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1.  Cost and outcome of behavioural activation versus cognitive behaviour therapy for depression (COBRA): study protocol for a randomised controlled trial 
Trials  2014;15:29.
Cognitive behaviour therapy (CBT) is an effective treatment for depression. However, CBT is a complex therapy that requires highly trained and qualified practitioners, and its scalability is therefore limited by the costs of training and employing sufficient therapists to meet demand. Behavioural activation (BA) is a psychological treatment for depression that may be an effective alternative to CBT and, because it is simpler, might also be delivered by less highly trained and specialised mental health workers.
COBRA is a two-arm, non-inferiority, patient-level randomised controlled trial, including clinical, economic, and process evaluations comparing CBT delivered by highly trained professional therapists to BA delivered by junior professional or para-professional mental health workers to establish whether the clinical effectiveness of BA is non-inferior to CBT and if BA is cost effective compared to CBT. Four hundred and forty patients with major depressive disorder will be recruited through screening in primary care. We will analyse for non-inferiority in per-protocol and intention-to-treat populations. Our primary outcome will be severity of depression symptoms (Patient Health Questionnaire-9) at 12 months follow-up. Secondary outcomes will be clinically significant change and severity of depression at 18 months, and anxiety (General Anxiety Disorder-7 questionnaire) and health-related quality of life (Short-Form Health Survey-36) at 12 and 18 months. Our economic evaluation will take the United Kingdom National Health Service/Personal Social Services perspective to include costs of the interventions, health and social care services used, plus productivity losses. Cost-effectiveness will explored in terms of quality-adjusted life years using the EuroQol-5D measure of health-related quality of life.
The clinical and economic outcomes of this trial will provide the evidence to help policy makers, clinicians and guideline developers decide on the merits of including BA as a first-line treatment of depression.
Trial registration
Current Controlled Trials ISRCTN27473954
PMCID: PMC3903024  PMID: 24447460
2.  Does the mode of exercise influence recovery of functional capacity in the early postoperative period after coronary artery bypass graft surgery? A randomized controlled trial† 
The purpose of this study was to compare the effectiveness of moderate-intensity stationary cycling and walking exercise programmes in the early postoperative period after first-time coronary artery bypass graft surgery.
In this prospective trial, 64 patients (57 men, 7 women, mean age = 66 ± 9 years) performed twice daily, moderate-intensity exercise sessions, of 10-min duration, from postoperative day 3 until discharge from hospital. Patients were randomly assigned to stationary cycling or walking exercise intervention groups. Preoperative and discharge functional exercise capacity and health-related quality of life were assessed using 6-min walk and cycle assessments and the SF-36 version 2.0 questionnaire. Compliance with exercise was calculated as the proportion of scheduled exercise sessions completed.
There were no significant differences between intervention groups at hospital discharge for 6-min walk distance (cyclists: 402 ± 93 m vs walkers: 417 ± 86 m, P = 0.803), 6-min cycle work (cyclists: 15.0 ± 6.4 kJ vs walkers: 14.0 ± 6.3 kJ, P = 0.798) or health-related quality of life. There was no significant difference between intervention groups for postoperative length of hospital stay (P = 0.335). Compliance rates for intervention groups were cyclists: 185/246 (75%) scheduled exercise sessions completed vs walkers: 199/242 (82%) scheduled exercise sessions completed (P = 0.162).
Stationary cycling provides a well-tolerated and clinically effective alternative to walking in the early postoperative period after coronary artery bypass graft surgery. The optimal frequency, intensity and duration of exercise in the early postoperative period require further investigation. (Clinical trials register: Australian New Zealand Clinical Trials Registry; identification number: ACTRN12608000359336;
PMCID: PMC3501312  PMID: 22976996
Coronary artery surgery; Exercise; Physical therapy modalities; Postoperative care
3.  Excessive activation of mTOR in postnatally-generated granule cells is sufficient to cause epilepsy 
Neuron  2012;75(6):1022-1034.
The dentate gyrus is hypothesized to function as a “gate”, limiting the flow of excitation through the hippocampus. During epileptogenesis, adult-generated granule cells (DGC) form aberrant neuronal connections with neighboring DGC, disrupting the dentate gate. Hyperactivation of the mTOR signaling pathway is implicated in driving this aberrant circuit formation. While the presence of abnormal DGC in epilepsy has been known for decades, direct evidence linking abnormal DGC to seizures has been lacking. Here, we isolate the effects of abnormal DGC using a transgenic mouse model to selectively delete PTEN from postnatally-generated DGC. PTEN deletion led to hyperactivation of the mTOR pathway, producing abnormal DGC morphologically similar to those in epilepsy. Strikingly, animals in which PTEN was deleted from ≥9% of the DGC population developed spontaneous seizures in about four weeks, confirming that abnormal DGC – which are present in both animals and humans with epilepsy – are capable of causing the disease.
