Hazel Taylor

Prophylactic radiotherapy for the prevention of procedure-tract metastases after surgical and large-bore pleural procedures in malignant pleural mesothelioma (SMART): a multicentre, open-label, phase 3, randomised controlled trial

Summary Background The use of prophylactic radiotherapy to prevent procedure-tract metastases (PTMs) in malignant pleural mesothelioma remains controversial, and clinical practice varies worldwide. We aimed to compare prophylactic radiotherapy with deferred radiotherapy (given only when a PTM developed) in a suitably powered trial. Methods We did a multicentre, open-label, phase 3, randomised controlled trial in 22 UK hospitals of patients with histocytologically proven mesothelioma who had undergone large-bore pleural interventions in the 35 days prior to recruitment. Eligible patients were randomised (1:1), using a computer-generated sequence, to receive immediate radiotherapy (21 Gy in three fractions within 42 days of the pleural intervention) or deferred radiotherapy (same dose given within 35 days of PTM diagnosis). Randomisation was minimised by histological subtype, surgical versus non-surgical procedure, and pleural procedure (indwelling pleural catheter vs other). The primary outcome was the incidence of PTM within 7 cm of the site of pleural intervention within 12 months from randomisation, assessed in the intention-to-treat population. This trial is registered with ISRCTN, number ISRCTN72767336. Findings Between Dec 23, 2011, and Aug 4, 2014, we randomised 203 patients to receive immediate radiotherapy (n=102) or deferred radiotherapy (n=101). The patients were well matched at baseline. No significant difference was seen in PTM incidence in the immediate and deferred radiotherapy groups (nine [9%] vs 16 [16%]; odds ratio 0·51 [95% CI 0·19–1·32]; p=0·14). The only serious adverse event related to a PTM or radiotherapy was development of a painful PTM within the radiotherapy field that required hospital admission for symptom control in one patient who received immediate radiotherapy. Common adverse events of immediate radiotherapy were skin toxicity (grade 1 in 50 [54%] and grade 2 in four [4%] of 92 patients vs grade 1 in three [60%] and grade 2 in two [40%] of five patients in the deferred radiotherapy group who received radiotherapy for a PTM) and tiredness or lethargy (36 [39%] in the immediate radiotherapy group vs two [40%] in the deferred radiotherapy group) within 3 months of receiving radiotherapy. Interpretation Routine use of prophylactic radiotherapy in all patients with mesothelioma after large-bore thoracic interventions is not justified. Funding Research for Patient Benefit Programme from the UK National Institute for Health Research.

The development of a new breast feeding assessment tool and the relationship with breast feeding self-efficacy

Objective to develop a breast feeding assessment tool to facilitate improved targeting of optimum positioning and attachment advice and to describe the changes seen following the release of a tongue-tie. Design development and validation of the Bristol Breastfeeding Assessment Tool (BBAT) and correlation with breast feeding self-efficacy. Setting maternity hospital in South West England. Participants 218 breast feeds (160 mother–infant dyads); seven midwife assessors. Findings the tool has more explanation than other tools to remind those supporting breast-feeding women about the components of an efficient breast feed. There was good internal reliability for the final 4-item BBAT (Cronbach׳s alpha=0.668) and the midwives who used it showed a high correlation in the consistency of its use (ICC=0.782). Midwives were able to score a breast feed consistently using the BBAT and felt that it helped them with advice to mothers about improving positioning and attachment to make breast feeding less painful, particularly with a tongue-tied infant. The tool showed strong correlation with breast feeding self-efficacy, indicating that more efficient breast feeding technique is associated with increased confidence in breast feeding an infant. Conclusions the BBAT is a concise breast feeding assessment tool facilitating accurate, rapid breast feeding appraisal, and targeting breast feeding advice to mothers acquiring early breast feeding skills or for those experiencing problems with an older infant. Accurate assessment is essential to ensure enhanced breast feeding efficiency and increased maternal self-confidence. Implications for practice the BBAT could be used both clinically and in research to target advice to improve breast feeding efficacy. Further research is needed to establish its wider usefulness.

