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Background: The way potential benefits and harms of trial interventions are shared within patient information leaflets (PILs) varies widely and may cause unnecessary harms (“nocebo effects”). The aim of this meta-analysis will be to evaluate the influence on recruitment rates and early effects on patient reported adverse events of principled patient information leaflets (PrinciPILs) compared with standard PILs. Methods: Eligible studies will include those that report the effects on recruitment and patient reported adverse events of PrinciPILs compared to standard PILs. We will include in this meta-analysis all the standard PILs in studies within trials (SWATs) of PrinciPILs that were developed as part of the Medical Research Council (MRC) funded PrinciPIL project. By publishing this as a living meta-analysis, we will allow the meta-analysis to be updated with future SWATs of PrinciPILs. We will use the Cochrane Risk of Bias tool to evaluate the risk of bias for each outcome. We will report the total number of studies and participants analysed and the characteristics of included studies (including details of intervention, comparators, outcomes). For dichotomous data, we will calculate the risk difference and the risk ratio (RR) and 95% confidence intervals (CIs). For continuous outcomes we will use weighted mean differences with 95% CIs or standardized mean differences with 95% CIs. We will investigate heterogeneity by visually inspecting the forest plot and by considering the I2 test result. We will assess the certainty warranted for each outcome using the Grading of Recommendations Assessment Development and Evaluation (GRADE). Ethics approval is not applicable since no original data will be collected. The results will be disseminated through peer-reviewed publication and conference presentations. Discussion: We will discuss the limitations of the meta-analysis including study risk of bias, inconsistency, heterogeneity, and imprecision. A general interpretation of the results and important implications will be provided.

Background: Patients with advanced oesophageal cancer have a median survival of 3–6 months, and most require intervention for dysphagia. Self-expanding metal stent (SEMS) insertion is the most typical form of palliation in these patients, but dysphagia deterioration and re-intervention are common. This study examined the efficacy of adjuvant external beam radiotherapy (EBRT) compared with usual care alone in preventing dysphagia deterioration and reducing service use after SEMS insertion. Methods: This was a multicentre, open-label, phase 3 randomised controlled trial based at cancer centres and acute care hospitals in England, Scotland, and Wales. Patients (aged ≥16 years) with incurable oesophageal carcinoma receiving stent insertion for primary management of dysphagia were randomly assigned (1:1) to receive usual care alone or EBRT (20 Gy in five fractions or 30 Gy in ten fractions) plus usual care after stent insertion. Usual care was implemented according to need as identified by the local multidisciplinary team (MDT). Randomisation was via the method of minimisation stratified by treating centre, stage at diagnosis (I–III vs IV), histology (squamous or non-squamous), and MDT intent to give chemotherapy (yes vs no). The primary outcome was difference in proportions of participants with dysphagia deterioration (>11 point decrease on patient-reported European Organisation for Research and Treatment of Cancer quality of life questionnaire-oesophagogastric module [QLQ-OG25], or a dysphagia-related event consistent with such a deterioration) or death by 12 weeks in a modified intention-to-treat (ITT) population, which excluded patients who did not have a stent inserted and those without a baseline QLQ-OG25 assessment. Secondary outcomes included survival, quality of life (QoL), morbidities (including time to first bleeding event or hospital admission for bleeding event and first dysphagia-related stent complications or re-intervention), and cost-effectiveness. Safety analysis was undertaken in the modified ITT population. The study is registered with the International Standard Randomised Controlled Trial registry, ISRCTN12376468, and ClinicalTrials.gov, NCT01915693, and is completed. Findings: 220 patients were randomly assigned between Dec 16, 2013, and Aug 24, 2018, from 23 UK centres. The modified ITT population (n=199) comprised 102 patients in the usual care group and 97 patients in the EBRT group. Radiotherapy did not reduce dysphagia deterioration, which was reported in 36 (49%) of 74 patients receiving usual care versus 34 (45%) of 75 receiving EBRT (adjusted odds ratio 0·82 [95% CI 0·40–1·68], p=0·59) in those with complete data for the primary endpoint. No significant difference was observed in overall survival: median overall survival was 19·7 weeks (95% CI 14·4–27·7) with usual care and 18·9 weeks (14·7–25·6) with EBRT (adjusted hazard ratio 1·06 [95% CI 0·78–1·45], p=0·70; n=199). Median time to first bleeding event or hospital admission for a bleeding event was 49·0 weeks (95% CI 33·3–not reached) with usual care versus 65·9 weeks (52·7–not reached) with EBRT (adjusted subhazard ratio 0·52 [95% CI 0·28–0·97], p=0·038; n=199). No time versus treatment interaction was observed for prespecified QoL outcomes. We found no evidence of differences between trial group in time to first stent complication or re-intervention event. The most common (grade 3–4) adverse event was fatigue, reported in 19 (19%) of 102 patients receiving usual care alone and 22 (23%) of 97 receiving EBRT. On cost-utility analysis, EBRT was more expensive and less efficacious than usual care. Interpretation: Patients with advanced oesophageal cancer having SEMS insertion for the primary management of their dysphagia did not gain additional benefit from concurrent palliative radiotherapy and it should not be routinely offered. For a minority of patients clinically considered to be at high risk of tumour bleeding, concurrent palliative radiotherapy might reduce bleeding risk and the need for associated interventions. Funding: National Institute for Health Research Health Technology Assessment Programme.

