Knowledge, safety, and impact of alcohol consumption in young adults with type 1 diabetes mellitus: a qualitative study.

PURPOSE: To explore the lived experiences of alcohol consumption among young adults with type 1 diabetes. METHODS: Fourteen semi-structured interviews were conducted amongst young adults aged between 18 and 25 years, inclusive, with type 1 diabetes and experience consuming alcohol. Interviews were transcribed verbatim and analysed to identify common themes regarding their experiences. RESULTS: The interviews confirmed that young adults with type 1 diabetes engage in social, and occasionally excessive, drinking behaviour. Furthermore, the interviews revealed four key themes: (i) Several sources contribute to a widely inconsistent understanding of the impact and management of alcohol consumption; (ii) Perceived inconvenience of maintaining healthy glycaemic control whilst drinking socially; (iii) Engagement in proactive strategies for harm reduction occurred when convenient; and (iv) Impact of modern diabetes technology in overcoming previous burdens and promoting glycaemic safety. CONCLUSION: Young adults with type 1 diabetes continue to need anticipatory education surrounding safe alcohol consumption and behaviours, as well as ongoing support and encouragement to ensure engagement with traditional self-management tasks. Significant alcohol-diabetes related safety issues, particularly hypoglycaemia do occur, and were captured within this small sample and study. Diabetes technology has an important complementary role along with education and tailored support strategies to support health and safe glucose control during alcohol consumption.

Reduction of quantitative systems pharmacology models using artificial neural networks.

Quantitative systems pharmacology models are often highly complex and not amenable to further simulation and/or estimation analyses. Model-order reduction can be used to derive a mechanistically sound yet simpler model of the desired input-output relationship. In this study, we explore the use of artificial neural networks for approximating an input-output relationship within highly dimensional systems models. We illustrate this approach using a model of blood coagulation. The model consists of two components linked together through a highly dimensional discontinuous interface, which creates a difficulty for model reduction techniques. The proposed approach enables the development of an efficient approximation to complex models with the desired level of accuracy. The technique is applicable to a wide variety of models and provides substantial speed boost for use of such models in simulation and control purposes.

Insulin regimens for newly diagnosed children with type 1 diabetes mellitus in Australia and New Zealand: A survey of current practice.

AIM: There is no consensus on the optimal insulin treatment for children newly diagnosed with type 1 diabetes mellitus (T1DM). The aims of this study were (i) to describe the insulin regimens used at diagnosis by patient age and geographical region and (ii) to explore differences between and within Australia (AU) and New Zealand (NZ) with regards to other aspects of patient management and education. METHODS: An online survey of medical professionals caring for children with T1DM in AU and NZ was undertaken. Questions included clinic demographics, insulin regimen/dosing choices and patient education. RESULTS: Of 110 clinicians identified, 100 responded (91%). The majority of those in AU (69%, P < 0.0001) favour multiple daily injections (MDI) for all ages. In NZ, for patients < 10 years old, (twice daily (BD)) BD therapy was favoured (75%, P < 0.0001), with MDI dominant for ages ≥ 10 years (82%, P < 0.0001). Insulin pump therapy was never considered at diagnosis in NZ, but 38% of clinicians in AU considered using pumps at diagnosis in patients <2 years, but rarely in patients aged 2 and over (16%). Differences in clinician choices were also seen in relation to starting insulin dose. CONCLUSION: This is the first study to examine current clinical practice with regards to children newly diagnosed with T1DM. Practice varies across Australasia by clinician and region. This lack of consensus is likely driven by ongoing debates in the current paediatric diabetes evidence base as well as by differences in clinician/centre preference, variations in resourcing and their interpretations of the influence of various patient factors.

Release and swelling studies of an innovative antidiabetic-bile acid microencapsulated formulation, as a novel targeted therapy for diabetes treatment.

In previous studies carried out in our laboratory, a bile acid formulation exerted a hypoglycaemic effect in a rat model of type 1 diabetes (T1D). When the antidiabetic drug gliclazide was added to the bile acid, it augmented the hypoglycaemic effect. In a recent study, we designed a new formulation of gliclazide-deoxycholic acid (G-DCA), with good structural properties, excipient compatibility and which exhibited pseudoplastic-thixotropic characteristics. The aim of this study is to test the slow release and pH controlled properties of this new formulation. The aim is also to examine the effect of DCA on G release kinetics at various pH values and different temperatures. Microencapsulation was carried out using our Buchi-based microencapsulating system developed in our laboratory. Using sodium alginate (SA) polymer, both formulations were prepared including: G-SA (control) and G-DCA-SA (test) at a constant ratio (1:3:30), respectively. Microcapsules were examined for efficiency, size, release kinetics, stability and swelling studies at pH 1.5, 3, 7.4 and 7.8 and temperatures of 25 °C and 37 °C. The new formulation is further optimised by the addition of DCA. DCA reduced bead-swelling of the microcapsules at pH 7.8 and 3 at 25 °C and 37 °C, and even though bead size remains similar after DCA addition, the percentage of G release was enhanced at high pH values (pH 7.4 and 7.8, p < 0.01). The new formulation exhibits colon-targeted delivery and the addition of DCA prolonged G release suggesting its suitability for the sustained and targeted delivery of G and DCA to the lower intestine.

