{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T01:52:42Z","timestamp":1791337962444,"version":"4.3.1"},"reference-count":33,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2023,10,19]],"date-time":"2023-10-19T00:00:00Z","timestamp":1697673600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/J012548\/1"],"award-info":[{"award-number":["MR\/J012548\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000769","name":"University of Oxford","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000769","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012141","name":"University Hospitals Bristol NHS Foundation Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012141","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Intern Med"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Primary adrenal insufficiency (PAI) mortality and morbidity remain unacceptably high, possibly arising as glucocorticoid replacement does not replicate natural physiology. A pulsatile subcutaneous pump can closely replicate cortisol's circadian and ultradian rhythm.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>To assess the effect of pump therapy on quality of life, mood, functional neuroimaging, behavioural\/cognitive responses, sleep and metabolism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A 6\u2010week randomised, crossover, double\u2010blinded and placebo\u2010controlled feasibility study of usual dose hydrocortisone in PAI administered as either pulsed subcutaneous or standard care in Bristol, United Kingdom (ISRCTN67193733). Participants were stratified by adrenal insufficiency type. All participants who received study drugs are included in the analysis. The primary outcome, the facial expression recognition task (FERT), occurred at week 6.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Between December 2014 and 2017, 22 participants were recruited \u2013 20 completed both arms, and 21 were analysed. The pump was well\u2010tolerated. No change was seen in the FERT primary outcome; however, there were subjective improvements in fatigue and mood. Additionally, functional magnetic resonance imaging revealed differential neural processing to emotional cues and visual stimulation. Region of interest analysis identified the left amygdala and insula, key glucocorticoid\u2010sensitive regions involved in emotional ambiguity. FERT post hoc analysis confirmed this response. There were four serious adverse events (AE): three intercurrent illnesses requiring hospitalisation (1\/3, 33.3% pump) and a planned procedure (1\/1, 100% pump). There was a small number of expected AEs: infusion site bruising\/itching (3\/5, 60% pump), intercurrent illness requiring extra (3\/7, 42% pump) and no extra (4\/6, 66% pump) steroid.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These findings support the administration of hormone therapy that mimics physiology.<\/jats:p><\/jats:sec>","DOI":"10.1111\/joim.13721","type":"journal-article","created":{"date-parts":[[2023,10,19]],"date-time":"2023-10-19T23:00:50Z","timestamp":1697756450000},"page":"51-67","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Ultradian hydrocortisone replacement alters neuronal processing, emotional ambiguity, affect and fatigue in adrenal insufficiency: The PULSES trial"],"prefix":"10.1111","volume":"295","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1299-4116","authenticated-orcid":false,"given":"Georgina","family":"Russell","sequence":"first","affiliation":[{"name":"Laboratories of Integrative Neuroscience and Endocrinology Bristol Medical School University of Bristol  Bristol UK"},{"name":"University Hospital Bristol and Weston NHS Foundation Trust  Bristol UK"},{"name":"North Bristol NHS Trust  Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Kalafatakis","sequence":"additional","affiliation":[{"name":"Laboratories of Integrative Neuroscience and Endocrinology Bristol Medical School University of Bristol  Bristol UK"},{"name":"Department of Informatics and Telecommunications, Human\u2010Computer Interaction Laboratory University of Ioannina  Arta Greece"},{"name":"Clinical Research and Imaging Centre University of Bristol  Bristol UK"},{"name":"Faculty of Medicine and Dentistry (Malta Campus) Queen Mary University of London  Victoria Malta"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Durant","sequence":"additional","affiliation":[{"name":"Department of Brain Sciences Faculty of Medicine Imperial College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Marchant","sequence":"additional","affiliation":[{"name":"Laboratories of Integrative Neuroscience and Endocrinology Bristol Medical School University of Bristol  Bristol UK"},{"name":"University Hospital Bristol and Weston NHS Foundation Trust  Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamini","family":"Thakrar","sequence":"additional","affiliation":[{"name":"Laboratories of Integrative Neuroscience and Endocrinology Bristol Medical School University of Bristol  Bristol UK"},{"name":"Clinical Research and Imaging Centre University of Bristol  Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell","family":"Thirard","sequence":"additional","affiliation":[{"name":"Bristol Trials Centre Bristol Medical School University of Bristol  Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jade","family":"King","sequence":"additional","affiliation":[{"name":"University Hospital Bristol and Weston NHS Foundation Trust  Bristol UK"},{"name":"North Bristol NHS Trust  Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Bowles","sequence":"additional","affiliation":[{"name":"Laboratories of Integrative Neuroscience and Endocrinology Bristol Medical School University of Bristol  Bristol UK"},{"name":"University Hospital Bristol and Weston NHS Foundation Trust  Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Upton","sequence":"additional","affiliation":[{"name":"Laboratories of Integrative Neuroscience and Endocrinology Bristol Medical School University of Bristol  Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ngoc Jade","family":"Thai","sequence":"additional","affiliation":[{"name":"Clinical Research and Imaging Centre University of Bristol  Bristol UK"},{"name":"Neurosciences and Mental Health Liverpool Health Partners  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan C. 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