Perioperative management of Obstructive Sleep Apnoea: Present themes and future directions.

PURPOSE OF REVIEW: Obstructive sleep apnoea (OSA) is an increasingly common pathology that all those involved in perioperative care will come across. Patients with the condition present a challenge at many stages along the perioperative journey, not least because many patients living with OSA are unaware of their diagnosis.Key interventions can be made pre, intra-, and postoperatively to improve outcomes. Knowledge of screening tools, diagnostic tests, and the raft of treatment options are important for anyone caring for these patients. RECENT FINDINGS: Recent literature has highlighted the increasing complexity of surgical patients and significant underdiagnosis of OSA in this patient population. Work has demonstrated how and why patients with OSA are at a higher perioperative risk and that effective positive airways pressure (PAP) therapy can reduce these risks, alongside evidencing how best to optimise adherence to therapy, a key issue in OSA. SUMMARY: OSA, and particularly undiagnosed OSA, presents a huge problem in the perioperative period. Perioperative PAP reduces the risk of postoperative complications but adherence remains an issue. Bespoke perioperative pathways should be developed to identify and optimise high risk patients, although at present evidence on how best to achieve this is lacking.

Obstructive sleep apnoea and perioperative medicine: a growing concern.

Obstructive sleep apnoea represents a sizable public health and economic burden. Owing to rising obesity rates, the prevalence of obstructive sleep apnoea is increasing, and it is a condition that is significantly underdiagnosed. Exacerbated by the COVID-19 pandemic, the backlog of elective surgeries is also sizable and growing. A combination of these factors means that many patients due to have surgery will have obstructive sleep apnoea, either diagnosed or otherwise. Patients with obstructive sleep apnoea have a significantly increased risk of operative complications, but the evidence base for optimum perioperative management of these patients is limited. This article reviews sleep apnoea, its prevalence and its impact on operative management and perioperative outcomes for patients. The evidence base for screening and treating undiagnosed obstructive sleep apnoea is also comprehensively assessed. Finally, a pathway to manage patients with possible undiagnosed obstructive sleep apnoea is proposed, and areas for further research identified.

Genetic common variants associated with cerebellar volume and their overlap with mental disorders: a study on 33,265 individuals from the UK-Biobank.

Interest in the cerebellum is expanding given evidence of its contributions to cognition and emotion, and dysfunction in various psychopathologies. However, research into its genetic architecture and shared influences with liability for mental disorders is lacking. We conducted a genome-wide association study (GWAS) of total cerebellar volume and underlying cerebellar lobe volumes in 33,265 UK-Biobank participants. Total cerebellar volume was heritable (h2SNP = 50.6%), showing moderate genetic homogeneity across lobes (h2SNP from 35.4% to 57.1%; mean genetic correlation between lobes rg ≈ 0.44). We identified 33 GWAS signals associated with total cerebellar volume, of which 6 are known to alter protein-coding gene structure, while a further five mapped to genomic regions known to alter cerebellar tissue gene expression. Use of summary data-based Mendelian randomisation further prioritised genes whose change in expression appears to mediate the SNP-trait association. In total, we highlight 21 unique genes of greatest interest for follow-up analyses. Using LD-regression, we report significant genetic correlations between total cerebellar volume and brainstem, pallidum and thalamus volumes. While the same approach did not result in significant correlations with psychiatric phenotypes, we report enrichment of schizophrenia, bipolar disorder and autism spectrum disorder associated signals within total cerebellar GWAS results via conditional and conjunctional-FDR analysis. Via these methods and GWAS catalogue, we identify which of our cerebellar genomic regions also associate with psychiatric traits. Our results provide important insights into the common allele architecture of cerebellar volume and its overlap with other brain volumes and psychiatric phenotypes.

Effects of Thyroid Status on Regional Brain Volumes: A Diagnostic and Genetic Imaging Study in UK Biobank.

