Children’s views on unlicensed/off-label paediatric prescribing and paediatric clinical trials.

Objectives: To explore the views and perspectives of children on the unlicensed/off-label use of medicines in children and on the participation of children in clinical trials. Methods: Focus-group discussions, involving school children, were carried out in a range of primary and secondary schools in Northern Ireland. A purposeful sample was chosen to facilitate representation of various socioeconomic groupings. Results: A total of 123 pupils, aged from 10 to 16 years, from six schools, participated in 16 focus groups. In general, pupils viewed the unlicensed/off-label use of medicines in children as unsafe and unethical and felt it is necessary to test medicines in children to improve the availability of licensed products. The majority felt that older children should be told, and that parents should be told, about the unlicensed/off-label use of medicines in children, yet they recognised some implications of this, such as potential medication non-adherence. Conclusions: This is the first study to explore the views of healthy children on unlicensed medicine use in children. Children were able to recognise potential risks associated with the unlicensed use of medicines and felt it is necessary to test and license more medicines in children. Practice implications Health care professionals should consider the views of children in decisions that affect their health.

Recent Innovations in Antibody-Mediated, Targeted Particulate Nanotechnology and Implications for Advanced Visualisation and Drug Delivery

Research into the targeting of drug substances to a specific disease site has enjoyed sustained activity for many decades. The reason for such fervent activity is the considerable clinical advantages that can be gained when the delivery system plays a pivotal role in determining where the drug is deposited. When compared to conventional formulations where no such control exists, such as parenteral and oral systems, the sophisticated targeting device can reduce side effects and limit collateral damage to surrounding normal tissue. No more so is this important than in the area of oncology when dose-limiting side effects are often encountered as an ever present difficulty. In this review, the types of colloidal carrier commonly used in targeted drug delivery are discussed, such as gold and polymeric colloids. In particular, the process of attaching targeting capabilities is considered, with reference to antibody technologies used as the targeting motifs. Nanotechnology has brought together a means to carry both a drug and targeting ligand in self-contained constructs and their applications to both clinical therapy and diagnosis are discussed.

Clinical consequences of mast cell heterogeneity

The heterogeneous morphological, biochemical and functional characteristics of mast cells from different species and from different tissue sites in the same species have been described for over 30 years. Far from being mere histochemical or pharmacological curiosities these differences have far reaching implications for therapeutic practice. This review concentrates on two important areas affected by mast cell heterogeneity, those of adverse reactions to therapeutic agents and the efficacy of anti-allergy therapy.

Development of a multi-media book for clinical supervision training in undergraduate nursing

There is an increased interest in higher education in the use of e-learning resources for students. This can be attributed to many factors including, the availability of advanced technology systems, a growing student population that is technology focused, financial implications and the recruitment of international students. However, the introduction of technology and e-learning into teaching has given rise to issues regarding quality and quantity of educational practice . The challenge now is for educationalists is to deliver an optimal learning experience that is effective and appropriate for students’ learning needs.

Response of red blood cell folate to intervention: implications for folate recommendations for the prevention of neural tube defects

Committees worldwide have set almost identical folate recommendations for the prevention of the first occurrence of neural tube defects (NTDs). We evaluate these recommendations by reviewing the results of intervention studies that examined the response of red blood cell folate to altered folate intake. Three options are suggested to achieve the extra 400 mu g folic acid/d being recommended by the official committees: increased intake of folate-rich foods, dietary folic acid supplementation, and folic acid fortification of food. A significant increase in foods naturally rich in folates was shown to be a relatively ineffective means of increasing red blood cell folate status in women compared with equivalent intakes of folic acid-fortified food, presumably because the synthetic form of the vitamin is more stable and more bioavailable. Although folic acid supplements are highly effective in optimizing folate status, supplementation is not an effective strategy for the primary prevention of NTDs because of poor compliance. Thus, food fortification is seen by many as the only option likely to succeed. Mandatory folic acid fortification of grain products was introduced recently in the United States at a level projected to provide an additional mean intake of 100 mu g folic acid/d, but some feel that this policy does not go far enough. A recent clinical trial predicted that the additional intake of folic acid in the United States will reduce NTDs by >20%, whereas 200 mu g/d would be highly protective and is the dose also shown to be optimal in lowering plasma homocysteine, with possible benefits in preventing cardiovascular disease. Thus, an amount lower than the current target of an extra 400 mu g/d may be sufficient to increase red blood cell folate to concentrations associated with the lowest risk of NTDs, but further investigation is warranted to establish the optimal amount.

