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. Methods: A simplified pharmacokinetic model is developed and applied to a variety of hyperbilirubinemic pathologies. A central feature of the model is based on the recent observation that double knockout of the rat OATP1A and OATP1B hepatic transporters produces a roughly 400-fold increase in plasma CB, indicating that there is a normal rapid recycling of CB from the cell to the plasma with reuptake via OATP. We use the experimental rat Km of OATP CB transport to show that OATP uptake becomes saturated at relatively low plasma CB concentrations, decreasing uptake, and producing massive (up to 1000-fold) increases in CB in some pathologies. It is assumed that UB and CB are competing for the OATP transporter, producing the increased plasma UB that is observed in "pure" CB pathologies. Results: The model accurately describes the clinically observed UB and CB for pure UB (Gilbert's, hemolytic anemia) and CB (Dubin-Johnson, Rotor syndrome, biliary atresia) pathologies as well as in cirrhosis. Conclusion: This model is a preliminary, first attempt to quantitatively describe UB and CB pharmacokinetics. It is hoped that it will stimulate more detailed measurements and analysis.

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. Factors such as decreased metabolism or excretion or altered extravascular distribution usually are ignored. As a prelude to a detailed analysis of all the factors producing altered plasma enzyme levels, we have reviewed the relevant literature describing the pharmacokinetics (PK) of 13 of the commonly measured plasma proteins and developed a PK model that provides a simple physiological description of all the data. Our model starts with the general 3-compartment, 6-parameter system previously developed for albumin and interprets the fluxes in terms of unidirectional sieved protein convectional volume flows from the plasma to the two tissue compartments and equal lymph flows returning to the plasma. This greatly constrains the model such that each protein is characterized by only two adjustable parameters (plasma clearance and sieving factor). In addition to accurately fitting the plasma kinetics, the model can accurately describe the tissue and lymph protein PK. For example, it can describe the thoracic duct lymph protein concentration following an intravenous infusion or the plasma concentration following a subcutaneous tissue injection. This simple model provides a satisfactory framework for the PK of 12 of the 13 proteins investigated. The glycoprotein intestinal alkaline phosphatase is the exception, requiring the addition of a liver recycling compartment involving the asialoglycoprotein receptor.

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. PARTICIPANTS: Sixty-two CYP who were ≤18 years on entry into offshore immigration detention on Nauru between 2013 and 2019. Mean age at health assessment was 9 years. MAIN MEASURES: Health outcomes were categorised as physical, mental or neurodevelopmental concerns/conditions. Risk and protective factor data were collected using the adverse childhood experiences and refugee-specific adverse childhood experiences tools. RESULTS: Over half of the CYP (n=32, 52%) were held on Nauru for ≥4 years. The vast majority of CYP had physical health (n=55, 89%) and mental health (n=49, 79%) concerns including self-harm or suicidal ideation/attempt (n=28, 45%). Mental health concerns were more likely in CYP who were school-aged (p=0.001), had been held on Nauru for ≥1 year (p=0.01); originated from the Eastern Mediterranean region (p<0.05); witnessed trauma (p<0.05) or had exposure to ≥4 refugee-specific adverse childhood experiences (p<0.05). Neurodevelopmental concerns were seen in eight children (13%). CONCLUSIONS: This study highlights the almost universal physical and mental health difficulties in a sample of CYP who experienced forced migration and were subjected to Australia's offshore immigration detention policy. Immigration detention in recipient countries, a known adverse childhood experience, may contribute to or exacerbate harmful outcomes in CYP seeking asylum.