PMCID: PMC3474536  PMID: 22998871
phosphatase and tensin homologue; PTEN; mammalian target of rapamycin; mTOR; epileptogenesis; dentate gate; hilar basal dendrite; ectopic dentate granule cell; mossy fiber sprouting; epilepsy
4.  Psychological treatments for common mental health problems experienced by informal carers of adults with chronic physical health conditions (Protocol) 
Systematic Reviews  2013;2:9.
Improved life expectancy is resulting in increased outpatient treatment of people with chronic physical health conditions and reliance on the provision of informal care in the community. However, informal care is also associated with increased risk of experiencing common mental health difficulties such as depression and anxiety. Currently there is a lack of evidence-based treatments for such difficulties, resulting in poor health outcomes for both the informal carer and care recipient.
Electronic databases will be systemically searched for randomised controlled trials examining the effectiveness of psychological interventions targeted at treating depression or anxiety experienced by informal carers of patients with chronic physical health conditions. Database searches will be supplemented by contact with experts, reference and citation checking and grey literature. Both published and unpublished research in English language will be reviewed with no limitations on year or source. Individual, group and patient-carer dyad focused interventions will be eligible. Primary outcomes of interest will be validated self-report or clinician administered measures of depression or anxiety. If data allows a meta-analysis will examine: (1) the overall effectiveness of psychological interventions in relation to outcomes of depression or anxiety; (2) intervention components associated with effectiveness.
This review will provide evidence on the effectiveness of psychological interventions for depression and anxiety experienced by informal carers of patients with chronic physical health conditions. In addition, it will examine intervention components associated with effectiveness. Results will inform the design and development of a psychological intervention for carers of people with chronic physical health conditions experiencing depression and anxiety.
PROSPERO registration number: CRD42012003114
PMCID: PMC3599247  PMID: 23369319
Caregivers; Chronic physical health condition; Depression; Anxiety; Treatment; Systematic review
5.  The effectiveness and cost-effectiveness of telephone triage of patients requesting same day consultations in general practice: study protocol for a cluster randomised controlled trial comparing nurse-led and GP-led management systems (ESTEEM) 
Trials  2013;14:4.
Recent years have seen an increase in primary care workload, especially following the introduction of a new General Medical Services contract in 2004. Telephone triage and telephone consultation with patients seeking health care represent initiatives aimed at improving access to care. Some evidence suggests that such approaches may be feasible but conclusions regarding GP workload, cost, and patients’ experience of care, safety, and health status are equivocal. The ESTEEM trial aims to assess the clinical- and cost-effectiveness of nurse-led computer-supported telephone triage and GP-led telephone triage, compared to usual care, for patients requesting same-day consultations in general practice.
ESTEEM is a pragmatic, multi-centre cluster randomised clinical trial with patients randomised at practice level to usual care, computer decision-supported nurse triage, or GP-led triage. Following triage of 350–550 patients per practice we anticipate estimating and comparing total primary care workload (volume and time), the economic cost to the NHS, and patient experience of care, safety, and health status in the 4-week period following the index same-day consultation request across the three trial conditions.
We will recruit all patients seeking a non-emergency same-day appointment in primary care. Patients aged 12.0–15.9 years and temporary residents will be excluded from the study.
The primary outcome is the number of healthcare contacts taking place in the 4-week period following (and including) the index same-day consultation request. A range of secondary outcomes will be examined including patient flow, primary care NHS resource use, patients’ experience of care, safety, and health status.
The estimated sample size required is 3,751 patients (11,253 total) in each of the three trial conditions, to detect a mean difference of 0.36 consultations per patient in the four week follow-up period between either intervention group and usual care 90% power, 5% alpha, and an estimated intracluster correlation coefficient ICC of 0.05. The primary analysis will be based on the intention-to-treat principle and take the form of a random effects regression analysis taking account of the hierarchical nature of the study design. Statistical models will allow for adjustment for practice level minimisation variables and patient-level baseline covariates shown to differ at baseline.
Trial registration
Current Controlled Trials ISCRTN20687662
PMCID: PMC3574027  PMID: 23286331
Primary care; Telephone triage; Decision support; General practitioner; Nurse; Workload; Satisfaction; Cost-effectiveness; Cluster randomised controlled trial
6.  Quantitative Dynamics of Telomere Bouquet Formation 
PLoS Computational Biology  2012;8(12):e1002812.
The mechanism by which homologous chromosomes pair during meiosis, as a prelude to recombination, has long been mysterious. At meiosis, the telomeres in many organisms attach to the nuclear envelope and move together to form the telomere bouquet, perhaps to facilitate the homologous search. It is believed that diffusion alone is not sufficient to account for the formation of the bouquet, and that some directed movement is also required. Here we consider the formation of the telomere bouquet in a wheat-rye hybrid both experimentally and using mathematical modelling. The large size of the wheat nucleus and wheat's commercial importance make chromosomal pairing in wheat a particularly interesting and important process, which may well shed light on pairing in other organisms. We show that, prior to bouquet formation, sister chromatid telomeres are always attached to a hemisphere of the nuclear membrane and tend to associate in pairs. We study a mutant lacking the Ph1 locus, a locus ensuring correct homologous chromosome pairing, and discover that bouquet formation is delayed in the wild type compared to the mutant. Further, we develop a mathematical model of bouquet formation involving diffusion and directed movement, where we show that directed movement alone is sufficient to explain bouquet formation dynamics.