Probucol release from novel multicompartmental microcapsules for the oral targeted delivery in type 2 diabetes.

In previous studies, we developed and characterised multicompartmental microcapsules as a platform for the targeted oral delivery of lipophilic drugs in type 2 diabetes (T2D). We also designed a new microencapsulated formulation of probucol-sodium alginate (PB-SA), with good structural properties and excipient compatibility. The aim of this study was to examine the stability and pH-dependent targeted release of the microcapsules at various pH values and different temperatures. Microencapsulation was carried out using a Büchi-based microencapsulating system developed in our laboratory. Using SA polymer, two formulations were prepared: empty SA microcapsules (SA, control) and loaded SA microcapsules (PB-SA, test), at a constant ratio (1:30), respectively. Microcapsules were examined for drug content, zeta potential, size, morphology and swelling characteristics and PB release characteristics at pH 1.5, 3, 6 and 7.8. The production yield and microencapsulation efficiency were also determined. PB-SA microcapsules had 2.6 ± 0.25% PB content, and zeta potential of -66 ± 1.6%, suggesting good stability. They showed spherical and uniform morphology and significantly higher swelling at pH 7.8 at both 25 and 37°C (p < 0.05). The microcapsules showed multiphasic release properties at pH 7.8. The production yield and microencapsulation efficiency were high (85 ± 5 and 92 ± 2%, respectively). The PB-SA microcapsules exhibited distal gastrointestinal tract targeted delivery with a multiphasic release pattern and with good stability and uniformity. However, the release of PB from the microcapsules was not controlled, suggesting uneven distribution of the drug within the microcapsules.

Consistent methods for fat-free mass, creatinine clearance, and glomerular filtration rate to describe renal function from neonates to adults.

Quantifying the effect of kidney disease on glomerular filtration rate (GFR) is important when describing variability in the clearance of drugs eliminated by the kidney. We aimed to develop a continuous model for renal function (RF) from prematurity to adulthood based on consistent models for fat-free mass (FFM), creatinine production rate (CPR), and GFR. A model for fractional FFM in premature neonates to adults was developed using pooled data from 4462 subjects and 2847 FFM observations. It was found that girls have an FFM higher than that predicted from adult women based on height, total body mass, and sex, and boys have an FFM lower than adult men until around the onset of puberty, when it approaches adult male values. Data from 108 subjects with measurements of serum creatinine (Scr) and GFR were used to construct a model for CPR. Creatinine clearance was predicted using a model for CPR (based on FFM, postmenstrual age, and sex) and Scr that avoids discontinuous predictions between neonates, children, and adults. Individual CPR may then be used with individual Scr to predict the estimated GFR (eGFR; eGFR = CPR/Scr). A previously published model for human GFR based on 1153 GFR observations in 923 subjects without known kidney disease was updated using the model for fractional FFM to predict individual size and age-consistent values for the expected normal GFR (nGFR). Individual renal function was then calculated using RF = eGFR/nGFR.

Identifying the core concepts of pharmacology education.

Pharmacology education currently lacks an agreed knowledge curriculum. Evidence from physics and biology education indicates that core concepts are useful and effective structures around which such a curriculum can be designed to facilitate student learning. Building on previous work, we developed a novel, criterion-based method to identify the core concepts of pharmacology education. Five novel criteria were developed, based on a literature search, to separate core concepts in pharmacology from topics and facts. Core concepts were agreed to be big ideas, enduring, difficult, applicable across contexts, and useful to solve problems. An exploratory survey of 33 pharmacology educators from Australia and New Zealand produced 109 terms, which were reduced to a working list of 26 concepts during an online workshop. Next, an expert group of 12 educators refined the working list to 19 concepts, by applying the five criteria and consolidating synonyms, and added three additional concepts that emerged during discussions. A confirmatory survey of a larger group resulted in 17 core concepts of pharmacology education. This list may be useful for educators to evaluate existing curricula, design new curricula, and to inform the development of a concept inventory to test attainment of the core concepts in pharmacology.

