Preventing work-related stress among staff working in children's cancer Principal Treatment Centres in the UK: a brief survey of staff support systems and practices.

Growing evidence of the association between health professionals' well-being and patient and organisational outcomes points to the need for effective staff support. This paper reports a brief survey of the UK's children's cancer Principal Treatment Centres (PTCs) regarding staff support systems and practices. A short on-line questionnaire, administered in 2012-2013, collected information about the availability of staff support interventions which seek to prevent work-related stress among different members of the multi-disciplinary team (MDT). It was completed by a member of staff with, where required, assistance from colleagues. All PTCs (n = 19) participated. Debriefs following a patient death was the most frequently reported staff support practice. Support groups were infrequently mentioned. There was wide variability between PTCs, and between professional groups, regarding the number and type of interventions available. Doctors appear to be least likely to have access to support. A few Centres routinely addressed work-related stress in wider staff management strategies. Two Centres had developed a bespoke intervention. Very few Centres were reported to actively raise awareness of support available from their hospital's Occupational Health department. A minority of PTCs had expert input regarding staff support from clinical psychology/liaison psychiatry.

Replacing home visits with telephone calls to support parents implementing a sleep management intervention: findings from a pilot study and implications for future research.

BACKGROUND: Resource constraints may inhibit the provision of appropriate interventions for children with neurodisabilities presenting with behavioural sleep problems. Telephone calls (TC), as opposed to home visits (HV), may be a more resource efficient means of supporting these families. OBJECTIVE: To conduct a preliminary investigation exploring the feasibility and acceptability of replacing HV with TC to support parents implementing sleep management strategies and to gather evidence to inform the design and methods of a full trial. METHODS: Parents referred to a sleep management intervention routinely delivered by a community paediatric team were alternately allocated to receive implementation support via HV (n = 7) or TC (n = 8). Activity logs recorded the frequency, duration and mode of support. Parents and practitioners were interviewed about their experiences of receiving/delivering the intervention. RESULTS: Intervention drop-out was low, the frequency, number of contacts and intervention duration appeared comparable. Parents allocated TC received less contact time. Parents valued implementation support irrespective of delivery mode and practitioners reported that despite initial reservations, implementation support via TC appeared to work well. CONCLUSIONS: TC appears an acceptable and convenient mode of delivering sleep support, valued by both parents and practitioners. We recommend a full-scale trial to investigate effectiveness.

Young adults as users of adult healthcare: experiences of young adults with complex or life-limiting conditions.

Awareness is growing that young adults may have distinctive experiences of adult healthcare and that their needs may differ from those of other adult users. In addition, the role of adult health teams in supporting positive transitions from paediatrics is increasingly under discussion. This paper contributes to these debates. It reports a qualitative study of the experiences of young adults - all with complex chronic health conditions - as users of adult health services. Key findings from the study are reported, including an exploration of factors that help to explain interviewees' experiences. Study findings are discussed in the context of existing evidence from young adults in adult healthcare settings and theories of 'young adulthood'. Implications for training and practice are considered, and priorities for future research are identified.

Staff burnout in paediatric oncology: new tools to facilitate the development and evaluation of effective interventions.

Working in paediatric oncology can be stressful, and staff may need support if they are to avoid burnout, but there is currently no evidence base to guide the development of interventions. As a significant barrier to addressing this gap is a lack of context specific research instruments, a project was undertaken to develop measures of the stressors and rewards experienced by staff. Measure development involved: (1) qualitative interviews with a purposive sample of paediatric oncology staff to develop an 'item pool' (n = 32); (2) selection of items for draft measures; (3) cognitive interviews (n = 7) to gather feedback on draft measures; (4) a survey of staff (n = 203) using the draft and comparator measures; (5) factor and Rasch analysis to determine the scaling properties of the measures; (6) an assessment of construct validity. As a result, the Work Stressors Scale - Paediatric Oncology (WSS-PO) and the Work Rewards Scale - Paediatric Oncology (WRS-PO) were created. Both measures have considerable content validity, and fulfil classical test theory requirements and Rasch model requirements for an interval level scale. These new measures can be used in research and clinical practice to investigate factors associated with burnout, and to facilitate and direct the development of staff interventions.

On the road to nowhere? Young disabled people and transition.

