similar morphological changes in the cortex, and in addition, also deficits in social behavior. Here, we subjected male and female 5-HT3A knockout mice and their non-transgenic littermates to several tests of social behavior. We found that 5-HT3A knockout mice display impaired social communication in the social transmission of food preference task. Interestingly, we showed that in the social interaction test only female 5-HT3A knockout mice spent less time in reciprocal social interaction starting after 5 min of testing. Moreover, we observed differences in preference for social novelty for male and female 5-HT3A knockout mice during the social approach test. However, no changes in olfaction, exploratory activity and anxiety were detected. These results indicate that the 5-HT3A knockout mouse displays impaired social behavior with specific changes in males and females, reminiscent to other mouse models in which serotonergic signaling is disturbed in the developing brain

Alterations in Apical Dendrite Bundling in the Somatosensory Cortex of 5-HT3A Receptor Knockout Mice

In various species and areas of the cerebral cortex, apical dendrites of pyramidal neurons form clusters which extend through several layers of the cortex also known as dendritic bundles. Previously, it has been shown that 5-HT3A receptor knockout mice show hypercomplex apical dendrites of cortical layer 2/3 pyramidal neurons, together with a reduction in reelin levels, a glycoprotein involved in cortical development. Other studies showed that in the mouse presubicular cortex, reelin is involved in the formation of modular structures. Here, we compare apical dendrite bundling in the somatosensory cortex of wildtype and 5-HT3A receptor knockout mice. Using a microtubule associated protein-2 immunostaining to visualize apical dendrites of pyramidal neurons, we compared dendritic bundle properties of wildtype and 5-HT3A receptor knockout mice in tangential sections of the somatosensory cortex. A Voronoi tessellation was performed on immunostained tangential sections to determine the spatial organization of dendrites and to define dendritic bundles. In 5-HT3A receptor knockout mice, dendritic bundle surface was larger compared to wildtype mice, while the number and distribution of reelin-secreting Cajal–Retzius cells was similar for both groups. Together with previously observed differences in dendritic complexity of cortical layer 2/3 pyramidal neurons and cortical reelin levels, these results suggest an important role for the 5-HT3 receptor in determining the spatial organization of cortical connectivity in the mouse somatosensory cortex

European youth care sites serve different populations of adolescents with cannabis use disorder. Baseline and referral data from the INCANT trial

Background: MDFT (Multidimensional Family Therapy) is a family based outpatient treatment programme for adolescent problem behaviour. MDFT has been found effective in the USA in adolescent samples differing in severity and treatment delivery settings. On request of five governments (Belgium, France, Germany, the Netherlands, and Switzerland), MDFT has now been tested in the joint INCANT trial (International Cannabis Need of Treatment) for applicability in Western Europe. In each of the five countries, study participants were recruited from the local population of youth seeking or guided to treatment for, among other things, cannabis use disorder. There is little information in the literature if these populations are comparable between sites/countries or not. Therefore, we examined if the study samples enrolled in the five countries differed in baseline characteristics regarding demographics, clinical profile, and treatment delivery setting.Methods: INCANT was a multicentre phase III(b) randomized controlled trial with an open-label, parallel group design. It compared MDFT with treatment as usual (TAU) at and across sites in Berlin, Brussels, Geneva, The Hague and Paris.Participants of INCANT were adolescents of either sex, from 13 through 18 years of age, with a cannabis use disorder (dependence or abuse), and at least one parent willing to take part in the treatment. In total, 450 cases/families were randomized (concealed) into INCANT.Results: We collected data about adolescent and family demographics (age, gender, family composition, school, work, friends, and leisure time). In addition, we gathered data about problem behaviour (substance use, alcohol and cannabis use disorders, delinquency, psychiatric co-morbidity).There were no major differences on any of these measures between the treatment conditions (MDFT and TAU) for any of the sites. However, there were cross-site differences on many variables. Most of these could be explained by variations in treatment culture, as reflected by referral policy, i.e., participants' referral source. We distinguished 'self-determined' referral (common in Brussels and Paris) and referral with some authority-related 'external' coercion (common in Geneva and The Hague). The two referral types were more equally divided in Berlin. Many cross-site baseline differences disappeared when we took referral source into account, but not all.Conclusions: A multisite trial has the advantage of being efficient, but it also carries risks, the most important one being lack of equivalence between local study populations. Our site populations differed in many respects. This is not a problem for analyses and interpretations if the differences somehow can be accounted for. To a major extent, this appeared possible in INCANT. The most important factor underlying the cross-site variations in baseline characteristics was referral source. Correcting for referral source made most differences disappear. Therefore, we will use referral source as a covariate accounting for site differences in future INCANT outcome analyses

