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Objective To develop and evaluate a questionnaire to assess the burden of vulval intraepithelial neoplasia ( VIN) in women. Design A questionnaire development study. Setting Vulval Disorders Clinic serving a regional population. Sample Fifty-eight women with a histological diagnosis of VIN registered with the Vulval Disorders Clinic. Methods A 37-item questionnaire was developed through a comprehensive literature review, consultation with specialist clinicians and pretesting to assess the burden experienced by women. The questionnaire was assessed for validity and reliability against existing questionnaires used in related disease areas. Main outcome measures Spearman correlations were calculated between items in the VIN questionnaire with the scores of the Dermatology Life Quality Index ( DLQI), Hospital Anxiety and Depression Scale ( HADS), Sabbatsberg Sexual Self-Rating Scale ( SSRS) and the Process Outcome Specific Measure ( POSM) to assess the new questionnaire's validity. Internal consistency was measured using Cronbach's alpha. Test-retest reliability was calculated using quadratic weighted kappa. Results The VIN questionnaire had a high degree of internal consistency (Cronbach's alpha, 0.89). Test-retest reliability was assessed, with most questions showing a quadratic weighted kappa value of 0.5 or above. Most questions showed a stronger correlation with the corrected total VIN score than with HADS anxiety and depression subscales and the SSRS, indicating discriminant validity. Most questions correlated significantly with the DLQI and POSM scores, indicating convergent validity. Conclusions Initial assessment of the VIN questionnaire demonstrated that it is a valid and reliable measure of the burden of disease for women. The questionnaire could be used to compare new and existing treatments for VIN or to assess or monitor the impact of care. [ABSTRACT FROM AUTHOR]

Background: Quality maternity care is known to improve a range of maternal and neonatal outcomes. The Lancet Series on Midwifery's Quality Maternal and Newborn Care (QMNC) Framework is a high-level synthesis of the global evidence on quality maternity care. Initial qualitative work demonstrated the Framework's adaptability in evaluating service user and provider perceptions of the quality of maternity care. However, evaluating services at scale requires a survey instrument. This paper reports the validation of the QMNC Framework index (QMNCFi), a five-part survey for the evaluation of maternity care across diverse settings., Methods: International online English language survey of women who had given birth in the previous year in Australia, Ghana, India and the United Kingdom (UK). It was distributed through service user networks (UK and Australia) and at postnatal clinics (Ghana and India). All forms were completed online. Test-retest was conducted to assess reliability., Results: Five hundred and forty mothers completed the survey (Australia 136; Ghana 131; India 153; UK 120). Construct validity: Cronbach's α in 12 of the survey's 13 sections ranged from 0.795 to 0.986; for the remaining section the alpha was 0.594. Reliability: 55 participants completed the QMNCFi a second time. Intraclass correlation coefficient results ranged from 0.657 to 0.939 across the 13 sections. Field researchers in Ghana and India reported that the survey was easily understood and completed., Conclusion: This survey has shown that, across diverse contexts, the QMNCFi is a valid, reliable, and comprehensive tool for measuring service user perceptions of the quality of care over time., (© 2024 The Author(s). Birth published by Wiley Periodicals LLC.)

Background: Hispanics in Lebanon and Reading, Pennsylvania, experience high levels of socioeconomic and health disparities in risk factors for chronic disease. In 2018, our community-academic coalition "Better Together" received a Racial and Ethnic Approaches to Community Health (REACH) award to improve healthy lifestyles. This report describes our work-in-progress and lessons learned to date from our REACH-supported initiatives in Lebanon and Reading., Methods: For the past 4 years, our coalition has leveraged strong community collaborations to implement and evaluate culturally-tailored practice- and evidence-based activities aimed at increasing physical activity, healthy nutrition, and community-clinical linkages. This community case report summarizes the context where our overall program was implemented, including the priority population, target geographical area, socioeconomic and health disparities data, community-academic coalition, conceptual model, and details the progress of the Better Together initiative in the two communities impacted., Results: To improve physical activity, we are: (1) creating new and enhancing existing trails connecting everyday destinations through city redesigning and master planning, (2) promoting outdoor physical activity, (3) increasing awareness of community resources for chronic disease prevention, and (4) supporting access to bikes for youth and families. To improve nutrition, we are: (1) expanding access to locally-grown fresh fruit and vegetables in community and clinical settings, through the Farmers Market Nutrition Program to beneficiaries of the Women, Infants, and Children (WIC) program and the Veggie Rx to patients who are at risk for or have diabetes, and (2) providing bilingual breastfeeding education. To enhance community-clinical linkages, we are training bilingual community health workers to connect at-risk individuals with diabetes prevention programs., Conclusions: Intervening in areas facing high chronic disease health disparities leads us to develop a community-collaborative blueprint that can be replicated across Hispanic communities in Pennsylvania and the United States., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Calo, Aumiller, Murray, Crawford, Bermudez, Weaver, Henao, Gray, DeLoatch, Rivera-Collazo, Gomez and Kraschnewski.)

Background: There is evidence that a woman who receives continuous labour support from a chosen companion can have shorter labour duration, is more likely to give birth without medical interventions, and report a satisfying childbirth experience. These outcomes result from the beneficial effects of emotional and practical support from the woman's chosen companion, and care provided by health providers. When a woman's chosen companion is her male partner, in addition to the above benefits, his presence can promote his bonding with the baby, and shared parenthood. However, there may be healthcare system barriers, including organisational, management and individual (staff) factors, that inhibit or restrict women's choice of companion. There are currently no suitable survey tools that can be used to assess the system level factors affecting the implementation of male partners' attendance at childbirth in low- and middle- income countries (LMICs)., Methods: We designed two questionnaires to help to address that gap: the Male Partners' Attendance at Childbirth-Questionnaire for Heads of Maternity Units (MPAC-QHMUs); and the Male Partners' Attendance at Childbirth-Questionnaire for Maternity Staff (MPAC-QMS). We carried out an extensive review to generate initial items of the two questionnaires. We assessed the content and face validity of the two questionnaires in a three-round modified Delphi study., Results: The Male Partners' Attendance at Childbirth-Questionnaire for Heads of Maternity Units (MPAC-QHMUs) focused on organisational and management factors. The Male Partners' Attendance at Childbirth-Questionnaire of Maternity Staff (MPAC-QMS) focused on individual staff factors. The final MPAC-QHMUs and MPAC-QMS included items which garnered over 80% content relevance according to the experts' rating. After all three consensus rounds of the Delphi study, 43 items were retained for the MPAC-QHMUs and 61 items were retained for the MPAC-QMS., Conclusions: The MPAC-QHMUs and the MPAC-QMS may help understanding of barriers affecting male partners' attendance at childbirth in LMICs in order to devise implementation strategies to enable wider availability and to maximize women's choices during labour and childbirth. The MPAC-QHMUs and the MPAC-QMS as newly-developed questionnaires require further validation of their acceptability and feasibility in different cultural contexts, and languages., (© 2023. The Author(s).)

