A randomized controlled trial protocol assessing the effectiveness, safety and cost-effectiveness of methotrexate vs. ciclosporin in the treatment of severe atopic eczema in children: the TREatment of severe Atopic eczema Trial (TREAT).

BACKGROUND: Oral systemic immunomodulatory medication is regularly used off-licence in children with severe atopic eczema. However, there is no firm evidence regarding the effectiveness, safety, cost-effectiveness and impact on quality of life from an adequately powered randomized controlled trial (RCT) using systemic medication in children. OBJECTIVES: To assess whether there is a difference in the speed of onset, effectiveness, side-effect profile and reduction in flares post-treatment between ciclosporin (CyA) and methotrexate (MTX), and also the cost-effectiveness of the drugs. Treatment impact on quality of life will also be examined in addition to whether FLG genotype influences treatment response. In addition, the trial studies the immune-metabolic effects of CyA and MTX. METHODS: Multicentre, parallel group, assessor-blind, pragmatic RCT of 36 weeks' duration with a 24-week follow-up period. In total, 102 children aged 2-16 years with moderate-to-severe atopic eczema, unresponsive to topical treatment will be randomized (1 : 1) to receive MTX (0·4 mg kg-1 per week) or CyA (4 mg kg-1 per day). RESULTS: The trial has two primary outcomes: change from baseline to 12 weeks in Objective Severity Scoring of Atopic Dermatitis (o-SCORAD) and time to first significant flare following treatment cessation. CONCLUSIONS: This trial addresses important therapeutic questions, highlighted in systematic reviews and treatment guidelines for atopic eczema. The trial design is pragmatic to reflect current clinical practice.

Circulating immune cells in multiple sclerosis.

Circulating T and B lymphocytes contribute to the pathogenesis of the neuroinflammatory autoimmune disease, multiple sclerosis (MS). Further progress in the development of MS treatments is dependent upon a greater understanding of the immunological disturbances that underlie the disease. Analyses of circulating immune cells by flow cytometry have revealed MS-associated alterations in the composition and function of T and B cell subsets, including temporal changes associated with disease activity. Disturbances in circulating immune populations reflect those observed in the central nervous system and include skewing towards proinflammatory CD4+ and CD8+ T cells and B cells, greater proportions of follicular T helper cells and functional defects in the corresponding T and B regulatory subsets. Utilizing the analytical power of modern flow cytometers, researchers are now well positioned to monitor immunological changes associated with disease activity or intervention, describe immunological signatures with predictive value and identify targets for therapeutic drug development. This review discusses the contribution of various T and B lymphocyte subsets to MS pathogenesis, provides current and relevant phenotypical descriptions to assist in experimental design and highlights areas of future research.

25-hydroxyvitamin D3 status is associated with developing adaptive and innate immune responses in the first 6 months of life.

BACKGROUND: Vitamin D (25[OH]D3) status in early life has been linked to the risk of allergic disease in multiple observational studies. While immunomodulating properties are well recognized, there are few longitudinal studies of 25(OH)D3 status, immune function and allergic disease in infants. OBJECTIVE: To investigate 25(OH)D3 levels at birth [cord blood (CB)] and at 6 months of age in relation to immune function at 6 months of age, and clinical outcomes up to 30 months of age in infants with a maternal history of atopy. METHODS: In a subset of infants (n = 225) enrolled in a RCT (ACTRN12606000281594), 25(OH)D3 levels were assessed in relation to peripheral blood mononuclear cell cytokine responses to house dust mite (HDM), ovalbumin (OVA) and ß-lactoglobulin allergens, or Toll-like receptor (TLR) ligands (lipopolysaccharide, lipoteichoic acid, polyinosinic : polycytidylic acid and CpG oligonucleotide) at 6 months of age, in addition to clinical outcomes (eczema, wheeze and allergen sensitisation) up to 30 months of age. RESULTS: Infants with higher 25(OH)D3 at birth (≥ 75 nmol/L, compared with < 50 nmol/L) had lower IL-5 and IL-13 responses to HDM by 6 months (P < 0.001 and P = 0.003, respectively). This was also reflected in strong inverse correlations between CB 25(OH)D3 levels and HDM IL-13 (ρ = -0.57; P = 0.0002) and IL-5 (ρ = -0.59, P = 0.0001) responses, with a similar trend for IL-5 (ρ = -0.29; P = 0.009) responses to OVA. For innate stimulations, higher 25(OH)D3 levels at 6 months were associated with greater responses to TLR ligands. Additionally, higher CB 25(OH)D3 was associated with reduced risk eczema at 6 months (P = 0.011) and 12 months (P = 0.034). CONCLUSION: This suggests that improving 25(OH)D3 status in pregnancy or early infancy may reduce the development of allergic disease in high-risk infants by inhibiting cytokine profiles associated with allergy. Results of clinical trials are awaited to determine the efficacy of vitamin D supplementation in allergy prevention.