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. We conducted individual semi-structured interviews, cognitive interviews, and focus groups with thyroid cancer patients, community providers, academic subspecialists, and participants with no thyroid cancer diagnosis (N = 31). The HSDs went through several iterations over the course of a year, in collaboration with a highly engaged community advisory board, laying the groundwork for HSDs that are comprehensible, comparable, and appropriate for stated-preference research. FINDINGS: Thyroid cancer survivors compared their experiences with those described in the HSDs. Feedback included concern for the emotional well-being of study participants who would be reading them. Providers were attuned to the need for clinical accuracy and made suggestions to reflect their clinical experience, including for patients with complications or disease progression. The pilot participants with no thyroid cancer were particularly valuable in promoting the need to simplify language and maximize readability. DISCUSSION: Stakeholder engagement was critical to being responsive to feedback as the iterations were refined and presented. Continuous engagement and consultation with multiple sources strengthened the HSDs. A secondary outcome from this project is that stakeholders expressed interest in adapting the HSDs into decision aids for people newly diagnosed with low-risk thyroid cancer.

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. Sixty participants with PWS will be randomised to receive either progressive resistance training (experimental) or non-progressive exercise (placebo control). Participants will be aged 13 to 60 years, be able to follow simple instructions in English and have no contraindications to performing progressive resistance training. The experimental group will complete progressive resistance training two times weekly for 24 weeks supervised by an exercise professional at a community gym. The control group will receive all aspects of the intervention except progressive overload. Outcomes will be assessed at week 25 (primary endpoint) and week 52 by a blinded assessor. The primary outcome is muscle strength assessed using one repetition maximum for upper limb and lower limb. Secondary outcomes are muscle mass, functional strength, physical activity, community participation, health-related quality of life and behaviour. Health economic analysis will evaluate cost-effectiveness. Process evaluation will assess safety and intervention fidelity, investigate mechanism of impact, explore participant experiences and identify contextual factors affecting implementation. Data collection commenced in February 2020 and will conclude in September 2023. ETHICS AND DISSEMINATION: Ethical approval was obtained from The Royal Children's Hospital Human Research Ethics Committee (HREC/50874/RCHM-2019) under the National Mutual Acceptance initiative. Research governance approvals were obtained from five clinical sites. Results will be disseminated through published manuscripts, conference presentations, public seminars and practical resources for stakeholder groups. TRIAL REGISTRATION NUMBER: ACTRN12620000416998; Australian and New Zealand Clinical Trial Registry.

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. Costs were estimated over a 12-month period from the perspective of the Australian health system. Health outcomes were valued as quality-adjusted life-years (QALYs). Caregiver productivity costs were included in an alternative base-case analysis, and key assumptions were tested in a series of one-way sensitivity analyses. A probabilistic sensitivity analysis was conducted to investigate the overall impact of uncertainty in the data. RESULTS: Children in the intervention arm incurred an average of $17 in additional health system costs (95% confidence interval -3861 to 1558) and gained an additional 0.031 QALYs (95% confidence interval -0.29 to 0.092) over 12 months, producing an incremental cost-effectiveness ratio of $548 per QALY. When uncertainty was considered, there was a 73% likelihood that care coordination was cost-effective from a health system perspective, assuming a willingness to pay of $50 000 per QALY. This increased to 78% when caregiver productivity costs were included. CONCLUSIONS: Care coordination is likely to be a cost-effective intervention for children with chronic noncomplex medical conditions in the Australian healthcare setting.

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. A novel aspect of this paper is the discussion of the previously neglected concept that defective enzyme elimination could play a major role in the pathogenesis of serum alkaline phosphatase elevations.

