Succinate dehydrogenase (SDH)-deficient renal carcinoma:a morphologically distinct entity: a clinicopathologic series of 36 tumors from 27 patients

Succinate dehydrogenase (SDH)-deficient renal carcinoma has been accepted as a provisional entity in the 2013 International Society of Urological Pathology Vancouver Classification. To further define its morphologic and clinical features, we studied a multi-institutional cohort of 36 SDH-deficient renal carcinomas from 27 patients, including 21 previously unreported cases. We estimate that 0.05% to 0.2% of all renal carcinomas are SDH deficient. Mean patient age at presentation was 37 years (range, 14 to 76 y), with a slight male predominance (M:F=1.7:1). Bilateral tumors were observed in 26% of patients. Thirty-four (94%) tumors demonstrated the previously reported morphology at least focally, which included: solid or focally cystic growth, uniform cytology with eosinophilic flocculent cytoplasm, intracytoplasmic vacuolations and inclusions, and round to oval low-grade nuclei. All 17 patients who underwent genetic testing for mutation in the SDH subunits demonstrated germline mutations (16 in SDHB and 1 in SDHC). Nine of 27 (33%) patients developed metastatic disease, 2 of them after prolonged follow-up (5.5 and 30 y). Seven of 10 patients (70%) with high-grade nuclei metastasized as did all 4 patients with coagulative necrosis. Two of 17 (12%) patients with low-grade nuclei metastasized, and both had unbiopsied contralateral tumors, which may have been the origin of the metastatic disease. In conclusion, SDH-deficient renal carcinoma is a rare and unique type of renal carcinoma, exhibiting stereotypical morphologic features in the great majority of cases and showing a strong relationship with SDH germline mutation. Although this tumor may undergo dedifferentiation and metastasize, sometimes after a prolonged delay, metastatic disease is rare in the absence of high-grade nuclear atypia or coagulative necrosis

Exploring masculinities, sexual health and wellbeing across areas of high deprivation in Scotland: the depth of the challenge to improve understandings and practices

Within and across areas of high deprivation, we explored constructions of masculinity in relation to sexual health and wellbeing, in what we believe to be the first UK study to take this approach. Our sample of 116 heterosexual men and women age 18–40 years took part in individual semi-structured interviews (n = 35) and focus group discussions (n = 18), across areas in Scotland. Drawing on a socio-ecological framework, findings revealed experience in places matter, with gender practices rooted in a domestically violent milieu, where localised, socio-cultural influences offered limited opportunities for more egalitarian performances of masculinity. We discuss the depths of the challenge in transforming masculinities in relation to sexual health and wellbeing in such communities

Chlamydia Screening in Ireland: a pilot study of opportunistic screening for genital Chlamydia trachomatis infection in Ireland (2007-2009). Economic evaluation

Economic Evaluation The aim of the economic evaluation was to examine the cost effectiveness of the two screening models tested in the Chlamydia Screening in Ireland Pilot (CSIP) study: (a) Clinical Setting screening, and (b) ’Pee-in-a-pot’ periodic screening in third level institution/college settings. The methodological approach comprised of a dynamic transmission model paired with an economic model. In both analyses, screening was compared to a control strategy of no organised screening, that is existing care in Ireland. A public health system or provider perspective was adopted with respect to costs. The analysis considered the cost of screening to the health service, and the costs of infection and complications, not any additional costs reported by young people in accepting a chlamydia screening test. Health outcomes were assessed in terms of major outcomes (MOs) averted and quality adjusted life years (QALYs) gained. The costs of Clinical Setting screening were presented in terms of the cost per offer (€26 ), the cost per negative case (€66), the cost per positive case (€152), and the cost per partner notified and treated (€74). The costs of ’Pee-in-a-pot’ screening were presented in terms of the cost per negative case (€39), the cost per positive case (€125), and the cost per partner notified and treated (€74). In both analyses, screening was estimated to result in fewer major outcomes, fewer QALYs lost, and higher healthcare costs compared to the control strategy. The incremental cost effectiveness analyses indicated that screening in the Clinical Setting would result in an incremental cost per MO averted of €6,093 and an incremental cost per QALY gained of €94,717. ’Pee-in-a-pot’ screening was estimated to result in incremental cost effectiveness ratios of €2,294 per MO averted and €34,486 per QALY gained respectively. In Ireland, there is no fixed and generally agreed cost effectiveness threshold below which health care technologies would be considered by policy makers to be costeffective. Nonetheless, on the basis of other technologies that are currently funded, it is not likely that screening delivered in the Clinical Setting, given an incremental cost per QALY in the region of the €94,717 found in this study, would be considered cost effective. ’Pee-in-a-pot’ screening in third level institution/college settings may be considered cost effective if a cost effectiveness threshold in the region of €45,000 per QALY gained is used. This is open to question, however, given the current economic climate and its resulting impact in terms of imposing further constraints on future healthcare budgets. It is also important to note that this strategy would have minimal in impact in reducing overall chlamydia prevalence in the population, if not supported by general population screening and prevention strategy

