Ultradian hydrocortisone replacement alters neuronal processing, emotional ambiguity, affect and fatigue in adrenal insufficiency: The PULSES trial.

BACKGROUND: 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. OBJECTIVES: To assess the effect of pump therapy on quality of life, mood, functional neuroimaging, behavioural/cognitive responses, sleep and metabolism. METHODS: A 6-week randomised, crossover, double-blinded and placebo-controlled 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. RESULTS: Between December 2014 and 2017, 22 participants were recruited - 20 completed both arms, and 21 were analysed. The pump was well-tolerated. 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-sensitive 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. CONCLUSIONS: These findings support the administration of hormone therapy that mimics physiology.

Modelling the COVID-19 pandemic: Focusing on the case of Greece.

The SARS-CoV-2 infection (COVID-19) pandemic created an unprecedented chain of events at a global scale, with European counties initially following individual pathways on the confrontation of the global healthcare crisis, before organizing coordinated public vaccination campaigns, when proper vaccines became available. In the meantime, the viral infection outbreaks were determined by the inability of the immune system to retain a long-lasting protection as well as the appearance of SARS-CoV-2 variants with differential transmissibility and virulence. How do these different parameters regulate the domestic impact of the viral epidemic outbreak? We developed two versions of a mathematical model, an original and a revised one, able to capture multiple factors affecting the epidemic dynamics. We tested the original one on five European countries with different characteristics, and the revised one in one of them, Greece. For the development of the model, we used a modified version of the classical SEIR model, introducing various parameters related to the estimated epidemiology of the pathogen, governmental and societal responses, and the concept of quarantine. We estimated the temporal trajectories of the identified and overall active cases for Cyprus, Germany, Greece, Italy and Sweden, for the first 250 days. Finally, using the revised model, we estimated the temporal trajectories of the identified and overall active cases for Greece, for the duration of the 1230 days (until June 2023). As shown by the model, small initial numbers of exposed individuals are enough to threaten a large percentage of the population. This created an important political dilemma in most countries. Force the virus to extinction with extremely long and restrictive measures or merely delay its spread and aim for herd immunity. Most countries chose the former, which enabled the healthcare systems to absorb the societal pressure, caused by the increased numbers of patients, requiring hospitalization and intensive care.

Modelling Hydrocortisone Pharmacokinetics on a Subcutaneous Pulsatile Infusion Replacement Strategy in Patients with Adrenocortical Insufficiency.

In the context of glucocorticoid (GC) therapeutics, recent studies have utilised a subcutaneous hydrocortisone (HC) infusion pump programmed to deliver multiple HC pulses throughout the day, with the purpose of restoring normal circadian and ultradian GC rhythmicity. A key challenge for the advancement of novel HC replacement therapies is the calibration of infusion pumps against cortisol levels measured in blood. However, repeated blood sampling sessions are enormously labour-intensive for both examiners and examinees. These sessions also have a cost, are time consuming and are occasionally unfeasible. To address this, we developed a pharmacokinetic model approximating the values of plasma cortisol levels at any point of the day from a limited number of plasma cortisol measurements. The model was validated using the plasma cortisol profiles of 9 subjects with disrupted endogenous GC synthetic capacity. The model accurately predicted plasma cortisol levels (mean absolute percentage error of 14%) when only four plasma cortisol measurements were provided. Although our model did not predict GC dynamics when HC was administered in a way other than subcutaneously or in individuals whose endogenous capacity to produce GCs is intact, it was found to successfully be used to support clinical trials (or practice) involving subcutaneous HC delivery in patients with reduced endogenous capacity to synthesize GCs.