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Mentally vulnerable defendants who struggle to effectively participate in their trial in the magistrates’ courts are not receiving the same protection as those who stand trial in the Crown Court. The Law Commission for England and Wales recognised this lacuna and suggested that the law relating to effective participation should be equally applicable in the magistrates’ courts. On closer examination of the law, the legal aid system and perspectives of legal professionals on the ‘front line’, it is clear that improvements in policy are of greater importance than legal reform and are more likely to meet the needs of these vulnerable individuals. The aim of this paper will be to demonstrate that reform of the law will be insufficient to adequately protect mentally vulnerable defendants in the magistrates’ courts and that changes in policy are needed in place of, or alongside, legal reforms.

Background Immunotherapy is revolutionising the treatment of patients diagnosed with melanoma and other cancers. The first immune checkpoint inhibitor, ipilimumab (targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)), showed a survival advantage over standard chemotherapy. Subsequently the anti-programmed cell death protein 1 (PD-1) antibodies, nivolumab and pembrolizumab were shown to be more effective than ipilimumab. Ipilimumab combined with nivolumab gives an incremental gain in overall survival compared with nivolumab alone but increases the risk of severe, potentially life-threatening toxicities. In contrast to ipilimumab monotherapy, anti-PD-1 antibodies are licensed to be continued until disease progression. Follow-up of patients recruited to the first trials evaluating 2 years of pembrolizumab showed that three-quarters of responding patients continue responding after stopping treatment. Suggestive of early response, we hypothesised that continuing anti-PD-1 treatment beyond 1 year in progression-free patients may be unnecessary and so designed the DANTE trial. Methods DANTE is a multicentre, randomised, phase III, non-inferiority trial to evaluate the duration of anti-PD-1 therapy in patients with metastatic (unresectable stage III and stage IV) melanoma. It uses a two-stage recruitment strategy, registering patients before they complete 1 year of first-line anti-PD-1 +/− CTLA-4 therapy and randomising eligible patients who have received 12 months of treatment and are progression-free at 1 year. At randomisation, 1208 patients are assigned (1:1) to either 1) continue anti-PD-1 treatment until disease progression/ unacceptable toxicity/ for at least 2 years in the absence of disease progression/ unacceptable toxicity or 2) to stop treatment. Randomisation stratifies for baseline prognostic factors. The primary outcome is progression-free survival at 3, 6, 9 and 12 months and then, 6-monthly for up to 4-years. Secondary outcomes collected at all timepoints include overall survival, response-rate and duration and safety, with quality of life and cost-effectiveness outcomes collected 3-monthly for up to 18-months. Sub-studies include a qualitative analysis of patient acceptance of randomisation and sample collection to inform future translational studies into response/ toxicity biomarkers. Discussion DANTE is a unique prospective trial investigating the optimal duration of anti-PD-1 therapy in metastatic melanoma patients. Outcomes will inform future use of these high burden drugs. Trial registration ISRCTN15837212, 31 July 2018.

IntroductionPoorly differentiated (PD), extrapulmonary (EP), neuroendocrine carcinomas (NECs) are rare but aggressive neuroendocrine neoplasms. First-line treatment for advanced disease is an etoposide and platinum-based chemotherapy combination. There is no established second-line treatment for patients with PD-EP-NEC, and this is an area of unmet need.Methods and analysisNET-02 is a UK, multicentre, randomised (1:1), parallel group, open-label, phase II, single-stage selection trial of liposomal irinotecan (nal-IRI)/5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy in patients with progressive PD-EP-NEC. One hundred and two eligible participants will be randomised to receive either nal-IRI/5-FU/folinic acid or docetaxel. The primary objective is to determine the 6-month progression-free survival (PFS) rate. The secondary objectives of this study are to determine PFS, overall survival, objective response rate, toxicity, quality of life and whether neuron-specific enolase is predictive of treatment response. If either treatment is found to have a 6-month PFS rate of at least 25%, that treatment will be considered for a phase III trial. If both treatments meet this target, prespecified selection criteria will be applied to establish which treatment to take forward.Ethics and disseminationThis study has ethical approval from the Greater Manchester Central Research Ethics Committee (reference no. 18/NW/0031) and clinical trial authorisation from the Medicine and Healthcare Products Regulatory Agency. Results will be published in peer-reviewed journals and uploaded to the European Union Clinical Trials Register.Trial registration numbersISRCTN10996604,NCT03837977, EudraCT Number: 2017-002453-11