Chlamydia Screening in Ireland: a pilot study of opportunistic screening for genital Chlamydia trachomatis infection in Ireland (2007-2009). Summary Integrated Report

Genital Chlamydia trachomatis (CT) infection is the most common curable, bacterial sexually transmitted infection (STI) worldwide [1, 2]. The number of cases notified in Ireland increased from 3,353 in 2005 to 5,781 in 2009 [3]. Notifications have increased since 2004 when legislation requiring laboratory notification came into effect. Chlamydia is usually a ‘silent’ asymptomatic infection, spread without the knowledge of those transmitting and contracting it: most cases remain undetected and thus untreated. It is a major public health problem because it causes pelvic inflammatory disease (PID) in up to 30% of infected women who are not treated, which can lead to ectopic pregnancy and tubal factor infertility, and it also facilitates the transmission of HIV in both women and men [1, 4]. Prevalence studies in Ireland have detected chlamydia in 4–11% of young people [5, 6, 7], with positivity rates of over 10% in some settings [8]. Similar rates have been found in large studies in the United Kingdom (UK) [9], elsewhere in Europe [10] and North America [11]. A 2004 review estimated UK rates of 4–5% for women under 20 years in the general population, and 8–17% in women under 20 years attending sexual health services [9]. The authors of the review assumed, in the absence of data, that males had similar rates. Age under 25 years is considered a risk factor for infection in England [12]. In the English National Chlamydia Screening Programme (NCSP) overall chlamydia positivity rates have averaged 7.6% in men and 9.3% in women, based on a total of 370,012 screening tests reported [13]. Chlamydia screening has become more feasible due to the development of urinebased laboratory tests, which can be used in clinical and non-clinical settings, instead of more invasive and uncomfortable methods such as endocervical and urethral swabs. Urine testing is now the norm for screening men for chlamydia. For these reasons and because most cases are asymptomatic and undetected, especially in women, several countries have introduced chlamydia screening interventions [1]. A 2005 report prepared by the Health Protection Surveillance Centre (HPSC) [14] concluded that an investigation of the feasibility, acceptability and likely uptake of chlamydia screening in various settings in Ireland should be prioritised. It also concluded that agreement on best practice for the management of identified infections and partner notification was urgently needed. Following a competitive tendering process in late 2006, the HPSC, supported by the Health Research Board (HRB), contracted a team of population health and other specialists from the Royal College of Surgeons in Ireland (RCSI), the National University of Ireland Galway (NUIG) and the Health Service Executive (HSE) to conduct a pilot study of chlamydia screening.The study ran from 2007 to 2009. Since 2009, several articles and reports have been published internationally, including reviews and the results of screening studies, which question the case for chlamydia screening in the general population. A systematic review of screening programmes concluded that the available evidence did not justify the establishment of opportunistic chlamydia screening programmes in under-25 year olds in the general population, given methodological weaknesses in the trials cited as justification for screening [4]. A review of the three phases of the English National Chlamydia Screening Programme (NCSP) reported screening coverage levels in the target population of only 4.8% in 2007–2008 [13]; although by 2009–2010, 47% of sexually active young women and 25% of men had been tested [15]. A review by the English National Audit Office [16] concluded that the NCSP had not demonstrated value for money, citing lack of efficiencies in purchasing and logistics. Also, models had shown that annual testing rates of young people of between 26% and 43% would be needed in order to significantly reduce the prevalence of chlamydia [17]. The recent higher coverage levels achieved by the NCSP in reaching these recommended levels is a cause for optimism, and valuable lessons will be learned from the English national programme. However, the potential of opportunistic chlamydia screening to prevent serious morbidity (chiefly pelvic inflammatory disease in women) has been challenged by the results of an important randomised control trial of screening among young female students in London [18]. The trial found that most episodes of PID (30 of 38) would not have been prevented by annual screening as they occurred in women who had tested negative for chlamydia at the start of the 12 months

