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People with anorexia nervosa (AN) commonly exhibit social difficulties, which may be related to problems with understanding the perspectives of others, commonly known as Theory of Mind (ToM) processing. However, there is a dearth of literature investigating the neural basis of these differences in ToM and at what age they emerge. This study aimed to test for differences in the neural correlates of ToM processes in young women with AN, and young women weight-restored (WR) from AN, as compared to healthy control participants (HC). Based on previous findings in AN, we hypothesized that young women with current or prior AN, as compared to HCs, would exhibit a reduced neural response in the medial prefrontal cortex (mPFC), the inferior frontal gyrus, and the temporo-parietal junction (TPJ) whilst completing a ToM task. We recruited 73 young women with AN, 45 WR young women, and 70 young women without a history of AN to take part in the current study. Whilst undergoing a functional magnetic resonance imaging (fMRI) scan, participants completed the Frith-Happé task, which is a commonly used measure of ToM with demonstrated reliability and validity in adult populations. In this task, participants viewed the movements of triangles, which depicted either action movements, simple interactions, or complex social interactions. Viewing trials with more complex social interactions in the Frith-Happé task was associated with increased brain activation in regions including the right TPJ, the bilateral mPFC, the cerebellum, and the dorsolateral prefrontal cortex. There were no group differences in neural activation in response to the ToM contrast. Overall, these results suggest that the neural basis of spontaneous mentalizing is preserved in most young women with AN., (Copyright © 2020 Leslie, Halls, Leppanen, Sedgewick, Smith, Hayward, Lang, Fonville, Simic, Mandy, Nicholls, Murphy, Williams and Tchanturia.) more...

Background: Sal-like protein 4 (SALL4), an embryonic stem cell factor, has been reported to play an essential role in embryogenesis and oncogenesis. As yet, however, the expression and role of this transcription factor in head and neck squamous cell carcinoma (HNSCC) has not been established., Methods: We assessed SALL4 mRNA expression in a well-characterised dataset of 230 HNSCC samples (test cohort 110 cases and validation cohort 120 cases). We also transfected HNSCC cells (FaDu and UM-SCC-6) with SALL4 siRNA and assessed its effects on proliferation and expression of specific epigenetic factors in order to uncover the role of SALL4 in HNSCC., Results: Overexpression of SALL4 was detected in tumour samples of both cohorts. HNSCC cells treated with SALL4 siRNA showed a reduction in growth and a decrease in DNA methyltransferase 3 alpha (DNMT3A) expression. In the patient cohorts, SALL4 overexpression was found to significantly correlate with disease recurrence (p < 0.001) and SALL4 methylation status (p = 0.002). We also found that DNMT3A was significantly upregulated upon SALL4 upregulation (p < 0.001). High expression levels of SALL4 correlated with decreases in disease-free survival (DFS) rates (log-rank test, p < 0.001). Multivariate analysis revealed that SALL4 expression served as an independent prognostic factor for DFS (hazard ratio: 2.566, 95% confidence interval: 1.598-4.121; p < 0.001)., Conclusions: Our findings indicate that SALL4 upregulation correlates with HNSCC tumour aggressiveness and an adverse patient outcome. Our findings also indicate that DNMT3A may synergistically contribute to the regulatory effects of SALL4. Our findings provide insight into SALL4-mediated HNSCC development via epigenetic modulation. more...

Human papilloma virus (HPV)-associated oropharyngeal cancer (OPC) is an independent tumour type with regard to cellular, biological, and clinical features. The use of non-invasive biomarkers such as circulating tumour DNA (ctDNA) may be relevant in early diagnosis and eventually improve the outcomes of patients with head and neck squamous cell carcinoma (HNSCC). Genome-wide discovery using RNA sequencing and reduced representation bisulfite sequencing yielded 21 candidates for methylation-targeted genes. A verification study (252 HNSCC patients) using quantitative methylation-specific PCR (Q-MSP) identified 10 genes (ATP2A1, CALML5, DNAJC5G, GNMT, GPT, LY6D, LYNX1, MAL, MGC16275, and MRGPRF) that showed a significant increase recurrence in methylation groups with OPC. Further study on ctDNA using Q-MSP in HPV-associated OPC showed that three genes (CALML5, DNAJC5G, and LY6D) had a high predictive ability as emerging biomarkers for a validation set, each capable of discriminating between the plasma of the patients from healthy individuals. Among the 42 ctDNA samples, methylated CALML5, DNAJC5G, and LY6D were observed in 31 (73.8%), 19 (45.2%), and 19 (45.2%) samples, respectively. Among pre-treatment ctDNA samples, methylated CALML5, DNAJC5G, and LY6D were observed in 8/8 (100%), 7/8 (87.5%), and 7/8 (87.5%) samples, respectively. Methylated CALML5, DNAJC5G, and LY6D were found in 2/8 (25.0%), 0/8 (0%), and 1/8 (12.5%) of the final samples in the series, respectively. Here, we present the relationship between the methylation status of three specific genes and cancer recurrence for risk classification of HPV-associated OPC cases. In conclusion, ctDNA analysis has the potential to aid in determining patient prognosis and real-time surveillance for disease recurrences and serves as an alternative method of screening for HPV-associated OPC. more...

DNA gyrase and topoisomerase IV are well-validated pharmacological targets, and quinolone antibacterial drugs are marketed as their representative inhibitors. However, in recent years, resistance to these existing drugs has become a problem, and new chemical classes of antibiotics that can combat resistant strains of bacteria are strongly needed. In this study, we applied our hit-to-lead (H2L) chemistry for the identification of a new chemical class of GyrB/ParE inhibitors by efficient use of thermodynamic parameters. Investigation of the core fragments obtained by fragmentation of high-throughput screening hit compounds and subsequent expansion of the hit fragment was performed using isothermal titration calorimetry (ITC). The 8-(methylamino)-2-oxo-1,2-dihydroquinoline derivative 13e showed potent activity against Escherichia coli DNA gyrase with an IC 50 value of 0.0017 μM. In this study, we demonstrated the use of ITC for primary fragment screening, followed by structural optimization to obtain lead compounds, which advanced into further optimization for creating novel antibacterial agents., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.) more...

Background: Eating disorder services are often separated into child and adolescent eating disorder services (CAEDSs) and adult eating disorder services (AEDSs). Most patients in CAEDSs present with first-episode illness of short duration, which with appropriate treatment, have a good prognosis. However, some individuals receive further treatment as adults. Little is known about service utilisation in adulthood following childhood/adolescent treatment of an eating disorder., Aims: This study aims (a) to estimate the proportion of patients in a CAEDS who use mental health services as young adults, (b) to delineate service utilisation following treatment in CAEDSs and (c) to identify factors in CAEDSs that predict service utilisation in young adulthood., Method: A consecutive cohort of 322 patients (aged 13-17 years) seen in a CAEDS in the UK over a 5-year period were included in this audit. Data regarding their use of UK-wide adult mental health services as young adults (i.e. when aged 18-25) were extracted from local and national hospital records., Results: A total of 68.3% of CAEDS patients received no mental health treatment as young adults. Although 13% of people seen in a CAEDS had brief eating disorder treatment as young adults, 10% received longer/or more intensive eating disorder treatment. Overall, 10.8% transitioned directly to an AEDS and 7.6% were re-referred following discharge from CAEDS. In our sample, older age and increased use of CAEDSs predicted increased eating disorder treatment in young adulthood., Conclusions: Our results indicate that most people seen in CAEDSs do not receive further mental health treatment as young adults. Several features in CAEDSs distinguish mental health service utilisation in young adulthood, which were identified clinically and could be targeted during treatment. more...

Irradiation, or chemoradiotherapy, is a curative treatment for oropharyngeal squamous cell carcinoma (OPSCC). Its invasiveness, however, can often negate its efficacy. Therefore, developing methods to predict which patients would benefit from irradiation is urgent. Promoter DNA hypermethylation was recently reported to correlate with favorable OPSCC prognosis. It is still unclear, however, whether there is an association between promoter DNA methylation and response to irradiation. In this study, we analyzed DNA methylation in the specimens from 40 OPSCC patients who had undergone irradiation, using the Infinium assay. Our results showed significant correlation between high levels of promoter DNA methylation and better response to treatment (P < 0.01). We used the 10 most differentially-methylated genes between responders and non-responders to develop a panel of predictive markers for efficacy. Our panel had high sensitivity, specificity and accuracy (92%, 93% and 93%, respectively). We conducted pyrosequencing to quantitatively validate the methylation levels of 8 of the 10 marker genes (ROBO1, ULK4P3, MYOD1, LBX1, CACNA1A, IRX4, DPYSL3 and ELAVL2) obtained by Infinium. The validation by pyrosequencing showed that these 8 genes had a high prediction performance for the training set of 40 specimens and for a validation set of 35 OPSCC specimens, showing 96% sensitivity, 89% specificity and 94% accuracy. Methylation of these markers correlated significantly with better progression-free and overall survival rates, regardless of human papillomavirus status. These results indicate that increased DNA methylation is associated with better responses to irradiation therapy and that DNA methylation can help establish efficacy prediction markers in OPSCC., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.) more...