This article asks whether the time is right for abolition of the offence/defence of infanticide. To this end, a two-pronged approach is taken, examining infanticide initially as an offence, and then as a defence. In terms of the offence of infanticide, consideration is given both to the concept of the ‘infanticidal mother’ and to the status of infants below the age of 12 months. When considering the defence of infanticide, examination is made of the exclusive nature of the defence and of the scope for an individual to be a ‘partial’ moral agent. The contradictory nature of infanticide, being both inculpatory and exculpatory, suggests the need for a theoretical rationale that justifies disallowing the offence/defence to, inter alia, those women who kill their own children over 12 months and to men who suffer similar ‘environmental’ postnatal depression. It is suggested that women who kill their children while suffering from the ‘after-effects’ of childbirth are either, depending on the severity of mental disorder, fully competent and therefore criminally responsible (although perhaps entitled to a lesser sentence due to a reduction in culpability) or fully incompetent, therefore incurring no criminal responsibility at all. This proposal can be achieved by recognising that there is a place for reduced culpability or a complete absence of responsibility to fall within the current defence of diminished responsibility or within the Law Commission’s recommended alternative to the insanity defence of ‘not criminally responsible by reason of recognised medical condition’.

Ahead of display, a non‐original layer was observed on the surface of a fragment of a wall painting by Ambrogio Lorenzetti (active 1319, died 1348/9). FTIR analysis suggested proteinaceous content. Mass spectrometry was used to better characterise this layer and revealed two protein components: sheep and cow glue and chicken and duck egg white. Analysis of post‐translational modifications detected several photo‐oxidation products, which suggest that the egg experienced prolonged exposure to UV light and was likely applied long before the glue layer. Additionally, glycation products detected may indicate naturally occurring glycoprotein degradation or reaction with a carbohydrate material such as starch, identified by ATR‐FTIR in a cross‐section of a sample taken from the painting. Palaeoproteomics is shown to provide detailed characterisation of organic layers associated with mural paintings and therefore aids reconstruction of the conservation history of these objects.

Background: GO2 sought to optimise chemotherapy dosing in older/frail patients with advanced gastroesophageal cancer, and explored baseline geriatric assessment (GA) as a tool for treatment decision-making. Methods: Patients were recruited for whom full-dose combination chemotherapy was considered unsuitable. Two randomisation options were available: CHEMO-INTENSITY compared oxaliplatin/capecitabine at Level A (doses as used in the standard epirubicin/oxaliplatin/capecitabine regimen), B (0·8x A) or C (0·6x A). Non-inferiority of PFS was assessed using boundary HR=1·34, selected by a forum of patients and clinicians. Overall Treatment Utility (OTU), which combines efficacy, toxicity, QL and patient value/acceptability, was scored at nine weeks. Alternatively, if the patient and clinician agreed the indication for chemotherapy was uncertain, they could enter the CHEMO-BSC randomisation, comparing Level C versus best supportive care. Findings: 514 patients entered the CHEMO-INTENSITY randomisation: non-inferior PFS was confirmed for B vs A (HR=1·09 [CI=0·89-1·32]) and C vs A (HR=1·10 [0·90-1·33]). Level C produced less toxicity and better OTU than A or B. No subgroup benefited from higher doses: Level C produced better OTU even in the younger, fitter patients. 45 patients entered the CHEMO-BSC randomisation: overall survival was non-significantly longer with chemotherapy: median 6·1 vs 3·0 months, HR=0·69 [0·32-1·48], p=0·34. In multivariate analysis, baseline frailty, QL and neutrophil:lymphocyte ratio were independently associated with OTU, so can be combined in a model to estimate the probability of better or worse outcome. Interpretation: Reduced-intensity chemotherapy provided non-inferior efficacy with an improved patient experience. Baseline geriatric assessment can help predict the utility of chemotherapy. Trial Registration: [Trial registration: ISRCTN44687907] Funding Statement: Cancer Research UK [CRUK/12/022] Declaration of Interests: Dr. Grabsch reports personal fees from Merck Sharpe Dome, outside the submitted work; all other authors have nothing to declare. Ethics Approval Statement: This study was approved by the UK National Research Ethics Service and overseen by independent Trial Steering and Data Monitoring & Ethics Committees (TSC; IDMC).

