Evaluación ética de la memoria económica de los contratos de ensayos clínicos con medicamentos en España

Objetivos: Analizar el grado de homogeneidad de la memoria económica incluida en los contratos de centros sanitarios españoles participantes en ensayos clínicos (EC) con medicamentos para detectar puntos de potencial conflicto de interés en la investigación clínica. Material y métodos: Se ha analizado, mediante un autocuestionario, la memoria económica de 40 contratos, 31 correspondientes a centros sanitarios privados y públicos seleccionados al azar y 9 correspondientes a las comunidades autónomas con modelo de contrato único. Resultados: El equipo investigador, en el 97,5% de los casos (39 contratos), es el destinatario mayoritario de la remuneración económica por participar en un EC. El porcentaje aportado difiere según el centro, siendo mayor si es público (p=0,021) pero sin especificarse en el 50% de los contratos. En 38 de los 40 contratos analizados no se proporciona un listado de precios de las pruebas complementarias. En el 57,5%, (23 contratos), no se especifica si los gastos de los pacientes son abonados por el promotor. En el 77,5% (31 casos) no se especifica si los gastos derivados de reuniones relacionadas con el EC se incluyen en la memoria económica. Conclusiones: Existe una elevada heterogeneidad en el contenido de la memoria económica. La implantación de un modelo de memoria económica que incluyera una cantidad económica de remuneración fija por cada paciente reclutado por parte del promotor, para todos los centros participantes, podría disminuir las desigualdades entre centros, los conflictos de intereses, y además, incrementaría la trasparencia y la calidad de los EC.Abstract: Objectives: To analyze the homogeneity of the economic report of the contracts of Spanish medical centers participating in clinical trials with medicinal products for detecting points of potential conflict of interest in clinical research. Material and methods: We analyzed, through a selfautoquestionnaire, the budgetary information of the 40 contracts, 31 of them corresponding to public and private healthcare centers, randomly selected, and 9 corresponding to the Spanish regions who have only a model contract. Results: The investigator team is the recipient majority (97.5% of cases) the economic remuneration for participating in a clinical trial. The percentage differs according to the center considered, being greater in the public setting (p=0.021) but no specified in 50% of the contracts. In 38 of the 40 contracts analyzed a price list of tests is not provided. In 57.5% of the patients are paid by the promoter. In 17.5% failed to mention that the comparative drug to be supplied free of charge. And, 77.5% did not specify whether the costs of meetings relating to the clinical trial or not to include in the expenses of the promoter. Conclusions: There is a high heterogeneity in the content of the budgetary information. The implementation of a single contract model would reduce the inequalities between schools, conflict of interest and increase transparency and quality of the clinical trial

Alzheimer's disease

Alzheimer's disease, the commonest cause of dementia, is a growing global health concern with huge implications for individuals and society. In this review, we outline the current understanding of the epidemiology, genetics, pathology and pathogenesis of Alzheimer's disease, before discussing its clinical presentation, and current treatment strategies. Finally, we discuss how our enhanced understanding of Alzheimer pathogenesis and the recognition of a protracted preclinical phase is informing new therapeutic strategies with the aim of moving from treatment to prevention

Short acquisition time PET quantification using MRI-based pharmacokinetic parameter synthesis

Positron Emission Tomography (PET) with pharmacokinetic (PK) modelling is a quantitative molecular imaging technique, however the long data acquisition time is prohibitive in clinical practice. An approach has been proposed to incorporate blood flow information from Arterial Spin Labelling (ASL) Magnetic Resonance Imaging (MRI) into PET PK modelling to reduce the acquisition time. This requires the conversion of cerebral blood flow (CBF) maps, measured by ASL, into the relative tracer delivery parameter (R 1 ) used in the PET PK model. This was performed regionally using linear regression between population R 1 and ASL values. In this paper we propose a novel technique to synthesise R 1 maps from ASL data using a database with both R 1 and CBF maps. The local similarity between the candidate ASL image and those in the database is used to weight the propagation of R 1 values to obtain the optimal patient specific R 1 map. Structural MRI data is also included to provide information within common regions of artefact in ASL data. This methodology is compared to the linear regression technique using leave one out analysis on 32 subjects. The proposed method significantly improves regional R 1 estimation (p < 0.001), reducing the error in the pharmacokinetic modelling. Furthermore, it allows this technique to be extended to a voxel level, increasing the clinical utility of the images