Challenges in modelling the reaction chemistry of interstellar dust.

Studies aiming to understand the physicochemical properties of interstellar dust and the chemical reactions that occur on and in it have traditionally been the preserve of astronomical observation and experimental attempts to mimic astronomically relevant conditions in the laboratory. Increasingly, computational modelling in its various guises is establishing a complementary third pillar of support to this endeavour by providing detailed insights into the complexities of interstellar dust chemistry. Inherently, the basis of computational modelling is to be found in the details (e.g. atomic structure/composition, reaction barriers) that are difficult to probe accurately from observation and experiment. This bottom-up atom-based theoretical approach, often itself based on deeper quantum mechanical principles, although extremely powerful, also has limitations when systems become too large or complex. In this Perspective, after first providing a general background to the current state of observational-based knowledge, we introduce a number of computational modelling methods with reference to recent state-of-the-art studies, in order to highlight the capabilities of such approaches in this field. Specifically, we first outline the use of computational chemistry methods for dust nucleation, structure, and individual reactions on bare and icy dust surfaces. Later, we review kinetic modelling of networks of reactions relevant to dust chemistry and how to take into account quantum tunnelling effects in the low temperature reactions in the interstellar medium. Finally, we point to the future challenges that need to be overcome for computational modelling to provide even more detailed and encompassing perspectives on the nature and reaction chemistry of interstellar dust.

Management of colorectal cancer explains differences in 1-year relative survival between France and England for patients diagnosed 1997-2004.

BACKGROUND: Few international population-based studies have provided information on potential determinants of international disparities in cancer survival. This population-based study was undertaken to identify the principal differences in disease characteristics and management that accounted for previously observed poorer survival in English compared with French patients with colorectal cancer. METHODS: The study population comprised all cases of colorectal cancer diagnosed between 1997 and 2004 in the areas covered by three population-based cancer registries in France and one in England (N=40 613). To investigate the influence of clinical and treatment variables on survival, we applied multivariable excess hazard modelling based on generalised linear models with Poisson error. RESULTS: Poorer survival for English patients was primarily due to a larger proportion dying within the first year after diagnosis. After controlling for inter-country differences in the use of chemotherapy and surgical resection with curative intent, country of residence was no-longer associated with 1-year survival for advanced colon cancer patients (excess hazard ratio (EHR)=0.99 (0.92-1.01), P=0.095)). Longer term (2-5 years) excess hazards of death for colon and rectal cancer patients did not differ between France and England. CONCLUSION: This study suggests that difference in management close to diagnosis of colon and rectum cancer is related to differences in survival observed between France and England. All efforts (collection and standardisation of additional variables such as co-morbidity) to investigate the reasons for these disparities in management between these two countries, and more generally across Europe, should be encouraged.

Extreme water-related weather events and waterborne disease.

