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.

Admissions to paediatric medical wards with a primary mental health diagnosis: a systematic review of the literature.

OBJECTIVE: To systematically review the literature describing children and young people (CYP) admissions to paediatric general wards because of primary mental health (MH) reasons, particularly in MH crisis. DESIGN: PubMed, Embase, PsycINFO, Web of Science and Google Scholar were searched, with no restriction on country or language. We addressed five search questions to inform: trends and/or the number of admissions, the risk factors for adverse care, the experiences of CYP, families/carers and healthcare professionals (HCPs) and the evidence of interventions aimed at improving the care during admissions.Two reviewers independently assessed the relevance of abstracts identified, extracted data and undertook quality assessment. This review was registered with PROSPERO (CRD42022350655). RESULTS: Thirty-two studies met the inclusion criteria. Eighteen addressed trends and/or numbers/proportions of admissions, 12 provided data about the views/experiences of HCPs, two provided data about CYP's experiences and four explored improving care. We were unable to identify studies examining risk factors for harm during admissions, but studies did report the length of stay in general paediatric/adult settings while waiting for specialised care, which could be considered a risk factor while caring for this group. CONCLUSIONS: MH admissions to children's wards are a long-standing issue and are increasing. CYP will continue to need to be admitted in crisis, with paediatric wards a common location while waiting for assessment. For services to be delivered effectively and for CYP and their families/carers to feel supported and HCPs to feel confident, we need to facilitate more integrated physical and MH pathways of care. PROSPERO REGISTRATION NUMBER: CRD42022350655.

Mental Health Admissions to Paediatric Wards Study (MAPS): protocol of a prospective study of mental health admissions to paediatric wards in England using surveillance and qualitative methods.

INTRODUCTION: Children and young people (CYP) presenting with a mental health (MH) crisis are frequently admitted to general acute paediatric wards as a place of safety. Prior to the pandemic, a survey in England showed that CYP occupied 6% of general paediatric inpatient beds due to an MH crisis, and there have been longstanding concerns about the quality of care to support these patients in this setting. MAPS aims to generate a Theory of Change (ToC) model to improve the quality of care for CYP admitted to acute paediatric services after presenting with an MH crisis. Here, we describe work packages (WPs) 2 and 3 of the study, which have been granted ethics approval. METHODS AND ANALYSIS: We will undertake a national (England), sequential, mixed-methods study to inform a ToC framework alongside a stakeholder group consisting of patients, families/carers and healthcare professionals (HCPs). Our study consists of four WPs undertaken over 30 months. WP2 is limited to working with stakeholders to develop a data collection instrument and then use this in a prospective study of MH admissions over 6 months in 15 purposively recruited acute paediatric wards across England. WP3 consists of gathering the views of CYP, their families/carers and HCPs during admissions using semistructured interviews. ETHICS AND DISSEMINATION: WP2 and WP3 received ethical approval (ref: 23/LO/0349). We will publish the overall synthesis of data and the final ToC to improve care of CYP with MH crisis admitted to general acute paediatric settings. As co-producers of the ToC, we will work with our stakeholder group to ensure wide dissemination of findings. Potential impacts will be upon service development, new models of care, training and workforce planning. PROSPERO REGISTRATION NUMBER: CRD42022350655.

Mental Health Admissions to Paediatric Wards Study (MAPS): a protocol for the analysis of Hospital Episode Statistics (HES) data.

INTRODUCTION: Children and young people (CYP) presenting with a mental health (MH) crisis are frequently admitted to general acute paediatric wards as a place of safety. Prior to the pandemic, a survey in England showed that CYP occupied 6% of general paediatric inpatient beds due to an MH crisis, and there have been longstanding concerns about the quality of care to support these patients in this setting. Mental Health Admissions to Paediatric Wards Study aims to generate a theory of change (ToC) model to improve the quality of care for CYP admitted to acute paediatric services after presenting in a MH crisis. METHODS AND ANALYSIS: We will undertake a national (England), sequential, mixed methods study to inform a ToC framework alongside a stakeholder group consisting of patients, families/carers and healthcare professionals (HCPs). Our study consists of four work packages (WP) undertaken over 30 months. WP1 is limited to using national routine administrative data to identify and characterise trends in MH admissions in acute paediatric wards in England between 2015- 2022. ETHICS AND DISSEMINATION: WP1 received ethical approval (Ref 23/NW/0192). We will publish the overall synthesis of data and the final ToC to improve care of CYP with MH crisis admitted to general acute paediatric settings. As coproducers of the ToC, we will work with our stakeholder group to ensure wide dissemination of findings. Potential impacts will be on service development, new models of care, training and workforce planning.

Multiplicity in the experience of voice-hearing: A phenomenological inquiry.

Although it is recognized that voice-hearers often report a large number and variety of voices there have been few investigations of this multiplicity. Understanding the phenomenology of voice-hearing can provide a firm foundation for theorizing about its causes. In this international online survey of voice-hearers, details were elicited of the content of up to five utterances associated with up to five voices from each respondent. The contents were independently rated and associated with characteristics of each voice such as its perceived age, whether it had changed over time, and whether it was of a familiar person. We investigated predictors (e.g., diagnoses, voice gender, age first heard) of utterance negativity, length, and whether voices referred to themselves. The average number of voices reported was approximately four. The majority were perceived as male and had negative content. Child-aged voices were significantly less negative than all other voices except those perceived as being elderly. Multi-level analyses indicated that there was significant variability at the level of different utterances within voices but variability was more prominent at the level of different voices within an individual. The data were inconsistent with general cognitive models for hearing voices such as the misattribution of inner speech and were more congruent with a dissociation model of voice-hearing. Our findings support approaches based on subtype or dimensional methods of classifying voices, and additionally indicate that research and clinical assessment may benefit from more systematic assessment of multiplicity.