Author Summary
The appearance of sexual reproduction over a billion years ago led to a revolution in how organisms pass on genetic material to their offspring. In sexually reproducing organisms parental diploid cells, containing two nearly identical copies of each chromosome (homologues), produce gametes containing only one copy of each chromosome. This in turn requires the pairing of the related homologous chromosomes to ensure their subsequent segregation into the gametes. How this pairing is achieved is poorly understood since chromosomes must search the entire nucleus for their homologous partner. Many organisms move the ends of each chromosome (the telomeres) along the periphery of the nucleus into a small patch forming the telomere bouquet. We show here that direct movement of telomeres towards the bouquet site, potentially driven by molecular motors, can explain bouquet formation dynamics. We focus in particular on a wheat-rye hybrid since understanding homologous pairing in wheat could have profound implications for breeding resistant crops by aiding the production of hybrids. We also show that wheat seems to have evolved a mechanism to delay the onset of telomere bouquet formation, perhaps in order to ensure chromosomes find their correct homologous partners.
PMCID: PMC3516562  PMID: 23236272
7.  Monocytes and Macrophages in Cancer: Development and Functions 
Cancer Microenvironment  2012;6(2):179-191.
Monocytes and tumor-associated macrophages are part of the myeloid family, a group of hematopoietic derived cells. Monocytes are direct precursors of hematopoietic stem cell-derived macrophages. After their recruitment into the tumor tissue, they can differentiate into tumor-associated macrophages, a very heterogeneous cell population in terms of phenotype and pro-tumor function, supporting tumor initiation, local progression and distant metastasis. Therefore, targeting monocytes and macrophages is a promising immunotherapeutic approach. This review will focus on the development of monocytes as macrophage precursors, the functions of tumor-associated macrophages and the possibility of interfering with tumor development and progression by targeting these myeloid cells.
PMCID: PMC3717063  PMID: 23179263
Tumor-associated macrophages; Monocytes; Myeloid cells; Immunotherapy
8.  Relationship between Serum Vitamin D, Disease Severity, and Airway Remodeling in Children with Asthma 
Little is known about vitamin D status and its effect on asthma pathophysiology in children with severe, therapy-resistant asthma (STRA).
Relationships between serum vitamin D, lung function, and pathology were investigated in pediatric STRA.
Serum 25-hydroxyvitamin D [25(OH)D3] was measured in 86 children (mean age, 11.7 yr): 36 with STRA, 26 with moderate asthma (MA), and 24 without asthma (control subjects). Relationships between 25(OH)D3, the asthma control test (ACT), spirometry, corticosteroid use, and exacerbations were assessed. Twenty-two of 36 children with STRA underwent fiberoptic bronchoscopy, bronchoalveolar lavage, and endobronchial biopsy with assessment of airway inflammation and remodeling.
Measurements and Main Results
25(OH)D3 levels (median [IQR]) were significantly lower in STRA (28 [22–38] nmol/L) than in MA (42.5 [29–63] nmol/L) and control subjects (56.5 [45–67] nmol/L) (P < 0.001). There was a positive relationship between 25(OH)D3 levels and percent predicted FEV1 (r = 0.4, P < 0.001) and FVC (r = 0.3, P = 0.002) in all subjects. 25(OH)D3 levels were positively associated with ACT (r = 0.6, P < 0.001), and inversely associated with exacerbations (r=−0.6, P < 0.001) and inhaled steroid dose (r=−0.39, P = 0.001) in MA and and STRA. Airway smooth muscle (ASM) mass, but not epithelial shedding or reticular basement membrane thickness, was inversely related to 25(OH)D3 levels (r=−0.6, P = 0.008). There was a positive correlation between ASM mass and bronchodilator reversibility (r = 0.6, P = 0.009) and an inverse correlation between ASM mass and ACT (r = −0.7, P < 0.001).
Lower vitamin D levels in children with STRA were associated with increased ASM mass and worse asthma control and lung function. The link between vitamin D, airway structure, and function suggests vitamin D supplementation may be useful in pediatric STRA.
PMCID: PMC3471128  PMID: 21908411
vitamin D; asthma; remodeling; airway smooth muscle; pediatrics
9.  1α,25-Dihydroxyvitamin D3 promotes CD200 expression by human peripheral and airway-resident T cells 
Thorax  2012;67(7):574-581.
CD200, a cell-surface immunoglobulin-like molecule expressed by immune and stromal cells, dampens the pro-inflammatory activity of tissue-resident innate cells via its receptor, CD200R. This interaction appears critical for peripheral immune tolerance, particularly in the airways where excessive inflammation is undesirable. Vitamin D contributes to pulmonary health and promotes regulatory immune pathways, therefore its influence on CD200 and CD200R was investigated.
