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Kirsty Sprange,1 Jules Beresford-Dent,2 Gail Mountain,2 Ben Thomas,3 Jessica Wright,3 Clare Mason,2 Cindy L Cooper3 1Nottingham Clinical Trials Unit, Faculty of Medicine, University of Nottingham, Nottingham, NG7 2RD, UK; 2University of Bradford, Bradford West Yorkshire, BD7 1DP, UK; 3Clinical Trials Research Unit, ScHARR, University of Sheffield, Sheffield, S1 4DP, UKCorrespondence: Kirsty SprangeNottingham Clinical Trials Unit, Building 42, Room A05, University of Nottingham, University Park, Nottingham, NG7 2RD, UKTel +44 0115 82 31574Email Kirsty.sprange@nottingham.ac.ukObjective: To identify the barriers and facilitators to the implementation of a complex psychosocial intervention though a study exploring the experiences of participants, carers and interventionists during a trial.Methods: Individual semi-structured interviews were conducted with participants, their carers, and interventionists from a sample of recruiting sites that took part in the Journeying through Dementia randomized controlled trial (RCT). Interview data were transcribed and analysed using framework analysis. Co-researcher data analysis workshops were also conducted to explore researcher interpretations of the data through the lens of those with lived experience of dementia. Triangulation enabled comparison of findings from the interviews with findings from the co-researcher workshops.Results: Three main themes emerged from the interview data: being prepared; intervention engagement; and participation and outcomes from engagement. From these themes, a number of factors that can moderate delivery and receipt of the intervention as intended were identified. These were context and environment; readiness, training, skills and competencies of the workforce; identifying meaningful participation and relationships.Conclusion: This study highlighted that the observed benefit of the intervention was nuanced for each individual. Mechanisms of change were influenced by a range of individual, social and contextual factors. Future research should therefore consider how best to identify and measure the multifaceted interplay of mechanisms of change in complex interventions.Trial Registration: ISRCTN17993825.Keywords: psychosocial, self-management, dementia, wellbeing, occupational therapy, qualitative

Jaehong Key,1,2 Deepika Dhawan,3 Christy L Cooper,3,4 Deborah W Knapp,3 Kwangmeyung Kim,5 Ick Chan Kwon,5 Kuiwon Choi,5 Kinam Park,1,6 Paolo Decuzzi,7–9 James F Leary1,3,41Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA; 2Department of Biomedical Engineering, Yonsei University, Wonju, Republic of Korea; 3School of Veterinary Medicine-Department of Basic Medical Sciences, Purdue University, West Lafayette, 4Birck Nanotechnology Center at Discovery Park, Purdue University, West Lafayette, IN, USA; 5Biomedical Research Center, Korea Institute of Science and Technology, Sungbook-Gu, Seoul, Republic of Korea; 6Department of Pharmaceutics, Purdue University, West Lafayette, IN, 7Department of Translational Imaging, 8Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX USA; 9Laboratory of Nanotechnology for Precision Medicine, Fondazione Istituto Italiano di Tecnologia (IIT), Genova, Italy Abstract: While current imaging modalities, such as magnetic resonance imaging (MRI), computed tomography, and positron emission tomography, play an important role in detecting tumors in the body, no single-modality imaging possesses all the functions needed for a complete diagnostic imaging, such as spatial resolution, signal sensitivity, and tissue penetration depth. For this reason, multimodal imaging strategies have become promising tools for advanced biomedical research and cancer diagnostics and therapeutics. In designing multimodal nanoparticles, the physicochemical properties of the nanoparticles should be engineered so that they successfully accumulate at the tumor site and minimize nonspecific uptake by other organs. Finely altering the nano-scale properties can dramatically change the biodistribution and tumor accumulation of nanoparticles in the body. In this study, we engineered multimodal nanoparticles for both MRI, by using ferrimagnetic nanocubes (NCs), and near infrared fluorescence imaging, by using cyanine 5.5 fluorescence molecules. We changed the physicochemical properties of glycol chitosan nanoparticles by conjugating bladder cancer-targeting peptides and loading many ferrimagnetic iron oxide NCs per glycol chitosan nanoparticle to improve MRI contrast. The 22 nm ferrimagnetic NCs were stabilized in physiological conditions by encapsulating them within modified chitosan nanoparticles. The multimodal nanoparticles were compared with in vivo MRI and near infrared fluorescent systems. We demonstrated significant and important changes in the biodistribution and tumor accumulation of nanoparticles with different physicochemical properties. Finally, we demonstrated that multimodal nanoparticles specifically visualize small tumors and show minimal accumulation in other organs. This work reveals the importance of finely modulating physicochemical properties in designing multimodal nanoparticles for bladder cancer imaging.Keywords: MRI, NIRF, multimodal imaging, chitosan, iron oxide, bladder cancer