Background The combination of nivolumab, a programmed death-1 (PD-1) targeted monoclonal antibody, with the cytotoxic T-lymphocyte antigen-4 (CTLA-4) targeted antibody, ipilimumab, represents a new standard of care in the first-line setting for patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC) based on recent phase III data. Combining ipilimumab with nivolumab increases rates of grade 3 and 4 toxicity compared with nivolumab alone, and the optimal scheduling of these agents when used together remains unknown. The aim of the PRISM study is to assess whether less frequent dosing of ipilimumab (12-weekly versus 3-weekly), in combination with nivolumab, is associated with a favourable toxicity profile without adversely impacting efficacy. Methods The PRISM trial is a UK-based, open label, multi-centre, phase II, randomised controlled trial. The trial population consists of patients with untreated locally advanced or metastatic clear cell RCC, and aims to recruit 189 participants. Participants will be randomised on a 2:1 basis in favour of a modified schedule of 4 doses of 12-weekly ipilimumab versus a standard schedule of 4 doses of 3-weekly ipilimumab, both in combination with standard nivolumab. The proportion of participants experiencing a grade 3 or 4 adverse reaction within 12 months forms the primary endpoint of the study, but with 12-month progression free survival a key secondary endpoint. The incidence of all adverse events, discontinuation rates, overall response rate, duration of response, overall survival rates and health related quality of life will also be analysed as secondary endpoints. In addition, the potential of circulating and tissue-based biomarkers as predictors of therapy response will be explored. Discussion The combination of nivolumab with ipilimumab is active in patients with mRCC. Modifying the frequency of ipilimumab dosing may mitigate toxicity rates and positively impact quality of life without compromising efficacy, a hypothesis being explored in other tumour types such as non-small cell lung cancer. The best way to give this combination to patients with mRCC must be similarly established. Trial registration PRISM is registered with ISRCTN (reference ISRCTN95351638, 19/12/2017). Trial status At the time of submission, PRISM is open to recruitment and data collection is ongoing.

Importance: Older and/or frail patients are underrepresented in landmark cancer trials. Tailored research is needed to address this evidence gap. Objective: The GO2 randomized clinical trial sought to optimize chemotherapy dosing in older and/or frail patients with advanced gastroesophageal cancer, and explored baseline geriatric assessment (GA) as a tool for treatment decision-making. Design, Setting, and Participants: This multicenter, noninferiority, open-label randomized trial took place at oncology clinics in the United Kingdom with nurse-led geriatric health assessment. Patients were recruited for whom full-dose combination chemotherapy was considered unsuitable because of advanced age and/or frailty. Interventions: There were 2 randomizations that were performed: CHEMO-INTENSITY compared oxaliplatin/capecitabine at Level A (oxaliplatin 130 mg/m 2on day 1, capecitabine 625 mg/m 2twice daily on days 1-21, on a 21-day cycle), Level B (doses 0.8 times A), or Level C (doses 0.6 times A). Alternatively, if the patient and clinician agreed the indication for chemotherapy was uncertain, the patient could instead enter CHEMO-BSC, comparing Level C vs best supportive care. Main Outcomes and Measures: First, broad noninferiority of the lower doses vs reference (Level A) was assessed using a permissive boundary of 34 days reduction in progression-free survival (PFS) (hazard ratio, HR = 1.34), selected as acceptable by a forum of patients and clinicians. Then, the patient experience was compared using Overall Treatment Utility (OTU), which combines efficacy, toxic effects, quality of life, and patient value/acceptability. For CHEMO-BSC, the main outcome measure was overall survival. Results: A total of 514 patients entered CHEMO-INTENSITY, of whom 385 (75%) were men and 299 (58%) were severely frail, with median age 76 years. Noninferior PFS was confirmed for Levels B vs A (HR = 1.09 [95% CI, 0.89-1.32]) and C vs A (HR = 1.10 [95% CI, 0.90-1.33]). Level C produced less toxic effects and better OTU than A or B. No subgroup benefited from higher doses: Level C produced better OTU even in younger or less frail patients. A total of 45 patients entered the CHEMO-BSC randomization: overall survival was nonsignificantly longer with chemotherapy: median 6.1 vs 3.0 months (HR = 0.69 [95% CI, 0.32-1.48], P =.34). In multivariate analysis in 522 patients with all variables available, baseline frailty, quality of life, and neutrophil to lymphocyte ratio were independently associated with OTU, and can be combined in a model to estimate the probability of different outcomes. Conclusions and Relevance: This phase 3 randomized clinical trial found that reduced-intensity chemotherapy provided a better patient experience without significantly compromising cancer control and should be considered for older and/or frail patients. Baseline geriatric assessment can help predict the utility of chemotherapy but did not identify a group benefiting from higher-dose treatment. Trial Registration: isrctn.org Identifier: ISRCTN44687907.

