Increasing access to children's palliative care education through e-learning: a review of the ICPCN experience.

Education is integral to the development of children's palliative care (CPC) globally; thus, the International Children's Palliative Care Network (ICPCN) developed a training programme including face-to-face and e-learning programmes to increase access to CPC. A review of ICPCN's e-learning programmes was undertaken in April/May 2018. At the time of writing, there are seven courses available, with more scheduled to be released in the near future. All courses are available in English, with some available in other languages, including Mandarin, Czech and Dutch. Between May 2016 and April 2018, 1501 individuals accessed the courses from 96 countries (39% nurses, 28% doctors). English was the prevalent language used (74%), followed by Spanish (8.5%). To date, over 3106 participants have accessed the e-learning programme from 124 countries. An evaluation in 2015/16 found that >80% of respondents said the courses were clear, understandable, rated them highly and found them useful. Some 75% of respondents reported improved knowledge, skills and change in attitude, while 61% reported a change in practice. The ICPCN e-learning platform is an innovative way of improving knowledge and understanding of CPC, thereby increasing the accessibility and availability of CPC.

Nickel Fluorocarbene Metathesis with Fluoroalkenes.

Alkene metathesis with directly fluorinated alkenes is challenging, limiting its application in the burgeoning field of fluoro-organic chemistry. A new nickel tris(phosphite) fluoro(trifluoromethyl)carbene complex ([P3 Ni]=CFCF3 ) reacts with CF2 =CF2 (TFE) or CF2 =CH2 (VDF) to yield both metallacyclobutane and perfluorocarbene metathesis products, [P3 Ni]=CF2 and CR2 =CFCF3 (R=F, H). The reaction of [P3 Ni]=CFCF3 with trifluoroethylene also yields metathesis products, [P3 Ni]=CF2 and cis/trans-CFCF3 =CFH. However, unlike reactions with TFE and VDF, this reaction forms metallacyclopropanes and fluoronickel alkenyl species, resulting presumably from instability of the expected metallacyclobutanes. DFT calculations and experimental evidence established that the observed metallacyclobutanes are not intermediates in the formation of the observed metathesis products, thus highlighting a novel variant of the Chauvin mechanism enabled by the disparate four-coordinate transition states.

Circulating tumor DNA reveals mechanisms of lorlatinib resistance in patients with relapsed/refractory ALK-driven neuroblastoma.

Activating point mutations in Anaplastic Lymphoma Kinase (ALK) have positioned ALK as the only mutated oncogene tractable for targeted therapy in neuroblastoma. Cells with these mutations respond to lorlatinib in pre-clinical studies, providing the rationale for a first-in-child Phase 1 trial (NCT03107988) in patients with ALK-driven neuroblastoma. To track evolutionary dynamics and heterogeneity of tumors, and to detect early emergence of lorlatinib resistance, we collected serial circulating tumor DNA samples from patients enrolled on this trial. Here we report the discovery of off-target resistance mutations in 11 patients (27%), predominantly in the RAS-MAPK pathway. We also identify newly acquired secondary compound ALK mutations in 6 (15%) patients, all acquired at disease progression. Functional cellular and biochemical assays and computational studies elucidate lorlatinib resistance mechanisms. Our results establish the clinical utility of serial circulating tumor DNA sampling to track response and progression and to discover acquired resistance mechanisms that can be leveraged to develop therapeutic strategies to overcome lorlatinib resistance.

Paediatric Palliative Care in Resource-Poor Countries.