Chlamydia Screening in Ireland: a pilot study of opportunistic screening for genital Chlamydia trachomatis infection in Ireland (2007-2009). Screening Intervention Report

This report summarises the findings of the Pilot Screening Intervention conducted in Ireland between 2008 and 2009 as part of the Chlamydia Screening in Ireland Pilot study. The studies aimed to pilot screening models and to evaluate their feasibility and effectiveness. The study was commissioned by the Health Protection Surveillance Centre (HPSC) and overseen by the Health Research Board (HRB). It was carried out by a team from the Division of Population Health Sciences at the Royal College of Surgeons (RSCI) in Ireland, the College of Medicine, Nursing and Health Sciences at the National University of Ireland Galway, and Consultants in Public Health Medicine from the Health Service Executive (HSE). ² Ethical approval for study components was provided by Research Ethics Committees of the RCSI, NUI Galway and the Irish College of General Practitioners (ICGP)

Vegetable, fruit and antioxidant nutrient consumption and subsequent risk of hepatocellular carcinoma: a prospective cohort study in Japan

In a population-based prospective study of 19 998 Japanese individuals, consumption of vegetables, green–yellow and green leafy vegetables was inversely associated with the risk of hepatocellular carcinoma (101 cases), with multivariable hazard ratios for the highest vs lowest tertile of 0.61 (95% confidence interval (CI)=0.36–1.03, Ptrend=0.07), 0.65 (95% CI=0.39–1.08, Ptrend=0.06) and 0.59 (95% CI=0.35–1.01, Ptrend=0.04), respectively

Electroactive smart materials: novel tools for tailoring bacteria behavior and fight antimicrobial resistance

Despite being very simple organisms, bacteria possess an outstanding ability to adapt to different environments. Their long evolutionary history, being exposed to vastly different physicochemical surroundings, allowed them to detect and respond to a wide range of signals including biochemical, mechanical, electrical, and magnetic ones. Taking into consideration their adapting mechanisms, it is expected that novel materials able to provide bacteria with specific stimuli in a biomimetic context may tailor their behavior and make them suitable for specific applications in terms of anti-microbial and pro-microbial approaches. This review maintains that electroactive smart materials will be a future approach to be explored in microbiology to obtain novel strategies for fighting the emergence of live threatening antibiotic resistance.This work was supported by national funds through FCT (Fundação para a Ciência e Tecnologia) and by ERDF through COMPETE2020—Programa Operacional Competitividade e Internacionalização (POCI) in the framework of the Strategic Programs UID/FIS/04650/2019. This work was also supported by FCT through project LungChek ENMed/0049/2016. MF and EC thank FCT for the SFRH/BPD/121464/2016 and SFRH/BD/145455/2019 grant, respectively. Finally, the authors acknowledge funding by the Spanish Ministry of Economy and Competitiveness (MINECO) through the project MAT201676039-C4-3-R (AEI/FEDER, UE) and from the Basque Government Industry and Education Departments under the ELKARTEK and PIBA (PIBA-2018-06) programs, respectively.info:eu-repo/semantics/publishedVersio

Development and Functional Analysis of Novel Genetic Promoters Using DNA Shuffling, Hybridization and a Combination Thereof

