Mirroring everyday clinical practice in clinical trial design: a new concept to improve the external validity of randomized double-blind placebo-controlled trials in the pharmacological treatment of major depression

Background: Randomized, double-blind, placebo-controlled trials constitute the gold standard in clinical research when testing the efficacy of new psychopharmacological interventions in the treatment of major depression. However, the blinded use of placebo has been found to influence clinical trial outcomes and may bias patient selection. Discussion: To improve clinical trial design in major depression so as to reflect clinical practice more closely we propose to present patients with a balanced view of the benefits of study participation irrespective of their assignment to placebo or active treatment. In addition every participant should be given the option to finally receive the active medication. A research agenda is outlined to evaluate the impact of the proposed changes on the efficacy of the drug to be evaluated and on the demographic and clinical characteristics of the enrollment fraction with regard to its representativeness of the eligible population. Summary: We propose a list of measures to be taken to improve the external validity of double-blind, placebocontrolled trials in major depression. The recommended changes to clinical trial design may also be relevant for other psychiatric as well as medical disorders in which expectations regarding treatment outcome may affect the outcome itself

Implementing an innovative consent form: the PREDICT experience

<p>Abstract</p> <p>Background</p> <p>In the setting of coronary angiography, generic consent forms permit highly variable communication between patients and physicians. Even with the existence of multiple risk models, clinicians have been unable to readily access them and thus provide patients with vague estimations regarding risks of the procedure.</p> <p>Methods</p> <p>We created a web-based vehicle, PREDICT, for embedding patient-specific estimates of risk from validated multivariable models into individualized consent documents at the point-of-care. Beginning August 2006, outpatients undergoing coronary angiography at the Mid America Heart Institute received individualized consent documents generated by PREDICT. In February 2007 this approach was expanded to all patients undergoing coronary angiography within the four Kansas City hospitals of the Saint Luke's Health System. Qualitative research methods were used to identify the implementation challenges and successes with incorporating PREDICT-enhanced consent documents into routine clinical care from multiple perspectives: administration, information systems, nurses, physicians, and patients.</p> <p>Results</p> <p>Most clinicians found usefulness in the tool (providing clarity and educational value for patients) and satisfaction with the altered processes of care, although a few cardiologists cited delayed patient flow and excessive patient questions. The responses from administration and patients were uniformly positive. The key barrier was related to informatics.</p> <p>Conclusion</p> <p>This preliminary experience suggests that successful change in clinical processes and organizational culture can be accomplished through multidisciplinary collaboration. A randomized trial of PREDICT consent, leveraging the accumulated knowledge from this first experience, is needed to further evaluate its impact on medical decision-making, patient compliance, and clinical outcomes.</p

Neuroendocrine carcinoma arising in soft tissue: three case reports and literature review

<p>Abstract</p> <p>Background</p> <p>Neuroendocrine tumours (NET) are tumours arising from neuroendocrine cells of neural crest origin. They are characterised by the presence of neurosecretory granules which react positively to silver stains and to specific markers including neuron specific enolase, synaptophysin and chromogranin. Metastasis to the skin occurs infrequently but primary soft tissue NET is excessively rare.</p> <p>Case presentation</p> <p>We report our experience with 3 such cases. In the first case, the NET originated in muscle and was treated with wide surgical excision and adjuvant radiotherapy. The second case presented as a subcutaneous mass in the foot and the tumour was positive on ¹²³I mIBG scan. She has had prolonged recurrence-free survival following primary hypo-fractionated radiotherapy. In the third case, a cutaneous nodule proved to be a NET and at surgery, lymph node disease was present. He has remained disease-free after surgical excision without the need for external beam radiotherapy.</p> <p>Conclusion</p> <p>These tumours appear to have a good prognosis. Complete excision offers potentially curative treatment. Adjuvant radiotherapy may be helpful when the tumour margin is narrow. For patients with unresectable disease or where surgery would not be appropriate, radiotherapy appears to be an effective therapeutic option.</p

Bidirectional Associations Between Sibling Relationships and Parental Support During Adolescence

