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Climate change and human-modified landscapes have led to an increase in global flood and drought risks, while biodiversity has declined. The concept of using nature-based solutions (NbS) to improve the water retention capacity at the landscape scale, also known as ‘sponge functioning of catchments,’ has been recognised to help reduce and delay peak flows and stimulate infiltration to the groundwater, thus reducing flood and drought risks. Although various effects of NbS have been demonstrated, there is limited evaluation of the combined multiple benefits for flood risk reduction, drought risk reduction, and biodiversity. To address this gap, we analysed various online databases on NbS and additional literature on the evaluated combined effects of NbS. We found that the quantitative evaluation of NbS is fragmented and not standard practice in many projects. Although many successfully implemented NbS have been reported in different environments globally, most cases lack evidence for their response to the combined impacts of floods, droughts, and biodiversity. Therefore, we propose four components to facilitate planning, design, implementation, and monitoring of NbS that improve sponge functioning for floods and droughts. First, we suggest increased understanding of how NbS affects the hydrological processes of both flood and drought events along the full range of potential conditions. Second, we recommend evaluating the effect of potential NbS measures at a landscape scale. Third, we propose that integrated modelling and upscaling techniques should be improved to quantify the impacts of NbS. Finally, we suggest using a consistent and socially relevant set of indicators to evaluate the NbS and communicate this with stakeholders. In conclusion, our analysis demonstrates a need for more comprehensive and standardised evaluation of NbS, particularly in relation to their combined impacts on floods, droughts, and biodiversity.

1. Riparian zones are vital areas of interaction between land and rivers and are often degraded by several pressures such as urbanisation, intensive agriculture and river engineering works. 2. This policy brief provides five key policy messages and recommendations to be considered by policy-makers, scientists, managers, and stakeholders to enhance riparian zone management. 3. Adopting an integrated socio-economic and environmentally dynamic view will ensure the sustainable management of riparian zones. 4. In light of climate change, it is critically important to conserve and/or restore the ecological integrity of riparian zones. 5. European Union Directives and national-scale legislation and regulations need updating to ensure coordinated implementation of riparian zone-related policies. 6. Stakeholder knowledge exchange, policy co-creation and adaptive management are key to enhancing riparian zone functions.

Musicians need to deal with a range of challenges during their performance career and in response to these have reported a number of conditions that impact on their performance. Although social support from peers and teachers has been identified as part of the process of dealing with these challenges, little is understood about musicians' coping methods, beliefs and their attitudes toward support. Therefore, this study aimed to explore (a) performers' previous experiences of psychological challenges, (b) the types of support they used and, (c) how this might inform future support programs in learning environments. Fifteen interviews were conducted with pre-elite (n = 5) transitioning elite (n = 3) and established elite performers (n = 7) in order to elicit data on psychological challenges, coping, beliefs and preferences for support. Inductive content analysis suggested that elite performers in this sample reported positive health habits, philosophical views of performance, health and life, positive anxiety reappraisal, and use of various psychological strategies, albeit without being explicitly aware of it. The need for various professional skills (e.g., communication, business, self-management, and organizational skills) was emphasized by all participants. Transition into conservatoire was marked by severe psychological challenges, disorders and trauma. Primary sources of support included friends, family and self-help literature. Professional help was predominantly sought for physical problems. The impact of teachers was paramount, yet securing good teachers was considered a matter of “luck.” The most negative aspects recounted included abusive teachers, unsupportive environments, social comparison, competition, and disillusionment after entering the profession. Participants believed that talent could be developed and also valued wellbeing in relation to performance. Positive effects of late specialization on social development and professional skills were also mentioned. Implications and suggestions are discussed.

Abstract Background Autism comprises a spectrum of behavioral and cognitive disturbances of childhood development and is known to be highly heritable. Although numerous approaches have been used to identify genes implicated in the development of autism, less than 10% of autism cases have been attributed to single gene disorders. Methods We describe the use of high-resolution genome-wide tilepath microarrays and comparative genomic hybridization to identify copy number variants within 119 probands from multiplex autism families. We next carried out DNA methylation analysis by bisulfite sequencing in a proband and his family, expanding this analysis to methylation analysis of peripheral blood and temporal cortex DNA of autism cases and matched controls from independent datasets. We also assessed oxytocin receptor (OXTR) gene expression within the temporal cortex tissue by quantitative real-time polymerase chain reaction (PCR). Results Our analysis revealed a genomic deletion containing the oxytocin receptor gene, OXTR (MIM accession no.: 167055), previously implicated in autism, was present in an autism proband and his mother who exhibits symptoms of obsessive-compulsive disorder. The proband's affected sibling did not harbor this deletion but instead may exhibit epigenetic misregulation of this gene through aberrant gene silencing by DNA methylation. Further DNA methylation analysis of the CpG island known to regulate OXTR expression identified several CpG dinucleotides that show independent statistically significant increases in the DNA methylation status in the peripheral blood cells and temporal cortex in independent datasets of individuals with autism as compared to control samples. Associated with the increase in methylation of these CpG dinucleotides is our finding that OXTR mRNA showed decreased expression in the temporal cortex tissue of autism cases matched for age and sex compared to controls. Conclusion Together, these data provide further evidence for the role of OXTR and the oxytocin signaling pathway in the etiology of autism and, for the first time, implicate the epigenetic regulation of OXTR in the development of the disorder. See the related commentary by Gurrieri and Neri: http://www.biomedcentral.com/1741-7015/7/63

Abstract Background The major histocompatibility complex (MHC) is essential for human immunity and is highly associated with common diseases, including cancer. While the genetics of the MHC has been studied intensively for many decades, very little is known about the epigenetics of this most polymorphic and disease-associated region of the genome. Methods To facilitate comprehensive epigenetic analyses of this region, we have generated a genomic tiling array of 2 Kb resolution covering the entire 4 Mb MHC region. The array has been designed to be compatible with chromatin immunoprecipitation (ChIP), methylated DNA immunoprecipitation (MeDIP), array comparative genomic hybridization (aCGH) and expression profiling, including of non-coding RNAs. The array comprises 7832 features, consisting of two replicates of both forward and reverse strands of MHC amplicons and appropriate controls. Results Using MeDIP, we demonstrate the application of the MHC array for DNA methylation profiling and the identification of tissue-specific differentially methylated regions (tDMRs). Based on the analysis of two tissues and two cell types, we identified 90 tDMRs within the MHC and describe their characterisation. Conclusion A tiling array covering the MHC region was developed and validated. Its successful application for DNA methylation profiling indicates that this array represents a useful tool for molecular analyses of the MHC in the context of medical genomics.

