Sequential psychological and pharmacological therapies for comorbid and primary insomnia: Study protocol for a randomized controlled trial

Background: Chronic insomnia is a prevalent disorder associated with significant psychosocial, health, and economic impacts. Cognitive behavioral therapies (CBTs) and benzodiazepine receptor agonist (BzRA) medications are the most widely supported therapeutic approaches for insomnia management. However, few investigations have directly compared their relative and combined benefits, and even fewer have tested the benefits of sequential treatment for those who do not respond to initial insomnia therapy. Moreover, insomnia treatment studies have been limited by small, highly screened study samples, fixed-dose, and fixed-agent pharmacotherapy strategies that do not represent usual clinical practices. This study will address these limitations. Methods/design: This is a two-site randomized controlled trial, which will enroll 224 adults who meet the criteria for a chronic insomnia disorder with or without comorbid psychiatric disorders. Prospective participants will complete clinical assessments and polysomnography and then will be randomly assigned to first-stage therapy involving either behavioral therapy (BT) or zolpidem. Treatment outcomes will be assessed after 6 weeks, and treatment remitters will be followed for the next 12 months on maintenance therapy. Those not achieving remission will be offered randomization to a second, 6-week treatment, again involving either pharmacotherapy (zolpidem or trazodone) or psychological therapy (BT or cognitive therapy (CT)). All participants will be re-evaluated 12 weeks after the protocol initiation and at 3-, 6-, 9-, and 12-month follow-ups. Insomnia remission, defined categorically as a score < 8 on the Insomnia Severity Index, a patient-reported outcome, will serve as the primary endpoint for treatment comparisons. Secondary outcomes will include sleep parameters derived from daily sleep diaries and from polysomnography, subjective measures of fatigue, mood, quality of life, and functional impairments; and measures of adverse events; dropout rates; and treatment acceptability. Centrally trained therapists will administer therapies according to manualized, albeit flexible, treatment algorithms. Discussion: This clinical trial will provide new information about optimal treatment sequencing and will have direct implication for the development of clinical guidelines for managing chronic insomnia with and without comorbid psychiatric conditions

Guidelines; from foe to friend? Comparative interviews with GPs in Norway and Denmark

<p>Abstract</p> <p>Background</p> <p>GPs follow clinical guidelines to varying degrees across practices, regions and countries, but a review study of GPs' attitudes to guidelines found no systematic variation in attitudes between studies from different countries. However, earlier qualitative studies on this topic are not necessarily comparable. Hence, there is a lack of empirical comparative studies of GP's attitudes to following clinical guidelines. In this study we reproduce a Norwegian focus group study of GPs' general attitudes to national clinical guidelines in Denmark and conduct a comparative analysis of the findings.</p> <p>Methods</p> <p>A strategic sample of GP's in Norway (27 GPs) and Denmark (18 GPs) was interviewed about their attitudes to guidelines, and the interviews coded and compared for common themes and differences.</p> <p>Results</p> <p>Similarities dominated the comparative material, but the analysis also revealed notable differences in attitudes between Norwegian and the Danish GPs. The most important difference was related to GP's attitudes to clinical guidelines that incorporated economic evaluations. While the Norwegian GPs were sceptical to guidelines that incorporated economic evaluation, the Danish GPs regarded these guidelines as important and legitimate. We suggest that the differences could be explained by the history of guideline development in Norway and Denmark respectively. Whereas government guidelines for rationing services were only newly introduced in Norway, they have been used in Denmark for many years.</p> <p>Conclusion</p> <p>Comparative qualitative studies of GPs attitudes to clinical guidelines may reveal cross-national differences relating to the varying histories of guideline development. Further studies are needed to explore this hypothesis.</p

Involvement of TLR2 in Recognition of Acute Gammaherpesvirus-68 Infection

Toll-like receptors (TLRs) play a crucial role in the activation of innate immunity in response to many viruses. We previously reported the implication of TLR2 in the recognition of Epstein-Barr virus (EBV) by human monocytes. Because murine gammaherpesvirus-68 (MHV-68) is a useful model to study human gammaherpesvirus pathogenesis in vivo, we evaluated the importance of mouse TLR2 in the recognition of MHV-68.In studies using transfected HEK293 cells, MHV-68 lead to the activation of NF-κB reporter through TLR2. In addition, production of interleukin-6 (IL-6) and interferon-α (IFN-α) upon MHV-68 stimulation was reduced in murine embryonic fibroblasts (MEFs) derived from TLR2-/- and MyD88-/- mice as compared to their wild type (WT) counterpart. In transgenic mice expressing a luciferase reporter gene under the control of the mTLR2 promoter, MHV-68 challenge activated TLR2 transcription. Increased expression levels of TLR2 on blood granulocytes (CD115(-)Gr1(+)) and inflammatory monocytes (CD115(+)Gr1(+)), which mobilized to the lungs upon infection with MHV-68, was also confirmed by flow cytometry. Finally, TLR2 or MyD88 deficiency was associated with decreased IL-6 and type 1 IFN production as well as increased viral burden during short-term challenges with MHV-68.TLR2 contributes to the production of inflammatory cytokines and type 1 IFN as well as to the control of viral burden during infection with MHV-68. Taken together, our results suggest that the TLR2 pathway has a relevant role in the recognition of this virus and in the subsequent activation of the innate immune response

