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1.  Systematic review of randomized controlled trials of probiotics, prebiotics, and synbiotics in inflammatory bowel disease 
Probiotics are microorganisms that are ingested either in combination or as a single organism in an effort to normalize intestinal microbiota and potentially improve intestinal barrier function. Recent evidence has suggested that inflammatory bowel disease (IBD) may result from an inappropriate immunologic response to intestinal bacteria and a disruption in the balance of the gastrointestinal microbiota in genetically susceptible individuals. Prebiotics, synbiotics, and probiotics have all been studied with growing interest as adjuncts to standard therapies for IBD. In general, probiotics have been shown to be well-tolerated with few side effects, making them a potential attractive treatment option in the management of IBD.
To perform a systematic review of randomized controlled trials on the use of probiotics, prebiotics, and synbiotics in IBD.
In our systematic review we found 14 studies in patients with Crohn’s disease (CD), 21 studies in patients with ulcerative colitis (UC), and five studies in patients with pouchitis. These were randomized controlled trials using probiotics, prebiotics, and/or synbiotics. In patients with CD, multiple studies comparing probiotics and placebo showed no significant difference in clinical outcomes. Adding a probiotic to conventional treatment improved the overall induction of remission rates among patients with UC. There was also a similar benefit in maintaining remission in UC. Probiotics have also shown some efficacy in the treatment of pouchitis after antibiotic-induced remission.
To date, there is insufficient data to recommend probiotics for use in CD. There is evidence to support the use of probiotics for induction and maintenance of remission in UC and pouchitis. Future quality studies are needed to confirm whether probiotics, prebiotics, and synbiotics have a definite role in induction or maintenance of remission in CD, UC, and pouchitis. Similar to probiotics, fecal microbiota transplantation provides an alternate modality of therapy to treat IBD by influencing the intestinal flora.
PMCID: PMC4266241  PMID: 25525379
inflammatory bowel disease; Crohn’s disease; ulcerative colitis; pouchitis; probiotics; prebiotics; synbiotics
2.  Developing stepped care treatment for depression (STEPS): study protocol for a pilot randomised controlled trial 
Trials  2014;15(1):452.
Stepped care is recommended and implemented as a means to organise depression treatment. Compared with alternative systems, it is assumed to achieve equivalent clinical effects and greater efficiency. However, no trials have examined these assumptions. A fully powered trial of stepped care compared with intensive psychological therapy is required but a number of methodological and procedural uncertainties associated with the conduct of a large trial need to be addressed first.
STEPS (Developing stepped care treatment for depression) is a mixed methods study to address uncertainties associated with a large-scale evaluation of stepped care compared with high-intensity psychological therapy alone for the treatment of depression. We will conduct a pilot randomised controlled trial with an embedded process study. Quantitative trial data on recruitment, retention and the pathway of patients through treatment will be used to assess feasibility. Outcome data on the effects of stepped care compared with high-intensity therapy alone will inform a sample size calculation for a definitive trial. Qualitative interviews will be undertaken to explore what people think of our trial methods and procedures and the stepped care intervention. A minimum of 60 patients with Major Depressive Disorder will be recruited from an Improving Access to Psychological Therapies service and randomly allocated to receive stepped care or intensive psychological therapy alone. All treatments will be delivered at clinic facilities within the University of Exeter. Quantitative patient-related data on depressive symptoms, worry and anxiety and quality of life will be collected at baseline and 6 months. The pilot trial and interviews will be undertaken concurrently. Quantitative and qualitative data will be analysed separately and then integrated.
The outcomes of this study will inform the design of a fully powered randomised controlled trial to evaluate the effectiveness and efficiency of stepped care. Qualitative data on stepped care will be of immediate interest to patients, clinicians, service managers, policy makers and guideline developers. A more informed understanding of the feasibility of a large trial will be obtained than would be possible from a purely quantitative (or qualitative) design.
Trial registration
Current Controlled Trials ISRCTN66346646 registered on 2 July 2014.