Metoclopramide or domperidone for increasing maternal breast milk output: a randomised controlled trial

Objective To compare the effects of metoclopramide and domperidone on the breast milk output of mothers with infants in neonatal intensive care. Design Double-blind randomised controlled trial. Setting Tertiary level neonatal intensive care unit (NICU). Sample Eighty mothers expressing breast milk for their infants (mean gestational age 28 weeks) based in NICU and the amounts expressed fell short of the prescribed target. Intervention Mothers were randomised to receive domperidone or metoclopramide for 10 days (10 mg three times a day). Outcome measures Total milk volume daily for up to 10 days before the medication, 10 days during the trial and up to 10 days after medication. Adverse side effects were also recorded. Results Mothers produced more milk in the domperidone group and achieved a mean of 96.3% increase in milk volume (mean increase/pretrial volume) compared with a 93.7% increase for metoclopramide. After adjusting for the amount of milk produced prior to medication, the mean amount of milk produced while taking medication for those on domperidone was 31.0 ml/24 h (95% CI −5.67 to 67.6) greater than the mean for those on metoclopramide. Seven mothers taking metoclopramide reported side effects and three taking domperidone; a further eight women (of 29) who had a follow-on prescription for metoclopramide also reported side effects. Conclusions Oral domperidone and metoclopramide increased the volume of milk produced by mothers who are expressing to feed their babies in NICU. There were small differences in milk output between the two medications and in the incidence of side effects, but the differences were non-significant.

A Randomized Trial of Tacrolimus versus Tacrolimus and Prednisone for the Maintenance of Disease Remission in Noninfectious Uveitis

PURPOSE To compare tacrolimus monotherapy with tacrolimus and prednisone therapy for the maintenance of disease remission in subjects with noninfectious posterior segment intraocular inflammation (PSII). DESIGN Randomized, controlled, phase 2b, open-label, dual-center noninferiority trial. PARTICIPANTS Fifty-eight patients with sight-threatening PSII. METHODS Patients requiring a second-line systemic immunosuppressive agent to control their PSII were treated with therapeutic doses of oral tacrolimus. Those subjects who subsequently were able to taper their prednisone dose to 10 mg daily without disease reactivation were assigned randomly either to stop prednisone or to continue 7.5 to 10 mg prednisone daily for 9 months. MAIN OUTCOME MEASURES Change in logarithm of the minimum angle of resolution (logMAR) visual acuity (VA) and rate of patient withdrawal resulting from treatment inefficacy or intolerance. RESULTS Thirty-five patients successfully tapered their prednisone to 10 mg daily. Of these, 16 were allocated randomly to receive tacrolimus monotherapy and 19 to continue taking prednisone and tacrolimus dual therapy. The difference in the mean change in VA for monotherapy compared with the dual therapy group was less than 1 logMAR letter (logMAR, -0.008; 95% confidence interval, -0.108 to 0.092; P = 0.870). The proportion of patients who tolerated treatment and maintained disease remission for 9 months after randomization also was similar in both groups (monotherapy, 62.5%; dual therapy, 68.4%; P = 0.694). All monotherapy treatment failures were the result of disease reactivation, whereas 50% of dual-therapy failures were the result of drug intolerance. CONCLUSIONS This study provides preliminary evidence that corticosteroids can be withdrawn in tacrolimus-treated patients who are able to achieve control of PSII with 10 mg prednisone daily, and any advantage of dual therapy in the prevention of disease reactivation was offset by its greater treatment intolerance. These findings support the further evaluation of corticosteroid-free treatment in future phase 3 trials (International Standard Randomised Controlled Trial Number Register identification, ISRCTN46576063). FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

The development of a tongue assessment tool to assist with tongue-tie identification

Aim To produce a simple tool with good transferability to provide a consistent assessment of tongue appearance and function in infants with tongue-tie. Methods The Bristol Tongue Assessment Tool (BTAT) was developed based on clinical practice and with reference to the Hazelbaker Assessment Tool for Lingual Frenulum Function (ATLFF). This paper documents 224 tongue assessments using the BTAT. There were 126 tongue assessments recorded using the BTAT and ATLFF tools to facilitate comparisons between them. Paired BTAT assessments were obtained from eight midwives who were using the new assessment tool. Results There was acceptable internal reliability for the four-item BTAT (Cronbachs α=0.708) and the eight midwives who used it showed good correlation in the consistency of its use (ICC=0.760). The BTAT showed a strong and significant correlation (0.89) with the ATLFF, indicating that the simpler BTAT could be used in place of the more detailed assessment tool to score the extent of a tongue-tie. Midwives found it quick and easy to use and felt that it would be easy to teach to others. Conclusions The BTAT provides an objective, clear and simple measure of the severity of a tongue-tie, to inform selection of infants for frenotomy and to monitor the effect of the procedure.