There is a great need for paediatric palliative care (PPC) services globally, but access to services is lacking in many parts of the world, particularly in resource-poor settings. Globally it is estimated that 21.6 million children need access to palliative care, with 8.2 needing specialist services. PC has been identified as important within the global health agenda e.g., within universal health coverage, and a recent Lancet commission report recognised the need for PPC. However, a variety of challenges have been identified to PPC development globally such as: access to treatment, access to medications such as oral morphine, opiophobia, a lack of trained health and social care professionals, a lack of PPC policies and a lack of awareness about PPC. These challenges can be overcome utilising a variety of strategies including advocacy and public awareness, education, access to medications, implementation and research. Examples will be discussed impacting on the provision of PPC in resource-poor settings. High-quality PPC service provision can be provided with resource-poor settings, and there is an urgent need to scale up affordable, accessible, and quality PPC services globally to ensure that all children needing palliative care can access it.

Comprehension and perceptions of study participants upon receiving perfluoroalkyl substance exposure biomarker results.

BACKGROUND: Measurement of environmental biomarkers in biomedia is increasingly used as a method of exposure characterization in human population studies. Reporting the results of biomarker measurements back to study participants has been controversial, including questions of ethics and whether the study participants would want to receive and would understand the results. METHODS: Recently we mailed individual measurements of two serum biomarkers, perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) to participants in three exposure studies of persons living in the Ohio River Valley, of whom 60 were parents of children who had been sampled. Many had serum concentrations of PFOA above the US population 95th percentile value. Reporting forms used in the three studies were somewhat different (either tables or charts for comparison to US population values) and varied in complexity. With all reports, we included information about concentrations of PFOA and PFOS in the general population, and a survey designed to ascertain the opinions of the study participants about the information they received. RESULTS: Approximately 33% (273/821) returned the survey, and of those, 96% reported that they were pleased that we had sent them the report. Most (86%) responded that the results were easy to understand and the enclosed fact sheet was helpful in answering questions (87%). Regarding the amount of information, most felt that we provided the "right amount" (78%) but some "too much" (7%) and some "too little" (15%). The majority (53%) were surprised at their serum concentrations. Of those with serum values > 13.0 ng/mL, 74% responded that they thought their serum concentration was "high", but only 22% of those with serum concentrations ≤5.6 responded that their concentration was "low". Surprisingly, many talked to no one about their levels; those who did were most likely to discuss the report with family members. CONCLUSIONS: Reporting back individual environmental biomarker results is generally well received by study participants, and those with high concentrations perceived them to be high. Questions remain as to why study participants did not discuss their results with others.

Inspiration, innovation and integration: highlights from the third ICPCN conference on children's palliative care, 30 May to 2 June 2018, Durban, South Africa.

The International Children's Palliative Care Network (ICPCN) held its third international conference on children's palliative care in Durban, South Africa, from May 30 2018 to 2 June 2018. The conference-inspiration, innovation and integration-brought together 250 participants from 41 countries and was held in conjunction with local partners-Umduduzi Hospice Care for Children, Palliative Treatment for Children South Africa (Patch SA) and the Hospice and Palliative Care Association of South Africa. It built on national and global developments in palliative care such as its inclusion in Universal health coverage (UHC), the Lancet Commission report on pain and palliative care and the sustainable development goals (SDGs), and aimed to raise the profile of children's palliative care in KwaZulu-Natal (KZN) and nationally. Seven pre-conference workshops were held prior to the conference on topics such as pain and symptom management, children's palliative care within a humanitarian crisis, perinatal palliative care, research, developing programmes, ethical issues and difficult conversations in children's palliative care. Delegates were welcomed in true Durban style at the welcome reception hosted by the City of Durban and uShaka Marine World. The opening plenary included entertainment from the Open Air School and Hillcrest Primary School, and inspirational talks from the Member of the Executive Council (MEC) for Health, a representative of the World Health Organization (WHO), the Chief Executive of ICPCN and the Noble Peace Prize Nominee Dr MR Rajagopal from Pallium India. Plenary sessions were interspersed throughout the conference with 56 oral concurrent presentations and workshops, six 'Meet the expert sessions' 100 poster presentations and the South African Premier of the film 'Hippocratic: 18 Experiments in gently shaking the world'. There was a great feeling of networking and learning throughout the conference, with the conference being well evaluated, and an increase in the level of presentations and research from previous conferences demonstrating the steps that are being taken in children's palliative care globally.