Abstract Background The male-specific region of the mouse Y chromosome long arm (MSYq) contains three known highly multi-copy X-Y homologous gene families, Ssty1/2, Sly and Asty. Deletions on MSYq lead to teratozoospermia and subfertility or infertility, with a sex ratio skew in the offspring of subfertile MSYqdel males Results We report the highly unusual genomic structure of a novel MSYq locus, Orly, and a diverse set of spermatid-specific transcripts arising from copies of this locus. Orly is composed of partial copies of Ssty1, Asty and Sly arranged in sequence. The Ssty1- and Sly-derived segments are in antisense orientation relative to each other, leading to bi-directional transcription of Orly. Genome search and phylogenetic tree analysis is used to determine the order of events in mouse Yq evolution. We find that Orly is the most recent gene to arise on Yq, and that subsequently there was massive expansion in copy number of all Yq-linked genes. Conclusion Orly has an unprecedented chimeric structure, and generates both "forward" (Orly) and "reverse" (Orlyos) transcripts arising from the promoters at each end of the locus. The region of overlap of known Orly and Orlyos transcripts is homologous to Sly intron 2. We propose that Orly may be involved in an intragenomic conflict between mouse X and Y chromosomes, and that this process underlies the massive expansion in copy number of the genes on MSYq and their X homologues.

Abstract Objective The purpose was to determine what strategies have been evaluated to disseminate cancer control interventions that promote the uptake of adult healthy diet? Methods A systematic review was conducted. Studies were identified by searching MEDLINE, PREMEDLINE, Cancer LIT, EMBASE/Excerpta Medica, PsycINFO, CINAHL, the Cochrane Database of Systematic Reviews, and reference lists and by contacting technical experts. English-language primary studies were selected if they evaluated the dissemination of healthy diet interventions in individuals, healthcare providers, or institutions. Studies of children or adolescents only were excluded. Results One hundred one articles were retrieved for full text screening. Nine reports of seven distinct studies were included; four were randomized trials, one was a cohort design and three were descriptive studies. Six studies were rated as methodologically weak, and one was rated as moderate. Studies were not meta-analyzed because of heterogeneity, low methodological quality, and incomplete data reporting. No beneficial dissemination strategies were found except one that looks promising, the use of peer educators in the worksite, which led to a short-term increase in fruit and vegetable intake. Conclusions and Implications Overall, the quality of the evidence is not strong and is primarily descriptive rather than evaluative. No clear conclusions can be drawn from these data. Controlled studies are needed to evaluate dissemination strategies, and to compare dissemination and diffusion strategies with different messages and different target audiences.

The rising global incidence of uterine cancer is linked to the escalating prevalence of obesity. Obesity results in alterations in adipocytokines and IGFs, driving cancer progression via inflammation, increased cell proliferation, and apoptosis inhibition, although the precise mechanisms are still unclear. This study examined a set of six markers, namely, adiponectin, leptin, IL6, TNFα, IGF1, and IGF2 and compared them between fifty age-matched endometrial cancer patients (study group) and non-cancer patients with benign gynaecological conditions (control group). We also assessed the relationship of these markers with obesity and explored the correlation between these markers and various tumour characteristics. In the cancer population, these markers were also assessed 24 h and 6 months post-surgery. Remarkably, low adiponectin levels were associated with a 35.8% increase in endometrial cancer risk. Interestingly, compared to control subjects where IGF levels decreased after menopause, post-menopausal women in the study group showed elevated IGF1 and IGF2 levels, suggesting a potential influence of endometrial cancer on the IGF system, particularly after menopause. Lastly, it is noteworthy that a discernible inverse relationship trend was observed in the levels of adipocytokines and IGFs 6 months post-surgery. This indicates that treatment for endometrial cancer may have a differential impact on adipocytokines and IGFs, potentially holding clinical significance that merits further investigation.

The first step in the evaluation of the short child is to decide whether growth parameters in the context of the history are abnormal or a variant of normal. If growth is considered abnormal, system and hormonal tests are likely to be required, followed by more directed testing, such as skeletal survey and/or genetic screening with karyotype or microarray. In a small percentage of short children in whom a diagnosis has not been reached, this will need to be followed by detailed genetic analysis; currently, exome sequencing using targeted panels relevant to the phenotype is the commonly used test. Clinical scenarios are presented that illustrate how such genetic testing can be used to establish a molecular diagnosis, and how that diagnosis contributes to the management of the short child. New genetic causes for short stature are being recognized on a frequent basis, while the clinical spectrum for known genes is being extended. We recommend that an international repository for short stature conditions is established for new findings to aid dissemination of knowledge, but also to help in the definition of the clinical spectrum both for new and established conditions., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Gene expression (GE) data have shown promise as a novel tool to aid in the diagnosis of childhood growth hormone deficiency (GHD) when comparing GHD children to normal children. The aim of this study was to assess the utility of GE data in the diagnosis of GHD in childhood and adolescence using non-GHD short stature children as a control group., Methods: GE data was obtained from patients undergoing growth hormone stimulation testing. Data were taken for the 271 genes whose expression was utilized in our previous study. The synthetic minority oversampling technique was used to balance the dataset and a random forest algorithm applied to predict GHD status., Results: 24 patients were recruited to the study and eight subsequently diagnosed with GHD. There were no significant differences in gender, age, auxology (height SDS, weight SDS, BMI SDS) or biochemistry (IGF-I SDS, IGFBP-3 SDS) between the GHD and non-GHD subjects. A random forest algorithm gave an AUC of 0.97 (95% CI 0.93 - 1.0) for the diagnosis of GHD., Conclusion: This study demonstrates highly accurate diagnosis of childhood GHD using a combination of GE data and random forest analysis., Competing Interests: PM has received honoraria from NovoNordisk. AS, PM, and PC have received speaker honoraria from Merck KGaA and a research grant from NovoNordisk. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Garner, Wangsaputra, Whatmore, Clayton, Stevens and Murray.)