Objective: To understand the process of formulating, implementing and enacting national recommendations into practice, by exploring the interactions between government policymakers and national and local organisations supporting and delivering policy implementation within a Child and Adolescent Mental Health Service (CAMHS) context in Scotland., Methods: Data collection involved 16 semi-structured individual and four focus group interviews with a purposeful sample of policymakers, national health and social care stakeholders and local outpatient and inpatient CAMHS teams representing three NHS health boards in Scotland., Results: Study participants highlighted the challenges of navigating through evolving and often conflicting policy agendas, seen to not acknowledging the current evidence base or experiential learning from services and prior evaluations. Accounts of transformation fatigue often emerged from increased expectations for staff to adopt new approaches to accommodate constantly changing recommendations. Participants also reported a lack of integration and implementation support from national health and social care organisations, leading to duplication of effort and gaps in provision or waste. Policy recommendations were perceived as sometimes vague, lacking clarity about how to deliver service transformation using a whole-system approach. The collective narratives reflected increased tension between the need for local autonomy to innovate and the limitations created vertically by the relative inflexibility of policy recommendations, and horizontally by the proliferation of national organisations delivering the same transformation aims using different approaches in a resource-constrained environment., Conclusion: The findings contribute to the wider literature by offering an exploration of importance of evaluation and evidence uptake in policy formulation; the roles and remits in supporting the implementation of policy recommendations; and how the dynamics of central control and local autonomy might impact on the local enactment of policy recommendations.

People who use drugs (PWUD) experience many social and health harms and are considered at greater risk of acquiring COVID-19. Little research has examined the impact of coronaviruses either on PWUD, or on services targeted to PWUD. We report the findings of a systematic review of empirical evidence from studies which have examined the impact of coronaviruses (Severe Acute Respiratory Syndrome (SARS-CoV-1) and Middle Eastern Respiratory Syndrome (MERS-CoV) and COVID-19) on PWUD or on service responses to them. Five databases were searched (MEDLINE, PsycINFO, CINAHL, ASSIA and EMBASE) as well as COVID-19 specific databases. Inclusion criteria were studies reporting any impact of SARS, MERS or COVID-19 or any service responses to those, published between January 2000 and October 2020. Weight of Evidence judgements and quality assessment were undertaken. In total, 27 primary studies were included and grouped by seven main themes: treatment/recovery services; emergency medical settings; low-threshold services; prison setting, PWUD/substance use disorder (SUD) diagnosis; people with SUD and HIV; 'Sexual minority' men. Overall, research in the area was scant, and of average/poor quality. More robust research is required to inform on-going and future responses to coronavirus epidemics for PWUD.

Increasing demand for outpatient appointments (OPA) is a global challenge for healthcare providers. Non-attendance rates are high, not least because of the challenges of attending hospital OPAs due to transport difficulties, cost, poor health, caring and work responsibilities. Digital solutions may help ameliorate these challenges. This project aimed to implement codesigned outpatient video consultations across National Health Service (NHS) Highland using system-wide quality improvement approaches to implementation, involving patients, carers, clinical and non-clinical staff, national and local strategic leads. System mapping; an intensive codesign process involving extensive stakeholder engagement and real-time testing; Plan, Do, Study, Act cycles; and collection of clinician and patient feedback were used to optimise the service. Standardised processes were developed and implemented, which made video consulting easy to use for patients, embedded video into routine health service systems for clinicians and non-clinical staff, and automated much of the administrative burden. All clinicians and staff are using the system and both groups identified benefits in terms of travel time and costs saved. Transferable lessons for other services are identified, providing a practical blueprint for others to adapt and use in their own contexts to help implement and sustain video consultation services now and in the future., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: This paper reports the results of the evaluation of the Scottish Quality and Safety Fellowship (SQSF)-a 10-month, lead-level international educational programme established in 2008 with the overarching aim of developing clinicians with advanced quality improvement knowledge, technical ability and essential leadership skills. The evaluation explores four levels of educational and practice outcomes associated with (1) the reaction of fellows to SQSF participation, (2) learning gained, (3) subsequent behaviour changes and (4) the overall impact on national and international level capability and capacity building., Methods: A theory-informed multi-method design was applied using (1) a search and review of the SQSF organisational database to tabulate personal, professional and demographic characteristics; (2) semi-structured telephone interviews with 16 participants using purposive and self-selected sampling; and (3) a cross-sectional online evaluation survey across all 10 cohorts involving 222 fellows RESULTS: SQSF was positively perceived as a high-quality learning experience containing a well-balanced mix of theory and practice, with a majority of respondents reporting career changing benefits. Most participants reported improved social, behavioural and emotional skills, knowledge and attitudes and, with sustained support of their host organisations, were able to apply and share learning in their workplace. The impact of the SQSF on a wider national and international level capability and capacity was both mediated and moderated by a wide range of interrelated contextual factors., Conclusions: This multi-method evaluation demonstrates that SQSF has achieved significant positive outcomes for the great majority of participants. Some tentative recommendations are provided with the aim of further enhancing fellowship content, delivery, transfer and future evaluations of wider impacts at regional, national and international health system levels., Competing Interests: Competing interests: MT, AB, NMG, DM and PB have no conflict of interest to declare. ST and LA are senior SQSF programme leaders and are responsible for its design and delivery., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Recognising the influence of context and the context-sensitive nature of quality improvement (QI) interventions is crucial to implementing effective improvements and successfully replicating them in new settings, yet context is still poorly understood. To address this challenge, it is necessary to capture generalisable knowledge, first to understand which aspects of context are most important to QI and why, and secondly, to explore how these factors can be managed to support healthcare improvement, in terms of implementing successful improvement initiatives, achieving sustainability and scaling interventions. The research question was how and why does context influence quality improvement initiatives in healthcare?, Methods: A realist review explored the contextual conditions that influence healthcare improvement. Realist methodology integrates theoretical understanding and stakeholder input with empirical research findings. The review aimed to identify and understand the role of context during the improvement cycle, i.e. planning, implementation, sustainability and transferability; and distil new knowledge to inform the design and development of context-sensitive QI initiatives. We developed a preliminary theory of the influence of context to arrive at a conceptual and theoretical framework., Results: Thirty-five studies were included in the review, demonstrating the interaction of key contextual factors across healthcare system levels during the improvement cycle. An evidence-based explanatory theoretical model is proposed to illustrate the interaction between contextual factors, system levels (macro, meso, micro) and the stages of the improvement journey. Findings indicate that the consideration of these contextual factors would enhance the design and delivery of improvement initiatives, across a range of improvement settings., Conclusions: This is the first realist review of context in QI and contributes to a deeper understanding of how context influences quality improvement initiatives. The distillation of key contextual factors offers the potential to inform the design and development of context-sensitive interventions to enhance improvement initiatives and address the challenge of spread and sustainability. Future research should explore the application of our conceptual model to enhance improvement-planning processes., Systematic Review Registration: PROSPERO CRD42017062135.

