MC3R links nutritional state to childhood growth and the timing of puberty.

The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development1. The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure2. Here we present evidence that MC3R regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, which are all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R, including a rare homozygote individual, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and circulating levels of IGF1. Mice lacking Mc3r had delayed sexual maturation and an insensitivity of reproductive cycle length to nutritional perturbation. The expression of Mc3r is enriched in hypothalamic neurons that control reproduction and growth, and expression increases during postnatal development in a manner that is consistent with a role in the regulation of sexual maturation. These findings suggest a bifurcating model of nutrient sensing by the central melanocortin pathway with signalling through MC4R controlling the acquisition and retention of calories, whereas signalling through MC3R primarily regulates the disposition of calories into growth, lean mass and the timing of sexual maturation.

Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis.

Uterine leiomyomata (UL) are the most common neoplasms of the female reproductive tract and primary cause for hysterectomy, leading to considerable morbidity and high economic burden. Here we conduct a GWAS meta-analysis in 35,474 cases and 267,505 female controls of European ancestry, identifying eight novel genome-wide significant (P < 5 × 10-8) loci, in addition to confirming 21 previously reported loci, including multiple independent signals at 10 loci. Phenotypic stratification of UL by heavy menstrual bleeding in 3409 cases and 199,171 female controls reveals genome-wide significant associations at three of the 29 UL loci: 5p15.33 (TERT), 5q35.2 (FGFR4) and 11q22.3 (ATM). Four loci identified in the meta-analysis are also associated with endometriosis risk; an epidemiological meta-analysis across 402,868 women suggests at least a doubling of risk for UL diagnosis among those with a history of endometriosis. These findings increase our understanding of genetic contribution and biology underlying UL development, and suggest overlapping genetic origins with endometriosis.

Voice break in boys-temporal relations with other pubertal milestones and likely causal effects of BMI.

STUDY QUESTION: How is timing of voice break related to other male pubertal milestones as well as to BMI? SUMMARY ANSWER: We provide a comprehensive temporal analysis of male pubertal milestones, including reproductive hormone dynamics, confirm voice break as a late milestone of male puberty and report a likely causal relationship between higher BMI and earlier age at voice break in men. WHAT IS KNOWN ALREADY: Voice break represents a late pubertal milestone and recalled age at voice break is frequently used in epidemiological studies as a measure of puberty. In contrast, clinical studies use mainly testicular enlargement and/or genital tanner stage as the marker of pubertal onset. However, neither correlation of pubertal milestones nor reproductive hormone dynamics have been assessed in detail previously. Further, although BMI and puberty timing are known to be closely linked, cause and effect between these traits are not known. STUDY DESIGN, SIZE, DURATION: The study included a population-based mixed cross-sectional and longitudinal cohort (2006-2014, COPENHAGEN Puberty Study) of 730 healthy Danish boys. Data for 55 871 male research participants from the 23andMe study were obtained, including genome-wide single nucleotide polymorphism data and age at voice break. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed a detailed evaluation of pubertal milestones and reproductive hormone levels (study population 1). A Mendelian randomization (MR) approach was used to determine the likely causal link between BMI and timing of voice break (study population 2). MAIN RESULTS AND THE ROLE OF CHANCE: Voice break occurred at mean age 13.6 (95% CI: 13.5-13.8) years. At voice break, mean (95% CI) testosterone levels, LH levels and bi-testicular volume were 10.9 (10.0-11.7) nmol/L, 2.4 (2.2-2.5) IU/L and 24 (23-25) mL, respectively. Voice break correlated moderately strongly with timing of male pubertal milestones, including testicular enlargement, gonadarche, pubarche, sweat odor, axillary hair growth and testosterone above limit of detection (r2 range: 0.43-0.61). Timing of all milestones was negatively associated with age-specific BMI (all P ≤ 0.001). MR analyses inferred likely causal effects of higher BMI on earlier voice break in males (-0.35 years/approximate SD, P < 0.001). LIMITATIONS, REASONS FOR CAUTION: Participation rate of the population-based cohort was 25%. Further, boys that were followed longitudinally were examined approximately every 6 months limiting the time resolution of pubertal milestones. Using adult BMI as exposure instead of prepubertal BMI in the MR analysis and the known inaccuracies of the testosterone immunoassay at low testosterone levels may be further limitations. WIDER IMPLICATIONS OF THE FINDINGS: We provide valuable normative data on the temporal relation of male pubertal milestones. Further, the likely causal relationship between BMI and puberty timing highlights the importance of preventing obesity in childhood. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Danish Agency for Science, Technology and Innovation (09-067 180); Danish Ministry of the Environment, CeHoS (MST-621-00 065); Capital Region of Denmark (R129-A3966); Ministry of Higher Education and Science (DFF-1331-00 113); Innovation Fund Denmark (InnovationsFonden, 14-2013-4); The International Center for Research and Research Training in Endocrine Disrupting Effects of Male Reproduction and Child Health. B.H., F.R.D., J.R.B.P. and K.K.O. are supported by the Medical Research Council (MC_UU_12015/2). The 23andMe study is supported by the National Human Genome Research Institute of the National Institutes of Health (R44HG006981). Members of the 23andMe Research Team are employees of 23andMe, Inc. and hold stock or stock options in 23andMe. TRIAL REGISTRATION NUMBER: NCT01411527.

