Identifying social outcomes of importance for childhood cancer survivors: an e-Delphi study.

PURPOSE: Childhood cancer survivors (CCS) are at risk of deficits in their social outcomes, a key aspect of overall health and quality of life. Social outcomes of import are ill-defined leading to potential gaps in research and service provision. In this study, we undertook a preliminary consensus seeking exercise to support the development of a framework of the important social outcomes for CCS. METHODS: A modified e-Delphi study was conducted with four groups: CCS, health professionals, social workers and teachers. Round 1, developed from a literature review, included 34 questions rated for importance on a 7-point Likert scale. Rounds 2 and 3 presented items not achieving consensus, additionally proposed items and in round 3, a ranking question. RESULTS: Survey 1 was completed by 38 participants, 31 (82%) completed survey 2 and 28 (76%) completed survey 3. A total of 36 items were prioritised across 6 domains (education, independence, work, relationships, community, lifestyle), together forming the final list of social outcomes. Of these, 22 items met consensus for importance. Items rated most important were "having autonomy" and "avoiding social isolation". Quantitative and qualitative results reflected that social outcomes for survivors and general public should be the same. CONCLUSION: We have generated initial consensus on important social outcomes for CCS, highlighting the need for these to be matched to those of the general population. It suggests strategies are required to ensure autonomy and appropriate support for independence and relationships are provided through long-term aftercare and beyond. Further work is needed to validate and develop these findings into a framework to support appropriate social aftercare for CCS.

Following treatment for childhood cancer, survivors may face problems with their social health. These are the parts of life, besides physical and mental health, that help people to lead full, happy and satisfied lives. Social health is important as it affects all areas of our lives and includes many areas such as education, work and relationships. It is essential that we understand what the most important areas of social health are for childhood cancer survivors so that we can support these. This will help survivors lead the lives they want as adults. In this study, 38 childhood cancer survivors, children's cancer doctors and nurses, social workers and teachers took part in a series of questionnaires designed to collect their views about social health for survivors. Participants established 22 areas of social health to be very important. 'Having autonomy' and 'avoiding social isolation' were selected as the most important. Participants felt that the aspects of social health which are important to survivors are the same outcomes as for the wider public. However, survivors may face many barriers to doing well in these areas. To fully identify the important areas of social health for childhood cancer survivors, we need to undertake further work to understand the views of other important groups, such as parents or carers. We also need to explore the barriers survivors face in achieving good social health.

Relative Oral Bioavailability and Food Effects of Two Sepiapterin Formulations in Healthy Participants.

Sepiapterin is an orally administered drug in development for the treatment of phenylketonuria, an inborn error of metabolism characterized by the deficiency of the phenylalanine-metabolizing enzyme phenylalanine hydroxylase. This study characterized the pharmacokinetics, safety, and tolerability of 2 clinical sepiapterin formulations (Phase 1/2, Phase 3) and the effects of food on the pharmacokinetics of the Phase 3 formulation in healthy participants. In Part A, 18 participants were randomized to one of 2 treatment sequences, each with 4 dosing periods comprising a single dose (20 or 60 mg/kg) of the Phase 1/2 or the Phase 3 formulation with a low-fat diet. In Part B, 14 participants were randomized to one of 2 sequences, each comprising 4 dosing periods of a single dose (20 or 60 mg/kg) of the Phase 3 formulation under fed (high-fat) or fasted conditions. Following oral administration, sepiapterin was quickly absorbed and rapidly and extensively converted to tetrahydrobiopterin (BH4). BH4 was the major circulating active moiety. Under low-fat conditions, the Phase 3 formulation was bioequivalent to the Phase 1/2 formulation at 20 mg/kg, while slightly lower BH4 exposure (approximately 0.81×) for the Phase 3 formulation was observed at 60 mg/kg. BH4 exposure increased to approximately 1.7× under the low-fat condition and approximately 2.8× under the high-fat condition at a dose of either 20 or 60 mg/kg for the Phase 3 formulation, compared with the fasted condition. Both sepiapterin formulations were well tolerated, with no serious or severe adverse events reported. All treatment-emergent adverse events were mild or moderate in severity.

Validation and application of volumetric absorptive microsampling (VAMS) dried blood method for phenylalanine measurement in patients with phenylketonuria.