Objectives: The quality and safety of drug therapy in primary care are global concerns. The Pharmacist and Data-Driven Quality Improvement in Primary Care (P-DQIP) intervention aims to improve prescribing safety via an informatics tool, which facilitates proactive management of drug therapy risks (DTRs) by health-board employed pharmacists with established roles in general practices. Study objectives were (1) to identify and prioritise factors that could influence P-DQIP implementation from the perspective of practice pharmacists and (2) to identify potentially effective, acceptable and feasible strategies to support P-DQIP implementation., Design: Semistructured face-to-face interviews using a Theoretical Domains Framework informed topic guide. The framework method was used for data analysis. Identified implementation factors were prioritised for intervention based on research team consensus. Candidate intervention functions, behavioural change techniques (BCTs) and policies targeting these were identified from the behavioural change wheel. The final intervention content and modes of delivery were agreed with local senior pharmacists., Setting: General practices from three Health and Social Care Partnerships in National Health Service (NHS) Tayside., Participants: 14 NHS employed practice pharmacists., Results: Identified implementation factors were linked to thirteen theoretical domains (all except intentions) and six (skill, memory/attention/decision making, behavioural regulation, reinforcement, environmental context/resources, social influences) were prioritised. Three intervention functions (training, enablement and environmental restructuring) were relevant and were served by two policy categories (guidelines, communication/marketing) and eight BCTs (instructions on how to perform a behaviour, problem solving, action planning, prompt/cues, goal setting, self-monitoring, feedback and restructuring the social environment). Intervention components encompass an informatics tool, written educational material, a workshop for pharmacists, promotional activities and small financial incentives., Conclusions: This study explored pharmacists' perceptions of implementation factors which could influence management of DTRs in general practices to inform implementation of P-DQIP, which will initially be implemented in one Scottish health board with parallel evaluation of effectiveness and implementation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Healthcare is a complex system, so quality improvement will commonly lead to unintended consequences which are rarely evaluated. In previous qualitative work, we proposed a framework for considering the range of these potential consequences, in terms of their desirability and the extent to which they were predictable or expected during planning. This paper elaborates on the previous findings, using consensus methods to examine what consequences should be identified, why and how to prioritise, evaluate and interpret all identified consequences, and what stakeholders should be involved throughout this process., Design: Two-round modified Delphi consensus study., Setting and Participants: Both rounds were completed by 60 panellists from an academic, clinical or management background and experience in designing, implementing or evaluating quality improvement programmes., Results: Panellists agreed that trade-offs (expected undesirable consequences) and unpleasant surprises (unexpected undesirable consequences) should be actively considered. Measurement of harmful consequences for patients, and those with high workload or financial impact was prioritised, and their evaluation could also involve the use of qualitative methods. Clinical teams were agreed as important to involve at all stages, from identifying potential consequences, prioritising which of those to systematically evaluate, undertaking appropriate evaluation and interpreting the findings. Patients were necessary in identifying consequences, managers in identifying and prioritising, and improvement advisors in interpreting the data., Conclusion: There was consensus that a balanced approach to considering all the consequences of improvement can be achieved by carefully considering predictable trade-offs from the outset and deliberately pausing after implementation to identify any unexpected surprises and make an informed decision as to whether quantitative or qualitative evaluation is needed and feasible. Stakeholders' roles in in the process of identifying, prioritising, evaluating and interpreting potential consequences should be explicitly addressed within planning and revisited during and after implementation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: As quality improvement (QI) programmes have become progressively larger scale, the risks of implementation having unintended consequences are increasingly recognised. More routine use of balancing measures to monitor unintended consequences has been proposed to evaluate overall effectiveness, but in practice published improvement interventions hardly ever report identification or measurement of consequences other than intended goals of improvement., Methods: We conducted 15 semistructured interviews and two focus groups with 24 improvement experts to explore the current understanding of balancing measures in QI and inform a more balanced accounting of the overall impact of improvement interventions. Data were analysed iteratively using the framework approach., Results: Participants described the consequences of improvement in terms of desirability/undesirability and the extent to which they were expected/unexpected when planning improvement. Four types of consequences were defined: expected desirable consequences ( goals ); expected undesirable consequences ( trade-offs ); unexpected undesirable consequences ( unpleasant surprises ); and unexpected desirable consequences ( pleasant surprises ). Unexpected consequences were considered important but rarely measured in existing programmes, and an improvement pause to take stock after implementation would allow these to be more actively identified and managed. A balanced accounting of all consequences of improvement interventions can facilitate staff engagement and reduce resistance to change, but has to be offset against the cost of additional data collection., Conclusion: Improvement measurement is usually focused on measuring intended goals , with minimal use of balancing measures which when used, typically monitor trade-offs expected before implementation. This paper proposes that improvers and leaders should seek a balanced accounting of all consequences of improvement across the life of an improvement programme, including deliberately pausing after implementation to identify and quantitatively or qualitatively evaluate any pleasant or unpleasant surprises., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Context shapes the effectiveness of knowledge implementation and influences health improvement. Successful healthcare quality improvement (QI) initiatives frequently fail to transfer to different settings, with local contextual factors often cited as the cause. Understanding and overcoming contextual barriers is therefore crucial to implementing effective improvement; yet context is still poorly understood. There is a paucity of information on the mechanisms underlying how and why QI projects succeed or fail in given settings. A realist review of empirical studies of healthcare QI initiatives will be undertaken to examine the influence and impact of contextual factors on quality improvement in healthcare settings and explore whether QI initiatives can work in all contexts., Methods: The review will explore which contextual factors are important, and how, why, when and for whom they are important, within varied settings. The dynamic nature of context and change over time will be explored by examining which aspects of context impact at key points in the improvement trajectory. The review will also consider the influence of context on improvement outcomes (provider- and patient-level), spread and sustainability. The review process will follow five iterative steps: (1) clarify scope, (2) search for evidence, (3) appraise primary studies and extract data, (4) synthesise evidence and draw conclusions and (5) disseminate findings. The reviewers will consult with experts and stakeholders in the early stages to focus the review and develop a programme theory consisting of explanatory 'context-mechanism-outcome' configurations. Searches for primary evidence will be conducted iteratively. Data will be extracted and tested against the programme theory. A review advisory group will oversee the review process. Review findings will follow RAMESES guidelines and will be disseminated via a report, presentations and peer-reviewed publications., Discussion: The review will update and consolidate evidence on the contextual conditions for effective improvement and distil new knowledge to inform the design and development of context-sensitive QI initiatives. This review ties in with the study of improvement programmes as vehicles of change and the development of an evidence base around healthcare improvement by addressing whether QI initiatives can work in all contexts., Systematic Review Registration: PROSPERO CRD42017062135.

Objectives: While there is strong evidence that regular participation in physical activity (PA) brings numerous health benefits to older adults, and interventions to effectively promote PA are being developed and tested, the characteristics and components of the most effective interventions remain unclear. This systematically conducted review of systematic reviews evaluated the effects and characteristics of PA promotion interventions aimed at community dwelling people over 50 years old., Methods: Major databases were searched for reviews from January 1990 to May 2015. TIDieR guidelines aided data extraction and the ROBIS tool was used to assess the risk of bias. Primary outcomes were objective and self-reported levels of PA. Indicators of psychological wellbeing and participation rates were secondary outcomes., Results: Of 1284 records identified, 19 reviews met inclusion criteria and eight included meta-analyses. Interventions typically incorporated behaviour change techniques (BCTs) and were delivered as face-to-face, remote, group, individual or as combined interventions. Despite their heterogeneity, interventions often resulted in sustained improvements in PA over the study period, typically at 12 months, and led to improvements in general wellbeing. However, ways to ensure effective maintenance beyond one year are unclear. Certain intervention components were more clearly associated with positive effects (e.g. tailoring promotion strategy with combination of cognitive and behavioural elements, low to moderate intensity activity recommended). We found no evidence that certain other intervention characteristics were superior in achieving positive outcomes (e.g. mode of delivery, setting, professional background of the intervention provider, type of PA recommended)., Conclusion: The evidence suggests that interventions to promote PA among older adults are generally effective but there is uncertainty around the most beneficial intervention components. There are indications that purely cognitive strategies and BCTs might be less suitable for older adults than motivators more meaningful to them, including social and environmental support, and enjoyment coming from being physically active. A whole system-oriented approach is required that is tailored to meet the needs of older adults and aligned with social, individual and environmental factors.

