ObjectivesDesigning studies with an internal pilot phase may optimise the use of pilot work to inform more efficient randomised controlled trials (RCTs). Careful selection of preagreed decision or ‘progression’ criteria at the juncture between the internal pilot and main trial phases provides a valuable opportunity to evaluate the likely success of the main trial and optimise its design or, if necessary, to make the decision not to proceed with the main trial. Guidance on the appropriate selection and application of progression criteria is, however, lacking. This paper outlines the key issues to consider in the optimal development and review of operational progression criteria for RCTs with an internal pilot phase.DesignA structured literature review and exploration of stakeholders' opinions at a Medical Research Council (MRC) Hubs for Trials Methodology Research workshop. Key stakeholders included triallists, methodologists, statisticians and funders.ResultsThere is considerable variation in the use of progression criteria for RCTs with an internal pilot phase, although 3 common issues predominate: trial recruitment, protocol adherence and outcome data. Detailed and systematic reporting around the decision-making process for stopping, amending or proceeding to a main trial is uncommon, which may hamper understanding in the research community about the appropriate and optimal use of RCTs with an internal pilot phase. 10 top tips for the development, use and reporting of progression criteria for internal pilot studies are presented.ConclusionsSystematic and transparent reporting of the design, results and evaluation of internal pilot trials in the literature should be encouraged in order to facilitate understanding in the research community and to inform future trials.

SummaryBackgroundSelf-harm in adolescents is common and repetition occurs in a high proportion of these cases. Scarce evidence exists for effectiveness of interventions to reduce self-harm.MethodsThis pragmatic, multicentre, randomised, controlled trial of family therapy versus treatment as usual was done at 40 UK Child and Adolescent Mental Health Services (CAMHS) centres. We recruited young people aged 11–17 years who had self-harmed at least twice and presented to CAMHS after self-harm. Participants were randomly assigned (1:1) to receive manualised family therapy delivered by trained and supervised family therapists or treatment as usual by local CAMHS. Participants and therapists were aware of treatment allocation; researchers were masked. The primary outcome was hospital attendance for repetition of self-harm in the 18 months after group assignment. Primary and safety analyses were done in the intention-to-treat population. The trial is registered at the ISRCTN registry, number ISRCTN59793150.FindingsBetween Nov 23, 2009, and Dec 31, 2013, 3554 young people were screened and 832 eligible young people consented to participation and were randomly assigned to receive family therapy (n=415) or treatment as usual (n=417). Primary outcome data were available for 795 (96%) participants. Numbers of hospital attendances for repeat self-harm events were not significantly different between the groups (118 [28%] in the family therapy group vs 103 [25%] in the treatment as usual group; hazard ratio 1·14 [95% CI 0·87–1·49] p=0·33). Similar numbers of adverse events occurred in both groups (787 in the family therapy group vs 847 in the treatment as usual group).InterpretationFor adolescents referred to CAMHS after self-harm, having self-harmed at least once before, our family therapy intervention conferred no benefits over treatment as usual in reducing subsequent hospital attendance for self-harm. Clinicians are therefore still unable to recommend a clear, evidence-based intervention to reduce repeated self-harm in adolescents.FundingNational Institute for Health Research Health Technology Assessment programme.

BackgroundPatients with pressure ulcers (PUs) report that pain is their most distressing symptom, but there are few PU pain prevalence studies. We sought to estimate the prevalence of unattributed pressure area related pain (UPAR pain) which was defined as pain, soreness or discomfort reported by patients, on an “at risk” or PU skin site, reported at a patient level.MethodsWe undertook pain prevalence surveys in 2 large UK teaching hospital NHS Trusts (6 hospitals) and a district general hospital NHS Trust (3 hospitals) during their routine annual PU prevalence audits. The hospitals provide secondary and tertiary care beds in acute and elective surgery, trauma and orthopaedics, burns, medicine, elderly medicine, oncology and rehabilitation. Anonymised individual patient data were recorded by the ward nurse and PU prevalence team. The analysis of this prevalence survey included data summaries; no inferential statistical testing was planned or undertaken. Percentages were calculated using the total number of patients from the relevant population as the denominator (i.e. including all patients with missing data for that variable).ResultsA total of 3,397 patients in 9 acute hospitals were included in routine PU prevalence audits and, of these, 2010 (59.2%) patients participated in the pain prevalence study. UPAR pain prevalence was 16.3% (327/2010). 1769 patients had no PUs and of these 223 patients reported UPAR pain, a prevalence of 12.6%. Of the 241 people with pressure ulcers, 104 patients reported pain, a UPAR pain prevalence of 43.2% (104/241).ConclusionOne in six people in acute hospitals experience UPAR pain on ‘at risk’ or PU skin sites; one in every 8 people without PUs and, more than 2 out of every five people with PUs. The results provide a clear indication that all patients should be asked if they have pain at pressure areas even when they do not have a PU.