Chronic inflammation has been closely linked to the development and progression of various cancers. The epithelial-mesenchymal transition (EMT) is a process involving the acquisition of mesenchymal features by carcinoma cells and is an important link between inflammation and cancer development. Inflammatory mediators in the tumour micro-environment, such as cytokines and chemokines, can promote EMT changes in cancer cells. The aim of this systematic review is to analyse the effect of cytokines on EMT in gynaecological cancers and discuss their possible therapeutic implications. A search of the databases CINAHL, Cochrane, Embase, Medline, PubMed, TRIP, and Web of Science was performed using the keywords: "cytokines" AND "epithelial mesenchymal transition OR transformation" AND "gynaecological cancer". Seventy-one articles reported that various cytokines, such as TGF-β, TNF-α, IL-6, etc., promoted EMT changes in ovarian, cervical, and endometrial cancers. The EMT changes included from epithelial to mesenchymal morphological change, downregulation of the epithelial markers E-cadherin/β-catenin, upregulation of the mesenchymal markers N-cadherin/vimentin/fibronectin, and upregulation of the EMT-transformation factors (EMT-TF) SNAI1/SNAI2/TWIST / ZEB . Cytokine-induced EMT can lead to gynaecological cancer development and metastasis and hence novel therapies targeting the cytokines or their EMT signalling pathways could possibly prevent cancer progression, reduce cancer recurrence, and prevent drug-resistance.

The objective of the study was to document the effect of adipocytokines on endometrial cancer progression. A search of the databases CINAHL, Medline, PubMed, Cochrane, Web of Science, Embase and Google Scholar was performed for English language articles from January 2000 to December 2020 using the keywords: (Endometrial cancer) AND (progression OR metastasis) AND (adipocytokine OR adiponectin OR leptin OR visfatin OR IL-6 OR TNF-α OR adipokine OR cytokine). Forty-nine studies on adipocytokines have been included in this review. Adiponectin has been linked with anti-proliferative and anti-metastatic effects on endometrial cancer cells and is associated with a better prognosis. Leptin, visfatin and resistin are linked to the stimulation of endometrial cancer growth, proliferation, invasion and metastasis and are associated with worse prognosis or with a higher grade/stage of endometrial cancer. IL-6, Il-11, IL-31, IL-33, TNF-α, TGF-β1, SDF-1 and CXCR are involved in endometrial cancer cell growth and metastasis or involved in epithelial mesenchymal transformation (EMT) or associated with advanced disease. Adipocytokines have been found to directly impact endometrial cancer cell proliferation, invasion and migration. These molecules and their signalling pathways may be used to determine prognosis and course of the disease and may also be exploited as potential targets for cancer treatment and prevention of progression., (© 2021. The Author(s).)

Objective: To assess the impact of the temporary cessation of orthodontic services on patients undergoing treatment during the COVID-19 pandemic., Design: Two-phase multicentre service evaluation., Setting: Secondary care orthodontic departments in the South West of England., Materials and Methods: Phase 1 - Patient-Reported Experience Measure questionnaire (PREM). The questionnaire was distributed to patients who had undergone orthodontic treatment during the COVID-19 pandemic once services had resumed. Phase 2 - assessment of treatment outcomes, specifically with the Peer Assessment Rating (PAR) Index. A total of 280 PAR scores were obtained from a cohort of patients treated before and during the pandemic., Results: A total of 711 PREM questionnaires were completed. Participants generally felt relaxed when visiting secondary care settings, orthodontic departments and whilst wearing orthodontic appliances during the pandemic. Nearly 40% of participants were concerned that the pandemic would impact on their treatment, particularly treatment length. Treatment outcomes revealed that patients treated before and during the pandemic experienced percentage PAR score reductions of 83.9% and 80.6%, respectively. Patients receiving treatment during the pandemic experienced longer treatment durations of 126 days., Conclusion: During the pandemic, low levels of anxiety were reported with respect to receiving orthodontic treatment in secondary care settings. Irrespective of the pandemic, a high standard of orthodontic treatment was provided. However, patient concerns regarding treatment length were justified.

Studies reported to date suggest that men with COVID-19 have more severe disease and worse outcomes when compared with women. The explanation for this finding is not entirely clear. The goal of this study was to compare clinical characteristics, inflammatory biomarkers and clinical outcome between men and women. This retrospective study included patients with COVID-19 admitted to 10 Virginia hospitals from January 1, 2020, to June 15, 2020. Demographic data, comorbidities, and inflammatory markers, including C reactive protein (CRP), D-dimer, ferritin, and the neutrophil:lymphocyte ratio, as well as patient outcomes, were compared between men and women. During the study period, 701 patients with PCR-confirmed COVID-19 infection were admitted. The patient's mean age was 61±17 years. There were 370 men (52.8%). There was no difference in age, racial distribution, and comorbidities in the male patients compared with the female patients. However, both the baseline and peak levels of CRP and ferritin were significantly higher in men as compared with women. While the baseline D-dimer was similar between the sexes, men had a significantly higher maximal D-dimer. Men had evidence of greater disease severity, with a significantly greater admission to the intensive care unit and borderline higher hospital mortality. Our study supports the observation that COVID-19 causes more severe disease in men. The greater disease severity in men was not due to the effect of age or comorbidities; however, in keeping with experimental studies, men had evidence of a heightened inflammatory response, likely contributing to disease severity., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Children with short stature of undefined aetiology (SS-UA) may have undiagnosed genetic conditions., Purpose: To identify mutations causing short stature (SS) and genes related to SS, using candidate gene sequence data from the European EPIGROW study., Methods: First, we selected exonic single nucleotide polymorphisms (SNPs), in cases and not controls, with minor allele frequency (MAF) < 2%, whose carriage fitted the mode of inheritance. Known mutations were identified using Ensembl and gene-specific databases. Variants were classified as pathogenic, likely pathogenic, or variant of uncertain significance using criteria from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. If predicted by ≥ 5/10 algorithms (eg, Polyphen2) to be deleterious, this was considered supporting evidence of pathogenicity. Second, gene-based burden testing determined the difference in SNP frequencies between cases and controls across all and then rare SNPs. For genotype/phenotype relationships, we used PLINK, based on haplotype, MAF > 2%, genotype present in > 75%, and Hardy Weinberg equilibrium P  > 10 -4 ., Results: First, a diagnostic yield of 10% (27/263) was generated by 2 pathogenic (nonsense in ACAN ) and a further 25 likely pathogenic mutations, including previously known missense mutations in FANCB , IGFIR , MMP13 , NPR2 , OBSL1 , and PTPN11 . Second, genes related to SS: all methods identified PEX2 . Another 7 genes ( BUB1B, FANCM, CUL7, FANCA, PTCH1, TEAD3, BCAS3 ) were identified by both gene-based approaches and 6 ( A2M, EFEMP1, PRKCH, SOS2, RNF135, ZBTB38 ) were identified by gene-based testing for all SNPs and PLINK., Conclusions: Such panels improve diagnosis in SS-UA, extending known disease phenotypes. Fourteen genes related to SS included some known to cause growth disorders as well as novel targets., (© Endocrine Society 2020.)

