STRENGTHENING COOPERATION WITH THIRD COUNTRIES IN THE FIELD OF HIGHER EDUCATION. 14388/01 (Presse 437-G), 29 November 2001

BACKGROUND: In many European countries, medicines promotion is governed by voluntary codes of practice administered by the pharmaceutical industry under its own system of self-regulation. Involvement of industry organizations in policing promotion has been proposed to deter illicit conduct, but few detailed studies on self-regulation have been carried out to date. The objective of this study was to examine the evidence for promotion and self-regulation in the UK and Sweden, two countries frequently cited as examples of effective self-regulation. METHODS AND FINDINGS: We performed a qualitative content analysis of documents outlining the constitutions and procedures of these two systems. We also gathered data from self-regulatory bodies on complaints, complainants, and rulings for the period 2004-2012. The qualitative analysis revealed similarities and differences between the countries. For example, self-regulatory bodies in both countries are required to actively monitor promotional items and impose sanctions on violating companies, but the range of sanctions is greater in the UK where companies may, for instance, be audited or publicly reprimanded. In total, Swedish and UK bodies ruled that 536 and 597 cases, respectively, were in breach, equating to an average of more than one case/week for each country. In Sweden, 430 (47%) complaints resulted from active monitoring, compared with only two complaints (0.2%) in the UK. In both countries, a majority of violations concerned misleading promotion. Charges incurred on companies averaged €447,000 and €765,000 per year in Sweden and the UK, respectively, equivalent to about 0.014% and 0.0051% of annual sales revenues, respectively. One hundred cases in the UK (17% of total cases in breach) and 101 (19%) in Sweden were highlighted as particularly serious. A total of 46 companies were ruled in breach of code for a serious offence at least once in the two countries combined (n = 36 in the UK; n = 27 in Sweden); seven companies were in serious violation more than ten times each. A qualitative content analysis of serious violations pertaining to diabetes drugs (UK, n = 15; Sweden, n = 6; 10% of serious violations) and urologics (UK, n = 6; Sweden, n = 13; 9%) revealed various types of violations: misleading claims (n = 23; 58%); failure to comply with undertakings (n = 9; 23%); pre-licensing (n = 7; 18%) or off-label promotion (n = 2; 5%); and promotion of prescription drugs to the public (n = 6; 15%). Violations that go undetected or unpunished by self-regulatory bodies are the main limitation of this study, since they are likely to lead to an underestimate of industry misconduct. CONCLUSIONS: The prevalence and severity of breaches testifies to a discrepancy between the ethical standard codified in industry Codes of Conduct and the actual conduct of the industry. We discuss regulatory reforms that may improve the quality of medicines information, such as pre-vetting and intensified active monitoring of promotion, along with larger fines, and giving greater publicity to rulings. But despite the importance of improving regulatory arrangements in an attempt to ensure unbiased medicines information, such efforts alone are insufficient because simply improving oversight and increasing penalties fail to address additional layers of industry bias

Inhibition of Nuclear Factor of Activated T-Cells (NFAT) Suppresses Accelerated Atherosclerosis in Diabetic Mice

OBJECTIVE OF THE STUDY: Diabetic patients have a much more widespread and aggressive form of atherosclerosis and therefore, higher risk for myocardial infarction, peripheral vascular disease and stroke, but the molecular mechanisms leading to accelerated damage are still unclear. Recently, we showed that hyperglycemia activates the transcription factor NFAT in the arterial wall, inducing the expression of the pro-atherosclerotic protein osteopontin. Here we investigate whether NFAT activation may be a link between diabetes and atherogenesis. METHODOLOGY AND PRINCIPAL FINDINGS: Streptozotocin (STZ)-induced diabetes in apolipoprotein E(-/-) mice resulted in 2.2 fold increased aortic atherosclerosis and enhanced pro-inflammatory burden, as evidenced by elevated blood monocytes, endothelial activation- and inflammatory markers in aorta, and pro-inflammatory cytokines in plasma. In vivo treatment with the NFAT blocker A-285222 for 4 weeks completely inhibited the diabetes-induced aggravation of atherosclerosis, having no effect in non-diabetic mice. STZ-treated mice exhibited hyperglycemia and higher plasma cholesterol and triglycerides, but these were unaffected by A-285222. NFAT-dependent transcriptional activity was examined in aorta, spleen, thymus, brain, heart, liver and kidney, but only augmented in the aorta of diabetic mice. A-285222 completely blocked this diabetes-driven NFAT activation, but had no impact on the other organs or on splenocyte proliferation or cytokine secretion, ruling out systemic immunosuppression as the mechanism behind reduced atherosclerosis. Instead, NFAT inhibition effectively reduced IL-6, osteopontin, monocyte chemotactic protein 1, intercellular adhesion molecule 1, CD68 and tissue factor expression in the arterial wall and lowered plasma IL-6 in diabetic mice. CONCLUSIONS: Targeting NFAT signaling may be a novel and attractive approach for the treatment of diabetic macrovascular complications