Background: Pressure ulcers are costly to the healthcare provider and can have a major impact on patient's quality of life. One of the most distressing symptoms reported is pain. There is very little published data on the prevalence and details of pain experienced by patients with pressure ulcers, particularly in community populations. The study was conducted in two community NHS sites in the North of England. Methods: The aim was to estimate the prevalence of pressure area related pain within a community population. We also explored the type and severity of the pain and its association with pressure ulcer classification. A cross-sectional survey was performed of community nurses caseloads to identify adult patients with pressure ulcers and associated pain. Consenting patients then had a full pain assessment and verification of pressure ulcer grade.

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Background Providing cancer care and treatment for ageing populations with complicating comorbidities like dementia is a growing global challenge. This study aimed to examine the hospital-based cancer care and treatment challenges and support needs of people with dementia, and identify potential ways to address these. Methods A two-site ethnographic study in England involving semi-structured interviews, observations and accompanying conversations, and medical record review. Participants (N = 58) were people with dementia and comorbid cancer (n = 17), informal caregivers (n = 22) and hospital staff (n = 19). Ethnographically informed thematic analysis was conducted. Results There was an accumulated complexity of living with both illnesses simultaneously. People with dementia and families could feel confused and uninformed due to difficulties understanding, retaining and using cancer information, which impacted their informed treatment decision-making. Dementia increased the complexity and burden of travelling to and navigating unfamiliar hospital environments, frequent lengthy periods of waiting in hospital, and self-managing symptoms and side-effects at home. Oncology staff were often working without the full picture, due to variable documenting of dementia in medical records, dementia training was limited, and time and resource pressures impeded the highly individualised, flexible cancer care required by people with dementia. Supportive family carers were crucial in enabling people with dementia to access, navigate and undergo cancer treatment and care. Conclusions Dementia complicates cancer care in a range of ways accumulating across the cancer pathway. Our findings suggest there are several strategies and interventions, which we list here, with potential to improve cancer care and treatment for people with dementia and their families.

Adjuvant bisphosphonates improve disease outcomes in postmenopausal early breast cancer (EBC) but the long-term effects are poorly described. The AZURE trial (ISRCTN79831382) was designed to determine whether adjuvant zoledronic acid (ZOL) improves disease outcomes in EBC. Previous analyses showed no effect on overall outcomes but identified benefits in postmenopausal women. Here we present the long-term risks and benefits of adjuvant ZOL with 10-years follow-up.Patients and methods3360 patients with stage II/III breast cancer were included in an academic, international, phase III, randomized, open label trial. Patients were followed up on a regular schedule until 10 years. Patients were randomized on a 1:1 basis to standard adjuvant systemic therapy +/− intravenous ZOL 4 mg every 3–4 weeks x6, and then at reduced frequency to complete 5 years treatment. The primary outcome was disease free survival (DFS). Secondary outcomes included invasive DFS (IDFS), overall survival (OS), sites of recurrence, skeletal morbidity and treatment outcomes according to primary tumor amplification of the transcription factor, MAF. Pre-planned subgroup analyses focused on interactions between menopausal status and treatment effects.ResultsWith a median follow up of 117 months [IQR 70.4–120.4), DFS and IDFS were similar in both arms (HRDFS = 0.94, 95%CI = 0.84–1.06, p = 0.340; HRIDFS = 0.91, 95%CI = 0.82–1.02, p = 0.116). However, outcomes remain improved with ZOL in postmenopausal women (HRDFS = 0.82, 95%CI = 0.67–1.00; HRIDFS = 0.78, 95%CI = 0.64–0.94). In the 79% of tested women with a MAF FISH negative tumor, ZOL improved IDFS (HRIDFS = 0.75, 95%CI = 0.58–0.97) and OS HROS = 0.69, 95%CI = 0.50–0.94), irrespective of menopause. ZOL did not improve disease outcomes in MAF FISH + tumors. Bone metastases as a first DFS recurrence (BDFS) were reduced with ZOL (HRB-DFS = 0.76, 95%CI = 0.63–0.92, p = 0.005). ZOL reduced skeletal morbidity with fewer fractures and skeletal events after disease recurrence. 30 cases of osteonecrosis of the jaw in the ZOL arm (1.8%) have occurred.ConclusionsDisease benefits with adjuvant ZOL in postmenopausal early breast cancer persist at 10 years of follow-up. The biomarker MAF identified a patient subgroup that derived benefit from ZOL irrespective of menopausal status.

