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Background Do not attempt cardiopulmonary resuscitation decisions have been widely criticised. The Recommended Summary Plan for Emergency Care and Treatment (ReSPECT) process was developed to facilitate shared decisions between patients and clinicians in relation to emergency treatments, including cardiopulmonary resuscitation. Objective To explore how, when and why ReSPECT plans are made and what effects the plans have on patient outcomes. Design A mixed-methods evaluation, comprising (1) a qualitative study of ReSPECT decision-making processes, (2) an interrupted time series examining process and survival outcomes following in-hospital cardiac arrest and (3) a retrospective observational study examining factors associated with ReSPECT recommendations and patient outcomes. Setting NHS acute hospitals and primary care and community services in England (2017–2020). Participants Hospital doctors, general practitioners, nurses, patients and families. Data sources The following sources were used: (1) observations of ReSPECT conversations at six hospitals and conversations with clinicians, patient, families and general practitioners, (2) survey and freedom of information data from hospitals participating in the National Cardiac Arrest Audit and (3) a review of inpatient medical records, ReSPECT forms and NHS Safety Thermometer data. Results By December 2019, the ReSPECT process was being used in 40 of 186 (22%) acute hospitals. In total, 792 of 3439 (23%) inpatients, usually those identified at risk of deterioration, had a ReSPECT form. Involvement of the patient and/or family was recorded on 513 of 706 (73%) ReSPECT forms reviewed. Clinicians said that lack of time prevented more conversations. Observed conversations focused on resuscitation, but also included other treatments and the patient’s values and preferences. Conversation types included open-ended conversations, with clinicians actively eliciting the patients’ wishes and preferences, a persuasive approach, swaying the conversation towards a decision aligned with medical opinion, and simply informing the patient/relative about a medical decision that had already been made. The frequency of harms reported on the NHS Safety Thermometer was similar among patients with or without a ReSPECT form. Hospital doctors and general practitioners gave different views on the purpose of the ReSPECT process and the type of recommendations they would record. Limitations The research was undertaken within the first 2 years following the implementation of ReSPECT. Local policies meant that doctors led these conversations. Most patients were seriously ill, which limited opportunities for interviews. Incomplete adoption of the ReSPECT process and problems associated with the NHS Safety Thermometer tool affected the evaluation on clinical outcomes. Conclusions Patients and families were involved in most ReSPECT conversations. Conversations focused on resuscitation, but also included other emergency treatments. Respect for patient autonomy and duty to protect from harm informed clinicians’ approach to varying degrees, depending on the clinical situation and their views of ReSPECT as a shared decision-making process. The complexity of these conversations and the clinical, emotional and organisational barriers observed suggest that a nuanced and multifaceted approach will be necessary to support good ReSPECT processes. Future work Further research is needed to understand the advantages and disadvantages to the adoption of a national emergency care and treatment plan system, the most effective national and local implementation approaches, and whether or not shared decision-making approaches in the context of emergency care and treatment plans could further enhance patient and family engagement. Study registration This study is registered as ISRCTN11112933. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme and will be published in full in Health and Social Care Delivery Research; Vol. 10, No. 40. See the NIHR Journals Library website for further project information.

Aims Observational studies indicate U-shaped associations of blood pressure (BP) and incident dementia in older age, but randomized controlled trials of BP-lowering treatment show mixed results on this outcome in hypertensive patients. A pooled individual participant data analysis of five seminal randomized double-blind placebo-controlled trials was undertaken to better define the effects of BP-lowering treatment for the prevention of dementia. Methods and results Multilevel logistic regression was used to evaluate the treatment effect on incident dementia. Effect modification was assessed for key population characteristics including age, baseline systolic BP, sex, and presence of prior stroke. Mediation analysis was used to quantify the contribution of trial medication and changes in systolic and diastolic BP on risk of dementia. The total sample included 28 008 individuals recruited from 20 countries. After a median follow-up of 4.3 years, there were 861 cases of incident dementia. Multilevel logistic regression reported an adjusted odds ratio 0.87 (95% confidence interval: 0.75, 0.99) in favour of antihypertensive treatment reducing risk of incident dementia with a mean BP lowering of 10/4 mmHg. Further multinomial regression taking account of death as a competing risk found similar results. There was no effect modification by age or sex. Mediation analysis confirmed the greater fall in BP in the actively treated group was associated with a greater reduction in dementia risk. Conclusion The first single-stage individual patient data meta-analysis from randomized double-blind placebo-controlled clinical trials provides evidence to support benefits of antihypertensive treatment in late-mid and later life to lower the risk of dementia. Questions remain as to the potential for additional BP lowering in those with already well-controlled hypertension and of antihypertensive treatment commenced earlier in the life-course to reduce the long-term risk of dementia. Classification of evidence Class I evidence in favour of antihypertensive treatment reducing risk of incident dementia compared with placebo.

Background Adolescent depression can place a young person at high risk of recurrence and a range of psychosocial and vocational impairments in adult life, highlighting the importance of early recognition and prevention. Parents/carers are well placed to notice changes in their child’s emotional wellbeing which may indicate risk, and there is increasing evidence that modifiable factors exist within the family system that may help reduce the risk of depression and anxiety in an adolescent. A randomised controlled trial (RCT) of the online personalised ‘Partners in Parenting’ programme developed in Australia, focused on improving parenting skills, knowledge and awareness, showed that it helped reduce depressive symptoms in adolescents who had elevated symptom levels at baseline. We have adapted this programme and will conduct an RCT in a UK setting. Methods In total, 433 family dyads (parents/carers and children aged 11–15) will be recruited through schools, social media and parenting/family groups in the UK. Following completion of screening measures of their adolescent’s depressive symptoms, parents/carers of those with elevated scores will be randomised to receive either the online personalised parenting programme or a series of online factsheets about adolescent development and wellbeing. The primary objective will be to test whether the personalised parenting intervention reduces depressive symptoms in adolescents deemed at high risk, using the parent-reported Short Mood & Feelings Questionnaire. Follow-up assessments will be undertaken at 6 and 15 months and a process evaluation will examine context, implementation and impact of the intervention. An economic evaluation will also be incorporated with cost-effectiveness of the parenting intervention expressed in terms of incremental cost per quality-adjusted life year gained. Discussion Half of mental health problems emerge before mid-adolescence and approximately three-quarters by mid-20s, highlighting the need for effective preventative strategies. However, few early interventions are family focused and delivered online. We aim to conduct a National Institute for Health and Care Research (NIHR) funded RCT of the online personalised ‘Partners in Parenting’ programme, proven effective in Australia, targeting adolescents at risk of depression to evaluate its effectiveness, cost-effectiveness and usability in a UK setting. Trial registration {2a} ISRCTN63358736. Registered 18 September 2019.

The literature on subjective memory concerns (SMC) as a predictor for future cognitive decline is varied. Furthermore, recent research has pointed to additional complexity arising from variability in the experience of SMC themselves (i.e. whether they are remitting or sustained over time). We investigated the associations between SMC and objectively measured cognition in an Australian population-based cohort. Four waves (4-year intervals between waves) of data from 1236 participants (aged 62.4 ± 1.5 years, 53% male) were used. We categorized participants as experiencing SMC, when they indicated that their memory problems might interfere with their day-to-day life and/or they had seen a doctor about their memory. SMC was categorized as "no" reported SMC, "remitting", "new-onset" or "sustained" SMC. Cognitive assessment of immediate and delayed recall, working memory, psychomotor speed, attention and processing speed were assessed using a neuropsychological battery. Eighteen percent of participants were characterised as having SMC: 6% (77) "remitting", 6% (77) "new-onset" and 6% (69) "sustained" SMC. There was no consistent evidence for an association between SMC and subsequent decline in cognition. However, SMC was associated with poorer performance on contemporaneous tasks of attention and processing speed compared to "no" SMC. Asking about SMC may indicate a current decline in cognitive function but, in this sample at least, did not indicate an increased risk of future decline.The online version contains supplementary material available at 10.1007/s10433-022-00694-2.

Purpose Young people transitioning from child to adult mental health services are frequently also known to social services, but the role of such services in this study and their interplay with mental healthcare system lacks evidence in the European panorama. This study aims to gather information on the characteristics and the involvement of social services supporting young people approaching transition. Design/methodology/approach A survey of 16 European Union countries was conducted. Country respondents, representing social services’ point of view, completed an ad hoc questionnaire. Information sought included details on social service availability and the characteristics of their interplay with mental health services. Findings Service availability ranges from a low of 3/100,000 social workers working with young people of transition age in Spain to a high 500/100,000 social workers in Poland, with heterogeneous involvement in youth health care. Community-based residential facilities and services for youth under custodial measures were the most commonly type of social service involved. In 80% of the surveyed countries, youth protection from abuse/neglect is overall regulated by national protocols or written agreements between mental health and social services, with the exception of Czech Republic and Greece, where poor or no protocols apply. Lack of connection between child and adult mental health services has been identified as the major obstacles to transition (93.8%), together with insufficient involvement of stakeholders throughout the process. Research limitations/implications Marked heterogeneity across countries may suggest weaknesses in youth mental health policy-making at the European level. Greater inclusion of relevant stakeholders is needed to inform the development and implementation of person-centered health-care models. Disconnection between child and adult mental health services is widely recognized in the social services arena as the major barrier faced by young service users in transition; this “outside” perspective provides further support for an urgent re-configuration of services and the need to address unaligned working practices and service cultures. Originality/value This is the first survey gathering information on social service provision at the time of mental health services transition at a European level; its findings may help to inform services to offer a better coordinated social health care for young people with mental health disorders.