A novel isolator-based system promotes viability of human embryos during laboratory processing

In vitro fertilisation (IVF) and related technologies are arguably the most challenging of all cell culture applications. The starting material is a single cell from which one aims to produce an embryo capable of establishing a pregnancy eventually leading to a live birth. Laboratory processing during IVF treatment requires open manipulations of gametes and embryos, which typically involves exposure to ambient conditions. To reduce the risk of cellular stress, we have developed a totally enclosed system of interlinked isolator-based workstations designed to maintain oocytes and embryos in a physiological environment throughout the IVF process. Comparison of clinical and laboratory data before and after the introduction of the new system revealed that significantly more embryos developed to the blastocyst stage in the enclosed isolator-based system compared with conventional open-fronted laminar flow hoods. Moreover, blastocysts produced in the isolator-based system contained significantly more cells and their development was accelerated. Consistent with this, the introduction of the enclosed system was accompanied by a significant increase in the clinical pregnancy rate and in the proportion of embryos implanting following transfer to the uterus. The data indicate that protection from ambient conditions promotes improved development of human embryos. Importantly, we found that it was entirely feasible to conduct all IVF-related procedures in the isolator-based workstations

Features of the primary wall CESA complex in wild type and cellulose-deficient mutants of Arabidopsis thaliana

Evidence from genetics, co-precipitation and bimolecular fluorescence complementation suggest that three CESAs implicated in making primary wall cellulose in Arabidopsis thaliana form a complex. This study shows the complex has a Mr of approximately 840 kDa in detergent extracts and that it has undergone distinctive changes when extracts are prepared from some cellulose-deficient mutants. The mobility of CESAs 1, 3, and 6 in a Triton-soluble microsomal fraction subject to blue native polyacrylamide gel electrophoresis was consistent with a Mr of about 840 kDa. An antibody specific to any one CESA pulled down all three CESAs consistent with their occupying the same 840 kDa complex. In rsw1, a CESA1 missense mutant, extracts of seedlings grown at the permissive temperature have an apparently normal CESA complex that was missing from extracts of seedlings grown at the restrictive temperature where CESAs precipitated independently. In prc1-19, with no CESA6, CESAs 1 and 3 were part of a 420 kDa complex in extracts of light-grown seedlings that was absent from extracts of dark-grown seedlings where the CESAs precipitated independently. Two CESA3 missense mutants retained apparently normal CESA complexes as did four cellulose-deficient mutants defective in proteins other than CESAs. The 840 kDa complex could contain six CESA subunits and, since loss of plasma membrane rosettes accompanies its loss in rsw1, the complex could form one of the six particles which electron microscopy reveals in rosettes

What we talk about when we talk about "global mindset": managerial cognition in multinational corporations

Recent developments in the global economy and in multinational corporations have placed significant emphasis on the cognitive orientations of managers, giving rise to a number of concepts such as “global mindset” that are presumed to be associated with the effective management of multinational corporations (MNCs). This paper reviews the literature on global mindset and clarifies some of the conceptual confusion surrounding the construct. We identify common themes across writers, suggesting that the majority of studies fall into one of three research perspectives: cultural, strategic, and multidimensional. We also identify two constructs from the social sciences that underlie the perspectives found in the literature: cosmopolitanism and cognitive complexity and use these two constructs to develop an integrative theoretical framework of global mindset. We then provide a critical assessment of the field of global mindset and suggest directions for future theoretical and empirical research