Interpersonal sensitivity in those at clinical high risk for psychosis mediates the association between childhood bullying victimisation and paranoid ideation: A virtual reality study.

BACKGROUND: Experience of bullying victimisation in childhood and heightened interpersonal sensitivity have been independently linked to the clinical high risk for psychosis. AIM: To examine the potential mediating effect of interpersonal sensitivity in explaining the link between childhood bullying victimisation and real-time paranoid ideation in adult participants at clinical high risk for psychosis. METHOD: In a cross-sectional study data were collected for 64 individuals at clinical high risk for psychosis. Measures included history of bullying victimisation, interpersonal sensitivity and state paranoid ideation following exposure to a social virtual reality environment. The virtual reality scenario was a London Underground journey. RESULTS: Path analysis indicated that interpersonal sensitivity fully explained the significant association between severe bullying victimisation in childhood and paranoid ideation in the clinical-high risk group. Based on AIC criteria the best model selected was the full mediation model: severe bullying→interpersonal sensitivity→state paranoid ideation. The results suggest that severity of bullying is more important than frequency of bullying in explaining state paranoid ideation. CONCLUSIONS: The significant role played by interpersonal sensitivity in the association between being bullied in childhood and paranoid ideation in the clinical high risk group suggests that this could become a target for intervention.

Associations between body mass index-related genetic variants and adult body composition: The Fenland cohort study.

BACKGROUND/OBJECTIVE: Body mass index (BMI) is a surrogate measure of adiposity but does not distinguish fat from lean or bone mass. The genetic determinants of BMI are thought to predominantly influence adiposity but this has not been confirmed. Here we characterise the association between BMI-related genetic variants and body composition in adults. SUBJECTS/METHODS: Among 9667 adults aged 29-64 years from the Fenland study, a genetic risk score for BMI (BMI-GRS) was calculated for each individual as the weighted sum of BMI-increasing alleles across 96 reported BMI-related variants. Associations between the BMI-GRS and body composition, estimated by dual-energy X-ray absorptiometry (DXA) scans, were examined using age-adjusted linear regression models, separately by sex. RESULTS: The BMI-GRS was positively associated with all fat, lean and bone variables. Across body regions, associations of the greatest magnitude were observed for adiposity variables, for example, for each s.d. increase in BMI-GRS predicted BMI, we observed a 0.90 s.d. (95% confidence interval (CI): 0.71, 1.09) increase in total fat mass for men (P=3.75 × 10-21) and a 0.96 s.d. (95% CI: 0.77, 1.16) increase for women (P=6.12 × 10-22). Associations of intermediate magnitude were observed with lean variables, for example, total lean mass: men: 0.68 s.d. (95% CI: 0.49, 0.86; P=1.91 × 10-12); women: 0.85 s.d. (95% CI: 0.65, 1.04; P=2.66 × 10-17) and of a lower magnitude with bone variables, for example, total bone mass: men: 0.39 s.d. (95% CI: 0.20, 0.58; P=5.69 × 10-5); women: 0.45 s.d. (95% CI: 0.26, 0.65; P=3.96 × 106). Nominally significant associations with BMI were observed for 28 single-nucleotide polymorphisms. All 28 were positively associated with fat mass and 13 showed adipose-specific effects. CONCLUSIONS: In adults, genetic susceptibility to elevated BMI influences adiposity more than lean or bone mass. This mirrors the association between BMI and body composition. The BMI-GRS can be used to model the effects of measured BMI and adiposity on health and other outcomes.