CD200 and CD200R expression were assessed by qPCR and immunoreactivity of human lymphoid, myeloid and epithelial cells following 1α,25-dihydroxyvitamin D3 (1α,25VitD3) exposure in vitro and in peripheral T cells following 1α,25VitD3 oral ingestion in vivo. The effect of 1α25VitD3 was also assessed in human airway-resident cells.
1α25VitD3 potently upregulated CD200 on peripheral human CD4+ T cells in vitro, and in vivo there was a trend towards upregulation in healthy, but not asthmatic individuals. CD200R expression was not modulated in any cells studied. CD200 induction was observed to a lesser extent in CD8+ T cells and not in B cells or airway epithelium. T cells isolated from the human airway also responded strongly to 1α25VitD3 to upregulate CD200.
The capacity of 1α,25-dihydroxyvitamin D3 to induce CD200 expression by peripheral and respiratory tract T cells identifies an additional pathway via which vitamin D can restrain inflammation in the airways to maintain respiratory health.
PMCID: PMC3471129  PMID: 22334534
10.  The role of 1α,25-dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3+ and IL-10+ CD4+ T cells 
European journal of immunology  2012;42(10):2697-2708.
1α,25-Dihydroxyvitamin D3 (1α25VitD3) has potent immunomodulatory properties. We have previously demonstrated that 1α25VitD3 promotes human and murine IL-10-secreting CD4+ T cells. Because of the clinical relevance of this observation, we characterized these cells further and investigated their relationship with Foxp3+ regulatory T (Treg) cells. 1α25VitD3 increased the frequency of both Foxp3+ and IL-10+ CD4+T cells in vitro. However, Foxp3 was increased at high concentrations of 1α25VitD3 and IL-10 at more moderate levels, with little coexpression of these molecules. The Foxp3+ and IL-10+ T-cell populations showed comparable suppressive activity. We demonstrate that the enhancement of Foxp3 expression by 1α25VitD3 is impaired by IL-10. 1α25VitD3 enables the selective expansion of Foxp3+ Treg cells over their Foxp3− T-cell counterparts. Equally, 1α25VitD3 maintains Foxp3+ expression by sorted populations of human and murine Treg cells upon in vitro culture. A positive in vivo correlation between vitamin D status and CD4+Foxp3+ T cells in the airways was observed in a severe pediatric asthma cohort, supporting the in vitro observations. In summary, we provide evidence that 1α25VitD3 enhances the frequency of both IL-10+ and Foxp3+ Treg cells. In a translational setting, these data suggest that 1α25VitD3, over a broad concentration range, will be effective in enhancing the frequency of Treg cells.
PMCID: PMC3471131  PMID: 22903229
1α,25-Dihydroxyvitamin D3; Asthma; Immune regulation; Regulatory T cells
11.  Segregation of PIP2 and PIP3 into distinct nanoscale regions within the plasma membrane 
Biology Open  2012;1(9):857-862.
PIP2 and PIP3 are implicated in a wide variety of cellular signaling pathways at the plasma membrane. We have used STORM imaging to localize clusters of PIP2 and PIP3 to distinct nanoscale regions within the plasma membrane of PC12 cells. With anti-phospholipid antibodies directly conjugated with AlexaFluor 647, we found that PIP2 clusters in membrane domains of 64.5±27.558 nm, while PIP3 clusters had a size of 125.6±22.408 nm. With two color direct STORM imaging we show that >99% of phospholipid clusters have only one or other phospholipid present. These results indicate that lipid nano-domains can be readily identified using super-resolution imaging techniques, and that the lipid composition and size of clusters is tightly regulated.
PMCID: PMC3507238  PMID: 23213479
PC12 cell; PIP3; PIP2; Lipid raft
12.  A Mathematical Modelling Approach for Systems Where the Servers Are Almost Always Busy 
The design and implementation of new configurations of mental health services to meet local needs is a challenging problem. In the UK, services for common mental health disorders such as anxiety and depression are an example of a system running near or at capacity, in that it is extremely rare for the queue size for any given mode of treatment to fall to zero. In this paper we describe a mathematical model that can be applied in such circumstances. The model provides a simple way of estimating the mean and variance of the number of patients that would be treated within a given period of time given a particular configuration of services as defined by the number of appointments allocated to different modes of treatment and the referral patterns to and between different modes of treatment. The model has been used by service planners to explore the impact of different options on throughput, clinical outcomes, queue sizes, and waiting times. We also discuss the potential for using the model in conjunction with optimisation techniques to inform service design and its applicability to other contexts.
PMCID: PMC3332185  PMID: 22567041
13.  Mechanistic Basis of Branch-Site Selection in Filamentous Bacteria 
PLoS Computational Biology  2012;8(3):e1002423.