Fortification with low amounts of folic acid makes a significant difference in folate status in young women: implications for the prevention of neural tube defects

Background: Mandatory fortification of grain products with folic acid was introduced recently in the United States, a policy expected to result in a mean additional intake of 100 mu g/d. One way of predicting the effectiveness of this measure is to determine the effect of removing a similar amount of folic acid as fortified food from the diets of young women who had been electively exposed to chronic fortification.

Objective: The objective was to examine the effect on folate status of foods fortified with low amounts of folic acid.

Design: We investigated the changes in dietary intakes and in red blood cell and serum concentrations of folate in response to removing folic acid-fortified foods for 12 wk from the diets of women who reportedly consumed such foods at least once weekly (consumers).

Results: Consumers (n = 21) had higher total folate intakes (P = 0.002) and red blood cell folate concentrations (P = 0.023) than nonconsumers (women who consumed folic acid-fortified foods less than once weekly; n = 30). Of greater interest, a 12-wk intervention involving the exclusion of these foods resulted in a decrease in folate intake of 78 +/- 56 mu g/d (P < 0.001), which was reflected in a significant reduction in red blood cell folate concentrations (P < 0.05).

Conclusions: Cessation of eating folic acid-fortified foods resulted in removing 78 mu g folic acid/d from the diet. Over 12 wk this resulted in a lowering of red blood cell folate concentrations by 111 nmol/L (49 mu g/L). This magnitude of change in folate status in women can be anticipated as a result of the new US fortification legislation and is predicted to have a significant, although not optimal, effect in preventing neural tube defects.

Posttranslational Inhibition of Proinflammatory Chemokine Secretion in Intestinal Epithelial Cells Implications for Specific IBD Indications

Background and Aim: Inflammatory bowel diseases (IBD) are immune-mediated chronic diseases that are characterized by an overreaction of the intestinal immune system to the intestinal microbiota. VSL#3, a mixture of 8 different lactic acid bacteria, is a clinically relevant probiotic compound in the context of IBD, but the bacterial structures and molecular mechanisms underlying the observed protective effects are largely unknown. The intestinal epithelium plays a very important role in the maintenance of the intestinal homeostasis, as the intestinal epithelial cells (IEC) are capable of sensing, processing, and reacting upon signals from the luminal microbiota and the intestinal immune system. This immune regulatory function of the IEC is lost in IBD owing to dysregulated activation of the IEC. Thus, the aim of this study was to reveal protective mechanisms of VSL#3 on IEC function.

Results: In vitro, VSL#3 was found to selectively inhibit activation-induced secretion of the T-cell chemokine interferon-inducible protein (IP)-10 in IEC. Cell wall-associated proteins of VSL#3-derived Lactobacillus casei (L. casei) were identified to be the active anti-inflammatory component of VSL#3. Mechanistically, L. casei did not impair initial IP-10 protein production, but induced posttranslational degradation of IP-10 in IEC. Feeding studies in tumor necrosis factor (TNF)(Delta ARE/+) mice, a mouse model for experimental ileitis, revealed that neither VSL#3 nor L. casei is capable of reducing ileal inflammation. Even preweaning feeding of VSL#3 did not prevent the development of severe ileitis in TNF Delta ARE/+ mice. In contrast, VSL#3 feeding studies in IL-10-/- mice, a model for experimental colitis, revealed that VSL#3 has local, intestinal compartment-specific protective effects on the development of inflammation. Reduced histopathologic inflammation in the cecum of IL-10-/- mice after VSL#3 treatment was found to correlate with reduced levels of IP-10 protein in primary cecal epithelial cells.