Background: Parkinson's disease (PD) involves motor and non-motor symptoms and loss of brain dopamine neurons. Nilotinib is a tyrosine kinase inhibitor that may alter brain dopamine metabolism. Methods: A phase II randomized, double-blind, placebo controlled trial to evaluate Nilotinib effects on safety, tolerability and clinical outcomes in PD. Seventy-five participants were randomized 1:1:1 into placebo, 150mg or 300mg Nilotinib once daily for 12 months. This study evaluated Nilotinib effects on top of the optimal standard of care in mid-stage PD (H&Y 2.5-3) at 6 and 12 months. Findings: Participants well tolerated Nilotinib and rare hematological, hepatic and other systems disorders were observed. Cardiovascular events were seen in all groups. Prior to randomization all participants were stabilized on either Levodopa and/or dopamine agonists and were tested ON time. As expected, all 3 groups were stable at 6 months, indicating the effects of PD medications. However, the placebo group declined on UPDRS II (2.39 points, p=0.007), total UPDRS I-III (4.78 points, p=0.031) and UPDRS I-IV (4.47 points, p=0.038) at 6-12 months but Nilotinib groups remained stable. Similarly, all groups were stable on PDQ39 SI and the emotional well-being subscale at 6 months but the placebo group declined (8.17 points, p=0.001 and 1.7 points, p=0.003, respectively) at 6-12 months, while Nilotinib groups remained stable. Interpretation: Nilotinib is well tolerated and appears to be safe in PD patients. Nilotinib appears to stop the decline in motor and non-motor functions up to 12 months, while the effects of optimized PD medications significantly wear off six months after treatment. Nilotinib may have a significant impact on the care and management of PD patients, leading to delay or elimination of dose adjustment of PD-medications, thus avoiding their side effects. Trial Registration: The study was conducted under FDA Investigational New Drug (IND) # 123183, and registered in ClinicalTrials.gov (NCT02954978). Funding Statement: Lasky and Barajas Family Fund and other philanthropies. Novartis Pharmaceuticals Corporation provided the study drug. Declaration of Interests: Charbel Moussa is an inventor on several US and International Georgetown University patents to use Nilotinib and other tyrosine kinase inhibitors as a treatment for neurodegenerative diseases. No other authors declare any conflict of interests with this study. Ethics Approval Statement: This study was conducted in accordance with Good Clinical Practice guidelines and was approved by the Institutional Review Board (IRB# 2016-0380) at Georgetown University Medical Center as well as by Georgetown-Howard Universities Center for Clinical and Translational Science (GHUCCTS) scientific review board. Informed consent was obtained from all participants and study partners

4051 Background: Before 2000, trials comparing BSC +/- chemo for aGOAC showed overall survival (OS) benefit, but in predominantly fit patients (pts). We have revisited this question in a modern context, using low-dose chemo in a frail population, with comprehensive baseline health and frailty assessment. Methods: In the GO2 trial, elderly and/or frail aGOAC pts with a “certain” indication for chemo were randomised between 3 chemo doses. In this GO2 substudy, pts with an “uncertain” indication for chemo were instead randomised to BSC ± the lowest dose chemo. Pts were eligible if clinician and pt agreed the indication for chemo was uncertain. There was no PS threshold, but eGFR ≥30 and bili < 2xULN were required. Baseline assessment included global QL, symptom & functional scales, frailty and comorbidity. Randomisation was 1:1 to BSC alone, or with oxaliplatin 78 mg/m2 d1, capecitabine 375 mg/m2 bd d1-21 (modified if eGFR 30-50 ml/min or bili 1.5-2.0 xULN), q21d. QL was reassessed after 9 and 18 wks. The primary endpoint analysis was OS, adjusted for baseline factors. The sample size for this exploratory sub-study was not pre-set, but around 60 pts were anticipated. Results: 558 pts entered GO2 at 61 centres 2014-17, of whom only 45 pts (8%) at 21 centres entered this uncertain randomisation. This would provide 80% power at p = 0.05 (2-tailed) to detect an OS HR of 0.3. OS was shorter in pts with worse baseline PS (p0.32. QL deteriorated less with BSC+chemo than with BSC alone. Conclusions: In this frail, poor PS population, we observed a small survival benefit with chemo but this did not reach statistical significance. Clinicians should carefully consider BSC alone as a valid treatment option for aGOAC pts with poor PS and/or frailty. Clinical trial information: 44687907. [Table: see text]