Immunohistochemical localization of phosphohistidine phosphatase PHPT1 in mouse and human tissues

Protein histidine phosphorylation accounts for about 6% of the total protein phosphorylation in eukaryotic cells; still details concerning histidine phosphorylation and dephosphorylation are limited. A mammalian 14-kDa phosphohistidine phosphatase, also denominated PHPT1, was found 6 years ago that provided a new tool in the study of phosphohistidine phosphorylation. The localization of PHPT1 mRNA by Northern blot analysis revealed high expression in heart and skeletal muscle. The main object of the present study was to determine the PHPT1 expression on protein level in mouse tissues in order to get further information on the physiological role of the enzyme. Tissue samples from adult mice and 14.5-day-old mouse embryos were processed for immunostaining using a PHPT1-specific polyclonal antibody. The same antibody was also provided to the Swedish human protein atlas project (HPR) (http://www.proteinatlas.org/index.php). The results from both studies were essentially consistent with the previously reported expression of mRNA of a few human tissues. In addition, several other tissues, including testis, displayed a high protein expression. A salient result of the present investigation was the ubiquitous expression of the PHPT1 protein and its high expression in continuously dividing epithelial cells

Recommendations for the transition of patients with ADHD from child to adult healthcare services:a consensus statement from the UK adult ADHD network

The aim of this consensus statement was to discuss transition of patients with ADHD from child to adult healthcare services, and formulate recommendations to facilitate successful transition. An expert workshop was convened in June 2012 by the UK Adult ADHD Network (UKAAN), attended by a multidisciplinary team of mental health professionals, allied professionals and patients. It was concluded that transitions must be planned through joint meetings involving referring/receiving services, patients and their families. Negotiation may be required to balance parental desire for continued involvement in their child’s care, and the child’s growing autonomy. Clear transition protocols can maintain standards of care, detailing relevant timeframes, responsibilities of agencies and preparing contingencies. Transition should be viewed as a process not an event, and should normally occur by the age of 18, however flexibility is required to accommodate individual needs. Transition is often poorly experienced, and adherence to clear recommendations is necessary to ensure effective transition and prevent drop-out from services

Prognostic imaging biomarkers for diabetic kidney disease (iBEAt): Study protocol

Background: Diabetic kidney disease (DKD) remains one of the leading causes of premature death in diabetes. DKD is classified on albuminuria and reduced kidney function (estimated glomerular filtration rate (eGFR)) but these have modest value for predicting future renal status. There is an unmet need for biomarkers that can be used in clinical settings which also improve prediction of renal decline on top of routinely available data, particularly in the early stages. The iBEAt study of the BEAt-DKD project aims to determine whether renal imaging biomarkers (magnetic resonance imaging (MRI) and ultrasound (US)) provide insight into the pathogenesis and heterogeneity of DKD (primary aim) and whether they have potential as prognostic biomarkers in DKD (secondary aim). Methods: iBEAt is a prospective multi-centre observational cohort study recruiting 500 patients with type 2 diabetes (T2D) and eGFR ≥30 ml/min/1.73m2. At baseline, blood and urine will be collected, clinical examinations will be performed, and medical history will be obtained. These assessments will be repeated annually for 3 years. At baseline each participant will also undergo quantitative renal MRI and US with central processing of MRI images. Biological samples will be stored in a central laboratory for biomarker and validation studies, and data in a central data depository. Data analysis will explore the potential associations between imaging biomarkers and renal function, and whether the imaging biomarkers improve the prediction of DKD progression. Ancillary substudies will: (1) validate imaging biomarkers against renal histopathology; (2) validate MRI based renal blood flow measurements against H2O15 positron-emission tomography (PET); (3) validate methods for (semi-)automated processing of renal MRI; (4) examine longitudinal changes in imaging biomarkers; (5) examine whether glycocalyx and microvascular measures are associated with imaging biomarkers and eGFR decline; (6) explore whether the findings in T2D can be extrapolated to type 1 diabetes. Discussion: iBEAt is the largest DKD imaging study to date and will provide valuable insights into the progression and heterogeneity of DKD. The results may contribute to a more personalised approach to DKD management in patients with T2D. Trial registration: Clinicaltrials.gov (NCT03716401)