Eric Druyts,1 Kristian Thorlund,2,3 Samantha Humphreys,4 Michaela Lion,4 Curtis L Cooper,5 Edward J Mills1,31Faculty of Health Sciences, University of Ottawa, Ottawa, Ontario, Canada; 2Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada; 3Stanford Prevention Research Centre, Department of Medicine, Stanford University, Palo Alto, CA, USA; 4Merck Sharp and Dohme Ltd, UK; 5Division of Infectious Diseases, Department of Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, CanadaAbstract: Indirect treatment comparison (ITC) and multiple treatment comparison (MTC) meta-analyses are increasingly being used to estimate the comparative effectiveness of interventions when head-to-head data do not exist. ITC meta-analyses can be conducted using simple methodology to compare two interventions. MTC meta-analyses can be conducted using more complex methodology, often employing Bayesian approaches, to compare multiple interventions. As the number of ITC and MTC meta-analyses increase, it is common to find multiple analyses evaluating the same interventions in similar therapeutic areas. Depending on the choice of the methodological approach, the conclusions about relative treatment efficacy may differ. Such situations create uncertainty for decision makers. An illustration of this is provided by four ITC and MTC meta-analyses assessing the efficacy of boceprevir and telaprevir for chronic hepatitis C virus infection. This paper examines why these evaluations provide discordant results by examining specific methodological issues that can strengthen or weaken inferences.Keywords: indirect treatment comparison, multiple treatment comparison, meta-analysis, hepatitis C virus

Curtis L Cooper1, Eric Druyts2, Kristian Thorlund3, Jean B Nachega4, Antoine C El Khoury5, Christopher O'Regan6, Edward J Mills2,31Division of Infectious Diseases, Faculty of Medicine, 2Faculty of Health Sciences, University of Ottawa, Ottawa, 3Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada; 4Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, 5Merck and Co, Inc, Whitehouse Station, NJ, 6Merck Sharp and Dohme Ltd, Hoddesdon, Hertfordshire, United KingdomBackground: The aim of this study was to examine the relative efficacy and safety of boceprevir and telaprevir, when used in combination with pegylated interferon alpha and ribavirin, using an indirect comparison meta-analysis.Methods: Published phase II and phase III randomized placebo-controlled trials examining the efficacy of boceprevir and telaprevir in chronic hepatitis C virus genotype 1 infected adult populations were included. The primary outcomes were sustained virologic response, relapse, and discontinuation of all study drugs. Secondary outcomes included the adverse events of anemia, neutropenia, rash, and pruritus. Results: Four boceprevir trials and six telaprevir trials were included. No significant differences were observed for sustained virologic response among either naïve (relative risk [RR] 1.14, 95% confidence interval [CI] 0.93–1.37, P = 0.20) or experienced patients (RR 0.81, 95% CI 0.52–1.23, P = 0.30). Similarly, for relapse among naïve (RR 0.80, 95% CI 0.18–3.45, P = 0.77) and experienced patients (RR 1.71, 95% CI 0.90–3.24, P = 0.10), or discontinuation of therapy for naïve (RR 0.80, 95% CI 0.28–2.29, P = 0.72) and experienced patients (RR 0.88, 95% CI 0.69–1.12, P = 0.30). Telaprevir was more likely to be associated with rash and pruritus, and boceprevir was more likely to be associated with neutropenia in certain patient populations.Conclusion: Boceprevir and telaprevir appear comparable in terms of sustained virologic response, relapse, or discontinuation of therapy for patients treated with standard-dose therapy durations and response-guided therapy durations.Keywords: direct-acting antivirals, boceprevir, telaprevir, hepatitis C, meta-analysis

