Reducing Asthma Attacks in Children using Exhaled Nitric Oxide as a biomarker to inform treatment strategy: a randomised trial (RAACENO).

BACKGROUND: Childhood asthma is a common condition. Currently there is no validated objective test which can be used to guide asthma treatment in children. This study tests the hypothesis that the addition of fractional exhaled nitric oxide (FENO) monitoring in addition to standard care reduces the number of exacerbations (or attacks) in children with asthma. METHODS: This is a multi-centre, randomised controlled study. Children will be included of age 6-16 years who have a diagnosis of asthma, currently use inhaled corticosteroids (ICSs) and have had an exacerbation in the previous 12 months. Exclusion criteria include being unable to provide FENO measurement at baseline assessment, having another chronic respiratory condition and being currently treated with maintenance oral steroids. Participants will be recruited in both primary and secondary care settings and will be randomised to either receive asthma treatment guided by FENO plus symptoms (FENO group) or asthma treatment guided by symptoms only (standard care group). Within the FENO group, different treatment decisions will be made dependent on changes in FENO. Participants will attend assessments 3, 6, 9 and 12 months post randomisation. The primary outcome is asthma exacerbation requiring prescription and/or use of an oral corticosteroid over 12 months as recorded by the participant/parent or in general practitioner records. Secondary outcomes include time to first attack, number of attacks, asthma control score and quality of life. Adherence to ICS treatment is objectively measured by an electronic logging device. Participants are invited to participate in a "phenotyping" assessment where skin prick reactivity and bronchodilator response are determined and a saliva sample is collected for DNA extraction. Qualitative interviews will be held with participants and research nurses. A health economic evaluation will take place. DISCUSSION: This study will evaluate whether FENO can provide an objective index to guide and stratify asthma treatment in children. TRIAL REGISTRATION: ISRCTN, ISRCTN67875351. Registered on 12 April 2017. Prospectively registered.

Achieving Self-Directed Integrated Cancer Aftercare (ASICA) in melanoma: protocol for a randomised patient-focused pilot trial of delivering the ASICA intervention as a means to earlier detection of recurrent and second primary melanoma.

BACKGROUND: Melanoma is common; 15,906 people in the UK were diagnosed with melanoma in 2015 and incidence has increased fivefold in 30 years. Melanoma affects old and young people, with poor prognosis once metastatic. UK guidelines recommend people treated for cutaneous melanoma receive extended outpatient, hospital follow up to detect recurrence or new primaries. Such follow up of the growing population of melanoma survivors is burdensome for both individuals and health services. Follow up is important since approximately 20% of patients with early-stage melanoma experience a recurrence and 4-8% develop a new primary; the risk of either is highest in the first 5 years. Achieving Self-directed Integrated Cancer Aftercare (ASICA) is a digital intervention to increase total-skin-self-examination (TSSE) by people treated for melanoma, with usual follow up. METHODS: We aim to recruit 240 adults with a previous first-stage 0-2C primary cutaneous melanoma, from secondary care in North-East Scotland and the East of England. Participants will be randomised to receive the ASICA intervention (a tablet-based digital intervention to prompt and support TSSE) or control group (treatment as usual). Patient-reported and clinical data will be collected at baseline, including the modified Melanoma Worry Scale (MWS), the Hospital Anxiety and Depression Scale (HADs), the EuroQoL 5-dimension 5-level questionnaire (EQ-5D-5 L), and questions about TSSE practice, intentions, self-efficacy and planning. Participants will be followed up by postal questionnaire at 3, 6 and 12 months following randomization, along with a 12-month review of clinical data. The primary timepoint for outcome analyses will be12 months after randomisation. DISCUSSION: If the ASICA intervention improves the practice of TSSE in those affected by melanoma, this may lead to improved psychological well-being and earlier detection of recurrent and new primary melanoma. This could impact both patients and National Health Service (NHS) resources. This study will determine if a full-scale randomised controlled trial can be undertaken in the UK NHS to provide the high-quality evidence needed to determine the effectiveness of the intervention. ASICA is a pilot study evaluating the effectiveness of the practice of digitally supported TSSE in those affected by melanoma. TRIAL REGISTRATION: Clinical Trials.gov, NCT03328247 . Registered on 1 November 2017.