Informed consent in trauma: Does written information improve patient recall of risks? A prospective randomised study

Informed consent is vital to good surgical practice. Pain, sedative medication and psychological distress resulting from trauma are likely to adversely affect a patients ability to understand and retain information thus impairing the quality of the consent process. This study aims to assess whether provision of written information improves trauma patients recall of the risks associated with their surgery. 121 consecutive trauma patients were randomised to receive structured verbal information or structured verbal information with the addition of supplementary written information at the time of obtaining consent for their surgery. Patients were followed up post-operatively (mean 3.2 days) with a questionnaire to assess recall of risks discussed during the consent interview and satisfaction with the consent process. Recall of risks discussed in the consent interview was found to be significantly improved in the group receiving written and verbal information compared to verbal information alone (mean questionnaire score 41% vs. 64%), p=0.0014 using the Mann-Whitney U test. Patient satisfaction with the consent process was improved in the group receiving written and verbal information and 90% of patients in both groups expressed a preference for both written and verbal information compared to verbal information alone. Patients awaiting surgery following trauma can pose a challenge to adequately inform about benefits conferred, the likely post operative course and potential risks. Written information is a simple and cost-effective means to improve the consent process and was popular with patients.

Protocol for the surgical and large bore procedures in malignant pleural mesothelioma and radiotherapy trial (SMART Trial): an RCT evaluating whether prophylactic radiotherapy reduces the incidence of procedure tract metastases

Introduction Patients with malignant pleural mesothelioma (MPM) may develop painful ‘procedure tract metastasis’ (PTM) at the site of previous pleural interventions. Prophylactic radiotherapy has been used to minimise this complication; however, three small randomised trials have shown conflicting results regarding its effectiveness. The surgical and large bore procedures in malignant pleural mesothelioma and radiotherapy trial (SMART Trial) is a suitably powered, multicentre, randomised controlled trial, designed to evaluate the efficacy of prophylactic radiotherapy within 42 days of pleural instrumentation in preventing the development of PTM in MPM. Methods and analysis 203 patients with a histocytologically proven diagnosis of MPM, who have undergone a large bore pleural intervention (thoracic surgery, large bore chest drain, indwelling pleural catheter or local anaesthetic thoracoscopy) in the previous 35 days, will be recruited from UK hospitals. Patients will be randomised (1:1) to receive immediate radiotherapy (21 Gy in 3 fractions over 3 working days within 42 days of the pleural intervention) or deferred radiotherapy (21 Gy in 3 fractions over 3 working days given if a PTM develops). Patients will be followed up for 12 months. The primary outcome measure is the rate of PTM until death or 12 months (whichever is sooner), as defined by the presence of a clinically palpable nodule of at least 1 cm diameter felt within 7 cm of the margins of the procedure site as confirmed by two assessors. Secondary outcome measures include chest pain, quality of life, analgaesic requirements, healthcare utilisation and safety (including radiotherapy toxicity). Ethics and dissemination The trial has received ethical approval from the Southampton B Research Ethics Committee (11/SC/0408). There is a Trial Steering Committee, including independent members and a patient and public representative. The trial results will be published in a peer-reviewed journal and presented at international conferences. Trial registration number ISRCTN72767336.