Many filamentous organisms, such as fungi, grow by tip-extension and by forming new branches behind the tips. A similar growth mode occurs in filamentous bacteria, including the genus Streptomyces, although here our mechanistic understanding has been very limited. The Streptomyces protein DivIVA is a critical determinant of hyphal growth and localizes in foci at hyphal tips and sites of future branch development. However, how such foci form was previously unknown. Here, we show experimentally that DivIVA focus-formation involves a novel mechanism in which new DivIVA foci break off from existing tip-foci, bypassing the need for initial nucleation or de novo branch-site selection. We develop a mathematical model for DivIVA-dependent growth and branching, involving DivIVA focus-formation by tip-focus splitting, focus growth, and the initiation of new branches at a critical focus size. We quantitatively fit our model to the experimentally-measured tip-to-branch and branch-to-branch length distributions. The model predicts a particular bimodal tip-to-branch distribution results from tip-focus splitting, a prediction we confirm experimentally. Our work provides mechanistic understanding of a novel mode of hyphal growth regulation that may be widely employed.
Author Summary
Amongst the great variety of shapes that organisms assume, many grow in a filamentous manner and develop at least partly into a network of branches. Examples include plant roots, fungi and some bacteria. Whereas the mechanisms of filamentous growth are partially understood in fungi, the same cannot be said in filamentous bacteria, where our knowledge of hyphal growth regulation is very limited. To rectify this we have studied the bacteria Streptomyces, which are an excellent model for all hyphal bacteria. The protein DivIVA is known to play a critical role in controlling filamentous growth in Streptomyces, forming large foci at branch tips and smaller foci that mark sites of future branch outgrowth. However, until now nothing was known about how these foci first appear. We have shown experimentally that new foci appear via a novel mechanism, whereby existing tip-foci split into two clusters. The larger cluster remains at the growing tip, while the smaller cluster fixes onto the adjacent lateral membrane, where it grows in size, eventually initiating a new branch. By mathematically modelling how DivIVA foci grow, we show how this one simple mechanism of focus formation can quantitatively capture the statistical properties of the entire hyphal branching network.
PMCID: PMC3297577  PMID: 22423220
14.  Delivering stepped care: an analysis of implementation in routine practice 
In the United Kingdom, clinical guidelines recommend that services for depression and anxiety should be structured around a stepped care model, where patients receive treatment at different 'steps,' with the intensity of treatment (i.e., the amount and type) increasing at each step if they fail to benefit at previous steps. There are very limited data available on the implementation of this model, particularly on the intensity of psychological treatment at each step. Our objective was to describe patient pathways through stepped care services and the impact of this on patient flow and management.
We recorded service design features of four National Health Service sites implementing stepped care (e.g., the types of treatments available and their links with other treatments), together with the actual treatments received by individual patients and their transitions between different treatment steps. We computed the proportions of patients accessing, receiving, and transiting between the various steps and mapped these proportions visually to illustrate patient movement.
We collected throughput data on 7,698 patients referred. Patient pathways were highly complex and very variable within and between sites. The ratio of low (e.g., self-help) to high-intensity (e.g., cognitive behaviour therapy) treatments delivered varied between sites from 22:1, through 2.1:1, 1.4:1 to 0.5:1. The numbers of patients allocated directly to high-intensity treatment varied from 3% to 45%. Rates of stepping up from low-intensity treatment to high-intensity treatment were less than 10%.
When services attempt to implement the recommendation for stepped care in the National Institute for Health and Clinical Excellence guidelines, there were significant differences in implementation and consequent high levels of variation in patient pathways. Evaluations driven by the principles of implementation science (such as targeted planning, defined implementation strategies, and clear activity specification around service organisation) are required to improve evidence on the most effective, efficient, and acceptable stepped care systems.
PMCID: PMC3283464  PMID: 22248385
15.  Altered patterning of dentate granule cell mossy fiber inputs onto CA3 pyramidal cells in limbic epilepsy 
Hippocampus  2011;21(1):93-107.
Impaired gating by hippocampal dentate granule cells may promote the development of limbic epilepsy by facilitating seizure spread through the hippocampal trisynaptic circuit. The second synapse in this circuit, the dentate granule cell≫CA3 pyramidal cell connection, may be of particular importance because pathological changes occurring within the dentate likely exert their principal effect on downstream CA3 pyramids. Here, we utilized GFP-expressing mice and immunolabeling for the zinc transporter ZnT-3 to reveal the pre- and postsynaptic components of granule cell≫CA3 pyramidal cell synapses following pilocarpine-epileptogenesis. Confocal analyses of these terminals revealed that while granule cell presynaptic giant boutons increased in size and complexity one month after status epilepticus, individual thorns making up the postsynaptic thorny excrescences of the CA3 pyramidal cells were reduced in number. This reduction, however, was transient, and three months after status, thorn density recovered. This recovery was accompanied by a significant change in the distribution of thorns along pyramidal cells dendrites. While thorns in control animals tended to be tightly clustered, thorns in epileptic animals were more evenly distributed. Computational modeling of thorn distributions predicted an increase in the number of boutons required to cover equivalent numbers of thorns in epileptic vs. control mice. Confirming this prediction, ZnT-3 labeling of presynaptic giant boutons apposed to GFP-expressing thorns revealed a near doubling in bouton density, while the number of individual thorns per bouton was reduced by half. Together, these data provide clear evidence of novel plastic changes occurring within the epileptic hippocampus.