HPA-axis function and grey matter volume reductions: imaging the diathesis-stress model in individuals at ultra-high risk of psychosis.

The onset of psychosis is thought to involve interactions between environmental stressors and the brain, with cortisol as a putative mediator. We examined the relationship between the cortisol stress response and brain structure in subjects at ultra-high risk (UHR) for psychosis. Waking salivary cortisol was measured in 22 individuals at UHR for psychosis and 17 healthy controls. Grey matter volume was assessed using magnetic resonance imaging at 3 T. The relationship between the stress response and grey matter volume was investigated using voxel-based analyses. Our predictions of the topography of cortisol action as a structural brain modulator were informed by measures of brain glucocorticoid and mineralcorticoid receptor distribution obtained from the multimodal neuroanatomical and genetic Allen Brain Atlas. Across all subjects, reduced responsivity of the hypothalamus-pituitary-adrenal (HPA) axis was correlated with smaller grey matter volumes in the frontal, parietal and temporal cortex and in the hippocampus. This relationship was particularly marked in the UHR subjects in the right prefrontal, left parahippocampal/fusiform and parietal cortices. The subgroup that subsequently developed psychosis showed a significant blunting of HPA stress response, observed at trend level also in the whole UHR sample. Altered responses to stress in people at high risk of psychosis are related to reductions in grey matter volume in areas implicated in the vulnerability to psychotic disorders. These areas may represent the neural components of a stress vulnerability model.

Body shape and size in 6-year old children: assessment by three-dimensional photonic scanning.

BACKGROUND: Body shape and size are typically described using measures such as body mass index (BMI) and waist circumference, which predict disease risks in adults. However, this approach may underestimate the true variability in childhood body shape and size. OBJECTIVE: To use a comprehensive three-dimensional photonic scan approach to describe variation in childhood body shape and size. SUBJECTS/METHODS: At age 6 years, 3350 children from the population-based 2004 Pelotas birth cohort study were assessed by three-dimensional photonic scanner, traditional anthropometry and dual X-ray absorptiometry. Principal component analysis (PCA) was performed on height and 24 photonic scan variables (circumferences, lengths/widths, volumes and surface areas). RESULTS: PCA identified four independent components of children's body shape and size, which we termed: Corpulence, Central:peripheral ratio, Height and arm lengths, and Shoulder diameter. Corpulence showed strong correlations with traditional anthropometric and body composition measures (r>0.90 with weight, BMI, waist circumference and fat mass; r>0.70 with height, lean mass and bone mass); in contrast, the other three components showed weak or moderate correlations with those measures (all r<0.45). There was no sex difference in Corpulence, but boys had higher Central:peripheral ratio, Height and arm lengths and Shoulder diameter values than girls. Furthermore, children with low birth weight had lower Corpulence and Height and arm lengths but higher Central:peripheral ratio and Shoulder diameter than other children. Children from high socio-economic position (SEP) families had higher Corpulence and Height and arm lengths than other children. Finally, white children had higher Corpulence and Central:peripheral ratio than mixed or black children. CONCLUSIONS: Comprehensive assessment by three-dimensional photonic scanning identified components of childhood body shape and size not captured by traditional anthropometry or body composition measures. Differences in these novel components by sex, birth weight, SEP and skin colour may indicate their potential relevance to disease risks.

Bullying victimisation and paranoid ideation in people at ultra high risk for psychosis.

