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2. Development of a pre-operative education and prehabilitation digital intervention for patients awaiting total knee replacement : a Virtual Knee School

Author

Anderson, Anna Mary, Redmond, Anthony C., McHugh, Gretl A., Comer, Christine, and Yardley, Lucy

Abstract

Background: Total knee replacement (TKR) is a common operation usually performed to relieve the symptoms of end-stage knee osteoarthritis. Patients often face a long wait for TKR whilst experiencing severe pain. Even after TKR, ~20% of patients continue to experience long-term pain. Providing pre-operative TKR education and prehabilitation (pre-operative health/wellbeing optimisation) support could improve pre- and post-operative outcomes. However, current pre-operative TKR services are variable, inefficient and often inadequate. A rigorously developed digital intervention could help address these problems. Aim: To develop a pre-operative TKR education and prehabilitation digital intervention, the 'Virtual Knee School' (VKS). Methods and findings: The VKS was developed using an evidence-, theory- and person-based approach and complex mixed methods design. A rapid review (n=52 studies) demonstrated that definitive evidence on the optimal content/delivery of pre-operative TKR interventions is lacking. A modified Delphi study (n=30 patients; n=30 professionals) enabled the development of recommendations on pre-operative TKR interventions, which support digital delivery formats. A qualitative descriptive study (n=14 patients) highlighted the VKS should account for individual differences and be tailored to the pre-operative context. Three theoretical modelling approaches helped guide the design, description and evaluation of the VKS. A VKS prototype was developed based on the preceding studies' findings and iteratively refined through think-aloud interviews (n=9 patients). The interviews evaluated the prototype's usability and explored patients' perspectives of it. The findings suggest the VKS would be a valuable resource for many patients pre- and post-TKR, but the digital delivery format is unlikely to meet all patients' individual needs. Conclusions: This project rigorously developed a novel pre-operative TKR digital intervention, which warrants further evaluation. Key implications include: comprehensive pre-operative TKR education and prehabilitation support should be rapidly accessible in digital and non-digital formats; pre-operative TKR digital interventions should employ computer- and self- tailoring to account for patients' individual needs/preferences.

Published
2022

3. Independent External Validation of Artificial Intelligence Algorithms for Automated Interpretation of Screening Mammography: A Systematic Review.

Author

Anderson, Anna, Marinovich, M, Houssami, Nehmat, Lowry, Kathryn, Elmore, Joann, Buist, Diana, Hofvind, Solveig, and Lee, Christoph

Subjects
Algorithms, Artificial Intelligence, Breast Neoplasms, Early Detection of Cancer, Female, Humans, Mammography, Retrospective Studies
Abstract

PURPOSE: The aim of this study was to describe the current state of science regarding independent external validation of artificial intelligence (AI) technologies for screening mammography. METHODS: A systematic review was performed across five databases (Embase, PubMed, IEEE Explore, Engineer Village, and arXiv) through December 10, 2020. Studies that used screening examinations from real-world settings to externally validate AI algorithms for mammographic cancer detection were included. The main outcome was diagnostic accuracy, defined by area under the receiver operating characteristic curve (AUC). Performance was also compared between radiologists and either stand-alone AI or combined radiologist and AI interpretation. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. RESULTS: After data extraction, 13 studies met the inclusion criteria (148,361 total patients). Most studies (77% [n = 10]) evaluated commercially available AI algorithms. Studies included retrospective reader studies (46% [n = 6]), retrospective simulation studies (38% [n = 5]), or both (15% [n = 2]). Across 5 studies comparing stand-alone AI with radiologists, 60% (n = 3) demonstrated improved accuracy with AI (AUC improvement range, 0.02-0.13). All 5 studies comparing combined radiologist and AI interpretation with radiologists alone demonstrated improved accuracy with AI (AUC improvement range, 0.028-0.115). Most studies had risk for bias or applicability concerns for patient selection (69% [n = 9]) and the reference standard (69% [n = 9]). Only two studies obtained ground-truth cancer outcomes through regional cancer registry linkage. CONCLUSIONS: To date, external validation efforts for AI screening mammographic technologies suggest small potential diagnostic accuracy improvements but have been retrospective in nature and suffer from risk for bias and applicability concerns.

Published
2022

9. Cellular regulation of cortisol in vivo by 11-beta hydroxysteroid dehydrogenase type 1

Author

Anderson, Anna Jane Claire, Walker, Brian, Reynolds, Rebecca, and Andrew, Ruth

Subjects
glucocorticoid excess, type 2 diabetes, 11ßHSD1, metformin, placebo
Abstract

Glucocorticoid excess as a result of Cushing’s syndrome or pharmacological treatment can result in the development of obesity and type 2 diabetes mellitus (T2DM). The reactivation of cortisone to cortisol is catalysed by 11βHSD1 which is expressed widely but notably in adipose tissue and liver. Studies have shown dysregulation of cortisol in these tissues with obesity potentially promoting the development of T2DM. Inhibition of 11βHSD1 has been attempted as a novel treatment for T2DM with observed improvement in glycaemic control, body weight and blood pressure. The efficacy of such agents has been disappointing with few reaching phase 2 trials. With recent evidence of bidirectional activity of 11βHSD1 in vivo it becomes apparent that dysregulation may occur at an intracellular rather than tissue level. In this thesis I address several key outstanding questions concerning the physiology and regulation of 11βHSD1 including: 1. Whether combined therapy with metformin alters 11βHSD1 activity and obscures the efficacy of 11βHSD1inhibitors; 2. Whether the contribution of 11βHSD1 to local cortisol concentrations has been under-estimated by considering total rather than free cortisol turnover; and 3. Whether recycling between cortisol and cortisone in adipose tissue and skeletal muscle in obesity is a neglected feature of 11βHSD1 biochemistry and function. Eight obese healthy men with and without type 2 diabetes were recruited to a randomised placebo controlled cross over trial. They received 4 weeks treatment with metformin and placebo. Participants with T2DM additionally received gliclazide as a further control. Using the deuterated tracer D4-cortisol 11βHSD1 activity was measured. Metformin treatment increased whole body 11βHSD1 in both groups postulated as a result of improved insulin sensitivity. 11βHSD1 is located within cells and so contributes to free tissue cortisol concentrations but perhaps less so to total (protein-bound) cortisol in plasma. It has been shown that 11βHSD1 contributes almost half of total circulating cortisol concentrations at rest. This measurement relied upon blood sampling during steady state deuterated cortisol (D4-cortisol) infusion with measurements of total (free plus protein bound) cortisol which may have underestimated true 11βHSD1 activity. This was therefore investigated by comparing 11βHSD1 activity as calculated using total compared with free cortisol tracer enrichments. Equilibrium dialysis was performed separating free from bound portions in plasma samples taken from healthy volunteers who received D4-cortisol infusion. Analysis revealed similar measurements of 11βHSD1 activity using free compared with total cortisol implicating rapid turnover of glucocorticoids between the free and bound pools. On first discovery 11βHSD1 was seen to be a dehydrogenase enzyme in vitro. Later work recognised reductase activity in vivo and up until recently 11βHSD1 has been viewed as a predominantly reductase enzyme. As with other enzymes in the same family, the ability to catalyse both reductase and dehydrogenase depends upon the availability of substrate and co substrate. Whether dysregulation of 11βHSD1 in the settings of obesity and T2DM is the result of alteration in directionality at a cellular level is not known. Firstly bidirectional activity of 11βHSD1 was confirmed in vitro using HEK-293 cells stably transfected with 11βHSD1. The influence of obesity and acute perturbation with hyperinsulinaemia was subsequently investigated in vivo in a random order cross over single blinded case control study involving ten normal weight and ten obese healthy male volunteers. D4-cortisol and deuterated cortisone (D2-cortisone) were infused for the measurement of reductase and dehydrogenase activity of 11βHSD1 respectively with measurements taken across forearm muscle and abdominal subcutaneous adipose tissue. Across whole body, lean and obese individuals displayed similar 11β-reductase and 11β-dehydrogenase activity. Across tissue, 11β-reductase and 11β-dehydrogenase activity was different from zero across adipose tissue in obese individuals and across skeletal muscle in lean individuals providing further evidence of tissue specific differences in 11βHSD1 with obesity. With the addition of hyperinsulinaemia, reductase and dehydrogenase activity was somewhat increased in lean individuals although there was no statistically significant difference between lean and obese individuals. Across tissue there was a trend for obese individuals to display increased 11β-reductase activity across adipose tissue with hyperinsulinaemia. Comparing the rates of reductase and dehydrogenase activity revealed predominantly reductase activity across tissue in obese and dehydrogenase activity in lean individuals. The development of direction specific inhibitors targeting reductase activity by 11βHSD1 may prove efficacious for the treatment of obesity. In conclusion, 11βHSD1 acts as a bidirectional enzyme in vitro and in vivo. Overall directionality of enzyme activity is altered in a tissue specific manner in the setting of obesity. We have shown that this intracellular regulation of cortisol is reflected equally in the metabolically active free pool and total plasma pool. The efficacy of 11βHSD1 inhibitors as novel agents for the treatment of T2DM and coexisting obesity is not diminished by co-prescription with metformin but may prove more efficacious through the development of reductase specific inhibitors.