TPS4158 Background: The prognosis for pts with PD-EP-NEC is poor. First-line treatment for advanced disease is etoposide/platinum-based chemotherapy, analogous to that of high grade lung NEC, with no standard second-line treatment, and is an area of unmet need. Methods: This is a multi-centre, randomised, phase II trial of nal-IRI; 80mg/m2 intravenously (IV) over 90 mins, prior to 5-FU; 2400 mg/m2 infusion over 46 hrs and folinic acid, Q14 days, or docetaxel; 75mg/m2 IV over 60 mins, Q21 days, as second-line therapy in pts with progressive PD-EP-NEC (Ki-67 > 20%), with the overall aim of selecting a treatment for continuation to a phase III trial. The standard arm is that used in high-grade lung NEC, of which docetaxel is a second-line therapy option (NCCN guidelines) and combination regimens such as Irinotecan/5-FU are a second-line therapy option currently used without trial evidence for this subset of pts. Pts must have had prior treatment with first-line platinum-based chemotherapy, have documented disease progression and have an ECOG performance status of ≤2. This study plans to recruit 102 pts from 16 UK centres (over 37 mths). Primary endpoint is 6-mth progression-free survival (PFS) rate; trial is designed to have an 80% chance of demonstrating that the one-sided 95% confidence interval of the 6 mth PFS rate excludes 15%, if the true rate is at least 30%, where 30% is the required level of efficacy, and a rate of < 15% would give grounds for rejection. If both treatment arms exceed the required level of efficacy to warrant further evaluation in a phase III trial, treatment with the higher PFS rate at 6 mths will be selected. Secondary endpoints include overall survival, objective response rate, toxicity, quality of life, serum neuron-specific enolase. Exploratory endpoints include quantification of circulating tumour cells (CTCs), circulating tumour deoxyribonucleic acid (ctDNA) and molecular profiling of CTCs, ctDNA and tumour tissue, and generation of CTC-derived xenografts. This trial is open and has enrolled 6 pts at time of submission. Clinical trial information: 10996604.

Background:\ud The tAnGo trial was designed to investigate the potential role of gemcitabine when added to anthracycline and taxane-containing adjuvant chemotherapy for early breast cancer. When this study was developed, gemcitabine had shown significant activity in metastatic breast cancer, and there was evidence of a favourable interaction with paclitaxel.\ud \ud Methods:\ud tAnGo was an international, open-label, randomised, phase 3 superiority trial that enrolled women aged 18 years or older with newly diagnosed, early-stage breast cancer who had a definite indication for chemotherapy, any nodal status, any hormone receptor status, Eastern Cooperative Oncology Group performance status of 0–1, and adequate bone marrow, hepatic, and renal function. Women were recruited from 127 clinical centres and hospitals in the UK and Ireland, and randomly assigned (1:1) to one of two treatment regimens: epirubicin, cyclophosphamide, and paclitaxel (four cycles of 90 mg/m2 intravenously administered epirubicin and 600 mg/m2 intravenously administered cyclophosphamide on day 1 every 3 weeks, followed by four cycles of 175 mg/m2 paclitaxel as a 3 h infusion on day 1 every 3 weeks) or epirubicin, cyclophosphamide, and paclitaxel plus gemcitabine (the same chemotherapy regimen as the other group, with the addition of 1250 mg/m2 gemcitabine to the paclitaxel cycles, administered intravenously as a 0·5 h infusion on days 1 and 8 every 3 weeks). Patients were randomly assigned by a central computerised deterministic minimisation procedure, with stratification by country, age, radiotherapy intent, nodal status, and oestrogen receptor and HER-2 status. The primary endpoint was disease-free survival and the trial aimed to detect 5% differences in 5-year disease-free survival between the treatment groups. Recruitment completed in 2004 and this is the final, intention-to-treat analysis. This trial is registered with EudraCT (2004-002927-41), ISRCTN (51146252), and ClinicalTrials.gov (NCT00039546).\ud \ud Findings:\ud Between Aug 22, 2001, and Nov 26, 2004, 3152 patients were enrolled and randomly assigned to epirubicin, cyclophosphamide, paclitaxel, and gemcitabine (gemcitabine group; n=1576) or to epirubicin, cyclophosphamide, and paclitaxel (control group; n=1576). 11 patients (six in the gemcitabine group and five in the control group) were ineligible because of pre-existing metastases and were therefore excluded from the analysis. At this protocol-specified final analysis (median follow-up 10 years [IQR 10–10]), 1087 disease-free survival events and 914 deaths had occurred. Disease-free survival did not differ significantly between the treatment groups at 10 years (65% [63–68] in the gemcitabine group vs 65% [62–67] in the control group), and median disease-free survival was not reached (adjusted hazard ratio 0·97 [95% CI 0·86–1·10], p=0·64). Toxicity, dose intensity, and a detailed safety substudy showed both regimens to be safe, deliverable, and tolerable. Grade 3 and 4 toxicities were reported at expected levels in both groups. The most common were neutropenia (527 [34%] of 1565 patients in the gemcitabine group vs 412 [26%] of 1567 in the control group), myalgia and arthralgia (207 [13%] vs 186 [12%]), fatigue (207 [13%] vs 152 [10%]), infection (202 [13%] vs 141 [9%]), vomiting (143 [9%] vs 108 [7%]), and nausea (132 [8%] vs 102 [7%]).\ud \ud Interpretation:\ud The addition of gemcitabine to anthracycline and taxane-based adjuvant chemotherapy at this dose and schedule confers no therapeutic advantage in terms of disease-free survival in early breast cancer, although it can cause increased toxicity. Therefore, gemcitabine has not been added to standard adjuvant chemotherapy in breast cancer for any subgroup.\ud \ud Funding:\ud Cancer Research UK core funding for Clinical Trials Unit at the University of Birmingham, Eli Lilly, Bristol-Myers Squibb, and Pfizer.

