Introduction

Collective identities and transnational networks in medieval and early modern Europe, 1000-180

Marketing a tourism industry in late stage decline: The case of the Isle of Man

Qualitative interviews in the Isle of Man uncovered local perceptions of a tourism industry in late stage decline. Social impacts of decline are pronounced including facilities loss, cultural changes and a heightening of perceived peripherality: which taken together undermine local identity. Tourists are welcomed as they help to affirm the pride residents have in their island in creating a more active atmosphere, provide social interaction opportunities and to combat negative stereotyping. Thus findings emphasise the diverse, unique and persistent benefits of tourism in the Isle of Man, despite its decline. Destination marketing recommendations are therefore made to better address the experiences and desires of communities experiencing decline

Sedimentary macrofossil records reveal ecological change in English lakes: implications for conservation

Aquatic macrophytes play a key role in providing habitat, refuge and food for a range of biota in shallow lakes. However, many shallow lakes have experienced declines in macrophyte vegetation in recent decades, principally due to eutrophication. As changes in macrophyte composition and abundance can affect overall ecological structure and function of a lake, an assessment of the timing and nature of such changes is crucial to our understanding of the wider lake ecosystem. In the typical absence of historical plant records, the macro-remains of macrophytes preserved in lake sediments can be used to assess long-term changes in aquatic vegetation. We generated recent (150–200 years) plant macrofossil records for six English lakes subject to conservation protection to define past macrophyte communities, assess trajectories of ecological change and consider the implications of our findings for conservation targets and strategies. The data for all six lakes reveal a diverse submerged macrophyte community, with charophytes as a key component, in the early part of the sedimentary records. The stratigraphies indicate considerable change to the aquatic vegetation over the last two centuries with a general shift towards species more typically associated with eutrophic conditions. A common feature is the decline in abundance of low-growing charophytes and an increase in tall canopy-forming angiosperms such as fine-leaved Potamogeton species, Zannichellia palustris and Callitriche species. We hypothesise, based on findings from long-term datasets and palaeoecological records from enriched shallow lakes where plants are now absent, that the observed shifts provide a warning to managers that the lakes are on a pathway to complete macrophyte loss such that nutrient load reduction is urgently needed. It is the sound understanding of present-day plant ecology that affords such reliable interpretation of the fossil data which, in turn, provide valuable context for current conservation decisions

Managing tourism decline: insights from the Isle of Man

Qualitative interviews conducted in the Isle of Man investigate local perceptions of a tourism industry in long-term decline: a development stage typically overlooked. Negative impacts of decline are revealed; including facilities loss, landscape erosion, and a heightened sense of peripherality. Together such impacts undermine local identity and attractiveness of place. Tourists are welcomed as they help to affirm the pride residents have in their island, create atmosphere, provide social interaction opportunities, stimulate positive emotions and combat negative stereotyping. Emphasised is the on-going importance of tourism impacts in a peripheral location. Practioner recommendations are therefore made calling attention to the need to more carefully manage the process of decline. Potential strategies for achieving this are signposted

Optimal Duration and Timing of Adjuvant Chemotherapy After Definitive Surgery for Ductal Adenocarcinoma of the Pancreas: Ongoing Lessons From the ESPAC-3 Study

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A three-arm randomised phase II study of the MEK inhibitor selumetinib alone or in combination with paclitaxel in metastatic uveal melanoma

\ua9 2024 The AuthorsAims: The MAPK pathway is constitutively activated in uveal melanoma (UM). Selumetinib (AZD6244, ARRY-142886), a MEK inhibitor, has shown limited activity as monotherapy in metastatic UM. Pre-clinical studies support synergistic cytotoxic activity for MEK inhibitors combined with taxanes, and here we sought to assess the clinical efficacy of combining selumetinib and paclitaxel. Patients and methods: Seventy-seven patients with metastatic UM who had not received prior chemotherapy were randomised to selumetinib alone, or combined with paclitaxel with or without interruption in selumetinib two days before paclitaxel. The primary endpoint was progression free survival (PFS). After amendment, the combination arms were combined for analysis and the sample size adjusted to detect a hazard ratio (HR): 0.55, 80% power at 1-sided 5% significance level. Results: The median PFS in the combination arms was 4.8 months (95% CI: 3.8 - 5.6) compared with 3.4 months (2.0 - 3.9) in the selumetinib arm (HR 0.62 [90% CI 0.41 - 0.92], 1-sided p-value = 0.022). ORR was 14% and 4% in the combination and monotherapy arms respectively. Median OS was 9 months for the combination and was not significantly different from selumetinib alone (10 months) with HR of 0.98 [90% CI 0.58 - 1.66], 1-sided p-value = 0.469. Toxicity was in keeping with the known profiles of the agents involved. Conclusions: SelPac met its primary endpoint, demonstrating an improvement in PFS for combination selumetinib and paclitaxel. No improvement in OS was observed, and the modest improvement in PFS is not practice changing