BACKGROUND: A key issue, and one known to be highly problematic and challenging, concerns the transition of young disabled people from children's services to adult services, and from childhood to adulthood. To inform its recommendations on this issue, the Disabled Children's External Working Group (EWG) for the Children's NSF commissioned a review of research on young disabled people and transition. METHODS: Given the preponderance of grey literature in this area, database searches were supplemented by hand searching of key journals and contacts with key individuals, research units, publishers and funding bodies in order to identify relevant literature on the experiences of transition from the perspectives of young people, parents and practitioners; the outcomes of transition; and evaluations of services provided during this life-stage. RESULTS: The evidence available with regard to transitions of young disabled people provides a clear and consistent picture of the way transitions are currently experienced by young disabled people and their families. There is limited evidence on what works to ensure smooth transitions between services and positive outcomes of transition for the young people themselves. CONCLUSIONS: Existing research is very persuasive on the need to improve transitions for young disabled people. It can also be used to provide clues as to the sorts of support and service configurations that need to be in place to ensure positive transitions. However, further research is needed both at the level of specific service/service model evaluation as well as holistic, longitudinal work to provide evidence on the long-term outcomes of young disabled people as they move into adulthood.

Effective targeting of magnetic radioactive 90Y-microspheres to tumor cells by an externally applied magnetic field. Preliminary in vitro and in vivo results.

Magnetic biodegradable poly(lactic acid) microspheres that incorporate both magnetite and the beta-emitter 90Y were prepared. By applying a directional external magnetic field gradient in excess of 0.02 Tesla/cm across a 96-well plate containing neuroblastoma cells incubated with the 90Y magnetite loaded microspheres, the radiation dose to the cells could be enhanced or reduced relative to the dose from a uniform loading of the well with 90Y-DTPA. Using the MTT assay, cell survival was measured for the magnetic field directed from above (cell sparing) and from below (cell targeting) the well plate, resulting in 65 +/- 8% or 18 +/- 5% survival respectively. This method was then applied to an in vivo murine tumor model. The biodistribution of intraperitoneally injected magnetic radioactive microspheres, after 24 h in mice, showed that 73 +/- 32% of the radioactivity was found on the subcutaneous tumor that had a rare earth magnet fixed above it. In contrast, the tumor radioactivity with no attached magnet was 6 +/- 4%. Magnetically targeted radiopolymers such as 90Y-microspheres show great promise for regional or intracavitary radiotherapy.

The spatial accuracy of cellular dose estimates obtained from 3D reconstructed serial tissue autoradiographs.

In order to better predict and understand the effects of radiopharmaceuticals used for therapy, it is necessary to determine more accurately the radiation absorbed dose to cells in tissue. Using thin-section autoradiography, the spatial distribution of sources relative to the cells can be obtained from a single section with micrometre resolution. By collecting and analysing serial sections, the 3D microscopic distribution of radionuclide relative to the cellular histology, and therefore the dose rate distribution, can be established. In this paper, a method of 3D reconstruction of serial sections is proposed, and measurements are reported of (i) the accuracy and reproducibility of quantitative autoradiography and (ii) the spatial precision with which tissue features from one section can be related to adjacent sections. Uncertainties in the activity determination for the specimen result from activity losses during tissue processing (4-11%), and the variation of grain count per unit activity between batches of serial sections (6-25%). Correlation of the section activity to grain count densities showed deviations ranging from 6-34%. The spatial alignment uncertainties were assessed using nylon fibre fiduciary markers incorporated into the tissue block, and compared to those for alignment based on internal tissue landmarks. The standard deviation for the variation in nylon fibre fiduciary alignment was measured to be 41 microns cm-1, compared to 69 microns cm-1 when internal tissue histology landmarks were used. In addition, tissue shrinkage during histological processing of up to 10% was observed. The implications of these measured activity and spatial distribution uncertainties upon the estimate of cellular dose rate distribution depends upon the range of the radiation emissions. For long-range beta particles, uncertainties in both the activity and spatial distribution translate linearly to the uncertainty in dose rate of < 15%. For short-range emitters (< 100 microns), such as alpha particle sources, the magnitude of the uncertainty in serial section alignment is comparable with the particle track length. Under these circumstances, dosimetric errors are introduced in proportion to the serial section alignment inaccuracy.

Magnetically directed poly(lactic acid) 90Y-microspheres: novel agents for targeted intracavitary radiotherapy.