Objective: To investigate the association between circulating levels of adipocytokines (adiponectin, leptin, tumour necrosis factor alpha (TNFα), interleukin 6 (IL-6)) and growth factors (insulin-like growth factor I (IGF-I) and II (IGF-II)), and the risk of endometrial cancer., Methods: Cochrane, CINAHL, Embase, Medline and Web of Science were searched for English-language manuscripts published between January 2000 and August 2018 using the following string of words: cancer and endometrial and (obesity or BMI) and (adiponectin or TNF* or IGF-I or IGF-II or IL-6 or leptin)., Results: Twenty articles were included in this meta-analysis, which corresponded to 18 studies involving 2921 endometrial carcinoma cases and 5302 controls. Fourteen articles reported circulating levels for adiponectin, seven for leptin, three for TNFα, three for IL-6 and one for IGF-I. No article reported values for IGF-II. Patients with circulating adiponectin levels in the highest tertile had decreased endometrial cancer risk compared to women with levels in the lowest tertile, (summary of odds ratio (SOR) 0.51, 95% confidence interval (CI): 0.38-0.69, p < 0.00001). Women with circulating leptin concentrations in the highest tertile had increased endometrial cancer risk compared to women with concentrations in the lowest tertile (SOR 2.19, 95% CI: 1.45-3.30, p = 0.0002). There was no difference in cancer risk between participants with the highest TNFα and IL-6 levels compared to the lowest levels (SOR 1.27, 95% CI: 0.88-1.83, p = 0.20 and SOR 1.20, 95% CI: 0.89-1.63, p = 0.23, respectively)., Conclusions: Endometrial cancer risk is inversely affected by adiponectin and leptin levels. There appears to be no relationship between TNFα and IL-6 and the overall risk of endometrial cancer., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We present the case of a 33-year-old woman with no significant past medical history who was admitted to an outside hospital for the abrupt onset of fevers, malaise and a diffuse mucocutaneous rash. Her constellation of symptoms and presentation were most consistent with a diagnosis of Stevens-Johnson syndrome/toxic epidermal necrolysis overlap syndrome secondary to ibuprofen exposure. Her rash continued to worsen and she was transferred to our medical intensive care unit (ICU), where broad-spectrum antibiotics were discontinued and she was treated with supportive care as well as 'low-dose' intravenous hydrocortisone, ascorbic acid (vitamin C) and thiamine (HAT therapy). After starting this therapy, the patient demonstrated a dramatic response with rapid improvement of her cutaneous and mucosal lesions. She was tolerating a diet provided by the hospital on day 4 and was discharged from the ICU a few days later., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

It is important that dental extractions under general anaesthesia (GA) are planned appropriately to avoid a repeat GA in the future. Current guidelines recommend the input of an orthodontist when the treatment plan involves a permanent tooth extraction but the number of children undergoing GA extractions makes this challenging. A model has been developed where the records of children planned for GA extraction of permanent teeth are triaged, via secure email, by an orthodontist. The orthodontist identifies patients where modification of the extraction pattern could be beneficial to longer-term oral health. For some patients this is possible from review of the records alone, but the triage also identifies those patients with more complex occlusal problems who require a face to face orthodontic assessment. This service review found that 22% of the patients triaged had their treatment plan modified by the orthodontist. For 76% of the patients, a review of their records was sufficient before finalising the plan and only 24% needed a further face to face orthodontic assessment. This model has been successful in reducing the burden of an additional orthodontic assessment for most patients while providing personalised care.

We report the case of a 45-year-old Caucasian woman with a history of psoriasis, admitted to our Medical intensive care unit following the acute onset of diffuse rash and progressive dyspnoea and hypoxaemia requiring escalating respiratory support (continuous positive airway pressure of 10 cm H 2 O). Her chest X-ray was consistent with findings of non-cardiogenic pulmonary oedema. Echocardiogram was normal. Dermatology considered her skin lesions to be consistent with psoriasis vulgaris with pustular flare. In the absence of an identifiable cause for her respiratory failure, she was diagnosed with acute respiratory distress syndrome due to her psoriatic flare. Treatment with cyclosporine was initiated together with low-dose systemic corticosteroids, intravenous vitamin C and thiamine. The patient made a dramatic recovery being weaned to nasal cannulae within 24 hours after the initiation of this treatment protocol and was discharged home a few days later., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Experimental studies often find that inbreeding depression is more severe in harsh environments, but the few studies of in situ wild populations available to date rarely find strong support for this effect. We investigated evidence for inbreeding depression by environment interactions in nine traits in the individually monitored Soay sheep population of St Kilda, using genomic inbreeding coefficients based on 37 037 single-nucleotide polymorphism loci, and population density as an axis of environmental variation. All traits showed variation with population density and all traits showed some evidence for depression because of either an individual's own inbreeding or maternal inbreeding. However, only six traits showed evidence for an interaction in the expected direction, and only two interactions were statistically significant. We identify three possible reasons why wild population studies may generally fail to find strong support for interactions between inbreeding depression and environmental variation compared with experimental studies. First, for species with biparental inbreeding only, the amount of observed inbreeding in natural populations is generally low compared with that used in experimental studies. Second, it is possible that experimental studies sometimes actually impose higher levels of stress than organisms experience in the wild. Third, some purging of the deleterious recessive alleles that underpin interaction effects may occur in the wild.