Objective: To evaluate whether total serum PSA, free-PSA ratio and PSA density have similar diagnostic properties for detecting prostate cancer (PCa) and clinically-significant (cs) PCa in men with normal testosterone compared to men with low testosterone with a prior negative biopsy., Methods: We conducted a retrospective analysis of 3295 men undergoing a 2-year prostate biopsy following a negative prestudy biopsy in the placebo arm of the Reduction by Dutasteride of PCa Events (REDUCE) study. Men were divided in 2 groups based on testosterone level < or ≥300 ng/dL. Diagnostic properties of total serum PSA, free-PSA ratio, and PSA density to predict PCa and csPCa, defined as Gleason score ≥7, were determined for several thresholds and plotted as receiver operator characteristic curves., Results: A total of 603 men (18.3%) had low testosterone. The prevalence of PCa and csPCa was 92 (15.3%) and 27 (4.5%), respectively, for low testosterone men compared to 458 (17.0%) and 138 (5.1%), correspondingly, for normal testosterone men. Total PSA, free-PSA ratio and PSA density showed similar sensitivity, specificity, and accuracy to predict PCa and csPCa among low testosterone men compared to normal testosterone men., Conclusion: Among subjects in a clinical trial with a prior negative biopsy, total PSA, free-PSA ratio and PSA density have comparable diagnostic characteristics for PCa screening in low and normal testosterone men., (Copyright © 2019 Elsevier Inc. All rights reserved.) more...

Pathological staging and histological grading systems are useful, but imperfect, predictors of recurrence in head and neck squamous cell carcinoma (HNSCC). Aberrant promoter methylation is the main type of epigenetic modification that plays a role in the inactivation of tumor suppressor genes. To identify new potential prognostic markers, we investigated the promoter methylation status of five neuropeptide receptor genes. The methylation status of the target genes was compared with clinical characteristics in 278 cases; 72 hypopharyngeal cancers, 54 laryngeal cancers, 75 oropharyngeal cancers, and 77 oral cavity cancers were studied. We found that the NTSR1, NTSR2, GHSR, MLNR, and NMUR1 promoters were methylated in 47.8%, 46.8%, 54.3%, 39.2%, and 43.5% of the samples, respectively. GHSR and NMUR1 promoter methylation independently predicted recurrence in HNSCC. In patients with oropharyngeal cancer (n = 75), GHSR and NMUR1 promoter methylation significantly correlates with survival in surgically treated patients. We classified our patients as having a low, intermediate, or high-risk of death based on three factors: HPV status, and GHSR and NMUR1 promoter methylation. The disease-free survival (DFS) rates were 87.1%, 42.7%, and 17.0%, respectively. Combined data analysis of the methylation status of ten-eleven translocation (TET) family genes indicated a trend toward greater methylation indices as the number of TET methylation events increased. In the current study, we presented the relationship between the methylation status of the GHSR and NMUR1 genes and recurrence in HNSCC, specifically in risk classification of oropharyngeal carcinomas cases with HPV status. more...

Background: Chronic inflammation is a risk factor for head and neck squamous cell carcinoma (HNSCC) and other diseases. Prostanoid receptors are clearly involved in the development of many types of cancer. However, their role is not simple and is poorly understood in HNSCC., Methods: Methylation profiles of prostanoid receptor family genes were generated for tumour samples obtained from 274 patients with HNSCC, including 69 hypopharynx, 51 larynx, 79 oral cavity, and 75 oropharynx tumour samples, by quantitative methylation-specific PCR. Promoter methylation was then evaluated with respect to various clinical characteristics and patient survival., Results: The mean number of methylated genes per sample was 2.05 ± 2.59 (range 0 to 9). Promoters of PTGDR1, PTGDR2, PTGER1, PTGER2, PTGER3, PTGER4, PTGFR, PTGIR, and TBXA2R were methylated in 43.8%, 18.2%, 25.5%, 17.5%, 41.2%, 8.0%, 19.3%, 20.4%, and 11.3% of the samples, respectively. Methylation indices for prostanoid receptor family genes tended to be higher as the number of TET methylation events increased. Patients with 5-9 methylated genes had a significantly lower survival rate than that of patients with 0-4 methylated genes (log-rank test, P= 0.007). In multivariate analyses, PTGDR1 methylation was most highly correlated with recurrence in patients with hypopharyngeal cancer (P = 0.014). A similar correlation was observed for PTGER4 in patients with laryngeal cancer (P = 0.046). Methylation of the PTGIR and TBXA2R promoters was positively correlated with recurrence in oropharyngeal cancer (P = 0.028 and P = 0.006, respectively). Moreover, Patients with 5-9 methylated genes were extremely lower of 5hmC levels (P = 0.035) and was correlated with increasing expression of DNMT3A and DNMT3B (P < 0.05 and P < 0.05, respectively)., Conclusion: We characterised the relationship between the methylation status of prostanoid receptor genes and recurrence in HNSCC. These results provide new perspectives for the development of molecular targeted treatment approaches. more...

Objectives: This study aimed to estimate the incidence of DSM5 anorexia nervosa in young people in contact with child and adolescent mental health services in the UK and Ireland., Design: Observational, surveillance study, using the Child and Adolescent Psychiatry Surveillance System, involving monthly reporting by child and adolescent psychiatrists between 1st February 2015 and 30th September 2015., Setting: The study was based in the UK and Ireland., Participants: Clinician-reported data on young people aged 8-17 in contact with child and adolescent mental health services for a first episode of anorexia nervosa., Main Outcome Measures: Annual incidence rates (IRs) estimated as confirmed new cases per 100 000 population at risk., Results: 305 incident cases of anorexia nervosa were reported over the 8-month surveillance period and assessed as eligible for inclusion. The majority were young women (91%), from England (70%) and of white ethnicity (92%). Mean age was 14.6 years (±1.66) and mean percentage of median expected body mass index for age and sex was 83.23% (±10.99%). The overall IR, adjusted for missing data, was estimated to be 13.68 per 100 000 population (95% CI 12.88 to 14.52), with rates of 25.66 (95% CI 24.09 to 27.30) for young women and 2.28 (95% CI 1.84 to 2.79) for young men. Incidence increased steadily with age, peaking at 15 (57.77, 95% CI 50.41 to 65.90) for young women and 16 (5.14, 95% CI 3.20 to 7.83) for young men. Comparison with earlier estimates suggests IRs for children aged 12 and under have increased over the last 10 years., Conclusion: These results provide new estimates of the incidence of anorexia nervosa in young people. Service providers and commissioners should consider evidence to suggest an increase in incidence in younger children., Trial Registration Number: ISRCTN12676087., Competing Interests: Competing interests: Tamsin Ford reports she is Chair of the Child and Adolescent Psychiatry Surveillance Service that was used to run part of the study, which is an unpaid position (other than travel expenses). Kandarp Joshi reports that he was principal investigator for the Aberdeen site for a Sunovion sponsored multisite trial on effectiveness of Lurasidone in paediatric schizophrenia., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.) more...

Objectives: To survey current prescribing practices of psychotropic drugs by child and adolescent eating disorder (CAED) psychiatrists in the treatment of anorexia nervosa (AN)., Design: Cross-sectional self-administered survey., Setting: All children and young people eating disorder services (CYP EDS) in England during a national training programme., Participants: 44 CAED psychiatrists practising in CYP EDS in England., Primary and Secondary Outcome Measures: CAED psychiatrists completed a questionnaire regarding the pattern of psychopharmacological care in AN that they provide and the medication treatment pattern at their CYP EDS. Secondary outcome measures included the process of continuing pharmacotherapy from secondary care to primary care., Results: Of the 77 CYP EDS representing every team in England, 44 teams represented by a CAED psychiatrist responded, despite 13 having no psychiatrists in post at the time of the study (response rate 69%). Most (40%) respondents estimated that <10% of patients with AN were prescribed psychotropic medications. Olanzapine was reported as the most commonly prescribed medication for AN by 38% of the respondents, followed by fluoxetine (29%) and sertraline (10%). The most common minimum olanzapine initiation dose in this study was at 2.5 mg/day for a duration of 2-4 weeks, reaching a maximum dose of 5 mg/day. Most (68%) reviewed medications every week (30%) or every 2 weeks (38%). Over 50% of the respondents reported continuation of olanzapine prescribing within the CYP EDS teams., Conclusions: This nationally representative survey showed that despite a lack of evidence, psychotropic medications are commonly prescribed to a minority of patients, most frequently, olanzapine. Further evidence is needed on which patients may potentially benefit from pharmacotherapy as an adjunct to psychological interventions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.) more...

