Management of blood glucose in critically Ill patients with pre-existing type 2 diabetes

This thesis comprises four distinct but complementary chapters on blood glucose management during critical illness, with a focus on management of patients with a pre-existing type 2 diabetes. The work submitted includes a narrative review, survey of clinical practice, study protocol and statistical analysis plan, and the conduct and report from a bi-national, multi-centre, parallel-group, randomised clinical trial. Dysglycaemia, or disordered glucose metabolism, is almost ubiquitous with severe critical illness, with marked increases in endogenous glucose production and counter-regulatory responses. The magnitude of dysregulation is associated with severity of illness on presentation to hospital and subsequent mortality. Despite longstanding knowledge about these associations, the threshold at which hyperglycaemia causes harm remains unknown. There is a further complicating factor to understanding the relationship between hyperglycaemia and harm, is that over a quarter of patients admitted to intensive care units (ICUs) have type 2 diabetes, and a pre-existing disordered glucose metabolism. Evidence to inform the management of blood glucose in critically ill patients is predominately from studies conducted in sample populations that have only a small proportion of patients with pre-existing diabetes. This creates clinical uncertainty in discrete populations, such as those with type 2 diabetes (Chapter 1.2). A survey of clinicians was performed to understand current practice and to determine whether they required further evidence to better care for patients (Chapter 1.3). Observational and exploratory studies have reported that patients with a higher HbA1c on ICU admission had a lower mortality rate if they had a modest elevation of blood glucose concentrations to >10 mmol/L during their ICU admission. Based on such data it is plausible that in patients with type 2 diabetes mild hyperglycaemia during critical illness is protective. Because hypoglycaemia has consistently been shown to be harmful to all patients, and the threshold blood glucose for harm may even be slightly greater in patients with pre-existing diabetes, ‘personalising’ or allowing for different blood glucose ranges based on an individual patient’s pre-existing glucose metabolism has the potential to improve care. Exploratory studies indicate that such a personalised approach did not detect a signal for harm, although the studies included relatively small sample populations and study methodology risked bias, such that there was inadequate evidence to inform practice. For these reasons, further evaluation using a rigorously designed randomised clinical trial was warranted (Chapter 2.2). Treatment of hyperglycaemia in critically ill patients typically utilises intravenous insulin, which poses a risk of causing hypoglycaemia if appropriate commencement and titration parameters are not selected. A pragmatic approach to achieving a more personalised target in patients with type 2 diabetes is to commence insulin at a greater blood glucose concentration (e.g., ≥14 mmol/L) and compare this to what occurs in usual practice (e.g., ≥10 mmol/L), which has been informed by trials conducted in populations predominately comprising patients without pre-existing diabetes. Given the strong relationships between harm and hypoglycaemia, hypoglycaemia is an appropriate outcome by which to measure the impact of an elevated commencement point for intravenous insulin administration (Chapter 3.2). The multicentre, open label, randomised clinical trial was conducted in critically ill patients with pre-existing type 2 diabetes and established that day-28 incidence hypoglycemia (<4.0mmol/L) was significantly reduced by the intervention. While this study was not powered for patient-centred outcomes, there was no benefit in any of the clinical outcomes measured. The implications for clinical practice from the trial conducted is that while optimal management of hyperglycaemia in critically ill patients with type 2 diabetes remains uncertain, current or usual practice should continue. Future trials may benefit from determination of a patients pre-existing glycaemia though HbA1c testing, as long as this can be conducted in a time efficient manner, and offers the potential to further personalise physiological targets. Technological advancements such as dynamic protocols, continuous blood glucose monitors and close-loop systems may offer the opportunity to achieve greater time within target ranges, and reduce the amount of time required to manage blood glucose. This has the potential to reduce the net cost while achieving optimal blood glucose management. Novel therapeutics, such as glucagon-like peptide-1 (GPL-1), may have innate properties that mitigate some of the limitations of intravenous insulin administration. These interventions have the possibility to improve patient outcomes and improve the care provided in intensive care units (Chapter 4.2). In summary, this program of work has contributed new and important information in the fields of glycaemic management, acute glycaemic targets in critically ill patients with type 2 diabetes, and the implications of a personalised approach to blood glucose management.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 202