The experience-based design (ebd) approach is a method of measuring patient experience, which deliberately draws out subjective, emotional and personal feelings of the patients using a service. We describe how the experience-based design approach has been used to measure the experiences of teenage patients at orthodontic consultation appointments in a district general hospital. This has allowed us to identify the points in the patient's journey where they experience most anxiety and nervousness and to target service improvements in these areas. We found the ebd approach effective in measuring patient experience in a teenage patient population. We demonstrate how the service improvements implemented have reduced negative feelings during new patient consultations., (© 2014 British Orthodontic Society.)

Isolated subclavian artery dissection is a very rare condition in the absence of trauma or procedures. A 36-year-old woman with a history significant for uncontrolled hypertension presented with a sudden onset of left shoulder and neck pain that woke the patient from sleep. A CT angiogram of the chest revealed a left subclavian artery dissection. The patient was admitted to the hospital for blood pressure control.

We present a 24-year-old man with a history significant for cystic fibrosis and insulin-dependent diabetes mellitus who developed anaemia in the setting of piperacillin-induced immune haemolysis. This case provided a diagnostic challenge, a rare association of piperacillin-induced haemolysis in those suffering from cystic fibrosis.

Introduction: This paper explores the impact of recruiting patients to a randomised controlled trial (RCT) at recruiting centres. This large multicentre RCT examining the efficacy of chewing gum compared to ibuprofen in the relief of orthodontic pain was carried out across nine recruiting centres., Method: The work diaries of clinicians and supporting staff at recruiting centres were analysed over a four-month period from September to December 2011. This quantified the amount of clinical and non-clinical time spent on research duties., Results: Over this time period 98 patients were recruited across seven trial sites. On average, patient recruitment had a direct clinical impact of 19 minutes per patient recruited. The time commitment on trial administration outside the clinical sessions was much higher, averaging at 110 minutes per patient recruited, giving the overall time spent on the trial 129 minutes per patient., Conclusions: This information will be valuable to lead researchers when calculating the full economic cost of a proposed clinical trial and therefore when applying for grant funding. It may also be valuable to clinicians and their managers when considering becoming a principle investigator (PI) in a RCT. Although the impact on clinical time was 19 minutes per patient recruited, there is a considerably higher (almost six times greater) time commitment in administration around the recruitment of patients.

A 26-year-old woman presented to hospital with acute chest pain, hypertension, tachycardia and an elevated serum creatinine. She developed respiratory distress requiring endotracheal intubation and mechanical ventilation. She progressed to multiorgan failure due to decompensated congestive heart failure. Echocardiography demonstrated global hypokinesis and an ejection fraction of <10%. Her cardiac function improved with fluid resuscitation and β blockade, and she was eventually discharged home. She was readmitted a few days later with pancreatitis after presenting with nausea, abdominal pain and hypertension. During hospitalisation she had paroxysms of headache, nausea and diaphoresis associated with hypertension and tachycardia. A CT scan of her abdomen revealed an adrenal mass and serum metanephrine studies confirmed the diagnosis of pheochromocytoma. After fluid resuscitation and sympathetic blockade her ejection fraction improved to 55%. The patient underwent an uneventful adrenalectomy and made a complete recovery.

Anion gap metabolic acidosis is commonly caused by lactic acidosis, ketoacidosis, and ingestion of methanol, salicylates, ethylene glycol or accumulation of organic/inorganic acids. However, rare causes of metabolic acidosis from enzyme defects, such as disturbances in the γ-glutamyl cycle, are being reported in higher frequencies in the adult population. Such disturbances cause an accumulation of 5-oxoproline and ultimately an anion gap metabolic acidosis. These disturbances are often associated with acetaminophen in the setting of certain risk factors such as sepsis, malnutrition, liver disease, female gender, pregnancy or renal failure.

Pituitary abscess is a rare condition. In the setting of multiple surgical interventions, the risk of its development increases. A 49-year-old man presented with episodes of altered mental status. He had two surgeries for a recurrent suprasellar arachnoid cyst. The second surgery was complicated by a persistent cerebrospinal fluid (CSF) leak that required two repairs following which he developed panhypopituitarism and central diabetes insipidus. Twelve months after his last surgery he was diagnosed with aseptic meningitis. This was followed by recurrent hospitalisations for severe hypernatremia blamed on poor medication compliance. He was subsequently hospitalised for the evaluation of a febrile illness. Brain MRI showed ventriculitis and enhancement of the sella. Exploratory surgery revealed a purulent collection in the sella and a mucosal graft which had been used to repair the CSF leak. After drainage of pus and replacement of the graft he recovered completely but requiring life-long hormonal replacement.

We present a 47-year-old Caucasian fire fighter who developed multisystem organ failure in the setting of a positive antineutrophil cytoplasmic autoantibody (myeloperoxidase) as well as confirmed Rocky Mountain spotted fever by skin biopsy PCR. This case provided a diagnostic challenge, a rare association of a Rickettsia infection and autoimmune vasculitis as well as a unique management approach.

Our understanding of the pathogenesis of Paget's disease of the vulva and the breast remains limited. Current evidence supports the fact that angiogenesis plays an important role in the pathogenesis of several diseases. Therefore, we sought to define its role, as correlated with microvessel density, in Paget's disease of the vulva and the breast. Microvessels were analysed using anti-von Willebrand factor antibody in 105 cases of Paget's disease of the vulva and the breast comprising 71 cases of Paget's disease of the vulva, including 8 cases with invasive disease, and 34 cases of Paget's disease of the breast. The latter included 12 cases with DCIS, 5 cases with both DCIS and invasive carcinoma, and 6 with carcinoma alone. Eleven cases had no underlying tumour identified. Increased microvessel density was demonstrated in Paget's disease of the breast with DCIS and with carcinoma alone compared to Paget's disease of the breast alone, P < 0.08 and P < 0.013, respectively. There were no significant differences in microvessel density in the vulval cases. Neovascularisation is an important process in the development of Paget's disease of the breast. Other biological and molecular processes are more involved in the pathogenesis of Paget's disease of the vulva.