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. A total of 81 children with chronic non-CMCs and their families participated in the trial for a period of up to 12 months between October 2017 to October 2020. Primary care reviews were offered at 1 week, 3 months, and 6 months after diagnosis. INTERVENTIONS: Eligible children were randomized 1:1 to receive care coordination or standard care. Families of children receiving care coordination were provided access to an Allied Health Liaison Officer, who was responsible for facilitation of health care access across hospital, education, primary care, and community sectors. MAIN OUTCOMES AND MEASURES: The primary outcomes were scores on the Pediatric Quality of Life Inventory (PedsQL), version 4.0, and the PedsQL Family Impact Module, version 2.0, measured at 6 and 12 months. An intent-to-treat approach was used to analyze the data. RESULTS: Of 81 children (mean [SD] age, 8.2 [3.5] years; 55 [67.9%] male), 42 (51.9%) were randomized to care coordination and 39 (48.1%) to standard care. Compared with standard care, care coordination resulted in greater improvements in overall PedsQL scores (difference in score changes between groups, 7.10; 95% CI, 0.44-13.76; P = .04), overall PedsQL Family Impact Module scores (difference in score changes between groups, 8.62; 95% CI, 1.07-16.16; P = .03), and family functioning QOL (difference in score changes between groups, 15.83; 95% CI, 5.05-26.62; P = .004) at 12 months after diagnosis. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, care coordination improved the quality of life of children with chronic non-CMCs and their families. Further studies should explore specific non-CMCs that may benefit most from care coordination and whether an orientation among health services to provide such a coordination model could lead to longer-term improved clinical outcomes. TRIAL REGISTRATION: http://anzctr.org.au Identifier: ACTRN12617001188325.

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. METHODS: The contents of six vMMI stations were similar to face-to-face MMI. Implementation required the identification of ZOOMTM as a preferred online platform, securing venues, communication, development of contingency plans and central coordination by the network. Candidates' experiences with vMMI were explored through thematic analysis of the qualitative data from focus groups and free text responses, and descriptive analysis of SurveyMonkey© questionnaire responses. Experiences between 'metropolitan' and 'regional and interstate' candidates were compared. RESULTS: 5-minute stations with 2-minute pre-reading were used. 78 candidates and 14 interviewers participated in the selection process. All candidates attended the focus group. 58.7% of candidates responded to post vMMI questionnaire. 93% of survey responders were happy to undertake vMMI in the future, with 23% feeling they would have performed better in face-to-face. Experiences between 'metropolitan' and 'other' groups were similar. Positive experiences of participants were related to the user-friendly IT platform, successful pre-interview communications, preparation, convenience, time, and cost savings. Stress related IT failures and difficulties establishing rapport with interviewers were reported as the main negative experiences. CONCLUSION: 'vMMI' is a feasible and acceptable method of selection into paediatric training. vMMI has many benefits and can be implemented relatively quickly by addressing key logistical requirements. The model under discussion could be adapted by other centres based on local needs.

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. METHODS: A randomized, parallel-group, superiority clinical trial was performed within an Australian children's hospital throughout 2 bronchiolitis seasons from May 2018 to October 2019. Infants <12 months hospitalized with bronchiolitis and requiring supplemental nasogastric feeding were randomly assigned to continuous or bolus nasogastric regimens. LOS was the primary outcome. Secondary outcome measures included pulmonary aspirations and admissions to intensive care. RESULTS: The intention-to-treat analysis included 189 patients: 98 in the bolus nasogastric feeding group and 91 in the continuous group. There was no significant difference in LOS (median LOS of the bolus group was 54.25 hours [interquartile range 40.25-82] and 56 hours [interquartile range 38-78.75] in the continuous group). A higher proportion of admissions to intensive care was detected in the continuous group (28.57% [26 of 91] of the continuous group vs 11.22% [11 of 98] of the bolus group [P value 0.004]). There were no clinically significant pulmonary aspirations or statistically significant differences in vital signs between the groups within 6 hours of feed initiation. CONCLUSIONS: No significant difference in LOS was found between bolus and continuous nasogastric feeding strategies for infants hospitalized with bronchiolitis. The continuous feeding group had a higher proportion of intensive care admissions, and there were no aspiration events.

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 < 8.0% and those with HbA1c ≥ 8.0% for subgroup analysis. RESULTS: The majority (71%) of patients correctly defined HbA1c and half were aware of their HbA1c target, but they were unable to correlate the correct average blood glucose for an HbA1c level of 7%. Worse control, defined as an HbA1c level of ≥ 8%, was associated with co-morbid disease, but was not associated with understanding HbA1c definition, target or socioeconomic disparities. Perceived glycemic control was congruent with the actual control in 46% of our patients. Ninety percent of those with HbA1c ≥ 8% perceived their control to be better than it actually was, and 97% of those with HbA1c < 8% perceived their control worse than it actually was (P < 0.00001). CONCLUSION: Although most patients knew the definition of HbA1c, they were unable to correlate HbA1c with average blood sugar. There remain opportunities to increase education for this vulnerable population with co-morbid disease on the use of the HbA1c disease marker as an education tool.