High energy beta-emitting radioisotopes like Yttrium-90 have a radiotoxic range of about one centimeter. For cancer treatment they must be brought near the tumor cells and kept there for as long as they are radioactive. We developed as carriers for the ionic form of 90Y a matrix-type polymeric drug delivery system, poly(lactic acid) (PLA) microspheres. This radiopharmaceutical could be selectively delivered to the target site after incorporating 10% Fe3O4 (magnetite) which made the magnetic microspheres (MMS) responsive to an external magnetic field. Furthermore, MMS are biodegradable and slowly hydrolyze into physiologic lactic acid after the radioactivity is completely decayed. Previously prepared 10-40 microns MMS were radiochemically loaded to high specific activity with 90Y at a pH of 5.7. Stability studies showed that approximately 95% of added 90Y is retained within the PLA matrix after 28 days (> 10 half-lives) at 37 degrees C in serum, and electron microscopy showed that the microspheres retained their characteristic morphologic appearance for the same time period. Cytotoxicity studies with SK-N-SH neuroblastoma cells growing in monolayer showed that the radiocytotoxicity of the microspheres could be directed magnetically to either kill or spare specific cell populations, thus making them of great interest for targeted intracavitary tumor therapy. We are currently optimizing this system for use in the treatment of neoplastic meningitis.

Radiobiologic studies of low-dose-rate 90Y-lymphoma therapy.

BACKGROUND: Radioimmunotherapy and other forms of biologically targeted radiopharmaceutic treatment appear to show unexpected efficacy in many patients with lymphoma, neuroblastoma, and several other types of nonepithelial malignancies. The radiobiologic mechanisms responsible for this high clinical radioresponsiveness are unclear, but must involve some sort of cytotoxic enhancement or sensitization to protracted courses of low-dose-rate radiation exposure. MATERIALS AND METHODS: A series of in vitro experiments was performed with malignant lymphoma cell lines exposed under various conditions to high-dose-rate external beam radiotherapy or low-dose-rate 90Y radiation. Data were collected on cell cycle effects, DNA fragmentation, and modulation of cytotoxicity by caffeine and treatment sequence alterations. RESULTS: The data showed that some malignant lymphoma lines are highly sensitive to low-dose-rate radiation and that a portion of the cytotoxicity appears to be mediated by the induction of radiation-associated apoptosis (programmed cell death). Cell cycle effects of low-dose-rate radiation (such as G2M block) appear to be relatively minor in this experimental system. Agents that modulate apoptosis (such as the calcium-releasing agent caffeine) significantly enhance cell kill and DNA fragmentation after 90Y treatment. CONCLUSIONS: These results suggest that radiation-associated apoptosis may be important in the radiobiology of targeted radiopharmaceutical therapy.

Resources and strategies: how parents cope with the care of a disabled child.

This review has considered the ways parents cope with the chronic strain and daily stressors associated with caring for and bringing up a disabled child. The review has been structured around key concepts from the process model of stress and coping. Coping resources--both personal and socio-ecological--have been described, and the notion of vulnerability when resources are not available has been considered. It is only recently that research has turned to look at the coping strategies parents use. The review drew on research using a variety of methodologies to demonstrate the range of strategies used by parents. The relationship between coping strategies and adjustment was explored, although certain methodological difficulties impede firm conclusions being drawn. Finally, the review examined whether the process model of stress and coping could be usefully operationalised to inform intervention practices with families caring for a disabled child.

Easing the strain: assessing the impact of a Family Fund grant on mothers caring for a severely disabled child.

Measures of perceptions of care-related stress and maternal adjustment were used to assess the extent to which receiving help from the Family Fund eases the stress of caring for a disabled child. A sample of 162 mothers completed a questionnaire before and after receiving help from the Family Fund. The findings suggest that the Family Fund has a significant impact on mothers' perceptions of the stresses of caring for their child, as well as improving mother's wellbeing and adjustment. However, receiving help from the Family Fund did not improve mothers' perceptions of the severity of the child's disability or the extent to which the disability had adversely affected their personal lives.

Cell cycle alterations, apoptosis, and response to low-dose-rate radioimmunotherapy in lymphoma cells.