Published
2017

11. Definition and Assessment of Paediatric Breakthrough Pain: A Qualitative Interview Study.

Author

Dawson, Eleanor, Greenfield, Katie, Carter, Bernie, Bailey, Simon, Anderson, Anna-Karenia, Rajapakse, Dilini, Renton, Kate, Mott, Christine, Hain, Richard, Harrop, Emily, Johnson, Margaret, and Liossi, Christina

Subjects
PAIN measurement, PATIENTS' families, PARENTS, PALLIATIVE treatment, QUALITATIVE research, INTERPROFESSIONAL relations, MEDICAL personnel, RESEARCH funding, INTERVIEWING, QUESTIONNAIRES, DESCRIPTIVE statistics, PEDIATRICS, THEMATIC analysis, SOUND recordings, CAREGIVERS, ATTITUDES of medical personnel, RESEARCH methodology, PAIN management, BREAKTHROUGH pain, DATA analysis software, ADOLESCENCE, CHILDREN
Abstract

Infants, children and young people with life-limiting or life-threatening conditions often experience acute, transient pain episodes known as breakthrough pain. There is currently no established way to assess breakthrough pain in paediatric palliative care. Anecdotal evidence suggests that it is frequently underdiagnosed and undertreated, resulting in reduced quality of life. The development of a standardised paediatric breakthrough pain assessment, based on healthcare professionals' insights, could improve patient outcomes. This study aimed to explore how healthcare professionals define and assess breakthrough pain in paediatric palliative care and their attitudes towards a validated paediatric breakthrough pain assessment. This was a descriptive qualitative interview study. Semi-structured interviews were conducted with 29 healthcare professionals working in paediatric palliative care across the UK. An inductive thematic analysis was conducted on the data. Five themes were generated: 'the elusive nature of breakthrough pain', 'breakthrough pain assessment', 'positive attitudes towards', 'reservations towards' and 'features to include in' a paediatric breakthrough pain assessment. The definition and assessment of breakthrough pain is inconsistent in paediatric palliative care. There is a clear need for a validated assessment questionnaire to improve assessment, diagnosis and management of breakthrough pain followed by increased healthcare professional education on the concept. [ABSTRACT FROM AUTHOR]

Published
2024
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14. Adapting an In-Flight Entertainment system to include Older Users

Author

Hallqvist, Siri, Anderson, Anna, Hallqvist, Siri, and Anderson, Anna

Abstract

Every year, the average age of the population is increasing as people live longer and fewer children are born. With age, it is not uncommon for cognitive abilities to deteriorate, affecting the ability to learn new things and process new information. As digitalization continues, some people are left behind and thus experience difficulties in using the newly developed digital environments. This is a problem that creates a demand for a more inclusive design of digital products that is to be used by everyone, including older adults with reduced cognitive abilities. This thesis aims to investigate how older adults are experiencing an existing In-Flight Entertainment system (IFEs) and with that knowledge implement improvements in the design where problem areas have been found, resulting in a broadened system where older adults feel more comfortable. A thoroughly iterative design process, mainly inspired by Design Thinking, has been conducted with a user-centered design approach in mind. The project included amongst other things a literature study, empathizing with the users in the forms of interviews, surveys, workshops, and user tests to define the existing problems, and then creating different Lo-Fi prototypes with implemented improvements aimed at more testing with the target group. The result is presented as a Hi-Fi prototype with solutions for the problem areas discovered, together with arguments for the various design decisions. Some improvements that have been implemented in the Hi-Fi prototype are fewer steps within the system that create greater transparency, clear scroll indicators when needed, and a design skeleton that gives the system consistency. Beyond that, an overall conclusion of this thesis was the importance of including end-users in the design process to prevent bias from taking place., Samtidigt som genomsnittsåldern för världens befolkning ökar, fortsätter digitaliseringen i rasande takt. Digitaliseringen bidrar till väldigt mycket positivt i människors liv, men tenderar att utelämna vissa slutanvändare om inte deras aspekter tas med i designprocessen tidigt.

Published
2023

16. In vivo base editing by a single i.v. vector injection for treatment of hemoglobinopathies

Author

Li, Chang, primary, Georgakopoulou, Aphrodite, additional, Newby, Gregory A., additional, Everette, Kelcee A., additional, Nizamis, Evangelos, additional, Paschoudi, Kiriaki, additional, Vlachaki, Efthymia, additional, Gil, Sucheol, additional, Anderson, Anna K., additional, Koob, Theodore, additional, Huang, Lishan, additional, Wang, Hongjie, additional, Kiem, Hans-Peter, additional, Liu, David R., additional, Yannaki, Evangelia, additional, and Lieber, André, additional

Published
2022
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17. Designing in Mass Timber: Current Work and Lessons Learned

Author

Anderson, Anna (architect), Craig, Brian (architect), Kantner, Matt, Ridderbos, Ben, Anderson, Anna (architect), Craig, Brian (architect), Kantner, Matt, and Ridderbos, Ben

Abstract

In this webinar from Michigan State University, Anna Anderson, Ben Ridderbos, and Matt Kanter describe current work and lessons learned in designing and executing mass timber projects. The panelists discuss the collaboration between Equilibrium Consulting and Lord Aeck Sargent, as well as past and current projects in designing mass timber architecture. As each mass timber project is presented, panelists discuss the design and construction methods used, as well as difficulties and successes. Reasons for using mass timber are also highlighted, which include sustainability reasons, aesthetic benefits, and more. Approaches in laminating timber, fabrication, construction types, design considerations, connections, and more mass timber design approaches are also explored. The video recording runs 1:00:35 minutes in length.