High flow in children with respiratory failure: A randomised controlled pilot trial - A paediatric acute respiratory intervention study.

AIMS: High-flow is increasingly used in children with acute hypoxaemic respiratory failure (AHRF), despite limited evidence. The primary feasibility endpoint for this pilot-study was the proportion of treatment failure, secondary outcomes being intensive care unit (ICU) admissions and proportion of patients requiring escalation of care. We measured duration of hospital stay, duration of oxygen therapy and rates of ICU admission. METHODS: An open-labelled randomised controlled trial feasibility design was used in two tertiary children's hospitals in the emergency department and general wards. Children aged 0-16 years with AHRF were randomised (1:1) to either high-flow or standard-oxygen. Children on standard-oxygen received rescue high-flow in general wards if failure criteria were met. RESULTS: Of 563 randomised, 283 received high-flow and 280 standard-oxygen with no adverse events. The proportion of children who failed treatment and receiving escalation of care was 11.7% (32/283 children) on high-flow and 18.1% (50/280 infants) on standard-oxygen (odds ratio 0.68, 95% confidence interval 0.38-1.00). In children with obstructive airway disease, 9.7% on high-flow and 17.4% on standard-oxygen required escalation (risk-difference -7.7% percentage points; 95% confidence interval -14.3, -1.1); in children with non-obstructive disease no difference was observed. Neither difference in ICU admissions nor any difference in length of hospital stay was observed. Sixty percent of children who failed standard-oxygen responded to rescue high-flow. CONCLUSION: High-flow outside ICU appears to be feasible in children with AHRF and the required proportion of escalation was lower compared to standard-oxygen. The trial design can be applied in a future large randomised controlled trial.

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. Our analysis suggests that due to exchange artifacts, the turnover rate of lactate and the lactate clearance are only about 60% of the values of 1.05 mmol/min/70 kg and 1.5 L/min/70 kg, respectively, determined from the standard tracer kinetics. Lactate turnover reflects lactate release primarily from muscle, gut, adipose, and erythrocytes and uptake by the liver and kidney, primarily for the purpose of energy production (TCA cycle) while the remainder is used for gluconeogenesis (Cori cycle). The well-studied physiology of exercise-induced hyperlactatemia demonstrates massive release from the contracting muscle accompanied by an increased lactate clearance that may occur in recovering nonexercising muscle as well as the liver. The very limited data on lactate kinetics in shock patients suggests that hyperlactatemia reflects both decreased clearance and increased production, possibly primarily in the gut. Our analysis of available data in health and shock suggests that the conventional concept of tissue hypoxia can account for most blood lactate findings and there is no need to implicate a purposeful production of lactate for export to other organs.

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. Minor increases in plasma D-lactate have been observed in various gastrointestinal conditions such as ischemia, appendicitis and Crohn's disease, a finding touted to have diagnostic utility. The novel aspect of this review paper is the application of numerical values to the processes involved in D-lactate homeostasis that previously have been described only in qualitative terms. This approach provides a number of new insights into normal and disordered production, catabolism and excretion of D-lactate, and identifies multiple gaps in our understanding of D-lactate physiology that should be amenable to relatively simple investigative study.

