A reformulation of pLSA for uncertainty estimation and hypothesis testing in bio-imaging.

MOTIVATION: Probabilistic latent semantic analysis (pLSA) is commonly applied to describe mass spectra (MS) images. However, the method does not provide certain outputs necessary for the quantitative scientific interpretation of data. In particular, it lacks assessment of statistical uncertainty and the ability to perform hypothesis testing. We show how linear Poisson modelling advances pLSA, giving covariances on model parameters and supporting χ2 testing for the presence/absence of MS signal components. As an example, this is useful for the identification of pathology in MALDI biological samples. We also show potential wider applicability, beyond MS, using magnetic resonance imaging (MRI) data from colorectal xenograft models. RESULTS: Simulations and MALDI spectra of a stroke-damaged rat brain show MS signals from pathological tissue can be quantified. MRI diffusion data of control and radiotherapy-treated tumours further show high sensitivity hypothesis testing for treatment effects. Successful χ2 and degrees-of-freedom are computed, allowing null-hypothesis thresholding at high levels of confidence. AVAILABILITY AND IMPLEMENTATION: Open-source image analysis software available from TINA Vision, www.tina-vision.net. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Quantifying biological samples using Linear Poisson Independent Component Analysis for MALDI-ToF mass spectra.

Motivation: Matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI) facilitates the analysis of large organic molecules. However, the complexity of biological samples and MALDI data acquisition leads to high levels of variation, making reliable quantification of samples difficult. We present a new analysis approach that we believe is well-suited to the properties of MALDI mass spectra, based upon an Independent Component Analysis derived for Poisson sampled data. Simple analyses have been limited to studying small numbers of mass peaks, via peak ratios, which is known to be inefficient. Conventional PCA and ICA methods have also been applied, which extract correlations between any number of peaks, but we argue makes inappropriate assumptions regarding data noise, i.e. uniform and Gaussian. Results: We provide evidence that the Gaussian assumption is incorrect, motivating the need for our Poisson approach. The method is demonstrated by making proportion measurements from lipid-rich binary mixtures of lamb brain and liver, and also goat and cow milk. These allow our measurements and error predictions to be compared to ground truth. Availability and implementation: Software is available via the open source image analysis system TINA Vision, www.tina-vision.net. Contact: paul.tar@manchester.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online.

A review of approaches to 18 F radiolabelling affinity peptides and proteins.

Affinity peptide and protein- (APP) based radiotracers are an increasingly popular class of radiotracer in positron emission tomography (PET), which was once dominated by the use of small molecule radiotracers. Radiolabelled monoclonal antibodies (mAbs) are important examples of APPs, yet a preference for smaller APPs, which exhibit fast pharmacokinetics and permit rapid PET aided diagnosis, has become apparent. 18 F exhibits favourable physical characteristics for APP radiolabelling and has been described as an ideal PET radionuclide. Notwithstanding, 18 F radiolabelling of APP is challenging, and this is echoed in the literature where a number of diverse approaches have been adopted. This review seeks to assess and compare the approaches taken to 18 F APP radiolabelling with the intention of highlighting trends within this expanding field. Generic themes have emerged in the literature, namely the use of mild radiolabelling conditions, a preference of site-specific methodologies with an impetus for short, automated procedures which produce high-yielding [18 F]APPs.

Nutrition-related hospital presentations and admissions among radiotherapy outpatients: a systematic literature review.

BACKGROUND: Unplanned presentations and admissions to hospital among outpatients with cancer are a key indicator of quality care in cancer services. Nutritional issues including malnutrition and dehydration, which fall under the dietitian's scope of practice, can result in unplanned contacts. The present review focused on cancer outpatients undergoing radiotherapy as a particular at risk group and aimed to provide a comprehensive overview of the range and prevalence of nutrition-related unplanned contacts and the associated factors, including the role of dietetic intervention. METHODS: A systematic review analysed studies published between 1990 and August 2016 from five databases. Eligible studies reported rates of nutrition-related unplanned contacts among adult nonhaematological cancer outpatients, treated with nonpalliative radiotherapy. Studies were screened for eligibility, extracted, descriptively analysed and synthesised. RESULTS: Fifteen studies were included. Common causes of nutrition-related unplanned contacts included dehydration and enteral feeding commencement and complications. Factors that influenced nutrition-related unplanned contacts included tumour location and stage, treatment modality and the presence of a feeding tube. There were issues in determining the prevalence and identifying dietetic interventions partly as a result of the heterogeneity in reported study designs and varying definitions of nutrition-related unplanned contacts. CONCLUSIONS: Nutrition-related problems appear to be associated with unplanned contacts in cancer outpatients undergoing radiotherapy. Hence, there is a strategic need for dietetic involvement aiming to reduce these. Further research is required to define the role of the dietitian in managing nutrition-related unplanned contacts, particularly for dehydration. This may help to define the full scope of practice for dietitians caring for these nutritionally vulnerable and complex outpatients.