Published
2022

25. Stable HIV decoy receptor expression after in vivoHSC transduction in mice and NHPs: Safety and efficacy in protection from SHIV

Author

Li, Chang, Anderson, Anna Kate, Wang, Hongjie, Gil, Sucheol, Kim, Jiho, Huang, Lishan, Germond, Audrey, Baldessari, Audrey, Nelson, Veronica, Bar, Katharine J., Peterson, Christopher W., Bui, John, Kiem, Hans-Peter, and Lieber, André

Abstract

We aim to develop an in vivohematopoietic stem cell (HSC) gene therapy approach for persistent control/protection of HIV-1 infection based on the stable expression of a secreted decoy protein for HIV receptors CD4 and CCR5 (eCD4-Ig) from blood cells. HSCs in mice and a rhesus macaque were mobilized from the bone marrow and transduced by an intravenous injection of HSC-tropic, integrating HDAd5/35++ vectors expressing rhesus eCD4-Ig. In vivoHSC transduction/selection resulted in stable serum eCD4-Ig levels of ∼100 μg/mL (mice) and >20 μg/mL (rhesus) with half maximal inhibitory concentrations (IC50s) of 1 μg/mL measured by an HIV neutralization assay. After simian-human-immunodeficiency virus D (SHIV.D) challenge of rhesus macaques injected with HDAd-eCD4-Ig or a control HDAd5/35++ vector, peak plasma viral load levels were ∼50-fold lower in the eCD4-Ig-expressing animal. Furthermore, the viral load was lower in tissues with the highest eCD4-Ig expression, specifically the spleen and lymph nodes. SHIV.D challenge triggered a selective expansion of transduced CD4+CCR5+cells, thereby increasing serum eCD4-Ig levels. The latter, however, broke immune tolerance and triggered anti-eCD4-Ig antibody responses, which could have contributed to the inability to eliminate SHIV.D. Our data will guide us in the improvement of the in vivoapproach. Clearly, our conclusions need to be validated in larger animal cohorts.

Published
2023
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28. Additional file 9 of Consensus on pre-operative total knee replacement education and prehabilitation recommendations: a UK-based modified Delphi study

Author

Anderson, Anna M., Comer, Christine, Smith, Toby O., Drew, Benjamin T., Pandit, Hemant, Antcliff, Deborah, Redmond, Anthony C., and McHugh, Gretl A.

Abstract

Additional file 9: Detailed importance ratings results. Detailed importance rating results for Round 1 (Supplementary Tables 6–10), Round 2 (Supplementary Tables 11–15) and Round 3 (Supplementary Tables 16–20).

Published
2021
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29. Additional file 3 of Consensus on pre-operative total knee replacement education and prehabilitation recommendations: a UK-based modified Delphi study

Author

Anderson, Anna M., Comer, Christine, Smith, Toby O., Drew, Benjamin T., Pandit, Hemant, Antcliff, Deborah, Redmond, Anthony C., and McHugh, Gretl A.

Abstract

Additional file 3: Formative categorisation matrix. Formative categorisation matrix developed from the Round 1 survey (Supplementary Table 2).

Published
2021
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31. Additional file 4 of Consensus on pre-operative total knee replacement education and prehabilitation recommendations: a UK-based modified Delphi study

Author

Anderson, Anna M., Comer, Christine, Smith, Toby O., Drew, Benjamin T., Pandit, Hemant, Antcliff, Deborah, Redmond, Anthony C., and McHugh, Gretl A.

Abstract

Additional file 4: Recruitment flow charts. Patient recruitment flow chart (Supplementary Fig. 1) and professional recruitment flow chart (Supplementary Fig. 2).

Published
2021
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32. Additional file 7 of Consensus on pre-operative total knee replacement education and prehabilitation recommendations: a UK-based modified Delphi study

Author

Anderson, Anna M., Comer, Christine, Smith, Toby O., Drew, Benjamin T., Pandit, Hemant, Antcliff, Deborah, Redmond, Anthony C., and McHugh, Gretl A.

Abstract

Additional file 7: Round 2 new items. New items generated from panellists’ Round 1 free-text responses and included in the Round 2 survey (Supplementary Table 5).

Published
2021
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33. Additional file 6 of Consensus on pre-operative total knee replacement education and prehabilitation recommendations: a UK-based modified Delphi study

Author

Anderson, Anna M., Comer, Christine, Smith, Toby O., Drew, Benjamin T., Pandit, Hemant, Antcliff, Deborah, Redmond, Anthony C., and McHugh, Gretl A.

Abstract

Additional file 6: Inductively generated main category. Inductively generated main category developed during the content analysis of panellists’ Round 1 free-text responses (Supplementary Table 4).

Published
2021
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34. Additional file 8 of Consensus on pre-operative total knee replacement education and prehabilitation recommendations: a UK-based modified Delphi study

Author

Anderson, Anna M., Comer, Christine, Smith, Toby O., Drew, Benjamin T., Pandit, Hemant, Antcliff, Deborah, Redmond, Anthony C., and McHugh, Gretl A.

Subjects
GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries)
Abstract

Additional file 8. Final list of recommendations. Final list of recommendations developed from the Round 3 results.

Published
2021
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36. Weber Herlinger, Ilse. Dancing on a Powder Keg: Letters and Poems. Translated from the German by Michal Schwartz, and Theresienstadt essay by Ruth Bondy. Charlottetown, PE and Jerusalem: Bunim and Bannigan and Yad Vashem, 2016.

Author

Anderson, Anna Marie and Anderson, Anna Marie

Abstract

Review of Weber Herlinger, Ilse. Dancing on a Powder Keg: Letters and Poems. Translated from the German by Michal Schwartz, with afterword by Ulrike Migdal, and Theresienstadt essay by Ruth Bondy. Charlottetown, PE and Jerusalem: Bunim and Bannigan and Yad Vashem, 2016.

Published
2021

38. A protocol for a systematic review and meta-analysis to identify measures of breakthrough pain and evaluate their psychometric properties

Author

Greenfield, Katie, primary, Holley, Simone, additional, Schoth, Daniel Eric, additional, Bayliss, Julie, additional, Anderson, Anna-Karenia, additional, Jassal, Satbir, additional, Rajapakse, Dilini, additional, Fraser, Lorna Katharine, additional, Mott, Christine, additional, Johnson, Margaret, additional, Wong, Ian, additional, Howard, Richard, additional, Harrop, Emily, additional, and Liossi, Christina, additional

Published
2020
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39. Pharmacological interventions for chronic pain in children : an overview of systematic reviews

Author

Eccleston, Christopher, Fisher, Emma, Cooper, Tess E., Gregoire, Marie-Claude, Heathcote, Lauren C., Krane, Elliot, Lord, Susan M., Sethna, Navil F., Anderson, Anna-Karenia, Anderson, Brian, Clinch, Jacqueline, Gray, Andrew L., Gold, Jeffrey, I, Howard, Richard F., Ljungman, Gustaf, Moore, R. Andrew, Schechter, Neil, Wiffen, Philip J., Wilkinson, Nick M. R., William, David G., Wood, Chantal, van Tilburg, Miranda A. L., Zernikow, Boris, Eccleston, Christopher, Fisher, Emma, Cooper, Tess E., Gregoire, Marie-Claude, Heathcote, Lauren C., Krane, Elliot, Lord, Susan M., Sethna, Navil F., Anderson, Anna-Karenia, Anderson, Brian, Clinch, Jacqueline, Gray, Andrew L., Gold, Jeffrey, I, Howard, Richard F., Ljungman, Gustaf, Moore, R. Andrew, Schechter, Neil, Wiffen, Philip J., Wilkinson, Nick M. R., William, David G., Wood, Chantal, van Tilburg, Miranda A. L., and Zernikow, Boris

Abstract

We know little about the safety or efficacy of pharmacological medicines for children and adolescents with chronic pain, despite their common use. Our aim was to conduct an overview review of systematic reviews of pharmacological interventions that purport to reduce pain in children with chronic noncancer pain (CNCP) or chronic cancer-related pain (CCRP). We searched the Cochrane Database of Systematic Reviews, Medline, EMBASE, and DARE for systematic reviews from inception to March 2018. We conducted reference and citation searches of included reviews. We included children (0-18 years of age) with CNCP or CCRP. We extracted the review characteristics and primary outcomes of >= 30% participant-reported pain relief and patient global impression of change. We sifted 704 abstracts and included 23 systematic reviews investigating children with CNCP or CCRP. Seven of those 23 reviews included 6 trials that involved children with CNCP. There were no randomised controlled trials in reviews relating to reducing pain in CCRP. We were unable to combine data in a meta-analysis. Overall, the quality of evidence was very low, and we have very little confidence in the effect estimates. The state of evidence of randomized controlled trials in this field is poor; we have no evidence from randomised controlled trials for pharmacological interventions in children with cancer-related pain, yet cannot deny individual children access to potential pain relief.