Ten-eleven translocation (TET) enzymes are implicated in DNA demethylation through dioxygenase activity, which converts 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC). However, the specific roles of TET enzymes and 5-hmC levels in head and neck squamous cell carcinoma (HNSCC) have not yet been evaluated. In this study, we analyzed 5-hmC levels and TET mRNA expression in a well-characterized dataset of 117 matched pairs of HNSCC tissues and normal tissues. 5-hmC levels and TET mRNA expression were examined via enzyme-linked immunosorbent assay and quantitative real-time PCR, respectively. 5-hmC levels were evaluated according to various clinical characteristics and prognostic implications. Notably, we found that 5-hmC levels were significantly correlated with tumor stage ( P = 0.032) and recurrence ( P = 0.018). Univariate analysis revealed that low levels of 5-hmC were correlated with poor disease-free survival (DFS; log-rank test, P = 0.038). The expression of TET family genes was not associated with outcomes. In multivariate analysis, low levels of 5-hmC were evaluated as a significant independent prognostic factor of DFS (hazard ratio: 2.352, 95% confidence interval: 1.136-4.896; P = 0.021). Taken together, our findings showed that reduction of TET family gene expression and subsequent low levels of 5-hmC may affect the development of HNSCC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).) more...

Background: The optimal treatment for isolated local recurrence (ILR) of pancreatic adenocarcinoma (PDAC) after surgical resection remains unclear. This study aimed to evaluate the safety and efficacy of proton radiotherapy (PRT) for ILR of PDAC after surgery., Methods: The medical records of patients with ILR of PDAC after surgery who underwent proton beam therapy between 2011 and 2015 at Hyogo Ion Beam Medical Center were retrospectively studied., Results: The study analyzed 30 patients (14 women and 16 men) with a median age of 65 years (range 38-81 years) who had initially undergone pancreatoduodenectomy (n = 23) or distal pancreatectomy (n = 7) for their primary tumors. Upon ILR, PRT was administered with a median total cumulative dose of 67.5 gray equivalent (GyE) (range 50-67.5 GyE) using 19 to 25 fractions. For 25 patients, concurrent chemotherapy was administered using gemcitabine (n = 18) or S-1 (n = 7). Four patients (13.3%) experienced acute grade ≥ 3 gastrointestinal toxicities. After a median follow-up period of 17.6 months (range 2.1-50.4 months), 23 patients had experienced tumor progression and 10 had died. Nine patients (30%) experienced local tumor progression. The median overall, progression-free, and local progression-free survival rates were 26.1, 12.3, and 41.2 months, respectively. Pre-PRT serum levels of cancer antigen 19-9 higher than 100 U/mL and duke pancreatic monoclonal antigen type 2 higher than 150 U/mL were significantly associated with shorter progression-free survival rates., Conclusions: Proton radiotherapy for ILR of PDAC after surgery is well tolerated and produces good locoregional control and should be considered for eligible patients. more...

Staging and pathological grading systems are convenient, but imperfect predictors of recurrence of head and neck squamous cell carcinoma. Therefore, to identify potential alternative prognostic markers, we investigated the methylation status of the promoter of Sal-like protein 2 ( SALL2 ). SALL2 mRNA expression was absent in 8/9 (88.9%) University of Michigan squamous cell carcinoma cell lines, whereas two nonmalignant cell lines had stable expression. The normalized methylation value of SALL2 in cancer cell lines was significantly higher than in normal cell lines. SALL2 methylation found in 74 of 233 (31.8%) tumor specimens was correlated with the methylation status of both SALL1 and SALL3 . SALL2 methylation was not associated with any difference in disease-free survival (DFS). Therefore, the presence of SALL2 methylation was statistically correlated with a decrease in DFS in patients with oral cancer (log-rank test, p  = 0.032). Furthermore, it was associated with disease recurrence in 36.2% of oral cancer cases, with an odds ratio of 2.922 (95% confidence interval = 1.198-7.130; p  = 0.018) by multivariate Cox proportional hazard regression analysis. This study suggests that cytosine-phosphate- guanosine (CpG) hypermethylation is a likely mechanism of SALL2 inactivation and supports the hypothesis that SALL2 could serve as an important clinical risk assessment. more...

Objective: Attention processing for food may be biased in people with Anorexia Nervosa (AN). However, previous studies have had inconsistent results. This is likely to be due to indirect assessment of attention, which does not inform on the underlying attention processes, and/or the heterogeneity of participants across studies, testing either adults or adolescents with AN, that is, people at very different developmental and illness stages., Method: Eye-tracking was employed as a direct assessment of attention during a visual probe task with food versus non-food pictures. Attention bias for food was measured in 39 adults and 34 adolescents with AN and in 53 adults and 31 adolescents without AN., Results: All participants had a direction bias for food, specifically for high-calorie food. However, adults with AN subsequently avoided maintaining attention on food versus non-food cues, compared to adults without AN. Adolescents with or without AN demonstrated increased attention maintenance on food versus non-food cues, and, contrary to our hypothesis, did not differ in their attention bias for food cues. Accordingly, adults with AN differed significantly from adolescents with AN in attention maintenance for food cues: while adolescents with AN showed significantly increased attention maintenance on food stimuli, adults avoided maintaining attention on food cues., Discussion: Adults with AN may apply attention strategies to facilitate restrictive eating. This strategy is absent in adolescents with AN. This difference in food-related attention bias between adolescents and adults with AN suggests that attention biases develop over time as the illness progresses., (© 2019 Wiley Periodicals, Inc.) more...

Purpose: Research is consistently reporting elevated levels of intolerance of uncertainty (IU) in individuals with an eating disorder (ED). Less is known about the phenomenology of uncertainty for this clinical group. The present study aims to advance our understanding of the relationship between IU and restrictive EDs by providing insight into young people's subjective experiences of uncertainty., Methods: Thirteen young people with a restrictive ED were recruited from multi-family therapy groups run within the Maudsley Centre for Child and Adolescent Eating Disorders at the South London and Maudsley NHS Foundation Trust. Three focus groups were conducted asking young people to discuss their views, experiences and coping strategies when faced with uncertainty., Results: Data were analysed using interpretative phenomenological analysis which yielded five superordinate themes: (1) young people perceived uncertainty as something negative; (2) high levels of anxiety and stress were identified as primary responses to uncertainty; (3) ED behaviours were given a functional role in reducing uncertainty; (4) need to control various aspects of young peoples' lives was of high importance; (5) young people discussed how they struggled to find ways to cope with uncertainty and often used behaviours associated with the eating disorder psychopathology as coping strategies., Conclusion: Young people's experiences of what uncertainty is like for them revealed a dynamic interplay between ED symptoms and fear of uncertainty. Findings support IU as a relevant concept for young people suffering from a restrictive ED and indicate that further exploration of IU from both theoretical and clinical perspectives could be fruitful., Level of Evidence: V. more...

Loss of heterozygosity (LOH) on chromosome 18q23 is associated with significantly decreased survival in head and neck cancer. In agreement with such tumor suppressive roles, the loss of function of genes located in this region can be achieved through LOH and promotor hypermethylation. In this study, the methylation status of promoters of 18q23 genes in 243 head and neck cancer patients was assessed by quantitative methylation-specific PCR. Promoter methylation was then compared to various clinical characteristics and patient survival. GALR1 and SALL3 promoter methylation correlated with reduced disease-free survival (log-rank test, p = 0.018 and p = 0.013, respectively). Furthermore, based on multivariate Cox proportional hazards analysis, these methylation events were associated with poor disease-free survival, with hazard ratios of 1.600 (95% confidence interval: CI, 1.027⁻2.493; p = 0.038) and 1.911 (95% CI, 1.155⁻3.162; p = 0.012), respectively. By comparison, GALR1 and SALL3 methylation were not prognostic for overall survival in The Cancer Genome Atlas (TCGA) cohort. Our findings suggest that the methylation status of 18q23 genes could serve as important biomarkers for the prediction of clinical outcomes in well-annotated head and neck squamous cell carcinoma cohorts. GALR1 and SALL3 methylation could thus help to facilitate risk stratification for individualized treatment., Competing Interests: The authors declare no conflict of interest. more...

Background: Attachment theory proposes that humans develop representations of self and other in early childhood which are relatively stable across the life-course, and play a key role in psychological adaptation. However, to date, the psychometric properties of attachment measures in middle childhood and adolescence have not been evaluated in a systematic review., Method: A systematic review (PROSPERO ID: CRD42017057772) was conducted using COSMIN criteria. Two researchers independently searched MEDLINE, PsychINFO and Embase databases for relevant articles., Results: Fifty-four studies were included in the review. The methodological quality of studies was typically fair or poor, with only a small number of studies being rated as of good or excellent quality. The measurement properties of attachment measures in this age group were frequently rated as inadequate according to COSMIN criteria. The Child Attachment Interview (CAI) has the best psychometric properties of the interview and projective measures, and the Inventory of Parent and Peer Attachment (IPPA) the best evidence of the self-report measures. Overall, the evidence for the CAI and IPPA included both positive and negative findings relating to adequacy of measurement properties., Conclusions: Attachment measures in middle childhood and adolescence currently have limited evidence for the adequacy of their psychometric properties., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.) more...