Purpose Constipation can be a significant problem in critically unwell patients, associated with detrimental outcomes. Opioids are thought to contribute to the mechanism of bowel dysfunction. We tested if methylnaltrexone, a pure peripheral mu-opioid receptor antagonist, could reverse opioid-induced constipation. Methods The MOTION trial is a multi-centre, double blind, randomised placebo-controlled trial to investigate whether methylnaltrexone alleviates opioid-induced constipation (OIC) in critical care patients. Eligibility criteria included adult ICU patients who were mechanically ventilated, receiving opioids and were constipated (had not opened bowels for a minimum 48 h) despite prior administration of regular laxatives as per local bowel management protocol. The primary outcome was time to significant rescue-free laxation. Secondary outcomes included gastric residual volume, tolerance of enteral feeds, requirement for rescue laxatives, requirement for prokinetics, average number of bowel movements per day, escalation of opioid dose due to antagonism/reversal of analgesia, incidence of ventilator-associated pneumonia, incidence of diarrhoea and Clostridium difficile infection and finally 28 day, ICU and hospital mortality. Results A total of 84 patients were enrolled and randomized (41 to methylnaltrexone and 43 to placebo). The baseline demographic characteristics of the two groups were generally well balanced. There was no significant difference in time to rescue-free laxation between the groups (Hazard ratio 1.42, 95% CI 0.82–2.46, p = 0.22). There were no significant differences in the majority of secondary outcomes, particularly days 1–3. However, during days 4–28, there were fewer median number of bowel movements per day in the methylnaltrexone group, (p = 0.01) and a greater incidence of diarrhoea in the placebo group (p = 0.02). There was a marked difference in mortality between the groups, with ten deaths in the methylnaltrexone group and two in the placebo group during days 4–28 (p = 0.007). Conclusion We found no evidence to support the addition of methylnaltrexone to regular laxatives for the treatment of opioid-induced constipation in critically ill patients; however, the confidence interval was wide and a clinically important difference cannot be excluded. Electronic supplementary material The online version of this article (10.1007/s00134-019-05913-6) contains supplementary material, which is available to authorized users.

Importance Platelet-rich plasma injections are used as a treatment for chronic midportion Achilles tendinopathy, but evidence for this treatment is limited. Objective In adults with midportion Achilles tendinopathy, to assess the effects of a single platelet-rich plasma injection, compared with sham injection, on the outcome of the Victorian Institute of Sport Assessment-Achilles (VISA-A) score (a single composite measure of Achilles tendinopathy severity). Design, Setting, and Participants A participant-blinded, multicenter randomized clinical trial that included 240 people from 24 sites assigned to either a platelet-rich plasma injection or a sham injection between April 2016 and February 2020. Final follow-up was July 2020. Participants were older than 18 years with midportion Achilles tendon pain for more than 3 months as confirmed by ultrasound, magnetic resonance imaging, or both. Interventions A single intratendinous platelet-rich plasma injection (n = 121) or a single sham injection (insertion of a subcutaneous dry needle not entering the tendon) (n = 119). Main Outcomes and Measures The primary outcome was the VISA-A score, measured 6 months after treatment allocation. The VISA-A score contains 8 questions that cover 3 domains of pain, function, and activity, analyzed as a composite score (range, 0 [worst symptoms] to 100 [no symptoms]; minimal clinically important difference in score, 12 points). The primary analysis was adjusted for laterality, age, sex, and baseline VISA-A score. Results Among 240 patients assigned to a platelet-rich plasma or sham injection (mean age, 52 years; 138 [58%] women), 221 (92%) completed the trial. At 6-month follow-up, mean VISA-A score values in the plasma-rich plasma group vs the sham injection group were 54.4 vs 53.4 (adjusted mean difference, −2.7 [95% CI, −8.8 to 3.3]). The most common adverse events compared between patients in the platelet-rich plasma group vs the sham group were injection site discomfort (97 vs 73 patients), swelling (56 vs 52 patients) and bruising (48 vs 49 patients). Conclusions and Relevance Among patients with chronic midportion Achilles tendinopathy, treatment with a single injection of intratendinous platelet-rich plasma, compared with insertion of a subcutaneous dry needle, did not reduce Achilles tendon dysfunction at 6 months. These findings do not support the use of this treatment for chronic midportion Achilles tendinopathy. Trial Registration isrctn.org Identifier:ISRCTN13254422

Aims To explore General Practice teams cultural-competence, in particular, ethnicity, linguistic skillset and cultural awareness. The practice teams’ access to diabetes-training, and overall perception of cultural-competence were also assessed. Methods A cross-sectional single-city-survey with one in three people with diabetes from an ethnic minority group, using 35 semi-structured questions was completed. Self-reported data analysed using descriptive statistics, interpreted with reference to the Culturally-Competent-Assessment-Tool. Results Thirty-four (52%) of all 66 practices in Coventry responded between November 2011 and January 2012. Key findings: (1) One in five practice staff was from a minority group in contrast with one in ten of Coventry’s population, (2) 164 practice staff (32%) spoke a second language relevant to the practice's minority population, (3) 56% of practices were highly culturally-competent at providing diabetes services for minority populations, (4) 94% of practices reported the ethnicity of their populations, and (5) the most frequently stated barriers to culturally-competent service delivery were language and knowledge of nutritional habits. Conclusions Culturally-competent diabetes care is widespread across the city. Language barriers are being addressed, cultural knowledge of diabetes-related-nutrition requires further improvement. Further studies should investigate if structured cultural-competence training for diabetes service providers produces positive effects in diabetes-related outcome-measures in minority populations.

Aims Many surgeons choose to perform total knee arthroplasty (TKA) surgery with the aid of a tourniquet. A tourniquet is a device that fits around the leg and restricts blood flow to the limb. There is a need to understand whether tourniquets are safe, and if they benefit, or harm, patients. The aim of this study was to determine the benefits and harms of tourniquet use in TKA surgery. Methods We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled trials, and trial registries up to 26 March 2020. We included randomized controlled trials (RCTs), comparing TKA with a tourniquet versus without a tourniquet. Outcomes included: pain, function, serious adverse events (SAEs), blood loss, implant stability, duration of surgery, and length of hospital stay. Results We included 41 RCTs with 2,819 participants. SAEs were significantly more common in the tourniquet group (53/901 vs 26/898, tourniquet vs no tourniquet respectively) (risk ratio 1.73 (95% confidence interval (CI) 1.10 to 2.73). The mean pain score on the first postoperative day was 1.25 points higher (95% CI 0.32 to 2.19) in the tourniquet group. Overall blood loss did not differ between groups (mean difference 8.61 ml; 95% CI -83.76 to 100.97). The mean length of hospital stay was 0.34 days longer in the group that had surgery with a tourniquet (95% CI 0.03 to 0.64) and the mean duration of surgery was 3.7 minutes shorter (95% CI -5.53 to -1.87). Conclusion TKA with a tourniquet is associated with an increased risk of SAEs, pain, and a marginally longer hospital stay. The only finding in favour of tourniquet use was a shorter time in theatre. The results make it difficult to justify the routine use of a tourniquet in TKA surgery. Cite this article: Bone Joint J 2021;103-B(5):830–839.

International audience; Transition-related discontinuity of care is a major socioeconomic and societal challenge for the EU. The current service configuration, with distinct Child and Adolescent Mental Health (CAMHS) and Adult Mental Health Services (AMHS), is considered a weak link where the care pathway needs to be most robust. Our aim was to delineate transitional policies and care across Europe and to highlight current gaps in care provision at the service interface. An online mapping survey was conducted across all 28 European Countries using a bespoke instrument: The Standardized Assessment Tool for Mental Health Transition (SATMEHT). The survey was directed at expert(s) in each of the 28 EU countries. The response rate was 100%. Country experts commonly (12/28) reported that between 25 and 49% of CAMHS service users will need transitioning to AMHS. Estimates of the percentage of AMHS users aged under 30~years who had has previous contact with CAMHS were most commonly in the region 20-30% (33% on average).Written policies for managing the interface were available in only four countries and half (14/28) indicated that no transition support services were available. This is the first survey of CAMHS transitional policies and care carried out at a European level. Policymaking on transitional care clearly needs special attention and further elaboration. The Milestone Study on transition should provide much needed data on transition processes and outcomes that could form the basis for improving policy and practice in transitional care.