PMCID: PMC4247766  PMID: 25409886
Stepped care; Major Depressive Disorder; Mixed methods; Feasibility study
3.  CASPER plus (CollAborative care in Screen-Positive EldeRs with major depressive disorder): study protocol for a randomised controlled trial 
Trials  2014;15(1):451.
Depression accounts for the greatest disease burden of all mental health disorders, contributes heavily to healthcare costs, and by 2020 is set to become the second largest cause of global disability. Although 10% to 16% of people aged 65 years and over are likely to experience depressive symptoms, the condition is under-diagnosed and often inadequately treated in primary care. Later-life depression is associated with chronic illness and disability, cognitive impairment and social isolation. With a progressively ageing population it becomes increasingly important to refine strategies to identity and manage depression in older people. Currently, management may be limited to the prescription of antidepressants where there may be poor concordance; older people may lack awareness of psychosocial interventions and general practitioners may neglect to offer this treatment option.
CASPER Plus is a multi-centre, randomised controlled trial of a collaborative care intervention for individuals aged 65 years and over experiencing moderate to severe depression. Selected practices in the North of England identify potentially eligible patients and invite them to participate in the study. A diagnostic interview is carried out and participants with major depressive disorder are randomised to either collaborative care or usual care. The recruitment target is 450 participants.
The intervention, behavioural activation and medication management in a collaborative care framework, has been adapted to meet the complex needs of older people. It is delivered over eight to 10 weekly sessions by a case manager liaising with general practitioners.
The trial aims to evaluate the clinical and cost effectiveness of collaborative care in addition to usual GP care versus usual GP care alone. The primary clinical outcome, depression severity, will be measured with the Patient Health Questionnaire-9 (PHQ-9) at baseline, 4, 12 and 18 months. Cost effectiveness analysis will assess health-related quality of life using the SF-12 and EQ-5D and will examine cost-consequences of collaborative care.
A qualitative process evaluation will be undertaken to explore acceptability, gauge the extent to which the intervention is implemented and to explore sustainability beyond the clinical trial.
Results will add to existing evidence and a positive outcome may lead to the commissioning of this model of service in primary care.
Trial registration
ISRCTN45842879 (24 July 2012).
PMCID: PMC4247639  PMID: 25409776
Depression; Major depressive disorder; Older people; Elderly population; Primary care; Collaborative care; Behavioural activation; Psychosocial interventions; Randomised controlled trial; Cost effectiveness analysis; Process evaluation
4.  The DiReCT study - improving recruitment into clinical trials: a mixed methods study investigating the ethical acceptability, feasibility and recruitment yield of the cohort multiple randomised controlled trials design 
Trials  2014;15(1):398.
The ‘cohort multiple Randomised Controlled Trial’ (cmRCT) design has been proposed as a potential solution to poor recruitment into clinical trials. The design randomly selects participants eligible for experimental treatments from a pre-enrolled cohort of patients, recruiting participants to multiple trials from a single cohort. Controls remain unaware of their participation in specific trials.
We undertook a mixed methods study to determine the ethical acceptability, the proportion of patients in a routine service consenting to cohort participation, the proportion of these who would consent to being hypothetically randomly selected to receive new treatments, and the views of clinicians on the acceptability of the design. We submitted our cmRCT design for ethical review and recruited participants from people with anxiety and depression attending a community mental health service of twenty-one clinicians. We recorded the proportion of patients who were offered participation in the DiReCT study and the proportion that consented to researcher contact, medical record sharing, and who accepted to be randomly allocated to active treatment procedures in future hypothetical unspecified clinical trials. We used a thematic framework analysis to analyse clinician interviews.