Published
2019
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41. Effects of Obesity and Insulin on Tissue-Specific Recycling Between Cortisol and Cortisone in Men.

Author

Anderson, Anna J., Andrew, Ruth, Homer, Natalie Z. M., Hughes, Katherine A., Boyle, Luke D., Nixon, Mark, Karpe, Fredrik, Stimson, Roland H., and Walker, Brian R.

Subjects
CORTISONE, GLUCOSE-6-phosphate dehydrogenase, HYDROCORTISONE, INSULIN, ADIPOSE tissues, SKELETAL muscle, OBESITY, ABDOMINAL adipose tissue, GLUCOSE metabolism, RESEARCH, LIVER, RESEARCH methodology, HYPERINSULINISM, MEDICAL cooperation, EVALUATION research, LEANNESS, COMPARATIVE studies, RANDOMIZED controlled trials, IMMUNITY, BODY mass index, CROSSOVER trials
Abstract

Context: 11β-Hydroxysteroid dehydrogenase 1 (11βHSD1) reduces inert cortisone into active cortisol but also catalyzes reverse dehydrogenase activity. Drivers of cortisol/cortisone equilibrium are unclear. With obesity, 11βHSD1 transcripts are more abundant in adipose, but the consequences for oxidation vs reduction remain unknown.Objective: This work aimed to determine whether 11βHSD1 equilibrium in metabolic tissues is regulated by insulin and obesity.Methods: A 2-phase, randomized, crossover, single-blinded study in a clinical research facility was conducted of 10 lean and obese healthy men. 11β-Reductase and 11β-dehydrogenase activities were measured during infusion of 9,11,12,12-[2H]4-cortisol and 1,2-[2H]2-cortisone, respectively, on 2 occasions: once during saline infusion and once during a hyperinsulinemic-euglycemic clamp. Arterialized and venous samples were obtained across forearm skeletal muscle and abdominal subcutaneous adipose. Steroids were quantified by liquid chromatography-tandem mass spectrometry and adipose tissue transcripts by quantitative polymerase chain reaction.Results: Neither whole-body nor tissue-specific rates of production of cortisol or cortisone differed between lean and obese men, however insulin attenuated the diurnal decrease. Whole-body 11β-HSD1 reductase activity tended to be higher in obesity (~ 10%) and was further increased by insulin. Across adipose tissue, 11β-reductase activity was detected in obese individuals only and increased in the presence of insulin (18.99 ± 9.62 vs placebo 11.68 ± 3.63 pmol/100 g/minute; P < .05). Across skeletal muscle, 11β-dehydrogenase activity was reduced by insulin in lean men only (2.55 ± 0.90 vs 4.50 ± 1.42 pmol/100 g/minute, P < .05).Conclusions: Regeneration of cortisol is upregulated by insulin in adipose tissue but not skeletal muscle. In obesity, the equilibrium between 11β-reductase and 11β-dehydrogenase activities likely promotes cortisol accumulation in adipose, which may lead to adverse metabolic consequences. [ABSTRACT FROM AUTHOR]

Published
2021
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42. Multicentrisk retikulohistiocytose er en sjælden form for paraneoplasi

Author

Anderson, Anna Maria, Todberg, Tanja, Kofoed, Kristian, Iversen, Trine Zeeberg, Andersen, Martin, Hjorth, Sofie Vetli, Fassi, Daniel El, Anderson, Anna Maria, Todberg, Tanja, Kofoed, Kristian, Iversen, Trine Zeeberg, Andersen, Martin, Hjorth, Sofie Vetli, and Fassi, Daniel El

Abstract

A 59-year-old woman developed a rash and severe arthralgia, which primarily affected her fingers. She displayed digital arthritis and nodules on the hands, chest, face, and oral cavity. Blood samples were normal. Skin biopsies revealed histiocytic proliferation. The surface marker profile and clinical findings were consistent with multicentric reticulohistiocytosis, which may occur as a paraneoplastic phenomenon. On workup, she was diagnosed with an otherwise asymptomatic stage IVC fallopian tube cancer. She experienced little effect of prednisolone, but her condition improved on antineoplastic treatment.

Published
2018

43. Hair cortisol in twins:heritability and genetic overlap with psychological variables and stress-system genes

Author

Rietschel, Liz, Streit, Fabian, McGrath, John, Davies, Gareth, Davies, Gail, de Geus, Eco J C, De Jager, Philip, Deary, Ian J, Degenhardt, Franziska, Dunn, Erin C, Ehli, Erik A, Eley, Thalia C, Escott-Price, Valentina, Hickie, Ian B, Esko, Tõnu, Finucane, Hilary K, Gill, Michael, Gordon, Scott D, Grove, Jakob, Hall, Lynsey S, Hansen, Thomas F, Søholm Hansen, Christine, Heath, Andrew C, Hansell, Narelle K, Henders, Anjali K, Herms, Stefan, Hoffmann, Per, Homuth, Georg, Horn, Carsten, Hottenga, Jouke- Jan, Hougaard, David, Huang, Hailiang, Ising, Marcus, Jansen, Rick, Wright, Margaret J, Jorgenson, Eric, Kloiber, Stefan, Knowles, James A, Kretzschmar, Warren W, Krogh, Jesper, Kutalik, Zoltán, Lang, Maren, Lewis, Glyn, Li, Yihan, MacIntyre, Donald J, Gillespie, Nathan A, Madden, Pamela Af, Marchine, Jonathan, Mbarek, Hamdi, McGuffin, Peter, Mehta, Divya, Metspalu, Andres, Middeldorp, Christel M, Mihailov, Evelin, Milani, Lili, Montgomery, Grant W, Forstner, Andreas J, Mostafavi, Sara, Mullins, Niamh, Nauck, Matthias, Ng, Bernard, Nordentoft, Merete, Nyholt, Dale R, O'Donovan, Michael C, O'Reilly, Paul F, Oskarsson, Hogni, Owen, Michael J, Schulze, Thomas G, Paciga, Sara A, Pedersen, Carsten Bøcker, Pedersen, Marianne Giørtz, Pedersen, Nancy L, Pergadia, Michele L, Peterson, Roseann E, Pettersson, Erik, Peyrot, Wouter J, Porteous, David J, Posthuma, Danielle, Wüst, Stefan, Potash, James B, Quiroz, Jorge A, Rice, John P, Riley, Brien P, Rivera, Margarita, Ruderfer, Douglas M, Saeed Mirza, Saira, Schoevers, Robert, Shen, Ling, Shi, Jianxin, Nöthen, Markus M, Sigurdsson, Engilbert, Sinnamon, Grant Cb, Smit, Johannes H, Smith, Daniel J, Smoller, Jordan W, Stephansson, Hreinn, Steinberg, Stacy, Strohmaier, Jana, Tansey, Katherine E, Teumer, Alexander, Baumgartner, Markus R, Thompson, Wesley, Thomson, Pippa A, Thorgeirsson, Thorgeir E, Treutlein, Jens, Trzaskowski, Maciej, Umbricht, Daniel, van der Auwera, Sandra, van Grootheest, Gerard, van Hemert, Albert M, Viktorin, Alexander, Zhu, Gu, Walker, Brian R, Völzke, Henry, Wang, Yunpeng, Webb, Bradley T, Weissman, Myrna M, Wellmann, Jürgen, Willemsen, Gonneke, Xi, Hualin S, Baune, Bernhard T, Blackwood, Douglas H R, Boomsma, Dorret I, Crawford, Andrew A, Børglum, Anders D, Buttenschøn, Henriette N, Cichon, Sven, Domenici, Enrico, Flint, Jonathan, Grabe, Hans J, Hamilton, Steven P, Kendler, Kenneth S, Li, Qingqin S, Lucae, Susanne, Colodro-Conde, Lucía, Magnusson, Patrik K, McIntosh, Andrew M, Mors, Ole, Bo Mortensen, Preben, Müller-Myhsok, Bertram, Penninx, Brenda Wjh, Perlis, Roy H, Preisig, Martin, Schaefer, Catherine, Medland, Sarah E, Stephansson, Kari, Tiemeier, Henning, Uher, Rudolf, Werge, Thomas, Winslow, Ashley R, Breen, Gerome, Levinson, Douglas F, Lewis, Cathryn M, Wray, Naomi R, Sullivan, Patrick F, Martin, Nicholas G, Rietschel, Marcella, Bolton, Jennifer L, Hayward, Caroline, Direk, Nese, Anderson, Anna, McAloney, Kerrie, Huffman, Jennifer, Wilson, James F, Campbell, Harry, Rudan, Igor, Wright, Alan, Hastie, Nicholas, Wild, Sarah H, Velders, Fleur P, Hofman, Albert, Uitterlinden, Andre G, Frank, Josef, Lahti, Jari, Räikkönen, Katri, Kajantie, Eero, Widen, Elisabeth, Palotie, Aarno, Eriksson, Johan G, Kaakinen, Marika, Järvelin, Marjo-Riitta, Timpson, Nicholas J, Davey Smith, George, Couvy-Duchesne, Baptiste, Ring, Susan M, Evans, David M, St Pourcain, Beate, Tanaka, Toshiko, Milaneschi, Yuri, Bandinelli, Stefania, Ferrucci, Luigi, van der Harst, Pim, Rosmalen, Judith Gm, Bakker, Stephen Jl, Witt, Stephanie H, Verweij, Niek, Dullaart, Robin Pf, Mahajan, Anubha, Lindgren, Cecilia M, Morris, Andrew, Lind, Lars, Ingelsson, Erik, Anderson, Laura N, Pennell, Craig E, Lye, Stephen J, Binz, Tina M, Matthews, Stephen G, Eriksson, Joel, Mellstrom, Dan, Ohlsson, Claes, Price, Jackie F, Strachan, Mark Wj, Reynolds, Rebecca M, Ripke, Stephan, Mattheisen, Manuel, CORtisolNETwork, Abdellaoui, Abdel, Adams, Mark J, Agerbo, Esben, Air, Tracy M, Andlauer, Till Fm, Bacanu, Silviu-Alin, Bækvad-Hansen, Marie, Beekman, Aartjan Tf, Bennett, David A, Berger, Klaus, Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics, Bigdeli, Tim B, Bybjerg-Grauholm, Jonas, Byrne, Enda M, Cai, Na, Castelao, Enrique, Clarke, Toni-Kim, Coleman, Jonathan Ri, Consortium, Converge, Craddock, Nick, Dannlowski, Udo, Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, APH - Mental Health, Internal medicine, Amsterdam Reproduction & Development (AR&D), Human genetics, APH - Methodology, APH - Digital Health, Centre of Excellence in Complex Disease Genetics, Research Programme of Molecular Medicine, Research Programs Unit, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, University of Zurich, Rietschel, Liz, Biological Psychology, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Health Behaviors & Chronic Diseases, and APH - Personalized Medicine