Self-Guided Psychological Treatment for Depressive Symptoms: A Meta-Analysis

Background: A number of trials have examined the effects of self-guided psychological intervention, without any contact between the participants and a therapist or coach. The results and sizes of these trials have been mixed. This is the first quantitative meta-analysis, aimed at organizing and evaluating the literature, and estimating effect size. Method: We conducted systematic literature searches in PubMed, PsycINFO and Embase up to January 2010, and identified additional studies through earlier meta-analyses, and the references of included studies. We identified seven randomized controlled trials that met our inclusion criteria, with a total of 1,362 respondents. The overall quality of the studies was high. A post-hoc power calculation showed that the studies had sufficient statistical power to detect an effect size of d = 0.19. Results: The overall mean effect size indicating the difference between self-guided psychological treatment and control groups at post-test was d = 0.28 (pless than0.001), which corresponds to a NNT of 6.41. At 4 to 12 months follow-up the effect size was d = 0.23. There was no indication for significant publication bias. Conclusions: We found evidence that self-guided psychological treatment has a small but significant effect on participants with increased levels of depressive symptomatology.Original Publication:Pim Cuijpers, Tara Donker, Robert Johansson, David C. Mohr, Annemieke van Straten and Gerhard Andersson, Self-Guided Psychological Treatment for Depressive Symptoms: A Meta-Analysis, 2011, PLoS ONE, (6), 6.http://dx.doi.org/10.1371/journal.pone.0021274Copyright: Public Library of Science (PLoS)http://www.plos.org

Prognostic imaging biomarkers for diabetic kidney disease (iBEAt):study protocol

Background: Diabetic kidney disease (DKD) remains one of the leading causes of premature death in diabetes. DKD is classified on albuminuria and reduced kidney function (estimated glomerular filtration rate (eGFR)) but these have modest value for predicting future renal status. There is an unmet need for biomarkers that can be used in clinical settings which also improve prediction of renal decline on top of routinely available data, particularly in the early stages. The iBEAt study of the BEAt-DKD project aims to determine whether renal imaging biomarkers (magnetic resonance imaging (MRI) and ultrasound (US)) provide insight into the pathogenesis and heterogeneity of DKD (primary aim) and whether they have potential as prognostic biomarkers in DKD (secondary aim). Methods: iBEAt is a prospective multi-centre observational cohort study recruiting 500 patients with type 2 diabetes (T2D) and eGFR ≥30 ml/min/1.73m2. At baseline, blood and urine will be collected, clinical examinations will be performed, and medical history will be obtained. These assessments will be repeated annually for 3 years. At baseline each participant will also undergo quantitative renal MRI and US with central processing of MRI images. Biological samples will be stored in a central laboratory for biomarker and validation studies, and data in a central data depository. Data analysis will explore the potential associations between imaging biomarkers and renal function, and whether the imaging biomarkers improve the prediction of DKD progression. Ancillary substudies will: (1) validate imaging biomarkers against renal histopathology; (2) validate MRI based renal blood flow measurements against H2O15 positron-emission tomography (PET); (3) validate methods for (semi-)automated processing of renal MRI; (4) examine longitudinal changes in imaging biomarkers; (5) examine whether glycocalyx and microvascular measures are associated with imaging biomarkers and eGFR decline; (6) explore whether the findings in T2D can be extrapolated to type 1 diabetes. Discussion: iBEAt is the largest DKD imaging study to date and will provide valuable insights into the progression and heterogeneity of DKD. The results may contribute to a more personalised approach to DKD management in patients with T2D. Trial registration: Clinicaltrials.gov (NCT03716401)