Immediate surgery compared with short-course neoadjuvant gemcitabine plus capecitabine, FOLFIRINOX, or chemoradiotherapy in patients with borderline resectable pancreatic cancer (ESPAC5): a four-arm, multicentre, randomised, phase 2 trial.

BACKGROUND: Patients with borderline resectable pancreatic ductal adenocarcinoma have relatively low resection rates and poor survival despite the use of adjuvant chemotherapy. The aim of our study was to establish the feasibility and efficacy of three different types of short-course neoadjuvant therapy compared with immediate surgery. METHODS: ESPAC5 (formerly known as ESPAC-5f) was a multicentre, open label, randomised controlled trial done in 16 pancreatic centres in two countries (UK and Germany). Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, biopsy proven pancreatic ductal adenocarcinoma in the pancreatic head, and were staged as having a borderline resectable tumour by contrast-enhanced CT criteria following central review. Participants were randomly assigned by means of minimisation to one of four groups: immediate surgery; neoadjuvant gemcitabine and capecitabine (gemcitabine 1000 mg/m2 on days 1, 8, and 15, and oral capecitabine 830 mg/m2 twice a day on days 1-21 of a 28-day cycle for two cycles); neoadjuvant FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, folinic acid given according to local practice, and fluorouracil 400 mg/m2 bolus injection on days 1 and 15 followed by 2400 mg/m2 46 h intravenous infusion given on days 1 and 15, repeated every 2 weeks for four cycles); or neoadjuvant capecitabine-based chemoradiation (total dose 50·4 Gy in 28 daily fractions over 5·5 weeks [1·8 Gy per fraction, Monday to Friday] with capecitabine 830 mg/m2 twice daily [Monday to Friday] throughout radiotherapy). Patients underwent restaging contrast-enhanced CT at 4-6 weeks after neoadjuvant therapy and underwent surgical exploration if the tumour was still at least borderline resectable. All patients who had their tumour resected received adjuvant therapy at the oncologist's discretion. Primary endpoints were recruitment rate and resection rate. Analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN, 89500674, and is complete. FINDINGS: Between Sept 3, 2014, and Dec 20, 2018, from 478 patients screened, 90 were randomly assigned to a group (33 to immediate surgery, 20 to gemcitabine plus capecitabine, 20 to FOLFIRINOX, and 17 to capecitabine-based chemoradiation); four patients were excluded from the intention-to-treat analysis (one in the capecitabine-based chemoradiotherapy withdrew consent before starting therapy and three [two in the immediate surgery group and one in the gemcitabine plus capecitabine group] were found to be ineligible after randomisation). 44 (80%) of 55 patients completed neoadjuvant therapy. The recruitment rate was 25·92 patients per year from 16 sites; 21 (68%) of 31 patients in the immediate surgery and 30 (55%) of 55 patients in the combined neoadjuvant therapy groups underwent resection (p=0·33). R0 resection was achieved in three (14%) of 21 patients in the immediate surgery group and seven (23%) of 30 in the neoadjuvant therapy groups combined (p=0·49). Surgical complications were observed in 29 (43%) of 68 patients who underwent surgery; no patients died within 30 days. 46 (84%) of 55 patients receiving neoadjuvant therapy were available for restaging. Six (13%) of 46 had a partial response. Median follow-up time was 12·2 months (95% CI 12·0-12·4). 1-year overall survival was 39% (95% CI 24-61) for immediate surgery, 78% (60-100) for gemcitabine plus capecitabine, 84% (70-100) for FOLFIRINOX, and 60% (37-97) for capecitabine-based chemoradiotherapy (p=0·0028). 1-year disease-free survival from surgery was 33% (95% CI 19-58) for immediate surgery and 59% (46-74) for the combined neoadjuvant therapies (hazard ratio 0·53 [95% CI 0·28-0·98], p=0·016). Three patients reported local disease recurrence (two in the immediate surgery group and one in the FOLFIRINOX group). 78 (91%) patients were included in the safety set and assessed for toxicity events. 19 (24%) of 78 patients reported a grade 3 or worse adverse event (two [7%] of 28 patients in the immediate surgery group and 17 [34%] of 50 patients in the neoadjuvant therapy groups combined), the most common of which were neutropenia, infection, and hyperglycaemia. INTERPRETATION: Recruitment was challenging. There was no significant difference in resection rates between patients who underwent immediate surgery and those who underwent neoadjuvant therapy. Short-course (8 week) neoadjuvant therapy had a significant survival benefit compared with immediate surgery. Neoadjuvant chemotherapy with either gemcitabine plus capecitabine or FOLFIRINOX had the best survival compared with immediate surgery. These findings support the use of short-course neoadjuvant chemotherapy in patients with borderline resectable pancreatic ductal adenocarcinoma. FUNDING: Cancer Research UK