BACKGROUND: Bullying victimisation has been suggested to contribute to paranoid ideation in general population samples and recent evidence found that individuals with an ultra high risk (UHR) for psychosis are twice as likely to have been bullied than controls. AIMS: This study sought to examine whether a history of bullying would be associated with higher levels of paranoid ideation in individuals with an UHR and in healthy controls (HCs). METHOD: The study included 64 UHR and 43 HC participants. Following the baseline assessment, participants entered a Virtual Reality (VR) London Underground train. Paranoid ideation was measured immediately after the end of the VR experience. RESULTS: Compared to HCs, UHR participants described higher levels of childhood bullying (OR 5.19, 95% CI=2.21-12.19, p<.001) and experienced more paranoid ideation during VR (χ(2)(1)=21.06, p<.001). Childhood bullying was associated with paranoid ideation during VR in both groups (χ(2)(1)=5.931, p=,021) but prolonged exposure to bullying was not associated with increased paranoid ideation. CONCLUSION: A history of bullying in childhood is particularly common in young adults at high risk for psychosis. However bullying is associated with paranoid ideation in later life, independent of clinical status, consistent with dimensional models of psychotic phenomena.

Pituitary gland volume and psychosocial stress among children at elevated risk for schizophrenia.

BACKGROUND: Pituitary volume enlargements have been observed among individuals with first-episode psychosis. These abnormalities are suggestive of hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, which may contribute to the development of psychosis. However, the extent to which these abnormalities characterize individuals at elevated risk for schizophrenia prior to illness onset is currently unclear, as volume increases, decreases and no volume differences have all been reported relative to controls. The current study aimed to determine whether antipsychotic-naive, putatively at-risk children who present multiple antecedents of schizophrenia (ASz) or a family history of illness (FHx) show pituitary volume abnormalities relative to typically developing (TD) children. An additional aim was to explore the association between pituitary volume and experiences of psychosocial stress. METHOD: ASz (n = 30), FHx (n = 22) and TD (n = 32) children were identified at age 9-12 years using a novel community-screening procedure or as relatives of individuals with schizophrenia. Measures of pituitary volume and psychosocial stress were obtained at age 11-14 years. RESULTS: Neither ASz nor FHx children showed differences in pituitary volume relative to TD children. Among FHx children only, pituitary volume was negatively associated with current distress relating to negative life events and exposure to physical punishment. CONCLUSIONS: The lack of pituitary volume abnormalities among ASz and FHx children is consistent with our previous work demonstrating that these children are not characterized by elevated diurnal cortisol levels. The findings imply that these biological markers of HPA axis hyperactivity, observed in some older samples of high-risk individuals, may emerge later, more proximally to disease onset.

Cannabis use and transition to psychosis in people at ultra-high risk.

BACKGROUND: Cannabis use is associated with an increased risk of developing a psychotic disorder but the temporal relationship between cannabis use and onset of illness is unclear. The objective of this study was to assess prospectively the influence of cannabis use on transition to psychosis in people at ultra-high risk (UHR) for the disorder. METHOD: Lifetime and continued cannabis use was assessed in a consecutively ascertained sample of 182 people (104 male, 78 female) at UHR for psychosis. Individuals were then followed clinically for 2 years to determine their clinical outcomes. RESULTS: Lifetime cannabis use was reported by 134 individuals (73.6%). However, most of these individuals had stopped using cannabis before clinical presentation (n=98, 73.1%), usually because of adverse effects. Among lifetime users, frequent use, early-onset use and continued use after presentation were all associated with an increase in transition to psychosis. Transition to psychosis was highest among those who started using cannabis before the age of 15 years and went on to use frequently (frequent early-onset use: 25%; infrequent or late-onset use: 5%; χ(2)1=10.971, p=0.001). However, within the whole sample, cannabis users were no more likely to develop psychosis than those who had never used cannabis (cannabis use: 12.7%; no use: 18.8%; χ(2)1=1.061, p=0.303). CONCLUSIONS: In people at UHR for psychosis, lifetime cannabis use was common but not related to outcome. Among cannabis users, frequent use, early-onset use and continued use after clinical presentation were associated with transition to psychosis.