Background: Hypertension is an increasing health issue in sub-Saharan Africa where malaria remains common in pregnancy. We established a birth cohort in Nigeria to evaluate the early impact of maternal malaria on newborn blood pressure (BP)., Methods: Anthropometric measurements, BP, blood films for malaria parasites and haematocrit were obtained in 436 mother-baby pairs. Women were grouped to distinguish between the timing of malaria parasitaemia as 'No Malaria', 'Malaria during pregnancy only' or 'Malaria at delivery', and parasite density as low (<1000 parasites/µl of blood) and high (≥ 1000/µl)., Results: Prevalence of maternal malaria parasitaemia was 48%, associated with younger maternal age (p<0.001), being primigravid (p = 0.022), lower haematocrit (p = 0.028). High parasite density through pregnancy had the largest effect on mean birth indices so that weight, length, head and mid-upper arm circumferences were smaller by 300 g, 1.1 cm, 0.7 cm and 0.4 cm respectively compared with 'No malaria' (all p ≤ 0.005). In babies of mothers who had 'malaria at delivery', their SBPs adjusted for other confounders were lower respectively by 4.3 and 5.7 mmHg/kg compared with 'malaria during pregnancy only' or 'none'. In contrast the mean newborn systolic (SBP) and diastolic BPs (DBP) adjusted for birth weight were higher by 1.7 and 1.4 mmHg/kg respectively in babies whose mothers had high compared with low parasitaemia., Conclusions: As expected, prenatal malarial exposure had a significant impact on fetal growth rates. Malaria at delivery was associated with the lowest newborn BPs while malaria through pregnancy, which may attenuate growth of the vascular network, generated higher newborn BPs adjusted for size. These neonatal findings have potential implications for cardiovascular health in sub-Saharan Africa.

Objectives: The growing prevalence of endometrial cancer has made it necessary to characterize its molecular and clinical properties and to develop new strategies in treating this disease. A number of molecular and genetic events have been observed in endometrial cancers, which have enabled us to have a better understanding of the biology and development of the disease. For example, PTEN/AKT pathway and its downstream targets and the mTOR (mammalian target of rapamycin) pathway have been shown to play an important role in endometrial cancer pathogenesis. Novel therapies, such as drugs that target cellular pathways, for example, mTOR inhibitor deforolimus, an analog of rapamycin, have been developed and used in clinical trials to treat women with progressive endometrial cancer. This review outlines the data on the molecular and translational aspects of endometrial cancers and the risk factors., Methods: A literature search was performed using PubMed and OvidSP entering the words endometrial cancer and molecular characteristics and endometrial cancer and risk factors., Results: An evidence-based summary of the data on the molecular and translational aspects of endometrial cancers and risk factors was obtained., Conclusions: Clear understanding of the cellular and molecular pathways and risk factors involved in endometrial tumorigenesis may allow us to identify women at risk of developing endometrial cancer and possibly intervene to prevent cancer development.

Aims: Loss of retinoblastoma protein expression and overexpression of cyclin D1 have been implicated in the development and progression of some cancers. Paget's disease of the vulva (PDV) and Paget's disease of the breast (PDB) are uncommon conditions and the pathogenesis of these diseases is still unclear. The aim was to examine the expression of the retinoblastoma and cyclin D1 proteins in PDV and PDB and to correlate any differences between PDV and PDB, and in the presence or absence of an underlying carcinoma., Methods and Results: Seventy-two archival cases of PDV including 10 with invasive disease and 36 cases of PDB were evaluated immunohistochemically for the expression of cyclin D1 and retinoblastoma protein. Forty-four percent (32/72) of cases of PDV showed loss of expression of the retinoblastoma protein, compared with 67% (24/36) of PDB cases. Fifty-nine percent (41/69) of PDV overexpressed cyclin D1. In PDB, 8% (3/34) overexpressed cyclin D1. There were no significant differences in the expression of retinoblastoma and cyclin D1 in PDV cases with or without underlying invasive disease. There were significant differences between the expression of retinoblastoma (P = 0.03) and cyclin D1 (P < 0.001) in PDV compared with PDB., Conclusions: The differences in the expression of cyclin D1 and retinoblastoma may indicate the differences in the pathogenesis of PDV and PDB.

Objective: To determine whether early routine grommet insertion in children with cleft palate has a beneficial effect on hearing and speech and language development compared with conservative management., Design: Systematic review of randomized controlled trials, controlled clinical trials, case series, and prospective and historical cohort studies., Main Outcome Measures: The main outcome measure was the effect of early routine grommet placement on the degree of conductive hearing loss. Secondary outcome measures included differences in hearing level, possible side effects, speech and language development, and quality of life., Results: We identified 368 citations for review. From a review of the titles, 34 potentially relevant papers were selected. Of these, 18 studies met our inclusion criteria, including eight case series, six historical cohort studies, three prospective cohort studies, and one randomized trial. Most studies were either small or of poor quality or both. The results of the studies were contradictory, with some studies suggesting early placement of grommets was beneficial and others reporting there was no benefit., Conclusions: There is currently insufficient evidence on which to base the clinical practice of early routine grommet placement in children with cleft palate.

The growth and metastasis of many cancers is due in part to loss of cell-cell adhesion. E-cadherin, plakoglobin and beta-catenin are important in cell adhesion. Our aim was to examine the presence of these molecules in Paget's disease of the vulva and Paget's disease of the breast, and to correlate any differences in their expression with the presence of invasive disease or an underlying carcinoma. Sixty-three archival cases of Paget's disease of the vulva, including eight associated with invasive disease, and 23 archival cases of Paget's disease of breast, which included 10 cases with ductal carcinoma in situ alone, four cases with both ductal carcinoma in situ and invasive carcinoma, and five cases with underlying invasive carcinoma alone, were analysed immunohistochemically for expression of E-cadherin, plakoglobin and beta-catenin proteins. The respective mRNAs were also detected by in situ hybridisation using digoxigenin-labelled cRNA probes. Seventy-six percent (41/54) of Paget's disease of vulva cases had >50% of Paget cells expressing the E-cadherin protein, compared with 28 % (2/7) of Paget's disease vulva with invasive disease. This result was significant, with a P-value of 0.039. Twenty-five percent (14/55) of the intraepidermal Paget's disease of the vulva cases had >50% of Paget cells expressing the plakoglobin protein, compared with 12% (1/8) of cases of Paget's disease of vulva with invasive disease, and for beta-catenin, 9% (5/55) of the non-invasive Paget's disease of the vulva had >50% of Paget cells expressing beta-catenin, compared with 12% (1/8) of Paget's disease of the vulva cases with invasive disease. Sixty-five percent (15/23) of the Paget's disease of the breast had >50% of Paget cells expressing E-cadherin, and for plakoglobin and beta-catenin it was 17% (4/23) and 28% (6/21), respectively. The results were not significant. The results suggest that reduced expression of E-cadherin may have a role to play in the pathogenesis of invasive Paget's disease of the vulva. Abnormal plakoglobin expression may be involved in the formation of some cases of Paget's of the vulva and the breast.