Grape powder attenuates the negative effects of GLP-1 receptor antagonism by exendin-3 (9-39) in a normoglycemic mouse model.

Prediabetes is a condition affecting 35% of US adults and about 50% of US adults age 65+. Foods rich in polyphenols, including flavanols and other flavonoids, have been studied for their putative beneficial effects on many different health conditions including type 2 diabetes mellitus and prediabetes. Studies have shown that some flavanols increase glucagon-like peptide 1 (GLP-1) secretion. GLP-1 is a feeding hormone that increases insulin secretion after carbohydrate consumption, and increased GLP-1 secretion may be responsible for some of the beneficial effects on glycemic control after flavanol consumption. The present study explored the effects of grape powder consumption on metrics of glycemic health in normoglycemic and prediabetic C57BL/6J mice; additionally, the mechanism of action of grape powder polyphenols was investigated. Grape powder significantly reduced (p < 0.01) blood glucose levels following oral glucose gavage after GLP-1 receptor antagonism by exendin-3 (9-39) compared to sugar-matched control, indicating that it was able to attenuate the hyperglycemic effects of GLP-1 receptor antagonism. Grape powder was employed in acute (1.6 g grape powder per kg bodyweight) and long-term high fat diet (grape powder incorporated into treatment diets at 5% w/w) feeding studies in normoglycemic and prediabetic (diet-induced obesity) mice; grape powder did not impove glycemic control in these studies versus sugar-matched control. The mechanisms by which grape powder ameliorates the deleterious effects of GLP-1 receptor antagonism warrant further study.

Repair of hypospadias fistula using a penile skin advancement flap with penile dartos interposition.

OBJECTIVE: We aim to report a single surgeon's experience of using a penile skin advancement flap with penile dartos interposition for hypospadias fistula repair. PATIENTS & METHODS: All hypospadias fistula repairs performed in our unit by this paediatric urologist between 2000 and 2012 were identified from a prospectively recorded database. Patients' case-notes were reviewed retrospectively gathering data on surgical technique, post-operative care and fistula recurrence on follow-up. Only those boys having repair by this advancement flap technique were included. A urethral catheter was left in situ in all patients for 5-7 days. Repairs performed using other techniques were excluded. RESULTS: 20 consecutive patients had fistula repair by the advancement flap technique. This was the primary repair in 19 boys, and was repair of a third fistula occurrence in one. The median age at fistula repair was 3.7 years (1.6-15.3). The median follow-up was 4 months (3-73). One boy failed to attend any follow-up. No recurrence has yet been identified in any of the 20 patients. CONCLUSION: The penile skin advancement flap with dartos interposition technique was very successful in our series in both primary fistula repair, and in a patient who had multiple previous operations.

Outcome of the Lima periurethral constrictor in children and adolescents: a European perspective.

PURPOSE: The Lima constrictor was described in 1996 as a less complex and less expensive alternative to the artificial urinary sphincter for use in cases of pediatric neuropathic sphincter incontinence. The device provides a fixed periurethral resistance which creates continence, yet allows urethral catheterization without the need to deflate the cuff. We report our multicenter experience, and continence, revision and erosion rates. MATERIALS AND METHODS: We performed a retrospective review of 14 consecutive patients who underwent insertion of the periurethral constrictor (Silimed, Rio de Janeiro, Brazil) between 2005 and 2011. Data are presented as medians (range). RESULTS: A total of 14 patients (13 male, 1 female) with spina bifida (10), sacral agenesis (3) and Hirschsprung disease (1) underwent insertion of the constrictor at a median age of 12 years (range 8 to 20). All patients were wet despite clean intermittent catheterization, medical therapy and/or previous surgery. Eleven patients underwent simultaneous bladder augmentation and/or Mitrofanoff formation. The constrictor was activated a median of 8 weeks (range 2 to 99) after the procedure in 11 patients whereas 3 became dry without activation. Complications occurred in 4 patients (29%), including spontaneous bladder perforation and constrictor erosion (1), tubing disconnection requiring revision (2) and wound infection (1). At a median of 23 months of followup (range 7 to 77) 13 patients were dry and 1 was damp. All patients performed urethral or Mitrofanoff clean intermittent catheterization. The continence rate with the device in situ was 92%. CONCLUSIONS: At a median followup of 23 months the Lima constrictor provided a 92% continence rate with erosion and revision rates of 7% and 14%, respectively. Interim results suggest that the constrictor provides a safe and effective surgical option, particularly in patients who are unable to void to completion.

