Pharmacokinetics/pharmacodynamics of glucocorticoids: modeling the glucocorticoid receptor dynamics and dose/response of commonly prescribed glucocorticoids.

Background And Purpose: The main features of the dynamics of the glucocorticoid receptor (GR) have been known for 50 years: 1) in the absence of glucocorticoid (G), the receptor is localized entirely in the cytoplasm; 2) upon G binding, GR is converted into a tightly bound G form and is rapidly imported into the nucleus where it can bind DNA and modulate transcription; 3) nuclear export of GR is very slow; and 4) the nuclear form of GR can recycle through an unbound form, back to the bound transcription modulating form without leaving the nucleus.

Experimental Approach: A kinetic model that captures these features is presented, a set of model parameters for dexamethasone is derived, and the clinical implication for the commonly used glucocorticoids is discussed.

Key Results: At the high concentrations normally used to describe G pharmacodynamics, the model reduces to the standard Michaelis-Menten equation with a that is a function of 4 model parameters.

Development of a Pharmacokinetic Model That Accounts for the Plasma Concentrations of Conjugated and Unconjugated Bilirubin Observed in a Variety of Disease States.

Introduction: For a large variety of liver pathologies, the plasma unconjugated (UB) and conjugated (CB) bilirubin concentrations appear to be coupled. For example, in alcoholic cirrhosis, UB and CB are roughly the same over a large range of total bilirubin, requiring an initial massive increase (about 40-fold) in plasma CB to reach the level of UB and then similar increases in UB and CB as the disease progresses. This coupling has been either unrecognized or ignored and this paper is the first attempt to try to explain it quantitatively in terms of known hepatic cell metabolic and membrane transport properties.

Development and application of a simple pharmacokinetic model that quantitatively describes the distribution and elimination of the commonly measured proteins.

Increased plasma concentrations of a variety of cellular enzymes (alanine transaminase, aspartate aminotransferase, alkaline phosphatase, amylase, etc.) are commonly used as routine screening tests for a range of conditions. An increased concentration usually is assumed to result from an increased rate of delivery to the plasma.

Offshore detention: cross-sectional analysis of the health of children and young people seeking asylum in Australia.

Objective: To describe the health and well-being of children and young people (CYP) seeking asylum subjected to Australia's immigration policy of indefinite mandatory detention on Nauru.

Design: Cross-sectional analysis of a cohort of CYP seeking asylum.

Setting: Australian paediatric clinicians from 10 health services completed detailed health assessments around the time of transfer from Nauru, mostly to Australia.

Progressive resistance training in young people with Prader-Willi syndrome: protocol for a randomised trial (PRESTO).

Introduction: Preliminary evidence suggests that progressive resistance training may be beneficial for people with Prader-Willi Syndrome (PWS), a rare genetic condition that results in muscle weakness and low muscle tone.To establish whether community-based progressive resistance training is effective in improving the muscle strength of people with PWS; to determine cost-effectiveness; and, to complete a process evaluation assessing intervention fidelity, exploring mechanisms of impact, understanding participant experiences and identifying contextual factors affecting implementation.

Methods And Analysis: A multisite, randomised controlled trial will be completed.

Constructing Health State Descriptions for Low-Risk Thyroid Cancer: Stakeholder Engagement and Formative Qualitative Research.

Overview: This paper describes stakeholder involvement and formative qualitative research in the creation of health state descriptions (HSDs) or vignettes for low-risk thyroid cancer. The aim of this project was to engage stakeholders in the contribution of a novel set of HSDs, an important first step in the process of assessing value in thyroid cancer health states.

Methods: We draw upon formative, descriptive qualitative methods, following a multi-stage framework of data collection.

Cost-Effectiveness of Care Coordination for Children With Chronic Noncomplex Medical Conditions: Results From a Multicenter Randomized Clinical Trial.

Objectives: To assess the cost-effectiveness of care coordination, compared with standard care, for children with chronic noncomplex medical conditions.

Methods: A total of 81 children aged between 2 and 15 years newly diagnosed with a noncomplex chronic condition were randomized to either care coordination or standard care as part of a multicenter randomized controlled trial. Families receiving care coordination were provided access to an Allied Health Liaison Officer, who facilitated family-centered healthcare access across hospital, education, primary care, and community sectors.

Severe atopic dermatitis in a 21-month-old boy successfully treated with dupilumab.

While dupilumab has emerged as a novel targeted systemic treatment for severe AD, efficacy and safety-based data in young children are limited. We discuss the case of a 21-month-old child with severe recalcitrant atopic dermatitis successfully treated with dupilumab.