BACKGROUND: Thyroid hormone is essential for optimal human neurodevelopment and may modify the risk of attention-deficit/hyperactivity disorder (ADHD). However, the brain structures involved are unknown and it is unclear if the adult brain is also susceptible to changes in thyroid status. METHODS: We used International Classification of Disease-10 codes, polygenic thyroid scores at different thresholds of association with thyroid traits (PT-values), and image-derived phenotypes in UK Biobank (n = 18 825) to investigate the effects of a recorded diagnosis of thyroid disease and genetic risk for thyroid status on cerebellar and subcortical gray matter volume. Regional genetic pleiotropy between thyroid status and ADHD was explored using the GWAS-pairwise method. RESULTS: A recorded diagnosis of hypothyroidism (n = 419) was associated with significant reductions in total cerebellar and pallidum gray matter volumes (ß [95% CI] = -0.14[-0.23, -0.06], P = 0.0005 and ß [95%CI] = -0.12 [-0.20, -0.04], P = 0.0042, respectively), mediated in part by increases in body mass index. While we found no evidence for total cerebellar volume alterations with increased polygenic scores for any thyroid trait, opposing influences of increased polygenic scores for hypo- and hyperthyroidism were found in the pallidum (PT < 1e-3: ß [95% CI] = -0.02 [-0.03, -0.01], P = 0.0003 and PT < 1e-7: ß [95% CI] = 0.02 [0.01, 0.03], P = 0.0003, respectively). Neither hypo- nor hyperthyroidism showed evidence of regional genetic pleiotropy with ADHD. CONCLUSIONS: Thyroid status affects gray matter volume in adults, particularly at the level of the cerebellum and pallidum, with potential implications for the regulation of motor, cognitive, and affective function.

Development of a pre-operative scoring system for predicting risk of post-operative paediatric cerebellar mutism syndrome.

BACKGROUND: Despite previous identification of pre-operative clinical and radiological predictors of post-operative paediatric cerebellar mutism syndrome (CMS), a unifying pre-operative risk stratification model for use during surgical consent is currently lacking. The aim of the project is to develop a simple imaging-based pre-operative risk scoring scheme to stratify patients in terms of post-operative CMS risk. METHODS: Pre-operative radiological features were recorded for a retrospectively assembled cohort of 89 posterior fossa tumour patients from two major UK treatment centers (age 2-23yrs; gender 28 M, 61 F; diagnosis: 38 pilocytic astrocytoma, 32 medulloblastoma, 12 ependymoma, 1 high grade glioma, 1 pilomyxoid astrocytoma, 1 atypical teratoid rhabdoid tumour, 1 hemangioma, 1 neurilemmoma, 2 oligodendroglioma). Twenty-six (29%) developed post-operative CMS. Based upon results from univariate analysis and C4.5 decision tree, stepwise logistic regression was used to develop the optimal model and generate risk scores. RESULTS: Univariate analysis identified five significant risk factors and C4.5 decision tree analysis identified six predictors. Variables included in the final model are MRI primary location, bilateral middle cerebellar peduncle involvement (invasion and/or compression), dentate nucleus invasion and age at imaging >12.4 years. This model has an accuracy of 88.8% (79/89). Using risk score cut-off of 203 and 238, respectively, allowed discrimination into low (38/89, predicted CMS probability <3%), intermediate (17/89, predicted CMS probability 3-52%) and high-risk (34/89, predicted CMS probability ≥52%). CONCLUSIONS: A risk stratification model for post-operative paediatric CMS could flag patients at increased or reduced risk pre-operatively which may influence strategies for surgical treatment of cerebellar tumours. Following future testing and prospective validation, this risk scoring scheme will be proposed for use during the surgical consenting process.

Analgesic exposure in pregnant rats affects fetal germ cell development with inter-generational reproductive consequences.

Analgesics which affect prostaglandin (PG) pathways are used by most pregnant women. As germ cells (GC) undergo developmental and epigenetic changes in fetal life and are PG targets, we investigated if exposure of pregnant rats to analgesics (indomethacin or acetaminophen) affected GC development and reproductive function in resulting offspring (F1) or in the F2 generation. Exposure to either analgesic reduced F1 fetal GC number in both sexes and altered the tempo of fetal GC development sex-dependently, with delayed meiotic entry in oogonia but accelerated GC differentiation in males. These effects persisted in adult F1 females as reduced ovarian and litter size, whereas F1 males recovered normal GC numbers and fertility by adulthood. F2 offspring deriving from an analgesic-exposed F1 parent also exhibited sex-specific changes. F2 males exhibited normal reproductive development whereas F2 females had smaller ovaries and reduced follicle numbers during puberty/adulthood; as similar changes were found for F2 offspring of analgesic-exposed F1 fathers or mothers, we interpret this as potentially indicating an analgesic-induced change to GC in F1. Assuming our results are translatable to humans, they raise concerns that analgesic use in pregnancy could potentially affect fertility of resulting daughters and grand-daughters.

Contribution of glycogen in supporting axon conduction in the peripheral and central nervous systems: the role of lactate.