Defining and unpacking the core concepts of pharmacology education.

Pharmacology education currently lacks a research-based consensus on which core concepts all graduates should know and understand, as well as a valid and reliable means to assess core conceptual learning. The Core Concepts in Pharmacology Expert Group (CC-PEG) from Australia and New Zealand recently identified a set of core concepts of pharmacology education as a first step toward developing a concept inventory-a valid and reliable tool to assess learner attainment of concepts. In the current study, CC-PEG used established methodologies to define each concept and then unpack its key components. Expert working groups of three to seven educators were formed to unpack concepts within specific conceptual groupings: what the body does to the drug (pharmacokinetics); what the drug does to the body (pharmacodynamics); and system integration and modification of drug-response. First, a one-sentence definition was developed for each core concept. Next, sub-concepts were established for each core concept. These twenty core concepts, along with their respective definitions and sub-concepts, can provide pharmacology educators with a resource to guide the development of new curricula and the evaluation of existing curricula. The unpacking and articulation of these core concepts will also inform the development of a pharmacology concept inventory. We anticipate that these resources will advance further collaboration across the international pharmacology education community to improve curricula, teaching, assessment, and learning.

An Extension of Janmahasatian's Fat-Free Mass Model for Universal Application Across Populations of Different Ethnicities.

BACKGROUND: Fat-free mass (FFM)-based dose scaling is increasingly being adopted in clinical pharmacology. Given the complexities with the measurement of FFM in clinical practice, choosing an appropriate equation for FFM is critical for accurate dose scaling. Janmahasatian's FFM model (FFMJan) has largely remained the preferred choice because of its mechanistic basis and good predictive properties. This model was, however, developed from a largely European cohort and has been shown to give biased predictions of FFM in Indian people. OBJECTIVE: The objective of this work was to derive an extended version of the FFMJan model (FFMExt) that accounts for the variation in body composition due to ethnicity, and to demonstrate its application by developing an extended FFM model in an Indian population (FFMExt,Ind). METHODS: The fundamental assumption of FFMJan model development was a linear relationship between bioimpedance and body mass index. In this extension to Janmahasatian's work, this assumption was extended to allow for potential non-linear relationships. While the original ZJan model parameters were kept fixed, a set of body composition-related parameters [Formula: see text] were incorporated, where [Formula: see text] and [Formula: see text] were the ethnicity factors to the intercept and the linear coefficient, respectively, and [Formula: see text] a non-linear exponent. The model was then applied to data arising from a south Indian population and the [Formula: see text] parameters were estimated by standard non-linear regression. The data were generated from a reference model for FFM for the Indian population, which was known to provide unbiased estimates for this population. RESULTS: The parameter estimates (%RSE) of the final FFMExt,Ind model were [Formula: see text] (fixed), [Formula: see text] (3.2%) for male patients, 0.70 (3.3%) for female patients, and [Formula: see text] (12.4%). The final model predictions were in good agreement with the reference model predictions. CONCLUSIONS: An FFMExt model has been achieved by extending the original FFMJan model assumptions to account for inter-ethnic differences in body composition. The extended model can be applied to any ethnic population by estimating a set of body composition-related parameters [Formula: see text]. This can be performed using bioimpedance data without the need for formal FFM measurements.

Evaluating Lean Liver Volume as a Potential Scaler for In Vitro-In Vivo Extrapolation of Drug Clearance in Obesity Using the Model Drug Antipyrine.

BACKGROUND: In vitro-in vivo extrapolation (IVIVE) of hepatic drug clearance (CL) involves the scaling of hepatic intrinsic clearance (CLint,uH) by functional liver size, which is approximated by total liver volume (LV) as per the convention. However, in most overweight and obese patients, LV includes abnormal liver fat, which is not thought to contribute to drug elimination, thus overestimating drug CL. Therefore, lean liver volume (LLV) might be a more appropriate scaler of CLint,uH. OBJECTIVE: The objective of this work was to assess the application of LLV in CL extrapolation in overweight and obese patients (BMI >25 kg/m2) using a model drug antipyrine. METHODS: Recently, a model to predict LLV from patient sex, weight, and height was developed and evaluated. In order to assess the LLV model's use in IVIVE, a correlation-based analysis was conducted using antipyrine as an example drug. RESULTS: In the overweight group (BMI >25 kg/m2), LLV could describe 36% of the variation in antipyrine CL (R2 = 0.36), which was >2-fold higher than that was explained by LV (R2 = 0.17). In the normal-weight group (BMI ≤25 kg/m2), the coefficients of determination were 58% (R2 = 0.58) and 43% (R2= 0.43) for LLV and LV, respectively. CONCLUSION: The analysis indicates that LLV is potentially a more appropriate descriptor of functional liver size than LV, particularly in overweight individuals. Therefore, LLV has a potential application in IVIVE of CL in obesity.