Alkaline Phosphatase Pathophysiology with Emphasis on the Seldom-Discussed Role of Defective Elimination in Unexplained Elevations of Serum ALP - A Case Report and Literature Review.

While serum alkaline phosphatase activity has become a routine clinical measurement, we have found that physicians' knowledge of the pathophysiology of this enzyme is almost solely limited to the concept that an elevated serum alkaline phosphatase suggests disease of liver or bone. For example, physicians at all levels of training had no understanding of such basic physiological information as the function of alkaline phosphatase in the liver or how this enzyme is eliminated from the serum. Based on a patient with an enormously elevated alkaline phosphatase, this report provides a review of existing clinically relevant information concerning the pathophysiology of alkaline phosphatase with emphasis on the mechanisms involved in the homeostasis of this enzyme.

Effect of Care Coordination Using an Allied Health Liaison Officer for Chronic Noncomplex Medical Conditions in Children: A Multicenter Randomized Clinical Trial.

Importance: There is a paucity of high-quality evidence on the effect of care coordination on health-related quality of life among children with chronic noncomplex medical conditions (non-CMCs).

Objective: To examine whether care coordination delivered by an Allied Health Liaison Officer results in improved quality-of-life (QOL) outcomes for children with chronic non-CMCs and their families.

Design, Setting And Participants: This multicenter, open label, randomized clinical trial was conducted in pediatric outpatient clinics at 3 Australian hospitals with tertiary- and secondary-level pediatric care facilities.

Bolus Versus Continuous Nasogastric Feeds for Infants With Bronchiolitis: A Randomized Trial.

Background And Objectives: Infants hospitalized with bronchiolitis are commenced on nasogastric feeding to maintain hydration. Feeding strategies vary according to physician or institution preference. The current study hypothesized that continuous nasogastric feeding would prolong length of stay (LOS) when compared to bolus feeding.

Implementation and evaluation of virtual multiple mini interviews as a selection tool for entry into paediatric postgraduate training: A Queensland experience.

Introduction: The Queensland Basic Paediatric Training Network (QBPTN) is the centralised pathway for entry into paediatric training in Queensland, Australia. In response to COVID-19 travel and social distancing restrictions imposed in 2020, QBPTN successfully adopted a Virtual Multiple Mini Interviews (vMMIs) model for the selection of candidates for entry into paediatric training. The authors describe the planning, implementation, challenges, and evaluation of candidates' and interviewers' experiences of vMMIs, including the differences between candidates from two geographical areas.

Knowledge of Hemoglobin A1c and Glycemic Control in an Urban Population.

Aim: Our study aims to assess the knowledge of hemoglobin A1c (HbA1c) and glycemic control in patients with diabetes mellitus (DM) at an urban academic institution.

Methods: This was a retrospective cross-sectional study that included a survey of 100 adult patients with DM. Our patient cohort was divided into those with recent HbA1c < 8.

Quantitative Assessment of Blood Lactate in Shock: Measure of Hypoxia or Beneficial Energy Source.

Blood lactate concentration predicts mortality in critically ill patients and is clinically used in the diagnosis, grading of severity, and monitoring response to therapy of septic shock. This paper summarizes available quantitative data to provide the first comprehensive description and critique of the accepted concepts of the physiology of lactate in health and shock, with particular emphasis on the controversy of whether lactate release is simply a manifestation of tissue hypoxia versus a purposeful transfer ("shuttle") of lactate between tissues. Basic issues discussed include (1) effect of nonproductive lactate-pyruvate exchange that artifactually enhances flux measurements obtained with labeled lactate, (2) heterogeneous tissue oxygen partial pressure (Krogh model) and potential for unrecognized hypoxia that exists in all tissues, and (3) pathophysiology that distinguishes septic from other forms of shock.

Quantitative Evaluation of D-Lactate Pathophysiology: New Insights into the Mechanisms Involved and the Many Areas in Need of Further Investigation.

In contrast to L-lactate, D-lactate is produced in minimal quantities by human cells, and the plasma D-lactate concentration normally is maintained at a concentration of only about 0.01 mM. However, in short bowel syndrome, colonic bacterial production of D-lactate may lead to plasma concentrations >3mM with accompanying acidosis and neurological symptoms - a syndrome known as D-lactic acidosis.

Asylum seeking children and adolescents in Australian immigration detention on Nauru: a longitudinal cohort study.