Physiologic and molecular consequences of endothelial Bmpr2 mutation

<p>Abstract</p> <p>Background</p> <p>Pulmonary arterial hypertension (PAH) is thought to be driven by dysfunction of pulmonary vascular microendothelial cells (PMVEC). Most hereditary PAH is associated with BMPR2 mutations. However, the physiologic and molecular consequences of expression of BMPR2 mutations in PMVEC are unknown.</p> <p>Methods</p> <p>In vivo experiments were performed on adult mice with conditional endothelial-specific expression of the truncation mutation Bmpr2^delx4+, with age-matched transactivator-only mice as controls. Phenotype was assessed by RVSP, counts of muscularized vessels and proliferating cells, and staining for thromboses, inflammatory cells, and apoptotic cells. The effects of BMPR2 knockdown in PMVEC by siRNA on rates of apoptosis were assessed. Affymetrix expression arrays were performed on PMVEC isolated and cultured from triple transgenic mice carrying the immortomouse gene, a transactivator, and either control, Bmpr2^delx4+or Bmpr2^R899Xmutation.</p> <p>Results</p> <p>Transgenic mice showed increased RVSP and corresponding muscularization of small vessels, with histologic alterations including thrombosis, increased inflammatory cells, increased proliferating cells, and a moderate increase in apoptotic cells. Expression arrays showed alterations in specific pathways consistent with the histologic changes. Bmpr2^delx4+and Bmpr2^R899Xmutations resulted in very similar alterations in proliferation, apoptosis, metabolism, and adhesion; Bmpr2^delx4+cells showed upregulation of platelet adhesion genes and cytokines not seen in Bmpr2^R899XPMVEC. Bmpr2 mutation in PMVEC does not cause a loss of differentiation markers as was seen with Bmpr2 mutation in smooth muscle cells.</p> <p>Conclusions</p> <p>Bmpr2 mutation in PMVEC <it>in vivo </it>may drive PAH through multiple, potentially independent, downstream mechanisms, including proliferation, apoptosis, inflammation, and thrombosis.</p

Screening and brief interventions for hazardous and harmful alcohol use in primary care: a cluster randomised controlled trial protocol

A large number of randomised controlled trials in health settings have consistently reported positive effects of brief intervention in terms of reductions in alcohol use. However,although alcohol misuse is common amongst offenders, there is limited evidence of alcohol brief interventions in the criminal justice field. This factorial pragmatic cluster randomised controlledtrial with Offender Managers (OMs) as the unit of randomisation will evaluate the effectiveness and cost-effectiveness of different models of screening to identify hazardous and harmful drinkers in probation and different intensities of brief intervention to reduce excessive drinking in probation clients. Ninety-six OMs from 9 probation areas across 3 English regions (the NorthEast Region (n = 4) and London and the South East Regions (n = 5)) will be recruited. OMs will berandomly allocated to one of three intervention conditions: a client information leaflet control condition (n = 32 OMs); 5-minute simple structured advice (n = 32 OMs) and 20-minute brieflifestyle counselling delivered by an Alcohol Health Worker (n = 32 OMs). Randomisation will be stratified by probation area. To test the relative effectiveness of different screening methods all OMs will be randomised to either the Modified Single Item Screening Questionnaire (M-SASQ) orthe Fast Alcohol Screening Test (FAST). There will be a minimum of 480 clients recruited into the trial. There will be an intention to treat analysis of study outcomes at 6 and 12 months postintervention. Analysis will include client measures (screening result, weekly alcohol consumption,alcohol-related problems, re-offending, public service use and quality of life) and implementation measures from OMs (the extent of screening and brief intervention beyond the minimum recruitment threshold will provide data on acceptability and feasibility of different models of brief intervention). We will also examine the practitioner and organisational factors associated with successful implementation.The trial will evaluate the impact of screening and brief alcohol intervention in routine probation work and therefore its findings will be highly relevant to probation teams and thus the criminal justice system in the UK

Sex-related differences in whole brain volumes at age 70 in association with hyperglycemia during adult life

Longitudinal studies of the relationship between hyperglycemia and brain health are rare and there is limited information on sex differences in associations. We investigated whether glycosylated haemoglobin (HbA1c) measured at ages of 53, 60-64 and 69 years, and cumulative glycemic index (CGI), a measure of cumulative glycemic burden, were associated with metrics of brain health in later life. Participants were from Insight 46, a sub-study of the Medical Research Council National Survey of Health and Development (NSHD) who undertook volumetric MRI, florbetapir amyloid-PET imaging and cognitive assessments at ages of 69-71. Analyses were performed using linear and logistic regression as appropriate, with adjustment for potential confounders. We observed a sex interaction between HbA1c and whole brain volume (WBV) at all three time points. Following stratification of our sample, we observed that HbA1c at all ages, and CGI were positively associated with lower WBV exclusively in females. HbA1c (or CGI) was not associated with amyloid status, white matter hyperintensities (WMHs), hippocampal volumes (HV) or cognitive outcomes in either sex. Higher HbA1c in adulthood is associated with smaller WBV at 69–71 years in females but not in males. This suggests that there may be preferential target organ damage in the brain for females with hyperglycemia