We obtained a favourable ethical opinion from the UK Health Research Authority. Clinicians approached 131/752 (17%) potentially eligible participants for consent. Of these 131, 84 (64%) initially consented to be contacted by a researcher and all but one consented to being randomised into future trials. We confirmed consent for 71 (54%) of participants approached by clinicians, of whom 69 (53%) consented to being randomised into hypothetical future trials, 9% (69/752) of all potentially eligible patients. The interviewed clinicians described issues impacting on their ability to recruit participants in terms of clinical concerns for patient wellbeing, work pressure, their views of both general research and the specific DiReCT study, and how they viewed patients’ responses to being offered participation in the study.
The cmRCT system offers the potential to improve the recruitment into clinical trials and is acceptable ethically and to many patients. Overcoming the multiple factors driving the difficulties clinicians experience in patient recruitment is likely to require the application of significant implementation science-informed effort.
PMCID: PMC4210622  PMID: 25318374
5.  Characteristics of Effective Collaborative Care for Treatment of Depression: A Systematic Review and Meta-Regression of 74 Randomised Controlled Trials 
PLoS ONE  2014;9(9):e108114.
Collaborative care is a complex intervention based on chronic disease management models and is effective in the management of depression. However, there is still uncertainty about which components of collaborative care are effective. We used meta-regression to identify factors in collaborative care associated with improvement in patient outcomes (depressive symptoms) and the process of care (use of anti-depressant medication).
Methods and Findings
Systematic review with meta-regression. The Cochrane Collaboration Depression, Anxiety and Neurosis Group trials registers were searched from inception to 9th February 2012. An update was run in the CENTRAL trials database on 29th December 2013. Inclusion criteria were: randomised controlled trials of collaborative care for adults ≥18 years with a primary diagnosis of depression or mixed anxiety and depressive disorder. Random effects meta-regression was used to estimate regression coefficients with 95% confidence intervals (CIs) between study level covariates and depressive symptoms and relative risk (95% CI) and anti-depressant use. The association between anti-depressant use and improvement in depression was also explored. Seventy four trials were identified (85 comparisons, across 21,345 participants). Collaborative care that included psychological interventions predicted improvement in depression (β coefficient −0.11, 95% CI −0.20 to −0.01, p = 0.03). Systematic identification of patients (relative risk 1.43, 95% CI 1.12 to 1.81, p = 0.004) and the presence of a chronic physical condition (relative risk 1.32, 95% CI 1.05 to 1.65, p = 0.02) predicted use of anti-depressant medication.
Trials of collaborative care that included psychological treatment, with or without anti-depressant medication, appeared to improve depression more than those without psychological treatment. Trials that used systematic methods to identify patients with depression and also trials that included patients with a chronic physical condition reported improved use of anti-depressant medication. However, these findings are limited by the observational nature of meta-regression, incomplete data reporting, and the use of study aggregates.
PMCID: PMC4180075  PMID: 25264616
6.  Cost-Effectiveness of Collaborative Care for Depression in UK Primary Care: Economic Evaluation of a Randomised Controlled Trial (CADET) 
PLoS ONE  2014;9(8):e104225.
Collaborative care is an effective treatment for the management of depression but evidence on its cost-effectiveness in the UK is lacking.
To assess the cost-effectiveness of collaborative care in a UK primary care setting.
An economic evaluation alongside a multi-centre cluster randomised controlled trial comparing collaborative care with usual primary care for adults with depression (n = 581). Costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICER) were calculated over a 12-month follow-up, from the perspective of the UK National Health Service and Personal Social Services (i.e. Third Party Payer). Sensitivity analyses are reported, and uncertainty is presented using the cost-effectiveness acceptability curve (CEAC) and the cost-effectiveness plane.
The collaborative care intervention had a mean cost of £272.50 per participant. Health and social care service use, excluding collaborative care, indicated a similar profile of resource use between collaborative care and usual care participants. Collaborative care offered a mean incremental gain of 0.02 (95% CI: –0.02, 0.06) quality-adjusted life-years over 12 months, at a mean incremental cost of £270.72 (95% CI: –202.98, 886.04), and resulted in an estimated mean cost per QALY of £14,248. Where costs associated with informal care are considered in sensitivity analyses collaborative care is expected to be less costly and more effective, thereby dominating treatment as usual.