Sibling relationships and parental support are important for adolescents’ development and well-being, yet both are likely to change during adolescence. Since adolescents participate in both the sibling relationship and the parent–child relationship, we can expect sibling relationships and parental support to be associated with each other. Theoretically, it can be expected that there is either a spillover from one relationship to another (congruence hypothesis) or that one relationship can compensate for the other (compensation hypothesis). However, research examining these associations in adolescence is limited. The present study longitudinally investigated the bidirectional associations between sibling relationships and parental support during adolescence. For five consecutive years, data were collected using self-reports of 428 families, consisting of a father, a mother, and two adolescent siblings. The mean ages of the first-born (52.8% males) and second-born (47.7% males) were 15 and 13 years at T1, respectively. For the second-born siblings, prospective associations were found between sibling relationships and adolescent-reported parental support in early adolescence, with no differences between same-sex and mixed-sex dyads. These associations were not found for first-born siblings or for parents’ reports of support. The findings suggest a spillover from the sibling relationship to adolescent-reported parental support only in early adolescence. Findings and implications are discussed in terms of the congruence/spillover and the compensation hypothesis

Health and literacy in first- and second-generation Moroccan Berber women in the Netherlands: Ill literacy?

AIM: The present study was aimed at investigating the role of literacy and generation in the self-reported general health status of Moroccan Berber speaking women in the Netherlands. METHOD: Fifty women in our sample (N = 75) were first generation women, from which group 25 were literates and 25 illiterates. Another group of 25 literate women belonged to the second generation. The three groups were matched for demographic characteristics. Questionnaires were administered reflecting all concepts under study. We hypothesized that, within the first generation, illiterates compared with literates would report worse health. Our second hypothesis was that literates of the first generation compared with those of the second generation would have a similar health condition. RESULTS: After controlling for age, having a job, and having an employed partner, the first generation literates compared with the illiterates of the first generation indeed reported significantly better health. Additionally, we did not find any differences in health condition between both literate groups, even after controlling for age, number of children, and marital status. Health complaints that were most frequently reported by both groups, concerned pain in shoulders, back and head. CONCLUSIONS: Our results underline the importance of offering immigrants optimal access to opportunities and facilities that can improve their literacy and reading ability

Meta-analysis of epigenome-wide association studies of carotid intima-media thickness

Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10-8) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10-13). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease

The Lausanne cohort Lc65+: a population-based prospective study of the manifestations, determinants and outcomes of frailty

BACKGROUND: Frailty is a relatively new geriatric concept referring to an increased vulnerability to stressors. Various definitions have been proposed, as well as a range of multidimensional instruments for its measurement. More recently, a frailty phenotype that predicts a range of adverse outcomes has been described. Understanding frailty is a particular challenge both from a clinical and a public health perspective because it may be a reversible precursor of functional dependence. The Lausanne cohort Lc65+ is a longitudinal study specifically designed to investigate the manifestations of frailty from its first signs in the youngest old, identify medical and psychosocial determinants, and describe its evolution and related outcomes. METHODS/DESIGN: The Lc65+ cohort was launched in 2004 with the random selection of 3054 eligible individuals aged 65 to 70 (birth year 1934-1938) in the non-institutionalized population of Lausanne (Switzerland). The baseline data collection was completed among 1422 participants in 2004-2005 through questionnaires, examination and performance tests. It comprised a wide range of medical and psychosocial dimensions, including a life course history of adverse events. Outcomes measures comprise subjective health, limitations in activities of daily living, mobility impairments, development of medical conditions or chronic health problems, falls, institutionalization, health services utilization, and death. Two additional random samples of 65-70 years old subjects will be surveyed in 2009 (birth year 1939-1943) and in 2014 (birth year 1944-1948). DISCUSSION: The Lc65+ study focuses on the sequence "Determinants --&gt; Components --&gt; Consequences" of frailty. It currently provides information on health in the youngest old and will allow comparisons to be made between the profiles of aging individuals born before, during and at the end of the Second World War

Assessment of α-Synuclein Secretion in Mouse and Human Brain Parenchyma

Genetic, biochemical, and animal model studies strongly suggest a central role for α-synuclein in the pathogenesis of Parkinson's disease. α-synuclein lacks a signal peptide sequence and has thus been considered a cytosolic protein. Recent data has suggested that the protein may be released from cells via a non-classical secretory pathway and may therefore exert paracrine effects in the extracellular environment. However, proof that α-synuclein is actually secreted into the brain extracellular space in vivo has not been obtained. We developed a novel highly sensitive ELISA in conjugation with an in vivo microdialysis technique to measure α-synuclein in brain interstitial fluid. We show for the first time that α-synuclein is readily detected in the interstitial fluid of both α-synuclein transgenic mice and human patients with traumatic brain injury. Our data suggest that α-synuclein is physiologically secreted by neurons in vivo. This interstitial fluid pool of the protein may have a role in the propagation of synuclein pathology and progression of Parkinson's disease