Objective: To compare psychosocial outcomes (follow-up related worries and satisfaction with follow-up related information and support) over 30 months of two alternative management policies for women with low-grade abnormal cervical cytology., Methods: Women aged 20-59 years with low-grade cytological abnormalities detected in the National Health Service Cervical Screening Programme were randomised to cytological surveillance or initial colposcopy. A total of 3399 women who completed psychosocial questionnaires at recruitment were invited to complete questionnaires at 12, 18, 24 and 30 months. Linear mixed models were used to investigate differences between arms in the two psychosocial outcomes. Each outcome had a maximum score of 100, and higher scores represented higher psychosocial morbidity., Results: On average, over 30 months, women randomised to colposcopy scored 2.5 points (95%CI -3.6 to -1.3) lower for follow-up related worries than women randomised to cytological surveillance. Women in the colposcopy arm also scored significantly lower for follow-up related satisfaction with information and support (-2.4; -3.3 to -1.4) over 30 months. For both outcomes, the average difference between arms was greatest at 12th- and 18th-month time points. These differences remained when the analysis was stratified by post-school education., Conclusions: Women with low-grade cytology, irrespective of their management, have substantial initial psychosocial morbidity that reduces over time. Implementation of newer screening strategies, which include surveillance, such as primary HPV screening, need to consider the information and support provided to women. © 2016 The Authors. Psycho-Oncology published by John Wiley & Sons Ltd., (© 2016 The Authors. Psycho-Oncology published by John Wiley & Sons Ltd.)

Background: A colposcopy examination is the main management option for women with an abnormal cervical screening test result. Although some women experience adverse psychological effects after colposcopy, those at greatest risk are unknown. We investigated predictors of worries about cervical cancer, sex, future fertility and general health during 12 to 30 months after colposcopy., Methods: We invited 1,515 women, aged 20 to 59 years with low-grade cervical cytology who attended colposcopy to complete questionnaires at recruitment (∼8 weeks after cytology result) and after 12, 18, 24, and 30 months of follow up. Outcomes were worries about having cervical cancer, having sex, future fertility, and general health at any time during follow-up. Factors significantly associated with each outcome were identified using multiple logistic regression., Results: At one or more time points during follow-up, 40% of women reported worries about having cervical cancer, 26% about having sex, 24% about future fertility, and 60% about general health. For all outcomes except sex, worries reported at recruitment were associated with significantly increased risk of worries during follow-up. Significant anxiety at recruitment was associated with all worries during follow-up. Women diagnosed with CIN2+ had significantly higher risks of worries about cervical cancer and future fertility. Management received was associated significantly with worries about cervical cancer and having sex. Younger women significantly more often reported worries about future fertility, whereas women who had children had reduced risk of future fertility worries but increased risk of cervical cancer worries., Conclusion: Clinical, sociodemographic, lifestyle, and psychological factors predicted risk of reporting worries after colposcopy., (Copyright © 2015 Jacobs Institute of Women's Health. Published by Elsevier Inc. All rights reserved.)

Purpose: This study explored whether longer provider delays (between first presentation and treatment) were associated with later stage and poorer survival in women with symptomatic breast cancer., Methods: Data from 850 women with symptomatic breast cancer were linked with the Scottish Cancer Registry; Death Registry; and hospital discharge dataset. Logistic regression and Cox survival analyses with restricted cubic splines explored relationships between provider delays, stage and survival, with sequential adjustment for patient and tumour factors., Results: Although confidence intervals were wide in both adjusted analyses, those with the shortest provider delays had more advanced breast cancer at diagnosis. Beyond approximately 20 weeks, the trend suggests longer delays are associated with more advanced stage, but is not statistically significant. Those with symptomatic breast cancer and the shortest presentation to treatment time (within 4 weeks) had the poorest survival. Longer time to treatment was not significantly associated with worsening mortality., Conclusions: Poor prognosis patients with breast cancer are being triaged for rapid treatment with limited effect on outcome. Prolonged time to treatment does not appear to be strongly associated with poorer outcomes for patients with breast cancer, but the power of this study to assess the effect of very long delays (>25 weeks) was limited. Efforts to reduce waiting times are important from a quality of life perspective, but tumour biology may often be a more important determinant of stage at diagnosis and survival outcome., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: Worldwide, each year, large numbers of women are referred for colposcopy following low-grade abnormal cervical cytology. Many have no visible abnormality on examination. The risk of cervical intra-epithelial neoplasia grade 2/3 (CIN2/3) in these women is low. It is unknown whether, for women, a normal colposcopy resolves the anxiety which often follows the receipt of an abnormal cytology result. We investigated the prevalence of adverse psychological outcomes over 30 months following a normal colposcopy., Methods: This cohort study was nested within the UK TOMBOLA randomized controlled trial. Women aged 20-59 years, with recent low-grade cytology, who had a satisfactory colposcopy examination and normal transformation zone, completed the Hospital Anxiety and Depression Scale (HADS) and Process Outcome Specific Measure (POSM) at recruitment and during follow-up (12, 18, 24 and 30 months post-recruitment). Outcomes included percentages reporting significant anxiety (HADS anxiety subscale score ≥11), significant depression (HADS depression subscale score ≥8) or worries about the result of the next cytology test, cervical cancer, having sex, future fertility and general health at each time point (point prevalence) and during follow-up (cumulative prevalence)., Results: The study included 727 women. All psychological measures (except depression) had high prevalence at recruitment, falling substantially by 12 months. During follow-up, the cumulative prevalence of significant anxiety was 27% and significant depression was 21%. The most frequently reported worry was that the next cytology test would be abnormal (cumulative prevalence of 71%; point prevalence of ≥50% at 12 and 18 months). The cumulative prevalence values of worries about cervical cancer, having sex and future fertility were 33%, 20% and 16%, respectively., Conclusions: For some women who have low-grade cytology, a normal colposcopy does not appear to provide psychological reassurance., (© 2014 John Wiley & Sons Ltd.)

Objective: It is well known that receipt of an initial abnormal cervical cytology test can trigger considerable anxiety among women. Less is known about the impact of follow-up by repeat cytology tests. We quantified prevalence, and identified predictors, of distress after repeat cytologic testing in women with a single low-grade test., Methods: Within the framework of the TOMBOLA randomized controlled trial of alternative managements, 844 women aged 20 to 59 years with a single routine cytology test showing borderline nuclear abnormalities (BNA; broadly equivalent to atypical squamous cells of undetermined significance) were assigned to follow-up by repeat cytology in primary care (the first test was due 6 months after the initial BNA result). Women completed sociodemographic and psychosocial questionnaires at recruitment and the Impact of Event Scale (IES) 6 weeks after their first follow-up cytology test. Factors associated with significant psychologic distress (IES ≥ 9) were identified using logistic regression., Results: The response rate was 74% (n = 621/844). Of all the respondents, 39% scored in the range for significant distress. Distress varied by follow-up cytology result: negative, 36%; BNA or mild dyskaryosis, 42%; other (including high grade and inadequate), 55%. After adjusting for the cytology result, risk of distress was significantly raised in women who had significant anxiety at recruitment, reported experiencing pain after the follow-up cytology, had children, or were dissatisfied with support they had received after their initial BNA test., Conclusions: Substantial proportions of women experience surveillance-related psychologic distress after a follow-up cytology test, even when the result is negative. This is an important, albeit unintended, consequence of cervical screening. Strategies to alleviate this distress merit attention.

Background: People living with colorectal cancer are at risk of anxiety and depression. We investigated what factors were most highly associated with these., Methods: Four hundred and ninety-six people with colorectal cancer completed the Hospital Anxiety and Depression Scale (HADS). Data on functioning, symptoms, illness perceptions and social difficulties were collected by questionnaire. Case-note-identified disease, treatment and co-morbidity data were recorded. Multiple logistic regression identified factors independently predictive of anxiety and depression caseness., Results: Self-reported history of anxiety/depression predicted anxiety but not depression caseness. Depression caseness predicted anxiety caseness (p = 0.043), as did poorer self-reported cognitive functioning (p = 0.001), dyspnoea (p = 0.015) or diarrhoea (p = 0.021), reporting a high negative life and emotional impact (p < 0.001) and having difficulties with finance (p = 0.007). Having neo-adjuvant radiotherapy increased the odds of depression caseness (p = 0.007), as did poorer physical (p = 0.007), cognitive (p < 0.001) and social (p < 0.001) functioning, having constipation (p = 0.011), reporting a high negative life and emotional impact (p < 0.001), having difficulties with personal care (p = 0.022) and communicating with others (p = 0.014)., Conclusion: Levels of anxiety caseness were similar to those of non-clinical samples, but depression caseness was higher, particularly in those who had received neo-adjuvant radiotherapy. Most factors associated with possible or probable depression may be modified with appropriate intervention.