Background Most patients with oesophageal cancer present with incurable disease. For those with advanced disease, the mean survival is 3–5 months. Treatment emphasis is therefore on effective palliation, with the majority of patients requiring intervention for dysphagia. Insertion of a self-expanding metal stent provides rapid relief but dysphagia may recur within 3 months owing to tumour progression. Evidence reviews have called for trials of interventions combined with stenting to better maintain the ability to swallow. Objectives The Radiotherapy after Oesophageal Cancer Stenting (ROCS) study examined the effectiveness of palliative radiotherapy, combined with insertion of a stent, in maintaining the ability to swallow. The trial also examined the impact that the ability to swallow had on quality of life, bleeding events, survival and cost-effectiveness. Design A pragmatic, multicentre, randomised controlled trial with follow-up every 4 weeks for 12 months. An embedded qualitative study examined trial experiences in a participant subgroup. Setting Participants were recruited in secondary care, with all planned follow-up at home. Participants Patients who were referred for stent insertion as the primary management of dysphagia related to incurable oesophageal cancer. Interventions Following stent insertion, the external beam radiotherapy arm received palliative oesophageal radiotherapy at a dose of 20 Gy in five fractions or 30 Gy in 10 fractions. Main outcome measures The primary outcome was the difference in the proportion of participants with recurrent dysphagia, or death, at 12 weeks. Recurrent dysphagia was defined as deterioration of ≥ 11 points on the dysphagia scale of the European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire oesophago-gastric module questionnaire. Secondary outcomes included quality of life, bleeding risk and survival. Results The study recruited 220 patients: 112 were randomised to the usual-care arm and 108 were randomised to the external beam radiotherapy arm. There was no evidence that radiotherapy reduced recurrence of dysphagia at 12 weeks (48.6% in the usual-care arm compared with 45.3% in the external beam radiotherapy arm; adjusted odds ratio 0.82, 95% confidence interval 0.40 to 1.68; p = 0.587) and it was less cost-effective than stent insertion alone. There was no difference in median survival or key quality-of-life outcomes. There were fewer bleeding events in the external beam radiotherapy arm. Exploration of patient experience prompted changes to trial processes. Participants in both trial arms experienced difficulty in managing the physical and psychosocial aspects of eating restriction and uncertainties of living with advanced oesophageal cancer. Limitations Change in timing of the primary outcome to 12 weeks may affect the ability to detect a true intervention effect. However, consistency of results across sensitivity analyses is robust, including secondary analysis of dysphagia deterioration-free survival. Conclusions Widely accessible palliative external beam radiotherapy in combination with stent insertion does not reduce the risk of dysphagia recurrence at 12 weeks, does not have an impact on survival and is less cost-effective than inserting a stent alone. Reductions in bleeding events should be considered in the context of patient-described trade-offs of fatigue and burdens of attending hospital. Trial design elements including at-home data capture, regular multicentre nurse meetings and qualitative enquiry improved recruitment/data capture, and should be considered for future studies. Future work Further studies are required to identify interventions that improve stent efficacy and to address the multidimensional challenges of eating and nutrition in this patient population. Trial registration Current Controlled Trials ISRCTN12376468 and Clinicaltrials.gov NCT01915693. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 31. See the NIHR Journals Library website for further project information.