Global climate change is expected to affect the frequency, intensity and duration of extreme water-related weather events such as excessive precipitation, floods, and drought. We conducted a systematic review to examine waterborne outbreaks following such events and explored their distribution between the different types of extreme water-related weather events. Four medical and meteorological databases (Medline, Embase, GeoRef, PubMed) and a global electronic reporting system (ProMED) were searched, from 1910 to 2010. Eighty-seven waterborne outbreaks involving extreme water-related weather events were identified and included, alongside 235 ProMED reports. Heavy rainfall and flooding were the most common events preceding outbreaks associated with extreme weather and were reported in 55·2% and 52·9% of accounts, respectively. The most common pathogens reported in these outbreaks were Vibrio spp. (21·6%) and Leptospira spp. (12·7%). Outbreaks following extreme water-related weather events were often the result of contamination of the drinking-water supply (53·7%). Differences in reporting of outbreaks were seen between the scientific literature and ProMED. Extreme water-related weather events represent a risk to public health in both developed and developing countries, but impact will be disproportionate and likely to compound existing health disparities.

Association between diet and physical activity and sedentary behaviours in 9-10-year-old British White children.

OBJECTIVES: To examine the association between diet and physical activity and sedentary behaviours in 9-10-year-old children. STUDY DESIGN: A cross-sectional study using data from the SPEEDY (Sport, Physical activity and Eating behaviour: Environmental Determinants in Young People) study undertaken in Norfolk, UK. METHODS: Data from 4-day food diaries and 7 days of accelerometery were matched on concurrent days. Time spent in moderate-to-vigorous physical activity (MVPA), time spent in sedentary behaviour and various measures of dietary intake were collected. Covariates included age, sex, weight status, family socio-economic status, and energy intake reporting quality. Multivariable regression models, adjusted for clustering of children by school and stratified by sex, were fitted to examine the associations between dietary measures and physical activity and sedentary outcomes. RESULTS: In total, 1317 children (584 boys and 733 girls) provided concurrent data. Boys in the highest quartile of energy percentage from protein spent approximately 6 min [95% confidence interval (CI) 0-12] less in MVPA compared with boys in the lowest quartile. Those in the highest quartiles of fruit and vegetable intake and fruit juice intake had respective average activity counts per minute that were 56 above (95% CI 8-105) and 48 below (95% CI 2-95) those in the lowest quartiles, whilst those in the highest quartile of fizzy drink consumption spent approximately 7 min (95% CI 2-13) more in MVPA and approximately 14 min (95% CI 5-24 min) less in sedentary behaviour. Boys in the highest quartile of savoury snack consumption spent approximately 8 min (95% CI 2-13 min) more in MVPA per day, and approximately 12 min (95% CI 2-23) less in sedentary behaviour. No significant associations were apparent among girls. CONCLUSIONS: Few associations were detected, and the directions of those that were apparent were mainly counterintuitive. The extent to which this reflects a true lack of association or is associated with the measurement methods used for diet and physical activity needs further investigation.

Review of emergency department wound management in soft tissue trauma - is there a plan?

OBJECTIVE: To assess current acute wound management in English emergency departments. METHOD: All English emergency departments including minor injury units (n=207) were successfully contacted and a telephone questionnaire was completed. This considered wound treatment policy; management including cleansing, analgesia, dressing selection, suturing, referral patterns, medical photography and antibiotic use. RESULTS: There was a 100% response. Only 40% of departments had a wound treatment policy. Most had implemented staff training, however the nature and timing of this was variable. Wound cleansing was performed by all departments. Most administered analgesia. Suturing was selectively performed by all departments. There was great diversity regarding dressing selection. The most common reasons for referral to specialist units were the complexity of injury and cosmetically sensitive areas. Photographs were regularly taken in one third of units questioned. CONCLUSION: This study confirmed an absence of a standard protocol for early soft tissue wound management in the emergency department setting. Key areas that could be improved are dressing simplification, more defined referral criteria and introduction of standardised protocols with structured teaching programmes. We propose a simple approach to management of acute soft tissue wounds that can be applied to most situations. DECLARATION OF INTEREST: There were no external sources of funding for this study. The authors have no conflicts of interest to declare.

Representation of plastic and cosmetic surgeons in British newspapers.