PURPOSE: In an attempt to elucidate some aspects of the radiobiological basis of radioimmunotherapy, we have evaluated the in vitro cellular response patterns for malignant lymphoma cell lines exposed to high- and low-dose-rate radiation administered within the physiological context of antibody cell-surface binding. METHODS AND MATERIALS: We used two different malignant lymphoma cell lines, a Thy1.2+ murine T-lymphoma line called EL-4 and a CD20+ human B-lymphoma line called Raji. Cells were grown in suspension cultures and exposed to high-dose-rate gamma radiation from an external 137Cs source or low-dose-rate beta radiation from DTPA-solubilized 90Y in solution. In some experiments, cells were pre-incubated with an excess of nonradioactive antibody in order to assess the effects of immunoglobulin surface binding during radiation exposure. Irradiated cells were evaluated for viability, cell-cycle changes, patterns of post-radiation morphologic changes, and biochemical hallmarks of radiation-associated necrosis and programmed cell death. RESULTS: The EL-4 line was sensitive to both high-dose-rate and low-dose-rate irradiation, while the Raji showed efficient cell kill only after high-dose-rate irradiation. Studies of radiation-induced cell cycle changes demonstrated that both cell lines were efficiently blocked at the G2/M interface by high-dose-rate irradiation, with the Raji cells appearing somewhat more susceptible than the EL-4 cells to low-dose-rate radiation-induced G2/M block. Electron microscopy and DNA gel electrophoresis studies showed that a significant proportion of the EL-4 cells appeared to be dying by radiation-induced programmed cell death (apoptosis) while the Raji cells appeared to be dying primarily by classical radiation-induced cellular necrosis. CONCLUSION: We propose that the unusual clinical responsiveness of some high and low grade lymphomas to modest doses of low-dose-rate radioimmunotherapy may be explained in part by the induction of apoptosis. The unusual dose-response characteristics observed in some experimental models of radiation-induced apoptosis may require a reappraisal of standard linear quadratic and alpha/beta algorithms used to predict target tissue cytoreduction after radioimmunotherapy.

Murine hematopoietic ablation by alpha-particle-emitting radiopharmaceuticals - a potential preparative regimen for bone-marrow transplantation.

Although short-lived alpha-particle-emitting radiopharmaceuticals are currently under evaluation for biologically targeted radiotherapy, very little is known about the dose-response kinetics of the hematosuppression produced by low level or transient exposure to these compounds while in the circulation. We have used hematopoietic progenitor cell colony-forming-unit assays to establish the dose-response curve for Bi-212 alpha particle radiation delivered in vitro, and have compared it to the dose-response curves for equivalent doses of Y-90 beta and Cs-137 gamma radiation. We then evaluated the dose-response effects for these radiopharmaceuticals after in vivo injection in mice. Both in vitro and in vivo, the Bi-212 was extremely hematosuppressive (50% inhibitory dose 20-30 cGy in culture) but this myelosuppression was transient at low or intermediate doses. Serum froin mice recovering from Bi-212-induced hematosuppression produced significant stimulation of naive syngeneic marrow progenitor cells, supporting the existence of a physiologic feedback mechanism that involves a poorly defined humoral factor released after radiation injury. Short-lived alpha emitters may be well suited to the development of tumor-seeking radiopharmaceuticals that can be used in the preparation of patients for autologous and allogeneic marrow transplantation.

Death certification in Western Australia--classification of major errors in certificate completion.

We aimed to develop a method to classify those errors in the completion of death certificates arising from misunderstanding of the certification process. We reviewed 430 Western Australian death certificates registered in March 1990 using a method devised to differentiate between major and minor errors. Major errors were found in 16 per cent of certificates (95 per cent confidence interval 12 to 20 per cent). The error rate did not vary significantly between city and country areas, nor between teaching hospitals and other locations. The method was validated on a separate sample of 120 certificates. It has potential as a tool to monitor a critical but neglected step in the production of mortality statistics and to assess understanding of the process of death certification.

Cellular kinetics, dosimetry, and radiobiology of alpha-particle radioimmunotherapy: induction of apoptosis.

Though clinical results for radioimmunoconjugate therapy of most common epithelial tumors have been disappointing, dramatic responses have been observed repeatedly in the treatment of high- and low-grade malignant lymphomas. This high clinical responsiveness after radioimmunoconjugate therapy sometimes appears to be out of proportion to the calculated radiation dose absorbed by the lymphoma tissue. Here we describe some key aspects of the kinetics, dosimetry, and cellular radiobiology of murine lymphoma cells exposed to 212Bi-radiolabeled alpha-particle-emitting immunoconjugates specific for the differentiation antigen Thy 1.2. Approximately 25 cell-bound alpha-particle-emitting immunoconjugates per target cell were required to reduce clonogenic survival by 90% (the radiobiological D10). Serial kinetic analyses of the antibody and radioisotope components of the immunoconjugates revealed significant levels of dechelation and up to 7.5% cellular internalization of the isotope. Cellular radiation dosimetry performed by Monte Carlo computer simulation of alpha-particle energy deposition patterns based on the observed radiopharmacokinetics showed that the D10 resulted from approximately four alpha-particle traversals through the nucleus, corresponding to an absorbed radiation dose of approximately 0.95 Gy to the cell nucleus. Electron micrographs and DNA gel studies of murine lymphoma cells undergoing radioimmunoconjugate therapy in vivo and in vitro demonstrated bizarre blebbing patterns, condensation of chromosomal material, and internucleosomal DNA fragmentation patterns characteristic of programmed cell death (apoptosis). We conjecture that the efficacy of radioimmunoconjugates against responsive cell types may be the result of passive DNA damage by ionizing radiation and the initiation of apoptosis in response to radioimmunotherapy.