Introduction: Immigration detention has a profound and negative impact on the physical health, mental health, development and social-emotional well-being of children, adolescents and their families. Australian clinicians will report results from detailed health and well-being assessments of asylum seeking children and adolescents who have experienced prolonged immigration detention.

Methods And Analysis: This is a national, multicentre study with a longitudinal cohort design that will document health and well-being outcomes of the children and adolescents who have been detained in offshore detention on the remote island of Nauru.

Use Of Quantitative Modelling To Elucidate The Roles Of The Liver, Gut, Kidney, And Muscle In Ammonia Homeostasis And How Lactulose And Rifaximin Alter This Homeostasis.

Humans must eliminate approximately 1M of ammonia per day while maintaining the blood concentration of this potent neurotoxin at a concentration of only about 30 µM. The mechanisms producing such effective ammonia homeostasis are poorly understood by clinicians due to the multiple organs (liver, gut, kidney and muscle) involved in ammonia homeostasis. Based on literature values we present a novel, simplified description of normal and disordered ammonia and the potential mechanisms whereby the drugs used to treat hepatic encephalopathy, lactulose and rifaximin, lower the blood ammonia concentration.

PKQuest: PBPK modeling of highly lipid soluble and extracellular solutes.

One of the primary objectives of physiologically based pharmacokinetics (PBPK) is the prediction of a drug's pharmacokinetics just from knowledge of its physicochemical structure. Unfortunately, at present, the accuracy of this prediction is limited for most drugs because of uncertainty about the drug's organ/blood partition coefficient (K). However, there are two classes of solutes which are exceptions to this: 1) the highly lipid soluble (HLS) solutes, and 2) the extracellular (ECS) solutes.

Australasian bronchiolitis guideline.

Aim: Bronchiolitis is the most common lower respiratory tract disorder in infants aged less than 12 months, and research has demonstrated that there is substantial variation in practice patterns despite treatment being well defined. In order to align and improve the consistency of the management of bronchiolitis, an evidence-based guideline was developed for the Australasian population.

Methods: The guideline development committee included representation from emergency and paediatric specialty medical and nursing personnel in addition to geographical representation across Australia and New Zealand - rural, remote and metropolitan.

A model of blood-ammonia homeostasis based on a quantitative analysis of nitrogen metabolism in the multiple organs involved in the production, catabolism, and excretion of ammonia in humans.

Increased blood ammonia (NH) is an important causative factor in hepatic encephalopathy, and clinical treatment of hepatic encephalopathy is focused on lowering NH. Ammonia is a central element in intraorgan nitrogen (N) transport, and modeling the factors that determine blood-NH concentration is complicated by the need to account for a variety of reactions carried out in multiple organs. This review presents a detailed quantitative analysis of the major factors determining blood-NH homeostasis - the N metabolism of urea, NH, and amino acids by the liver, gastrointestinal system, muscle, kidney, and brain - with the ultimate goal of creating a model that allows for prediction of blood-NH concentration.

Insulin Pump and Continuous Glucose Monitor Initiation in Hospitalized Patients with Type 2 Diabetes Mellitus.

Background: Insulin pumps and continuous glucose monitoring (CGM) are commonly used by patients with diabetes mellitus in the outpatient setting. The efficacy and safety of initiating inpatient insulin pumps and CGM in the nonintensive care unit setting is unknown.

Materials And Methods: In a prospective pilot study, inpatients with type 2 diabetes were randomized to receive standard subcutaneous basal-bolus insulin and blinded CGM (group 1, n = 5), insulin pump and blinded CGM (group 2, n = 6), or insulin pump and nonblinded CGM (group 3, n = 5).

Renal Transplant-Associated Thyroid Tuberculosis.

Tuberculosis is common among solid-organ transplant recipients, including renal transplants. Tuberculosis of the thyroid gland is a rare diagnosis. We report on a renal transplant recipient with subacute fever associated with a neck mass diagnosed as thyroid tuberculosis.

The Effect of Continuous Glucose Monitoring in Preventing Inpatient Hypoglycemia in General Wards: The Glucose Telemetry System.

Background: Few studies have examined the use of continuous glucose monitoring (CGM) devices in the general wards. The aim of this pilot study was to examine whether CGM readings can be successfully transmitted from the bedside to a central monitoring device in the nursing station, and whether a glucose telemetry system can prevent hypoglycemic events.

Methods: We present pilot data on 5 consecutive insulin treated general medicine patients with type 2 diabetes (T2DM) whose glucose values were observed with CGM (DEXCOM) and the results were transmitted to a central nursing station monitoring system using DEXCOM Follow and Share 2 software.