BACKGROUND: The aim of this study was to investigate the use of the terms "plastic surgeon" or "cosmetic surgeon" in British newspapers. METHODS: Based on readership volume, the top eight British newspapers were searched for articles written between 09/2016-09/2021 for their use of keywords "plastic surgeon" OR "cosmetic surgeon". The names of the doctors referenced were searched in the GMC register to determine their speciality registration. RESULTS: A total of 2326 articles were read. 2107 (91%) articles were excluded as they did not refer to a specifically named doctor. Of the 219 articles remaining, 136 referenced "plastic surgeons". 22 (16%) doctors referred to as "plastic surgeons" were not on the GMC speciality register for plastic surgery. 83 articles made reference to "cosmetic surgeons". 39 (47%) were on the plastic surgery register but 11 (13%) were on other higher surgical registers [ENT (2) and ophthalmology (9)]. 18 (22%) cosmetic surgeons were registered as GPs and 15 (18%) were not on any speciality register. DISCUSSION: There is mis-representation of individuals performing cosmetic procedures as plastic surgeons regardless of their speciality or training. This prevents public awareness of the true scope of plastic and reconstructive surgery as a speciality in its own right.

The use of the 5-year-olds' index: comparison between study models and intraoral photographs.

OBJECTIVE: To determine if photographs may be used instead of dental study models to assess the outcome of primary surgery in 5- to 6-year-olds who were born with complete unilateral cleft lip and palate. DESIGN: Retrospective method comparison study. SETTING: Five U.K. cleft units. SUBJECTS: Records of 96 children born with complete unilateral cleft lip and palate. METHOD: Dental study models and photographs including an overjet measurement taken from both the most prominent and retrusive tooth in each case were scored using the 5-year-olds' index. RESULTS: There was moderate to very good agreement between the methods of using study models or photographs. Intraexaminer agreement was moderate to very good for study models. For the photographs it was good to very good. Overall interexaminer agreement was moderate for both study models and photographs. CONCLUSIONS: When impressions are difficult to obtain, intraoral photographs with clinically recorded overjet measurements may be used for the 5-year-olds' index.

Enhancing fraction measured using dynamic contrast-enhanced MRI predicts disease-free survival in patients with carcinoma of the cervix.

BACKGROUND: There is a need for simple imaging parameters capable of predicting therapeutic outcome. METHODS: This retrospective study analysed 50 patients with locally advanced carcinoma of the cervix who underwent dynamic contrast-enhanced MRI before receiving potentially curative radiotherapy. The proportion of enhancing pixels (E(F)) in the whole-tumour volume post-contrast agent injection was calculated and assessed in relation to disease-free survival (DFS). RESULTS: Tumours with high E(F) had a significantly poorer probability of DFS than those with low E(F) (P=0.011). INTERPRETATION: E(F) is a simple imaging biomarker that should be studied further in a multi-centre setting.

Geographical access to healthcare in Northern England and post-mortem diagnosis of cancer.

BACKGROUND: There is some previous evidence that diagnosis of cancer at death, recorded as registry death certificate only records, is associated with problems of access to care. METHODS: Records from the Northern and Yorkshire Cancer Registry for patients registered with breast, colorectal, lung, ovarian or prostate cancer between 1994 and 2002 were supplemented with measures of travel time to general practitioner and hospital services, and social deprivation. Logistic regression was used to identify predictors of records where diagnosis was at death. RESULTS: There was no association between the odds diagnosis at death and access to primary care. For all sites except breast, the highest odds of being a cancer diagnosed at death fell among those living in the highest quartile of hospital travel time, although it was only statistically significant for colorectal and ovary tumours. Those in the most deprived and furthest travel time to hospital quartile were 2.6 times more likely to be a diagnosis at death case compared with those in the most affluent and proximal areas. CONCLUSIONS: There is some evidence that poorer geographical access to tertiary care, in particular when coupled with social disadvantages, may be associated with increased odds of diagnosis at death.

Social and geographical factors affecting access to treatment of lung cancer.