The Law Commission published Consultation Paper No. 197 in October 2010 on unfitness to plead. This article will focus on the trial of facts hearing and the Law Commission's proposals in this regard. An examination will also be made of the Court of Appeal's judgment in R v MB given since the publication of the Law Commission Consultation Paper. The preferred route chosen by the Law Commission will be advocated, subject to concerns of properly balancing the need to protect both the vulnerable defendant from an unfair hearing and the public from the dangerous individual.

The Law Commission published Consultation Paper No. 197 in October 2010 on unfitness to plead. This article will focus on the relationship between the proposed capacity test and the abolition of the defence of doli incapax for children aged 10 or above.

The Law Commission published Consultation Paper No. 197 in October 2010 on unfitness to plead. Among the many issues to be covered were: an examination of the test for capacity which is narrower than the test for capacity under the Mental Capacity Act 2005; the scope of the trial of facts; and whether accident, mistake or self-defence could be raised as part of the defence in the context of unfitness to plead. This article will examine some of the proposals made in the Law Commission's Consultation Paper with particular focus on the meaning of capacity, along with the scope and limitations of the current law on unfitness to plead.

Gallium nitride (GaN) and related alloys are important semiconductor materials for fabricating novel photonic devices such as ultraviolet (UV) light-emitting diodes (LEDs) and vertical cavity surface-emitting lasers (VCSELs). Recent technical advances have made free-standing GaN substrates available and affordable. However, these materials are strongly resistant to wet chemical etching and also, low etch rates restrict the use of dry etching. Thus, to develop alternative high-resolution processing for these materials is increasingly important. In this paper, we report the fabrication of microstructures in free-standing GaN using pulsed UV lasers. An effective method was first developed to remove the re-deposited materials due to the laser machining. In order to achieve controllable machining and high resolution in GaN, machining parameters were carefully optimised. Under the optimised conditions, precision features such as holes (through holes, blind or tapered holes) on a tens of micrometer length scale have been machined. To fabricate micro-trenches in GaN with vertical sidewalls and a flat bottom, different process strategies of laser machining were tested and optimised. Using this technique, we have successfully fabricated high-quality micro-trenches in free-standing GaN with various widths and depths. The approach combining UV laser micromachining and other processes is also discussed. Our results demonstrate that the pulsed UV laser is a powerful tool for fabricating precision microstructures and devices in gallium nitride.

This article examines the need for a new insanity defence in the light of the inadequacies of the M'Naghten Rules. Consideration is given to some of the theoretical and practical issues which must be addressed in drafting a new insanity defence. Attention is given to American versions of the insanity defence and other proposals for reform. Tentatively, a new form of defence is suggested.