A synthetic technique inspired by the biomineralisation process in nacre has been previously reported to be effective in replicating the nanostructural elements of nacre in 2D chitosan hydrogel films. Here we evaluate the applicability of this synthetic biomineralisation technique, herein called the McGrath method, in replicating the flat tabular morphology of calcium carbonate and other nanostructural elements obtained when 2D chitosan hydrogel films were used, on a 3D porous chitosan hydrogel-based scaffold, hence developing 3D chitosan-calcium carbonate composites. Nozzle extrusion-based 3D printing technology was used to develop 3D porous scaffolds using chitosan hydrogel as the printing ink in a custom-designed 3D printer. The rheology of the printing ink and print parameters were optimised in order to fabricate 3D cylindrical structures with a cubic lattice-based internal structure. The effects of various dehydration techniques, including air-drying, critical point-drying and freeze-drying, on the structural integrity of the as-printed scaffolds from the nano to macroscale, were evaluated. The final 3D composite materials were characterised using scanning electron microscopy, X-ray diffraction and energy dispersive X-ray spectroscopy. The study has shown that McGrath method can be used to develop chitosan-calcium carbonate composites wherein the mineral and matrix are in intimate association with each other at the nanoscale. This process can be successfully integrated with 3D printing technology to develop 3D compartmentalised polymer-mineral composites. more...

Background: Perspectives of young people with eating disorders and their parents on helpful aspects of care should be incorporated into evidence-based practice and service design, but data are limited.AimsTo explore patient and parent perspectives on positive and negative aspects of care for young people with eating disorders., Method: Six online focus groups with 19 young people aged 16-25 years with existing or past eating disorders and 11 parents., Results: Thematic analysis identified three key themes: the need to (a) shift from a weight-focused to a more holistic, individualised and consistent care approach, with a better balance in targeting psychological and physical problems from an early stage; (b) improve professionals' knowledge and attitude towards patients and their families at all levels of care from primary to 'truly specialist'; (c) enhance peer and family support., Conclusions: Young people and parents identified an array of limitations in approaches to care for young people with eating disorders and raised the need for change, particularly a move away from a primarily weight-focused treatment and a stronger emphasis on psychological needs and individualised care.Declaration of interestNone. more...

An increase in the copper pool in body fluids has been related to a number of pathological conditions, including infections. Copper ions may affect antibiotics via the formation of coordination bonds and/or redox reactions. Herein, we analyzed the interactions of Cu 2+ with eight β-lactam antibiotics using UV-Vis spectrophotometry, EPR spectroscopy, and electrochemical methods. Penicillin G did not show any detectable interactions with Cu 2+ . Ampicillin, amoxicillin and cephalexin formed stable colored complexes with octahedral coordination environment of Cu 2+ with tetragonal distortion, and primary amine group as the site of coordinate bond formation. These β-lactams increased the solubility of Cu 2+ in the phosphate buffer. Ceftazidime and Cu 2+ formed a complex with a similar geometry and gave rise to an organic radical. Ceftriaxone-Cu 2+ complex appears to exhibit different geometry. All complexes showed 1:1 stoichiometry. Cefaclor reduced Cu 2+ to Cu 1+ that further reacted with molecular oxygen to produce hydrogen peroxide. Finally, meropenem underwent degradation in the presence of copper. The analysis of activity against Escherichia coli and Staphylococcus aureus showed that the effects of meropenem, amoxicillin, ampicillin, and ceftriaxone were significantly hindered in the presence of copper ions. The interactions with copper ions should be taken into account regarding the problem of antibiotic resistance and in the selection of the most efficient antimicrobial therapy for patients with altered copper homeostasis., (Copyright © 2018 Elsevier Inc. All rights reserved.) more...

Background: The usefulness of particle therapy for skull base chordoma has not been established. The aim of this retrospective study was to analyse the treatment outcomes of proton therapy (PT) and carbon ion therapy (CIT) in patients with skull base chordoma at a single institution., Methods: All patients who underwent PT or CIT with curative intent between 2003 and 2014 at Hyogo Ion Beam Medical Center were included in this study. Twenty-four patients were enrolled. Eleven (46%) received PT and 13 (54%) received CIT. Overall survival (OS), progression-free survival (PFS) and local control (LC) were calculated using the Kaplan-Meier method. Late toxicities were evaluated according to the Common Terminology Criteria for Adverse Events version 4.0., Results: The median follow-up was 71.5 months (range, 14-175 months). The five-year LC, PFS and OS rates were 85, 81, and 86%, respectively. The LC (P = 0.048), PFS (P = 0.028) and OS (P = 0.012) were significantly improved in patients who had undergone surgery before particle therapy. No significant differences were observed in the LC rate and the incidence of grade 2 or higher late toxicities between patients who received PT and CIT., Conclusions: Both PT and CIT appear to be effective and safe treatments and show potential to become the standard treatments for skull base chordoma. To increase the local control, surgery before particle therapy is preferable. more...

Enhancer of Zeste homologue 2 (EZH2) overexpression is associated with tumor proliferation, metastasis, and poor prognosis. Targeting and inhibition of EZH2 is a potentially effective therapeutic strategy for head and neck squamous cell carcinoma (HNSCC). We analyzed EZH2 mRNA expression in a well-characterized dataset of 230 (110 original and 120 validation cohorts) human head and neck cancer samples. This study aimed to investigate the effects of inhibiting EZH2, either via RNA interference or via pharmacotherapy, on HNSCC growth. EZH2 upregulation was significantly correlated with recurrence ( p < 0.001) and the methylation index of tumor suppressor genes ( p < 0.05). DNMT3A was significantly upregulated upon EZH2 upregulation ( p = 0.043). Univariate analysis revealed that EZH2 upregulation was associated with poor disease-free survival (log-rank test, p < 0.001). In multivariate analysis, EZH2 upregulation was evaluated as a significant independent prognostic factor of disease-free survival (hazard ratio: 2.085, 95% confidence interval: 1.390⁻3.127; p < 0.001). Cells treated with RNA interference and DZNep, an EZH2 inhibitor, showed the most dramatic changes in expression, accompanied with a reduction in the growth and survival of FaDu cells. These findings suggest that EZH2 upregulation is correlated with tumor aggressiveness and adverse patient outcomes in HNSCC. Evaluation of EZH2 expression might help predict the prognosis of HNSCC patients. more...

Objective: Family Therapy for Anorexia Nervosa (FT-AN) is the first line treatment for adolescents with anorexia nervosa in the UK. However, research suggests between 10 and 40% of young people have a poor outcome. For those for whom FT-AN alone is not effective there is a clear need to develop additional treatments. This paper describes the effectiveness of an additional treatment for adolescents who had not responded to FT-AN, the Intensive Day Treatment Program (ITP) embedded within a comprehensive outpatient service at the Maudsley Hospital., Method: Data from a retrospective chart review of patient files were analyzed for 105 young people aged 11-18 with restrictive eating disorders referred to the program in the first four and a half years of its operation., Results: Young people attended ITP for only on average 28.41 days. Over this time they made significant improvements in a range of domains, including weight gain, eating disorder symptomatology, motivation to recover, quality of life and comorbid symptomatology. Young people continued to make improvements post ITP in outpatient treatment provided by the same service and 73.2% had a good or an intermediate outcome at the point of discharge from the service., Discussion: This uncontrolled case series indicates that ITP can contribute to positive outcomes for young people who require intensification of treatment. ITP outcomes are discussed in comparison to the published literature concerning day programs for adolescents with a diagnosis of an eating disorder., (© 2018 Wiley Periodicals, Inc.) more...

Axon specification is morphologically reproducible in vitro, whereas dendrite formation differs in vitro and in vivo. Cortical neurons initially develop immature neurites, but in ;vivo these are eliminated concurrently with the formation of a leading process, the future dendrite. However, the molecular mechanisms underlying these neuronal maturation events remain unclear. Here we show that caveolin-1, a major component of caveolae that are never observed in neurons, regulates in vivo-specific steps of neuronal maturation. Caveolin-1 is predominantly expressed in immature cortical neurons and regulates clathrin-independent endocytosis. In vivo knockdown of caveolin-1 disturbs immature neurite pruning, leading process elongation, and subsequent neuronal migration. Importantly, N-cadherin and L1, which are required for immature neurite formation, undergo caveolin-1-mediated endocytosis to eliminate immature neurites. Collectively, our findings indicate that caveolin-1 regulates N-cadherin and L1 trafficking independent of caveolae, which contributes to spatiotemporally restricted cellular events; immature neurite pruning and leading process elongation during early neuronal maturation., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.) more...

Rab family small GTPases play essential roles in various cellular events via the regulation of intracellular logistics comprising a large number of membrane traffic pathways. Emerging evidence reveals the physiological roles of Rab proteins in several tissues, including developing brains. Many Rab proteins, such as Rab5, Rab6, Rab7, Rab8, Rab10, Rab11, Rab17 and Rab18, are shown to regulate neurite outgrowth in PC12 cells and/or axon and dendrite formation in primary cultured neurons. Recent studies have also revealed in vivo roles of several Rab family small GTPases in brain development and its related neurological disorders. In this review, we introduce the physiological function of Rab family proteins in neural development with particular focus on neurite outgrowth and neuronal migration. more...