Subjects
Male, Oncology, Netherlands Twin Register (NTR), Multifactorial Inheritance, Hydrocortisone, lcsh:Medicine, 340 Law, Genome-wide association study, 3124 Neurology and psychiatry, 0302 clinical medicine, Twins, Dizygotic, SOCIOECONOMIC-STATUS, Young adult, lcsh:Science, Child, 610 Medicine & health, Genetics, Multidisciplinary, Depression, PSYCHIATRIC-DISORDERS, 10218 Institute of Legal Medicine, Neuroticism, DEPRESSIVE SYMPTOMS, MORNING CORTISOL, Female, FUTURE-DIRECTIONS, Adult, medicine.medical_specialty, Cortisol awakening response, Adolescent, PERCEIVED STRESS, Biology, Genetic correlation, Article, LONG-TERM CORTISOL, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Journal Article, Humans, neoplasms, Behavioural genetics, 1000 Multidisciplinary, Models, Genetic, lcsh:R, Twins, Monozygotic, ADRENAL AXIS ACTIVITY, MAJOR DEPRESSION, Heritability, Twin study, R1, digestive system diseases, 030227 psychiatry, ddc:000, INTRAINDIVIDUAL STABILITY, lcsh:Q, Stress, Psychological, 030217 neurology & neurosurgery, Hair
Abstract