Comparison of one-year costs of type 2 diabetes treatment with insulin glargine or insulin detemir in a basal supported oral therapy (BOT) in Germany.

OBJECTIVE: A one-year cost analysis comparing basal insulin analogues glargine (IG, Lantus) versus detemir (ID, Levemir) in combination with oral antidiabetic drugs (basal supported oral therapy; BOT) in insulin naive Type 2 diabetes patients in Germany based on the results of a randomized controlled clinical trial (RCT). The trial demonstrated equivalent treatment efficacy. MATERIALS AND METHODS: Total direct diabetes treatment costs were estimated from the perspective of the German statutory health insurance (SHI) for the time horizon of one-year. Simulated resources included medication (insulin, oral antidiabetic drugs) and consumable items (needles, blood glucose test strips and lancets). Initial and final insulin doses per kg body weight and proportion of patients with once/twice daily insulin injection were taken from the above mentioned RCT. Unit costs were taken from official German price lists and sources. Deterministic-(DTA) and probabilistic sensitivity analyses (PSA) on resource use and unit costs were performed to test robustness of the results. RESULTS: Average annual treatment costs per patient (base case) were euro 849 for glargine and euro 1,334 for detemir resulting in cost savings of euro 486 per patient per year (36%). Costs of insulins were euro 469 (IG) and euro 746 (ID). Costs of consumable items amounted at euro 380 (IG) and euro 588 (ID) respectively. Sensitivity analyses confirmed the findings in favor of insulin glargine. PSA results found cost savings ranging from euro 429 to euro 608 (5th/95th percentiles). CONCLUSIONS: The current model estimated that insulin glargine was associated with lower annual treatment costs of euro 486 (36%) compared to the use of insulin detemir while the same glycemic control is expected to be achieved.

Improving the sensitivity of the time trade-off method: results of an experiment using chained TTO questions.

We test a chained time trade-off (TTO) approach to estimating health gains from interventions by asking respondents to directly compare the "before" and "after" intervention health states in the TTO framework. Respondents with experience of both health states were used, thus minimising biases stemming from confusion surrounding health descriptions. We found that responses to these direct comparisons were much more likely to capture a perceived change in health status than the conventional approach to TTO estimation. This is an important finding because the TTO method is preferred by practitioners to many other direct generic methods of health status valuation both on empirical grounds and because it is based on the notion of opportunity cost, which is central to consumer theory, requiring respondents to express their preferences in terms of foregoing some of one good in exchange for more of another (unlike a rating scale).

Measuring the effects of seating on people with profound and multiple disabilities--a preliminary study.

This paper describes a preliminary study to investigate a range of approaches that might be used for measuring the effects of special seating on people with profound and multiple disabilities and their carers. A number of tools are proposed for measuring the effects on quality of life, function and carer satisfaction. The results of applying these tools to measure the effects of intervention with customized molded seating on nine people with multiple disabilities are described. The results suggest that these tools are sensitive to this intervention, showing a general beneficial effect with good carer satisfaction. The study points the way towards application of these tools to people with a wider range of disabilities and to different interventions.

Interpreting reported health-care benefits.

When reading published reports on the benefits of different treatments or health-care programmes, readers are generally interested in judging the applicability of the results to their own settings. Thus they need to be able to identify what consequences (and costs) were included in the evaluation. This short paper describes the different categories of 'benefit' that may arise from health-care interventions and explains some of the methodological considerations in their measurement. It provides simple advice on avoiding the common pitfalls when interpreting the value offered by a particular treatment or configuration of health services.

Interpreting reported health-care costs.

This short paper describes the different categories of health-care costs and methodological considerations in cost measurement. It provides simple advice on avoiding some of the common pitfalls in cost interpretation and should help readers in assessing the usefulness of reported costs.

Women's lay knowledge of cervical cancer/cervical screening: accounting for non-attendance at cervical screening clinics.