Evaluating the Relationship Between Lean Liver Volume and Fat-Free Mass.

BACKGROUND: Fat-free mass has gained wide acceptance as a scaler of the maintenance dose rate in obese patients. The choice of fat-free mass as a size scaler for the maintenance dose rate is based on its relationship with drug clearance, on the basis that only lean tissue is sufficiently metabolically active to provide capacity for elimination. For xenobiotics, the majority of biotransformation occurs in the liver and hence fat-free mass is implied to scale linearly with the component of liver that is metabolically active. The liver, like the body, can be assumed to comprise two components, lean mass and fat mass. We expect the lean liver mass (or volume) to be the component that most closely relates to drug clearance. OBJECTIVE: The objective of this study was to investigate the relationship of lean liver volume and fat-free mass. METHODS: Total liver volume and liver fat volume were measured in 100 Indian adults by computed tomography. Lean liver volume was derived as the difference between the two measurements (as liver volume - liver fat volume). Covariate modelling to describe lean liver volume, using NONMEM version 7.3, involved testing the influence of body weight, sex, body surface area and fat-free mass with or without allometric scaling (by estimating the exponent) and the influence of clinical chemistry variables. RESULTS: The final model did not exclude a linear relationship between lean liver volume and fat-free mass, while allometric scaling by body weight0.75 was also supported by the data. While scaling by fat-free mass, the coefficient of proportionality (i.e. lean liver volume per kg fat-free mass) was higher in female (31.25 mL) than male (25.81 mL) subjects. CONCLUSIONS: A model to predict lean liver volume from readily available patient data was developed and evaluated. Fat-free mass plus sex was found to be the best body descriptor to scale lean liver volume. The utility of this model in scaling drug clearance and dose requirements of hepatically cleared drugs needs further exploration.

The time course of drug effects.

This review aims to introduce the concepts and principles underpinning the time course of drug effects. Models describing the time course of drug concentrations (pharmacokinetic models) and the ensuing concentration-effect (pharmacodynamics models) as well as the linked time-effect (pharmacokinetic-pharmacodynamic models) are introduced. Different types of drug time-effects models are discussed with examples which aim to explain the time course of onset, duration, and maximal effect that occurs from any given dosing schedule. These drug effects are also described in relation to disease progression models.

Choosing the Allometric Exponent in Covariate Model Building.

BACKGROUND: Allometric scaling is often used to describe the covariate model linking total body weight (WT) to clearance (CL); however, there is no consensus on how to select its value. OBJECTIVES: The aims of this study were to assess the influence of between-subject variability (BSV) and study design on (1) the power to correctly select the exponent from a priori choices, and (2) the power to obtain unbiased exponent estimates. METHODS: The influence of WT distribution range (randomly sampled from the Third National Health and Nutrition Examination Survey, 1988-1994 [NHANES III] database), sample size (N = 10, 20, 50, 100, 200, 500, 1000 subjects), and BSV on CL (low 20%, normal 40%, high 60%) were assessed using stochastic simulation estimation. A priori exponent values used for the simulations were 0.67, 0.75, and 1, respectively. RESULTS: For normal to high BSV drugs, it is almost impossible to correctly select the exponent from an a priori set of exponents, i.e. 1 vs. 0.75, 1 vs. 0.67, or 0.75 vs. 0.67 in regular studies involving < 200 adult participants. On the other hand, such regular study designs are sufficient to appropriately estimate the exponent. However, regular studies with < 100 patients risk potential bias in estimating the exponent. CONCLUSION: Those study designs with limited sample size and narrow range of WT (e.g. < 100 adult participants) potentially risk either selection of a false value or yielding a biased estimate of the allometric exponent; however, such bias is only relevant in cases of extrapolating the value of CL outside the studied population, e.g. analysis of a study of adults that is used to extrapolate to children.

Insulin pump initiation and education for children and adolescents - a qualitative study of current practice in New Zealand.