Introduction: Previous research has shown that ibuprofen provides effective relief from orthodontic pain. The aim of this study was to ascertain whether paracetamol (also known as acetaminophen) provided pain relief of equivalent or greater magnitude., Methods: A multicenter, noninferiority, randomized clinical trial was conducted in 3 orthodontic clinics; 159 patients aged 12 to 16 years attending for routine orthodontic treatment were randomly allocated to receive either 400 mg of oral ibuprofen or 1 g of oral paracetamol an hour before and again 6 hours after separator placement. Pain scores were recorded on 7 visual analog scales (10 cm) over a week. The margin of equivalence was defined as 10 mm., Results: Mean orthodontic pain from 2 hours after separation to bedtime was 8.5 mm (90% CI: lower, 3.7; upper,13.2) higher in the paracetamol group. This confidence interval lies partly outside the margin of equivalence, suggesting that paracetamol is not equivalent, and excludes the value 0, suggesting that ibuprofen is superior. From day 1 onward, there was a trend for patients who had taken ibuprofen to experience less pain at most time intervals compared with the paracetamol group. Two doses of ibuprofen, taken on the day of separator placement, were insufficient to control orthodontic pain on day 1 after placement., Conclusions: A combination of preoperative and postoperative ibuprofen is more effective than paracetamol in the control of orthodontic pain.

Adrenal hypoplasia congenita (AHC) is a rare condition and causes primary adrenal insufficiency. X-linked (OMIM 300200) and autosomal recessive (OMIM 240200) forms are recognized. Recently, an association between Intrauterine growth restriction, Metaphyseal dysplasia, Adrenal hypoplasia congenita, and Genital abnormalities (IMAGe syndrome; OMIM 300290) has been described. We present the clinical features of two sisters with intrauterine growth restriction, AHC, and dysmorphic features. Interesting histopathologic findings of one sister are also presented. We suggest that IMAGe syndrome is the most plausible diagnosis and that autosomal recessive inheritance is likely. We analyzed genes that were postulated candidates for IMAGe syndrome (SF1, DAX-1, and STAR), and no mutations were found. Other cases of IMAGe syndrome are reviewed.

This is a case report of a child who experienced a possible adverse reaction to paracetamol, in a randomized clinical trial comparing paracetamol with ibuprofen for control of orthodontic pain. Through this case report we highlight the importance of formulating a protocol for management of adverse events when designing a randomized clinical trial.

Objective: To objectively define criteria for intracranial optic nerve (ON) size in ON hypoplasia (ONH) on magnetic resonance imaging (MRI) scans., Study Design: Intracranial ON sizes from MRI were compared between 46 children with ONH diagnosed by ophthalmoscopy (group 1, isolated ONH, 8 children; and group 2, ONH associated with abnormalities of the hypothalamic-pituitary axis and septum pellucidum, 38 children) and children with multiple pituitary hormone deficiency (group 3, multiple pituitary hormone deficiency, 14 children), isolated growth hormone deficiency (group 4, isolated growth hormone deficiency, 15 children), and idiopathic short stature (group 5, idiopathic short stature, 10 children). Intracranial ON size was determined by the cross-sectional area, calculated as [pi x (1/2) height x (1/2) width]., Results: Groups 1 and 2 had lower intracranial ON size than did groups 3, 4, and 5 (P < .001). No patients in groups 3 through 5 who had MRI after 12 months of age (when 95% adult size of ONs is attained) had ONs <2.9 mm 2 . Visual acuity correlated significantly with ON size (P < .01)., Conclusions: Magnetic resonance imaging of the ONs with cross-sectional area <2.9 mm 2 in a short child more than 12 months of age, with or without hypothalamic-pituitary axis abnormalities, confirms the clinical diagnosis of ONH.

Paget's disease of the vulva is an uncommon lesion, and gynaecologists and dermatologists generally have limited experience in its management. The British Society for the Study of Vulval Disease has established a register of cases, and we present a review of 76 cases registered to date. The majority of patients were treated by surgical excision and reconstruction, but non-surgical therapies are an option. Recent literature is reviewed to allow comparison.

Objective: To assess whether articulating casts in centric relation (CR) compared with intercuspal position (ICP) makes a difference to treatment planning., Design: Reliability analysis., Subjects: Ten orthodontists., Methods: Twenty case vignettes were examined on three occasions: twice with the casts in ICP and once in CR. A series of dichotomous decisions were made relating to the treatment need and treatment mechanics., Main Outcome Measures: The changes in treatment decisions were examined. Intra-examiner agreement between the two hand-held cast assessments (H1 v. H2) and between the first set of hand-held casts compared with the articulated casts (H1 v. A1) were evaluated using the kappa statistic. The differences between the kappa statistics for H1 v. H2 and H1 v. A1 were then tested with the Wilcoxon matched pairs signed rank sum test., Results: The only statistically significant change in the kappa score between H1 v. H2 and H1 v. A1 was for the extraction decision (P= 0.007). No other statistically significant differences were found for the other treatment decisions, although trends were identified for orthognathic surgery and anchorage support decisions., Conclusion: Routine articulation of study models for all orthodontic patients is not supported by the results of this study. Articulation of the study models did not affect the treatment planning decisions in a meaningful manner. Further work with selected samples is required to determine if articulation is helpful for specific malocclusions.

Orthodontic treatment carries with it the risks of tissue damage, treatment failure and an increased predisposition to dental disorders. The dentist must be aware of these risks in order to help the patient make a fully informed choice whether to proceed with orthodontic treatment. This paper outlines the potential hazards and suggests how they may be avoided or minimized.