Abundance profiles and cool cores in galaxy groups

Using data from the Two Dimensional XMM-Newton Group Survey (2dXGS), we have examined the abundance profile properties of both cool core (CC) and non cool core (NCC) galaxy groups. The ten NCC systems in our sample represent a population which to date has been poorly studied in the group regime. Fitting the abundance profiles as a linear function of log radius, we find steep abundance gradients in cool core (CC) systems, with a slope of -0.54+/-0.07. In contrast, non cool core (NCC) groups have profiles consistent with uniform metallicity. Many CC groups show a central abundance dip or plateau, and we find evidence for anticorrelation between the core abundance gradient and the 1.4 GHz radio power of the brightest group galaxy (BGG) in CC systems. This may indicate the effect of AGN-driven mixing within the central ~0.1r_500. It is not possible to discern whether such behaviour is present in the NCC groups, due to the small and diverse sample with the requisite radio data. The lack of strong abundance gradients in NCC groups, coupled with their lack of cool core, and evidence for enhanced substructure, leads us to favour merging as the mechanism for disrupting cool cores, although we cannot rule out disruption by a major AGN outburst. Given the implied timescales, the disruptive event must have occurred within the past few Gyrs in most NCC groups.Comment: 15 pages, 12 figures, accepted for publication in MNRA

Chronic Obstructive Pulmonary Disease Patients Have Greater Systemic Responsiveness to Ex Vivo Stimulation with Swine Dust Extract and its Components Versus Healthy Volunteers

Chronic obstructive pulmonary disease (COPD) is characterized by an airway and systemic inflammatory response. Bioaerosols/organic dusts are important agricultural pollutants that may lead to COPD. These environments are complex containing a rich source of various microbial components. The objective of this study was to determine whether individuals with COPD have enhanced systemic responsiveness to settled swine facility organic dust extract (ODE) or its main pathogenic components (peptidoglycan [PGN], lipopolysaccharide [LPS]) versus healthy volunteers. A modified whole blood assay (WBA) that included occupational levels of ODE and concentrations of LPS and PGN found in ODE was used to determine systemic responsiveness (mediator release), and sputum inflammatory markers were measured to explore for systemic and airway associations. Sputum samples were evaluated for cell counts, and TNF-α, IL-8/CXCL8, IL-6, and IL-10. Ex vivo whole blood stimulation with ODE, LPS, and PGN each resulted in significant mediator release in all subjects, the highest occurring with ODE; PGN resulted in significantly enhanced TNF-α and IL-8 as compared to LPS. COPD subjects demonstrated greater systemic responsiveness using the modified WBA versus healthy controls. Within COPD subjects, blood baseline TNF-α, IL-8, and IL-10 and ODE, PGN, and LPS-stimulated IL-8 levels significantly correlated with lung function. In conclusion, dust-induced mediator release was robust, and PGN, in part, resembled dust-induced mediator release. Subjects with COPD demonstrated increased mediator release following ex vivo whole blood stimulation with bioaerosol components suggesting that circulating blood cells in COPD subjects may be primed to respond greater to microbial/inflammatory insult

αβ T cells and a mixed Th1/Th17 response are important in organic dust-induced airway disease

Abstract Background Organic dust exposure in agricultural environments induces an inflammatory response that attenuates over time, yet repetitive dust exposures result in chronic lung diseases. Animal models resembling this chronic lung inflammatory response have been developed, yet the underlying cellular mechanisms are not well defined. Objective Because mice repetitively exposed to organic dust extracts (DE) display increased CD3+ T cell lung infiltrates, we sought to determine the phenotype and importance of these cells. Methods Mice received swine confinement DE repetitively for 3 weeks by established intranasal inhalation protocol. Studies were conducted with peptidoglycan (PGN) because it is a major DE component in large animal farming environments and has shared similar biologic effects with DE. Enumeration of T cells and intracellular cytokine profiles were conducted by flow cytometry techniques. Whole lung homogenate cytokines were analyzed by multiplex immunoassay. T cell receptor (TCR) αβ knockouts were used to determine the functional importance of αβ-expressing T cells. Results DE increased lung-associated CD3+CD4+ T cells and interleukin (IL)-17 (but not IL-4, interferon [IFN]-γ, IL-10) producing CD4+ T cells. PGN treatment resulted in increased IL-17 and IFN-γ producing CD4+ T cells and IFN-γ producing CD8+ T cells. Both DE and PGN augmented expression of cytokines associated with Th1 and Th17 polarization in lung homogenates. DE-induced lung mononuclear aggregates and bronchiolar compartment inflammation were significantly reduced in TCR knockout animals; however, neutrophil influx and alveolar compartment inflammation were not affected. Conclusion Studies demonstrated that DE and PGN exposure promote a Th1/Th17 lung microenvironment and that αβ-expressing T cells are important in mediating DE-induced lung pathologic conditions