Different APC genotypes in proximal and distal sporadic colorectal cancers suggest distinct WNT/ß-catenin signalling thresholds for tumourigenesis.

Biallelic protein-truncating mutations in the adenomatous polyposis coli (APC) gene are prevalent in sporadic colorectal cancer (CRC). Mutations may not be fully inactivating, instead producing WNT/ß-catenin signalling levels 'just-right' for tumourigenesis. However, the spectrum of optimal APC genotypes accounting for both hits, and the influence of clinicopathological features on genotype selection remain undefined. We analysed 630 sporadic CRCs for APC mutations and loss of heterozygosity (LOH) using sequencing and single-nucleotide polymorphism microarrays, respectively. Truncating APC mutations and/or LOH were detected in 75% of CRCs. Most truncating mutations occurred within a mutation cluster region (MCR; codons 1282-1581) leaving 1-3 intact 20 amino-acid repeats (20AARs) and abolishing all Ser-Ala-Met-Pro (SAMP) repeats. Cancers commonly had one MCR mutation plus either LOH or another mutation 5' to the MCR. LOH was associated with mutations leaving 1 intact 20AAR. MCR mutations leaving 1 vs 2-3 intact 20AARs were associated with 5' mutations disrupting or leaving intact the armadillo-repeat domain, respectively. Cancers with three hits had an over-representation of mutations upstream of codon 184, in the alternatively spliced region of exon 9, and 3' to the MCR. Microsatellite unstable cancers showed hyper-mutation at MCR mono- and di-nucleotide repeats, leaving 2-3 intact 20AARs. Proximal and distal cancers exhibited different preferred APC genotypes, leaving a total of 2 or 3 and 0 to 2 intact 20AARs, respectively. In conclusion, APC genotypes in sporadic CRCs demonstrate 'fine-tuned' interdependence of hits by type and location, consistent with selection for particular residual levels of WNT/ß-catenin signalling, with different 'optimal' thresholds for proximal and distal cancers.

Blue-phase templated fabrication of three-dimensional nanostructures for photonic applications.

A promising approach to the fabrication of materials with nanoscale features is the transfer of liquid-crystalline structure to polymers. However, this has not been achieved in systems with full three-dimensional periodicity. Here we demonstrate the fabrication of self-assembled three-dimensional nanostructures by polymer templating blue phase I, a chiral liquid crystal with cubic symmetry. Blue phase I was photopolymerized and the remaining liquid crystal removed to create a porous free-standing cast, which retains the chiral three-dimensional structure of the blue phase, yet contains no chiral additive molecules. The cast may in turn be used as a hard template for the fabrication of new materials. By refilling the cast with an achiral nematic liquid crystal, we created templated blue phases that have unprecedented thermal stability in the range -125 to 125 °C, and that act as both mirrorless lasers and switchable electro-optic devices. Blue-phase templated materials will facilitate advances in device architectures for photonics applications in particular.

Interpersonal sensitivity in the at-risk mental state for psychosis.

BACKGROUND: Interpersonal sensitivity is a personality trait described as excessive awareness of both the behaviour and feelings of others. Although interpersonal sensitivity has been found to be one of the vulnerability factors to depression, there has been little interest in its relationship with the prodromal phase of psychosis. The aims of this study were to examine the level of interpersonal sensitivity in a sample of individuals with an at-risk mental state (ARMS) for psychosis and its relationship with other psychopathological features. METHOD: Sixty-two individuals with an ARMS for psychosis and 39 control participants completed a series of self-report questionnaires, including the Interpersonal Sensitivity Measure (IPSM), the Prodromal Questionnaire (PQ), the Ways of Coping Questionnaire (WCQ) and the Depression and Anxiety Stress Scale (DASS). RESULTS: Individuals with an ARMS reported higher interpersonal sensitivity compared to controls. Associations between interpersonal sensitivity, positive psychotic symptoms (i.e. paranoid ideation), avoidant coping and symptoms of depression, anxiety and stress were also found. CONCLUSIONS: This study suggests that being 'hypersensitive' to interpersonal interactions is a psychological feature of the putatively prodromal phase of psychosis. The relationship between interpersonal sensitivity, attenuated positive psychotic symptoms, avoidant coping and negative emotional states may contribute to long-term deficits in social functioning. We illustrate the importance, when assessing a young client with a possible ARMS, of examining more subtle and subjective symptoms in addition to attenuated positive symptoms.

