User Experiences of Development of Dependence on the Synthetic Cannabinoids, 5f-AKB48 and 5F-PB-22, and Subsequent Withdrawal Syndromes

Emergence of synthetic cannabinoids (SCBs) in herbal smoking mixtures is a public health concern. New SCB’s such as 5f-AKB48 and 5F-PB-22 have been detected in French seizures and in sudden death post mortems in the US. The aim was to describe development of dependence on herbal smoking mixtures containing the SCB’s, 5f-AKB48 and 5F-PB-22 and subsequent withdrawal syndromes. Dependent users of herbal smoking mixtures known to contain the SCB’s 5f-AKB48 and 5F-PB-22 with an average Severity of Dependence Score (SDS) of 13 were interviewed using a structured guide (three males/three females). Narratives were analysed using the Empirical Phenomenological Psychological (EPP) five step method. Six themes with 68 categories emerged from the analysis. Themes are illustrated as 1) Networks and Product Availability; 2) Drivers and Motives for Use; 3) Effect and Pathways toward Dependence; 4) Poly Substance Use and Comparisons to Natural Cannabis; 5) Dependence and Withdrawal and 6) Self-detoxification Attempts. Two higher levels of abstraction above these theme-levels emerged from the data, with sole use of herbal smoking mixtures containing 5f-AKB48 and 5F-PB-22 centering on the interplay between intense cravings, compulsive all-consuming seeking, use and re-dose behaviours, and fear of the psychiatric and self-harms caused when in withdrawal. This is the first study describing dependence and withdrawal experiences in users dependent on 5f-AKB48 and 5F-PB-22. Given the potential for adverse psychiatric and physical consequences of dependent use, further development of specific clinical responses and clinical research around toxicity and withdrawal severity are warranted

Collaborative stepped care for anxiety disorders in primary care: aims and design of a randomized controlled trial

Background. Panic disorder (PD) and generalized anxiety disorder (GAD) are two of the most disabling and costly anxiety disorders seen in primary care. However, treatment quality of these disorders in primary care generally falls beneath the standard of international guidelines. Collaborative stepped care is recommended for improving treatment of anxiety disorders, but cost-effectiveness of such an intervention has not yet been assessed in primary care. This article describes the aims and design of a study that is currently underway. The aim of this study is to evaluate effects and costs of a collaborative stepped care approach in the primary care setting for patients with PD and GAD compared with care as usual. Methods/design. The study is a two armed, cluster randomized controlled trial. Care managers and their primary care practices will be randomized to deliver either collaborative stepped care (CSC) or care as usual (CAU). In the CSC group a general practitioner, care manager and psychiatrist work together in a collaborative care framework. Stepped care is provided in three steps: 1) guided self-help, 2) cognitive behavioral therapy and 3) antidepressant medication. Primary care patients with a DSM-IV diagnosis of PD and/or GAD will be included. 134 completers are needed to attain sufficient power to show a clinically significant effect of 1/2 SD on the primary outcome measure, the Beck Anxiety Inventory (BAI). Data on anxiety symptoms, mental and physical health, quality of life, health resource use and productivity will be collected at baseline and after three, six, nine and twelve months. Discussion. It is hypothesized that the collaborative stepped care intervention will be more cost-effective than care as usual. The pragmatic design of this study will enable the researchers to evaluate what is possible in real clinical practice, rather than under ideal circumstances. Many requirements for a high quality trial are being met. Results of this study will contribute to treatment options for GAD and PD in the primary care setting. Results will become available in 2011. Trial registration. NTR1071

Piloting online self-audit of methadone treatment in Irish general practice: results, reflections and educational outcomes

Background: Work based learning underpins the training and CPD of medical practitioners. Medical audit operates on two levels; individual self-assessment and professional/practice development. In Ireland, annual practice improvement audit is an essential requirement for the successful completion of continuous professional development (CPD) as determined by the regulatory body, the Irish Medical Council. All general practice (GP) doctors providing methadone maintenance treatment (MMT) in Ireland have a contractual obligation to partake in a yearly methadone practice audit. The Irish College of General Practitioners (ICGP) as national training provider is tasked to facilitate this annual audit process. The purpose of this audit is to assess the quality of care provided to patients against an agreed set of national standards, enhance learning, and promote practice improvement and reflective practice. The aim was to present an online MTP self-audit and evaluate results from a 12-month pilot among GPs providing MMT in Ireland. Method A mixed method study describing three phases (design and development, pilot/implementation and evaluation) of a new online self –audit tool was conducted. Descriptive and thematic analysis of audit and evaluation data was conducted. Results: Survey Monkey is a suitable software package for the development and hosting of an easy to use online audit for MMT providing doctors. Analysis of the audit results found that the majority of GPs scored 80% or over for the 25 identified essential criteria for MMT provision. The evaluation of the GP audit experience underscores the positive outcomes of the online self-audit in terms of improving practice systems, encouraging reflective practice, enhanced patient care and doctor commitment to continued provision of MMT in addiction clinics and in primary care. Conclusions: Results from this audit demonstrate a high level of compliance with best practise MMT guidelines by Irish GPs providing MMT. The online self-audit process was well received and encouraged reflective practice. The audit process hinged on the individual GP’s ability to review and critically analyse their professional practice, and manage change. This model of audit could be adapted and used to monitor the management of other chronic illnesses in general practice

Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.Peer reviewe

Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs

Placental abruption recorded with real-time electrohysterography : case report

Brief Introduction: A non-invasive technique based on real-time electrohysterography (EHG) is recently developed by our group and being tested at the labour ward (PUREtrace, Nemo Healthcare, Eindhoven, the Netherlands). We present a case of placental abruption and uterine hypertonia recorded with real-time EHG. Materials & Methods: Not applicable. Clinical Cases or Summary Results: A 33-year-old pregnant woman at 35 weeks of gestational age in her second pregnancy presented with vaginal blood loss. Her obstetric history revealed a uterus unicollis bicornis and an intrauterine fetal demise due to placental abruption at 26 weeks of gestational age. In the current pregnancy, prophylactic aspirin 80 mg was described from 12 up to 36 weeks. At admission there were no signs of fetal distress or retroplacental hematoma. The vaginal bleeding stopped, however several days later the pregnancy was complicated by preterm rupture of membranes followed by contractions and two centimetres of dilation. The fetal heart rate tracings showed a normal fetal condition, while monitoring uterine activity using external tocodynamometry was inconclusive. Therefore it was decided to use the EHG, by means of the Nemo Healthcare system consisting of a single abdominal electrode patch (Tocopatch, see Figure 1) and PUREtrace module connected to a Philips Avalon FM30 fetal monitor (Philips, Eindhoven, the Netherlands), which provided a cardiotocogram for real-time interpretation. Only half an hour later the pregnant woman presented acute onset of classical abruption signs such as severe abdominal pain, nausea, vomiting and fetal heart rate abnormality. The electrohysterogram showed a typical pattern of extreme uterine hypertonia (see Figure 2). Maternal vital signs were stable without vaginal blood loss. Within 15 minutes after the event an emergency caesarean delivery was performed, showing total detachment of the placenta. The neonate was born with a heart rate of 30 beats per minute and required neonatal resuscitation: Apgar score 0/6/8, umbilical artery pH 7.00, base deficit 17 mmol/L and neonatal body weight 2560 grams. During admission at the neonatal intensive care unit the newborn infant showed good clinical condition and no neurological sequels. Conclusions: This is the first report of real-time electrohysterography during placental abruption. The EHG showed a very typical pattern. Early recognition of this typical pattern might become important in patients with high risk of placental abruption. (Figure presented)

A mathematical model for simulation of early decelerations in the cardiotocogram during labor

Fetal welfare during labor and delivery is commonly monitored through the cardiotocogram (CTG), the combined registration of uterus contractions and fetal heart rate (FHR). The CTG gives an indication of the main determinant of the acute fetal condition, namely its oxygen state. However, interpretation is complicated by the complex relationship between the two. Mathematical models can be used to assist with the interpretation of the CTG, since they enable quantitative modeling of the cascade of events through which uterine contractions affect fetal oxygenation and FHR. We developed a mathematical model to simulate ‘early decelerations’, i.e. variations in FHR originating from caput compression during uterine contractions, as mediated by cerebral flow reduction, cerebral hypoxia and a vagal nerve response to hypoxia. Simulation results show a realistic response, both for fetal and maternal hemodynamics at term, as for FHR variation during early decelerations. The model is intended to be used as a training tool for gynaecologists. Therefore 6 clinical experts were asked to rate 5 real and 5 model-generated CTG tracings on overall realism and realism of selected aspects. Results show no significant differences between real and computer-generated CTG tracings

Simulation of reflex late decelerations in labor with a mathematical model

Fetal welfare during labor and delivery is commonly monitored through the cardiotocogram (CTG), the combined registration of uterus contractions and fetal heart rate (FHR). From the CTG, the fetal oxygen state is estimated as the main indicator of the fetal condition, but this estimate is difficult to make, due to the complex relation between CTG and oxygen state. Mathematical models can be used to assist in the interpretation of the CTG, since they enable quantitative modeling of the flow of events through which uterine contractions affect fetal oxygenation and FHR. We propose a mathematical model to simulate reflex ‘late decelerations’, i.e. variations in FHR originating from uteroplacental flow reduction during uterine contractions and mediated by the baroreflex and the chemoreflex. Results for the uncompromised fetus show that partial oxygen pressures reduce in relation to the strength and duration of the contraction. Above a certain threshold, hypoxemia will evoke a late deceleration. Results for uteroplacental insufficiency, simulated by reduced uterine blood supply or reduced placental diffusion capacity, demonstrated lower baseline FHR and smaller decelerations during contraction. Reduced uteroplacental blood volume was found to lead to deeper decelerations only. The model response in several nerve blocking simulations was similar to experimental findings by Martin et al. [18], indicating a correct balance between vagal and sympathetic reflex pathways