Isotopes in pyrogenic carbon: a review

Pyrogenic carbon (PC; also known as biochar, charcoal, black carbon and soot) derived from natural and anthropogenic burning plays a major, but poorly quantified, role in the global carbon cycle. Isotopes provide a fundamental fingerprint of the source of PC and a powerful tracer of interactions between PC and the environment. Radiocarbon and stable carbon isotope techniques have been widely applied to studies of PC in aerosols, soils, sediments and archaeological sequences, with the use of other isotopes currently less developed. This paper reviews the current state of knowledge regarding (i) techniques for isolating PC for isotope analysis and (ii) processes controlling the carbon (&lt;sup&gt;13&lt;/sup&gt;C and &lt;sup&gt;14&lt;/sup&gt;C), nitrogen, oxygen, hydrogen and sulfur isotope composition of PC during formation and after deposition. It also reviews the current and potential future applications of isotope based studies to better understand the role of PC in the modern environment and to the development of records of past environmental change

CD11c + /CD11b + Cells Are Critical for Organic Dust–Elicited Murine Lung Inflammation

Organic dust exposure in the agricultural industry results in significant lung disease. Macrophage infiltrates are increased in the lungs after organic dust exposures, yet the phenotype and functional importance of these cells remain unclear. Using an established intranasal inhalation murine model of dust-induced lung inflammation, animals were treated once or daily for 3 weeks with swine confinement organic dust extract (DE). Repetitive DE treatment for 3 weeks resulted in significant increases in CD11c+/CD11b+ macrophages in whole lung–associated tissue. These cells displayed increased costimulatory molecule (CD80 and CD86) expression, enhanced phagocytic ability, and an increased production of IL-6, CXCL1, and CXCL2. Similar findings were observed with the CD11c+/CD11b+ macrophage infiltrate after repetitive exposure to peptidoglycan, a major DE component. To determine the functional importance of macrophages in mediating DE-induced airway inflammation, lung macrophages were selectively depleted using a well-established intranasal clodronate liposome depletion/suicide strategy. First, macrophage depletion by clodronate liposomes resulted in significant reductions in airway neutrophil influx and TNF-α and IL-6 production after a single exposure to DE. In contrast, after repetitive 3-week exposure to DE, airway lavage fluid and lung tissue neutrophils were significantly increased in clodronate liposome–treated mice compared with control mice. A histological examination of lung tissue demonstrated striking increases in alveolar and bronchiolar inflammation, as well as in the size and distribution of cellular aggregates in clodronate–liposome versus saline–liposome groups repetitively exposed to DE. These studies demonstrate that DE elicits activated CD11c+/CD11b+ macrophages in the lung, which play a critical role in regulating the outcome of DE-induced airway inflammation

Detailed Clinical and Psychological Phenotype of the X-linked HNRNPH2-Related Neurodevelopmental Disorder

Objective: To expand the clinical phenotype of the X-linked HNRNPH2-related neurodevelopmental disorder in 33 individuals. Methods: Participants were diagnosed with pathogenic or likely pathogenic variants in HNRNPH2 using American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria, largely identified via clinical exome sequencing. Genetic reports were reviewed. Clinical data were collected by retrospective chart review and caregiver report including standardized parent report measures. Results: We expand our clinical characterization of HNRNPH2-related disorders to include 33 individuals, aged 2-38 years, both females and males, with 11 different de novo missense variants, most within the nuclear localization signal. The major features of the phenotype include developmental delay/intellectual disability, severe language impairment, motor problems, growth, and musculoskeletal disturbances. Minor features include dysmorphic features, epilepsy, neuropsychiatric diagnoses such as autism spectrum disorder, and cortical visual impairment. Although rare, we report early stroke and premature death with this condition. Conclusions: The spectrum of X-linked HNRNPH2-related disorders continues to expand as the allelic spectrum and identification of affected males increases.Grant support for L. Boyle provided by TL1TR001875.info:eu-repo/semantics/publishedVersio