IntroductionTourniquets are routinely used during total knee replacement (TKR) surgery. They could increase the risk of thromboembolic events including cerebral emboli, cognitive decline, pain and other adverse events (AEs). A randomised controlled trial to assess whether tourniquet use might safely be avoided is therefore warranted but it is unclear whether such a trial would be feasible.MethodsIn a single-site feasibility study and pilot randomised controlled trial, adults having a TKR were randomised to surgery with an inflated tourniquet versus a non-inflated tourniquet. Participants underwent brain MRI preoperatively and within 2 days postoperatively. We assessed cognition using the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA) and Oxford Cognitive Screen (OCS) and thigh pain using a Visual Analogue Scale at baseline and days 1 and 2, and 1 week postsurgery. AEs related to surgery were recorded up to 12 months.ResultsWe randomised 53 participants (27 tourniquet inflated and 26 tourniquet not inflated). Fifty-one participants received care per-protocol (96%) and 48 (91%) were followed up at 12 months. One new ischaemic brain lesion was detected. Of the cognitive tests, MoCA was easy to summarise, sensitive to change with lower ceiling effects compared with OCS and MMSE. There was a trend towards more thigh pain (mean 49.6 SD 30.4 vs 36.2 SD 28 at day 1) and more AEs related to surgery (21 vs 9) in participants with an inflated tourniquet compared with those with a tourniquet not inflated.ConclusionA full trial is feasible, but using MRI as a primary outcome is unlikely to be appropriate or feasible. Suitable primary outcomes would be cognition measured using MoCA, pain and AEs, all of which warrant investigation in a large multicentre trial.Trial registration numberISRCTN20873088.

This randomized clinical trial uses data from the Early Venous Reflux Ablation trial to evaluate the long-term clinical and cost benefits of combined early endovenous ablation and compression compared with compression therapy alone and deferred ablation for treating superficial venous reflux of the leg., Key Points Question In patients with venous leg ulceration and superficial reflux, what is the clinical and cost-effectiveness of early endovenous ablation of reflux? Findings In this 450-patient, multicenter, randomized clinical trial, early endovenous ablation with compression accelerated venous ulcer healing, reduced the overall incidence of ulcer recurrence, and was highly cost-effective compared with compression with deferred intervention. Meaning To deliver clinical and cost benefits, leg ulcer care pathways should be revised to include early assessment and treatment of superficial venous reflux., Importance One-year outcomes from the Early Venous Reflux Ablation (EVRA) randomized trial showed accelerated venous leg ulcer healing and greater ulcer-free time for participants who are treated with early endovenous ablation of lower extremity superficial reflux. Objective To evaluate the clinical and cost-effectiveness of early endovenous ablation of superficial venous reflux in patients with venous leg ulceration. Design, Setting, and Participants Between October 24, 2013, and September 27, 2016, the EVRA randomized clinical trial enrolled 450 participants (450 legs) with venous leg ulceration of less than 6 months’ duration and superficial venous reflux. Initially, 6555 patients were assessed for eligibility, and 6105 were excluded for reasons including ulcer duration greater than 6 months, healed ulcer by the time of randomization, deep venous occlusive disease, and insufficient superficial venous reflux to warrant ablation therapy, among others. A total of 426 of 450 participants (94.7%) from the vascular surgery departments of 20 hospitals in the United Kingdom were included in the analysis for ulcer recurrence. Surgeons, participants, and follow-up assessors were not blinded to the treatment group. Data were analyzed from August 11 to November 4, 2019. Interventions Patients were randomly assigned to receive compression therapy with early endovenous ablation within 2 weeks of randomization (early intervention, n = 224) or compression with deferred endovenous treatment of superficial venous reflux (deferred intervention, n = 226). Endovenous modality and strategy were left to the preference of the treating clinical team. Main Outcomes and Measures The primary outcome for the extended phase was time to first ulcer recurrence. Secondary outcomes included ulcer recurrence rate and cost-effectiveness. Results The early-intervention group consisted of 224 participants (mean [SD] age, 67.0 [15.5] years; 127 men [56.7%]; 206 White participants [92%]). The deferred-intervention group consisted of 226 participants (mean [SD] age, 68.9 [14.0] years; 120 men [53.1%]; 208 White participants [92%]). Of the 426 participants whose leg ulcer had healed, 121 (28.4%) experienced at least 1 recurrence during follow-up. There was no clear difference in time to first ulcer recurrence between the 2 groups (hazard ratio, 0.82; 95% CI, 0.57-1.17; P = .28). Ulcers recurred at a lower rate of 0.11 per person-year in the early-intervention group compared with 0.16 per person-year in the deferred-intervention group (incidence rate ratio, 0.658; 95% CI, 0.480-0.898; P = .003). Time to ulcer healing was shorter in the early-intervention group for primary ulcers (hazard ratio, 1.36; 95% CI, 1.12-1.64; P = .002). At 3 years, early intervention was 91.6% likely to be cost-effective at a willingness to pay of £20 000 ($26 283) per quality-adjusted life year and 90.8% likely at a threshold of £35 000 ($45 995) per quality-adjusted life year. Conclusions and Relevance Early endovenous ablation of superficial venous reflux was highly likely to be cost-effective over a 3-year horizon compared with deferred intervention. Early intervention accelerated the healing of venous leg ulcers and reduced the overall incidence of ulcer recurrence. Trial Registration ClinicalTrials.gov identifier: ISRCTN02335796

Recent advancement in the immunological understanding of genesis of hepatocellular carcinoma (HCC) has implicated a decline in anti-tumour immunity on the background of chronic inflammatory state of liver parenchyma. The development of HCC involves a network of immunological activity in the tumour microenvironment involving continuous interaction between tumour and stromal cells. The reduction in anti-tumour immunity is secondary to changes in various immune cells and cytokines, and the tumour microenvironment plays a critical role in modulating the process of liver fibrosis, hepatocarcinogenesis, epithelial-mesenchymal transition (EMT), tumor invasion and metastasis. Thus, it is considered as one of primary factor behind the despicable tumour behavior and observed poor survival; along with increased risk of recurrence following treatment in HCC. The primary intent of the present review is to facilitate the understanding of the complex network of immunological interactions of various immune cells, cytokines and tumour cells associated with the development and progression of HCC.

Background: Transition from distinct Child and Adolescent Mental Health (CAMHS) to Adult Mental Health Services (AMHS) is beset with multitude of problems affecting continuity of care for young people with mental health needs. Transition-related discontinuity of care is a major health, socioeconomic and societal challenge globally. The overall aim of the Managing the Link and Strengthening Transition from Child to Adult Mental Health Care in Europe (MILESTONE) project (2014–19) is to improve transition from CAMHS to AMHS in diverse healthcare settings across Europe. MILESTONE focuses on current service provision in Europe, new transition-related measures, long term outcomes of young people leaving CAMHS, improving transitional care through 'managed transition', ethics of transitioning and the training of health care professionals.Methods: Data will be collected via systematic literature reviews, pan-European surveys, and focus groups with service providers, users and carers, and members of youth advocacy and mental health advocacy groups. A prospective cohort study will be conducted with a nested cluster randomised controlled trial in eight European Union (EU) countries (Belgium, Croatia, France, Germany, Ireland, Italy, Netherlands, UK) involving over 1000 CAMHS users, their carers, and clinicians.Discussion: Improving transitional care can facilitate not only recovery but also mental health promotion and mental illness prevention for young people. MILESTONE will provide evidence of the organisational structures and processes influencing transition at the service interface across differing healthcare models in Europe and longitudinal outcomes for young people leaving CAMHS, solutions for improving transitional care in a cost-effective manner, training modules for clinicians, and commissioning and policy guidelines for service providers and policy makers.Trial registration: "MILESTONE study" registration: ISRCTN ISRCTN83240263 Registered 23 July 2015; ClinicalTrials.gov NCT03013595 Registered 6 January 2017.