Hair cortisol concentration (HCC) is a promising measure of long-term hypothalamus-pituitary-adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-individual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC; (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism; using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables. Consortia CORtisolNETwork (CORNET) Consortium Jennifer L. Bolton21 Caroline Hayward23 Nese Direk24,25 Anna Anderson21 Jennifer Huffman23 James F. Wilson26 Harry Campbell26 Igor Rudan26 Alan Wright23 Nicholas Hastie23 Sarah H. Wild26 Fleur P. Velders24 Albert Hofman24 Andre G. Uitterlinden24,27 Jari Lahti28 Katri Räikkönen28 Eero Kajantie29 Elisabeth Widen30 Aarno Palotie30,31 Johan G. Eriksson29,32,33,34,35 Marika Kaakinen36 Marjo-Riitta Järvelin36,37,38,39 Nicholas J. Timpson40 George Davey Smith40 Susan M. Ring41 David M. Evans40 Beate St Pourcain41 Toshiko Tanaka42 Yuri Milaneschi42,43 Stefania Bandinelli44 Luigi Ferrucci42 Pim van der Harst45,46,47 Judith GM Rosmalen48 Stephen JL Bakker49 Niek Verweij45 Robin PF Dullaart49 Anubha Mahajan50 Cecilia M. Lindgren50 Andrew Morris50 Lars Lind51 Erik Ingelsson51 Laura N. Anderson52 Craig E. Pennell53 Stephen J. Lye52 Stephen G. Matthews54 Joel Eriksson55 Dan Mellstrom55 Claes Ohlsson55 Jackie F. Price26 Mark WJ Strachan21 Rebecca M. Reynolds21 Henning Tiemeier24,56,57 Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium (PGC) Stephan Ripke58,59,60 Manuel Mattheisen61,62,63 Abdel Abdellaoui64 Mark J. Adams65 Esben Agerbo66,8,67 Tracy M. Air68 Till FM Andlauer69,70 Silviu-Alin Bacanu71 Marie Bækvad-Hansen67,72 Aartjan TF Beekman43 David A. Bennett73 Klaus Berger74 Tim B. Bigdeli71,11 Jonas Bybjerg-Grauholm67,72 Enda M. Byrne5 Na Cai75 Enrique Castelao76 Toni-Kim Clarke65 Jonathan RI Coleman77 Converge Consortium78 Nick Craddock79 Udo Dannlowski80,81 Gareth Davies82 Gail Davies83 Eco. J. C. de Geus64,84 Philip De Jager85 Ian J. Deary83 Franziska Degenhardt12,13 Erin C. Dunn86,87,88 Erik A. Ehli82 Thalia C. Eley77 Valentina Escott-Price89 Tõnu Esko58,90,91,92 Hilary K. Finucane93,94 Michael Gill95 Scott D. Gordon96 Jakob Grove61,62,67,97 Lynsey S. Hall65,98 Thomas F. Hansen99,100 Christine Søholm Hansen67,72 Thomas F. Hansen101 Andrew C. Heath102 Anjali K. Henders5 Stefan Herms12,13,15 Per Hoffmann12,13,15 Georg Homuth103 Carsten Horn104 Jouke- Jan Hottenga64 David Hougaard67,72 Hailiang Huang59,86,105 Marcus Ising106 Rick Jansen43 Eric Jorgenson107 Stefan Kloiber108,109 James A Knowles110 Warren W. Kretzschmar50 Jesper Krogh111 Zoltán Kutalik112,113 Maren Lang3 Glyn Lewis114 Yihan Li50 Donald J. MacIntyre115,116 Pamela AF Madden102 Jonathan Marchine117 Hamdi Mbarek118,64 Peter McGuffin77 Divya Mehta119 Andres Metspalu92,120 Christel M. Middeldorp64 Evelin Mihailov92,121 Lili Milani92 Grant W. Montgomery122 Sara Mostafavi123,124 Niamh Mullins77 Matthias Nauck125,126 Bernard Ng124 Merete Nordentoft67,127 Dale R. Nyholt128 Michael C. O’Donovan129 Paul F. O’Reilly77 Hogni Oskarsson130 Michael J. Owen129 Sara A. Paciga131 Carsten Bøcker Pedersen66,67,8 Marianne Giørtz Pedersen66,67,8 Nancy L. Pedersen132 Michele L. Pergadia133 Roseann E. Peterson11,71 Erik Pettersson134 Wouter J. Peyrot43 David J. Porteous135 Danielle Posthuma136,137 James B. Potash138 Jorge A. Quiroz139 John P. Rice102 Brien P. Riley71 Margarita Rivera77,140 Douglas M. Ruderfer141 Saira Saeed Mirza24 Robert Schoevers142 Ling Shen107 Jianxin Shi143 Engilbert Sigurdsson144 Grant CB Sinnamon145 Johannes H. Smit43 Daniel J. Smith146 Jordan W. Smoller86 Hreinn Stephansson147 Stacy Steinberg147 Jana Strohmaier3 Katherine E. Tansey148 Alexander Teumer149 Wesley Thompson100,135,150,151,152 Pippa A. Thomson135 Thorgeir E. Thorgeirsson147 Jens Treutlein3 Maciej Trzaskowski153 Daniel Umbricht154 Sandra van der Auwera155 Gerard van Grootheest43 Albert M. van Hemert156 Alexander Viktorin132 Henry Völzke149 Yunpeng Wang67,100,151 Bradley T. Webb157 Myrna M. Weissman158,159 Jürgen Wellmann74 Gonneke Willemsen64 Hualin S. Xi160 Bernhard T. Baune68 Douglas H. R. Blackwood65 Dorret I. Boomsma64 Anders D. Børglum61,62,67 Henriette N. Buttenschøn62,67,161 Sven Cichon12,162,163,164 Enrico Domenici165 Jonathan Flint50,166 Hans J. Grabe155 Steven P. Hamilton167 Kenneth S. Kendler71 Qingqin S. Li168 Susanne Lucae106 Patrik K. Magnusson132 Andrew M. McIntosh65,83 Ole Mors67,169 Preben Bo Mortensen62,8,67 Bertram Müller-Myhsok69,70,170 Brenda WJH Penninx43 Roy H. Perlis87,171 Martin Preisig76 Catherine Schaefer107 Jordan W. Smoller87,88 Kari Stephansson147 Henning Tiemeier24,56,57 Rudolf Uher172 Thomas Werge100,150,173 Ashley R. Winslow174,175 Gerome Breen77,176 Douglas F. Levinson177 Cathryn M. Lewis77,178 Naomi R. Wray5,153 Patrick F. Sullivan134,179,180 23MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK. 24Department of Epidemiology, Erasmus Medical Centre, Rotterdam, Netherlands. 25Psychiatry, Dokuz Eylul University School Of Medicine, Izmir, TR, Turkey. 26Centre for Population Health Sciences, Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH8 9AG, UK. 27Internal Medicine, Erasmus MC, Rotterdam, NL, Netherlands. 28Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland. 29National Institute for Health and Welfare, Helsinki, Finland. 30Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. 31Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland. 32Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland. 33Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland. 34Folkhalsan Research Centre, Helsinki, Finland. 35Vasa Central Hospital, Vasa, Finland. 36Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland. 37Department of Children and Yond People and Families, National Institute for Health and elfare, Oulu, Finland. 38Department of Epidemiology and Biostatistics, MRC-HPA Centre for Environment and Health, Imperial College London, London, UK. 39Unit of Primary Care, Oulu University Hospital, Oulu, Finland. 40MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, UK. 41School of Social and Community Medicine, University of Bristol, Bristol, UK. 42Longitudinal Studies Section, Clinical Research Branch, National Institute on Aging, Baltimore, MD, USA. 43Department of Psychiatry, VU University Medical Center/GGZ inGeest, Amsterdam, Netherlands. 44Geriatric Unit, ASF, Florence, Italy. 45University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, Netherlands. 46University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, Netherlands. 47Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, Netherlands. 48University of Groningen, University Medical Center Groningen, Interdisciplinary Center for Psychiatric Epidemiology, Groningen, Netherlands. 49University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, Netherlands. 50Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. 51Department of Medical Sciences, Uppsala University, Uppsala, Sweden. 52Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. 53School of Women’s and Infant’s Health, The University of Western Australia, Crawley, Australia. 54Department of Physiology, University of Toronto, Toronto, Ontario, Canada. 55Center for Bone and Arthritis Research, Institute of Medicin, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 56Child and Adolescent Psychiatry, Erasmus MC, Rotterdam, Netherlands. 57Psychiatry, Erasmus MC, Rotterdam, Netherlands. 58Medical and Population Genetics, Broad Institute, Cambridge, USA. 59Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, USA. 60Department of Psychiatry and Psychotherapy, Universitätsmedizin Berlin Campus Charité Mitte, Berlin, Germany. 61Department of Biomedicine, Aarhus University, Aarhus, Denmark. 62iSEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark. 63iSPYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark. 64Dept of Biological Psychology, VU University Amsterdam, Amsterdam, Netherlands. 65Division of Psychiatry, University of Edinburgh, Edinburgh, UK. 66Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark. 67iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark. 68Discipline of Psychiatry, University of Adelaide, Adelaide, Australia. 69Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany. 70Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. 71Department of Psychiatry, Virginia Commonwealth University, Richmond, USA. 72Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark. 73Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, USA. 74Institute of Epidemiology and Social Medicine, University of Muenster, Muenster, UK. 75Human Genetics, Wellcome Trust Sanger Institute, Cambridge, UK. 76Department of Psychiatry, University Hospital of Lausanne, Prilly, Switzerland. 77MRC Social Genetic and Developmental Psychiatry Centre, King’s College London, London, UK. 78University of Oxford, Oxford, UK. 79Psychological Medicine, Cardiff University, Cardiff, UK. 80Department of Psychiatry, University of Marburg, Marburg, Germany. 81Department of Psychiatry, University of Münster, Münster, Germany. 82Avera Institute for Human Genetics, Sioux Falls, USA. 83Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK. 84EMGO+ Institute, VU University Medical Center, Amsterdam, Netherlands. 85Neurology, Brigham and Women’s Hospital, Boston, USA. 86Stanley Center for Psychiatric Research, Broad Institute, Cambridge, USA. 87Department of Psychiatry, Massachusetts General Hospital, Boston, USA. 88Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Massachusetts General Hospital, Boston, USA. 89Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK. 90Division of Endocrinology, Children’s Hospital Boston, Boston, USA. 91Department of Genetics, Harvard Medical School, Boston, USA. 92Estonian Genome Center, University of Tartu, Tartu, Estonia. 93Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, USA. 94Department of Mathematics, Massachusetts Institute of Technology, Cambridge, USA. 95Department of Psychiatry, Trinity College Dublin, Dublin, Ireland. 96Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia. 97Bioinformatics Research Centre (BiRC), Aarhus University, Aarhus, Denmark. 98Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK. 99Danish Headache Centre, Department of Neurology, Rigshospitalet Glostrup, Glostrup, Denmark. 100Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Capital Region of Denmark, Roskilde, Denmark. 101iPSYCH, The Lundbeck Foundation Initiative for Psychiatric Research, Copenhagen, Denmark. 102Department of Psychiatry, Washington University in Saint Louis School of Medicine, Saint Louis, USA. 103Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine and Ernst Moritz Arndt University Greifswald, Greifswald, Germany. 104Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland. 105Department of Medicine, Harvard Medical School, Boston, USA. 106Max Planck Institute of Psychiatry, Munich, Germany. 107Division of Research, Kaiser Permanente Northern California, Oakland, USA. 108Centre for Addiction and Mental Health, Toronto, Canada. 109Department of Psychiatry, University of Toronto, Toronto, Canada. 110Psychiatry & The Behavioral Sciences, University of Southern California, Los Angeles, USA. 111Department of Endocrinology at Herlev University Hospital, University of Copenhagen, Copenhagen, Denmark. 112Swiss Institute of Bioinformatics, Lausanne, Switzerland. 113Institute of Social and Preventive Medicine (IUMSP), Lausanne University Hospital, Lausanne, Switzerland. 114Division of Psychiatry, University College London, London, UK. 115Mental Health NHS 24, Glasgow, UK. 116Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK. 117Statistics, University of Oxford, Oxford, UK. 118EMGO+ Institute for Health and Care Research, Amsterdam, Netherlands. 119School of Psychology and Counseling, Queensland University of Technology, Brisbane, Australia. 120Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia. 121Estonian Biocentre, Tartu, Estonia. 122Institute for Molecular Biology, University of Queensland, Brisbane, Australia. 123Medical Genetics, University of British Columbia, Vancouver, Canada. 124Statistics, University of British Columbia, Vancouver, Canada. 125DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, University Medicine, Matthias Nauck, Greifswald, Germany. 126Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany. 127Mental Health Centre Copenhagen, Copenhagen Universtity Hospital, Copenhagen, Denmark. 128Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia. 129MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK. 130Humus, Reykjavik, Iceland. 131Human Genetics and Computational Biomedicine, Pfizer Global Research and Development, Groton, USA. 132Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 133Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, USA. 134Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 135Medical Genetics Section, CGEM, IGMM, University of Edinburgh, Edinburgh, UK. 136Complex Trait Genetics, VU University Amsterdam, Amsterdam, Netherlands. 137Clinical Genetics, VU University Medical Center, Amsterdam, Netherlands. 138Psychiatry, University of Iowa, Iowa City, USA. 139Solid GT, Boston, USA. 140Department of Biochemistry and Molecular Biology II, Institute of Neurosciences, Center for Biomedical Research, University of Granada, Granada, Spain. 141Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA. 142Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, Netherlands. 143Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, USA. 144Faculty of Medicine, Department of Psychiatry, School of Health Sciences, University of Iceland, Reykjavik, Iceland. 145School of Medicine and Dentistry, James Cook University, Townsville, Australia. 146Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK. 147deCODE Genetics/Amgen, Reykjavik, Iceland. 148College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK. 149Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany. 150iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Copenhagen, Denmark. 151KG Jebsen Centre for Psychosis Research, Norway Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. 152Department of Psychiatry, University of California, San Diego, San Diego, USA. 153Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia. 154Roche Pharmaceutical Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases Discovery & Translational Medicine Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland. 155Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany. 156Department of Psychiatry, Leiden University Medical Center, Leiden, Netherlands. 157Virginia Institute of Psychiatric & Behavioral Genetics, Virginia Commonwealth University, Richmond, USA. 158Psychiatry, Columbia University College of Physicians and Surgeons, New York, USA. 159Division of Epidemiology, New York State Psychiatric Institute, New York, USA. 160Computational Sciences Center of Emphasis, Pfizer Global Research and Development, Cambridge, USA. 161Department of Clinical Medicine, Translational Neuropsychiatry Unit, Aarhus University, Aarhus, Denmark. 162Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany. 163Department of Biomedicine, University of Basel, Basel, CH, Switzerland. 164Division of Medical Genetics, University of Basel, Basel, CH, Switzerland. 165Centre for Integrative Biology, Università degli Studi di Trento, Trento, Italy. 166Psychiatry, University of California Los Angeles, Los Angeles, USA. 167Psychiatry, Kaiser Permanente Northern California, San Francisco, USA. 168Neuroscience Therapeutic Area, Janssen Research and Development, LLC, Titusville, USA. 169Psychosis Research Unit, Aarhus University Hospital, Risskov, Aarhus, Denmark. 170Institute of Translational Medicine, University of Liverpool, Liverpool, UK. 171Psychiatry, Harvard Medical School, Boston, USA. 172Psychiatry, Dalhousie University, Halifax, Canada. 173Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. 174Human Genetics and Computational Biomedicine, Pfizer Global Research and Development, Cambridge, USA. 175Orphan Disease Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA. 176NIHR BRC for Mental Health, King’s College London, London, UK. 177Psychiatry & Behavioral Sciences, Stanford University, Stanford, USA. 178Department of Medical & Molecular Genetics, King’s College London, London, UK. 179Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, USA. 180Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, USA.