Patients need to be informed about potential risks of taking part in clinical trials. A problem is that there are no standards telling researchers or ethics committees how these risks need to be communicated. Our background research suggests that the way harms are communicated can actually increase the risks of the harms occurring. Over half of our sample of 250,000 patients who took placebo pills (like sugar pills) in clinical trials reported some negative side effect (like pain or nausea but also more serious things). The aim of this study is to understand what information about trial harms and benefits stakeholders consider to be important for ‘principled participant information leaflets’ or ‘PrinciPILs’ to contain. The stakeholders will include patients, ethics committee members, industry representatives, medico-legal experts, psychologists, and trial managers.

Background Hate crimes – those perpetrated because of perceived difference, including disability, race, religion, sexual orientation or transgender status – have not been studied at the point of the victim's hospital emergency department (ED) use. Aim To investigate the frequency, levels of physical harm and circumstances of targeted violence in those seeking treatment at EDs in three UK cities. Method In a multimethods study, face‐to‐face semi‐structured interviews were conducted with 124 adult ED attenders with violent injuries. Victim and perpetrator socio‐demographics were recorded. Patient narratives about perceived motives and circumstances were transcribed, uploaded onto NVivo for thematic analysis. Results Nearly a fifth (23, 18.5%) of the injured patients considered themselves to have been attacked by others motivated by hostility or prejudice to their ‘difference’ (targeted violence). Thematic analyses suggested these prejudices were to appearance (7 cases), racial tension (5 cases), territorial association (3 cases) and race, religious or sexual orientation (8 cases). According to victims, alcohol intoxication was particularly relevant in targeted violence (estimated reported frequency 90% and 56% for targeted and non‐targeted violence, respectively). Conclusions Our findings support a broader concept of hate victimisation and suggest that emergency room violence surveys could act as a community tension sensor and early warning system in this regard. Tackling alcohol misuse seems as important in this as in other forms of violence perpetration. Copyright © 2017 John Wiley & Sons, Ltd.

Hate crimes - those perpetrated because of perceived difference, including disability, race, religion, sexual orientation or transgender status - have not been studied at the point of the victim's hospital emergency department (ED) use.To investigate the frequency, levels of physical harm and circumstances of targeted violence in those seeking treatment at EDs in three UK cities.In a multimethods study, face-to-face semi-structured interviews were conducted with 124 adult ED attenders with violent injuries. Victim and perpetrator socio-demographics were recorded. Patient narratives about perceived motives and circumstances were transcribed, uploaded onto NVivo for thematic analysis.Nearly a fifth (23, 18.5%) of the injured patients considered themselves to have been attacked by others motivated by hostility or prejudice to their 'difference' (targeted violence). Thematic analyses suggested these prejudices were to appearance (7 cases), racial tension (5 cases), territorial association (3 cases) and race, religious or sexual orientation (8 cases). According to victims, alcohol intoxication was particularly relevant in targeted violence (estimated reported frequency 90% and 56% for targeted and non-targeted violence, respectively).Our findings support a broader concept of hate victimisation and suggest that emergency room violence surveys could act as a community tension sensor and early warning system in this regard. Tackling alcohol misuse seems as important in this as in other forms of violence perpetration. Copyright © 2017 John WileySons, Ltd.

Bipolar Disorder (BD) is a serious mental health condition that is characterized by recurring affective episodes, interspersed with periods of remission. Current treatment for BD focuses on pharmacological and therapeutic techniques to control the condition. In addition to this, a significant number of people with BD adopt self-management techniques in order to help maintain a stable life pattern and control their condition. There are two significant drawbacks to current selfmanagement in that current systems tend to be paper based and reliant on user self-insight, which is frequently lost in the run up to an affective episode. These two shortcomings can be addressed with a technology-enabled solution. Through the use of specific sensors and an electronic mood diary, the important indicators of relapse in BD can be monitored and users alerted to potential indicators of relapse in a timely manner so that they can take appropriate action. This paper presents work that has been carried out in the development of the Auto-Motive system on the quantification of indicator metrics in BD for use in a technology-enabled selfmanagement system. We present the methodology and results from a series of focus groups that have been carried out with users and professionals to identify the important indicators in BD and the way in which the can be quantified for use in a decision support system. Results from the focus groups are in line with the literature and professional insight and point to sleep (hours of sleep and sleep quality), physical activity, time at home and at work and medication compliance as being particularly important indicators to quantify and use in the Auto-Motive system.