Presenting symptoms and long-term survival in head and neck cancer.

OBJECTIVES: To assess how type and number of symptoms are related to survival in patients with head and neck cancer. DESIGN: Patients were followed up for over 10 years from the Scottish Audit of Head and Neck Cancer (national cohort of head and neck cancer patients in Scotland 1999-2001). September 2013, cohort was linked to national mortality data. First, second and third presenting symptoms were recorded at diagnosis. SETTING: National prospective audit-Scotland. PARTICIPANTS: A subset of 1589 patients, from the original cohort of 1895, who had cancer arising from one of the four main subsites; larynx, oropharynx, oral cavity and hypopharynx. MAIN OUTCOME MEASURES: Median survival in relation to patients' presenting symptoms. RESULTS: A total of 1146 (72%) males and 443 (28%) females, mean age at diagnosis 64 years (13-95). There was a significant difference in survival in relation to the number of the patient's presenting symptoms; one symptom had a median survival of 5.3 years compared with 1.1 years for three symptoms. Patients who presented with weight loss had a median survival of 0.8 years, compared to 4.2 years if they did not (P < .001). Patients who presented with hoarseness had a median survival of 5.9 years compared to 2.6 years without (P < .001). There was no significant difference in long-term survival for patients who presented with an ulcer, compared to those that did not (P = .105). CONCLUSIONS: This study highlights the importance of patients' presenting symptoms, giving valuable information in highlighting appropriate "red flag" symptoms and subsequent treatment planning and prognosis.

Patient-centred dietetic care from the perspectives of older malnourished patients.

BACKGROUND: Governing organisations for health services currently recommend a patient-centred (PC) approach to practice for all health professions, including dietetics. For the vulnerable older malnourished patient, this approach needs to be prioritised to improve outcomes. The paucity of patient experience data likely limits evidence-based, patient-centred care (PCC) from being implemented effectively. The present study aimed to identify quality indicators of dietetic services from the perspectives of older malnourished patients to inform evidence-based PC dietetic care. METHODS: Surveys were completed by a sample of 28 females and 28 males (mean age 81 years) who had been seen by a dietitian for malnutrition assessment. In-depth, face-to-face, semi-structured interviews were undertaken with a sub-sample of four females and six males (mean age 81 years). Interviews were transcribed verbatim. Thematic analysis of transcripts and open-ended survey responses was conducted to determine patient-identified quality indicators. RESULTS: Three structure indicators (continuity of care through regular contact and post-discharge dietetic follow-up; interdisciplinary coordination and collaboration; and high-quality hospital food services), five process indicators (addressing a patient's primary medical concern; involving the patient's family; providing clear and simple dietetic information; providing expert dietary knowledge; utilising interpersonal communication skills) and three outcome indicators (improvement in health status; improvement or maintenance of independence; weight gain) were identified. The experiences of older malnourished patients with dietetic services, as described in the present study, reinforce the importance of ensuring high-quality and tailored dietetic care as a key element of PC dietetic services. CONCLUSIONS: The quality indicators of dietetic services identified in the present study may facilitate dietitians to provide evidence-based PCC for older malnourished patients.

Linking routinely collected social work, education and health data to enable monitoring of the health and health care of school-aged children in state care ('looked after children') in Scotland: a national demonstration project.