Purpose: This retrospective study aimed to determine the clinical outcomes following particle monotherapy (ie, proton therapy [PT] or carbon ion therapy [CIT]) in patients with sinonasal squamous cell carcinoma at a single institution., Methods and Materials: Between August 2001 and March 2012, 59 patients were treated with definitive PT or CIT; none underwent chemotherapy or surgery. Of the patients, 22 (37%) had unresectable disease. PT was used in 38 patients (64%); CIT, 21 patients (36%). Almost half of the patients (n = 29, 47%) received 65.0 Gy (relative biological effectiveness) in 26 fractions., Results: The median follow-up period was 30 months (range, 8-127 months) for all patients and 65 months (range, 9-127 months) for the survivors. The 3- and 5-year overall survival rates were 56.2% and 41.6%, respectively; progression-free survival rates, 42.9% and 34.7%, respectively; and local control rates, 54.0% and 50.4%, respectively. Late toxicities of grade ≥3 occurred in 13 patients (22%)., Conclusions: To our knowledge, this is the largest retrospective study of sinonasal squamous cell carcinoma treated with particle therapy alone. The efficacy of PT and CIT indicated that particle therapy can serve an important role in treating this disease., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.) more...

Fucoxanthinol (FxOH) is a strong anticancer metabolite of fucoxanthin that accumulates in abundance in edible brown algae and promises human health benefits. FxOH has been shown to suppress tumorigenicity and sphere formation in human colorectal cancer stem cell (CCSC)-like spheroids (colonospheres, Csps). In the present study, we aimed to clarify the inhibitory activity of FxOH on epithelial-mesenchymal transition (EMT), which is essential for cancer recurrence and distant metastasis, and to identify intracellular low-molecular-weight metabolites that may be useful for evaluating the cellular effects of FxOH on CCSCs. FxOH significantly suppressed sphere-forming activity, migration and invasion in a dose-dependent manner. In addition, treatment with 50 µmol/l FxOH suppressed N-cadherin and vimentin expression and the activation of integrin signaling linked to EMT suppression by western blot analysis. MAPK signaling and STAT signaling related to cell growth and apoptosis in Csps derived from human CRC HT-29 and HCT116 cells were also altered. According to our metabolite profiling by GC-MS analysis, reduced glycine and succinic acid levels were correlated with EMT suppression and apoptosis induction in Csps. Our data indicate that simple amino acids such as glycine and succinic acid may be good prognostic indicators of physiological changes to CCSCs induced by FxOH treatment. more...

Purpose of Review: Global industrialization has increased population exposure to environmental toxins. A global decline in sperm quality over the last few decades raises questions about the adverse impact of environmental toxins on male reproductive health., Recent Findings: Multiple animal- and human-based studies on exposure to environmental toxins suggest a negative impact on semen quality, in terms of sperm concentration, motility, and/or morphology. These toxins may exert estrogenic and/or anti-androgenic effects, which in turn alter the hypothalamic-pituitary-gonadal axis (HPGA), induce sperm DNA damage, or cause sperm epigenetic changes. This chapter will discuss the most recent literature about the most common environmental toxins and their impact on spermatogenesis and its consequences on male fertility. Understanding the presence and underlying mechanism of these toxins will help us preserve the integrity of the male reproduction system and formulate better regulations against their indiscriminate use. more...

The aim of this study was to clarify the epigenetic regulation of ten eleven translocation protein (TET) family genes, which can provide insights into the mechanisms of tumorigenesis and the risk of disease recurrence in head and neck squamous cell carcinoma (HNSCC). We generated methylation profiles of TET1 , TET2 and TET3 genes in tumor samples obtained from 233 patients with HNSCC; these included 57 hypopharynx, 44 larynx, 69 oral cavity, and 63 oropharynx tumor samples. The mRNA expression and promoter DNA methylation of TET family genes were examined via quantitative RT-PCR and methylation-specific PCR, respectively. Promoter methylation was compared with various clinical characteristics and the TET methylation index (TE-MI). The TE-MI, representing the number of methylation events in TET family genes, was positively correlated with alcohol consumption (P = 0.004), high-risk human papilloma virus (HPV) status (P = 0.004) and disease recurrence (P = 0.002). The simultaneous methylation analysis of TET family genes was correlated with reduced disease-free survival in unfavorable event groups (log-rank test, P = 0.026). In the multivariate Cox proportional hazards analysis, TET3 methylation in T1 and T2 tumor stages, oropharyngeal cancer, and oral cancer patients exhibited high association with poor survival (hazard ratio: 2.64, P = 0.014; 3.55, P = 0.048; 2.63, P = 0.028, respectively). A joint analysis of the tumor suppressor gene methylation index showed a significant trend toward a higher TE-MI. The methylation status of TET3 was independently associated with aggressive tumor behavior and a global effect on DNA methylation status in HNSCC., Competing Interests: CONFLICTS OF INTEREST No potential conflicts of interest are disclosed. more...

We analyzed the gizzards, and grits retained in the gizzards of 41 cranes that migrated to the Izumi Plain during the winter of 2015/2016 and died there, either due to accident or disease. These included 31 Hooded Cranes (Grus monacha) and 10 White-naped Cranes (G. vipio). We determined body weight, gizzard weight, total grit weight and number per gizzard, and size, shape, and surface roundness of the grits. Average gizzard weights were 92.4 g for Hooded Cranes and 97.1 g for White-naped Cranes, and gizzard weight positively correlated with body weight in both species. Average total grit weights per gizzard were 19.7 g in Hooded Cranes and 25.7 g in White-naped Cranes, and were significantly higher in the latter. Average percentages of body weight to grit weight were 0.8% in Hooded Cranes and 0.5% in White-naped Cranes. Average grit number per gizzard was 693.5 in Hooded Cranes and 924.2 in White-naped Cranes, and were significantly higher in the latter. The average grit size was 2.8 mm in both species. No differences were found in the shape and surface roundness of grits between the two species. To the best of our knowledge, this is the first study on the grits retained in the gizzards of Hooded and White-naped Cranes. more...

Background: Staging and pathological grading systems are convenient but imperfect predictors of recurrence in head and neck squamous cell carcinoma (HNSCC). Identifying biomarkers for HNSCC that will progress and cause death is a critical research area, particularly if the biomarker can be linked to selection of patients. Therefore, to identify potential alternative prognostic markers, we investigated the methylation status of five neuropeptide gene promoters. The promoter methylation status was determined by quantitative methylation-specific PCR in 230 cases of HNSCC; 58 hypopharynx, 45 larynx, 56 oropharynx, and 71 oral cavity tumor samples were studied., Results: The somatostatin ( SST ), tachykinin precursor 1 ( TAC1 ), hypocretin neuropeptide precursor ( HCRT ), neuropeptide Y ( NPY ), and galanin ( GAL ) promoters were methylated in 84.3, 63.5, 32.6, 28.3, and 20.0%, respectively, of the samples. The mean number of methylated genes per sample was 2.29 (range, 0-5). Disease-free survival was lower in patients with 3-5 methylated genes than in those with 0-2 methylated genes (log-rank test, P  = 0.007). In multivariate Cox proportional hazards analysis, TAC1 and GAL promoter methylation independently predicted recurrence (odds ratios 1.620, 95% confidence interval [CI] 1.018-2.578, P  = 0.042, and odds ratios 1.692, 95% CI 1.063-2.694, P  = 0.027, respectively). In patients with oral cancer, TAC1 methylation showed the best correlation with poor survival (odds ratio 4.427, 95% CI 1.634-12.00, P  = 0.003). Similar findings were observed for HCRT and GAL in patients with laryngeal cancer and oropharyngeal cancer, respectively., Conclusion: In this study, we demonstrated the methylation status of the neuropeptide-encoding genes SST , TAC1 , HCRT , NPY , and GAL and its relationship with recurrence and survival in HNSCC. These methylation changes may serve as potential molecular markers for defining the risk and prognosis of HNSCC., Competing Interests: These tissue samples were obtained with informed written consent following protocols approved by the research ethics board of the Hamamatsu University School of Medicine.Consent for publication was obtained from all patients.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. more...