This study attempts to record the ancient ‘reredos’ at Adisham Church, Kent, a monument that is very little known. It is an exotic survival from the pre-history of English wooden church furniture. The ambiguous assemblage too often seems to sabotage one's efforts to make sense of it, yet demands to be taken seriously. We attempt to explain what its original function was, with the help of dendrochronological and polychrome analysis, as well as a rigorous examination of the joinery construction. Bearing in mind its traditional provenance to Christ Church, Canterbury, it was tempting to try to prove the posited metropolitan link. However, in the end we must reluctantly accept that a specific attribution to any particular greater church in Kent is impossible. Such an attempt would distract from the better appreciation of this incontrovertibly important object.

Little systematic analysis has been undertaken of late mediaeval wall painting in England, but the early fifteenth-century paintings at Farleigh Hungerford have recently been subjected to detailed examination. Despite previous invasive conservation treatments, this revealed a highly sophisticated use of translucent glazes over gold and silver leaf, a wide range of pigments including orpiment and lead-tin yellow, and oil as a medium. These materials, the techniques of their application and aspects of their alteration in situ are considered within the context of other English wall painting of the period, as well as the sophistication of the scheme attributed to the patronage of Sir Walter Hungerford.

This task is a vital part of drawing up a staff training and development programme. Helen Howard provides guidance on how to carry it out.

It is important that staff have the right qualifications and training to meet residents' care needs. Helen Howard provides guidance for managers on how to organize this.

In 2010, the University of Leeds introduced an academic skills strategy with the ambition of embedding academic skills into the curriculum across all faculties for all students. This case study outlines one of the approaches taken by Leeds to support the implementation of the strategy. An online portfolio of teaching resources designed to encourage and support academic staff to embed skills teaching in the curriculum was developed. The case study describes the way in which the resource was designed and developed. Feedback received thus far and plans for the future are also discussed.

How can you provide care that takes culture and ethnicity into account? Helen Howard helps you to explore your own culture and ethnicity and think how you can use that knowledge as a carer.

Background Over recent years a number of novel therapies have shown promise in advanced renal cell carcinoma (RCC). Internationally the standard of care of first-line therapy is sunitinib™, after a clear survival benefit was demonstrated over interferon-α. Convention dictates that sunitinib is continued until evidence of disease progression, assuming tolerability, although there is no evidence that this approach is superior to intermittent periods of treatment. The purpose of the STAR trial is to compare the standard treatment strategy (conventional continuation strategy, CCS) with a novel drug free interval strategy (DFIS) which includes planned treatment breaks. Methods/Design The STAR trial is an NIHR HTA-funded UK pragmatic randomised phase II/III clinical trial in the first-line treatment of advanced RCC. Participants will be randomised (1:1) to either a sunitinib CCS or a DFIS. The overall aim of the trial is to determine whether a DFIS is non-inferior, in terms of 2-year overall survival (OS) and quality adjusted life years (QALY) (averaged over treatment and follow up), compared to a CCS. The QALY primary endpoint was selected to assess whether any detriment in terms of OS could be balanced with improvements in quality of life (QoL). This is a complex trial with a number of design challenges, and to address these issues a feasibility stage is incorporated into the trial design. Predetermined recruitment (stage A) and efficacy (stage B) intermediary endpoints must be met to allow continuation to the overall phase III trial (stage C). An integral qualitative patient preference and understanding study will occur alongside the feasibility stage to investigate patients’ feelings regarding participation or non-participation in the trial. Discussion The optimal duration of continuing sunitinib in advanced RCC is unknown. Novel targeted therapies do not always have the same constraints to treatment duration as standard chemotherapeutic agents and currently there are no randomised data comparing different treatment durations. Incorporating planned treatment breaks has the potential to improve QoL and cost effectiveness, hopefully without significant detriment on OS, as has been demonstrated in other cancer types with other treatments. Trial Registration Controlled-trials.com ISRCTN 06473203

This paper looks at factors influencing the development of information literacy (IL) teaching within UK Higher Education (HE). It includes a review of recent literature on the current HE climate, curricula developments and the scope and breadth of IL. Using the experience at Leeds University Library as a case study, the paper outlines the development of a new strategy to deliver IL teaching and support to students. It describes the process of developing an academic skills strategy, which places IL within a broader range of academic skills, with the aim of contributing to the overall learning development of students. The case study describes the implementation of the strategy and the key stakeholders involved in this, including faculty team librarians , academic skills development officers and academic staff. The paper concludes that there were significant external and internal developments which had an impact on the direction taken by the strategy, specifically in embedding IL within an academic skills framework. In looking at the broad picture and by providing a case study from one of the few UK HE libraries to have progressed the academic skills agenda, it is hoped that the issues raised in the paper allow for reflection of the position of IL at the current time by all those involved in ensuring the acquisition of these skills by students.