Background: There is a need for an instrument to measure the psychosocial burden of receiving an abnormal cervical cytology result which can be used regardless of the clinical management women receive.Methods: 3331 women completed the POSM as part of baseline psychosocial assessment in a trial of management of low grade cervical cytological abnormalities. Factor analysis and reliability assessment of the POSM were conducted.Results: Two factors were extracted from the POSM: Factor 1, containing items related to worry; and Factor 2 containing items relating to satisfaction with information and support received and change in the way women felt about themselves. Factor 1 had good reliability (Cronbach's alpha 0.769), however reliability of the Factor 2 was poorer(0.482). Data collected at four subsequent time points demonstrated that the factor structure was stable over time.Conclusion: This study demonstrates the presence and reliability of a scale measuring worries within the POSM. This analysis will inform its future use in this population and in other related contexts.

Background: Large numbers of women who participate in cervical screening require follow-up for minor cytological abnormalities. Little is known about the psychological consequences of alternative management policies for these women. We compared, over 30-months, psychosocial outcomes of two policies: cytological surveillance (repeat cervical cytology tests in primary care) and a hospital-based colposcopy examination., Methods: Women attending for a routine cytology test within the UK NHS Cervical Screening Programmes were eligible to participate. 3399 women, aged 20-59 years, with low-grade abnormal cytology, were randomised to cytological surveillance (six-monthly tests; n = 1703) or initial colposcopy with biopsies and/or subsequent treatment based on colposcopic and histological findings (n = 1696). At 12, 18, 24 and 30-months post-recruitment, women completed the Hospital Anxiety and Depression Scale (HADS). A subgroup (n = 2354) completed the Impact of Event Scale (IES) six weeks after the colposcopy episode or first surveillance cytology test. Primary outcomes were percentages over the entire follow-up period of significant depression (≥ 8) and significant anxiety (≥ 11; "30-month percentages"). Secondary outcomes were point prevalences of significant depression, significant anxiety and procedure-related distress (≥ 9). Outcomes were compared between arms by calculating fully-adjusted odds ratios (ORs) for initial colposcopy versus cytological surveillance., Results: There was no significant difference in 30-month percentages of significant depression (OR = 0.99, 95% CI 0.80-1.21) or anxiety (OR = 0.97, 95% CI 0.81-1.16) between arms. At the six-week assessment, anxiety and distress, but not depression, were significantly less common in the initial colposcopy arm (anxiety: 7.9% vs 13.4%; OR = 0.55, 95% CI 0.38-0.81; distress: 30.6% vs 39.3%, OR = 0.67 95% CI 0.54-0.84). Neither anxiety nor depression differed between arms at subsequent time-points., Conclusions: There was no difference in the longer-term psychosocial impact of management policies based on cytological surveillance or initial colposcopy. Policy-makers, clinicians, and women themselves can be reassured that neither management policy has a significantly greater psychosocial cost., Trial Registration: Controlled-Trials.com ISRCTN 34841617.

Objective: To assess the health-related quality of life (HRQoL) over 30 months among women who received colposcopy following low-grade abnormal cervical cytology., Design: 751 women with low-grade abnormal cytology were seen for colposcopy. Of these, 350 additionally underwent either immediate treatment by large loop excision of the transformation zone (LLETZ) or investigation by punch biopsy followed by treatment of high-grade cervical intraepithelial neoplasia if present. The HRQoL of the women was assessed on seven separate occasions over 30 months by means of the EQ-5D instrument. Outcomes for women receiving colposcopy only, colposcopy with biopsy and colposcopy with LLETZ were compared., Results: Women experienced modest short-term increases in HRQoL, statistically significant for the colposcopy only and biopsy groups but not for the LLETZ group. HRQoL in all three groups thereafter fell until 12 months following recruitment, significantly so for the LLETZ group. Changes in EQ-5D index score arose primarily from changes in severities in the "pain and discomfort" and "anxiety and depression" domains. Changes in the visual analogue scale (VAS) representations of quality of life corresponded closely to those of the index scores and most of the VAS scores themselves did not differ from VAS population norms. All inter-assessment changes in index scores were smaller than the minimum important difference for the instrument. Beyond 18 months from recruitment, HRQoL stabilised in all three groups., Conclusion: Women referred to colposcopy following a low-grade abnormal smear test result experienced a short-term improvement in their health-related quality of life, but the long-term effect was insubstantial. HRQoL over the post-recruitment follow-up period did not vary by intervention., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: There is a paucity of methodologically robust vocational rehabilitation (VR) intervention trials. This study assessed the feasibility and acceptability of a VR trial of women with breast cancer to inform the development of a larger interventional study., Methods: Women were recruited in Scotland and randomised to either a case management VR service or to usual care. Data were collected on eligibility, recruitment and attrition rates to assess trial feasibility, and interviews conducted to determine trial acceptability. Sick leave days (primary outcome) were self-reported via postal questionnaire every 4 weeks during the first 6 months post-surgery and at 12 months. Secondary outcome measures were change in employment pattern, quality of life and fatigue., Results: Of the 1,114 women assessed for eligibility, 163 (15%) were eligible. The main reason for ineligibility was age (>65 years, n = 637, 67%). Of those eligible, 111 (68%) received study information, of which 23 (21%) consented to participate in the study. Data for 18 (78%) women were analysed (intervention: n = 7; control: n = 11). Participants in the intervention group reported, on average, 53 fewer days of sick leave over the first 6 months post-surgery than those in the control group; however, this difference was not statistically significant (p = 0.122; 95% confidence interval -15.8, 122.0). No statistically significant differences were found for secondary outcomes. Interviews with trial participants indicated that trial procedures, including recruitment, randomisation and research instruments, were acceptable., Conclusions: Conducting a pragmatic trial of effectiveness of a VR intervention among cancer survivors is both feasible and acceptable, but more research about the exact components of a VR intervention and choice of outcomes to measure effectiveness is required. VR to assist breast cancer patients in the return to work process is an important component of cancer survivorship plans., Trial Registration: ISRCTN29666484.

Objectives: To develop and pilot a theory and evidence-based intervention to improve quality of life (QoL) in people with colorectal cancer., Design: A complex intervention development study., Setting: North East Scotland and Glasgow., Participants: Semistructured interviews with people with colorectal cancer (n=28), cancer specialists (n=16) and primary care health professionals (n=14) and pilot testing with patients (n=12)., Interventions: A single, 1 h nurse home visit 6-12 weeks after diagnosis, and telephone follow-up 1 week later (with a view to ongoing follow-up in future)., Primary and Secondary Outcome Measures: Qualitative assessment of intervention feasibility and acceptability., Results: Modifiable predictors of QoL identified previously were symptoms (fatigue, pain, diarrhoea, shortness of breath, insomnia, anorexia/cachexia, poor psychological well-being, sexual problems) and impaired activities. To modify these symptoms and activities, an intervention based on Control Theory was developed to help participants identify personally important symptoms and activities; set appropriate goals; use action planning to progress towards goals; self-monitor progress and identify (and tackle) barriers limiting progress. Interview responses were generally favourable and included recommendations about timing and style of delivery that were incorporated into the intervention. The pilot study demonstrated the feasibility of intervention delivery., Conclusions: Through multidisciplinary collaboration, a theory-based, acceptable and feasible intervention to improve QoL in colorectal cancer patients was developed, and can now be evaluated.