Challenges and opportunities for ELSI early career researchers

Background: Over the past 25 years, there has been growing recognition of the importance of studying the Ethical, Legal and Social Implications (ELSI) of genetic and genomic research. A large investment into ELSI research from the National Institutes of Health (NIH) Human Genomic Project budget in 1990 stimulated the growth of this emerging field; ELSI research has continued to develop and is starting to emerge as a field in its own right. The evolving subject matter of ELSI research continues to raise new research questions as well as prompt re-evaluation of earlier work and a growing number of scholars working in this area now identify themselves as ELSI scholars rather than with a particular discipline. Main text: Due to the international and interdisciplinary nature of ELSI research, scholars can often find themselves isolated from disciplinary or regionally situated support structures. We conducted a workshop with Early Career Researchers (ECRs) in Oxford, UK, and this paper discusses some of the particular challenges that were highlighted. While ELSI ECRs may face many of the universal challenges faced by ECRs, we argue that a number of challenges are either unique or exacerbated in the case of ELSI ECRs and discuss some of the reasons as to why this may be the case. We identify some of the most pressing issues for ELSI ECRs as: interdisciplinary angst and expertise, isolation from traditional support structures, limited resources and funding opportunities, and uncertainty regarding how research contributions will be measured. We discuss the potential opportunity to use web 2.0 technologies to transform academic support structures and address some of the challenges faced by ELSI ECRs, by helping to facilitate mentoring and support, access to resources and new accreditation metrics. Conclusion: As our field develops it is crucial for the ELSI community to continue looking forward to identify how emerging digital solutions can be used to facilitate the international and interdisciplinary research we perform, and to offer support for those embarking on, progressing through, and transitioning into an ELSI research career

Indications for coronary revascularisation: a Dutch perspective

OBJECTIVE: To assess the appropriateness of indications for coronary artery bypass graft (CABG) surgery and percutaneous transluminal coronary angioplasty (PTCA). METHODS: A modified Delphi group judgement process with input from a panel of six interventional cardiologists and six cardiopulmonary surgeons. There was one clinician from each of the 12 tertiary referral heart centres in The Netherlands. MAIN OUTCOME MEASURE: Ratings by panel members, on a 1 to 9 scale, of indications presented as a choice between two treatments (CABG v medical treatment, PTCA v medical treatment, and CABG v PTCA) for 1182 model cases. Each case represented a unique combination of clinical features in terms of symptoms, medical history, and results of tests. Ratings were analysed with respect to degree of agreement among panelists, degree of appropriateness of indications, and panel's preference for invasive or medical treatment. RESULTS: The panel agreed on 58.6% and disagreed on 3.2% of the indications. The panel opted for invasive treatment in 48.2% and medical treatment in 22.8%, and had no clear preference for either method in 29.0% of the cases. When compared with medical treatment, CABG was more often rated appropriate than PTCA: 35.4% v 21.6% (P < 0.001). Panel scores depended on severity of anatomical disease. For instance, for 51.5% of the model cases with one-vessel disease not including the proximal left anterior descending artery, the panel preferred medical treatment to invasive treatment, while the latter was preferred in 18% of the cases. In cases with type C lesions, the panel frequently rated PTCA as inappropriate. Panel scores were also affected by nonclinical factors. Cardiologists and surgeons rated the procedure of their own specialty higher than the alternative invasive intervention. CONCLUSIONS: The panel method yields logically consistent scores of the appropriateness of indications for carrying out medical procedures. It may be an aid in formulating clinical practice guidelines