Attenuated humoral responses in HLA-A*24-positive individuals at risk of type 1 diabetes

Aims/hypothesisThe rate of progression from islet autoimmunity to clinical type 1 diabetes depends on the rate of beta cell destruction. The HLA-A*24 gene is associated with early diabetes onset, but previous studies have shown attenuated humoral responses to islet antigens in individuals with both recent and long-standing type 1 diabetes carrying HLA-A*24. We aimed to establish whether HLA-A*24 is also associated with attenuated humoral responses in individuals at high risk of type 1 diabetes.MethodsWe established HLA-A*24, DQ and rs9258750 (an HLA-A*24 tagged single-nucleotide polymorphism) genotype, as well as GAD, zinc transporter 8 (ZnT8), insulin, islet antigen-2 (IA-2), and IA-2β autoantibody status in 373 islet cell antibody-positive first-degree relatives participating in the European Nicotinamide Diabetes Intervention Trial.ResultsUnivariate regression analyses showed that humoral responses to GAD, ZnT8 and insulin were less common in relatives carrying HLA-A*24. The prevalence of GAD and ZnT8 autoantibodies remained negatively associated with HLA-A*24 and rs9258750 after adjusting for age, sex, proband relationship and HLA class II genotype.Conclusions/interpretationHLA-A*24 is associated with attenuated humoral responses in individuals at high risk of type 1 diabetes, and this may reflect a distinct phenotype of rapid beta cell loss.

Home or hospital for people with dementia and one or more other multimorbidities: What is the potential to reduce avoidable emergency admissions? the HOMEWARD Project Protocol

Introduction Older people with multimorbidities frequently access 999 ambulance services. When multimorbidities include dementia, the risk of ambulance use, accident and emergency (A&E) attendance and hospital admission are all increased, even when a condition is treatable in the community. People with dementia tend to do poorly in the acute hospital setting and hospital admission can result in adverse outcomes. This study aims to provide an evidence-based understanding of how older people living with dementia and other multimorbidities are using emergency ambulance services. It will also provide evidence of how paramedics make decisions about taking this group of patients to hospital, and what resources would allow them to make more person-focused decisions to enable optimal patient care. Methods and analysis Phase 1: retrospective data analysis: quantitative analysis of ambulance service data will investigate: how often paramedics are called to older people with dementia; the amount of time paramedics spend on scene and the frequency with which these patients are transported to hospital. Phase 2: observational case studies: detailed case studies will be compiled using qualitative methods, including non-participant observation of paramedic decision-making, to understand why older people with multimorbidities including dementia are conveyed to A&E when they could be treated at home or in the community. Phase 3: needs analysis: nominal groups with paramedics will investigate and prioritise the resources that would allow emergency, urgent and out of hours care to be effectively delivered to these patients at home or in a community setting. Ethics and dissemination Approval for the study has been obtained from the Health Research Authority (HRA) with National Health Service (NHS) Research Ethics Committee approval for phase 2 (16/NW/0803). The dissemination strategy will include publishing findings in appropriate journals, at conferences and in newsletters. We will pay particular attention to dissemination to the public, dementia organisations and ambulance services.

How do people with dementia use the ambulance service? A retrospective study in England: the HOMEWARD project

Objectives An increasing number of older people are calling ambulances and presenting to accident and emergency departments. The presence of comorbidities and dementia can make managing these patients more challenging and hospital admission more likely, resulting in poorer outcomes for patients. However, we do not know how many of these patients are conveyed to hospital by ambulance. This study aims to determine: how often ambulances are called to older people; how often comorbidities including dementia are recorded; the reason for the call; provisional diagnosis; the amount of time ambulance clinicians spend on scene; the frequency with which these patients are transported to hospital. Methods We conducted a retrospective cross-sectional study of ambulance patient care records (PCRs) from calls to patients aged 65 years and over. Data were collected from two ambulance services in England during 24 or 48 hours periods in January 2017 and July 2017. The records were examined by two researchers using a standard template and the data were extracted from 3037 PCRs using a coding structure. Results Results were reported as percentages and means with 95% CIs. Dementia was recorded in 421 (13.9%) of PCRs. Patients with dementia were significantly less likely to be conveyed to hospital following an emergency call than those without dementia. The call cycle times were similar for patients regardless of whether or not they had dementia. Calls to people with dementia were more likely to be due to injury following a fall. In the overall sample, one or more comorbidities were reported on the PCR in over 80% of cases. Conclusion Rates of hospital conveyance for older people may be related to comorbidities, frailty and complex needs, rather than dementia. Further research is needed to understand the way in which ambulance clinicians make conveyance decisions at scene.