Eric Druyts1, Edward J Mills1,2, Jean Nachega3, Christopher O'Regan4, Curtis L Cooper51Faculty of Health Sciences, University of Ottawa, Ottawa, ON, Canada; 2Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada; 3Centre for Infectious Diseases, Stellenbosch University, Stellenbosch, South Africa; 4Division of Outcomes Research, Merck, Shire and Dohme, Hoddesdon, UK; 5Division of Infectious Diseases, University of Ottawa at The Ottawa Hospital, Ottawa, ON, CanadaBackground: With the development of new direct acting antiviral (DAA) therapy for hepatitis C, the backbone peginterferon alpha used may be of importance in maximizing treatment outcomes. To this end, the rates of sustained virologic response (SVR), relapse, and treatment discontinuation among hepatitis C genotype 1-infected patients given peginterferon alpha-2a plus ribavirin or peginterferon alpha-2b plus ribavirin were determined using a meta-analysis.Methods: Randomized trials examining peginterferon alpha-2a or peginterferon alpha-2b co-administered with ribavirin for 48 weeks were included. Data were extracted on SVR, relapse, and treatment discontinuations for treatment-naïve and treatment-experienced patients. Pooled proportions using fixed and random effects meta-analysis were calculated.Results: Twenty-six trials provided data on patients treated with peginterferon alpha-2a plus ribavirin, and 19 trials provided data on patients treated with peginterferon alpha-2b plus ribavirin. Five trials were direct head-to-head evaluations. In the subset of trials that included head-to-head evaluations, no significant differences were observed between the two treatments for treatment-naïve (relative risk [RR]: 1.07, 95% confidence intervals [CI]: 0.97–1.18) and treatment-experienced patients (RR: 1.27, 95% CI: 0.58–2.77). Using only active trial arms, a larger proportion of the treatment-naïve patients who were provided peginterferon alpha-2a plus ribavirin achieved a SVR (47%), which is greater than that of treatment-naïve patients who were provided peginterferon alpha-2b plus ribavirin (40% SVR achievement); however, a larger proportion of treatment-experienced patients who were provided peginterferon alpha-2b plus ribavirin achieved a SVR (16%) when compared with treatment-experienced patients given peginterferon alpha-2a plus ribavirin (12% SVR achievement). A larger proportion of relapses occurred among both treatment-naïve and treatment-experienced patients given peginterferon alpha-2a plus ribavirin, when compared with treatment-naïve and treatment-experienced patients taking peginterferon alpha-2b plus ribavirin. The proportion of patients discontinuing treatment was greater among treatment-naïve patients taking peginterferon alpha-2a plus ribavirin, but smaller among treatment-experienced patients.Conclusion: There are small differences in treatment outcomes for different types of peginterferon-alpha. Patient status and complexity of administration may differentiate clinical outcomes.Keywords: hepatitis C, genotype 1, peginterferon, ribavirin, sustained virologic response, meta-analysis

Objective To investigate health researchers' attitudes to involving the public in research. Background Public involvement in research is encouraged by the Department of Health in the UK. Despite this, the number of health researchers actively involving the public in research appears to be limited. There is little research specifically addressing the attitudes of health researchers towards involving the public: how they interpret the policy, what motivates and de-motivates them and what their experiences have been to date. Design A qualitative research design, using semi-structured telephone interviews. Setting and participants Fifteen purposively sampled UK-based University health researchers were the participants. Interviews were conducted over the telephone. Findings The participants suggested varying constructions of public involvement in research. Arguments based on moral and political principles and consequentialist arguments for involving the public in research were offered and most participants highlighted the potential benefits of involving the public. However, feelings of apprehension expressed by some participants imply that a number of researchers may still be uncomfortable with involving the public, as it presents a different way of working. [ABSTRACT FROM AUTHOR]