PMCID: PMC2888689  PMID: 20014385
16.  Spatial Regulation of Exocytic Site and Vesicle Mobilization by the Actin Cytoskeleton 
PLoS ONE  2011;6(12):e29162.
Numerous studies indicate a role for the actin cytoskeleton in secretion. Here, we have used evanescent wave and widefield fluorescence microscopy to study the involvement of the actin cytoskeleton in secretion from PC12 cells. Secretion was assayed as loss of ANF-EmGFP in widefield mode. Under control conditions, depolarization induced secretion showed two phases: an initial rapid rate of loss of vesicular cargo (tau = 1.4 s), followed by a slower, sustained drop in fluorescence (tau = 34.1 s). Pretreatment with Latrunculin A changed the kinetics to a single exponential, slightly faster than the fast component of control cells (1.2 s). Evanescent wave microscopy allowed us to examine this at the level of individual events, and revealed equivalent changes in the rates of vesicular arrival at the plasma membrane immediately following and during the sustained phase of release. Co-transfection of mCherry labeled β-actin and ANF-EmGFP demonstrated that sites of exocytosis had an inverse relationship with sites of actin enrichment. Disruption of visualized actin at the membrane resulted in the loss of specificity of exocytic site.
PMCID: PMC3237607  PMID: 22195014
17.  Identifying barriers to mental health system improvements: an examination of community participation in assertive community treatment programs 
Integrating the best available evidence into program standards is essential if system-wide improvements in the delivery of community-based mental health services are to be achieved. Since the beginning of the Assertive Community Treatment (ACT) program movement, program standards have included a role for the community. In particular, ACT program standards have sought to ensure that members of the local community are involved in governance and that former clients participate in service delivery as "Peer Support Specialists". This paper reports on the extent to which ACT program standards related to community participation have been implemented and identifies barriers to full compliance.
Qualitative and quantitative data were collected through a telephone survey of ACT Program Coordinators in Ontario, Canada, using a census sample of the existing 66 ACT programs. A thematic approach to content analysis was used to analyze respondents' qualitative comments. Quantitative data were analyzed using SPSS 16.0 and included means, frequencies, independent t-tests and Pearson Correlations.
An 85% response rate was achieved. Of the 33 program standards, the two that received the lowest perceived compliance ratings were the two standards directly concerning community participation. Specifically, the standard to have a functioning Community Advisory Body and the standard requiring the inclusion of a Peer Support Specialist. The three major themes that emerged from the survey data with respect to the barriers to fully implementing the Community Advisory Body were: external issues; standard related issues; and, organizational/structural related issues. The three major themes concerning barriers to implementing the Peer Support Specialist role were: human resource related issues; organizational/structural related issues; and, standard related issues.
The reasons for low compliance of ACT programs with community participation standards are complex and are tied to structural and human resources barriers (both internal and external to the ACT programs) as well as to the requirements of the standards themselves. In order for improvements to the mental health system to be achieved there is a need to identify and address these barriers. Failure to do so will result in less than optimal client, family and economic efficiency outcomes.
PMCID: PMC3223489  PMID: 22059856
health policy; peer support; fidelity; mental health system improvement; evidence-based practice; Ontario
18.  A randomised evaluation of CollAborative care and active surveillance for Screen-Positive EldeRs with sub-threshold depression (CASPER): study protocol for a randomized controlled trial 
Trials  2011;12:225.
Depression accounts for the greatest burden of disease among all mental health problems, and is expected to become the second-highest amongst all general health problems by 2020. By the age of 75, 1 in 7 older people meet formal diagnostic criteria for depression. Efforts to ameliorate the burden of illness and personal suffering associated with depression in older people have focussed on those with more severe depressive syndromes. Less attention has been paid to those with mild disorders/sub-threshold depressive syndromes but these patients also suffer impairments in their quality of life and level of functioning.
The CASPER study has been designed to assemble an epidemiological cohort of people over 75 years of age (the CASPER cohort), from which we will identify those eligible to participate in a trial of collaborative care for sub-threshold depression (the CASPER trial).
We aim to undertake a pragmatic randomised controlled multi-centre trial evaluating the effectiveness and cost-effectiveness of collaborative care; a low intensity psychological intervention in addition to usual general practitioner care versus usual general practitioner care alone. General practitioners from practices based in the North of England will be asked to identify potentially eligible patients over the age of 75 years. Patients will be sent a letter inviting them to participate in the study.
We aim to recruit approximately 540 participants for the CASPER trial. A diagnostic interview will be carried out to ascertain trial eligibility with the major depressive episode module of the Mini International Neuropsychiatric Interview (M.I.N.I.), eligible participants randomised to either the intervention or usual care. The primary outcome will be measured with the Patient Health Questionnaire-9 (PHQ-9) and additional quality of life measures will be collected. Data will be collected at baseline, 4 and 12 months for both trial and cohort participants.
Trial Registration
PMCID: PMC3204244  PMID: 21988800
19.  The compression type of coronary artery motion in patients with ST-segment elevation acute myocardial infarction and normal controls: a case-control study 
BMC Research Notes  2011;4:51.