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. Outcome measures will be reported from the time arrival in Australia and repeated over a 5-year follow-up period. Measures include demographics, residency history and refugee status, physical health and well-being outcomes (including mental health, development and social-emotional well-being), clinical service utilisation and psychosocial risk and protective factors for health and well-being (eg, adverse childhood experiences). Longitudinal follow-up will capture outcomes over a 5-year period after arrival in Australia. Analysis will be undertaken to explore baseline risk and protective factors, with regression analyses to assess their impact on health and well-being outcomes. To understand how children's outcomes change over time, multilevel regression analysis will be utilised. Structural equation modelling will be conducted to explore the correlation between baseline factors, mediational factors and outcomes to assess trajectories over time. ETHICS AND DISSEMINATION: This research project was approved by the Sydney Children's Hospitals Network Human Research Ethics Committee. Subsequent site-specific approvals have been approved in 5 of the 11 governing bodies where the clinical consultations took place. In order to ensure this research is relevant and sensitive to the needs of the cohort, our research team includes an asylum seeker who has spent time in Australian immigration detention. Results will be presented at conferences and published in peer-reviewed Medline-indexed journals.

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. Concepts discussed include the following: 1) only about 44 mmol of ammonia/day (4.4% of total production) reaches the peripheral circulation due to the efficient linkage of amino deamination and the urea cycle in hepatic mitochondria; 2) the gut and kidney contribute roughly equally to delivery of this 44 mmol/day to systemic blood; 3) the bulk of gut ammonia production seemingly originates in the small bowel from bacterial deamination of urea by bacteria and mucosal deamination of circulating and ingested glutamine; 4) the apparent production of ammonia in the small bowel markedly exceeds that quantity that enters the portal blood, indicating that ammonia disposal mechanisms in the small bowel play a major role in ammonia homeostasis. With regard to the hyperammonemia of chronic liver disease: 1) shunting of portal blood around the liver, by itself, can account for commonly observed ammonia elevations; 2) severe portal hypertension causes an increased release of ammonia by the kidney; 3) high blood ammonia is associated with an unexplained massive increase in the muscle uptake of ammonia that could play an important role in limiting hyperammonemia; and 4) a major action of lactulose administration may be the enhancement of ammonia uptake by small bowel bacteria, while the mechanism of action of rifaximin is unclear.

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. Since the HLS drugs (eg, volatile anesthetics, propofol, cannabinol) have lipid/water partition coefficients (PL/W) of 100 or greater, their K is dominated by the tissue fat fraction and one can accurately predict K just from in vitro measurements of PL/W along with prior anatomic measurements of the fat fraction of the organs in the PBPK model. Since the ECS drugs, such as most antibiotics, cannot penetrate cells, they are not subject to the intracellular binding that complicates the prediction of K for the weak bases and acids. The ECS K is determined primarily by plasma and interstitial albumin binding and can be predicted from in vitro measurements of plasma albumin binding along with prior measurements of interstitial tissue volume and albumin concentrations. This review provides an in depth discussion of the PBPK modeling of these two drug classes along with many specific clinical examples illustrating the good PBPK predictions possible with just zero (volatile anesthetics) or 1 (the clearance) adjustable parameter. The PBPK analysis uses PKQuest, a freely distributed, general purpose pharmacokinetic program. PKQuest is designed so that application to the HLS and ECS solute classes is especially easy. The user only needs to enter the specific parameters that are required to characterize the drug (eg, PL/W for HLS or plasma albumin binding for ECS) with all the other PBPK parameters (organ blood flow, fat fraction, extracellular volumes, etc.) are set by default.

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. Formulation of the guideline included identification of population, intervention, comparator, outcomes and time questions and was associated with an extensive literature search from 2000 to 2015. Evidence was summarised and graded using the National Health and Medical Research Council and Grading of Recommendations Assessment, Development and Evaluation methodology, and consensus within the guideline group was sought using nominal group technique principles to formulate the clinical practice recommendations. The guideline was reviewed and endorsed by key paediatric health bodies. RESULTS: The guideline consists of a usable clinical interface for bedside functionality supported by evidence summary and tables. The Grading of Recommendations Assessment, Development and Evaluation and National Health and Medical Research Council processes provided a systematic and transparent process to review and assess the literature, resulting in a guideline that is relevant to the management of bronchiolitis in the Australasian setting. CONCLUSION: This is the first robust Australasian acute paediatric guideline and provides clear guidance for the management of the vast majority of patients seen in Australasian emergency departments and general paediatric wards with bronchiolitis.