Assessing the evolution of primary healthcare organizations and their performance (2005-2010) in two regions of Québec province: Montréal and Montérégie

<p>Abstract</p> <p>Background</p> <p>The Canadian healthcare system is currently experiencing important organizational transformations through the reform of primary healthcare (PHC). These reforms vary in scope but share a common feature of proposing the transformation of PHC organizations by implementing new models of PHC organization. These models vary in their performance with respect to client affiliation, utilization of services, experience of care and perceived outcomes of care.</p> <p>Objectives</p> <p>In early 2005 we conducted a study in the two most populous regions of Quebec province (Montreal and Montérégie) which assessed the association between prevailing models of primary healthcare (PHC) and population-level experience of care. The <b>goal </b>of the present research project is to track the <it>evolution </it>of PHC organizational models and their relative performance through the reform process (from 2005 until 2010) and to assess factors at the organizational and contextual levels that are associated with the transformation of PHC organizations and their performance.</p> <p>Methods/Design</p> <p>This study will consist of three interrelated surveys, hierarchically nested. The first survey is a population-based survey of randomly-selected adults from two populous regions in the province of Quebec. This survey will assess the current affiliation of people with PHC organizations, their level of utilization of healthcare services, attributes of their experience of care, reception of preventive and curative services and perception of unmet needs for care. The second survey is an organizational survey of PHC organizations assessing aspects related to their vision, organizational structure, level of resources, and clinical practice characteristics. This information will serve to develop a taxonomy of organizations using a mixed methods approach of factorial analysis and principal component analysis. The third survey is an assessment of the organizational context in which PHC organizations are evolving. The five year prospective period will serve as a natural experiment to assess contextual and organizational factors (in 2005) associated with migration of PHC organizational models into new forms or models (in 2010) and assess the impact of this evolution on the performance of PHC.</p> <p>Discussion</p> <p>The results of this study will shed light on changes brought about in the organization of PHC and on factors associated with these changes.</p

Cerebellum Abnormalities in Idiopathic Generalized Epilepsy with Generalized Tonic-Clonic Seizures Revealed by Diffusion Tensor Imaging

Although there is increasing evidence suggesting that there may be subtle abnormalities in idiopathic generalized epilepsy (IGE) patients using modern neuroimaging techniques, most of these previous studies focused on the brain grey matter, leaving the underlying white matter abnormalities in IGE largely unknown, which baffles the treatment as well as the understanding of IGE. In this work, we adopted multiple methods from different levels based on diffusion tensor imaging (DTI) to analyze the white matter abnormalities in 14 young male IGE patients with generalized tonic-clonic seizures (GTCS) only, comparing with 29 age-matched male healthy controls. First, we performed a voxel-based analysis (VBA) of the fractional anisotropy (FA) images derived from DTI. Second, we used a tract-based spatial statistics (TBSS) method to explore the alterations within the white matter skeleton of the patients. Third, we adopted region-of-interest (ROI) analyses based on the findings of VBA and TBSS to further confirm abnormal brain regions in the patients. At last, considering the convergent evidences we found by VBA, TBSS and ROI analyses, a subsequent probabilistic fiber tractography study was performed to investigate the abnormal white matter connectivity in the patients. Significantly decreased FA values were consistently observed in the cerebellum of patients, providing fresh evidence and new clues for the important role of cerebellum in IGE with GTCS