Prediction of the location of culprit lesions responsible for ST-segment elevation myocardial infarctions may allow for prevention of these events. A retrospective analysis of coronary artery motion (CAM) was performed on coronary angiograms of 20 patients who subsequently had ST-segment elevation myocardial infarction treated by primary or rescue angioplasty and an equal number of age and sex matched controls with normal angiograms.
There was no statistically significant difference between the frequency of CAM types of the ST-segment elevation acute myocardial infarction and control patients (p = 0.97). The compression type of CAM is more frequent in the proximal and mid segments of all three coronary arteries. No statistically significant difference was found when the frequency of the compression type of CAM was compared between the ST-segment elevation acute myocardial infarction and control patients for the individual coronary artery segments (p = 0.59).
The proportion of the compression type of coronary artery motion for individual artery segments is not different between patients who have subsequent ST-segment elevation myocardial infarctions and normal controls.
PMCID: PMC3063224  PMID: 21385385
20.  Antibody Response Patterns to Bordetella pertussis Antigens in Vaccinated (Primed) and Unvaccinated (Unprimed) Young Children with Pertussis▿  
In a previous study, it was found that the antibody response to a nonvaccine pertussis antigen in children who were vaccine failures was reduced compared with the response in nonvaccinated children who had pertussis. In two acellular pertussis vaccine efficacy trials in Sweden, we studied the convalescent-phase enzyme-linked immunosorbent assay (ELISA) geometric mean values (GMVs) in response to pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin (PRN), and fimbriae (FIM 2/3) in vaccine failures and controls with pertussis. In Germany, the antibody responses to Bordetella pertussis antigens PT, FHA, PRN, and FIM-2 were analyzed by ELISA according to time of serum collection after onset of illness in children with pertussis who were vaccine failures or who were previously unvaccinated. Antibody values were also compared by severity of clinical illness. In Sweden, infants who had received a PT toxoid vaccine and who were vaccine failures had a blunted response to the nonvaccine antigen FHA compared with the response in children who had received a PT/FHA vaccine. Similarly, infants who had pertussis and who had received a PT/FHA vaccine had a blunted response to the nonvaccine antigens PRN and FIM 2/3 compared with the response in children who were vaccine failures and who had received a PT, FHA, PRN, and FIM 2/3 vaccine. In Germany, in sera collected from 0 to 15 days after pertussis illness onset, the GMVs for all 4 antigens (PT, FHA, PRN, and FIM-2) were significantly lower in an unvaccinated group than in children who were diphtheria-tetanus-acellular pertussis (DTaP) vaccine failures. In the unvaccinated group, the GMV of the PT antibody rose rapidly over time so that it was similar to that of the DTaP vaccine recipients at the 16- to 30-day period. In contrast, the antibody responses to FHA, PRN, and FIM-2 at all time periods were lower in the diphtheria-tetanus vaccine (DT) recipients than in the DTaP vaccine failures. In both Sweden and Germany, children with less severe illness had lower antibody responses than children with typical pertussis. Our findings indicate that upon exposure and infection, previous vaccinees have more-robust antibody responses to the antigens contained in the vaccine they had received than to Bordetella antigens that were not in the vaccine they had received. In addition, over time the antibody responses to FHA, PRN, and FIM-2 were greater in children with vaccine failure (primed subjects) than in unvaccinated children (unprimed subjects) whereas the responses to PT were similar in the primed and unprimed children, as determined from sera collected after 15 days of illness. Our findings lend support to the idea that DTaP vaccines should contain multiple antigens.
PMCID: PMC2863370  PMID: 20335431
21.  A role for statin therapy in Alzheimer's disease 
Genome Biology  2010;11(Suppl 1):P33.
PMCID: PMC3026263
22.  An argument for the conservative management of small traumatic pneumathoraces in populations with high prevalence of HIV and tuberculosis: an evidence-based review of the literature 
Traumatic pneumothoraces are common. Many are managed with tube thoracostomy. However, there is a high complication rate from chest tube placement, particularly in patients with HIV, TB, or both.
We sought to investigate the literature on the conservative management of traumatic pneumothorax in patients with HIV and/or TB.
The literature search was broken into two parts. In the first part, we searched for articles comparing tube thoracostomy versus conservative management in traumatic pneumothorax. In the second part, we sought articles describing the incidence and outcome of pneumothoraces in patients with pre-existing HIV or tuberculosis. In both, relevant articles were reviewed, and citations were hand-searched.
For the first portion, we identified 384 papers. From these, six studies were relevant. For the second portion, we identified 327 articles. A total of four unique articles were selected. The heterogeneity of the studies did not allow any pooled analysis. The studies of conservative management demonstrated a low percentage of patients with small pneumothoraces (most often <1.5 cm or less than 10%) later required tube thoracostomy for clinical deterioration (range 6–25%). No studies focused exclusively on pneumothoraces in patients with TB. In patients with HIV, there were no prospective trials of conservative management. Mortality for all HIV-infected patients with pneumothorax was high (25–50%), and the rate of complications from tube thoracostomy was also high. Pneumocystits carinii pneumonia (PCP) independently increased mortality.