Delusional ideation, manic symptomatology and working memory in a cohort at clinical high-risk for psychosis: a longitudinal study.

We followed up a cohort (n=35) of clients with an "At Risk Mental State" (ARMS) for almost 2 years (mean 21.3 months). At baseline, these clients had taken part in research looking at the relationship between reasoning biases, memory, personality styles and delusional ideation. During the follow-up period, clients underwent a package of intervention from a specialist early detection team. Eighty percent (n=28) of these clients were successfully re-interviewed. There was improvement across the cohort as a whole, however five participants (17.9%) had made the transition to psychosis at follow-up. Those who had become psychotic had lower levels of manic symptomatology at baseline than those who did not enter the first episode. Further, across the cohort, impaired working memory and delusional ideation at baseline combined to predict 45% of the delusional ideation at follow-up. These preliminary findings suggest that working memory impairments may be linked to the persistence of delusional ideation and that manic symptoms in someone with an ARMS may suggest that such an individual is less likely to develop a frank psychotic episode.

FDG-PET metabolic response predicts outcomes in anal cancer managed with chemoradiotherapy.

BACKGROUND: The aim was to investigate the correlation between (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) metabolic response to chemoradiotherapy and clinical outcomes in squamous cell carcinoma (SCC) of the anus. METHODS: A total of 48 patients with biopsy-proven anal SCC underwent FDG-PET scans at baseline and post chemoradiotherapy (54 Gy, concurrent 5-FU/mitomycin). Kaplan-Meier analysis was used to determine survival outcomes according to FDG-PET metabolic response. RESULTS: In all, 79% patients (n=38) had a complete metabolic response (CMR) at all sites of disease, 15% (n=7) had a CMR in regional nodes but only partial response in the primary tumour (overall partial metabolic response (PMR)) and 6% (n=3) had progressive distant disease despite CMR locoregionally (overall no response (NR)). The 2-year progression-free survival (PFS) was 95% for patients with a CMR, 71% for PMR and 0% for NR (P<0.0001). The 5-year overall survival (OS) was 88% in CMR, 69% in PMR and 0% in NR (P<0.0001). Cox proportional hazards regression analyses for PFS and OS found significant associations for incomplete (PMR+NR) vs complete FDG-PET response to treatment only, (HR 4.1 (95% CI: 1.5-11.5, P=0.013) and 6.7 (95% CI: 2.1-21.6, P=0.002), respectively). CONCLUSION: FDG-PET metabolic response to chemoradiotherapy in anal cancer is significantly associated with PFS and OS, and in this cohort incomplete FDG-PET response was a stronger predictor than T or N stage.

Neurofibromatosis type 1-associated wild-type gastrointestinal stromal tumor treated with anti-IGF-1R monoclonal antibody.

Gastrointestinal stromal tumors lacking mutations in KIT or PDGFRα are known as wild type (WT) and are less responsive to imatinib. These WT tumors are hypothesized to be dependent on signaling through the insulin-like growth factor 1 receptor (IGF-1R). We report the case of a 29-year-old woman with neurofibromatosis type 1-associated WT GIST treated with an anti-IGF-1R monoclonal antibody. Treatment was ineffective, and the potential basis for lack of response is discussed in the context of IGF-1R expression levels measured within this patients' primary tumor. We suggest that future clinical trials of anti-IGF-1R therapies prospectively determine tumor IGF-1R expression levels for correlation with response to treatment.

Phase I trial of docetaxel, cisplatin and concurrent radical radiotherapy in locally advanced oesophageal cancer.