BACKGROUND AND OBJECTIVES: Children in state care ('looked after children') have poorer health than children who are not looked after. Recent developments in Scotland and elsewhere have aimed to improve services and outcomes for looked after children. Routine monitoring of the health outcomes of looked after children compared to those of their non-looked after peers is currently lacking. Developing capacity for comparative monitoring of population-based outcomes based on linkage of routinely collected administrative data has been identified as a priority. To our knowledge there are no existing population-based data linkage studies providing data on the health of looked after and non-looked after children at national level. Smaller scale studies that are available generally provide very limited information on linkage methods and hence do not allow scrutiny of bias that may be introduced through the linkage process. STUDY DESIGN AND METHODS: National demonstration project testing the feasibility of linking routinely collected looked after children, education and health data. PARTICIPANTS: All children in publicly funded school in Scotland in 2011/12. RESULTS: Linkage between looked after children data and the national pupil census classified 10,009 (1.5%) and 1757 (0.3%) of 670,952 children as, respectively, currently and previously looked after. Recording of the unique pupil identifier (Scottish Candidate Number, SCN) on looked after children returns is incomplete, with 66% of looked after records for 2011/12 for children of possible school age containing a valid SCN. This will have resulted in some under-ascertainment of currently and, particularly, previously looked after children within the general pupil population. Further linkage of the pupil census to the National Health Service Scotland master patient index demonstrated that a safe link to the child's unique health service (Community Health Index) number could be obtained for a very high proportion of children in each group (94%, 95% and 95% of children classified as currently, previously, and non-looked after, respectively). In general, linkage rates were higher for older children and those living in more affluent areas. Within the looked after group, linkage rates were highest for children with the fewest placements and for those in permanent fostering. CONCLUSIONS: This novel data linkage demonstrates the feasibility of monitoring population-based health outcomes of school-aged looked after and non-looked after children using linked routine administrative data. Improved recording of the unique pupil identifier number on looked after data returns would be beneficial. Extending the range of personal identifiers on looked after children returns would enable linkage to health data for looked after children who are not in publicly funded schooling (i.e. those who are preschool or postschool, home schooled or in independent schooling).

In vivo characterisation of a therapeutically relevant self-assembling 18 F-labelled ß-sheet forming peptide and its hydrogel using positron emission tomography.

Positron emission tomography (PET) and fluorescence labelling have been used to assess the pharmacokinetics, biodistribution and eventual fate of a hydrogel-forming nonapeptide, FEFKFEFKK (F9), in healthy mice, using 18 F-labelled and fluorescein isothiocyanate (FITC)-labelled F9 analogues. F9 was site-specifically radiolabelled with 2-[18 F]fluoro-3-pyridinecarboxaldehyde ([18 F]FPCA) via oxime bond formation. [18 F]FPCA-F9 in vivo fate was evaluated both as a solution, following intravenous administration, and as a hydrogel when subcutaneously injected. The behaviour of FITC-F9 hydrogel was assessed following subcutaneous injection. [18 F]FPCA-F9 demonstrated high plasma stability and primarily renal excretion; [18 F]FPCA-F9 when in solution and injected into the bloodstream displayed prompt bladder uptake (53.4 ± 16.6 SUV at 20 minutes postinjection) and rapid renal excretion, whereas [18 F]FPCA-F9 hydrogel, formed by co-assembly of [18 F]FPCA-F9 monomer with unfunctionalised F9 peptide and injected subcutaneously, showed gradual bladder accumulation of hydrogel fragments (3.8 ± 0.4 SUV at 20 minutes postinjection), resulting in slower renal excretion. Gradual disaggregation of the F9 hydrogel from the site of injection was monitored using FITC-F9 hydrogel in healthy mice (60 ± 3 over 96 hours), indicating a biological half-life between 1 and 4 days. The in vivo characterisation of F9, both as a gel and a solution, highlights its potential as a biomaterial.

Erring on the side of caution: pregnant women's perceptions of consuming fish in a risk averse society.

BACKGROUND: Fish and seafood are good sources of several nutrients that are important for foetal growth and development. Despite guidelines encouraging the eating of fish during pregnancy, research indicates that pregnant women may be limiting or avoiding these foods. Possible factors contributing to this include concerns regarding levels of mercury and other contaminants and pregnant women's purported heightened risk consciousness. The present study aimed to explore pregnant women's perceptions of consuming fish and seafood during pregnancy. METHODS: Semi-structured telephone interviews were conducted with 15 pregnant women across all three trimesters in New South Wales, Australia. Questions focussed on exploring nutrition information received during pregnancy, dietary changes made during pregnancy and, more specifically, perceptions of fish and seafood, as well as views on information of fish and seafood commonly provided to pregnant women. Data were collected, then transcribed and analysed using an inductive coding process, guided by the qualitative theory grounded approach. RESULTS: Multiple inter-related themes were found to shape pregnant women's perceptions related to fish and seafood consumption during pregnancy; namely, the understanding of fish and seafood as part of a healthy diet, external factors such as cost, individual preferences such as taste, and confidence in choosing and preparing fish. The context of a risk adverse society permeated these themes. CONCLUSIONS: The present study provides insight into the inter-related factors that influence pregnant women's consumption or avoidance of fish and seafood.