Conclusion and Outlook: These results suggest that the inhibitory effect of VSL#3-derived L. casei on IP-10 secretion in IEC is an important probiotic mechanism that contributes to the anti-inflammatory effects of VSL#3 in specific subsets of patients with IBD. An important future aim is the identification of the active probiotic protein, which could serve as a basis for the development of new efficient therapies in the context of IBD.

Children’s Views Matter Too! A Pilot Project Assessing Children’s and Adolescents’ Experiences of Clinical Psychology Services

This pilot study explored the experiences and understanding of clinical psychology practices and services of children and adolescents attending clinical psychology outpatient appointments. Fifteen young participants took part in the study. A content analysis indicated that young children and adolescents have an appropriate understanding of the role of the clinical psychologist, with older children commenting on the uniqueness and value of the therapeutic relationship. Attendance was rated as positive and helpful with regards to difficulties across all ages; however, many children were not consulted with at the point of referral and many did not know why they were attending. Implications for assessing children's and adolescents’ experiences of clinical psychology services are discussed.

The clinical effectiveness and cost-effectiveness of screening for open angle glaucoma:A systematic review and economic evaluation

Objectives: To assess whether open angle glaucoma (OAG) screening meets the UK National Screening Committee criteria, to compare screening strategies with case finding, to estimate test parameters, to model estimates of cost and cost-effectiveness, and to identify areas for future research. Data sources: Major electronic databases were searched up to December 2005. Review methods: Screening strategies were developed by wide consultation. Markov submodels were developed to represent screening strategies. Parameter estimates were determined by systematic reviews of epidemiology, economic evaluations of screening, and effectiveness (test accuracy, screening and treatment). Tailored highly sensitive electronic searches were undertaken. Results: Most potential screening tests reviewed had an estimated specificity of 85% or higher. No test was clearly most accurate, with only a few, heterogeneous studies for each test. No randomised controlled trials (RCTs) of screening were identified. Based on two treatment RCTs, early treatment reduces the risk of progression. Extrapolating from this, and assuming accelerated progression with advancing disease severity, without treatment the mean time to blindness in at least one eye was approximately 23 years, compared to 35 years with treatment. Prevalence would have to be about 3-4% in 40 year olds with a screening interval of 10 years to approach cost-effectiveness. It is predicted that screening might be cost-effective in a 50-year-old cohort at a prevalence of 4% with a 10-year screening interval. General population screening at any age, thus, appears not to be cost-effective. Selective screening of groups with higher prevalence (family history, black ethnicity) might be worthwhile, although this would only cover 6% of the population. Extension to include other at-risk cohorts (e.g. myopia and diabetes) would include 37% of the general population, but the prevalence is then too low for screening to be considered cost-effective. Screening using a test with initial automated classification followed by assessment by a specialised optometrist, for test positives, was more cost-effective than initial specialised optometric assessment. The cost-effectiveness of the screening programme was highly sensitive to the perspective on costs (NHS or societal). In the base-case model, the NHS costs of visual impairment were estimated as £669. If annual societal costs were £8800, then screening might be considered cost-effective for a 40-year-old cohort with 1% OAG prevalence assuming a willingness to pay of £30,000 per quality-adjusted life-year. Of lesser importance were changes to estimates of attendance for sight tests, incidence of OAG, rate of progression and utility values for each stage of OAG severity. Cost-effectiveness was not particularly sensitive to the accuracy of screening tests within the ranges observed. However, a highly specific test is required to reduce large numbers of false-positive referrals. The findings that population screening is unlikely to be cost-effective are based on an economic model whose parameter estimates have considerable uncertainty, in particular, if rate of progression and/or costs of visual impairment are higher than estimated then screening could be cost-effective. Conclusions: While population screening is not cost-effective, the targeted screening of high-risk groups may be. Procedures for identifying those at risk, for quality assuring the programme, as well as adequate service provision for those screened positive would all be needed. Glaucoma detection can be improved by increasing attendance for eye examination, and improving the performance of current testing by either refining practice or adding in a technology-based first assessment, the latter being the more cost-effective option. This has implications for any future organisational changes in community eye-care services. Further research should aim to develop and provide quality data to populate the economic model, by conducting a feasibility study of interventions to improve detection, by obtaining further data on costs of blindness, risk of progression and health outcomes, and by conducting an RCT of interventions to improve the uptake of glaucoma testing. © Queen's Printer and Controller of HMSO 2007. All rights reserved.