BACKGROUND: Frequent blood phenylalanine (Phe) measurement is required for phenylketonuria (PKU) patients for diagnosis and disease status monitoring. Though various methods are available for blood Phe measurement, there is a lack of validated quantitative methods for measuring Phe with less than 15% variability. A method to allow at home blood sample collection for the PKU community is in high demand. METHODS: A volumetric absorptive microsampling (VAMS) dried blood collection high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed and fully validated for blood Phe measurement in compliance with regulatory guidances. The method accuracy, precision, stability, selectivity, matrix and hematocrit effects were assessed. A venous plasma collection HPLC-MS/MS method was developed and validated as a reference method. 311 matching VAMS and plasma samples were collected from 24 PKU subjects in a Phase 2 clinical study. Phe measurements using the two methods were compared. RESULTS: Both VAMS and the plasma sample collection methods met the acceptance criteria for Good Laboratory Practice (GLP) bioanalytical analysis. Comparisons showed a high Pearson's correlation of 0.9813. The Passing-Bablok analysis showed that the difference was estimated to be less than 5% and Bland Altman analysis indicated that the difference was proportional with Phe concentration and for the majority of samples (88.85%) the measurement was within ±20% difference. Following 7 days treatment with 60 or 20 mg/kg/day PTC923 (Sepiapterin) or 20 mg/kg/day sapropterin, PKU patients exhibited respectively -206.4, -146.9, and -91.5 µmol/L reductions of blood Phe as measured by the VAMS method. CONCLUSIONS: Concordant results were obtained using VAMS and plasma methods, which demonstrated that VAMS is a reliable method for clinical applications to monitor blood Phe for PKU patients.

Identifying the important social outcomes for childhood cancer survivors: an e-Delphi study protocol.

INTRODUCTION: Optimising the health of childhood cancer survivors is important given the high long-term survival rate coupled with a significant late effects burden. Included within the WHO's definition of 'Health' are social outcomes. These are of interest given their impact on adult functioning within society, complex interactions with physical and mental health outcomes and potential for cross generational effects. Categories included within the definition of social outcomes are ill defined leading to potential gaps in research and service provision which could affect the ability of survivors to achieve their maximal potential. An e-Delphi study will be used to achieve expert consensus on the most important social outcomes for childhood cancer survivors to inform future research and ultimately, service provision. METHODS AND ANALYSIS: A heterogeneous sample of at least 48 panel members will be recruited across four groups chosen to provide different perspectives on the childhood cancer journey: childhood cancer survivors, health professionals, social workers and teachers. Purposive sampling from a UK, regional long-term follow-up clinic will be used to recruit a representative sample of survivors. Other panel members will be recruited through local channels and national professional working groups. Opinions regarding breakdown and relevance of categories of social outcome will be collected through 3-5 rounds of questionnaires using an e-Delphi technique. Open ended, 7-point Likert scale and ranking questions will be used. Each round will be analysed collectively and per group to assess inter-rater agreement. Agreement and strength of agreement will be indicated by a median score of 6 or 7 and mean absolute deviation from the median, respectively. ETHICS AND DISSEMINATION: Ethical approval for this study has been granted by Regional Ethics Committee 4, West of Scotland (ID 297344). Study findings will be disseminated to involved stakeholders, published in a peer-reviewed journal and presented at conferences.

Paediatric rhombencephalitis presenting with bradycardia: a good recovery despite cardiac involvement.

Rhombencephalitis is a rare condition, often caused by infection, commonly presenting with myoclonic jerks, ataxia and cranial nerve palsy. Typically, it has a high morbidity and mortality, with worse prognosis associated with cardiopulmonary involvement. Herein, we present the case of a 10-year-old boy, presenting with headache, vomiting, symptomatic bradycardia and rapidly progressing ophthalmoplegia from a sixth nerve palsy, without additional brainstem symptoms. Previously, pericarditis, myocarditis and heart failure have been associated with rhombencephalitis, but not bradycardia. The cause of his rhombencephalitis was presumed viral, but despite extensive screening, the virus responsible was never isolated. Following treatment with intravenous antibiotics and antivirals in a high dependency unit, he recovered well with no neurological deficit on discharge and marked radiological improvement on MRI 4 weeks later. Although rare, rhombencephalitis should be considered in a child presenting with neurological symptoms, particularly alongside a cranial nerve palsy, developing over a rapid time course.

Neonicotinoids and bumblebees (Bombus terrestris): effects on nectar consumption in individual workers.

BACKGROUND: The objective of this study was to quantify whether the presence of three different neonicotinoid insecticides (imidacloprid, thiamethoxam or clothianidin) in sucrose solution results in antifeedant effects in individual worker bumblebees (Bombus terrestris), and, if so, whether this effect is reversible if bees are subsequently offered untreated feed. RESULTS: Bees exposed to imidacloprid displayed a significant dose-dependent reduction in consumption at 10 and 100 µg L(-1), which was reversed when untreated feed was offered. No consistent avoidance/antifeedant response to nectar substitute with thiamethoxam was detected at the more field-realistic dose rates of 1 and 10 µg L(-1), and exposure to the very high 100 µg L(-1) dose rate was followed by 100% mortality of experimental insects. No reduction in food intake was recorded at 1 µg clothianidin L(-1), reduced consumption was noted at 10 µg clothianidin L(-1) and 100% mortality occurred when bees were exposed to rates of 100 µg clothianidin L(-1). CONCLUSION: This study provides evidence of a direct antifeedant effect of imidacloprid and clothianidin in individual bumblebees but highlights that this may be a compound-specific effect.