Building bridges in dietary counselling: an exploratory study examining the usefulness of wellness and wellbeing concepts.

BACKGROUND: Over the last decade, professional discourse around health ownership has been evolving to recognise an individually-driven wellness/wellbeing approach. Concurrently, dietetic competencies have changed to include client-centred counselling incorporating individual client's perspectives within dietary prescriptions. The present exploratory research aimed to explore how client-centred counselling practice was being represented in the dietetic literature and to examine dietitians' perspectives about working with clients in the current environment. METHODS: To explore the professional position, a literature search was conducted using keywords encompassing client-centred care and competency within professional dietetic journals (2001-2010). To develop a contextual case study, 10 in-depth interviews with dietitians delivering weight-loss prescriptions within a clinical trial were conducted. Recordings of their perspectives on roles, opportunities/barriers and counselling strategies were transcribed verbatim and examined using inductive thematic and content analysis. RESULTS: Eleven articles were incorporated into a narrative review describing practice issues related to traditional forms of consultation and the effectiveness of client-centred approaches. The over-riding theme from the interviews (Professional Identity Dilemma) highlighted tension felt by dietitians in their dual role as nutrition expert and counsellor, trained to deliver biomedical imperatives (clinical targets), and their challenge to accept client-defined health perspectives. Supporting themes (Adherence factors and Constructs of health) exposed details on barriers to dietary change and the impact of contextual factors on this change that were linked to wellness and wellbeing concepts. CONCLUSIONS: Appreciating wellness and wellbeing concepts may add a useful adjunct to client-centred approaches to dietary counselling through building bridges between clinical targets and client health perspectives.

A new technique for the radiolabelling of mixed leukocytes with zirconium-89 for inflammation imaging with positron emission tomography.

Mixed leukocyte (white blood cells [WBCs]) trafficking using positron emission tomography (PET) is receiving growing interest to diagnose and monitor inflammatory conditions. PET, a high sensitivity molecular imaging technique, allows precise quantification of the signal produced from radiolabelled moieties. We have evaluated a new method for radiolabelling WBCs with either zirconium-89 ((89) Zr) or copper-64 ((64) Cu) for PET imaging. Chitosan nanoparticles (CNs) were produced by a process of ionotropic gelation and used to deliver radiometals into WBCs. Experiments were carried out using mixed WBCs freshly isolated from whole human blood. WBCs radiolabelling efficiency was higher with [(89) Zr]-loaded CN (76.8 ± 9.6% (n = 12)) than with [(64) Cu]-loaded CN (26.3 ± 7.0 % (n = 7)). [(89) Zr]-WBCs showed an initial loss of 28.4 ± 5.8% (n = 2) of the radioactivity after 2 h. This loss was then followed by a plateau as (89) Zr remains stable in the cells. [(64) Cu]-WBCs showed a loss of 85 ± 6% (n = 3) of the radioactivity after 1 h, which increased to 96 ± 6% (n = 3) loss after 3 h. WBC labelling with [(89) Zr]-loaded CN showed a fast kinetic of leukocyte association, high labelling efficiency and a relatively good retention of the radioactivity. This method using (89) Zr has a potential application for PET imaging of inflammation.

What do the terms wellness and wellbeing mean in dietary practice: an exploratory qualitative study examining women's perceptions.