Purpose: To evaluate the efficacy and safety of definitive proton beam therapy (PBT) for primary sacral chordoma., Methods and Materials: We conducted a retrospective analysis of the clinical outcomes of eligible patients with primary sacral chordoma who had undergone definitive PBT with 70.4 Gy (relative biological effectiveness) in 32 fractions at our institution from September 2009 to October 2015. Local progression-free survival, distant metastasis-free survival, disease-free survival, cause-specific survival, and overall survival were evaluated. To explore the factors that influenced local progression, the following parameters were analyzed: sex, the presence of a spacer (Gore-Tex sheets), gross tumor volume, and extent of cranial tumor extension. Adverse events were evaluated using the Common Terminology Criteria for Adverse Events, version 4.0. To assess the impact of PBT on pain relief, the change in pain grades was investigated between the initiation of PBT and the last follow-up visit., Results: Thirty-three eligible patients were analyzed. The median follow-up period was 37 months. The 3-year estimated local progression-free survival, distant metastasis-free survival, disease-free survival, cause-specific survival, and overall survival rates were 89.6%, 88.2%, 81.9%, 95.7%, and 92.7%, respectively. No significant association was between the patients' clinicopathologic characteristics and local progression-free survival. Four patients developed grade 3 adverse events, including acute dermatitis (n = 1), ileus (n = 1), and pain due to sacral insufficiency fractures (n = 2). The pain grades had improved, were unchanged, or had deteriorated in 15, 7, and 11 patients, respectively., Conclusions: Definitive PBT with 70.4 Gy (relative biological effectiveness) in 32 fractions is an effective treatment with acceptable toxicity for primary sacral chordoma and has the potential to reduce pain., (Copyright © 2017 Elsevier Inc. All rights reserved.) more...

Background: Self-harm in adolescents is common and repetition rates high. There is limited evidence of the effectiveness of interventions to reduce self-harm., Objectives: To assess the clinical effectiveness and cost-effectiveness of family therapy (FT) compared with treatment as usual (TAU)., Design: A pragmatic, multicentre, individually randomised controlled trial of FT compared with TAU. Participants and therapists were aware of treatment allocation; researchers were blind to allocation., Setting: Child and Adolescent Mental Health Services (CAMHS) across three English regions., Participants: Young people aged 11-17 years who had self-harmed at least twice presenting to CAMHS following self-harm., Interventions: Eight hundred and thirty-two participants were randomised to manualised FT delivered by trained and supervised family therapists ( n  = 415) or to usual care offered by local CAMHS following self-harm ( n  = 417)., Main Outcome Measures: Rates of repetition of self-harm leading to hospital attendance 18 months after randomisation., Results: Out of 832 young people, 212 (26.6%) experienced a primary outcome event: 118 out of 415 (28.4%) randomised to FT and 103 out of 417 (24.7%) randomised to TAU. There was no evidence of a statistically significant difference in repetition rates between groups (the hazard ratio for FT compared with TAU was 1.14, 95% confidence interval 0.87 to 1.49; p  = 0.3349). FT was not found to be cost-effective when compared with TAU in the base case and most sensitivity analyses. FT was dominated (less effective and more expensive) in the complete case. However, when young people's and caregivers' quality-adjusted life-year gains were combined, FT incurred higher costs and resulted in better health outcomes than TAU within the National Institute for Health and Care Excellence cost-effectiveness range. Significant interactions with treatment, indicating moderation, were detected for the unemotional subscale on the young person-reported Inventory of Callous-Unemotional Traits ( p  = 0.0104) and the affective involvement subscale on the caregiver-reported McMaster Family Assessment Device ( p  = 0.0338). Caregivers and young people in the FT arm reported a range of significantly better outcomes on the Strengths and Difficulties Questionnaire. Self-reported suicidal ideation was significantly lower in the FT arm at 12 months but the same in both groups at 18 months. No significant unexpected adverse events or side effects were reported, with similar rates of expected adverse events across trial arms., Conclusions: For adolescents referred to CAMHS after self-harm, who have self-harmed at least once before, FT confers no benefits over TAU in reducing self-harm repetition rates. There is some evidence to support the effectiveness of FT in reducing self-harm when caregivers reported poor family functioning. When the young person themselves reported difficulty expressing emotion, FT did not seem as effective as TAU. There was no evidence that FT is cost-effective when only the health benefits to participants were considered but there was a suggestion that FT may be cost-effective if health benefits to caregivers are taken into account. FT had a significant, positive impact on general emotional and behavioural problems at 12 and 18 months., Limitations: There was significant loss to follow-up for secondary outcomes and health economic analyses; the primary outcome misses those who do not attend hospital following self-harm; and the numbers receiving formal FT in the TAU arm were higher than expected., Future Work: Evaluation of interventions targeted at subgroups of those who self-harm, longer-term follow-up and methods for evaluating health benefits for family groups rather than for individuals., Trial Registration: Current Controlled Trials ISRCTN59793150., Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 22, No. 12. See the NIHR Journals Library website for further project information., Competing Interests: Amanda J Farrin is a member of the Health Technology Assessment (HTA) Clinical Evaluation and Trials Board and the HTA Commissioning Strategy Group. Allan O House is a member of the HTA Efficient Study Designs Board. Sarah Fortune worked as a Consultant Clinical Psychologist in the NHS prior to this project. Sandy Tubeuf is a member of the National Institute for Health Research Programme Grants for Applied Research Committee. more...

Background: Self-harm in adolescents is common and repetition occurs in a high proportion of these cases. Scarce evidence exists for effectiveness of interventions to reduce self-harm., Methods: This pragmatic, multicentre, randomised, controlled trial of family therapy versus treatment as usual was done at 40 UK Child and Adolescent Mental Health Services (CAMHS) centres. We recruited young people aged 11-17 years who had self-harmed at least twice and presented to CAMHS after self-harm. Participants were randomly assigned (1:1) to receive manualised family therapy delivered by trained and supervised family therapists or treatment as usual by local CAMHS. Participants and therapists were aware of treatment allocation; researchers were masked. The primary outcome was hospital attendance for repetition of self-harm in the 18 months after group assignment. Primary and safety analyses were done in the intention-to-treat population. The trial is registered at the ISRCTN registry, number ISRCTN59793150., Findings: Between Nov 23, 2009, and Dec 31, 2013, 3554 young people were screened and 832 eligible young people consented to participation and were randomly assigned to receive family therapy (n=415) or treatment as usual (n=417). Primary outcome data were available for 795 (96%) participants. Numbers of hospital attendances for repeat self-harm events were not significantly different between the groups (118 [28%] in the family therapy group vs 103 [25%] in the treatment as usual group; hazard ratio 1·14 [95% CI 0·87-1·49] p=0·33). Similar numbers of adverse events occurred in both groups (787 in the family therapy group vs 847 in the treatment as usual group)., Interpretation: For adolescents referred to CAMHS after self-harm, having self-harmed at least once before, our family therapy intervention conferred no benefits over treatment as usual in reducing subsequent hospital attendance for self-harm. Clinicians are therefore still unable to recommend a clear, evidence-based intervention to reduce repeated self-harm in adolescents., Funding: National Institute for Health Research Health Technology Assessment programme., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.) more...

This study examined Sal-like protein ( SALL)1 methylation profiles in head and neck squamous-cell carcinoma (HNSCC) patients at diagnosis and follow-up, and evaluated their prognostic significance and value as a biomarker. SALL1 expression was examined in a panel of cell lines by quantitative reverse transcription PCR (qRT-PCR). Promoter methylation was determined by quantitative methylation-specific polymerase chain reaction (qMSP) and was compared to the clinical characteristics of 205 samples. SALL1 promoter methylation was associated with transcriptional inhibition and was correlated with disease recurrence in 31.7% of cases, with an odds ratio of 1.694 (95% confidence interval: 1.093-2.626; P = 0.018) by multivariate Cox proportional hazard regression analysis. SALL1 promoter hypermethylation showed highly discriminatory receiver operator characteristic curve profiles that clearly distinguished HNSCC from adjacent normal mucosal tissue, and was correlated with reduced disease-free survival in early stage T1 and T2 patients (log-rank test, P < 0.001). SALL1 methylation was significantly correlated with the methylation status of both SALL3 and CDH1 . This study suggests that CpG hypermethylation is a likely mechanism of SALL1 gene inactivation, supporting the hypothesis that SALL1 might play a role in HNSCC tumorigenesis and could serve as an important biomarker., Competing Interests: Competing Interests: The authors have declared that no competing interest exists. more...

Clarifying the epigenetic regulation of tumor-related genes (TRGs) can provide insights into the mechanisms of tumorigenesis and the risk for disease recurrence in HPV-negative head and neck cancers, originating in the hypopharynx, larynx, and oral cavity. We analyzed the methylation status of the promoters of 30 TRGs in 178 HPV-negative head and neck cancer patients using a quantitative methylation-specific PCR. Promoter methylation was correlated with various clinical characteristics and patient survival. The mean number of methylated TRGs was 14.2 (range, 2-25). In the multivariate Cox proportional hazards analysis, the methylation of COL1A2 and VEGFR1 was associated with poor survival for hypopharyngeal cancer, with hazard ratios: 3.19; p = 0.009 and 3.07; p = 0.014, respectively. The methylation of p16 and COL1A2 were independent prognostic factors for poor survival in laryngeal cancer (hazard ratio: 4.55; p = 0.013 and 3.12; p = 0.035, respectively). In patients with oral cancer, the methylation of TAC1 and SSTR1 best correlated with poor survival (hazard ratio: 4.29; p = 0.005 and 5.38; p = 0.029, respectively). Our findings suggest that methylation status of TRGs could serve as important site-specific biomarkers for prediction of clinical outcomes in patients with HPV-negative head and neck cancer., Competing Interests: The authors declare no conflict of interest. more...