The STAR trial is a UK randomized phase II/III study of first-line sunitinib in locally advanced/metastatic clear cell renal carcinoma (mRCC). It compares the utilization of a sunitinib conventional continuation strategy (CCS) with an experimental sunitinib drug-free interval strategy (DFIS). Sunitinib is approved for the first-line treatment of mRCC and convention dictates that it is continued until disease progression or unacceptable toxicity. Duration of chemotherapy is frequently determined by cumulative toxicity, but this is not necessarily the case for targeted therapies, and the default has previously been to continue these treatments for longer. A DFIS has the potential advantage of improved quality of life (QoL) and cost-effectiveness, due to longer time-periods off-treatment. The STAR trial is unique in determining whether QoL benefits from a DFIS can offset any potential detriment in overall survival (OS). Endpoints will assess both survival and QoL separately, but will also assess averaged QALY (quality of life year). Temporarily stopping a treatment, which is working, is recognized to be potentially challenging for patients, and a qualitative substudy will be performed alongside the phase II trial, to explore patient feelings regarding trial entry and stopping treatment. Results from this will inform recruitment strategies in phase III. The multi-stage design maximizes resource efficacy by facilitating a seamless transition between the phase II and III parts, assuming attainment of the phase II endpoints (recruitment rate and time to strategy failure). It also enables the QALY data from the initial phase II part of the trial to be used to inform and verify the powering of the overall phase III trial, as minimal data was available during initial trial design to power on a QALY outcome. Other novel outcome measures (time to strategy failure and summative progression free interval) have also been required, due to the intermittent nature of the DFIS reducing the utility of the standard progression free survival endpoint. With increasing use of targeted therapies and interest in DFIS due to potential QoL and cost effectiveness benefits, these novel endpoints will be increasing required in future clinical trial designs. The STAR trial will be an exemplar trial in the evaluation of optimal treatment strategies for targeted therapies in other diseases. We will discuss issues relating to the trial design and the methodology relating to the novel endpoints in this study, as well as comment on the implications for future trial design.

There is growing enthusiasm for robotic-assisted laparoscopic operations across many surgical specialities, including colorectal surgery, often not supported by robust clinical or cost-effectiveness data. A proper assessment of this new technology is required, prior to widespread recommendation or implementation.The ROLARR trial is a pan-world, prospective, randomised, controlled, unblinded, superiority trial of robotic-assisted versus standard laparoscopic surgery for the curative treatment of rectal cancer. It will investigate differences in terms of the rate of conversion to open operation, rate of pathological involvement of circumferential resection margin, 3-year local recurrence, disease-free and overall survival rates and also operative morbidity and mortality, quality of life and cost-effectiveness. The primary outcome measure is the rate of conversion to open operation. For 80% power at the 5% (two-sided) significance level, to identify a relative 50% reduction in open conversion rate (25% to 12.5%), 336 patients will be required. The target recruitment is 400 patients overall to allow loss to follow-up. Patients will be followed up at 30 days and 6 months post-operatively and then annually until 3 years after the last patient has been randomised.In many centres, robotic-assisted surgery is being implemented on the basis of theoretical advantages, which have yet to be confirmed in practice. Robotic surgery is an expensive health care provision and merits robust evaluation. The ROLARR trial is a pragmatic trial aiming to provide a comprehensive evaluation of both robotic-assisted and standard laparoscopic surgery for the curative resection of rectal cancer.

Multispectral and hyperspectral imaging are efficient methods of measuring spectral reflectance at high spatial resolution. This non-invasive technique has been applied to the imaging of paintings over the last 20 years. PRISMS (Portable Remote Imaging System for Multispectral Scanning) was designed specifically for imaging wall paintings. Optical Coherence Tomography (OCT) is a low coherence interferometric technique capable of fast non-invasive imaging of subsurface microstructure. This paper shows the first application of in situ OCT imaging of a wall painting. The combination of PRISMS and OCT gives information on the varnish and paint layer structure, pigment identification, the state of degradation of the paint and varnish layers and informing curators on the painting schemes and techniques.