BACKGROUND: Wellness and wellbeing are terms associated with health within dietetic discourse. More broadly, these terms are found in social discourse as represented in food and nutrition consumer communications. With the increasing requirement for evidence-based healthcare, there is an imperative to understand whether these terms are meaningful to individuals typically targeted for nutrition interventions and whether there are any implications for dietetic education. METHODS: To explore the understanding of these terms, eight semi-structured focus groups were conducted with 32 female participants (age range 23-79 years) who were actively engaged in managing their health. Overall understanding of the terms, factors that impacted perceptions and any relationships with food behaviour were investigated with the groups. Group discussions were transcribed verbatim and each transcript was examined by two researchers. Inductive analysis linking codes into main thematic categories was conducted using the constant comparison approach across the full data set. RESULTS: Wellness and wellbeing were identified as meaningful terms associated with health. A theoretical framework of wellness and wellbeing reflecting these meanings was developed linking four dominant thematic areas. These were Desired outcomes (most sought after result); Taking control (self management strategies); Internal influences (various personal inner factors influencing behaviours); and External influences (plethora of peripheral factors influencing behaviours). CONCLUSIONS: Wellness and wellbeing are terms that are relevant and aspirational for individuals typically targeted for nutrition intervention. A theoretical framework of dominant areas of influence on notions of wellness and wellbeing was identified. This theoretical framework is worthy of further research to determine usefulness and effectiveness in dietetic practice settings.

Primary-care observational database study of the efficacy of GLP-1 receptor agonists and insulin in the UK.

AIMS: We investigated use and efficacy of glucagon-like peptide-1 (GLP-1) receptor agonists in UK practice. METHODS: People starting a GLP-1 receptor agonist (exenatide, liraglutide) or insulin (glargine, detemir, NPH) after a regimen of two or three oral glucose-lowering agents were identified from The Health Information Network observational primary care database (2007-2011). Mean change in HbA1c and body weight were compared at 1 year between cohorts, adjusting for baseline characteristics. RESULTS: Baseline characteristics of GLP-1 receptor agonist (n = 1123) vs. insulin (n = 1842) users were HbA1c 78 vs. 84 mmol/mol (9.3 vs. 9.8%) and BMI 38.2 vs. 30.9 kg/m². The GLP-1 receptor agonist cohort was younger, had shorter diabetes duration and follow-up, less microvascular disease and heart failure, higher estimated glomerular filtration rate and more use of oral glucose-lowering agents. Lower HbA1c reduction on GLP-1 receptor agonist [7 vs. 13 mmol/mol (0.6 vs. 1.2%) (n = 366 vs. 892)] was not statistically significant [adjusted mean difference -1.4 (95% CI -4.1, 1.2) mmol/mol], except in the highest HbA1c quintile [>96 mmol/mol (>10.9%); adjusted mean difference -17.8 (-28.6, -7.0) mmol/mol]. GLP-1 receptor agonist users lost weight [-4.5 vs. +1.5 kg; adjusted mean difference 4.7 (3.7, 5.8) kg; n = 335 vs. 634]. A UK 6-month target reduction for GLP-1 receptor agonists of 11 mmol/mol (1.0%) HbA1c and 3% weight was reached by 24.9% of those continuing treatment. CONCLUSIONS: Those starting GLP-1 receptor agonists are heavier with better glycaemic control than those starting basal insulin. Subsequently, they have improved weight change, with similar HbA1c reduction unless baseline HbA1c is very high. The UK 6-month GLP-1 receptor agonist target is usually not reached.

Assessing the risk of endogeneity bias in health and mortality inequalities research using composite measures of multiple deprivation which include health-related indicators: A case study using the Scottish Index of Multiple Deprivation and population health and mortality data.

The inclusion of health-related indicators in composite measures of multiple deprivation introduces a risk of endogeneity bias when using the latter in health inequalities research. This bias may ultimately result in the inappropriate allocation of healthcare resources and maintenance of preventable health inequalities. Mitigation strategies to avoid this bias include removing the health-related indicators or using single constituent domains (such as income or employment class) in isolation. These strategies have not been widely validated. This study used population-level health and mortality data with a contemporary composite measure of multiple deprivation (Scottish Index of Multiple Deprivation; SIMD) to assess these mitigation strategies. The differences between deprivation methods (original, health excluded, and income domain) were negligible. The results of quantitative research on health inequalities are unlikely to be affected by endogeneity bias.

Economic Evaluation of the Protecting Teeth @ 3 Randomized Controlled Trial.