Radiation hormesis.

"Radiation hormesis" is the name given to the putative stimulatory effects of low level ionizing radiation (generally in the range of 1-50 cGy of low-LET radiation). Based on historical and pharmacologic principles reminiscent of some of the major tenets of homeopathy, most of these effects are now generally ascribed to protective feedback systems that, upon exposure to low concentrations of toxins, proceed to stimulate metabolic detoxification and repair networks. The activation of these networks may then result in net beneficial effects on the cell, organism or species. Discussions of possible stimulatory effects of low levels of ionizing radiation have recently become entangled with the separate but related question of whether a threshold dose level exists on the radiotoxicologic dose-response curve. This review summarizes some of the relevant historical and scientific data bearing on the question of radiation hormesis. We find the data in support of most of the hormesis postulates intriguing but inconclusive.

Protein phosphorylation during activation of Na+/H+ exchange by phorbol esters and by osmotic shrinking. Possible relation to cell pH and volume regulation.

In lymphocytes, the Na+/H+ antiport can be stimulated by 12-O-tetradecanoylphorbol 13-acetate (TPA) and by osmotic shrinking. Since TPA acts by stimulating protein kinase C, we undertook experiments to determine if protein phosphorylation also underlies the osmotic stimulation of the antiport. We found that at least one of the membrane polypeptides labeled in cells treated with TPA is also phosphorylated by hypertonic shrinking. In both instances phosphorylation is alkali labile and associated with serine and threonine residues. We tested the possibility that shrinking activates phospholipase C, thereby stimulating protein kinase C through release of diacylglycerol. No decrease in phosphatidylinositol 4,5-bisphosphate levels was detected in hypertonically treated cells. Moreover, the concentrations of inositol phosphates, including inositol trisphosphate, were not altered in shrunken cells. Thus, shrinking does not appear to activate phospholipase C. Whereas TPA induced intracellular redistribution of soluble protein kinase C, no such effect was detected in osmotically activated cells. It was concluded that osmotic stimulation of the Na+/H+ antiport is associated with activation of protein phosphorylation by a kinase that is similar, but not identical to protein kinase C. Experiments in Na+-free or amiloride-containing media indicate that phosphorylation is not a consequence of activation of the antiport.

A tumor promoter enhances the phosphorylation of polyphosphoinositides while decreasing phosphatidylinositol labelling in lymphocytes.

12-O-Tetradecanoyl-phorbol-13-acetate, a comitogen for lymphocytes, suppresses the concanavalin A-induced accumulation of 3 2P-phosphatidyl-inositol, in mouse spleen lymphocytes incubated with 3 2P-orthophosphate. The comitogenic tumor promoter does not affect the rate of de novo synthesis of phosphatidylinositol, as measured by [3H]-glycerol incorporation. Mitogen stimulates the incorporation of [3 2P]-phosphate into phosphatidylinositol, phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-bisphosphate, but the tumor promoter suppresses only the increased labelling of the phosphatidylinositol, while it enhances phosphorylation of the polyphosphoinositides.

Brachial muscles in the chick embryo: the fate of individual somites.

The wing and wing-associated muscles of the shoulder and thorax in the bird all cleave from common myogenic masses in the developing wing bud and are referred to collectively as brachial muscles. In this study the precise embryonic origin of the brachial muscles was determined using chick-quail chimaeras. Such chimaeras consisted of a graft of one somite taken from a 2-day quail donor embryo transplanted to the equivalent location in a 2-day chick host embryo. The chimaeras were analysed at 9.5-10.0 days in ovo to determine the location of the grafted cells and therefore the structures that were derived from the transplanted somite. The somites that were studied in this matter were somites 13 to 23 inclusive. The results show that only somites 16 to 21 inclusive contribute cells to the brachial musculature; moreover, the cells from a given somite are not distributed randomly among the brachial muscles but populate specific muscles only: thus it has been possible to map the somitic origin of individual brachial muscles. Moreover, there is an indication that each somite plays a unique role in the development of the brachial muscles.