BACKGROUND: UK residents' healthcare is free of charge but uptake varies. Cancer survival is inferior to that of other Western European countries. We have used cancer registry data to assess factors associated with access to diagnosis and treatment of lung cancer in northern England. METHOD: We assigned 34 923 lung cancer patients diagnosed between 1994 and 2002 to quartiles for the deprivation score associated with their postcode and for the travel time to the relevant healthcare facility. Odds ratios, adjusted for age and sex, for undergoing interventions were calculated relative to the least deprived quartile living closest to the facility. The odds ratio for receiving chemotherapy for small-cell lung cancer (SCLC) was calculated according to the type of hospital where it was diagnosed. RESULTS: The odds ratio for attainment of a histological diagnosis for the least deprived/furthest residence group was 0.83 (95% confidence 0.70-0.97) for the most deprived/nearest residence group was 0.74(0.62-0.87) and for the most deprived/furthest residence group it was 0.61 (0.49-0.75). The corresponding odds ratios for receipt of any active treatment were 0.93 (0.80-1.07), 0.74 (0.64-0.86), and 0.55 (0.46-0.67). The odds ratios for receipt of chemotherapy for SCLC were 1.27 (0.89-1.82), 1.21 (0.85-1.74) and 0.81 (0.52-1.28). Odds ratios for undergoing surgery for non-small cell lung cancer using (1) travel time to diagnosing hospital were 0.88 (0.70-1.11), 0.74 (0.59-0.94) and 0.60 (0.44-0.84). Using (2) travel time to a thoracic surgery facility they were 0.83 (0.65-1.06), 0.70 (0.55-0.89) and 0.55 (0.49-0.76). CONCLUSION: Living in a deprived locality reduces the likelihood of undergoing definitive management for lung cancer with the exception of chemotherapy for SCLC. This is amplified by travel time to services.

Obesity and adipocyte abnormalities in offspring of rats undernourished during pregnancy.

Pregnant rats underfed in the first 2 weeks of gestation had offspring with normal body weight at birth and weaning. However, starting at about 5 weeks of age the male offspring became hyperphagic and gained more weight than the controls. The female offspring did not overeat and did not become obese. Both male and female progeny showed increased fat cell size as adults. In males the epididymal and retroperitoneal fat pads were significantly enlarged nd adipocytes in these pads were hypertrophied. In females and fat pads were not enlarged, but adipocytes in the parametrial pads were hypertrophied.

Use of prehospital dressings in soft tissue trauma: is there any conformity or plan?

BACKGROUND: Acute soft tissue wounds are commonly seen in the prehospital setting. It was hypothesised that there is a lack of consistency in early management of trauma wounds, particularly in the dressings used. METHODS: In January 2007 a questionnaire-based study was undertaken to evaluate the early management of such injuries. All 13 UK ambulance services were contacted, as well as 2 voluntary ambulance services. The questionnaire considered the implementation of a wound treatment policy and staff training, immediate wound management including haemostasis, cleansing, analgesia, dressings and the use of antibiotics. RESULTS: The response rate was 100%. Only 27% of services had a wound treatment policy in place, but all services implemented staff training. All services regularly achieved haemostasis of wounds using a combination of pressure and elevation. Regular cleansing was performed by 47% of services and those that did so used normal saline or water. All ambulance services administered analgesics. The most commonly used analgesics were Entonox and intravenous morphine. Other analgesics administered were paracetamol and ibuprofen. No local anaesthesia was used. Dressings were applied regularly by all services; 13 different types of dressings were in regular use. CONCLUSIONS: This study confirmed that there is currently no national standard protocol for early acute wound management in the prehospital care setting. The key areas for improvement are cleansing, simplification of dressings and the introduction of standardised protocols and teaching.

Defining consensus opinion to develop randomised controlled trials in rare diseases using Bayesian design: An example of a proposed trial of adalimumab versus pamidronate for children with CNO/CRMO.

