How does discharge against medical advice affect risk of mortality and unplanned readmission? A retrospective cohort study set in a large UK medical admissions unit.

OBJECTIVES: To assess the frequency of discharge against medical advice (DAMA) in a large UK teaching hospital, explore factors which increase the risk of DAMA and identify how DAMA impacts patient risk of mortality and readmission. DESIGN: Retrospective cohort study. SETTING: Large acute teaching hospital in the UK. PATIENTS: 36 683 patients discharged from the acute medical unit of a large UK teaching hospital between 1 January 2012 and 31 December 2016. MEASUREMENTS: Patients were censored on 1 January 2021. Mortality and 30-day unplanned readmission rates were assessed. Deprivation, age and sex were taken as covariates. RESULTS: 3% of patients discharged against medical advice. These patients were younger (median age (years) (IQR)): planned discharge (PD) 59 (40-77); DAMA 39 (28-51), predominantly of male sex (PD 48%; DAMA 66%) and were of greater social deprivation (in three most deprived quintiles PD 69%; DAMA 84%). DAMA was associated with increased risk of death in patients under the age of 33.3 years (adjusted HR 2.6 (1.2-5.8)) and increased incidence of 30-day readmission (standardised incidence ratio 1.9 (1.5-2.2)). LIMITATIONS: Readmission to acute hospitals outside of the local health board may have been missed. We were unable to include information regarding comorbidity or severity of presentation. CONCLUSIONS: These data highlight the vulnerability of younger patients who DAMA, even in a free-at-the-point-of-delivery healthcare setting.

Prospective, multicentre study of screening, investigation and management of hyponatraemia after subarachnoid haemorrhage in the UK and Ireland.

BACKGROUND: Hyponatraemia often occurs after subarachnoid haemorrhage (SAH). However, its clinical significance and optimal management are uncertain. We audited the screening, investigation and management of hyponatraemia after SAH. METHODS: We prospectively identified consecutive patients with spontaneous SAH admitted to neurosurgical units in the United Kingdom or Ireland. We reviewed medical records daily from admission to discharge, 21 days or death and extracted all measurements of serum sodium to identify hyponatraemia (<135 mmol/L). Main outcomes were death/dependency at discharge or 21 days and admission duration >10 days. Associations of hyponatraemia with outcome were assessed using logistic regression with adjustment for predictors of outcome after SAH and admission duration. We assessed hyponatraemia-free survival using multivariable Cox regression. RESULTS: 175/407 (43%) patients admitted to 24 neurosurgical units developed hyponatraemia. 5976 serum sodium measurements were made. Serum osmolality, urine osmolality and urine sodium were measured in 30/166 (18%) hyponatraemic patients with complete data. The most frequently target daily fluid intake was >3 L and this did not differ during hyponatraemic or non-hyponatraemic episodes. 26% (n/N=42/164) patients with hyponatraemia received sodium supplementation. 133 (35%) patients were dead or dependent within the study period and 240 (68%) patients had hospital admission for over 10 days. In the multivariable analyses, hyponatraemia was associated with less dependency (adjusted OR (aOR)=0.35 (95% CI 0.17 to 0.69)) but longer admissions (aOR=3.2 (1.8 to 5.7)). World Federation of Neurosurgical Societies grade I-III, modified Fisher 2-4 and posterior circulation aneurysms were associated with greater hazards of hyponatraemia. CONCLUSIONS: In this comprehensive multicentre prospective-adjusted analysis of patients with SAH, hyponatraemia was investigated inconsistently and, for most patients, was not associated with changes in management or clinical outcome. This work establishes a basis for the development of evidence-based SAH-specific guidance for targeted screening, investigation and management of high-risk patients to minimise the impact of hyponatraemia on admission duration and to improve consistency of patient care.

Corticotroph isolation from Pomc-eGFP mice reveals sustained transcriptional dysregulation characterising a mouse model of glucocorticoid-induced suppression of the hypothalamus-pituitary-adrenal axis.