Moving Beyond the Administrative: Supervisors' Perspectives on Clinical Supervision in Child Welfare

This study contributes to the emerging knowledge base of child welfare supervision. An exploratory study examined the beliefs, practices, and experiences of 51 child welfare supervisors in Ontario, Canada. Eight focus groups were held with supervisors from a range of settings cross the province. The study identified a number of interwoven factors at the organizational, supervisory, and practice level that affect the nature of supervision offered. Implications are drawn for child welfare practice, models of supervision which integrate administrative, clinical and educational features, organizational culture, and training new supervisors.

Bystander Signalling: Exploring Clinical Relevance Through New Approaches and New Models

Classical radiation biology research has centred on nuclear DNA as the main target of radiation-induced damage. Over the past two decades, this has been challenged by a significant amount of scientific evidence clearly showing radiation-induced cell signalling effects to have important roles in mediating overall radiobiological response. These effects, generally termed radiation-induced bystander effects (RIBEs) have challenged the traditional DNA targeted theory in radiation biology and highlighted an important role for cells not directly traversed by radiation. The multiplicity of experimental systems and exposure conditions in which RIBEs have been observed has hindered precise definitions of these effects. However, RIBEs have recently been classified for different relevant human radiation exposure scenarios in an attempt to clarify their role in vivo. Despite significant research efforts in this area, there is little direct evidence for their role in clinically relevant exposure scenarios. In this review, we explore the clinical relevance of RIBEs from classical experimental approaches through to novel models that have been used to further determine their potential implications in the clinic. 

Implications of Intercellular Signaling for Radiation Therapy: A Theoretical Dose-Planning Study

Purpose
Recent in vitro results have shown significant contributions to cell killing from signaling effects at doses that are typically used in radiation therapy. This study investigates whether these in vitro observations can be reconciled with in vivo knowledge and how signaling may have an impact on future developments in radiation therapy.
Methods and Materials
Prostate cancer treatment plans were generated for a series of 10 patients using 3-dimensional conformal therapy, intensity modulated radiation therapy (IMRT), and volumetric modulated arc therapy techniques. These plans were evaluated using mathematical models of survival following modulated radiation exposures that were developed from in vitro observations and incorporate the effects of intercellular signaling. The impact on dose-volume histograms and mean doses were evaluated by converting these survival levels into "signaling-adjusted doses" for comparison.
Results
Inclusion of intercellular communication leads to significant differences between the signalling-adjusted and physical doses across a large volume. Organs in low-dose regions near target volumes see the largest increases, with mean signaling-adjusted bladder doses increasing from 23 to 33 Gy in IMRT plans. By contrast, in high-dose regions, there is a small decrease in signaling-adjusted dose due to reduced contributions from neighboring cells, with planning target volume mean doses falling from 74 to 71 Gy in IMRT. Overall, however, the dose distributions remain broadly similar, and comparisons between the treatment modalities are largely unchanged whether physical or signaling-adjusted dose is compared. Conclusions Although incorporating cellular signaling significantly affects cell killing in low-dose regions and suggests a different interpretation for many phenomena, their effect in high-dose regions for typical planning techniques is comparatively small. This indicates that the significant signaling effects observed in vitro are not contradicted by comparison with clinical observations. Future investigations are needed to validate these effects in vivo and to quantify their ranges and potential impact on more advanced radiation therapy techniques.