Many surgeons prefer to perform total knee replacement surgery with the aid of a tourniquet. A tourniquet is an occlusive device that restricts distal blood flow to help create a bloodless field during the procedure. A tourniquet may be associated with increased risk of pain and complications.To determine the benefits and harms of tourniquet use in knee replacement surgery.We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) up to 26 March 2020. We searched clinicaltrials.gov, the World Health Organization trials portal, and several international registries and joint registries up to March 2020.We included randomised controlled trials (RCTs) comparing knee replacement with use of a tourniquet versus without use of a tourniquet and non-randomised studies with more than 1000 participants. Major outcomes included pain, function, global assessment of success, health-related quality of life, serious adverse events (including venous thromboembolism, infection, re-operation, and mortality), cognitive function, and survival of the implant. Minor outcomes included blood loss, economic outcomes, implant stability, and adverse events.Two review authors screened abstracts and full texts, extracted data, performed risk of bias assessments, and assessed the certainty of the evidence using the GRADE approach.We included 41 RCTs with 2819 participants. Trials included from 20 to 199 participants. Mean age ranged between 58 and 84 years. More than half of the RCTs had unclear risk of selection bias and unclear risk of performance and detection bias due to absence of blinding of participants and surgeons. Major outcomes Pain: at postoperative day 1, pain (on a scale from zero to 10, with higher scores indicating worse pain) was ranked at 4.56 points after surgery without a tourniquet and at 1.25 points (MD) higher (95% CI 0.32 higher to 2.19 higher) with a tourniquet (8 studies; 577 participants), for an absolute difference of 12.5% higher pain scores (95% CI 3.2% higher to 21.9% higher) and a relative difference of 19% higher pain scores (95% CI 3.4% higher to 49% higher) with a tourniquet. Evidence for these findings was of moderate certainty, downgraded due to risk of bias. Knee replacement with a tourniquet probably led to higher postoperative pain scores at day 1, although this difference may or may not be noticeable to patients (based on a minimal clinically important difference (MCID) of 1.0). Function: at 12 months, tourniquet use probably makes little or no difference to function, based on an MCID of 5.3 for Knee Society Score (KSS) and 5.0 for Oxford Knee Score (OKS). Mean function (on a scale from 0 to 100, with higher scores indicating better outcomes) was 90.03 points after surgery without a tourniquet and was 0.29 points worse (95% CI 1.06 worse to 0.48 better) on a 0 to 100 scale, absolute difference was 0.29% worse (1.06% worse to 0.48% better), with a tourniquet (5 studies; 611 participants). This evidence was downgraded to moderate certainty due to risk of bias. Global assessment of success: low-certainty evidence (downgraded due to bias and imprecision) indicates that tourniquet use may have little or no effect on success. At six months, 47 of 50 (or 940 per 1000) reported overall successful treatment after surgery without a tourniquet and 47 of 50 (or 940 per 1000) with a tourniquet (risk ratio (RR) 1.0, 95% CI 0.91 to 1.10) based on one study with 100 participants. Health-related quality of life: at six months, tourniquet may have little or no effect on quality of life. The 12-Item Short Form Survey (SF-12) score (mental component from zero to 100 (100 is best)) was 54.64 after surgery without a tourniquet and 1.53 (MD) better (95% CI 0.85 worse to 3.91 better) with a tourniquet (1 study; 199 participants); absolute difference was 1.53% better (0.85% worse to 3.91% better). Evidence was of low certainty, downgraded due to risk of bias and small number of participants. Serious adverse events: the risk of serious adverse events was probably higher with tourniquet; 26 of 898 (29 per 1000) reported events following surgery without a tourniquet compared to 53 of 901 (59 per 1000) with a tourniquet (RR 1.73, 95% CI 1.10 to 2.73) in 21 studies (1799 participants). Twenty-nine more per 1000 patients (95% CI 3 to 50 more per 1000 patients) had a serious adverse event with a tourniquet. Forty-eight (95% CI 20 to 345) participants would need to have surgery without a tourniquet to avoid one serious adverse event. This evidence was downgraded to moderate certainty due to risk of bias. Cognitive function: one study reported cognitive function as an outcome; however the data were incompletely reported and could not be extracted for analysis. Survival of implant: it is uncertain if tourniquet has an effect on implant survival due to very low certainty evidence (downgraded for bias, and twice due to very low event rates); 2 of 107 (19 per 1000) required revision surgery in the surgery with a tourniquet group compared to 1 of 107 (9 per 1000) without a tourniquet group at up to two years' follow-up (RR 1.44, 95% CI 0.23 to 8.92). This equates to a 0.4% (0.7% lower to 7% more) increased absolute risk in surgery with a tourniquet.Moderate certainty evidence shows that knee replacement surgery with a tourniquet is probably associated with an increased risk of serious adverse events. Surgery with a tourniquet is also probably associated with higher postoperative pain, although this difference may or may not be noticeable to patients. Surgery with a tourniquet does not appear to confer any clinically meaningful benefit on function, treatment success or quality of life. Further research is required to explore the effects of tourniquet use on cognitive function and implant survival, to identify any additional harms or benefits. If a tourniquet continues to be used in knee replacement surgery, patients should be informed about the potential increased risk of serious adverse events and postoperative pain.Muchos cirujanos prefieren realizar una cirugía de reemplazo total de rodilla con la ayuda de un torniquete. Un torniquete es un dispositivo oclusivo que restringe el flujo sanguíneo distal para ayudar a crear un campo sin sangre durante el procedimiento. El torniquete se puede asociar con un mayor riesgo de dolor y complicaciones.Determinar los efectos beneficiosos y perjudiciales del uso de torniquetes en la cirugía de reemplazo de rodilla. MÉTODOS DE BÚSQUEDA: Se hicieron búsquedas en MEDLINE, Embase y en el Registro Cochrane central de ensayos controlados (CENTRAL) hasta el 26 de marzo de 2020. Se realizaron búsquedas en clinicaltrials.gov, el portal de ensayos de la Organización Mundial de la Salud, y en varios registros internacionales y registros conjuntos hasta marzo de 2020. CRITERIOS DE SELECCIÓN: Se incluyeron los ensayos controlados aleatorizados (ECA) que compararon el reemplazo de rodilla con el uso de un torniquete versus sin el uso de un torniquete y los estudios no aleatorizados con más de 1000 participantes. Los desenlaces principales fueron el dolor, la funcionalidad, la evaluación general del éxito, la calidad de vida relacionada con la salud, los eventos adversos graves (incluido el tromboembolismo venoso, la infección, la reintervención y la mortalidad), la función cognitiva y la supervivencia del implante. Los desenlaces secundarios incluyeron la pérdida de sangre, los desenlaces económicos, la estabilidad del implante y los eventos adversos. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores de la revisión examinaron los resúmenes y los textos completos, extrajeron los datos, realizaron las evaluaciones del riesgo de sesgo y evaluaron la certeza de la evidencia utilizando el enfoque GRADE.Se incluyeron 41 ECA con 2819 participantes. Los ensayos incluyeron de 20 a 199 participantes. La media de edad varió entre 58 y 84 años. Más de la mitad de los ECA tenían riesgo incierto de sesgo de selección y riesgo incierto de sesgo de realización y detección debido a la falta de cegamiento de los participantes y los cirujanos. Desenlaces principales Dolor: en el primer día después de la cirugía, el dolor (en una escala de 0 a 10, con puntuaciones mayores que indican un peor dolor) se clasificó en 4,56 puntos después de la cirugía sin torniquete y en 1,25 puntos (DM) mayor (IC del 95%: 0,32 mayor a 2,19 mayor) con un torniquete (ocho estudios; 577 participantes), para una diferencia absoluta de 12,5% de puntuaciones mayores de dolor (IC del 95%: 3,2% mayor a 21,9% mayor) y una diferencia relativa de 19% de puntuaciones mayores de dolor (IC del 95%: 3,4% mayor a 49% mayor) con un torniquete. La evidencia de estos hallazgos fue de certeza moderada, disminuida debido al riesgo de sesgo. El reemplazo de rodilla con un torniquete probablemente dio lugar a mayores puntuaciones de dolor en el primer día después de la cirugía, aunque esta diferencia puede o no ser perceptible para los pacientes (sobre la base de una diferencia mínima clínicamente importante [DMCI] de 1,0). Funcionalidad: a los 12 meses el uso de torniquetes probablemente da lugar a poca o ninguna diferencia en la funcionalidad, según una DMCI de 5,3 en la Knee Society Score (KSS) y de 5,0 en la Oxford Knee Score (OKS). La funcionalidad media (en una escala de 0 a 100, con puntuaciones más altas que indican mejores desenlaces) fue de 90,03 puntos después de la cirugía sin torniquete y fue 0,29 puntos peor (IC del 95%: 1,06 peor a 0,48 mejor) en una escala de 0 a 100, la diferencia absoluta fue 0,29% peor (1,06% peor a 0,48% mejor), con un torniquete (cinco estudios; 611 participantes). Esta evidencia se disminuyó a certeza moderada debido al riesgo de sesgo. Evaluación general del éxito: evidencia de certeza baja (disminuida debido al sesgo y la imprecisión) indica que el uso de torniquetes puede tener poco o ningún efecto en el éxito. A los seis meses, 47 de 50 (o 940 por 1000) informaron de un tratamiento general exitoso después de la cirugía sin torniquete y 47 de 50 (o 940 por 1000) con torniquete (razón de riesgos [RR] 1,0; IC del 95%: 0,91 a 1,10), según un estudio con 100 participantes. Calidad de vida relacionada con la salud: a los seis meses, el torniquete puede tener poco o ningún efecto en la calidad de vida. La puntuación de la 12‐Item Short Form Survey (SF‐12) (componente mental de 0 a 100 [100 es mejor]) fue de 54,64 después de la cirugía sin torniquete y 1,53 (DM) mejor (IC del 95%: 0,85 peor a 3,91 mejor) con torniquete (un estudio; 199 participantes); la diferencia absoluta fue 1,53% mejor (0,85% peor a 3,91% mejor). La evidencia fue de certeza baja, y se disminuyó debido al riesgo de sesgo y al escaso número de participantes. Eventos adversos graves: el riesgo de eventos adversos graves probablemente fue mayor con el uso de un torniquete; 26 de 898 (29 por 1000) notificaron eventos después de la cirugía sin torniquete en comparación con 53 de 901 (59 por 1000) con un torniquete (RR 1,73; IC del 95%: 1,10 a 2,73) en 21 estudios (1799 participantes). Veintinueve más por cada 1000 pacientes (95% CI 3 a 50 más por 1000 pacientes) presentaron un evento adverso grave con un torniquete. Cuarenta y ocho (IC del 95%: 20 a 345) participantes tendrían que ser operados sin torniquete para evitar un evento adverso grave. Esta evidencia se disminuyó a certeza moderada debido al riesgo de sesgo. Función cognitiva: un estudio informó de la función cognitiva como un desenlace; sin embargo, los datos se informaron de manera incompleta y no se pudieron extraer para el análisis. Supervivencia del implante: no está claro si el torniquete tiene un efecto sobre la supervivencia del implante debido a evidencia de certeza muy baja (disminuida por el sesgo, y dos veces debido a las tasas de eventos muy bajas); dos de 107 (19 por 1000) requirieron cirugía de revisión en el grupo de cirugía con torniquete en comparación con uno de 107 (nueve por 1000) en el grupo sin torniquete hasta los dos años de seguimiento (RR 1,44; IC del 95%: 0,23 a 8,92). Esto equivale a un 0,4% (0,7% menos a 7% más) de aumento del riesgo absoluto en la cirugía con torniquete.Evidencia de certeza moderada muestra que la cirugía de reemplazo de rodilla con torniquete probablemente se asocia con un mayor riesgo de eventos adversos graves. La cirugía con torniquete también se asocia probablemente con un mayor dolor posoperatorio, aunque esta diferencia puede o no ser perceptible para los pacientes. La cirugía con torniquete no parece conferir efectos beneficiosos clínicamente significativos en la funcionalidad, el éxito del tratamiento o la calidad de vida. Se necesitan estudios de investigación adicionales para explorar los efectos del uso de torniquetes en la función cognitiva y la supervivencia del implante, para identificar cualquier efecto perjudicial o beneficioso adicional. Si se sigue utilizando un torniquete en la cirugía de reemplazo de rodilla, se debe informar a los pacientes sobre el posible aumento del riesgo de que se produzcan efectos adversos graves y dolor posoperatorio.