Collaborative care offers health gains at a relatively low cost, and is cost-effective compared with usual care against a decision-maker willingness to pay threshold of £20,000 per QALY gained. Results here support the commissioning of collaborative care in a UK primary care setting.
PMCID: PMC4133193  PMID: 25121991
7.  Behavioural Activation for Depression; An Update of Meta-Analysis of Effectiveness and Sub Group Analysis 
PLoS ONE  2014;9(6):e100100.
Depression is a common, disabling condition for which psychological treatments are recommended. Behavioural activation has attracted increased interest in recent years. It has been over 5 years since our meta-analyses summarised the evidence supporting and this systematic review updates those findings and examines moderators of treatment effect.
Randomised trials of behavioural activation for depression versus controls or anti-depressant medication were identified using electronic database searches, previous reviews and reference lists. Data on symptom level and study level moderators were extracted and analysed using meta-analysis, sub-group analysis and meta-regression respectively.
Twenty six randomised controlled trials including 1524 subjects were included in this meta-analysis. A random effects meta-analysis of symptom level post treatment showed behavioural activation to be superior to controls (SMD −0.74 CI −0.91 to −0.56, k = 25, N = 1088) and medication (SMD −0.42 CI −0.83 to-0.00, k = 4, N = 283). Study quality was low in the majority of studies and follow- up time periods short. There was no indication of publication bias and subgroup analysis showed limited association between moderators and effect size.
The results in this meta-analysis support and strengthen the evidence base indicating Behavioural Activation is an effective treatment for depression. Further high quality research with longer term follow-up is needed to strengthen the evidence base.
PMCID: PMC4061095  PMID: 24936656
8.  Depigmented-polymerised allergoids favour regulatory over effector T cells: enhancement by 1α, 25-dihydroxyvitamin D3 
BMC Immunology  2014;15:21.
Allergen immunotherapy (SIT) is the only treatment for allergic disease capable of modifying disease long term. To reduce the risk of anaphylaxis from SIT, allergen-extracts have been modified by polymerisation with glutaraldehyde to reduce IgE binding. It is suggested that these allergoid extracts also have reduced T cell activity, which could compromise clinical efficacy. Effective SIT is thought to act through regulatory T cells (Tregs) rather than activation of effector T cells. There is no published data on the activity of modified extracts on Tregs.
We compared the capacity of modified (depigmented-polymerised) versus unmodified (native) allergen extracts of grass pollen and house dust mite to stimulate proliferation/cytokine production and to modulate Treg/effector T cell frequency in cultures of peripheral blood mononuclear cells (PBMC), from volunteers sensitised to both allergens in vitro. Depigmented-polymerised allergen extracts stimulated less proliferation of PBMC, and reduced effector cell numbers after 7 days in culture than did native extracts. However, the frequency of Foxp3+ Tregs in cultures were similar to those seen with native extract so that ratios of regulatory to effector T cells were significantly increased in cultures stimulated with depigmented-polymerised extracts. Addition of 1α, 25-dihydroxyvitamin D3 further favoured Treg, and reduced effector cytokine production, but not interleukin-10.
Depigmented-polymerised allergen extracts appear to favour Treg expansion over activation of effector T cells and this may relate to their demonstrated efficacy and safety in SIT. 1α, 25-dihydroxyvitamin D3 further reduces effector T cell activation by allergen extracts and may be a useful adjuvant for SIT.
PMCID: PMC4051145  PMID: 24884430
Allergen extract; Depigmented-polymerised; Immunotherapy; Regulatory T cell; Vitamin D
9.  Supported cognitive-behavioural self-help versus treatment-as-usual for depressed informal carers of stroke survivors (CEDArS): study protocol for a feasibility randomized controlled trial 
Trials  2014;15:157.
