Basal Cell Carcinoma in Type 2 Segmental Darier's Disease

Background. Darier's disease (DD), also known as Keratosis Follicularis or Darier-White disease, is a rare disorder of keratinization. DD can present as a generalized autosomal dominant condition as well as a localized or segmental postzygotic condition (Vázquez et al., 2002). Clinical features of DD include greasy, warty papules and plaques on seborrheic areas, dystrophic nails, palmo-plantar pits, and papules on the dorsum of the hands and feet. Objective. We report a case of basal cell carcinoma developing in a patient with type 2 segmental DD. Conclusion. According to the current literature, Type 2 segmental disease is a rare presentation of Darier's disease with only 8 previous cases reported to date. In addition, nonmelanoma skin cancer (NMSC) arising from DD is rarely reported; however, there may be an association between DD and risk of carcinogenesis

Policy addressing suicidality in children and young people: a scoping review protocol

Introduction Suicide is one of the leading causes of death among children and young people globally and a major public health issue. Government policies determine how much recognised health issues are prioritised and set the context for investment, development and delivery of services. A review of policies concerning children and young people who are suicidal could shed light on the extent that this public health issue is prioritised and highlight examples of best practice in this area. There has never been a review to explore how policy worldwide addresses the specific needs of this vulnerable population. This review will map the key policy documents and identify their relevance to the review question: how does policy address the treatment and care of children and young people who experience suicidality? (international, national (UK) and local (Scotland)). Methodology Employing scoping review methodological guidance a systematic and transparent approach will be taken. Preliminary searches will facilitate the identification of MeSh terms, subject headings, individual database and platform nuances. A full search strategy will be created to search five databases: CINAHL, PsychInfo, Medline, Web of Science and Cochrane. Government and other key agency websites (eg, WHO, Unicef) will be searched to identify policy documents. The reference lists of identified documents will be checked. A second reviewer will independently screen and cross validate eligible studies for final inclusion. A data extraction template will then be used to extract key information. We will report our findings using narrative synthesis and tabulate findings, by agreed key components. Ethics and dissemination Ethical approval is not required to conduct a scoping review. We will disseminate the findings through a peer-reviewed publication and conference presentation

Policy addressing suicidality in children and young people: An international scoping review

Suicide is a global health policy priority. As many as 800,000 lives are lost to suicide annually, in what is arguably a preventable cause of death. The World Health Organisation’s Mental Health Action Plan 2013-20 sets a target of reducing suicide rates by 10% by 2020, with member states agreeing to work towards this outcome. However, public policies instituted at national level can vary in how they translate this target into practical support. Suicide is a leading cause of death among children and young people (CYP) worldwide, with an estimated 1 in 3 children in some countries having considered suicide in the past year. Despite acknowledgment that children and young people have different needs to adults, most suicide prevention and mental health strategies take a universal approach, in which the specific needs for children and young people risk becoming lost. As the WHO’s target date of 2020 approaches, this briefing paper summarises a global review of national policy documents, considering how they address the treatment and care needs of suicidal children and young people. In doing so, it highlights best practice for how policy can influence the resourcing of services, and identifies gaps in policy provision for this vulnerable population. The paper aims to support both the WHO and individual countries that wish to develop new, or refine existing policies that address suicidality in children and young people

Characteristics and outcomes of referrals to CAMHS for children who are thinking about or attempted suicide: A retrospective cohort study in two Scottish CAMHS

Suicide among children and young people (CYP) is a leading cause of death. In the UK children identified as suicidal are referred to Child and Adolescent Mental Health Services (CAMHS) for assessment and treatment. However, the number of children referred for suicidality, and their care journey is unknown. This retrospective cohort study conducted in two distinct CAMHS teams, in Scotland, UK, aimed to quantify the numbers of children referred for suicidality, describing this population and the outcomes of these referrals. All CAMHS referrals (n = 1159) over a 6-month period (Jan-June 2019) were screened to identify those referred primarily for suicidality. Data extracted included: age, gender, source of referral, reason for referral including underlying issues, whether offered an assessment, and referral outcome. Area based deprivation scores were attached to each referral. Associations between the referred CYP's characteristics (including source of referral and underlying issues) and referral outcomes were explored using Chi Square, Fishers Exact test, and one-way ANOVA. Referrals for 284 children were identified as being for suicidality across the two sites (Site A n = 104; Site B n = 180). These represented 25% of all referrals to these CAMHS over a six-month period. One third of these concerned children under 12. The underlying issues, referrals sources, and demographic indicators were similar in both sites. In site A 31% were offered an assessment, whilst in Site B which had a dedicated team for suicidal CYP, 82% were offered an assessment. Similarly, more children in Site B were offered treatment (47.8%), than Site A (7.7%). Referrals from A&E were prioritized in both areas, and those who had attempted suicide offered an assessment more often. Older children were more likely to be offered treatment, although they were more likely to present with a history of self-harming behavior and/or previous suicide attempt. There are high numbers of children being referred to CAMHS for suicidality, and many are young children (<12). There is variation within and between services in terms of assessment, referral outcomes and care pathways for these children. Having a dedicated team to respond to referrals for suicidality appears to support access to assessment and treatment