Hepatitis C (HCV) infection in substance addicted patients is common and represents a therapeutically challenging co-morbidity. Alcohol and perhaps other substances of abuse directly influence the natural progression of HCV disease. Concurrent mental health illness, poor socioeconomic status, and unstructured life styles are often incompatible with safe and successful delivery of HCV treatment. These issues and their effect on treatment suitability and outcome are considered in this review. Funding for HCV-addiction research and strong political backing for interventions proven to benefit those struggling with addiction are paramount to increasing access to and uptake of HCV treatment. These interventions include substance cessation programs, safe injection settings to reduce HCV incidence and multidisciplinary teams to facilitate HCV treatment provision. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) and hepatitis B virus (HBV) co-infection may differentially influence HIV treatment duration and outcome. This was assessed at The Ottawa Hospital Immunodeficiency Clinic in first-time highly active antiretroviral therapy (HAART) recipients visited between January 2000 and December 2004. Of 968 patients, 526/700 (75%) HIV, 173/230 (75%) HIV-HCV and 30/38 (79%) HIV-HBV-infected patients initiated HAART. Co-infected patients stopped treatment sooner (HBV - 10 months, HCV - 9 months) than HIV mono-infected (17 months) (P<0.001). Injection drug history predicted shorter treatment duration (odds ratio [OR]1.59, P<0.001). Use of non-nucleoside-reverse-transcriptase-inhibitor-containing HAART (OR 0.76, P<0.01) and low-dose ritonavir (<400 mg twice daily)-based HAART (OR 0.83, P = 0.06) predicted longer treatment duration. HCV co-infection did not predict duration of therapy (OR 1.19, P=0.19) once controlled for by these three variables. Poor adherence was a major explanation for eventual treatment interruption in those with HIV-HCV (22% versus 5% in HIV alone; P<0.001) as was substance abuse (7% versus < 1% in HIV; P<0.001). Metabolic complications resulted in HAART interruption in HIV mono-infection (8%) but not with HBV or HCV co-infection (both <1%; P<0.001). Antiretroviral selection is critical to the longevity of initially prescribed regimens, irrespective of viral hepatitis co-infection. Attention to this and strategies targeting substance abuse and adherence in HIV-HCV are predicted to increase the duration of HAART. [ABSTRACT FROM AUTHOR]

BACKGROUND: Patients may find it difficult to distinguish between the symptoms of anxiety and those of asthma. Findings are equivocal on whether there is a specific link between anxiety and asthma. The aims of this study were to i) to identify the prevalence of anxiety, depression and panic fear in adults with asthma compared with that of the general population ii) to investigate whether there is a specific relationship between asthma and anxiety. METHODS: An epidemiological survey of 872 adults with a diagnosis of asthma identified from six General Practices in Sheffield, England. Community postal survey using self-completion questionnaire. RESULTS: The response rate was 59%. People with asthma had higher mean Hospital Anxiety and Depression Scale (HADS) anxiety scores than UK norms with a higher proportion above the clinical cut-off. Mean HADS depression scores were significantly higher than UK norms and norms for a general population sample of people registered with the same practice. These effects were age-related with the relationship between asthma and psychological distress most marked over the age of 45. The prevalence of asthma-specific panic fear was 15.7%. CONCLUSION: A significant minority of people have high levels of panic fear (as measured by the Asthma Symptom Checklist) associated with asthma. However, in adults with asthma there is also high prevalence of both generalised anxiety and depression (as measured by the HADS), suggesting that the link of anxiety to asthma may be part of a broader relationship between psychological distress and chronic disease rather than a specific one. [ABSTRACT FROM AUTHOR]