Children draw upon knowledge and experience from their wider life to make sense of learning in the classroom. This chapter examines the nature of child development and explores three areas of development foundational to learning: physical, social and emotional, and communication and language. It introduces some of the key child development theorists and explores how their research has impacted on classroom practice. The chapter emphasises that our knowledge of child development is open to challenge, that developmental norms are socially constructed, and that they have often been based on Western industrialised childhoods. T. Campbell’s research convincingly shows that in-class ‘ability grouping’ may be instrumental in contributing to the effect of age-in-cohort on children’s academic achievement. A growing body of research has examined the effects of disrupted childhoods on children’s development. Jean Piaget believed that successful negotiation through these stages was achieved through the child’s active interaction with their environment, both socially and physically.

High blood pressure (BP) has been associated with an increased risk of cerebrovascular disease, stroke, and Alzheimer disease pathology. Epidemiologic studies are consistent in showing that high BP, particularly in midlife, is a risk factor for the development of dementia in late life. However, supporting randomized evidence of the inference that BP-lowering therapy can prevent dementia has been slow in coming over the last 30 years. The most recent randomized trial, the Systolic Blood Pressure Intervention Trial—Memory and Cognition in Decreased Hypertension (SPRINT-MIND), therefore, makes a pivotal contribution to the field, reemphasizing broader public health benefits of BP lowering and directing future research.1

Mammographic density is a strong risk factor for breast cancer, but its potential application in risk management is not clear, partly due to uncertainties about its interaction with other breast cancer risk factors. We aimed to quantify the impact of mammographic density on breast cancer risk in women aged 40-49 at intermediate familial risk of breast cancer (average lifetime risk of 23%), in particular in premenopausal women, and to investigate its relationship with other breast cancer risk factors in this population. We present the results from a case-control study nested with the FH01 cohort study of 6,710 women mostly aged 40-49 at intermediate familial risk of breast cancer. One hundred and three cases of breast cancer were age-matched to one or two controls. Density was measured by semiautomated interactive thresholding. Absolute density, but not percent density, was a significant risk factor for breast cancer in this population after adjusting for area of nondense tissue (OR per 10 cm(2) = 1.07, 95% CI 1.00-1.15, p = 0.04). The effect was stronger in premenopausal women, who made up the majority of the study population. Absolute density remained a significant predictor of breast cancer risk after adjusting for age at menarche, age at first live birth, parity, past or present hormone replacement therapy, and the Tyrer-Cuzick 10-year relative risk estimate of breast cancer. Absolute density can improve breast cancer risk stratification and delineation of high-risk groups alongside the Tyrer-Cuzick 10-year relative risk estimate.

The original version of this article contained an error in Table 1. The correct table is presented below.

The integrin avβ6 promotes migration, invasion and survival of cancer cells, but the biological relevance has yet to be ascertained in breast cancer. Our immunhistochemical analysis of over 2000 breast cancers has revealed that high expression of the protein for the integrin subunit beta6 (β6) is associated with very poor survival (HR = 1.99, P = 2.9×10-6) and increased metastases to distant sites (P = 0·02). This correlation was confirmed at the mRNA level via bioinformatic analysis of the 2000 women in the METABRIC cohort. Furthermore, co-expression of HER2 gave a significantly worse prognosis (HR = 3.43, P = 4×10-12), which we investigated further. We report from in vitro studies that HER2-driven invasion is mediated by αvβ6 in an Akt2-dependent manner. Using the well-tolerated αvβ6-blocking antibody 264RAD in vivo we show that antibody-blockade of this integrin suppressed growth of BT-474 and MCF-7/HER2-18 human breast cancer xenografts similarly to trastuzumab alone (P 264RAD or trastuzumab prolonged survival to a similar degree (14.3% and 33.33% treated mice alive after 100d, respectively, no significant difference) but again, when both drugs were combined 85.7% of mice were alive after 100d, a highly significant response compared with PBS (P Since 70% of women treated with trastuzumab either have, or develop resistance, we suggest combined targeting of αvβ6 and HER2 could provide an important novel therapy for thousands of women with breast cancer. In fact, over 39,000 American women annually (NIH statistics) will develop HER2+ breast cancers for which no specific therapies exist. Our data shows that in excess of 40% of these women with trastuzumab-resistant disease are also likely to express high levels of αvβ6. Our data also suggest that routine determination of the level of expression of αvβ6 on breast cancers would be a valuable clinical tool as it identifies novel high-risk groups of women that require enhanced therapeutic intervention. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-15-01.

Aim: National guidelines for colorectal cancer management aim to optimize cancer outcomes irrespective of postcode. However, in order to ensure equal performance of cancer services, variation in outcome must be monitored and intelligently assessed. In this study, detailed regional cancer registry data were used to quantify and explore the reasons for variation in colorectal cancer outcomes at nine hospitals in East Anglia. Method: We analysed data on colorectal cancers registered by the Eastern Cancer Registry and Information Centre (ECRIC) between 1999 and 2005. Tumours were grouped by site, in keeping with surgical resection. Multivariable Cox regression models were used to identify the effects of patient, disease and treatment variables on an individual's risk of death. Results: After adjusting for demographic, disease and treatment variables there were significant differences in survival among hospitals in emergency admissions with cancer of the right colon, in elective admissions with cancer of the left, sigmoid or recto-sigmoid colon and in emergency admissions with cancer of the rectum. There were also differences among hospitals in terms of perioperative death, nonsurgical management and numbers of nodes examined. For rectal cancers, rates of anterior resection compared with abdominoperineal excision differed, as well as the use of neoadjuvant radiotherapy. Conclusion: Detailed analysis of demographic, disease and treatment factors are required when comparing the survival of individuals with colorectal cancer across hospitals. The results imply that cancer management was not consistent across East Anglia in 1999–2005 but the reasons for this are uncertain. Nevertheless, 5-year age-standardized survival with colon cancer in the Anglia Cancer Network region is currently among the best in the UK.

Since the identification of the BRCA1 and BRCA2 genes speculation has continued regarding the breast and ovarian cancer risk associated with mutations in these genes. Also, as to whether mutations in these genes account for the majority of the association between breast and ovarian cancer. Identification of RAD51C and RAD51D mutations in breast/ovarian cancer families has reawakened the debate as to whether it is safe to reassure women from BRCA negative families that they are not at increased risk of ovarian cancer. 1433 women from breast cancer families that had tested negative for BRCA1/2 were followed for a total of between 0.04 and 25 years and checked against a cancer registry for ovarian cancer incidence. Data was censored at ovarian cancer diagnosis, oophorectomy or death. During 16358 women years of follow up no invasive epithelial ovarian cancer occurred, although 2 borderline tumors were diagnosed. Expected rates for this cohort from cancer registry data were 2.75 epithelial ovarian tumors with 2.52 for invasive cancer and 0.23 for borderline tumors. The upper confidence limit for invasive RR was 1.3 and for borderline tumors 0.97–31. In conclusion this the largest prospective follow up of a BRCA negative cohort has demonstrated that there is no increase in risk of invasive ovarian cancer in families that have tested negative for BRCA1/2. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-08-01.

BRCA1 and BRCA2 are major breast cancer susceptibility genes. Nineteen single nucleotide polymorphisms (SNPs) at 18 loci have been associated with breast cancer. We aimed to determine whether these predict breast cancer incidence in women with BRCA1/BRCA2 mutations. BRCA1/2 mutation carriers identified through the Manchester genetics centre between 1996 and 2011 were included. Using published odds ratios (OR) and risk allele frequencies, we calculated an overall breast cancer risk SNP score (OBRS) for each woman. The relationship between OBRS and age at breast cancer onset was investigated using the Cox proportional hazards model, and predictive ability assessed using Harrell's C concordance statistic. In BRCA1 mutation carriers we found no association between OBRS and age at breast cancer onset: OR for the lowest risk quintile compared to the highest was 1.20 (95% CI 0.82–1.75, Harrell's C = 0.54), but in BRCA2 mutation carriers the association was significant (OR for the lowest risk quintile relative to the highest was 0.47 (95% CI 0.33–0.69, Harrell's C = 0.59). The 18 validated breast cancer SNPs differentiate breast cancer risks between women with BRCA2 mutations, but not BRCA1. It may now be appropriate to use these SNPs to help women with BRCA2 mutations make maximally informed decisions about management options.