BACKGROUND: Locally advanced oesophageal cancer (LAEC) is associated with poor survival and more effective treatments are needed. The aim of this phase I trial was to assess the maximum tolerated dose (MTD) of a novel weekly docetaxel and cisplatin regimen concurrent with radical radiotherapy. METHODS: Patients with unresectable, non-metastatic LAEC were eligible. Treatment comprised docetaxel 15-30 mg m(-2) per week and cisplatin 15-30 mg m(-2) per week in six planned dose levels (DLs) in 3-6 patient cohorts with 50 Gy radiotherapy in 25 fractions. Maximum tolerated dose was based on defined dose-limiting toxicities (DLTs) during therapy and 2 weeks post therapy. RESULTS: A total of 24 patients were enrolled. There were two DLTs: grade 3 fever in DL1 (docetaxel 15 mg m(-2), cisplatin 15 mg m(-2)) and grade 3 nausea in DL2 (20 mg m(-2), 15 mg m(-2)). These DLs were each expanded to six patients without further DLTs. The most common acute toxicity was grade 3 radiation oesophagitis (37.5%). There were no grade 4 toxicities, and haematologic toxicity was minimal. Cisplatin and docetaxel dose intensity was 100% at the highest dose level (DL6). A MTD was not reached in this trial. Tumour overall response rate was 50% (33% complete, 17% partial). CONCLUSION: Cisplatin and docetaxel each 30 mg m(-2) per week concurrent with 50 Gy radiotherapy is recommended for use in phase II clinical trials in oesophageal cancer.

A glaucoma equity profile: correlating disease distribution with service provision and uptake in a population in Northern England, UK.

AIMS: Glaucoma is a significant health problem, with associated inequalities. Equity profiles are an established public health tool to examine the scale of health inequalities and to imbed action into the commissioning cycle. This is the first equity profile conducted in the United Kingdom for an ophthalmic condition. This methodology also provides a model for use in other localities and for other eye conditions. METHODS: Existing services were mapped and need identified. A wide variety of data sources were analysed. Mapping was undertaken using Mapinfo Professional Geographical Information Systems software. Statistical analysis was conducted using Microsoft Excel 2003. RESULTS: No single data source provided a fully informed perspective. A clear mismatch between areas of deprivation and location of optometry was observed. Secondary analysis of electronic patient records revealed a significant association between 'late presentation' and older age (mean age of late presenters=76.4 years, 95% CI=75.1-77.6 compared with earlier presenters, 72.4 years, 95% CI=71.7-73.1). Late presentation was also associated with living in an area of high deprivation (chi(2)=7.1, df, P<0.05). Ethnicity data was poorly recorded. Qualitative data provided invaluable insights. CONCLUSIONS: Increasing access to services involves collaboration with optometrists, ophthalmologists, public health, and commissioners. It is no longer acceptable to rely on private high street optometry to provide primary eye care services in areas of high need. Outreach services must be developed and evaluated in areas of relative deprivation if world class eye services are to be achieved.

Social dysfunction predicts two years clinical outcome in people at ultra high risk for psychosis.

The experience of a first psychotic episode is associated with a marked impairment in psychosocial functioning. However, the decline may be already evident in the pre-psychotic phases and play a significant role in the etiopathology of the disease onset. A sample of subjects at ultra high clinical risk for psychosis ("At Risk Mental State", ARMS, n=152) was compared with a demographically-matched general population (n=98,072) on different measures of psychosocial functioning. The proportion of subjects with an ARMS living in communal establishments or living at home with their parents was significantly higher than that of the local population (p<0.001). Subjects with an ARMS showed also higher rates of unemployment as compared to the general population (p<0.001). GAF scores at baseline were significantly lower in unemployed ARMS as compared to students and employed ARMS (p=0.002). ARMS subjects living in communal establishments presented higher rates of co-morbid psychiatric conditions (p=0.007) and lower GAF scores at baseline (p=0.017). Finally, baseline unemployment and living in a communal establishment were associated with an increased risk of developing a psychotic episode within the following two years (p<0.05). We concluded that the "At Risk Mental State" is a clinical condition which is characterized by marked psychosocial impairment and by an increased vulnerability to psychosis. Unemployment at the first contact with the prodromal service may be a risk factor for the development of a psychotic episode.