For an organization to prevent occupational stress problems, it is necessary to correctly diagnose the characteristics of the work and employment conditions that are perceived as risks by employees and to investigate the consequences of these risks. Clarke and Cooper propose a methodology to assess which organizational factors pose the highest levels of risk to the well-being of employees. A level of risk is calculated based on the exposure level of a hazard and on the level of negative consequences associated with this exposure. The methodology has proven to be useful to prioritize and target specific areas for interventions. The present study introduced significant developments to this methodology by incorporating a coping dimension into the formula in order to better reflect the theoretical stress model. Tested on a sample of employees from a hospital centre (N = 1229), the introduction of coping strategies in the computation of risk level increases the strength of the relationship between risk exposure and outcomes, illustrating that the improved formula constitutes a more precise method to assess risk. [ABSTRACT FROM AUTHOR]

Objectives Despite the benefits of HAART, initiation of antiretroviral therapy in HIV-HCV co-infected patients is often delayed as a consequence of patient and physician concern pertaining to liver toxicity. It is unclear whether this is justified. Methods We retrospectively evaluated treatment duration and outcome in 186 patients initiating a first HAART regimen. Results Despite frequent HIV RNA suppression and CD4 T-cell increase following initiation of HAART, the median duration of therapy was only 8 months. Therapy was discontinued primarily for gastrointestinal intolerance (26%), poor adherence (19%), neurocognitive side effects (13%), and substance abuse (6%). Regimes were changed to reduce pill burden and/or frequency of dosing as well (11%). Only six (4%) subjects interrupted therapy as a result of clinically apparent liver toxicity. None were on low dose ritonavir-containing therapy. In those subjects remaining on HAART for at least 12 months, the median ALT level increased marginally from a baseline of 44 IU/mL to 56 IU/mL. The median AST was 44 IU/mL at baseline and at month 12. Conclusions These results support our contention that regimen potency, durability, and extrahepatic side effect profile should remain the paramount considerations related to the selection of HAART regimen in HIV-HCV co-infection. [ABSTRACT FROM AUTHOR]

The aim of this paper is to investigate the impact of 'negative behaviours' and 'bullying' in the workplace on the health and well-being of employees, to what extent the effects remain beyond the period of the experience as well as the extent to which they affect third-parties or witnesses. The paper also raises the question whether some behaviours associated with bullying may be more damaging than others. Potential sex differences and differences between occupational contexts are considered. To achieve these aims, a national cross-sectional study (N=5,388) was carried out. In absolute terms those who labelled their experience as bullying had substantially worse health than those who were not bullied. However, counter to what was expected, stronger associations were found between negative behaviour and adverse health effects than for self-reported (self-labelled) bullying and health. Previous targets as well as witnesses also reported worse health than those who were neither bullied nor had witnessed bullying. The findings also imply that some negative behaviours were more difficult to deal with than others. In all cases differences between the sexes and between occupational contexts emerged. [ABSTRACT FROM AUTHOR]

Much of the research on the work-strain relationship utilizes models which are narrowly focused on only a few job characteristics. These models are often global in their approach, failing to account for specific situations. Addressing these two issues, the present study investigated the influence of seven job characteristics; namely work control and six sources of work pressure, across a range of occupations, on mental and physical ill-health. Pooled within-group correlations were performed on data from 7099 employees from 13 occupations to clarify which of the seven job characteristics were significantly associated with both mental and physical ill-health. Results indicated all seven variables were significantly important. Mean score and correlational analyses for each occupation revealed many differences between the groups, with some job characteristics significantly associated with mental and physical ill-health In one occupation but not in another. It was concluded that to understand fully the work-strain relationship, research should incorporate a greater range of variables which are specific to a particular workplace. Using more job-specific models, encompassing a range of identified job and organizational stressors would also be more effective, practically, for inter\'entions in the workplace to improve worker health and well-being. [ABSTRACT FROM AUTHOR]

The present study was based on an integrative work stress model proposed by Cooper and his associates (Cooper et al., 1988), which focused on stress perception and outcomes, as well as potential moderating variables such as personality and coping efforts. Specifically, this article examines occupational stress in clinical nurses who worked in various hospitals in southern Taiwan. When compared with Chinese industrial white and blue-collar workers, nurses experienced higher work stress, more physical and mental ill-health, lower job satisfaction, and also made more efforts to cope with work stress. There were also some interesting differences in types of stressors experienced by nurses and industrial workers. [ABSTRACT FROM AUTHOR]