Changes in cannabis potency and first-time admissions to drug treatment: a 16-year study in the Netherlands

BACKGROUND: The number of people entering specialist drug treatment for cannabis problems has increased considerably in recent years. The reasons for this are unclear, but rising cannabis potency could be a contributing factor. METHODS: Cannabis potency data were obtained from an ongoing monitoring programme in the Netherlands. We analysed concentrations of δ-9-tetrahydrocannabinol (THC) from the most popular variety of domestic herbal cannabis sold in each retail outlet (2000-2015). Mixed effects linear regression models examined time-dependent associations between THC and first-time cannabis admissions to specialist drug treatment. Candidate time lags were 0-10 years, based on normative European drug treatment data. RESULTS: THC increased from a mean (95% CI) of 8.62 (7.97-9.27) to 20.38 (19.09-21.67) from 2000 to 2004 and then decreased to 15.31 (14.24-16.38) in 2015. First-time cannabis admissions (per 100 000 inhabitants) rose from 7.08 to 26.36 from 2000 to 2010, and then decreased to 19.82 in 2015. THC was positively associated with treatment entry at lags of 0-9 years, with the strongest association at 5 years, b = 0.370 (0.317-0.424), p < 0.0001. After adjusting for age, sex and non-cannabis drug treatment admissions, these positive associations were attenuated but remained statistically significant at lags of 5-7 years and were again strongest at 5 years, b = 0.082 (0.052-0.111), p < 0.0001. CONCLUSIONS: In this 16-year observational study, we found positive time-dependent associations between changes in cannabis potency and first-time cannabis admissions to drug treatment. These associations are biologically plausible, but their strength after adjustment suggests that other factors are also important

Effects of an ACTH 4-9 related peptide upon intracranial self stimulation and general activity in the rat

Adult male Sprague-Dawley rats were stereotactically implanted with electrodes within the anterior medial forebrain bundle: The rats were trained to respond for intracranial self-stimulation (ICS) and treated with control solution or varying doses of an ACTH 4-9 related synthetic peptide (Org 2766; H-Met(O 2 )-Glu-His-Phe- d -Lys-Phe-OH). The drug affected ICS as measured in overnight response records, with the highest dose reliably increasing the amount of responding. In a second experiment rats were similarly treated and general activity was assessed. No remarkable changes in activity were present at any tested dose. The findings corroborate previous reports suggesting ACTH-related peptides may be active in a variety of motivated tasks, but less active with respect to general activity.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46417/1/213_2004_Article_BF00433254.pd

Methodological advances in imaging intravital axonal transport.

Axonal transport is the active process whereby neurons transport cargoes such as organelles and proteins anterogradely from the cell body to the axon terminal and retrogradely in the opposite direction. Bi-directional transport in axons is absolutely essential for the functioning and survival of neurons and appears to be negatively impacted by both aging and diseases of the nervous system, such as Alzheimer's disease and amyotrophic lateral sclerosis. The movement of individual cargoes along axons has been studied in vitro in live neurons and tissue explants for a number of years; however, it is currently unclear as to whether these systems faithfully and consistently replicate the in vivo situation. A number of intravital techniques originally developed for studying diverse biological events have recently been adapted to monitor axonal transport in real-time in a range of live organisms and are providing novel insight into this dynamic process. Here, we highlight these methodological advances in intravital imaging of axonal transport, outlining key strengths and limitations while discussing findings, possible improvements, and outstanding questions