Introduction Gastrointestinal dysmotility and constipation are common problems in intensive care patients. The majority of critical care patients are sedated with opioids to facilitate tolerance of endotracheal tubes and mechanical ventilation, which inhibit gastrointestinal motility and lead to adverse outcomes. Methylnaltrexone is a peripheral opioid antagonist that does not cross the blood–brain barrier and can reverse the peripheral side effects of opioids without affecting the desired central properties. This trial will investigate whether methylnaltrexone can reverse opioid-induced constipation and gastrointestinal dysmotility. Methods This is a single-centre, multisite, double-blind, randomised, placebo-controlled trial. 84 patients will be recruited from 4 intensive care units (ICUs) within Imperial College Healthcare NHS Trust. Patients will receive intravenous methylnaltrexone or placebo on a daily basis if they are receiving opioid infusion to facilitate mechanical ventilation and have not opened their bowels for 48 hours. All patients will receive standard laxatives as per the clinical ICU bowel protocol prior to randomisation. The primary outcome of the trial will be time to significant rescue-free laxation following randomisation. Secondary outcomes will include tolerance of enteral feed, gastric residual volumes, incidence of pneumonia, blood stream and Clostridium difficile infection, and any reversal of central opioid effects. Ethics and dissemination The trial protocol, the patient/legal representative information sheets and consent forms have been reviewed and approved by the Harrow Research Ethics Committee (REC Reference 14/LO/2004). An independent Trial Steering Committee and Data Monitoring Committee are in place, with patient representation. On completion, the trial results will be published in peer-reviewed journals and presented at national and international scientific meetings. Trial registration number 2014-004687-37; Pre-results.

Breast cancer is not only increasing in the west but also particularly rapidly in eastern countries where traditionally the incidence has been low. The rise in incidence is mainly related to changes in reproductive patterns and lifestyle. These trends could potentially be reversed by defining women at greatest risk and offering appropriate preventive measures. A model for this approach was the establishment of Family History Clinics (FHCs), which have resulted in improved survival in younger women at high risk. New predictive models of risk that include reproductive and lifestyle factors, mammographic density and measurement of risk-associated single nucleotide polymorphisms (SNPs) may give more precise information concerning risk and enable better targeting for mammographic screening programmes and of preventive measures. Endocrine prevention using anti-oestrogens and aromatase inhibitors is effective, and observational studies suggest lifestyle modification may also be effective. However, referral to FHCs is opportunistic and predominantly includes younger women. A better approach for identifying older women at risk may be to use national breast screening programmes. Here were described pilot studies to assess whether the routine assessment of breast cancer risk is feasible within a population-based screening programme, whether the feedback and advice on risk-reducing interventions would be welcomed and taken up, and to consider whether the screening interval should be modified according to breast cancer risk.

This paper reports the perspectives of male trainees on mechanisms instituted to support them during their Post-Graduate Certificate of Education in Early Years and Primary Education in England. The male trainees were interviewed towards the end of their training, using semi-structured interviews that provided scope for pursuing several lines of enquiry around their experiences as males on the course. In this paper the authors examine specifically the male trainees’ responses to innovations in Faculty support for male trainees, rather than focusing on their broader experiences as males in primary education. The authors are thus concerned to interpret and understand the trainees’ perspectives on how support mechanisms did, or did not, ensure a more positive training experience. Most prominent amongst these mechanisms, in this pilot year, was the formation of a male-only support group. The findings support the idea that, for these trainees at least, focused meetings addressing the concerns of men in primary...

During the uploading of data for submission to the EudraCT results database, a discrepancy was identified. It was noted that the number of deaths per group was not consistent with the number in the final report and trial publication. This discrepancy was found to relate to two randomisation numbers. During the trial, the randomisation database had been held separately from the trial database, with manual transcription of randomisation numbers from the randomisation database to the trial database. Two randomisation numbers had been entered incorrectly into the trial database and, although this was documented at the time, the correction had not been made in the analysis data set. The two infants in question received the correct treatment in accordance with their allocation, but were analysed according to the wrong treatment group. Following the identification of this error, all analyses were repeated. It was confirmed that this error had a negligible impact on the study results. Furthermore, the two infants in question had not been included in the primary and secondary outcome analyses, as one had died and the other had withdrawn prior to the primary end-point assessment, so the key study outcomes remain unchanged. The only changes to the results are in the number of serious adverse events and minor changes to the data in demographics tables mostly affecting decimal points and the CONSORT diagram. Our interpretation of the study results remains unchanged.

Background: Currently there are no real attempts internationally to tailor breast screening programmes to individual risk Methods: We have assessed the feasibility of collecting breast cancer risk information during routine mammographic screening in the National Health Service Breast Screening Programme (NHSBSP) in England, in order to consider, ultimately, adapting the screening interval to risk of breast cancer and introducing preventive strategies in women at high risk. The study Predicting Risk Of Cancer At Screening (PROCAS) aims to recruit 60,000 women over 3 years. Results: 26,000 women (June 8th 2011) have so far given consent to join the study. Thirty six percent of the first 20,000 women in nineteen screening sites in Manchester consented to enter the study and completed a risk factor questionnaire. The median 10 year breast cancer risk was 2.65%, with 926 (9.26%) of the first 10,000 women having a 10 year risk of ≥5% and 92 (0.92%) having a 10 year risk of ≥8% (Tyrer-Cuzick), IQR:1.35. 832 (8.32%) women had a mammographic density of 60% or greater (Visual Analogue Scale). We collected saliva samples from 1019 women for genetic analysis and will extend this to 18% of participants. Of those who agreed to participate in the study, 94% indicated that they wished to know their breast cancer risk. Women with a 10-year risk of ≥8%, and women with a 10-year risk of ≥5% and mammographic density ≥60% were invited to attend or be telephoned to be counselled. To date 138 have accepted with 135, so far, having received risk counselling. Nineteen percent of the high-risk women identified subsequently decided to enter a randomised breast cancer prevention study with either a dietary or drug intervention (IBIS2, anastrazole vs placebo). Results from the first 1,000 women who provided DNA samples suggest that the risk information from the 18 validated SNPS may enhance existing risk models. Conclusion: This study demonstrates that it is feasible to determine individual breast cancer risk and offer women appropriate risk-reducing interventions within the context of a population-based mammographic screening programme. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-11-07.

Mammographic breast density is a strong risk factor for breast cancer. Tamoxifen, which reduces the risk of breast cancer in women at high risk, also reduces mammographic breast density. However, it is not known if tamoxifen-induced reductions in breast density can be used to identify women who will benefit the most from prophylactic treatment with this drug.We conducted a nested case-control study within the first International Breast Cancer Intervention Study, a randomized prevention trial of tamoxifen vs placebo. Mammographic breast density was assessed visually and expressed as a percentage of the total breast area in 5% increments. Case subjects were 123 women diagnosed with breast cancer at or after their first follow-up mammogram, which took place 12-18 months after trial entry, and control subjects were 942 women without breast cancer. Multivariable logistic regression was used to adjust for other risk factors. All statistical tests were two-sided.In the tamoxifen arm, 46% of women had a 10% or greater reduction in breast density at their 12- to 18-month mammogram. Compared with all women in the placebo group, women in the tamoxifen group who experienced a 10% or greater reduction in breast density had 63% reduction in breast cancer risk (odds ratio = 0.37, 95% confidence interval = 0.20 to 0.69, P = .002), whereas those who took tamoxifen but experienced less than a 10% reduction in breast density had no risk reduction (odds ratio = 1.13, 95% confidence interval = 0.72 to 1.77, P = .60). In the placebo arm, there was no statistically significant difference in breast cancer risk between subjects who experienced less than a 10% reduction in mammographic density and subjects who experienced a greater reduction.The 12- to 18-month change in mammographic breast density is an excellent predictor of response to tamoxifen in the preventive setting.

Background: Molecular profiling has identified at least four subtypes of invasive breast carcinoma, which exhibit distinct clinical behaviour. There is good evidence now that DCIS represents the non-obligate precursor to invasive breast cancer and therefore it should be possible to identify similar molecular subtypes at this stage. In addition to a limited five-marker system to identify molecular subtypes in invasive breast cancer, it is evident that other biological molecules may identify distinct tumour subsets, though this has not been formally evaluated in DCIS.\ud \ud Methods: Tissue microarrays were constructed for 188 cases of DCIS. Immunohistochemistry was performed to examine the expression patterns of oestrogen receptor (ER), progesterone receptor (PR), Her2, EGFR, cytokeratin (CK) 5/6, CK14, CK17, CK18, β4-integrin, β6-integrin, p53, SMA, maspin, Bcl-2, topoisomerase IIα and P-cadherin. Hierarchical clustering analysis was undertaken to identify any natural groupings, and the findings were validated in an independent sample series.\ud \ud Results: Each of the intrinsic molecular subtypes described for invasive breast cancer can be identified in DCIS, though there are differences in the relative frequency of subgroups, in particular, the triple negative and basal-like phenotype is very uncommon in DCIS. Hierarchical cluster analysis identified three main subtypes of DCIS determined largely by ER, PR, Her2 and Bcl-2, and this classification is related to conventional prognostic indicators. These subtypes were confirmed in an analysis on independent series of DCIS cases.\ud \ud Conclusion: This study indicates that DCIS may be classified in a similar manner to invasive breast cancer, and determining the relative frequency of different subtypes in DCIS and invasive disease may shed light on factors determining disease progression. It also demonstrates a role for Bcl-2 in classifying DCIS, which has recently been identified in invasive breast cancer.