Background: People with colorectal cancer have impaired quality of life (QoL). We investigated what factors were most highly associated with it., Methods: Four hundred and ninety-six people with colorectal cancer completed questionnaires about QoL, functioning, symptoms, co-morbidity, cognitions and personal and social factors. Disease, treatment and co-morbidity data were abstracted from case notes. Multiple linear regression identified modifiable and unmodifiable factors independently predictive of global quality of life (EORTC-QLQ-C30)., Results: Of unmodifiable factors, female sex (P<0.001), more self-reported co-morbidities (P=0.006) and metastases at diagnosis (P=0.036) significantly predicted poorer QoL, but explained little of the variability in the model (R(2)=0.064). Adding modifiable factors, poorer role (P<0.001) and social functioning (P=0.003), fatigue (P=0.001), dyspnoea (P=0.001), anorexia (P<0.001), depression (P<0.001) and worse perceived consequences (P=0.013) improved the model fit considerably (R(2)=0.574). Omitting functioning subscales resulted in recent diagnosis (P=0.002), lower perceived personal control (P=0.020) and travel difficulties (P<0.001) becoming significant predictors., Conclusion: Most factors affecting QoL are modifiable, especially symptoms (fatigue, anorexia, dyspnoea) and depression. Beliefs about illness are also important. Unmodifiable factors, including metastatic (or unstaged) disease at diagnosis, have less impact. There appears to be potential for interventions to improve QoL in patients with colorectal cancer.

Background: Due to improvements in cancer survival the number of people of working age living with cancer across Europe is likely to increase. UK governments have made commitments to reduce the number of working days lost to ill-health and to improve access to vocational rehabilitation (VR) services. Return to work for people with cancer has been identified as a priority. However, there are few services to support people to remain in or return to work after cancer and no associated trials to assess their impact. A pilot randomised controlled trial among women with breast cancer has been designed to assess the feasibility of a larger definitive trial of VR services for people with cancer., Methods: Patients are being recruited from three clinical sites in two Scottish National Health Service (NHS) Boards for 6 months. Eligible patients are all women who are: (1) aged between 18 and 65 years; (2) in paid employment or self-employed; (3) living or working in Lothian or Tayside, Scotland, UK; (4) diagnosed with an invasive breast cancer tumour; (5) treated first with surgery. Patients are randomly allocated to receive referral to a VR service or usual care, which involves no formal employment support. The primary outcome measure is self-reported sickness absence in the first 6 months following surgery. Secondary outcome measures include changes in quality of life (FACT-B), fatigue (FACIT-Fatigue) and employment status between baseline and 6- and 12-months post-surgery. A post-trial evaluation will be conducted to assess the acceptability of the intervention among participants and the feasibility of a larger, more definitive, trial with patients with lung and prostate cancer., Discussion: To our knowledge this is the first study to determine the feasibility of a randomised controlled trial of the effectiveness of VR services to enable people with cancer to remain in or return to employment. The study will provide evidence to assess the relevance and feasibility of a larger future trial involving patients with breast, prostate or lung cancer and inform the development of appropriate VR services for people living with cancer.

Background: Women testing positive for human papillomavirus (HPV) infection experience increased levels of anxiety that have been attributed to fears of stigmatization and developing cervical cancer. The objective of this study was to investigate the association between HPV infection and anxiety in women who were unaware they had been tested specifically for HPV, to determine if any anxiety experienced by HPV-positive women could be due to causes other than learning of test results., Methods: This study was nested within a randomised controlled trial of management of women with abnormal cervical cytology conducted in the United Kingdom with recruitment between 1999 and 2002. At baseline, prior to having a sample taken for HPV testing, the results of which were not disclosed, women were assessed for anxiety using the Hospital Anxiety and Depression Scale and asked about fears of developing cervical cancer ("cancer worries"); this assessment was repeated at 12, 18, 24, and 30 months of follow-up. Logistic regression and generalized estimating equations were used for the cross-sectional (baseline) and longitudinal analyses, respectively., Results: Among the 2842 participants, there was no association between HPV status and anxiety among white women. Among non-white women, however, anxiety was less common among HPV-positive than HPV-negative women (adjusted odds ratio 0.41, 95% confidence interval 0.22 to 0.77). Among non-smokers, cancer worry was more common in HPV-positive than HPV-negative women; the opposite association was observed among ex-smokers., Conclusions: Associations between HPV status and anxiety may be explained by factors other than learning of test results and may vary by ethnicity and lifestyle factors.

Advances in scientific understanding of disease together with introduction of new high throughput technologies have led to increased demand for human tissue in research. In general, patients are willing to donate for research, particularly samples that are surplus to diagnostic or therapeutic requirements. New tissue-specific regulations in the UK are intended to facilitate the use of human tissue in research. Despite this positive environment there are challenges to researcher access. Coordinated, systematic collection and storage, via a biobank can provide easier access. However translating a vision for a biobank into reality whether in the public or private sector, has never been simple. But it can be done.

The psychologic and psychosexual sequelae of cervical screening and disease are well recognized but most research has focused on women with cervical intraepithelial neoplasia (CIN) or women with early (stage IB) to advanced cervical cancer. There has been little work looking at women with microinvasive cancer as a unique clinical identity. Many of these women have a similar diagnostic, treatment, and follow-up pathway to those with high-grade CIN. This could result in unrecognized and ongoing health concerns. We report on a questionnaire-based case-control study, comparing the concerns of women with microinvasive cervical cancer with those of women with high-grade CIN. Women with microinvasive cancer and controls with CIN2/3 diagnosed between 2000 and 2006, from a geographically defined population, were recruited and invited to complete a postal questionnaire consisting of the Hospital Anxiety and Depression Scale (HADS) and the Process Outcome Specific Measure (POSM). Twenty-eight women diagnosed with microinvasive cancer were identified and 18 participated (response rate 64%). Fifty-eight controls were matched by age and year of treatment with 26 responding (45%). About 18% of women with microinvasive cancer had a HADS depression score of 8 or more, compared to 12% of those with CIN (P = not significant). The HADS anxiety score of 8 or more occurred in 35% of each group. There were no significant differences in terms of POSM results for sexual activity, fertility, and developing cervical cancer in the future between cases and controls. We did not find a difference between women with a previous diagnosis of microinvasive cancer and those with high-grade CIN, in terms of ongoing concerns during their follow-up. We did not identify any additional concerns for women with microinvasive cancer in the care provided in the colposcopy service.

Previous analyses have shown that secondarily aquatic tetrapods, including whales, exhibit osteological adaptations to life in water as part of their complex buoyancy control systems. These structural specializations of bone span hyperostosis through osteoporosis. The past 15 years of paleontological effort has provided an unprecedented opportunity to examine the osteological transformation of whales as they make their transition to an obligate aquatic lifestyle over a 10-million-year period. It is hypothesized that whales manifest their osteological specialization in the same manner as extant semiaquatic and fully aquatic mammals. This study presents and analysis of the microstructural features of bone in early and late archaic cetaceans, and in a comparative sample of modern terrestrial, semiaquatic, and aquatic mammals. Bone histology was examined from the ribs of 10 fossilized individuals representing five early cetacean families, including Pakicetidae, Ambulocetidae, Protocetidae, Remintonocetidae, and Basilosauridae. Comparisons were then made with rib histology from nine genera of extant mammals including: Odocoileus (deer), Bos (cow), Equus (horse), Canis (dog), Lutra (river otter), Enhydra (sea otter), Choeropsis (pygmy hippo), Trichechus (sea cow), and Delphinus (dolphin). Results show that the transition from terrestrial, to semiaquatic, to obligate aquatic locomotion in archaeocetes involved a radical shift in bone function achieved by means of profound changes at the microstructural level. A surprising finding was that microstructural change predates gross anatomical shift in archaeocetes associated with swimming. Histological analysis shows that high bone density is an aquatic specialization that provides static buoyancy control (ballast) for animals living in shallow water, while low bone density is associated with dynamic buoyancy control for animals living in deep water. Thus, there was a shift from the typical terrestrial form, to osteopetrosis and pachyosteosclerosis, and then to osteoporosis in the first quarter of cetacean evolutionary history., (2007 Wiley-Liss, Inc.)