Psycho-education is an established intervention for various physical and mental health conditions. This article describes a psycho-education programme developed for people with bipolar disorder. The courses appear to have been beneficial to participants and appraisal of the intervention is ongoing. One area that needs further consideration is whether courses should be run by a person who has bipolar disorder; the advantages and disadvantages of this are discussed.

2-Nitrophenol (2-NP) is the major detoxification metabolite of an important industrial pollutant and a potent carcinogen, 2-nitroanisole (2-NA). Characterization of the products of 2-NP metabolism by rat hepatic microsomes containing cytochromes P450 (CYPs) and identification of the major CYP enzymes participating in this process are aims of this study.HPLC with UV detection was employed for the separation and characterization of 2-NP metabolites. Inducers and inhibitors of CYPs and rat recombinant CYPs were used to characterize the enzymes participating in 2-NP oxidation.Rat hepatic microsomes oxidize 2-NP to its hydroxylated metabolite, 2,5-dihydroxynitrobenzene (2,5-DNB). No nitroreductive metabolism leading to the formation of o-aminophenol was evident when using rat hepatic microsomes. Selective CYP inhibitors and hepatic microsomes of rats pre-treated with specific CYP inducers were used to characterize CYPs oxidizing 2-NP in rat livers. Based on these studies, we attribute most of 2-NP oxidation in rat liver to CYP2E1 and 3A, followed by CYP2D and 2C. Among recombinant rat CYP enzymes tested in this study, CYP2E1 and 2C11 were the most effective enzymes oxidizing 2-NP. Oxidation of 2-NP by rat CYP2E1 exhibits the Michaelis-Menten kinetics, having the Km value of 0.35 mM.The results found in this study, the first report on the metabolism of 2-NP by rat hepatic microsomes and rat CYP enzymes, demonstrate that CYP2E1 is the major enzyme oxidizing this compound in rat liver.

Purpose The purpose of this study was to investigate the status and potential of Emergency Department (ED) data for identifying and preventing hate violence. Methods Face-to-face interviews with patients attending three EDs in England and Wales (Blackburn, Cardiff and Leicester) with injuries sustained in violence were undertaken; 120 semistructured interviews, 40 in each centre. Interviews were also conducted with Crime and Disorder Reduction Partnership/Community Safety Partnership members and ED staff to evaluate violence data sharing protocols. All interviews were audio recorded, transcribed and uploaded onto QSR Internationals NVivo 8 software for analysis. Results The 124 respondents comprised 99 men (79.8%) and 25 women (20.2%); 55 were aged 16–24 years (44.4%). The ethnic group most often represented were White British, English, Irish or Scottish (103 respondents; 83.0%). Altogether, there were eight definite cases of hate violence, accounting for 6.5% of all assaults. Seven of these were racially and religiously aggravated (5.6% of all assaults), while one (0.9%) was aggravated by sexual orientation. Alcohol consumption was a contributing factor in 75% of hate violence. In two of the three centres studied, ED violence data were not being utilised for violence prevention. Conclusions From these findings, alcohol intoxication promotes hate violence. Although EDs are a valuable source of information about this problem routine collection of the relevant data is not practical, reflecting the need for substantial time and qualitative interview skills which are not available in EDs.

We have analyzed the hemoglobin abnormalities in nearly 50 Albanian patients with a significant hemoglobinopathy and included 37 relatives in this study. Sickle cell anemia (SS) is a common disorder; all 15 sickle cell anemia patients had the complications expected for this disease. The beta S haplotype was type 19 (Benin); alpha-thalassemia-2 was rare. Three beta-thalassemia alleles (IVS-I-110, G-->A; codon 39, C-->T; IVS-I-6, T-->C) were present in nearly 85% of the beta-thalassemia alleles; their frequencies were intermediate between those observed in the populations of neighboring countries. A few rare mutations were also found, which might have originated in India, Turkey, Macedonia, and Greece. Nearly all patients with Hb S-beta-thalassemia had the IVS-I-110 (G-->A) mutation. The frequencies of 11 beta-thalassemia mutations in 17 mostly Mediterranean countries have been reviewed.