Glucocorticoids (GC) are prescribed for periods > 3 months to 1%-3% of the UK population; 10%-50% of these patients develop hypothalamus-pituitary-adrenal (HPA) axis suppression, which may last over 6 months and is associated with morbidity and mortality. Recovery of the pituitary and hypothalamus is necessary for recovery of adrenal function. We developed a mouse model of dexamethasone (DEX)-induced HPA axis dysfunction aiming to further explore recovery in the pituitary. Adult male wild-type C57BL6/J or Pomc-eGFP transgenic mice were randomly assigned to receive DEX (approximately 0.4 mg kg-1 bodyweight day-1 ) or vehicle via drinking water for 4 weeks following which treatment was withdrawn and tissues were harvested after another 0, 1, and 4 weeks. Corticotrophs were isolated from Pomc-eGFP pituitaries using fluorescence-activated cell sorting, and RNA extracted for RNA-sequencing. DEX treatment suppressed corticosterone production, which remained partially suppressed at least 1 week following DEX withdrawal. In the adrenal, Hsd3b2, Cyp11a1, and Mc2r mRNA levels were significantly reduced at time 0, with Mc2r and Cyp11a1 remaining reduced 1 week following DEX withdrawal. The corticotroph transcriptome was modified by DEX treatment, with some differences between groups persisting 4 weeks following withdrawal. No genes supressed by DEX exhibited ongoing attenuation 1 and 4 weeks following withdrawal, whereas only two genes were upregulated and remained so following withdrawal. A pattern of rebound at 1 and 4 weeks was observed in 14 genes that increased following suppression, and in six genes that were reduced by DEX and then increased. Chronic GC treatment may induce persistent changes in the pituitary that may influence future response to GC treatment or stress.

Investigation and management of serum sodium after subarachnoid haemorrhage (SaSH): a survey of practice in the United Kingdom and Republic of Ireland.

BACKGROUND: Hyponatraemia is a common complication of aneurysmal subarachnoid haemorrhage (SAH). We aimed to determine current neurosurgical practice for the identification, investigation and management of hyponatraemia after SAH. METHODS: An online questionnaire was completed by UK and Irish neurosurgical trainees and consultant collaborators in the Sodium after Subarachnoid Haemorrhage (SaSH) audit. RESULTS: Between August 2019 and June 2020, 43 responses were received from 31 of 32 UK and Ireland adult neurosurgical units (NSUs). All units reported routine measurement of serum sodium either daily or every other day. Most NSUs reported routine investigation of hyponatraemia after SAH with paired serum and urinary osmolalities (94%), urinary sodium (84%), daily fluid balance (84%), but few measured glucose (19%), morning cortisol (13%), or performed a short Synacthen test (3%). Management of hyponatraemia was variable, with units reporting use of oral sodium supplementation (77%), fluid restriction (58%), hypertonic saline (55%), and fludrocortisone (19%). CONCLUSIONS: Reported assessment of serum sodium after SAH was consistent between units, whereas management of hyponatraemia varied. This may reflect the lack of a specific evidence-base to inform practice.

The impact of obesity on male fertility.

Obesity in men of reproductive age is globally on the increase. There is clear evidence from epidemiological studies that obesity impacts negatively on male fertility; it is associated with hypogonadism, although it is less consistently linked to impaired spermatogenesis and tests of sperm function, including DNA fragmentation. Sperm from obese men used for in vitro fertilisation/intra cytoplasmic sperm injection is associated with a greater number of pregnancy losses and is less likely to result in live births. There are also increasing data from animal studies that paternal obesity may impact negatively on the reproductive and metabolic health of offspring and grand-offspring. It has been suggested that high-fat dietary exposures could affect the epigenetic content of sperm or the endocrine content of seminal fluid and thus impact early fetal development. Experimental and epidemiological data show that male fertility, and offspring health, can be improved by weight loss in obese and overweight males.

Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells.

Fetal growth plays a role in programming of adult cardiometabolic disorders, which in men, are associated with lowered testosterone levels. Fetal growth and fetal androgen exposure can also predetermine testosterone levels in men, although how is unknown, because the adult Leydig cells (ALCs) that produce testosterone do not differentiate until puberty. To explain this conundrum, we hypothesized that stem cells for ALCs must be present in the fetal testis and might be susceptible to programming by fetal androgen exposure during masculinization. To address this hypothesis, we used ALC ablation/regeneration to identify that, in rats, ALCs derive from stem/progenitor cells that express chicken ovalbumin upstream promoter transcription factor II. These stem cells are abundant in the fetal testis of humans and rodents, and lineage tracing in mice shows that they develop into ALCs. The stem cells also express androgen receptors (ARs). Reduction in fetal androgen action through AR KO in mice or dibutyl phthalate (DBP) -induced reduction in intratesticular testosterone in rats reduced ALC stem cell number by ∼40% at birth to adulthood and induced compensated ALC failure (low/normal testosterone and elevated luteinizing hormone). In DBP-exposed males, this failure was probably explained by reduced testicular steroidogenic acute regulatory protein expression, which is associated with increased histone methylation (H3K27me3) in the proximal promoter. Accordingly, ALCs and ALC stem cells immunoexpressed increased H3K27me3, a change that was also evident in ALC stem cells in fetal testes. These studies highlight how a key component of male reproductive development can fundamentally reprogram adult hormone production (through an epigenetic change), which might affect lifetime disease risk.