An assessment of women's knowledge of cervical screening and cervical cancer was considered important as up to 92% of those dying from this form of cancer had never been tested. What were the reasons which determined their non-attendance? Issues to be addressed were reactions to invitation, women's knowledge of screening, and the possible factors which they envisaged as being associated with cervical cancer. Other issues to be considered were practical problems associated with attendance, and preference for the sex and professional status of the health professionals involved; 187 women in a general practitioner practice in Lothian, Scotland were targeted by questionnaire. As with other studies in this field 50% of those contacted were ineligible for a variety of reasons. Seventy-two women completed the questionnaire, providing a mix of qualitative and quantitative data. Although the majority of women felt the invitation to attend screening was clear and easy to understand, there was a lack of knowledge with regard to both the screening itself and the possible causes of cervical cancer. The main 'causes' were seen as higher sexual activity among those aged under 37 and smoking and a virus by those over 37. The majority of women showed preference for a female professional to take the smear. Practical problems of time and venue were not considered insurmountable. The main reasons cited for non-compliance were the fear and dislike of the test itself.

Faecal occult blood screening for colorectal cancer: is it cost-effective?

Recently published evidence from two large-scale clinical trials conducted in England and in Denmark suggests that faecal occult blood screening for colorectal cancer significantly reduces mortality. However, before screening can be advocated as part of national health policy, its cost-effectiveness must be demonstrated. The English screening trial has been the subject of a detailed economic evaluation over the past 10 years In this paper, cost-effectiveness estimates of screening are presented, based on cost and outcome data combined in a mathematical model developed from the trial's clinical findings The estimates of cost per quality-adjusted life-year gained from colorectal cancer screening show the procedure to be of similar cost-effectiveness to breast cancer screening in the short term. Over the longer term, however, the estimates for colorectal cancer screening appear superior.

Symptoms before and after surgery for colorectal cancer.

Questionnaires were completed by a sample (n = 53) of patients at two points in time, prior to surgery for colorectal cancer and three months thereafter. The questionnaires comprised the Nottingham Health Profile, as a general health status measure, and a specific checklist of 30 symptoms. Of the physical symptoms, loss of appetite, rectal bleeding and urgency of bowel movement appeared to decline after treatment, whilst other potential symptoms, such as vomiting, appeared to occur only rarely, both before and after surgery. Pre-treatment symptoms of psychological distress appeared to have dissipated by three months, suggesting that they were more likely to have resulted from the anticipation of treatment rather from the disease itself. A logistic regression model suggests that the presence of certain symptoms, such as rectal bleeding and heartburn, is more likely to be associated with the presence of late- as opposed to early-stage cancer.

Cost-effectiveness of screening for colorectal cancer: a simulation model.

Colorectal cancer is a major cause of mortality in Western countries, although early detection of the disease is known to improve survival. Recent developments in medical technology have made mass population screening a practicable proposition and a number of randomized controlled trials of screening are currently being conducted. This paper reports on the construction of a computer simulation model of the cost-effectiveness of colorectal cancer screening, being developed in conjunction with a major UK trial. Based on accumulated trial data and semi-Markov descriptions of the disease process, the model will facilitate the assessment of the cost-effectiveness of a variety of screening modalities, with a view to informing policy in the future.

Determinants of persistent compliance with screening for colorectal cancer.

Mass population screening for colorectal cancer is currently being evaluated by means of randomized controlled trials. These trials point to the likelihood that, if implemented, the level of both initial and sustained compliance will prevent the full potential of screening being realised. The paper opens by reviewing the evidence on determinants of compliance, both initial and longer term, although little empirical evidence on adherence to repeated screening is currently available. The paper then presents the results of a survey of persistent compliers and non-compliers within the English screening trial, in order to identify those characteristics most closely associated with persistent compliance behaviour. Persistent compliers are found, inter alia, to be of higher socio-economic classes than persistent non-compliers, to have more personal and family experiences of illness and to visit their dentists more regularly. The results suggest that generalized attempts at compliance enhancement would be ineffectual against the prevailing background characteristics of the non-compliant population, and that the more overt targeting of efforts in this respect is to be preferred.

Mimosine arrests DNA synthesis at replication forks by inhibiting deoxyribonucleotide metabolism.