Published
2017

44. Opioids for cancer-related pain in children and adolescents

Author

Wiffen, Philip J, Cooper, Tess E, Anderson, Anna-Karenia, Gray, Andrew L, Grégoire, Marie-Claude, Ljungman, Gustaf, Zernikow, Boris, Wiffen, Philip J, Cooper, Tess E, Anderson, Anna-Karenia, Gray, Andrew L, Grégoire, Marie-Claude, Ljungman, Gustaf, and Zernikow, Boris

Abstract

BACKGROUND: Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization (WHO) guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. Views on children's pain have changed over time and relief of pain is now seen as important. In the past, pain was largely dismissed and was frequently left untreated, and it was assumed that children quickly forgot about painful experiences.We designed a suite of seven reviews in chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol) to review the evidence for children's pain using pharmacological interventions.As one of the leading causes of mortality and morbidity for children and adolescents in the world today, childhood cancer (and its associated pain) is a major health concern. Cancer pain in infants, children, and adolescents is primarily nociceptive pain with negative long term effects. Cancer-related pain is generally caused directly by the tumour itself such as compressing on the nerve or inflammation of the organs. Cancer-related pain generally occurs as a result of perioperative procedures, nerve damage caused by radiation or chemotherapy treatments, or mucositis. However, this review focused on pain caused directly by the tumour itself such as nerve infiltration, external nerve compression, and other inflammatory events.Opioids are used worldwide for the treatment of pain. Currently available opioids include: buprenorphine, codeine, fentanyl, hydromorphone, methadone, morphine, oxycodone, and tramadol. Opioids are generally available in healthcare settings across most developed countries but access may be restricted in developing countries. To achieve adequate pain relief in children using opioids, with

Published
2017
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45. Carbonyl reductase 1 catalyzes 20 beta-reduction of glucocorticoids, modulating receptor activation and metabolic complications of obesity

Author

Morgan, Ruth A., Beck, Katharina R., Nixon, Mark, Homer, Natalie Z. M., Crawford, Andrew A., Melchers, Diana, Houtman, René, Meijer, Onno C., Stomby, Andreas, Anderson, Anna J., Upreti, Rita, Stimson, Roland H., Olsson, Tommy, Michoel, Tom, Cohain, Ariella, Ruusalepp, Arno, Schadt, Eric E., Björkegren, Johan L. M., Andrew, Ruth, Kenyon, Christopher J., Hadoke, Patrick W. F., Odermatt, Alex, Keen, John A., Walker, Brian R., Morgan, Ruth A., Beck, Katharina R., Nixon, Mark, Homer, Natalie Z. M., Crawford, Andrew A., Melchers, Diana, Houtman, René, Meijer, Onno C., Stomby, Andreas, Anderson, Anna J., Upreti, Rita, Stimson, Roland H., Olsson, Tommy, Michoel, Tom, Cohain, Ariella, Ruusalepp, Arno, Schadt, Eric E., Björkegren, Johan L. M., Andrew, Ruth, Kenyon, Christopher J., Hadoke, Patrick W. F., Odermatt, Alex, Keen, John A., and Walker, Brian R.