Modelling the dynamic interaction of systemic inflammation and the hypothalamic-pituitary-adrenal (HPA) axis during and after cardiac surgery.

Major surgery and critical illness produce a potentially life-threatening systemic inflammatory response. The hypothalamic-pituitary-adrenal (HPA) axis is one of the key physiological systems that counterbalances this systemic inflammation through changes in adrenocorticotrophic hormone (ACTH) and cortisol. These hormones normally exhibit highly correlated ultradian pulsatility with an amplitude modulated by circadian processes. However, these dynamics are disrupted by major surgery and critical illness. In this work, we characterize the inflammatory, ACTH and cortisol responses of patients undergoing cardiac surgery and show that the HPA axis response can be classified into one of three phenotypes: single-pulse, two-pulse and multiple-pulse dynamics. We develop a mathematical model of cortisol secretion and metabolism that predicts the physiological mechanisms responsible for these different phenotypes. We show that the effects of inflammatory mediators are important only in the single-pulse pattern in which normal pulsatility is lost-suggesting that this phenotype could be indicative of the greatest inflammatory response. Investigating whether and how these phenotypes are correlated with clinical outcomes will be critical to patient prognosis and designing interventions to improve recovery.

Dynamic Pituitary-Adrenal Interactions in the Critically Ill after Cardiac Surgery.

CONTEXT: Patients with critical illness are thought to be at risk of adrenal insufficiency. There are no models of dynamic hypothalamic-pituitary-adrenal (HPA) axis function in this group of patients and thus current methods of diagnosis are based on aggregated, static models. OBJECTIVE: To characterize the secretory dynamics of the HPA axis in the critically ill (CI) after cardiac surgery. DESIGN: Mathematical modeling of cohorts. SETTING: Cardiac critical care unit. PATIENTS: 20 male patients CI at least 48 hours after cardiac surgery and 19 healthy (H) male volunteers. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Measures of hormone secretory dynamics were generated from serum adrenocorticotrophic hormone (ACTH) sampled every hour and total cortisol every 10 min for 24 h. RESULTS: All CI patients had pulsatile ACTH and cortisol profiles. CI patients had similar ACTH secretion (1036.4 [737.6] pg/mL/24 h) compared to the H volunteers (1502.3 [1152.2] pg/mL/24 h; P = .20), but increased cortisol secretion (CI: 14 447.0 [5709.3] vs H: 5915.5 [1686.7)] nmol/L/24 h; P < .0001). This increase in cortisol was due to nonpulsatile (CI: 9253.4 [3348.8] vs H: 960 [589.0] nmol/L/24 h, P < .0001), rather than pulsatile cortisol secretion (CI: 5193.1 [3018.5] vs H: 4955.1 [1753.6] nmol/L/24 h; P = .43). Seven (35%) of the 20 CI patients had cortisol pulse nadirs below the current international guideline threshold for critical illness-related corticosteroid insufficiency, but an overall secretion that would not be considered deficient. CONCLUSIONS: This study supports the premise that current tests of HPA axis function are unhelpful in the diagnosis of adrenal insufficiency in the CI. The reduced ACTH and increase in nonpulsatile cortisol secretion imply that the secretion of cortisol is driven by factors outside the HPA axis in critical illness.

Widening Access to Bayesian Problem Solving.

Bayesian reasoning and decision making is widely considered normative because it minimizes prediction error in a coherent way. However, it is often difficult to apply Bayesian principles to complex real world problems, which typically have many unknowns and interconnected variables. Bayesian network modeling techniques make it possible to model such problems and obtain precise predictions about the causal impact that changing the value of one variable may have on the values of other variables connected to it. But Bayesian modeling is itself complex, and has until now remained largely inaccessible to lay people. In a large scale lab experiment, we provide proof of principle that a Bayesian network modeling tool, adapted to provide basic training and guidance on the modeling process to beginners without requiring knowledge of the mathematical machinery working behind the scenes, significantly helps lay people find normative Bayesian solutions to complex problems, compared to generic training on probabilistic reasoning. We discuss the implications of this finding for the use of Bayesian network software tools in applied contexts such as security, medical, forensic, economic or environmental decision making.

A comparison of methods for forensic DNA extraction: Chelex-100® and the QIAGEN DNA Investigator Kit (manual and automated).

Efficient isolation of DNA from a sample is the basis for successful forensic DNA profiling. There are many DNA extraction methods available and they vary in their ability to efficiently extract the DNA; as well as in processing time, operator intervention, contamination risk and ease of use. In recent years, automated robots have been made available which speed up processing time and decrease the amount of operator input. This project was set up to investigate the efficiency of three DNA extraction methods, two manual (Chelex(®)-100 and the QIAGEN DNA Investigator Kit) and one automated (QIAcube), using both buccal cells and blood stains as the DNA source. Extracted DNA was quantified using real-time PCR in order to assess the amount of DNA present in each sample. Selected samples were then amplified using AmpFlSTR SGM Plus amplification kit. The results suggested that there was no statistical difference between results gained for the different methods investigated, but the automated QIAcube robot made sample processing much simpler and quicker without introducing DNA contamination.