BackgroundThe Pressure UlceR Programme Of reSEarch (PURPOSE) consisted of two themes. Theme 1 focused on improving our understanding of individuals’ and organisational risk factors and on improving the quality of risk assessments (work packages 1–3) and theme 2 focused on developing patient-reported outcome measures (work packages 4 and 5).MethodsThe programme comprised 21 individual pieces of work. Pain: (1) multicentre pain prevalence study in acute hospitals, (2) multicentre pain prevalence study in community localities incorporating (3) a comparison of case-finding methods, and (4) multicentre, prospective cohort study. Severe pressure ulcers: (5) retrospective case study, (6) patient involvement workshop with the Pressure Ulcer Research Service User Network for the UK (PURSUN UK) and (7) development of root cause analysis methodology. Risk assessment: (8) systematic review, (9) consensus study, (10) conceptual framework development and theoretical causal pathway, (11) design and pretesting of draft Risk Assessment Framework and (12) field test to assess reliability, validity, data completeness and clinical usability. Quality of life: (13) conceptual framework development (systematic review, patient interviews), (14 and 15) provisional instrument development, with items generated from patient interviews [from (1) above] two systematic reviews and experts, (16) pretesting of the provisional Pressure Ulcer Quality of Life (PU-QOL) instrument using mixed methods, (17) field test 1 including (18) optimal mode of administration substudy and item reduction with testing of scale formation, acceptability, scaling assumptions, reliability and validity, and (19) field test 2 – final psychometric evaluation to test scale targeting, item response categories, item fit, response bias, acceptability, scaling assumptions, reliability and validity. Cost–utility: (20) time trade-off task valuations of health states derived from selected PU-QOL items, and (21) validation of the items selected and psychometric properties of the new Pressure Ulcer Quality of Life Utility Index (PUQOL-UI).Key findingsPain: prevalence studies – hospital and community patients experience both pressure area-related and pressure ulcer pain; pain cohort study – indicates that pain is independently predictive of category 2 (and above) pressure ulcer development. Severe pressure ulcers: these were more likely to develop in contexts in which clinicians failed to listen to patients/carers or recognise/respond to high risk or the presence of an existing pressure ulcer and services were not effectively co-ordinated; service users found the interactive workshop format valuable; including novel components (interviews with patients and carers) in root cause analysis improves the quality of the insights captured. Risk assessment: we developed a Pressure Ulcer Risk Assessment Framework, the PURPOSE-T, incorporating the Minimum Data Set, a screening stage, a full assessment stage, use of colour to support decision-making, and decision pathways that make a clear distinction between patients with an existing pressure ulcer(s) (or scarring from previous ulcers) who require secondary prevention and treatment and those at risk who require primary prevention (http://medhealth.leeds.ac.uk/accesspurposet). Quality of life: the final PU-QOL instrument consists of 10 scales to measure pain, exudate, odour, sleep, vitality, mobility/movement, daily activities, emotional well-being, self-consciousness and appearance, and participation (http://medhealth.leeds.ac.uk/puqol-ques). Cost–utility: seven items were selected from the PU-QOL instrument for inclusion in the PUQOL-UI (http://medhealth.leeds.ac.uk/puqol-ui); secondary study analysis indicated that item selection for the PUQOL-UI was appropriate and that the index was acceptable to patients and had adequate levels of validity.ConclusionsThe PURPOSE programme has provided important insights for pressure ulcer prevention and treatment and involvement of service users in research and development, with implications for patient and public involvement, clinical practice, quality/safety/health service management and research including replication of the pain risk factor study, work exploring ‘best practice’ settings, the impact of including skin status as an indicator for escalation of preventative interventions, further psychometric evaluation of PU-QOL and PUQOL-UI the measurement of ‘disease attribution.’FundingThe National Institute for Health Research Programme Grants for Applied Research programme.