What are the main inefficiencies in trial conduct : a survey of UKCRC registered clinical trials units in the UK

BACKGROUND: The UK Clinical Research Collaboration (UKCRC) registered Clinical Trials Units (CTUs) Network aims to support high-quality, efficient and sustainable clinical trials research in the UK. To better understand the challenges in efficient trial conduct, and to help prioritise tackling these challenges, we surveyed CTU staff. The aim was to identify important inefficiencies during two key stages of the trial conduct life cycle: (i) from grant award to first participant, (ii) from first participant to reporting of final results. METHODS: Respondents were asked to list their top three inefficiencies from grant award to recruitment of the first participant, and from recruitment of the first participant to publication of results. Free text space allowed respondents to explain why they thought these were important. The survey was constructed using SurveyMonkey and circulated to the 45 registered CTUs in May 2013. Respondents were asked to name their unit and job title, but were otherwise anonymous. Free-text responses were coded into broad categories. RESULTS: There were 43 respondents from 25 CTUs. The top inefficiency between grant award and recruitment of first participant was reported as obtaining research and development (R&D) approvals by 23 respondents (53%), contracts by 22 (51%), and other approvals by 13 (30%). The top inefficiency from recruitment of first participant to publication of results was failure to meet recruitment targets, reported by 19 (44%) respondents. A common comment was that this reflected overoptimistic or inaccurate estimates of recruitment at site. Data management, including case report form design and delays in resolving data queries with sites, was reported as an important inefficiency by 11 (26%) respondents, and preparation and submission for publication by 9 (21%). CONCLUSIONS: Recommendations for improving the efficiency of trial conduct within the CTUs network include: further reducing unnecessary bureaucracy in approvals and contracting; improving training for site staff; realistic recruitment targets and appropriate feasibility; developing training across the network; improving the working relationships between chief investigators and units; encouraging funders to release sufficient funding to allow prompt recruitment of trial staff; and encouraging more research into how to improve the efficiency and quality of trial conduct

The Extent and Role of Domestic Tourism in a Small Island: The Case of the Isle of Man

This article presents a case concerning microdomestic tourism on the Isle of Man, British Isles. Despite being a small island, research highlights that considerable domestic tourism occurs (referred to as microdomestic tourism to reflect the small island size and distinguish from wider British Isles tourism), including day trips and overnight stays. Participants identified such behavior as touristic, and distinct from other leisure activities. Qualitative interviews with residents explore the nature of and reasons for microdomestic tourism within a small island. Breaks from routine, entertaining friends and family, and exploring less well known landscapes are shown to underpin. Highlighted is that microdomestic tourism has a variety of potential benefits, which may counter some of the restrictions typically faced by a small island community. Support for an otherwise ailing tourism industry may help to protect facilities and infrastructure used by the wider community, maintain tourism capacity, and provide atmosphere attractive to foreign visitors