Background Clinical breast examination (CBE) remains an essential part of triple assessment of breast lumps, but to date there are no performance measures for clinicians using this technique. The aim of this retrospective audit was to compare the performance and accuracy of CBE to identify key indicators that could be used to monitor performance prospectively. Methods Clinical examination findings (E1, normal, to E5, malignant) for 16 585 patients who had CBE as part of triple assessment were obtained from electronic medical records. The performance of CBE, by age group, mammographic density and clinician, was assessed by calculating the sensitivity, specificity and area under the receiver operating characteristic (ROC) curve. Results There was marked variation in sensitivity between clinicians (range 44·6–65·9 per cent). There was a strong downward trend in the percentage classified as E5 as sensitivity for breast cancer detection decreased, and a corresponding strong downward trend in the proportion of E4 and E5 cancers classified as E5. Both of these measures could be used as indicators to monitor CBE performance. Conclusion The performance measures outlined here could help to identify clinicians who have a lower sensitivity for CBE and who may therefore require feedback and further training.

Objective To establish the optimal management strategy for women with suspected stage 1 ovarian cancer. Design We created a flowchart to illustrate each of six hypothetical management strategies. These considered two surgical approaches (systematic lymphadenectomy versus no lymph node dissection at all) in combination with three different policies for giving adjuvant chemotherapy. Setting Gynaecological cancer centre, London, UK. Data sources Patient data and published papers. Methods We developed a deterministic model that uses information from multiple sources to estimate patient flow through each level of a hypothesised decision tree. Results We estimated that for every 100 cases of suspected early-stage ovarian cancer, there would be 37 cases with ‘apparent’ stage 1 disease and that of these, two (6%) would be denied potentially life-saving adjuvant treatment if systematic lymphadenectomy was not performed. The number of women given chemotherapy would not, according to our estimates, differ greatly between the two surgical approaches, the 7% increase with systematic lymphadenectomy being because of cases identified as having nodal metastases. Conclusions We present a model of the intraoperative decision-making process that determines the extent of the staging procedure to be performed within our department when early-stage ovarian cancer is suspected. Unless adjuvant chemotherapy is prescribed for all, systematic pelvic and para-aortic node dissection is required to optimise survival. However, in our department, this would result in 32% of women with suspected early-stage ovarian cancer undergoing systematic node dissection. This flexible focused model may facilitate multidisciplinary team discussion when this part of the surgical staging procedure is considered within the context of the population presenting to the team, the morbidity of the procedure within the department and the predictive values of frozen section within that department. As the model is not disease-specific, it may be useful for decision making in other medical disciplines.

Contains fulltext : 79506.pdf (Publisher’s version ) (Closed access) BACKGROUND: Evidence of the impact of breast screening is limited by biases inherent in non-randomised studies and often by lack of complete population data. We address this by estimating the effect of screen detection on cause-specific fatality in breast cancer, corrected for all potential biases, using population cancer registry data. METHODS: Subjects (N = 26,766) comprised all breast cancers notified to the West Midlands Cancer Intelligence Unit and diagnosed in women aged 50-74, from 1988 to 2004. These included 10,100 screen-detected and 15,862 symptomatic breast cancers (6,009 women with interval cancers and 9,853 who had not attended screening). Our endpoint was survival to death from breast cancer. We estimated the relative risk (RR) of 10-year cause-specific fatality (screen-detected compared to symptomatic cancers) correcting for lead time bias and performing sensitivity analyses for length bias. To exclude self-selection bias, survival analyses were also performed with interval cancers as the comparator symptomatic women. FINDINGS: Uncorrected RR associated with screen-detection was 0.34 (95% CI 0.31-0.37). Correcting for lead time, RR was 0.49 (95% CI 0.45-0.53); length bias analyses gave a range of RR corrected for both phenomena of 0.49-0.59, with a median of 0.51. Self-selection bias-corrected estimates yielded a median RR of 0.68. INTERPRETATION: After adjusting for various potential biases, women with screen-detected breast cancer have a substantial survival advantage over those with symptomatic breast cancer.

Background: Evidence of the impact of breast screening is limited by biases inherent in non-randomised studies and often by lack of complete population data. We address this by estimating the effect of screen detection on cause-specific fatality in breast cancer, corrected for all potential biases, using population cancer registry data. Methods: Subjects (N = 26,766) comprised all breast cancers notified to the West Midlands Cancer Intelligence Unit and diagnosed in women aged 50–74, from 1988 to 2004. These included 10,100 screen-detected and 15,862 symptomatic breast cancers (6,009 women with interval cancers and 9,853 who had not attended screening). Our endpoint was survival to death from breast cancer. We estimated the relative risk (RR) of 10-year cause-specific fatality (screen-detected compared to symptomatic cancers) correcting for lead time bias and performing sensitivity analyses for length bias. To exclude self-selection bias, survival analyses were also performed with interval cancers as the comparator symptomatic women. Findings: Uncorrected RR associated with screen-detection was 0.34 (95% CI 0.31–0.37). Correcting for lead time, RR was 0.49 (95% CI 0.45–0.53); length bias analyses gave a range of RR corrected for both phenomena of 0.49–0.59, with a median of 0.51. Self-selection bias-corrected estimates yielded a median RR of 0.68. Interpretation: After adjusting for various potential biases, women with screen-detected breast cancer have a substantial survival advantage over those with symptomatic breast cancer.

In case-control evaluations of cancer screening, subjects who have died from the cancer in question (cases) are compared with those who have not (controls) with respect to screening histories. This method is subject to a rather subtle bias, among others, whereby the cases have greater opportunity to have been screened than the controls. In this paper, we propose a method of correction for this bias. We demonstrate its use on two case-control studies of mammographic screening for breast cancer.

A population-based case-control proband study was undertaken to elucidate familial aggregation, independent environmental factors, and the interaction between them. A total of 7308 metabolic syndrome (MET-S) cases were identified from the Keelung community-based integrated screening programme between 1999 and 2002. The study has a case-control/family sampling design. A total of 1417 case probands were randomly selected from 3225 metabolic syndrome cases and the corresponding 2458 controls selected from 16,519 subjects without metabolic syndrome by matching on sex, age (+/-3 years) and place of residence. The generalized estimation equation model was used to estimate odds ratios and corresponding 95% confidence intervals. The risk for having metabolic syndrome among family members for cases versus control probands was 1.56-fold (1.29-1.89) after controlling for significant environmental factors. Higher risk of metabolic syndrome was found in parents than spouse. Low education against high education had 2.06-fold (1.36-3.13) risk for metabolic syndrome. Betel quid chewing was positively associated with the risk of MET-S, with 1.99-fold (1.13-3.53) risk for 1-9 pieces and 1.76-fold (0.96-3.23) risk for >or=10 pieces compared with non-chewer. Moderate and high intensity of non-occupational exercise led to 21.0% (OR=0.79 (0.63-0.98)) and 26.0% (OR=0.74 (0.59-0.94)) reduction in the risk for metabolic syndrome, respectively. The frequent consumption of vegetable reduced 24.0% (OR=0.76 (0.62-0.92)) risk for MET-S. The frequent consumption of coffee was associated the increased risk for metabolic syndrome (OR=1.32 (1.07-1.64)). The present study confirmed the risk of metabolic syndrome not only has the tendency towards familial aggregation but is affected by independent effect of environmental or individual correlates.