Family physicians' perspectives on practice guidelines related to cancer control

BACKGROUND: Family physicians (FPs) play an important role in cancer control. While FPs' attitudes towards, and use of guidelines in general have been explored, no study has looked at the needs of FPs with respect to guidelines for the continuum of cancer control. The objective of this study was to understand which guideline topics FPs consider important. METHODS: Five group interviews were conducted by telephone with FPs from across Ontario, Canada. Transcripts were analyzed inductively. Content analysis identified emergent themes. Themes are illustrated by representative quotes taken from the transcripts. RESULTS: The main areas where FPs felt guidelines were needed most included screening – a traditional area of responsibility for FPs – and treatment and follow-up – areas where they felt they lacked the knowledge to best support patients. Confusion over best practice when faced with conflicting guidelines varied according to disease site. FPs defined good guideline formats; the most often cited forms of presentation were tear-off sheets to use interactively with patients, or a binder. Computer-based dissemination was acknowledged as the best way of widely distributing material that needs frequent updates. However, until computer use is a common aspect of practice, mail was considered the most viable method of dissemination. Guidelines designed for use by patients were supported by FPs. CONCLUSIONS: Preferred guideline topics, format, dissemination methods and role of patient guidelines identified by FPs in this study reflect the nature of their practice situations. Guideline developers and those supporting use of evidence-based guidelines (e.g., Canadian Strategy for Cancer Control) have a responsibility to ensure that FPs are provided with the resources they identify as important, and to provide them in a format that will best support their use

Do Larval Supply and Recruitment Vary among Chemosynthetic Environments of the Deep Sea?

BACKGROUND: The biological communities that inhabit chemosynthetic environments exist in an ephemeral and patchily distributed habitat with unique physicochemical properties that lead to high endemicity. Consequently, the maintenance and recovery from perturbation of the populations in these habitats is, arguably, mainly regulated by larval supply and recruitment. METHODOLOGY/PRINCIPAL FINDINGS: WE USE DATA FROM THE PUBLISHED SCIENTIFIC LITERATURE TO: (1) compare the magnitudes of and variability in larval supply and settlement and recruitment at hydrothermal vents, seeps, and whale, wood and kelp falls; (2) explore factors that affect these life history processes, when information is available; and (3) explore taxonomic affinities in the recruit assemblages of the different chemosynthetic habitats, using multivariate statistical techniques. Larval supply at vents can vary across segments by several orders of magnitude for gastropods; for bivalves, supply is similar at vents on different segments, and at cold seeps. The limited information on larval development suggests that dispersal potential may be highest for molluscs from cold seeps, intermediate for siboglinids at vents and lowest for the whale-bone siboglinid Osedax. Settlement is poorly studied and only at vents and seeps, but tends to be highest near an active source of emanating fluid in both habitats. Rate of recruitment at vents is more variable among studies within a segment than among segments. Across different chemosynthetic habitats, recruitment rate of bivalves is much more variable than that of gastropods and polychaetes. Total recruitment rate ranges only between 0.1 and 1 ind dm(-2) d(-1) across all chemosynthetic habitats, falling above rates in the non-reducing deep sea. The recruit assemblages at vents, seeps and kelp falls have lower taxonomic breadth, and include more families and genera that have many species more closely related to each other than those at whale and wood falls. Vents also have the most uneven taxonomic structure, with fewer recruits represented by higher taxonomic levels (phyla, orders, classes) compared to seeps and wood and kelp falls, whereas the opposite is true at whale falls. CONCLUSIONS/SIGNIFICANCE: Based on our evaluation of the literature, the patterns and regulatory factors of the early history processes in chemosynthetic environments in the deep sea remain poorly understood. More research focused on these early life history stages will allow us to make inferences about the ecological and biogeographic linkages among the reducing habitats in the deep sea

Bilateral effects of unilateral cerebellar lesions as detected by voxel based morphometry and diffusion imaging

Over the last decades, the importance of cerebellar processing for cortical functions has been acknowledged and consensus was reached on the strict functional and structural cortico-cerebellar interrelations. From an anatomical point of view strictly contralateral interconnections link the cerebellum to the cerebral cortex mainly through the middle and superior cerebellar peduncle. Diffusion MRI (dMRI) based tractography has already been applied to address cortico-cerebellar-cortical loops in healthy subjects and to detect diffusivity alteration patterns in patients with neurodegenerative pathologies of the cerebellum. In the present study we used dMRI-based tractography to determine the degree and pattern of pathological changes of cerebellar white matter microstructure in patients with focal cerebellar lesions. Diffusion imaging and high-resolution volumes were obtained in patients with left cerebellar lesions and in normal controls. Middle cerebellar peduncles and superior cerebellar peduncles were reconstructed by multi fiber diffusion tractography. From each tract, measures of microscopic damage were assessed, and despite the presence of unilateral lesions, bilateral diffusivity differences in white matter tracts were found comparing patients with normal controls. Consistently, bilateral alterations were also evidenced in specific brain regions linked to the cerebellum and involved in higher-level functions. This could be in line with the evidence that in the presence of unilateral cerebellar lesions, different cognitive functions can be affected and they are not strictly linked to the side of the cerebellar lesion