'Disaster day': global health simulation teaching.

BACKGROUND: As society diversifies and globalisation quickens, the importance of teaching global health to medical undergraduates increases. For undergraduates, the majority of exposure to 'hands-on' teaching on global health occurs during optional elective periods. This article describes an innovative student-led initiative, 'Disaster Day', which used simulation to teach global health to undergraduates. METHODS: The teaching day began with an introduction outlining the work of Médecins Sans Frontières and the basic principles of resuscitation. Students then undertook four interactive simulation scenarios: Infectious Diseases in a Refugee Camp, Natural Disaster and Crush Injury, Obstetric Emergency in a Low-Income Country, and Warzone Gunshot Wound. Sessions were facilitated by experienced doctors and fourth-year students who had been trained in the delivery of the scenarios. Students completed pre- and post-session evaluation forms that included the self-rating of confidence in eight learning domains (using a five-point Likert scale). RESULTS: Twenty-seven students voluntarily attended the session, and all provided written feedback. Analysis of the pre- and post-session evaluations demonstrated statistically significant improvements in confidence across all but one domains (Wilcoxon signed rank test). Free-text feedback was overwhelmingly positive, with students appreciating the practical aspect of the scenarios. For undergraduates, the majority of exposure to 'hands-on' teaching on global health occurs during optional elective periods DISCUSSION: Simulation-based teaching can provide students with 'hands-on' exposure to global health in a controlled, reproducible fashion and appears to help develop their confidence in a variety of learning domains. The more widespread use of such teaching methods is encouraged: helping tomorrow's doctors develop insight into global health challenges may produce more rounded clinicians capable of caring for more culturally diverse populations.

Characterisation of olanzapine-induced weight gain and effect of aripiprazole vs olanzapine on body weight and prolactin secretion in female rats.

RATIONALE: Atypical antipsychotic drug (APD)-induced weight gain causes non-compliance, increasing the risk of relapse and medical complications. OBJECTIVES: In an animal model, we assessed body weights, food intake, body fat/lean body mass contents and blood serum levels of glucose and lipids in female rats treated with olanzapine (Experiment 1). Also, we investigated the effect of aripiprazole vs olanzapine treatment on weight gain (WG) and plasma prolactin secretion in two strains (Wistar and Sprague-Dawley) and in two housing conditions (singly and group housed; Experiment 2). METHODS: In Experiment 1, Wistar females received either vehicle or olanzapine (5.0 mg kg(-1), p.o.) twice daily for 14 days. In Experiment 2, female rats (Wistar or Sprague-Dawley), housed singly or in groups, received either vehicle, aripiprazole (2.0-8.0 mg kg(-1), p.o.), or olanzapine (1.0-10 mg kg(-1), p.o.) twice daily for 7 days. Body weights and food intake were assessed daily. Body composition and blood assays were analyzed at the end of the treatment. RESULTS: WG induced by chronic olanzapine treatment was characterised by hyperphagia, increased body fat, and serum free fatty acid content and reduced lean tissue and serum glucose content. Subchronic aripiprazole treatment resulted in rapid and robust WG similar to those observed with olanzapine. In spite of similar effects on body weight, aripiprazole and olanzapine stimulated markedly different patterns of prolactin secretion. Body weight changes and prolactin secretion induced by these APDs were significantly modulated by housing and by strain. CONCLUSION: Assessment of body weight in the present model may not have predictive validity, and other measures may be needed to differentiate between WG-inducing and weight-neutral drugs.

The discovery and optimization of pyrimidinone-containing MCH R1 antagonists.

Optimization of a series of constrained melanin-concentrating hormone receptor 1 (MCH R1) antagonists has provided compounds with potent and selective MCH R1 activity. Details of the optimization process are provided and the use of one of the compounds in an animal model of diet-induced obesity is presented.