INTRODUCTION: An economic evaluation (EE) was conducted alongside a randomized controlled trial (the Protecting Teeth @ 3 Study [PT@3]), exploring the additional preventive value of fluoride varnish (FV) application at 6-monthly intervals in nursery schools compared to treatment as usual (TAU) in the same nurseries. TAU represented a multicomponent national child oral health improvement intervention, the Childsmile program, apart from nursery FV. METHODS: The EE was a within-trial cost-utility analysis (CUA) comparing the FV and TAU groups. The CUA was conducted from a National Health Service perspective and followed relevant methods guidance. Within-trial costs included intervention costs and health care resource use costs. Health outcomes were expressed in quality-adjusted life years (QALYs) accrued over the 2-y follow-up period. The Child Health Utility 9 Dimensions questionnaire was used to obtain utility scores. National reference costs were used, a discount rate of 1.5% for public health interventions was adopted, multiple imputation methods for missing data were employed, sensitivity analyses were conducted, and incremental cost-utility ratios were calculated. RESULTS: Data from 534 participants from the 2014-2015 PT@3 intake were used in the EE analyses, n = 265 (50%) in the FV arm and n = 269 (50%) in the TAU arm. Mean incremental cost per child in the FV arm was £68.37 (P = 0.382; 95% confidence interval [CI], -£18.04 to £143.82). Mean incremental QALY was -0.004 (P = 0.636; 95% CI, -0.016 to 0.007). The probability that the FV intervention was cost-effective at the UK £20,000 threshold was 11.3%. CONCLUSION: The results indicate that applying FV in nurseries in addition to TAU (all other components of Childsmile, apart from nursery FV) would not be deemed cost-effective given current UK thresholds. In view of previously proven clinical effectiveness and economic worthiness of the universal nursery toothbrushing component of Childsmile, continuation of the additional, targeted nursery FV component in its pre-COVID-19 form should be reviewed given its low probability of cost-effectiveness. KNOWLEDGE TRANSFER STATEMENT: The results of this study can be used by child oral health policy makers and dental public health professionals. They can form part of the evidence to inform the Scottish, UK, and international guidance on community-based child oral health promotion programs.

Drowning in antibiotics.

INTRODUCTION: The National Confidential Enquiry into Perioperative Deaths (NCEPOD) report recommended that 'fluid prescribing be given the same value as drug prescribing', yet fluid prescription is commonly delegated to junior doctors despite being a notoriously challenging topic. When antibiotics are given as an infusion they are diluted in 100ml of fluid, which is often unaccounted for when thinking about a patient's fluid requirements. This closed-loop audit aimed to assess first, intravenous (IV) fluid therapy and second, electrolyte prescribing compliance with National Institute for Health and Care Excellence (NICE) guidelines, with and without the additional fluid given with antibiotic administration. METHODS: Two retrospective audits were performed. Total fluid and electrolyte volume received with and without antibiotic fluids was correlated with recommendations in the NICE guidelines. Between cycles 1 and 2, potassium chloride with sodium chloride and glucose (PSG) was introduced as an alternative to IV maintenance fluid, and bolusing of antibiotics was mandatory. RESULTS: When analysing total fluid volume input per day, 10.4% and 7.45% of patients met their fluid requirement accurately in the first and second cycles, respectively. Within cycle 1, the mean total additional fluid that was given over 3 days with antibiotics was 1,572.73ml. In cycle 2, this decreased to 469.44ml when antibiotics were given as a bolus. CONCLUSIONS: In this closed-loop audit we noted that patients receiving IV fluids and IV antibiotics received too much additional fluid when the antibiotic dilution fluid was taken into account. Additional fluid was reduced alongside the proportion of electrolyte complications when bolusing of antibiotics was introduced. We recommend that that all nurses are trained to give antibiotics as a bolus because it can help to reduce fluid-related complications.

Noggin is a mesenchymally derived stimulator of hair-follicle induction.

The induction of developmental structures derived from the ectoderm, such as the neural tube or tooth, occurs through neutralization of the inhibitory activity of members of the bone-morphogenetic protein (BMP) family by BMP antagonists. Here we show that, during hair-follicle development, the neural inducer and BMP-neutralizing protein Noggin is expressed in the follicular mesenchyme, that noggin-knockout mice show significant retardation of hair-follicle induction, and that Noggin neutralizes the inhibitory action of BMP-4 and stimulates hair-follicle induction in embryonic skin organ culture. As a crucial mesenchymal signal that stimulates hair-follicle induction, Noggin operates through antagonistic interactions with BMP-4, which result in upregulation of the transcription factor Lef-1 and the cell-adhesion molecule NCAM, as well as through BMP4-independent downregulation of the 75 kD neurotrophin receptor in the developing hair follicle.