Abstract

Carbonyl Reductase 1 (CBR1) is a ubiquitously expressed cytosolic enzyme important in exogenous drug metabolism but the physiological function of which is unknown. Here, we describe a role for CBR1 in metabolism of glucocorticoids. CBR1 catalyzes the NADPH-dependent production of 20 beta-dihydrocortisol (20 beta-DHF) from cortisol. CBR1 provides the major route of cortisol metabolism in horses and is up-regulated in adipose tissue in obesity in horses, humans and mice. We demonstrate that 20 beta-DHF is a weak endogenous agonist of the human glucocorticoid receptor (GR). Pharmacological inhibition of CBR1 in diet-induced obesity in mice results in more marked glucose intolerance with evidence for enhanced hepatic GR signaling. These findings suggest that CBR1 generating 20 beta-dihydrocortisol is a novel pathway modulating GR activation and providing enzymatic protection against excessive GR activation in obesity.

Published
2017
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46. Metformin increases cortisol regeneration by 11βHSD1 in obese men with and without type 2 diabetes mellitus

Author

Anderson, Anna J, Andrew, Ruth, Homer, Natalie Z, Jones, Gregory C, Smith, Kenneth, Livingstone, Dawn E, Walker, Brian R, and Stimson, Roland H

Subjects
endocrine system diseases, nutritional and metabolic diseases, cortisol, metformin, tracer methodology, liver, adipose tissue
Abstract

CONTEXT: The mechanism of action of metformin remains unclear. Given regulation of the cortisol-regenerating enzyme 11βHSD1 by insulin, and limited efficacy of selective 11βHSD1 inhibitors to lower blood glucose when co-prescribed with metformin, we hypothesized that metformin reduces 11βHSD1 activity.OBJECTIVE: To determine whether metformin regulates 11βHSD1 activity in vivo in obese men with and without type 2 diabetes.DESIGN: Double blind randomised placebo controlled crossover study Setting: A hospital clinical research facility Participants: Eight obese non-diabeticmen (OND) and eight obesemenwith type 2 diabetes (ODM) Intervention: Participants received 28 days of metformin (1g twice daily), placebo, or (in the ODM group) gliclazide (80mg twice daily) in random order. A deuterated cortisol infusion at the end of each phase measured cortisol regeneration by 11βHSD1. Oral cortisone was given to measure hepatic 11βHSD1 activity in the ODM group. The effect of metformin on 11βHSD1 was also assessed in human hepatocytes and SGBS adipocytes.MAIN OUTCOME MEASURES: The effect of metformin on whole body and hepatic 11βHSD1 activity.RESULTS: Whole body 11βHSD1 activity was ~25% higher in the ODM than OND group. Metformin increased whole body cortisol regeneration by 11βHSD1 in both groups compared with placebo and gliclazide, and tended to increase hepatic 11βHSD1 activity. In vitro, metformin did not increase 11βHSD1 activity in hepatocytes or adipocytes.CONCLUSIONS: Metformin increases whole body cortisol generation by 11βHSD1 probably through an indirect mechanism, potentially offsetting other metabolic benefits of metformin. Co-prescription with metformin should provide a greater target for selective 11βHSD1 inhibitors.

Published
2016

47. COMMITTEE REPORTS

Author

Meyer, H. H. B., Brigham, Harold F., Richardson, Ernest C., Ommen, Alfred E., Barmby, Mary, French, Randall, Rogers, Violet J., Balz, Leonard, Archer, John, Cannon, Carl L., Butler, Pierce, Granniss, Ruth S., Kyte, E. Cockburn, Overton, Jacqueline M., van Patten, Nathan, Stevens, Edward F., Gjelsness, Rudolph, Spaulding, Forrest B., Kaiser, John B., Rathbone, Josephine Adams, Hamilton, William J., Joeckel, Carleton B., Rothrock, Mary U., Sumner, Clarence W., Severance, Henry O., Herbert, Clara W., Merrill, Julia Wright, Britton, Jasmine, Brigham, Johnson, Cullen, Elizabeth O., Lester, Clarence B., Long, Harriet C., Morgan, Joy E., Price, Miles O., Redstone, Edward H., Tolman, Frank L., Munn, Ralph, Shearer, Augustus H., Pomeroy, Elizabeth, Caldwell, Gladys, Gerould, James Thayer, Lydenberg, H. M., Lucas, E. Louise, Jones, E. Kathleen, Corbin, William L., Doane, Gilbert H., James, Helen C., Smith, Charles Henry, Graves, C. Edward, Webb, William, Vance, John T., Smith, Susan T., Dickerson, L. L., Butlin, Iva M., Gerould, James T., Mulheron, Anne M., Rush, Charles E., Wellman, Hiller C., Ranck, Samuel H., Anderson, Anna M., Andrews, Siri M., Davis, Mary Gould, Grout, Dorothy K., Latimer, Louise P., Martin, Helen, Overman, Ruth A., Smith, Lillian H., McGregor, Della, Barnett, Claribel R., Sawyer, R. A., Askew, Sarah B., Marzolf, Marie Cecilia, Henderson, Glieth, Henshaw, Francis, Morgan, Lucy L., Waples, Douglas, Williamson, Charles C., Wheeler, Joseph L., Andrus, Gertrude E., Bement, Constance, Sanderson, Charles R., Truf, Mary A., Roberts, Flora B., Henry, Edward A., Bailey, Louis J., Booth, Mary J., Evans, Lillian M., Flexner, Jennie M., Hopper, Franklin F., Howard, James A., Hunt, M. Louise, Hyde,, Dorsey W., Manchester, Earl N., Perry, Leta, Robinson, E. S., Compton, C. H., Bowerman, George F., Williamson, C. C., Wigginton, May Wood, Austen, Willard, Bostwick, Arthur E., Lydenberg, Harry M., Hooker, David Ashley, Carson, Annie E., and Phillips, Edna

Published
1931

48. Carbonyl reductase 1 catalyzes 20β-reduction of glucocorticoids, modulating receptor activation and metabolic complications of obesity

Author

Morgan, Ruth A., primary, Beck, Katharina R., additional, Nixon, Mark, additional, Homer, Natalie Z. M., additional, Crawford, Andrew A., additional, Melchers, Diana, additional, Houtman, René, additional, Meijer, Onno C., additional, Stomby, Andreas, additional, Anderson, Anna J., additional, Upreti, Rita, additional, Stimson, Roland H., additional, Olsson, Tommy, additional, Michoel, Tom, additional, Cohain, Ariella, additional, Ruusalepp, Arno, additional, Schadt, Eric E., additional, Björkegren, Johan L. M., additional, Andrew, Ruth, additional, Kenyon, Christopher J., additional, Hadoke, Patrick W. F., additional, Odermatt, Alex, additional, Keen, John A., additional, and Walker, Brian R., additional

Published
2017
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50. The landscape of child protection research in the UK:A UK mapping review

Author

Taylor, Julie, Mackay, Kirsteen, Jones, Christine, Soliman, Francesca, Clayton, Estelle, Anderson, Anna, Gadda, Andressa, and Jones, Derek

Abstract

This study, undertaken for the NSPCC, is the first comprehensive systematic search and review of research undertaken in all four nations of the United Kingdom on the subject of child protection. It covers the five year timespan January, 2010 through December, 2014 to produce a mapping review on the landscape of child protection.The research questions were:1) How can child protection research be classified?2) What child protection research has been published between January, 2010 and December, 2014?a. What proportion of the published research was undertaken within academia?b. Who undertakes child protection research in the UK?c. In which disciplines was the research undertaken?d. On what aspects of child protection has the research focused?e. What research designs have been used?f. What types of data have been used?g. Whose perspectives have been included?3) Who funded the research and how much money has been allocated to the research?

Published
2015

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