INTRODUCTION: Chronic nonbacterial osteomyelitis (CNO) is a rare autoinflammatory bone disorder primarily affecting children and adolescents. It can lead to chronic pain, bony deformities and fractures. The pathophysiology of CNO is incompletely understood. Scientific evidence suggests dysregulated expression of pro- and anti-inflammatory cytokines to be centrally involved. Currently, treatment is largely based on retrospective observational studies and expert opinion. Treatment usually includes nonsteroidal anti-inflammatory drugs and/or glucocorticoids, followed by a range of drugs in unresponsive cases. While randomised clinical trials are lacking, retrospective and prospective non-controlled studies suggest effectiveness of TNF inhibitors and bisphosphonates. The objective of the Bayesian consensus meeting was to quantify prior expert opinion. METHODS: Twelve international CNO experts were randomly chosen to be invited to a Bayesian prior elicitation meeting. RESULTS: Results showed that a typical new patient treated with pamidronate would have an 84% chance of improvement in their pain score relative to baseline at 26 weeks and an 83% chance on adalimumab. Experts thought there was a 50% chance that a new typical patient would record a pain score of 28mm (pamidronate) to 30mm (adalimumab) or better at 26 weeks. There was a modest trend in prior opinion to indicate an advantage of pamidronate vs adalimumab, with a 68% prior chance that pamidronate is superior to adalimumab by some margin. However, it is clear that there is considerable uncertainty about the precise relative merits of the two treatments. CONCLUSIONS: The rarity of CNO leads to challenges in conducting randomised controlled trials with sufficient power to provide a definitive outcome. We address this using a Bayesian design, and here describe the process and outcome of the elicitation exercise to establish expert prior opinion. This opinion will be tested in the planned prospective CNO study. The process for establishing expert consensus opinion in CNO will be helpful for developing studies in other rare paediatric diseases.

Travel time to hospital and treatment for breast, colon, rectum, lung, ovary and prostate cancer.

The aim was to examine the effect of geographical access to treatment services on cancer treatment patterns. Records for patients in northern England with breast, colon, rectal, lung, ovary and prostate tumours were augmented with estimates of travel time to the nearest hospital providing surgery, chemotherapy or radiotherapy. Using logistic regression to adjust for age, sex, tumour stage, selected tumour pathology characteristics and deprivation of place of residence, the likelihood of receiving radiotherapy was reduced for all sites studied with increasing travel time to the nearest radiotherapy hospital. Lung cancer patients living further from a thoracic surgery hospital were less likely to receive surgery, and both lung cancer and rectal cancer patients were less likely to receive chemotherapy if they lived distant from these services. Services provided in only a few specialised centres, involving longer than average patient journeys, all showed an inverse association between travel time and treatment take-up.

Travel times to health care and survival from cancers in Northern England.

The aim was to assess the effect of geographical accessibility on the stage of cancer at diagnosis and survival. Records of 117,097 cases of breast, colorectal, lung, ovary and prostate cancer diagnosed in Northern England between 1994 and 2002 were supplemented with estimates of travel times to the patients' general practitioners (GPs) and hospitals attended, together with measures of access to public transport. Logistic regression and Cox proportional hazards models were used, adjusting for age, sex, whether the first hospital visited was a cancer centre and deprivation of area of residence. Late stage at diagnosis was associated with increasing travel time to GP for breast and colorectal cancers and risk of death was associated with travel time to GP for prostate cancer. Travel times to hospital and other accessibility measures showed no consistent associations with stage at diagnosis or survival, so travel to GP was the only influential factor.

Development and application of a one-step low cost procedure to concentrate viruses from seawater samples.

A novel and simple procedure for concentrating adenoviruses from seawater samples is described. The technique entails the adsorption of viruses to pre-flocculated skimmed milk proteins, allowing the flocs to sediment by gravity, and dissolving the separated sediment in phosphate buffer. Concentrated virus may be detected by PCR techniques following nucleic acid extraction. The method requires no specialized equipment other than that usually available in routine public health laboratories, and due to its straightforwardness it allows the processing of a larger number of water samples simultaneously. The usefulness of the method was demonstrated in concentration of virus in multiple seawater samples during a survey of adenoviruses in coastal waters.

Travel time to radiotherapy and uptake of breast-conserving surgery for early stage cancer in Northern England.

Patients with early stage breast cancer can opt for either mastectomy or breast-conserving surgery (BCS), but BCS requires daily radiotherapy for some weeks. The hypothesis that ease of access to radiotherapy might affect choice of surgery was investigated using records of 6014 breast cancer patients in Northern England. Adjusting for the effects of age, deprivation and hospital type, the choice of BCS was not associated with the estimated car journey time to radiotherapy for most women but there was an association for patients living in places without a regular bus service, so transport problems might influence surgery choice for a minority of women.