A review of the literature suggests that selected small pneumothoraces may be managed conservatively and that there is a high rate of complications related to tube thoracostomy in HIV patients. We propose a trial of the safety of conservative management of traumatic pneumothoraces in an area with a high prevalence of HIV and TB.
PMCID: PMC3047831  PMID: 21373311
Pneumothorax; Tube thoracostomy; Chest tube; Chest trauma; HIV; Human immunodeficiency virus; AIDS; Acquired immunodeficiency syndrome; Emergency medicine; Trauma; Africa; Global health
23.  Do all psychological treatments really work the same in posttraumatic stress disorder? 
Clinical Psychology Review  2010;30(2):269-276.
A recent meta-analysis by Benish, Imel, and Wampold (2008, Clinical Psychology Review, 28, 746–758) concluded that all bona fide treatments are equally effective in posttraumatic stress disorder (PTSD). In contrast, seven other meta-analyses or systematic reviews concluded that there is good evidence that trauma-focused psychological treatments (trauma-focused cognitive behavior therapy and eye movement desensitization and reprocessing) are effective in PTSD; but that treatments that do not focus on the patients' trauma memories or their meanings are either less effective or not yet sufficiently studied. International treatment guidelines therefore recommend trauma-focused psychological treatments as first-line treatments for PTSD. We examine possible reasons for the discrepant conclusions and argue that (1) the selection procedure of the available evidence used in Benish et al.'s (2008)meta-analysis introduces bias, and (2) the analysis and conclusions fail to take into account the need to demonstrate that treatments for PTSD are more effective than natural recovery. Furthermore, significant increases in effect sizes of trauma-focused cognitive behavior therapies over the past two decades contradict the conclusion that content of treatment does not matter. To advance understanding of the optimal treatment for PTSD, we recommend further research into the active mechanisms of therapeutic change, including treatment elements commonly considered to be non-specific. We also recommend transparency in reporting exclusions in meta-analyses and suggest that bona fide treatments should be defined on empirical and theoretical grounds rather than by judgments of the investigators' intent.
PMCID: PMC2852651  PMID: 20051310
Posttraumatic stress disorder; Meta-analysis; Cognitive behavior therapy; EMDR; Psychotherapy; Clinical trials
24.  What work has to be done to implement collaborative care for depression? Process evaluation of a trial utilizing the Normalization Process Model 
There is a considerable evidence base for 'collaborative care' as a method to improve quality of care for depression, but an acknowledged gap between efficacy and implementation. This study utilises the Normalisation Process Model (NPM) to inform the process of implementation of collaborative care in both a future full-scale trial, and the wider health economy.
Application of the NPM to qualitative data collected in both focus groups and one-to-one interviews before and after an exploratory randomised controlled trial of a collaborative model of care for depression.
Findings are presented as they relate to the four factors of the NPM (interactional workability, relational integration, skill-set workability, and contextual integration) and a number of necessary tasks are identified. Using the model, it was possible to observe that predictions about necessary work to implement collaborative care that could be made from analysis of the pre-trial data relating to the four different factors of the NPM were indeed borne out in the post-trial data. However, additional insights were gained from the post-trial interview participants who, unlike those interviewed before the trial, had direct experience of a novel intervention. The professional freedom enjoyed by more senior mental health workers may work both for and against normalisation of collaborative care as those who wish to adopt new ways of working have the freedom to change their practice but are not obliged to do so.
The NPM provides a useful structure for both guiding and analysing the process by which an intervention is optimized for testing in a larger scale trial or for subsequent full-scale implementation.
PMCID: PMC2829490  PMID: 20181163
25.  Improving access to psychological therapy: Initial evaluation of two UK demonstration sites 
Behaviour Research and Therapy  2009;47(11):910-920.
Recently the UK Government announced an unprecedented, large-scale initiative for Improving Access to Psychological Therapies (IAPT) for depression and anxiety disorders. Prior to this development, the Department of Health established two pilot projects that aimed to collect valuable information to inform the national roll-out. Doncaster and Newham received additional funds to rapidly increase the availability of CBT-related interventions and to deploy them in new clinical services, operating on stepped-care principles, when appropriate. This article reports an evaluation of the new services (termed ‘demonstration sites’) during their first thirteen months of operation. A session-by-session outcome monitoring system achieved unusually high levels of pre to post-treatment data completeness. Large numbers of patients were treated, with low-intensity interventions (such as guided self-help) being particularly helpful for achieving high throughput. Clinical outcomes were broadly in line with expectation. 55–56% of patients who had attended at least twice (including the assessment interview) were classified as recovered when they left the services and 5% had improved their employment status. Treatment gains were largely maintained at 10 month follow-up. Opening the services to self-referral appeared to facilitate access for some groups that tend to be underrepresented in general practice referrals. Outcomes were comparable for the different ethnic groups who access the services. Issues for the further development of IAPT are discussed.
PMCID: PMC3111658  PMID: 19647230
Dissemination; CBT; IAPT; Outcome monitoring; Routine services; Depression; Anxiety disorders

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