BackgroundParenteral nutrition (PN) is central to the care of very immature infants. Early intakes of higher amounts of amino acids and the use of lipid emulsions containing fish oils are recommended by current international recommendations.ObjectiveTo confirm the safety and demonstrate efficacy of the immediate introduction of the recommended daily intake of amino acids (Imm-RDI) and soya bean oil, medium-chain triglycerides, olive oil and fish oil lipid in PN to increase non-adipose (lean) body mass and decrease intrahepatocellular lipid (IHCL) content.DesignMulticentre, double-blind, 2 × 2 factorial and randomised controlled trial (RCT).SettingNeonatal units in London and south-east England, UK.ParticipantsExtremely preterm infants born before 31 weeks of gestation without major congenital or life-threatening abnormalities who could to be randomised to receive PN within 24 hours of birth.InterventionsInfants were randomised within 24 hours of birth to receive PN containing either high [RDI of amino acids (Imm-RDI)] or low [incremental amino acids (Inc-AA) control] levels of amino acids. In addition, infants were randomised to receive either 20% SMOFlipid®(Fresenius Kabi AG, Richmond Hill, ON, Canada) or 20% Intralipid®(Fresenius Kabi AG, Richmond Hill, ON, Canada) (control). This resulted in four groups: (1) Inc-AA/Intralipid, (2) Inc-AA/SMOFlipid, (3) Imm-RDI/Intralipid and (4) Imm-RDI/SMOFlipid. The intervention was continued until infants were receiving 150 ml/kg/day of enteral feeds for 24 hours.Primary outcome measureFor the amino acid intervention, this was non-adipose or lean body mass measured by magnetic resonance imaging. For the lipid composition intervention, this was IHCL content as measured by hepatic magnetic resonance spectroscopy. Primary outcomes were measured at term age equivalent, between 37 and 44 weeks postmenstrual age.ResultsWe randomised 168 infants born before 31 weeks of gestation. We evaluated outcomes, at term, in 133 infants. There were no significant differences in non-adipose mass between the Imm-RDI and Inc-AA groups [adjusted mean difference 1.0 g, 95% confidence interval (CI) –108 to 111 g] or in levels of IHCLs between the SMOFlipid and Intralipid groups (adjusted mean SMOFlipid to Intralipid ratio 1.1, 95% CI 0.8 to 1.6). Infants receiving the Imm-RDI were more likely than Inc-AA infants to have blood urea nitrogen levels > 7 mmol/l [75% vs. 49% (p 10 mmol/l [49% vs. 18% (p p = 0.02). There were no significant differences in any prespecified secondary outcomes, including adiposity, liver function tests, weight, length and mortality.LimitationsNot all eligible babies were available for recruitment, as pharmacy staff trained in clinical trial procedures were unavailable at weekends in three of the four centres. We were able to assess brain volumes in only one-third of participants, as imaging was carried out while the participants were sleeping naturally and we measured primary outcomes first and continued to brain imaging only if the infant remained asleep.ConclusionsImmediate delivery of the recommended daily intake of parenteral amino acids does not benefit body composition or growth to term and may be harmful; SMOFlipid does not affect IHCL content.Future workThe long-term functional outcomes of early administration of RDI of amino acids and the use of SMOFlipid, including neurodevelopment, body composition and metabolic health, should be evaluated.Trial registrationCurrent Controlled Trials ISRCTN29665319 and EudraCT 2009-016731-34.FundingThis project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership.

Laparoscopic hysterectomy (LH) is increasingly used for the management of endometrial malignancy. Its benefits may be particularly pronounced as these women are more likely to be older or obese. The aim of this study was to determine whether outcomes for LH are comparable to the open hysterectomy (OH).This was a prospective cohort study nested within the multicenter ASTEC (A Study in the Treatment of Endometrial Cancer) randomized controlled trial (1998-2005).Women with presumed early endometrial cancer were included.Laparoscopic hysterectomy was compared with OH with or without systematic lymphadenectomy.Overall survival, time to first recurrence, complication rates, and surgical outcomes were the main outcome measures.Of 1408 women, 1309 (93%) received OH, and 99 (7%) had LH. LH was associated with longer operating time (median, LH 105 minutes [interquartile range (IQR), 60-150] vs OH 80 minutes [IQR, 60-95]; P0.001) but 50% shorter hospital stay (median, LH 4 days [IQR, 3-5] vs OH 6 days [IQR, 5-7]). The number of harvested lymph nodes was similar (median, LH 13 [IQR, 10-16] vs OH 12 [IQR, 11-13]; P = 0.67). LH had fewer intraoperative and postoperative adverse events (9% difference, LH 21% vs OH 30%; borderline significance; P = 0.07). The rate of conversion to laparotomy for the LH group was high (27%). The median follow-up was 37 months. After adjusting for significant prognostic factors, the hazard ratio for overall survival in those who underwent LH compared with those who underwent OH was 0.67 (95% confidence interval, 0.31-1.43) (P = 0.30).Laparoscopic hysterectomy for early endometrial cancer is safe. Although it requires longer operating time it is associated with shorter hospital stay and favorable morbidity profile. Further studies are required to assess the long-term safety.

In some limited-resource areas, a state-of-the-art mammography program is not affordable. In such circumstances, one might consider a less resource-intensive, but also less sensitive screening tool such as clinical breast examination (CBE). We used data from the Swedish Two-County Trial to estimate the shift in tumor size resulting from invitation to mammographic screening. By postulating a lesser benefit of a less sensitive screening tool (CBE), particularly in terms of detecting very small tumors, we predicted its likely effect on tumor size distribution. In addition, using the observed association between tumor size and nodal status, and between tumor size and fatality, we predicted the likely benefit in terms of reductions in node-positive disease and in breast cancer mortality. An invitation to mammographic screening was associated with a 27% reduction in the number of node-positive tumors and a 31% reduction in the number of breast cancer deaths. We estimate that in the trial population, screening with CBE alone would have led to an 11% reduction in node-positive tumors and an 11% reduction in breast cancer deaths (approximately 42 deaths prevented per 1,000 cases). Assuming instead a tumor size distribution typical of a limited-resource setting (70% of tumors are 30 mm at presentation), we estimate that screening with CBE alone would lead to a 13% reduction in node-positive tumors and a 12% reduction in breast cancer deaths (approximately 72 deaths prevented per 1,000 cases). Thus, although the relative benefit of CBE is only slightly greater in the limited-resource setting, the absolute reduction in deaths per case is about 70% higher. Our findings suggest that a less sensitive tool might be expected to confer a breast cancer mortality reduction about half of that observed with mammography.

Background Treatment for hypertension with antihypertensive medication has been shown to reduce stroke, cardiovascular events, and mortality in older adults, but there is concern that such treatment may not be appropriate in frailer older adults. To investigate whether there is an interaction between effect of treatment for hypertension and frailty in older adults, we calculated the frailty index (FI) for all available participants from the HYpertension in the Very Elderly Trial (HYVET) study, a double-blind, placebo-controlled study of antihypertensives in people with hypertension aged 80 and over, and obtained frailty adjusted estimates of the effect of treatment with antihypertensive medication on risk of stroke, cardiovascular events, and mortality. Methods Participants in HYVET were randomised 1:1 to active treatment with indapamide sustained release 1.5 mg ± perindopril 2 to 4 mg or to matching placebo. Data relating to blood pressure, comorbidities, cognitive function, depression, and quality of life were collected at entry into the study and at subsequent follow-up visits. The FI was calculated at entry, based on 60 potential deficits. The distribution of FI was similar to that seen in population studies of adults aged 80 years and above (median FI, 0.17; IQR, 0.11–0.24). Cox regression was used to assess the impact of FI at entry to the study on subsequent risk of stroke, total mortality, and cardiovascular events. Models were stratified by region of recruitment and adjusted for sex and age at entry. Extending these models to include a term for a possible interaction between treatment for hypertension and FI provided a formula for the treatment effect as a function of FI. For all three models, the point estimates of the hazard ratios for the treatment effect decreased as FI increased, although to varying degrees and with varying certainty. Results We found no evidence of an interaction between effect of treatment for hypertension and frailty as measured by the FI. Both the frailer and the fitter older adults with hypertension appeared to gain from treatment. Conclusions Further work to examine whether antihypertensive treatment modifies frailty as measured by the FI should be explored. Trial registration ClinicalTrials.gov NCT00122811 (July 2005) Electronic supplementary material The online version of this article (doi:10.1186/s12916-015-0328-1) contains supplementary material, which is available to authorized users.

A novel method is proposed for choosing the tuning parameter associated with a family of robust estimators. It consists of minimising estimated mean squared error, an approach that requires pilot estimation of model parameters. The method is explored for the family of minimum distance estimators proposed by [Basu, A., Harris, I.R., Hjort, N.L. and Jones, M.C., 1998, Robust and efficient estimation by minimising a density power divergence. Biometrika, 85, 549–559.] Our preference in that context is for a version of the method using the L 2 distance estimator [Scott, D.W., 2001, Parametric statistical modeling by minimum integrated squared error. Technometrics, 43, 274–285.] as pilot estimator.

SummaryThe instigation of mass screening for breast cancer has, over the last three decades, raised various statistical issues and led to the development of new statistical approaches. Initially, the design of screening trials was the main focus of research but, as the evidence in favour of population-based screening programmes mounts, a variety of other applications have also been identified. These include administrative and quality control tasks, for monitoring routine screening services, as well as epidemiological modelling of incidence and mortality. We review the commonly used methods of cancer screening evaluation, highlight some current issues in breast screening and, using examples from randomized trials and established screening programmes, illustrate the role that statistical science has played in the development of clinical research in this field.

A general method for selecting the tuning parameter in minimum distance estimators is proposed. The performance of this method, which involves minimising a data-based estimate of the asymptotic mean squared error function, is illustrated by its application to three different minimum distance estimators using simulated data. The choice of model family is subjective but information about the number and magnitude of outliers in the data is not needed because thereafter the method is entirely data-based. This approach is shown to optimise the performance of minimum distance methods by delivering estimators which are appropriate for the data. That is to say that, providing the correct family of models is chosen, the resulting estimators will be highly efficient when the method is applied to clean data and robust under contamination. Furthermore, utilising the asymptotic mean squared error function as a joint measure of robustness and efficiency in this way leads to a common framework for assessing the performance of many different minimum distance estimators. The relative merits of the three minimum distance estimators considered here are compared in detail and their performance, when the model family is normal, shown to rival that of the Huber estimator.