BACKGROUND: Development of novel synthetic promoters with enhanced regulatory activity is of great value for a diverse range of plant biotechnology applications. METHODOLOGY: Using the Figwort mosaic virus full-length transcript promoter (F) and the sub-genomic transcript promoter (FS) sequences, we generated two single shuffled promoter libraries (LssF and LssFS), two multiple shuffled promoter libraries (LmsFS-F and LmsF-FS), two hybrid promoters (FuasFScp and FSuasFcp) and two hybrid-shuffled promoter libraries (LhsFuasFScp and LhsFSuasFcp). Transient expression activities of approximately 50 shuffled promoter clones from each of these libraries were assayed in tobacco (Nicotiana tabacum cv. Xanthi) protoplasts. It was observed that most of the shuffled promoters showed reduced activity compared to the two parent promoters (F and FS) and the CaMV35S promoter. In silico studies (computer simulated analyses) revealed that the reduced promoter activities of the shuffled promoters could be due to their higher helical stability. On the contrary, the hybrid promoters FuasFScp and FSuasFcp showed enhanced activities compared to F, FS and CaMV 35S in both transient and transgenic Nicotiana tabacum and Arabidopsis plants. Northern-blot and qRT-PCR data revealed a positive correlation between transcription and enzymatic activity in transgenic tobacco plants expressing hybrid promoters. Histochemical/X-gluc staining of whole transgenic seedlings/tissue-sections and fluorescence images of ImaGene Green™ treated roots and stems expressing the GUS reporter gene under the control of the FuasFScp and FSuasFcp promoters also support the above findings. Furthermore, protein extracts made from protoplasts expressing the human defensin (HNP-1) gene driven by hybrid promoters showed enhanced antibacterial activity compared to the CaMV35S promoter. SIGNIFICANCE/CONCLUSION: Both shuffled and hybrid promoters developed in the present study can be used as molecular tools to study the regulation of ectopic gene expression in plants

Cells of the human intestinal tract mapped across space and time

Acknowledgements We acknowledge support from the Wellcome Sanger Cytometry Core Facility, Cellular Genetics Informatics team, Cellular Generation and Phenotyping (CGaP) and Core DNA Pipelines. This work was financially supported by the Wellcome Trust (W1T20694, S.A.T.; 203151/Z/16/Z, R. A. Barker.); the European Research Council (646794, ThDefine, S.A.T.); an MRC New Investigator Research Grant (MR/T001917/1, M.Z.); and a project grant from the Great Ormond Street Hospital Children’s Charity, Sparks (V4519, M.Z.). The human embryonic and fetal material was provided by the Joint MRC/Wellcome (MR/R006237/1) Human Developmental Biology Resource (https://www.hdbr.org/). K.R.J. holds a Non-Stipendiary Junior Research Fellowship from Christ’s College, University of Cambridge. M.R.C. is supported by a Medical Research Council Human Cell Atlas Research Grant (MR/S035842/1) and a Wellcome Trust Investigator Award (220268/Z/20/Z). H.W.K. is funded by a Sir Henry Wellcome Fellowship (213555/Z/18/Z). A.F. is funded by a Wellcome PhD Studentship (102163/B/13/Z). K.T.M. is funded by an award from the Chan Zuckerberg Initiative. H.H.U. is supported by the Oxford Biomedical Research Centre (BRC) and the The Leona M. and Harry B. Helmsley Charitable Trust. We thank A. Chakravarti and S. Chatterjee for their contribution to the analysis of the enteric nervous system. We also thank R. Lindeboom and C. Talavera-Lopez for support with epithelium and Visium analysis, respectively; C. Tudor, T. Li and O. Tarkowska for image processing and infrastructure support; A. Wilbrey-Clark and T. Porter for support with Visium library preparation; A. Ross and J. Park for access to and handling of fetal tissue; A. Hunter for assistance in protocol development; D. Fitzpatrick for discussion on developmental intestinal disorders; and J. Eliasova for the graphical images. We thank the tissue donors and their families, and the Cambridge Biorepository for Translational Medicine and Human Developmental Biology Resource, for access to human tissue. This publication is part of the Human Cell Atlas: https://www.humancellatlas.org/publications.Peer reviewedPublisher PD

Cells of the human intestinal tract mapped across space and time.

Funder: Medical Research CouncilThe cellular landscape of the human intestinal tract is dynamic throughout life, developing in utero and changing in response to functional requirements and environmental exposures. Here, to comprehensively map cell lineages, we use single-cell RNA sequencing and antigen receptor analysis of almost half a million cells from up to 5 anatomical regions in the developing and up to 11 distinct anatomical regions in the healthy paediatric and adult human gut. This reveals the existence of transcriptionally distinct BEST4 epithelial cells throughout the human intestinal tract. Furthermore, we implicate IgG sensing as a function of intestinal tuft cells. We describe neural cell populations in the developing enteric nervous system, and predict cell-type-specific expression of genes associated with Hirschsprung's disease. Finally, using a systems approach, we identify key cell players that drive the formation of secondary lymphoid tissue in early human development. We show that these programs are adopted in inflammatory bowel disease to recruit and retain immune cells at the site of inflammation. This catalogue of intestinal cells will provide new insights into cellular programs in development, homeostasis and disease