Objectives: The aim of this study was to estimate the time and travel costs generated by women when attending for Papanicolaou (Pap) smear tests or colposcopy appointments in the United Kingdom, both absolutely and relative to the health service cost of the national cervical cancer screening programs., Methods: Data were obtained from questionnaires completed by two samples of women participating in a three-center trial of management of low-grade abnormalities detected by screening (n = 1,106 for Pap smears and n = 1,203 for colposcopy appointments). Women were 20 to 59 years of age and resident in Grampian or Tayside, Scotland, or Nottingham, England. Questionnaire data were supplemented with sociodemographic information previously collected at the time of recruitment to the trial., Results: The mean total time and travel costs per attendance at a smear test and at a colposcopy appointment were estimated to be 9.2 pounds and 27.4 pounds, respectively, averaged across the three trial areas (valued at 2002 prices). Statistically significant intercenter disparities in time and travel costs were identified, particularly with respect to colposcopy appointments. For these, time and travel costs in Nottingham were substantially less than those in Grampian and Tayside (22.9 pounds, 30.2 pounds, and 32.1 pounds, respectively). Time and travel costs amount to 26 and 33 percent, approximately, over and above the direct health service costs of the English and Scottish screening programs, respectively., Conclusions: The time and travel costs associated with participation in the UK cervical cancer screening programs are substantial and are not spatially uniform across the country.

This article details the authors' experience establishing infrastructure for tissue collection, storage and distribution for biomedical research, firstly within a public healthcare service and latter in the pharmaceutical industry. Access to human tissue in the context of public-private collaboration in research and development is essential to the provision of high-quality medicines and healthcare and is now supported by a new legal framework in England and Wales. Through collaborations there are opportunities for mutual benefit for patients and professionals alike. Attention to the wishes of tissue donors through informed consent at the outset ensured confidence and continued activity when so-called 'organ retention scandals' emerged midway through this period. The overwhelming majority of potential donors support the use of their tissues in biomedical research irrespective of where the research is carried out., ((c) 2007 S. Karger AG, Basel.)

Cycloxygenase (COX) pathways have long been targeted for the treatment of inflammatory pain, initially through the use of NSAIDs. With the demonstration of two major COX isoforms, COX-1 and COX-2, involved in the production of prostanoids, but with different distribution and regulation, selective COX-2 inhibitors have been developed. This review covers factors influencing COX enzyme activity, the role of their products in the development and maintenance of pain and discusses recent safety concerns of COX-2 inhibitors.

Cervical screening reduces the risk of cervical cancer by detecting and treating cervical intraepithelial neoplasia (CIN). The management of women with low-grade cervical abnormalities is controversial. Two management policies exist: repeat smears in primary care and colposcopy examination. It is not clear which of these is the more effective and efficient. There is also uncertainty as to the most effective and efficient management of women at colposcopy when an area of abnormality is seen on the cervix - immediate treatment or biopsy and selective recall for treatment if the biopsy result suggests this is necessary. The result of a human papillomavirus (HPV) test might assist in deciding the appropriate management of women with low-grade abnormalities. TOMBOLA, a pragmatic randomised-controlled trial set within the cervical screening programmes in Scotland and England, addresses these three areas of uncertainty. Almost four and a half thousand women aged 20-59 with a low-grade cervical abnormality have been recruited and randomised to either repeat smears or colposcopy examination. Women in the colposcopy arm of the trial are further randomised to a policy of either immediate treatment or biopsy and selective recall for treatment if they have an abnormal transformation zone. Women are followed up to an exit examination at 3 years. HPV testing is undertaken at recruitment and at the exit examination. The primary endpoint is cumulative incidence of CIN2/3. A range of other clinical, psychosocial and economic outcomes is being considered. This paper describes the design of the trial, and discusses the rationale underlying aspects of the design and the challenges faced in designing and implementing the trial.

Background and Objectives: It is important to maximize response rates to postal questionnaires. We compared the impact of three low-cost interventions on response rates., Methods: A 2 x 2 x 2 factorial trial was conducted, nested within TOMBOLA (Trial Of Management of Borderline and Other Low-grade Abnormal smears). Three interventions were evaluated: (1) enclosing a TOMBOLA-branded pen with the questionnaire (as opposed to no pen); (2) sending the questionnaires by first class post (as opposed to second class); and (3) enclosing a preaddressed return envelope on which there was a second class postage stamp (rather than a freepost business-reply envelope). Nine hundred thirty women, aged 20-59 years, due to receive a TOMBOLA psychosocial questionnaire by post during June-August 2003 were randomized., Results: Enclosing a pen resulted in a statistically significant 7.0% increase in the cumulative proportion of questionnaires returned (from 61.5 to 68.5%; P = .002). The adjusted odds of response was significantly raised (odds ratio [OR] = 1.38, 95% confidence interval [CI] 1.04-1.82). Neither first class post nor providing a stamped envelope had a significant impact on response. There were no interactions between the interventions., Conclusions: Enclosing a pen with a questionnaire can significantly increase response. This low-cost strategy was effective against a background of "good practice" with regard to the administration of postal questionnaires.

Receipt of an abnormal cervical smear result often generates fear and confusion and can have a negative impact on a woman's well-being. Most previous studies have focussed on high-grade abnormal smears. This study describes the psychological and psychosocial effects, on women, of having received a low-grade abnormal smear result. Over 3500 women recruited to TOMBOLA (Trial Of Management of Borderline and Other Low-grade Abnormal smears) participated in this study. Anxiety was assessed using the Hospital Anxiety and Depression Scale (HADS) at recruitment. Socio-demographic and lifestyle factors, locus of control and factors associated with the psychosocial impact of the abnormal smear result were also assessed. Women reported anxiety levels consistent with those found in previous studies of women with high-grade smear results. Women at highest risk of anxiety were younger, had children, were current smokers, or had the highest levels of physical activity. Interventions that focus particularly on women's understanding of smear results and pre-cancer, and/or directly address their fears about cancer, treatment and fertility might provide the greatest opportunity to reduce the adverse psychosocial impact of receiving a low-grade abnormal cervical smear result.

Background: Better understanding of motivators for, and barriers to, participation in randomized controlled trials (RCTs) in different study populations and settings has the potential to improve participation of historically under-represented groups (eg, women) in future trials., Purpose: To investigate reasons why women agreed, or declined, to participate in a RCT., Methods: In two postal questionnaire-based studies, we investigated women's reasons for participation or non-participation in TOMBOLA, a RCT comparing management policies for low-grade cervical abnormalities. Four-hundred and ninety-two TOMBOLA participants (response rate 56%) completed questionnaires on reasons for participation. One-hundred and thiry-seven women (38%) who declined TOMBOLA participation completed questionnaires on reasons for this., Results: Eighty percent of women reported that one of their reasons for attending their TOMBOLA recruitment appointment was worries about their smear result. Ninety-four percent participated in the RCT because it was a worthwhile contribution to the cervical screening programme and other women; for 70% this was the most important reason. These proportions did not vary by socio-demographic factors. Thirty-two percent thought participation would result in better care. The most common reason for non-participation was preference for follow-up from the woman's GP. Logistical issues (eg, inconvenient appointments, travel time, arranging time off work or child-care) were commonly cited. Fourteen percent were too frightened to participate; this was unrelated to the grade of the recruitment smear., Limitations: Response rates were not high, but there was little evidence of response bias. Structured questionnaires were used., Conclusions: Future research should address how best to deliver information to ensure different social groups appreciate potential benefits of RCT participation and provide reassurance regarding fears about participation. Simple strategies (eg, appealing to the altruism of potential participants or offering flexible recruitment clinic locations and times) might enhance RCT recruitment rates. This in turn would ensure best use of research resources thus bringing the greatest benefits to participants and the population.

This paper describes the process of developing and testing a new questionnaire, Process Outcome Specific Measure (POSM), including an assessment of its content validity and reliability. The questionnaire was developed within the context of Trial Of Management of Borderline and Other Low-grade Abnormal smears (TOMBOLA) to assess the psychosocial impact of a low-grade abnormal cervical smear result and the subsequent management. A literature search, focus groups and thorough pre-testing involving experts and patients resulted in a short (15-item), easily completed and understood questionnaire. Questions address issues including cancer, health, fertility and sexual concerns. Repeatability was assessed in 110 TOMBOLA recruits using weighted k; all but one of the questions showed levels of reliability near to, or above, 0.5. Cronbach's standardised alpha was 0.73, indicating acceptable internal consistency. Each POSM item was correlated with the anxiety and depression sub-scales of the Hospital Anxiety Depression Scale (HADS). All except one of the questions correlated more highly with the total POSM score than with the HADS sub-scales thus indicating discriminant validity. The POSM will enable comparison of the alternative management policies for low-grade cervical smears in terms of the benefits (or otherwise) perceived by the women managed by these policies.

A recombinant vaccinia virus, expressing the NS3-to-NS5 region of the N clone of hepatitis C virus (HCV), was generated and utilized both in a gel-based assay and in an enzyme-linked immunosorbent assay (ELISA) to evaluate the pyrrolidine-5,5-trans-lactams, a series of inhibitors of the HCV NS3/4A protease. The absolute levels of processed, mature HCV nonstructural proteins in this system were found to decrease in the presence of the trans-lactams. Monitoring of this reduction enabled end points and 50% inhibitory concentrations to be calculated in order to rank the active compounds according to potency. These compounds had no effect on the transcription or translation of the NS3-5 polyprotein at concentrations shown to inhibit NS3/4A protease, and they were shown to be specific inhibitors of this protease. The ELISA, originally developed using the vaccinia virus expression system, was modified to utilize Huh-7 cells containing an HCV replicon. Results with this assay correlated well with those obtained with the recombinant vaccinia virus assays. These results demonstrate the utility of these assays for the characterization of NS3/4A protease inhibitors. In addition, inhibitors of other viral targets, such as polymerase and helicase, can be evaluated in the context of the replicon ELISA.

The term "promiscuous" inhibitors has been coined for compounds whose inhibition mechanism involves the interaction of aggregates of many compound molecules with the target protein, rather than the binding of individual molecules. This paper demonstrates that promiscuous inhibitors can be differentiated from classical 1:1 inhibitors by the judicious use of detergents, making it possible to configure assays that significantly reduce this undesirable mechanism of inhibition without compromising assay performance.

[reaction: see text] In this, the first of two letters, we outline the use of the pyrrolidine-5,5-trans-lactam template to design small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. The hitherto unreported reaction of the acyl iminium ion precursor 4 with dialkyl-substituted silyl ketene acetals (e.g., 8b) is described. Compound 12b, with a spirocyclobutyl P1 substituent and a cyclopropylacyl substituent on the lactam nitrogen, has a k(obs)/I of 400 M(-)(1) s(-)(1) and demonstrates activity in a replicon cell-based surrogate HCV assay.

The purpose of this case report is to illustrate the research potential of the tissue obtained from a single donor referred to the Peterborough Hospitals NHS Trust (PHNHST) Research Tissue Bank. Tissue retrieval was done 19 hours after death and 453 tissue units processed on site were despatched to 20 mainly commercial client research organisations.

The Peterborough Hospital Human Tissue Bank (PHHTB) and National Blood Service Tissue Services (London and South East Zone) (NBSTS) operate within the U.K. National Health Service (NHS) and have a system in place to retrieve cadaveric tissues for commercial sector research. The collaboration meets the aims of PHHTB and NBSTS and is legal, ethical and safe. This paper presents the results of the first 20 successful retrievals referred from NBSTS to PHHTB. Cadaveric retrieval of tissue for research extends the options for donors and their relatives. The research option is particularly welcomed in cases where clinical retrieval for tissue transplantation is contraindicated. We believe the system is applicable to other centres.

Background: An employer's 'duty of care' is enshrined in statute and common law. This responsibility extends to identifying areas of risk to employee's safety and emotional well being., Objective: To identify the views of NHS staff on their safety and exposure to assault and other forms of abuse., Design: A survey by questionnaire and semi-structured interview of the staff of an NHS Trust., Setting: A large Scottish NHS Trust., Subjects: All 5365 staff of the Trust., Results: Two thousand two hundred and ninety four (43%) employees contributed to this survey. With regard to exposure to hazardous substances and serious infection, most staff were satisfied with safety standards and guidelines. Over a 12 month period 23% of the workforce had been assaulted, mainly by patients and 63% had experienced verbal abuse, again, mainly from patients. There were differences among occupational groups but overall 16% had been bullied; 18% had suffered discrimination; 22% had experienced harassment, and 13% had been victimized. Only 42% of individuals reported their most distressing incidents; 56% of them regarded the outcome of their reports as satisfactory., Conclusions: Staff are generally satisfied with the steps taken to safeguard them against hazardous substances and serious infection. Assault by and abuse from patients is a considerable risk, especially for trained nurses. In terms of bullying, harassment, discrimination and victimization, the abuse of power by colleagues is also a distressing and under-reported phenomenon which needs to be addressed by regular audit and the creation of a climate in which employees feel secure enough to report such abuse and to have faith in the mechanisms set up to deal with such complaints.

Objective: To identify the effect of patients' suicide on consultant psychiatrists in Scotland., Design: Confidential coded postal questionnaire survey., Participants: Of 315 eligible consultant psychiatrists, 247 (78%) contributed., Setting: Scotland., Main Outcome Measures: Experience of patient suicide; the features and impact of "most distressing" suicide and what helped them to deal with it., Results: 167 (68%) consultants had had a patient commit suicide under their care. Fifty four (33%) reported being affected personally in terms of low mood, poor sleep, or irritability. Changes in professional practice were described by 69 (42%) of the psychiatrists-for example, a more structured approach to the management of patients at risk and increased use of mental health legislation. Twenty four (15%) doctors considered taking early retirement because of a patient's suicide. Colleagues and family or friends were the best sources of help, and team and critical incident reviews were also useful., Conclusions: Suicide by patients has a substantial emotional and professional effect on consultant psychiatrists. Support from colleagues is helpful, and professional reviews provide opportunities for learning and improved management of suicide and its aftermath.

National Health Service (NHS) histopathology laboratories are ideally placed to bank cadaveric and surplus surgical tissue to supply the needs of research organisations, whether in the NHS, universities or the commercial sector. This review outlines the constraints to setting up a human tissue bank in an NHS histopathology laboratory, identifies the controls required and answers the question: is it ethical and legal?