Math and Technology Leadership Academy: Impact on Mathematics Teacher Sense of Efficacy

The Math and Technology Leadership Academy (MTLA) was a three-year initiative awarded by Toyota USA Foundation to advance elementary teachers’ instructional techniques in mathematics, leadership, and technology. Over the three years, fourteen teacher participants of grade levels spanning from kindergarten through sixth grade engaged in three mathematics pedagogy courses and monthly seminars. Teacher participants then implemented the innovative math strategies into their classrooms. This paper will discuss the design of MTLA and the research plan and results. The study found significant results from the Mathematics Teaching Efficacy Beliefs Instrument (MTEBI) in the Self-Efficacy construct. After three years of participation in MTLA, the teachers in the MTLA demonstrated significantly higher self-efficacy than their control teacher of elementary mathematics; however, both groups of teachers demonstrated similar beliefs about outcomes expectations or the belief that effective mathematics instruction can affect student learning outcomes

PADI4 genotype is not associated with rheumatoid arthritis in a large UK Caucasian population

BACKGROUND: Polymorphisms of the peptidylarginine deiminase type 4 (PADI4) gene confer susceptibility to rheumatoid arthritis (RA) in East Asian people. However, studies in European populations have produced conflicting results. This study explored the association of the PADI4 genotype with RA in a large UK Caucasian population. METHODS: The PADI4_94 (rs2240340) single nucleotide polymorphism (SNP) was directly genotyped in a cohort of unrelated UK Caucasian patients with RA (n=3732) and population controls (n=3039). Imputed data from the Wellcome Trust Case Control Consortium (WTCCC) was used to investigate the association of PADI4_94 with RA in an independent group of RA cases (n=1859) and controls (n=10 599). A further 56 SNPs spanning the PADI4 gene were investigated for association with RA using data from the WTCCC study. RESULTS: The PADI4_94 genotype was not associated with RA in either the present cohort or the WTCCC cohort. Combined analysis of all the cases of RA (n=5591) and controls (n=13 638) gave an overall OR of 1.01 (95% CI 0.96 to 1.05, p=0.72). No association with anti-CCP antibodies and no interaction with either shared epitope or PTPN22 was detected. No evidence for association with RA was identified for any of the PADI4 SNPs investigated. Meta-analysis of previously published studies and our data confirmed no significant association between the PADI4_94 genotype and RA in people of European descent (OR 1.06, 95% CI 0.99 to 1.13, p=0.12). CONCLUSION: In the largest study performed to date, the PADI4 genotype was not a significant risk factor for RA in people of European ancestry, in contrast to Asian populations

Dissecting the transcriptional networks underlying breast cancer: NR4A1 reduces the migration of normal and breast cancer cell lines

Introduction: Breast cancer currently accounts for more than one-quarter of all female cancers and, despite the great progress in treatment observed in the past few years, the need for identification of new gene targets that can be used for diagnosis, prognosis and therapy is evident. A previous study identified the transcription factor NR4A1 as a gene upregulated in primary breast cancer compared with normal tissue by microarray analysis and sequencing technologies. The purpose of the study was to identify the role of NR4A1 in normal mammary epithelial and breast cancer cell biology.Methods: NR4A1 expression in breast tumours was assessed by semiquantitative and real-time PCR using RNA from normal and tumour samples or breast cancer cell lines. Immunohistochemistry on tissue microarrays was performed to check NR4A1 protein expression in breast tumours. MCF-10A and 226L normal mammary epithelial cells as well as the tumour lines PMC42, ZR-75-1 and MDA-MB-231 were transduced with full-length NR4A1, and the ability of NR4A1-overexpressing cells to migrate was tested using scratch wound or transwell migration assays. Proliferation was measured using the MTT and BrdU assays, while apoptosis was determined by the Annexin V assay. The ability of the cells to adhere to extracellular matrix was tested by adhesion assays and integrin cell surface expression was measured by flow cytometry. Activation of the FAK as well as ERK1/2 and PI3K pathways was checked by western blotting.Results: Breast tissue microarray analysis showed NR4A1 expression in primary tumours, which was reduced in higher grade and metastatic tumours. Ectopic expression of NR4A1 in MCF-10A, 226L, PMC42 and ZR-75-1 cells led to reduced ability of the cells to migrate, while no differences were observed in their proliferation and apoptotic index. NR4A1 expression altered the ability of the MCF-10A cells to adhere to the extracellular matrix and affected cell surface expression of integrins.Conclusions: NR4A1 acts as an antimigratory factor in two normal mammary epithelial and two breast cancer cell lines tested. It is therefore possible that NR4A1 acts as an antimigratory factor in breast tumours, and further studies should be conducted to understand the mechanisms involved