The aim of this study was to use standardised, clinical assessment tools to explore the presence of Autism Spectrum Disorder (ASD) symptoms in a sample of adolescent females with Anorexia Nervosa (AN), receiving either day-patient or inpatient treatment for their eating disorder and to determine whether any such symptoms were present during the early developmental period, a requirement for a diagnosis of ASD. Using a cross-sectional design, 40 females aged between 12 and 18 were recruited from inpatient and day-patient eating disorder services. All participants had a diagnosis of AN and were assessed for symptoms of ASD using the Autism Diagnostic Observation Schedule, 2nd edition (ADOS-2). If participants scored at or above clinical cut-off on the ADOS-2, their parents were asked to complete the Developmental, Dimensional and Diagnostic Interview, short version (3Di-sv). Of the 40 participants assessed, 21 scored above cut-off on the ADOS-2. When developmental history was obtained, only four participants scored above cut-off on all sub-scales of the 3Di-sv, thus meeting full research criteria for ASD. This study suggests that 10% of adolescents with AN from inpatient or day-patient settings may have diagnosable ASD, while a further 40% may show symptoms of ASD, which may arise from the ill-state of AN or are not supported by parental report. more...

Loneliness in later life is a common problem with poor health outcomes. However, interventions to prevent or ameliorate loneliness have a weak evidence base. The views of older people experiencing or at risk of loneliness in the community are important in identifying features of potential support, but have been little studied. Twenty-eight community dwelling people, aged 65 and over who reported being 'lonely much of the time' or identified as lonely from the de Jong Gierveld six-item loneliness scale in a larger study, participated in in-depth interviews, between June 2013 and May 2014. Views and experiences on seeking support from primary care and community based one-to-one and group based activities, including social and shared interest groups, were explored. Interviews were recorded and transcribed. Thematic analysis was conducted by a multidisciplinary team, including older people. Using two different measures of loneliness enabled a spectrum of loneliness experience to be explored. Two-thirds of the participants were the 'younger old' and all were able to leave their homes independently. Older people with characteristics of loneliness were generally knowledgeable about local social and community resources but, for the majority, community and primary care based services for their loneliness were not considered desirable or helpful at this point in their lives. However, group based activities with a shared interest were thought preferable to one-to-one support (befriending) or groups with a social focus. Descriptions of support as being for loneliness and specific to older people discouraged engagement. Older people experiencing or at risk of loneliness did not consider that primary care has a role in alleviating loneliness because it is not an illness. They thought primary care practitioners lack understanding of non-physical problems and that a good relationship was necessary to discuss sensitive issues like loneliness. For many, loneliness was a complex and private matter that they wished to manage without external support., (© 2017 The Authors. Health and Social Care in the Community Published by John Wiley & Sons Ltd.) more...

Since 2005, health trainers and other lay public health workers (LPHWs) have been increasingly active in the UK. Although elsewhere in the world LPHWs are expected to come from the communities within which they work and know that their knowledge is valued, neither is the case for LPHWs in the UK. This study sought to discover the lay knowledge of health trainers and other LPHWs, aiming to ascertain how this knowledge might more effectively be utilised within UK public health services. This paper describes a participatory and ethnographic case study research project undertaken on an anonymised urban estate in North East England. Findings were generated by a range of means including by participant observation and semi-structured interviews. Seven LPHWs took part, as did 32 other community members. This study found that the lay health knowledge of an individual UK LPHW is determined primarily by his or her position within, or in relation to, the community within which he or she works. Insider LPHWs possess an embodied knowledge and incomer LPHWs possess an experiential knowledge which, although different from one another, are essentially interpersonal in nature. Lay health knowledge can take different forms, and different LPHWs can provide different forms of lay health knowledge. Public health structures and services in the UK should make better use of all forms of LPHW knowledge, and should seek from LPHWs training on how to engage the most 'hard-to-reach' or 'difficult-to-engage' groups. Services recruiting LPHWs should decide whether they are seeking embodied insider LPHW knowledge, experiential incomer LPHW knowledge or a mixture of both., (© 2017 John Wiley & Sons Ltd.) more...

Objectives: A drug like Sildenafil is commonly used for the treatment of erectile dysfunction. Eruca sativa is known as a garden plant used in folk medicine to enhance the sexual desire in males. Nevertheless, the interaction of Sildenafil and Eruca sativa was not studied. In the current study, we aimed to examine the influence of Eruca sativa on Sildenafil pharmacokinetics in rats., Study Design: A crossover experiment with washout period of two weeks was conducted. To one group of animals, Eruca sativa was given as food and a drinking solution to rats for 12 hours before the day of the experiment. On the day of the experiment, the same group received 5 ml (50 mg/ml) orally and a half an hour later animals received 1 ml Sildenafil citrate (2.85 mg/kg) oral administrated to the study group. The other group of rats only received Sildenafil. Two-weeks later a cross-over design on the same animals was conducted. Blood samples were collected from optical vein on different time intervals, samples were analyzed using validated (HPLC-UV) method., Results and Conclusion: Pre-administration of Eruca sativa has increased Sildenafil Cmax from 226.72 to 345.25 ng/ml, (p<0.05). In addition, the AUC of Sildenafil has significantly increased when it was pre-administered with Eruca sativa (550.59 vs. 916.48 ng/ml*hr). Our findings suggest that co-administration of Eruca sativa with Sildenafil enhances the pharmacokinetics of Sildenafil in rats plasma. more...

Staging and pathological grading systems are useful but imperfect predictors of recurrence in head and neck squamous cell carcinoma (HNSCC). To identify potential prognostic markers, we examined the methylation status of eight neuropeptide receptor gene promoters in 231 head and neck squamous cell carcinomas. The NPFFR1 , NPFFR2 , HCRTR1 , HCRTR2 , NPY1R , NPY2R , NPY4R , and NPY5R promoters were methylated in 80.5%, 79.2%, 67.1%, 73.2%, 35.1%, 36.4%, 38.5%, and 35.9% of the samples, respectively. In a multivariate Cox proportional hazards analysis, the odds ratio for recurrence was 2.044 (95% confidence interval [CI], 1.323-3.156; P = 0.001) when the NPY2R promoter was methylated. In patients without lymph node metastasis (n = 100), methylation of NPY2R (compared with methylation of the other seven genes) best correlated with poor disease-free survival (DFS) (odds ratio, 2.492; 95% CI, 1.190-5.215; P = 0.015). In patients with oral cancer (n = 69), methylated NPY1R and NPY2R were independent prognostic factors for poor DFS, both individually and, even more so, in combination (odds ratio, 3.90; 95% CI, 1.523-9.991; P = 0.005). Similar findings were observed for NPY2R and NPY4R in patients with oropharyngeal cancer (n = 162) (odds ratio, 5.663; 95% CI, 1.507-21.28; P = 0.010)., Competing Interests: CONFLICTS OF INTEREST The authors have no conflicts of interest to declare. more...

The aim of this study was to determine the methylation status of the genes encoding the vascular endothelial growth factor receptors and to evaluate the usefulness of VEGFR methylation as a prognostic indicator in head and neck squamous cell carcinoma. VEGFR messenger RNA expression and promoter methylation were examined in a panel of cell lines via quantitative reverse transcription and methylation-specific polymerase chain reaction, respectively. Promoter methylation was compared with clinical characteristics in 128 head and neck squamous cell carcinoma samples. The normalized methylation values for the VEGFR1, VEGFR2 and VEGFR3 promoters tended to be higher in the tumour cell lines than in normal tonsil samples, whereas amounts of VEGFR1, VEGFR2 and VEGFR3 messenger RNA were significantly higher. Methylation of the VEGFR1 promoter (p = 0.003; 66/128 head and neck squamous cell carcinoma samples, 52%) and VEGFR3 promoter (p = 0.043; 53/128 head and neck squamous cell carcinoma samples, 41%) significantly correlated with recurrence, whereas methylation of the VEGFR2 promoter significantly correlated with lymph node metastasis (p = 0.046; 47/128 head and neck squamous cell carcinoma samples, 37%). Concurrent methylation of the VEGFR1 and VEGFR3 promoters significantly correlated with reduced disease-free survival (log-rank test, p = 0.009). In a multivariate logistic regression analysis, methylation of the VEGFR1, VEGFR3 and both the VEGFR1 and VEGFR3 promoters independently predicted recurrence (odds ratios and 95% confidence intervals: 3.19, 1.51-6.75 (p = 0.002); 2.24, 1.06-4.76 (p = 0.035); and 2.56, 1.09-6.05 (p = 0.032), respectively). Methylation of the VEGFR promoters predicts poor prognosis in head and neck squamous cell carcinoma patients. more...