Mimosine has been reported to specifically prevent initiation of DNA replication in the chromosomes of mammalian nuclei. To test this hypothesis, the effects of mimosine were examined in several DNA replication systems and compared with the effects of aphidicolin, a specific inhibitor of replicative DNA polymerases. Our results demonstrated that mimosine inhibits DNA synthesis in mitochondrial, nuclear, and simian virus 40 (SV40) genomes to a similar extent. Furthermore, mimosine and aphidicolin were indistinguishable in their ability to arrest SV40 replication forks and mammalian nuclear chromosomal replication forks. In contrast to aphidicolin, mimosine did not inhibit DNA replication in lysates of mammalian cells supplied with exogenous deoxyribonucleotide triphosphate precursors for DNA synthesis. Mimosine also had no effect on initiation or elongation of DNA replication in Xenopus eggs or egg extracts containing high levels of deoxyribonucleotide triphosphates. In parallel with its inhibitory effect on DNA synthesis in mammalian cells, mimosine altered deoxyribonucleotide triphosphate pools in a manner similar to that reported for another DNA replication inhibitor that affects deoxyribonucleotide metabolism, hydroxyurea. Taken together, these results show that mimosine inhibits DNA synthesis at the level of elongation of nascent chains by altering deoxyribonucleotide metabolism.

Colorectal cancer screening and quality of life.

To evaluate the quality of life of patients following surgery for colorectal cancer, and to compare the quality of life between patients whose cancer was detected as a result of faecal occult blood screening with that of patients whose cancer presented symptomatically, an analysis was conducted within the context of the randomized controlled trial of colorectal cancer screening, University Hospital, Nottingham, UK. A total of 418 survivors of the trial's test and control groups and 33 randomly selected cancer patients completed quality of life questionnaires (Nottingham Health Profile and Health Measurement Questionnaire). The mode of entry to diagnosis and treatment (screening vs. non-screening) appeared to exert no major impact on post-intervention quality of life. The stage of cancer progression was not closely related to outcome life quality. A quality of life coefficient for surviving patients based on the Rosser classification was estimated to lie within the range 0.948-0.981. This figure accords well with the estimates of other studies of interventions in populations of similar age. Overall, there are no grounds for believing that faecal occult blood screening for colorectal cancer per se significantly influences patients' post-intervention quality of life.

Bioavailability of chlorocatechols in naturally contaminated sediment samples and of chloroguaiacols covalently bound to c(2)-guaiacyl residues.

Bacteria in anaerobic enrichment cultures that dechlorinated a range of chlorocatechols were used to examine the stability of endogenous chlorocatechols in a contaminated sediment sample and in interstitial water prepared from it. During incubation of the sediment sample for 450 days with or without added cells, there was a decrease in the concentration of solvent-extractable chlorocatechols but not in that of the total chlorocatechols, including sediment-associated components. In the presence of azide, the decrease in the concentrations of the former was eliminated or substantially decreased. Control experiments in which 3,4,5-trichlorocatechol was added to the sediment suspensions after 130 days showed that its dechlorination was accomplished not only by the added cells but also by the endemic microbial flora. It was concluded that the endogenous chlorocatechols in the sediment were not accessible to microorganisms with dechlorinating activity. On the other hand, microorganisms were apparently responsible for decreasing the solvent extractability of the chlorocatechols, and this effect decreased with increasing length of exposure time. Similar experiments carried out for 70 days with the sediment interstitial water showed that the chlorocatechols that were known to be associated with organic matter were also inaccessible to microbial dechlorination. Experiments with model compounds in which 4,5,6-trichloroguaiacol and tetrachloroguaiacol were covalently linked to C(2)-guaiacyl residues showed that these compounds were resistant to O demethylation or dechlorination during incubation with a culture having these activities. The only effect of microbial action was the quantitative reduction in 12 days of the C'1 keto group to an alcohol which was stable against further transformation for up to 65 days. The results of these experiments are consistent with the existence of chlorocatechols and chloroguaiacols in contaminated sediments and illustrate the cardinal significance of bioavailability in determining their recalcitrance to dechlorination and O demethylation, respectively. It is suggested that bioavailability is an important factor in determining the persistence of xenobiotics in natural ecosystems and that its omission represents a serious limitation in the interpretation of many laboratory experiments directed towards determining the persistence of xenobiotics in aquatic ecosystems.