Symptoms and Endoscopic Features at Barrett's Esophagus Diagnosis: Implications for Neoplastic Progression Risk

OBJECTIVES: Risk stratification of Barrett's esophagus (BE) patients based on clinical and endoscopic features may help to optimize surveillance practice for esophageal adenocarcinoma (EAC) development. The aim of this study was to investigate patient symptoms and endoscopic features at index endoscopy and risk of neoplastic progression in a large population-based cohort of BE patients.

METHODS: A retrospective review of hospital records relating to incident BE diagnosis was conducted in a subset of patients with specialized intestinal metaplasia from the Northern Ireland BE register. Patients were matched to the Northern Ireland Cancer Registry to identify progressors to EAC or esophageal high-grade dysplasia (HGD). Cox proportional hazards models were applied to evaluate the association between endoscopic features, symptoms, and neoplastic progression risk.

RESULTS: During 27,997 person-years of follow-up, 128 of 3,148 BE patients progressed to develop HGD/EAC. Ulceration within the Barrett's segment, but not elsewhere in the esophagus, was associated with an increased risk of progression (hazard ratio (HR) 1.72; 95% confidence interval (CI): 1.08–2.76). Long-segment BE carried a significant sevenfold increased risk of progression compared with short-segment BE; none of the latter group developed EAC during the study period. Conversely, the absence of reflux symptoms was associated with an increased risk of cancer progression (HR 1.61; 95% CI: 1.05–2.46).

CONCLUSIONS: BE patients presenting with a long-segment BE or Barrett's ulcer have an increased risk of progressing to HGD/EAC and should be considered for more intense surveillance. The absence of reflux symptoms at BE diagnosis is not associated with a reduced risk of malignant progression, and may carry an increased risk of progression.

Therapeutic implications of the sentinel lymph node in breast cancer

Immunohistochemistry of histologically negative axillary lymph nodes in breast-cancer patients resulted in upstaging of the sentinel lymph node in eight (14%) of 52 patients, The resulting information altered clinical management in six of these patients. Thus, this technique may affect clinical decision-making in breast-cancer patients.

Respiratory Infections Cause the Release of Extracellular Vesicles: Implications in Exacerbation of Asthma/COPD

Background: Infection-related exacerbations of respiratory diseases are a major health concern; thus understanding the mechanisms driving them is of paramount importance. Despite distinct inflammatory profiles and pathological differences, asthma and COPD share a common clinical facet: raised airway ATP levels. Furthermore, evidence is growing to suggest that infective agents can cause the release of extracellular vesicle (EVs) in vitro and in bodily fluids. ATP can evoke the P2X7/caspase 1 dependent release of IL-1β/IL-18 from EVs; these cytokines are associated with neutrophilia and are increased during exacerbations. Thus we hypothesized that respiratory infections causes the release of EVs in the airway and that the raised ATP levels, present in respiratory disease, triggers the release of IL-1β/IL-18, neutrophilia and subsequent disease exacerbations.

Methods: To begin to test this hypothesis we utilised human cell-based assays, ex vivo murine BALF, in vivo pre-clinical models and human samples to test this hypothesis.

Results: Data showed that in a murine model of COPD, known to have increased airway ATP levels, infective challenge causes exacerbated inflammation. Using cell-based systems, murine models and samples collected from challenged healthy subjects, we showed that infection can trigger the release of EVs. When exposed to ATP the EVs release IL-1b/IL-18 via a P2X₇/caspase-dependent mechanism. Furthermore ATP challenge can cause a P2X₇ dependent increase in LPS-driven neutrophilia.

Conclusions: This preliminary data suggests a possible mechanism for how infections could exacerbate respiratory diseases and may highlight a possible signalling pathway for drug discovery efforts in this area.