Background: This study examined Sal-like protein ( SALL)3 methylation profiles of head and neck cancer (HNSCC) patients at diagnosis and follow-up and evaluated their prognostic significance and value as a biomarker. SALL3 expression was examined in a panel of cell lines by quantitative reverse transcription polymerase chain reaction (RT-PCR). The methylation status of the SALL3 promoter was examined by quantitative methylation-specific PCR., Results: SALL3 promoter methylation was associated with transcriptional inhibition and was correlated with disease recurrence in 64.8% of cases, with an odds ratio of 1.914 (95% confidence interval: 1.157-3.164; P  = 0.011) by multivariate Cox proportional hazard regression analysis. SALL3 promoter hypermethylation showed highly discriminatory receiver operator characteristic curve profiles that clearly distinguished HNSCC from adjacent normal mucosal tissue, and was correlated with reduced disease-free survival (DFS) (log-rank test, P  = 0.01). Hypermethylation of tumor-related genes was higher among patients with SALL3 methylation than among those without methylation ( P  < 0.001). Furthermore, SALL3 hypermethylation was associated with expression of TET1 , TET2 , and DNMT3A genes., Conclusions: This study suggests that CpG hypermethylation is a likely mechanism of SALL3 gene inactivation, supporting the hypothesis that the SALL3 gene may play a role in the tumorigenesis of HNSCC and may serve as an important biomarker. more...

Aims: This study examined the prevalence of loneliness among the oldest old within a 10-year period and studied the influence of various sociodemographic, social and health characteristics on loneliness., Methods: The study used population-based data from the Umeå85+/GErontological Regional DAtabase-study (GERDA) for the years 2000-2002, 2005-2007 and 2010-2012 including 85-year-old, 90-year-old and ⩾95-year-old participants. A final sample of 304 participants in 2000-2002, 329 participants in 2005-2007 and 401 participants in 2010-2012 was included in the analyses., Results: Although the level of loneliness was already high in 2000-2002 (49.3% reported frequent loneliness), the results showed limited changes in loneliness during the 10-year study period. Loneliness was closely related to living alone, depressive symptoms and living in institutional settings., Conclusions: Although societal changes such as solitary living and growing urbanization suggest a changing trend in loneliness, we found that the prevalence of loneliness was relatively stable in this study. Nevertheless, loneliness is common among the oldest old and a focus on social issues related to living arrangements and on depressive symptoms is important in understanding loneliness. more...

Background: With population ageing, research is needed into new low-cost, scalable methods of effective promotion of health and wellbeing for older people. We aimed to assess feasibility, reach and costs of implementing a new tailored computer-aided health and social risk appraisal system in primary care., Methods: Design: Feasibility study., Setting: Five General Practices in London (Ealing) and Hertfordshire, United Kingdom (UK) Participants: Random sample of patients aged 65 + years., Intervention: The Multi-dimensional Risk Appraisal for Older people (MRA-O) system includes: 1) Postal questionnaire including health, lifestyle, social and environmental domains; 2) Software system generating a personalised feedback report with advice on health and wellbeing; 3) Follow-up of people with new concerning or complex needs by GPs or practice nurses., Evaluation: Feasibility of implementation; participant wellbeing, functional ability and quality of life; social needs, health risks, potential lifestyle changes; and costs of implementation., Results: Response rates to initial postal invitations were low (526/1550, 34%). Of these, 454/526 (86%) completed MRA-O assessments. Compared to local UK Census data on older people, participants were younger, more were owner-occupiers and fewer were from ethnic minority groups than expected. A range of problems was identified by participants, including pain in last week (269/438, 61.4%), low physical activity (173/453, 38.2%), sedentary lifestyle (174/447, 38.3%), falls (117/439, 26.7%), incontinence (111/441 25.2%), impaired vision 116/451 (25.7%), impaired hearing (145/431, 33.6%), depressed mood (71/451, 15.7%), impaired memory (44/444 9.9%), social isolation (46/449, 10.2%) and loneliness (31/442, 7.0%). Self-rated health was good/excellent in 312/437 (71.4%), and quality of life and well-being were slightly above age-specific population norms. Implementation costs were low. Practices reviewed medical records of 143/454 (31.5%) of participants as a consequence of their responses, and actively followed up 110/454 (24.2%) of their patients., Conclusions: A computer-aided risk appraisal system was feasible for General Practices to implement, yields useful information about health and social problems, and identifies individual needs. Participation rates were however low, particularly for the oldest old, the poorest, and ethnic minority groups, and this type of intervention may increase inequalities in access. Widespread implementation of this approach would require work to address potential inequalities. more...

The aim of this study was to evaluate the prognostic value of the promoter methylation status of galanin (GAL) and galanin receptor 1/2 (GALR1/2) by assessing their association with disease-free survival and known prognostic factors in head and neck cancer. We generated methylation profiles of GAL and GALR1/2 in tumor samples obtained from 202 patients with head and neck squamous cell carcinoma (HNSCC); these included 43 hypopharynx, 42 larynx, 59 oral cavity, and 58 oropharynx tumor samples. CpG island hypermethylation status of the three genes was analyzed using quantitative methylation-specific PCR (Q-MSP). In order to determine the prognostic value of the methylation status of these genes, the associations between methylation index and various clinical characteristics, especially tumor site, were assessed for tumors from patients with HNSCC. The methylation index was positively correlated with female gender (P = 0.008) and disease recurrence (P = 0.01) in oral cancer and human papillomavirus (HPV)-positive (P = 0.004) status and disease recurrence (P = 0.005) in oropharyngeal cancer. Among patients with oral and oropharyngeal cancer, promoter hypermethylation of GAL, GALR1, or GALR2 was statistically correlated with a decrease in disease-free survival (log-rank test, P = 0.036 and P = 0.042, respectively). Furthermore, methylation of GAL, GALR1, or GALR2 exhibited the highest association with poor survival (log-rank test, P = 0.018) in patients with HPV-negative oropharyngeal cancers. As such, GAL and GALR1/2 methylation status may serve as an important site-specific biomarker for prediction of clinical outcome in patients with HNSCC. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.) more...

Evidence links high levels of Autism Spectrum Disorder Traits in women with chronicity of anorexia nervosa. This study reports through clinical audit the impact of ASD traits on treatment outcomes of girls who were referred for treatment in a specialist eating disorder service. Presence of current, but not early childhood, ASD traits was elevated in comparison with previously reported community samples. Current ASD traits were correlated with emotional disorders and with need for treatment augmentation (psychiatric inpatient or day patient admission), but this relationship was not significant after the contribution of depression had been controlled for. There was no difference in Morgan Russell Outcomes at discharge for those with high and low current ASD traits. Parent-reported ASD-related developmental difficulties were associated with attenuated change in self-reported cognitive symptoms of AN. This study highlights the need for further understanding of the aetiology, diagnostic significance and predictive utility for future relapse of elevated ASD traits in childhood eating disorders. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association., (Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association.) more...

As Chinese immigrants in the United Kingdom age, they experience an increasing need to access health and care services. It has, however, been reported that older Chinese immigrants have difficulties in accessing these services. This study explored the experiences of this population in using health and care services and the strategies that they adopted to address their difficulties. A grounded theory method with a two-staged research design was used. Stage 1 explored the participants' experiences of ageing and use of health and social care services through focus group interviews. Stage 2 investigated the strategies individuals used to support access to and use of services through individual interviews. Forty-four older Chinese people and 15 supporters participated in interviews during August 2011 and May 2013. These older Chinese immigrants were challenged in knowing about and in accessing services. Their difficulties were attributed to language barriers, lack of information and instrumental support, and emotional and cultural issues regarding use of health and care services. Their supporters facilitated access to services and acted as a bridge between the service and the user; therefore, they were given the title 'Bridge People'. Bridge People have different backgrounds: family and friends, public sector workers and staff from community-based Chinese organisations. The defining attributes of these supporters were: bilinguality, bicultural, multifunctionality and accessibility. There is no charge for this support; and the relationship between the Bridge Person and recipient involves trust and influence over decisions regarding use of health and care services. Bridge People should be recognised and identified by health, social care and housing services to promote engagement and use of services by older immigrant Chinese people., (© 2016 John Wiley & Sons Ltd.) more...

This paper recounts the process of undertaking a randomised controlled trial which was designed to examine the effectiveness of an intervention for socially isolated older people aged 75 years and over. It describes the reasons for early cessation of the study and raises the implications of this outcome for policy, practice and research. The intervention under investigation was designed to alleviate loneliness and foster companionship. It involves participants being linked with a small group of others through a teleconferencing system with each group being facilitated by trained volunteers. There was a requirement to recruit and train a minimum of 30 and a maximum of 60 volunteers over 1 year to facilitate 20 friendship groups to meet the number of older people required to be recruited to the study. Problems with recruiting and retaining the volunteer workforce by the voluntary sector organisation, who were commissioned to do so, led to the study closing even though older people were recruited in sufficient numbers. The paper draws upon analysis of various data sources from the study to identify the potential reasons. The discussion raises considerations regarding the extent of infrastructure required to deliver community services to vulnerable user groups at scale, identifies some of the issues that need to be addressed if such volunteer-initiated services are to be successful and informs future research programmes in this area., (© 2015 John Wiley & Sons Ltd.) more...