Objective: To report on a study where 97 subjects were screened for mutations in the Treacher Collins syndrome (TCS) gene TCOF1., Method: Ninety-seven subjects with a clinical diagnosis of TCS were screened for potential mutations in TCOF1, by means of single strand conformation polymorphism (SSCP) analysis. In those subjects where potential mutations were detected, sequence analysis was performed to determine the site and type of mutation present., Results: Thirty-six TCS-specific mutations are reported including 27 deletions, six point mutations, two splice junction mutations, and one insertion/deletion. This brings the total number of mutations reported to date to 105., Conclusion: The importance of detection of these mutations is mainly in postnatal diagnosis and genetic counselling. Knowledge of the family specific mutation may also be used in prenatal diagnosis to confirm whether the foetus is affected or not, and give the parents the choice of whether to continue with the pregnancy.

Meeting the demands of chronic illness and disease states is challenging, at best. Too often, the chronicity of the illness hastens death. The physical, psychological, and sociological changes that accompany the death of an individual require attention and forethought if the life transition is to be made with elegance and grace. This article addresses the caregiving demands for the professional and familial/social support surrounding the chronically ill individual at the end of life. Focus is placed on the preparation of advance directives-legal documents that set clear boundaries for honoring the wishes of the patient., (Copyright 2002 Wiley Periodicals, Inc.)

Objective: Paget's disease of the vulva (PDV) and Paget's disease of the breast (PDB) are uncommon diseases, accounting for approximately 1% of all vulval neoplasms and 0.5-4% of all breast cancers, respectively. In 10-30% of vulval cases an invasive adenocarcinoma is present. In such cases the disease is often aggressive and recurrence rate is high. This is in contrast to PDB where the general consensus is that almost all cases are associated with an in situ or invasive ductal carcinoma. Our aim was to examine the presence of the tumor suppressor protein p53 and the proliferation marker Ki67 in PDV and PDB and correlate any differences in the expression of these two proteins with the presence of an underlying carcinoma., Methods: Immunohistochemistry was performed on 52 archival cases of PDV, which included 10 with associated invasive adenocarcinoma of the vulva, and on 37 archival cases of PDB, including 26 with available associated ductal carcinoma in situ (DCIS) or invasive carcinoma of the breast. All cases were formalin-fixed and paraffin wax-embedded. Monoclonal antibodies were used with microwave antigen retrieval. Streptavidin-biotin-horseradish peroxidase and 3,3'-diaminobenzidine detection methods were employed to visualize antibody binding and staining. A section was scored positive for p53 if more than 10% of cell nuclei were stained brown and Ki67 was expressed as a percentage of positive cells to the nearest 5% of cells showing nuclear positivity (Ki67 staining index)., Results: p53 was expressed in 15 of 52 (29%) PDV cases and 5 of 37 (13%) cases of PDB. Four of the ten cases (40%) of PDV associated with invasive disease expressed p53 compared with 11 of 42 (26%) cases without invasive disease. The mean Ki67 staining index for PDV associated with invasion was 19%, and for that without invasion, 16%. In the breast cases, the mean staining index was 11%., Conclusion: Our data suggest that p53 may have a role to play in PDV progression, and may be a late event in some cases, especially those associated with invasive disease. Ki67 has no apparent prognostic role in PDV as there was no significant difference between those cases associated with and those without invasive disease. Neither p53 nor Ki67 appears to have a prognostic role to play in PDB.

Background: Paget's disease of the vulva and the breast are uncommon conditions. The pathogenesis underlying these diseases is still unclear. Vascular endothelial growth factor-A (VEGF-A), a potent angiogenic factor, has been demonstrated in a variety of tumour cell types and is thought to be involved in tumour expansion. Platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP) has also been shown to stimulate angiogenesis., Materials and Methods: Fifty-four cases of Paget's disease of the vulva, including 10 with an associated invasive adenocarcinoma, and 38 cases of Paget's disease of the breast, including 26 with available associated ductal carcinoma in situ (DCIS) and/or invasive carcinoma of the breast, were evaluated immunohistochemically for the expression of VEGF-A and PD-ECGF/TP., Results: VEGF-A was not expressed in Paget's disease of the vulva or breast. PD-ECGF/TP was expressed in 22 out of 54 (41%) cases of Paget's disease of the vulva. Four of the cases associated with invasive disease (40%) expressed PD-ECGF/TP. Twenty-one out of 38 (55%) cases of Paget's disease of the breast were positive for PD-ECGF/TP., Conclusion: Our data suggest that PD-ECGF/TP may have a role to play in the pathogenesis of Paget's disease of the vulva and the breast. The role of VEGF-A in Paget's disease of the vulva and the breast remains to be fully elucidated.

Dentists applying to a specialist training programme often receive conflicting advice over what to put in their curriculum vitae (CV). We conducted a survey of the Training Programme Directors of the dental specialties to determine what aspects of CV content and presentation styles are considered important. This has allowed us to construct guidelines for what to put in a CV. Recently, structured application forms have become increasingly popular and may be a more objective way to carry out the shortlisting process. The guidelines presented could also be used as a framework for medical personnel departments if structured application forms eventually replace the CV.

The challenge of rehabilitating young, healthy transfemoral amputees may extend beyond the boundaries of teaching them to adapt to functional activities of daily living. The goal for several of these amputees is to participate and sometimes even compete in recreational activities, including running. These amputee runners require prosthetic adaptations as well as a comprehensive individualized training programme to ensure that their running is as safe and energy efficient as possible. To help amputees achieve this, clinicians must understand normal and prosthetic locomotion. This paper compares the biomechanical differences between walking and running in normal locomotion and analyses the running modes used by transfemoral amputees. The modified running mode achieved with the Terry Fox Running Prosthesis subjectively "looks" more energy efficient to the observer and "feels" more energy efficient to the user. These assumptions have yet to be confirmed or refuted by a rigorous scientific research study. An outline of the proposed physiotherapy protocol includes the familiarization, treatment, and training phases. Physiotherapists involved in amputation rehabilitation may not be commonly confronted with this level of patient expectation. It is their responsibility to give realistic guidance to these amputees so that they can safely and independently pursue their recreational running activities. This need can best be fulfilled by providing sound clinical advice which has been validated by research findings.