Increased life expectancy has resulted in a greater provision of informal care within the community for patients with chronic physical health conditions. Informal carers are at greater risk of poor mental health, with one in three informal carers of stroke survivors experiencing depression. However, currently no psychological treatments tailored to the unique needs of depressed informal carers of stroke survivors exist. Furthermore, informal carers of stroke survivors experience a number of barriers to attending traditional face-to-face psychological services, such as lack of time and the demands of the caring role. The increased flexibility associated with supported cognitive behavioral therapy self-help (CBTsh), such as the ability for support to be provided by telephone, email, or face-to-face, alongside shorter support sessions, may help overcome such barriers to access. CBTsh, tailored to depressed informal carers of stroke survivors may represent an effective and acceptable solution.
This study is a Phase II (feasibility) randomized controlled trial (RCT) following guidance in the MRC Complex Interventions Research Methods Framework. We will randomize a sample of depressed informal carers of stroke survivors to receive CBT self-help supported by mental health paraprofessionals, or treatment-as-usual. Consistent with the objectives of assessing the feasibility of trial design and procedures for a potential larger scale trial we will measure the following outcomes: a) feasibility of patient recruitment (recruitment and refusal rates); (b) feasibility and acceptability of data collection procedures; (c) levels of attrition; (d) likely intervention effect size; (e) variability in number, length and frequency of support sessions estimated to bring about recovery; and (f) acceptability of the intervention. Additionally, we will collect data on the diagnosis of depression, symptoms of depression and anxiety, functional impairment, carer burden, quality of life, and stroke survivor mobility skill, self-care and functional ability, measured at four and six months post-randomization.
This study will provide important information for the feasibility and design of a Phase III (effectiveness) trial in the future. If the intervention is identified to be feasible, effective, and acceptable, a written CBTsh intervention for informal carers of stroke survivors, supported by mental health paraprofessionals, could represent a cost-effective model of care.
Trial registration
Current Controlled Trials ISRCTN63590486.
PMCID: PMC4017968  PMID: 24886151
Randomized controlled trial; Cognitive behavioral therapy (CBT); Self-help; Depression; Stroke; Informal caregivers
10.  Facilitating professional liaison in collaborative care for depression in UK primary care; a qualitative study utilising normalisation process theory 
BMC Family Practice  2014;15:78.
Collaborative care (CC) is an organisational framework which facilitates the delivery of a mental health intervention to patients by case managers in collaboration with more senior health professionals (supervisors and GPs), and is effective for the management of depression in primary care. However, there remains limited evidence on how to successfully implement this collaborative approach in UK primary care. This study aimed to explore to what extent CC impacts on professional working relationships, and if CC for depression could be implemented as routine in the primary care setting.
This qualitative study explored perspectives of the 6 case managers (CMs), 5 supervisors (trial research team members) and 15 general practitioners (GPs) from practices participating in a randomised controlled trial of CC for depression. Interviews were transcribed verbatim and data was analysed using a two-step approach using an initial thematic analysis, and a secondary analysis using the Normalisation Process Theory concepts of coherence, cognitive participation, collective action and reflexive monitoring with respect to the implementation of CC in primary care.
Supervisors and CMs demonstrated coherence in their understanding of CC, and consequently reported good levels of cognitive participation and collective action regarding delivering and supervising the intervention. GPs interviewed showed limited understanding of the CC framework, and reported limited collaboration with CMs: barriers to collaboration were identified. All participants identified the potential or experienced benefits of a collaborative approach to depression management and were able to discuss ways in which collaboration can be facilitated.
Primary care professionals in this study valued the potential for collaboration, but GPs’ understanding of CC and organisational barriers hindered opportunities for communication. Further work is needed to address these organisational barriers in order to facilitate collaboration around individual patients with depression, including shared IT systems, facilitating opportunities for informal discussion and building in formal collaboration into the CC framework.
Trial registration
ISRCTN32829227 30/9/2008.
PMCID: PMC4030004  PMID: 24885746
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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