The role of glycogen in the central nervous system is intimately linked with the glycolytic pathway. Glycogen is synthesized from glucose, the primary substrate for glycolysis, and degraded to glucose-6-phosphate. The metabolic cost of shunting glucose via glycogen exceeds that of simple phosphorylation of glucose to glucose-6-phosphate by hexokinase; thus, there must be a metabolic advantage in utilizing this shunt pathway. The dogmatic view of glycogen as a storage depot persists, based on initial descriptions of glycogen supporting neural function in the face of aglycemia. The variable latency to conduction failure, dependent upon tissue glycogen levels, provided convincing evidence of the role played by glycogen in supporting neural function. Glycogen is located predominantly in astrocytes in the central nervous system, thus for glycogen to benefit neural elements, intercellular metabolic communication must exist in the form of astrocyte to neuron substrate transfer. Experimental evidence supports a model where glycogen is metabolized to lactate in astrocytes, with cellular expression of monocarboxylate transporters and enzymes appropriately located for lactate shuttling between astrocytes and neural elements, where lactate acts as a substrate for oxidative metabolism. Biosensor recordings have demonstrated a significant steady concentration of lactate present on the periphery of both central white matter and peripheral nerve under unstimulated baseline conditions, indicating continuous cellular efflux of lactate to the interstitium. The existence of this lactate pool argues we must reexamine the "on demand" shuttling of lactate between cellular elements, and suggests continuous lactate efflux surplus to immediate neural requirements.

A primary care register for impaired glucose handling (IGH): impact on cardiometabolic profile.

OBJECTIVE: Diet and exercise reduce the incidence of diabetes in high-risk individuals as does metformin, although less dramatically. Here we evaluated if lifestyle and pharmacological intervention, for people at risk of diabetes, resulted in an improvement in their cardiometabolic risk profile. RESEARCH DESIGN/METHODS: In a primary care based study, 92 individuals screened opportunistically and identified to have impaired glucose handling were offered detailed lifestyle advice, at 6 monthly intervals, with targeting of cardiovascular risk factors. Duration of follow-up was 4 years. The relation between fasting and 2h glucose with different cardio-metabolic risk factors over time was assessed using multi-level modeling. RESULTS: There was no significant weight reduction. At 24 months, mean fasting glucose level (6.4 mmol/L (95% CI 6.0-6.8)) was slightly lower than at baseline (6.6 mM (95% CI: 6.4-6.9), F=3.67; p<0.001). For men and women combined, systolic blood pressure (mean difference=-6 mmHg, p=0.013), total cholesterol (-0.66 mmol/L, p<0.0001) and triglycerides (-0.13 mmol/L, p=0.133) fell, whilst HDL-cholesterol (0.12 mmol/L, p=0.047) rose. Diabetes developed in 18/92 participants during follow-up (up to 4 years). Five per cent of participants were started on metformin, 88.5% on lipid lowering agents and 85.4% on anti-hypertensive agents. After adjusting for age, sex and BMI, 2 h glucose was independently and negatively associated with HDL-cholesterol (ß=-2.17, p=0.041), and positively with systolic BP (ß=0.24, p=0.004, per 5 mmHg). CONCLUSIONS: Targeted intervention had an effective role in improving lipid and BP profile in individuals with impaired glucose handling, with limited impact on glycaemia and no impact on weight. More work needs be done to evaluate the potential benefit of insulin sensitizing agents in this setting.

Wnt signaling in estrogen-induced lactotroph proliferation.

Prolactinomas are the most common type of functioning pituitary adenoma in humans, but the control of lactotroph proliferation remains unclear. Here, using microarray analysis, we show that estrogen treatment increased expression of Wnt4 mRNA in adult Fischer rat pituitary tissue. Dual immunofluorescence analysis revealed that Wnt4 expression was not confined to lactotrophs, but that it was expressed in all anterior pituitary cell types. Estradiol induced proliferation in the somatolactotroph GH3 cell line, in parallel with Wnt4 mRNA and protein induction. A reporter gene assay for TCF- and LEF-dependent transcription revealed that there was no activation of the canonical Wnt pathway in GH3 cells upon stimulation with Wnt-conditioned culture medium or coexpression of constitutively active mutant ß-catenin. Expression of ß-catenin in both GH3 cells and normal rat anterior pituitary cells was restricted to the cell membrane and was unaltered by treatment with estradiol, with no nuclear ß-catenin being detected under any of the conditions tested. We show for the first time that Wnt4 affects non-canonical signaling in the pituitary by inhibiting Ca(2+) oscillations in GH3 cells, although the downstream effects are as yet unknown. In summary, Wnt4 is expressed in the adult pituitary gland, and its expression is increased by estrogen exposure, suggesting that its involvement in adult tissue plasticity is likely to involve ß-catenin-independent signaling pathways.