Macrophage phenotype is associated with disease severity in preterm infants with chronic lung disease.

The etiology of persistent lung inflammation in preterm infants with chronic lung disease of prematurity (CLD) is poorly characterized, hampering efforts to stratify prognosis and treatment. Airway macrophages are important innate immune cells with roles in both the induction and resolution of tissue inflammation

The epidemiology of adolescents living with perinatally acquired HIV: A cross-region global cohort analysis

Background Globally, the population of adolescents living with perinatally acquired HIV (APHs) continues to expand. In this study, we pooled data from observational pediatric HIV cohorts and cohort networks, allowing comparisons of adolescents with perinatally acquired HIV in “real-life” settings across multiple regions. We describe the geographic and temporal characteristics and mortality outcomes of APHs across multiple regions, including South America and the Caribbean, North America, Europe, sub-Saharan Africa, and South and Southeast Asia. Methods and findings Through the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), individual retrospective longitudinal data from 12 cohort networks were pooled. All children infected with HIV who entered care before age 10 years, were not known to have horizontally acquired HIV, and were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Our primary analysis describes patient and treatment characteristics of APHs at key time points, including first HIV-associated clinic visit, antiretroviral therapy (ART) start, age 10 years, and last visit, and compares these characteristics by geographic region, country income group (CIG), and birth period. Our secondary analysis describes mortality, transfer out, and lost to follow-up (LTFU) as outcomes at age 15 years, using competing risk analysis. Among the 38,187 APHs included, 51% were female, 79% were from sub-Saharan Africa and 65% lived in low-income countries. APHs from 51 countries were included (Europe: 14 countries and 3,054 APHs; North America: 1 country and 1,032 APHs; South America and the Caribbean: 4 countries and 903 APHs; South and Southeast Asia: 7 countries and 2,902 APHs; sub-Saharan Africa, 25 countries and 30,296 APHs). Observation started as early as 1982 in Europe and 1996 in sub-Saharan Africa, and continued until at least 2014 in all regions. The median (interquartile range [IQR]) duration of adolescent follow-up was 3.1 (1.5–5.2) years for the total cohort and 6.4 (3.6–8.0) years in Europe, 3.7 (2.0–5.4) years in North America, 2.5 (1.2–4.4) years in South and Southeast Asia, 5.0 (2.7–7.5) years in South America and the Caribbean, and 2.1 (0.9–3.8) years in sub-Saharan Africa. Median (IQR) age at first visit differed substantially by region, ranging from 0.7 (0.3–2.1) years in North America to 7.1 (5.3–8.6) years in sub-Saharan Africa. The median age at ART start varied from 0.9 (0.4–2.6) years in North America to 7.9 (6.0–9.3) years in sub-Saharan Africa. The cumulative incidence estimates (95% confidence interval [CI]) at age 15 years for mortality, transfers out, and LTFU for all APHs were 2.6% (2.4%–2.8%), 15.6% (15.1%–16.0%), and 11.3% (10.9%–11.8%), respectively. Mortality was lowest in Europe (0.8% [0.5%–1.1%]) and highest in South America and the Caribbean (4.4% [3.1%–6.1%]). However, LTFU was lowest in South America and the Caribbean (4.8% [3.4%–6.7%]) and highest in sub-Saharan Africa (13.2% [12.6%–13.7%]). Study limitations include the high LTFU rate in sub-Saharan Africa, which could have affected the comparison of mortality across regions; inclusion of data only for APHs receiving ART from some countries; and unavailability of data from high-burden countries such as Nigeria. Conclusion To our knowledge, our study represents the largest multiregional epidemiological analysis of APHs. Despite probable under-ascertained mortality, mortality in APHs remains substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe. Collaborations such as CIPHER enable us to monitor current global temporal trends in outcomes over time to inform appropriate policy responses

CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study

BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC