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

Understanding the solution behavior of minor actinides in the presence of EDTA(4-), carbonate, and hydroxide ligands

Understanding the solution behavior of minor actinides in the presence of EDTA(4-), carbonate, and hydroxide ligand

Altered dynamic postural stability and joint position sense following British Army foot-drill

Impaired proprioceptive acuity negatively affects both joint position sense and postural control and is a risk factor for lower-extremity musculoskeletal injury in athletes and military personnel. British Army foot-drill is an occupational military activity involving cyclical high impact loading forces greater than those observed in athletes during high level plyometrics. Foot-drill may contribute to the high rates of lower-extremity overuse injuries observed in recruits during basic training. There is limited research investigating foot-drill specific injury risk factors in women. This study aimed to quantify changes in ankle joint proprioception and dynamic postural stability following a period of British Army foot-drill. Fourteen recruit age-matched women underwent pre-post foot-drill measures of frontal plane ankle joint position sense (JPS) and dynamic postural stability using the dynamic postural stability index (DPSI). Passive ankle JPS was assessed from relative test angles of inversion (IN) and eversion (EV) 30% and IN60% using an isokinetic dynamometer. The DPSI and the individual stability indices (medio-lateral [MLSI], anterior-posterior [APSI] and vertical [VSI]) were calculated from lateral and forward jump-landing conditions using force plates. Foot-drill was conducted by a serving British Army drill instructor. Significantly greater absolute mean JPS error for IN30% and EV30% was observed post foot-drill (p ? 0.016, d ? 0.70). For both the lateral and forward jump-landing conditions, significantly greater stability index scores were observed for MLSI, APSI and DPSI (p ? 0.017, d ? 0.52). Significantly greater JPS error and stability index scores are associated with the demands of British Army foot-drill. These results provide evidence that foot-drill negatively affects lower-extremity proprioceptive acuity in recruit age-matched women, which has implications for increased injury risk during subsequent military physical activity, occurring in a normal training cycle

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

A worked example of initial theory-building: PARTNERS2 collaborative care for people who have experienced psychosis in England

YesIn this article, we present an exemplar of the initial theory-building phase of theory-driven evaluation for the PARTNERS2 project, a collaborative care intervention for people with experience of psychosis in England. Initial theory-building involved analysis of the literature, interviews with key leaders and focus groups with service users. The initial programme theory was developed from these sources in an iterative process between researchers and stakeholders (service users, practitioners, commissioners) involving four activities: articulation of 442 explanatory statements systematically developed using realist methods; debate and consensus; communication; and interrogation. We refute two criticisms of theory-driven evaluation of complex interventions. We demonstrate how the process of initial theory-building made a meaningful contribution to our complex intervention in five ways. Although time-consuming, it allowed us to develop an internally coherent and well-documented intervention. This study and the lessons learnt provide a detailed resource for other researchers wishing to build theory for theory-driven evaluation.This research was funded by a UK NIHR Programme Grant (RP-PG-0611- 20004) and the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care South West Peninsula (NIHR CLAHRC South West Peninsula)

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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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

The impact of diabetes mellitus on survival following resection and adjuvant chemotherapy for pancreatic cancer

BACKGROUND: Diabetes mellitus is frequently observed in pancreatic cancer patients and is both a risk factor and an early manifestation of the disease. METHODS: We analysed the prognostic impact of diabetes on the outcome of pancreatic cancer following resection and adjuvant chemotherapy using individual patient data from three European Study Group for Pancreatic Cancer randomised controlled trials. Analyses were carried out to assess the association between clinical characteristics and the presence of preoperative diabetes, as well as the effect of diabetic status on overall survival. RESULTS: In total, 1105 patients were included in the analysis, of whom 257 (23%) had confirmed diabetes and 848 (77%) did not. Median (95% confidence interval (CI)) unadjusted overall survival in non-diabetic patients was 22.3 (20.8–24.1) months compared with 18.8 (16.9–22.1) months for diabetic patients (P=0.24). Diabetic patients were older, had increased weight and more co-morbidities. Following adjustment, multivariable analysis demonstrated that diabetic patients had an increased risk of death (hazard ratio: 1.19 (95% CI 1.01, 1.40), P=0.034). Maximum tumour size of diabetic patients was larger at randomisation (33.6 vs 29.7 mm, P=0.026). CONCLUSIONS: Diabetes mellitus was associated with increased tumour size and reduced survival following pancreatic cancer resection and adjuvant chemotherapy

Evaluation of a primary care-based collaborative care model (PARTNERS2) for people with diagnoses of schizophrenia, bipolar, or other psychoses: study protocol for a cluster randomised controlled trial

YesCurrent NHS policy encourages an integrated approach to provision of mental and physical care for individuals with long term mental health problems. The 'PARTNERS2' complex intervention is designed to support individuals with psychosis in a primary care setting. The trial will evaluate the clinical and cost-effectiveness of the PARTNERS2 intervention. This is a cluster randomised controlled superiority trial comparing collaborative care (PARTNERS2) with usual care, with an internal pilot to assess feasibility. The setting will be primary care within four trial recruitment areas: Birmingham & Solihull, Cornwall, Plymouth, and Somerset. GP practices are randomised 1:1 to either (a) the PARTNERS2 intervention plus modified standard care ('intervention'); or (b) standard care only ('control'). PARTNERS2 is a flexible, general practice-based, person-centred, coaching-based intervention aimed at addressing mental health, physical health, and social care needs. Two hundred eligible individuals from 39 GP practices are taking part. They were recruited through identification from secondary and primary care databases. The primary hypothesis is quality of life (QOL). Secondary outcomes include: mental wellbeing, time use, recovery, and process of physical care. A process evaluation will assess fidelity of intervention delivery, test hypothesised mechanisms of action, and look for unintended consequences. An economic evaluation will estimate its cost-effectiveness. Intervention delivery and follow-up have been modified during the COVID-19 pandemic. The overarching aim is to establish the clinical and cost-effectiveness of the model for adults with a diagnosis of schizophrenia, bipolar, or other types of psychoses.PARTNERS2 is funded by the National Institute for Health Research (NIHR) under its Programme Grant for Applied Research Programme (grant number: RP-PG- 200625). This research was also supported by the NIHR Collaboration for Leadership in Applied Health Research and Care South West Peninsula at the Royal Devon and Exeter NHS Foundation Trust

Both “illness and temptation of the enemy”: melancholy, the medieval patient and the writings of King Duarte of Portugal (r. 1433–38)

Recent historians have rehabilitated King Duarte of Portugal, previously maligned and neglected, as an astute ruler and philosopher. There is still a tendency, however, to view Duarte as a depressive or a hypochondriac, due to his own description of his melancholy in his advice book, the Loyal Counselor. This paper reassesses Duarte's writings, drawing on key approaches in the history of medicine, such as narrative medicine and the history of the patient. It is important to take Duarte's views on his condition seriously, placing them in the medical and theological contexts of his time and avoiding modern retrospective diagnosis. Duarte's writings can be used to explore the impact of plague, doubt and death on the life of a well-educated and conscientious late-medieval ruler