Induction of dopaminergic neuron phenotype in the midbrain by Sonic hedgehog protein.

Loss of substantia nigra dopaminergic neurons, which develop from the ventral region of the midbrain, is associated with Parkinson's disease. During embryogenesis, induction of these and other ventral neurons is influenced by interactions with the induction of mesoderm of the notochord and the floor plate, which lies at the ventral midline of the developing CNS. Sonic hedgehog encodes a secreted peptide, which is expressed in notochord and floor plate cells and can induce appropriate ventral cell types in the basal forebrain and spinal cord. Here we demonstrate that Sonic hedgehog is sufficient to induce dopaminergic and other neuronal phenotypes in chick mesencephalic explants in vitro. We find that Sonic hedgehog is a general ventralizing signal in the CNS, the specific response being determined by the receiving cells. These results suggest that Sonic hedgehog may have utility in the induction of clinically important cell types.

Changes and predictors for change to thiazolidinedione prescribing in UK primary care following the rosiglitazone safety warning.

OBJECTIVE: To investigate switching from thiazolidinediones, and predictors for switching treatment, after publication of a meta-analysis reporting an increased risk of myocardial infarction associated with rosiglitazone use. RESEARCH DESIGN AND METHODS: Using the Health Information Network (THIN) UK primary care database, the number of people with type 2 diabetes prescribed either thiazolidinedione, rosiglitazone (n = 10,062) or pioglitazone (n = 4454), and the rate of switching from thiazolidinediones (n = 3301 and 1106, respectively), were computed for each month, May 2006 to January 2008. The probability of switching post-publication, May 2007 to January 2008, was modelled by logistic regression in a forward stepwise model. Variables included demographics, history of ischaemic heart disease (IHD), heart failure (HF) or stroke, risk factors for IHD, glucose-lowering and cardiovascular drug use, HbA(1c) and diabetes duration. RESULTS: There was a sharp increase in switching from both thiazolidinediones in summer 2007; rosiglitazone prescription numbers then decreased while pioglitazone prescribing increased. Switching from rosiglitazone was associated with IHD [adjusted odds ratio (OR) 1.72; 95% confidence intervals (CI) 1.47-2.00], insulin treatment (OR 5.10; 95% CI 3.21-8.10), HF (OR 2.26; 95% CI 1.62-3.18), a recent sulphonylurea prescription (OR 1.33; 95% CI 1.17-1.51) gender (OR men vs. women 0.79; 95% CI 0.70, 0.90) and duration of therapy. Switching from pioglitazone was associated with HF (OR 3.05; 95% CI 1.77-5.26), duration of therapy, and number of glucose-lowering treatments. CONCLUSIONS: Prescribing habits for both thiazolidinediones changed immediately following the safety warning. IHD was associated with switching from rosiglitazone; otherwise reasons for change appear to be complex, not directly related to the findings of the meta-analysis.

Life course social mobility and risk of upper aerodigestive tract cancer in men.

The aim of this study was to explore associations between social mobility and tumours of the upper aero-digestive tract (UADT), focussing on life-course transitions in social prestige (SP) based on occupational history. 1,796 cases diagnosed between 1993 and 2005 in ten European countries were compared with 1585 controls. SP was classified by the Standard International Occupational Prestige Scale (SIOPS) based on job histories. SIOPS was categorised in high (H), medium (M) and low (L). Time weighted average achieved and transitions between SP with nine trajectories: H --> H, H --> M, H --> L, M --> H, M --> M, M --> L, L --> H, L --> M and L --> L were analysed. Odds ratios (ORs) and 95%-confidence intervals [95%-CIs] were estimated with logistic regression models including age, consumption of fruits/vegetables, study centre, smoking and alcohol consumption. The adjusted OR for the lowest versus the highest of three categories (time weighted average of SP) was 1.28 [1.04-1.56]. The distance of SP widened between cases and controls during working life. The downward trajectory H --> L gave an OR of 1.71 [0.75-3.87] as compared to H --> H. Subjects with M --> M and L --> L trajectories ORs were also elevated relative to subjects with H --> H trajectories. The association between SP and UADT is not fully explained by confounding factors. Downward social trajectory during the life course may be an independent risk factor for UADT cancers.