PURPOSE: Worldwide, the use of insulin pumps for the management of type 1 diabetes is increasing. There are no national or international published guidelines and few guidance recommendations detailing the education and training required to commence insulin pump therapy. The aim of this study is to describe current clinical practice regarding initiation of insulin pump therapy in children and adolescents with type 1 diabetes in New Zealand. METHODS: Pediatric diabetes nurse specialists from selected New Zealand hospitals (n = 16) were identified and invited to participate in this qualitative study. For those consenting, structured interviews were conducted. The questions covered basic hospital demographics and various aspects of insulin pump initiation including pump start planning, education, and aspects of follow-up and after-care. RESULTS: The response rate was 100% (16 out of 16 hospitals). Diabetes clinics interviewed varied in size from 50 to 450 pediatric patients and frequency of insulin pump use from 11% - 46%. Clinical practice differed between clinics. Important differences related to: use of continuous glucose monitoring (12/16); and differing views on immediate vs. delayed use of pump advanced features. Location of pump starts also varied, with both in-patient (2/16) and out-patient (14/16) approaches seen. The motivations and beliefs relating to these various pump start approaches also varied. CONCLUSIONS: Differences seen between hospitals reflected team preference, and possibly a lack of consensus/guidance from the medical literature. Lessons may be learnt and further rationalisation and improvement in education remains possible by combining and adopting strengths from different hospitals.

Newborn Vitamin K Prophylaxis: A Historical Perspective to Understand Modern Barriers to Uptake.

Since its initial discovery almost a century ago, vitamin K has been labeled as both lifesaving and malignancy causing. This has led to debate of not only its use in general but also regarding its appropriate dose and route. In this article, we review through a historical lens the past 90 years of newborn vitamin K from its discovery through to its modern use of preventing vitamin K deficiency bleeding (VKDB). Although researchers in surveillance studies have shown considerable reductions in VKDB following intramuscular vitamin K prophylaxis, ongoing barriers to the universal uptake of vitamin K prophylaxis remain. Reviewing the history of newborn vitamin K provides an opportunity for a greater understanding of the current barriers to uptake that we face. Although at times difficult, improving this understanding may allow us to address contentious issues related to parental and health professional beliefs and values as well as improve overall communication. The ultimate goal is to improve and maintain the uptake of vitamin K to prevent VKDB in newborns.

A Review of the Methods and Associated Mathematical Models Used in the Measurement of Fat-Free Mass.

Fat-free mass (FFM) represents the lean component of the body devoid of fat. It has been shown to be a useful predictor of drug dose requirements, particularly in obesity where the excess fat mass does not contribute to drug clearance. However, measuring FFM involves complex and/or expensive experimental methodologies that preclude their use in routine clinical practice. Thus, models to predict FFM from readily measurable variables, such as body weight and height, have been developed and are used in both population pharmacokinetic modelling and clinical practice. In this review, methods used to measure FFM are explained and compared in terms of their assumptions, precision, and limitations. These methods are broadly classified into six different principles: densitometry, hydrometry, bioimpedance, whole-body counting, dual energy X-ray absorptiometry, and medical imaging. They vary in their processes and key biological assumptions that are often not applicable in certain populations (e.g. children, elderly, and certain disease states). This review provides a summary of the various methods of FFM measurement and estimation, and links these methods to a scientific framework to help clinicians and researchers understand the usefulness and potential limitations of these methods.

The influence of patient variables on insulin total daily dose in paediatric inpatients with new onset type 1 diabetes mellitus.

PURPOSE: Insulin dose requirements at new diagnosis of type 1 diabetes mellitus (T1DM) vary widely. Current guidelines recommend an initial total daily dose (TDD) ranging from 0.5 to 1.0 IU/kg/day. It often takes several days of frequent dose adjustments before an optimal insulin dose is achieved. The aim of this study was to identify the influence of patient variables on the dose-requirement of insulin in newly diagnosed children with T1DM. METHODS: A retrospective chart review of children (≤ 18 years old) admitted to hospital between 2010 and 2016 due to new onset T1DM was undertaken. Demographic, clinical, insulin dosing, and laboratory data were recorded. The influence of patient characteristics on insulin TDD was analysed statistically by performing univariate and multivariate linear regression analyses. RESULTS: Complete clinical records for 70 patients were available for analysis. The median insulin TDD on first day of admission was 21 (4.5 to 75 units) and that on the day before discharge was 27 (5.5 to 124 units). In the multivariate regression analysis, body size (total body weight and fat-free mass), glycated haemoglobin (HbA1C), and blood ketone concentration were found to be significant predictors of optimal insulin TDD (p < 0.05). CONCLUSION: In addition to body size, HbA1c and ketone concentrations are useful in calculating initial TDD in newly diagnosed children with T1DM. This could potentially decrease the number of days needed to reach a stable dose and result in improved early glycaemic control.