Technical education and training: with special reference to developing countries

The typesetting book content by the jointed authors, D. D. Waters and J. W. Gailer

Methylated Trivalent Arsenic-Glutathione Complexes are More Stable than their Arsenite Analog

The trivalent arsenic glutathione complexes arsenic triglutathione, methylarsonous diglutathione, and dimethylarsinous glutathione are key intermediates in the mammalian metabolism of arsenite and possibly represent the arsenic species that are transported from the liver to the kidney for urinary excretion. Despite this, the comparative stability of the arsenic-sulfur bonds in these complexes has not been investigated under physiological conditions resembling hepatocyte cytosol. Using size-exclusion chromatography and a glutathione-containing phosphate buffered saline mobile phase (5 or 10 mM glutathione, pH 7.4) in conjunction with an arsenic-specific detector, we chromatographed arsenite, monomethylarsonous acid, and dimethylarsinous acid. The on-column formation of the corresponding arsenic-glutathione complexes between 4 and 37°C revealed that methylated arsenic-glutathione complexes are more stable than arsenic triglutathione. The relevance of these results with regard to the metabolic fate of arsenite in mammals is discussed

Prospective evaluation of a primary care referral pathway for patients with non-alcoholic fatty liver disease.

BACKGROUND & AIMS: We aimed to develop and evaluate a pathway for management of patients with non-alcoholic fatty liver disease (NAFLD) using blood tests to stratify patients in primary care to improve detection of cases of advanced fibrosis and cirrhosis, and avoid unnecessary referrals to secondary care. METHODS: This was a prospective longitudinal cohort study with before-and-after analysis and comparison to unexposed controls. We used a two-step algorithm combining the use of FIB-4 followed by the ELF test if required RESULTS: In total, 3,012 patients were analysed. Use of the pathway detected 5 times more cases of advanced fibrosis (Kleiner F3) and cirrhosis (OR=5.18; 95%CI=2.97 to 9.04; p<0.0001). Unnecessary referrals from primary care to secondary care fell by 81% (OR=0.193; 95%CI 0.111 to 0.337; p<0.0001). Three times more cases of cirrhosis were diagnosed (OR=3.14; 95%CI=1.57 to 24; p=0.00011). Although it was used for only 48% of referrals, significant benefits were observed across all referrals from the practices exposed to the pathway. Unnecessary referrals fell by 77% (OR=0.23; 95% CI=0.658 to 0.082; p=0.006) with a 4-fold improvement in detection of cases of advanced fibrosis and cirrhosis (OR=4.32; 95% CI=1.52 to 12.25; p=0.006). Compared to referrals made before introduction of the pathway, unnecessary referrals fell from 79/83 referrals (95.2%) to 107/152 (70.4%) representing an 88% reduction in unnecessary referrals when the pathway was followed (OR=0.12; 95%CI=0.042 to 0.349; p<0.0001). CONCLUSIONS: The use of non-invasive blood tests for liver fibrosis to stratify patients with NAFLD improves the detection of cases of advanced fibrosis and cirrhosis and reduces unnecessary referrals to secondary care of patients with lesser degrees of liver fibrosis. This strategy improves resource use and benefits patients. LAY SUMMARY: Non-alcoholic fatty liver disease effects up to 30% of the population but only a minority of cases develop liver disease. Our study has shown that established blood tests can be used in primary care to stratify patients with fatty liver disease to reduce unnecessary referrals by 80% and improve the detection of cases of advanced fibrosis 5 fold and cirrhosis 3 fold

Development and validation of the medication regimen simplification guide for residential aged CarE (MRS GRACE)

Background: Residents of aged care facilities use increasingly complex medication regimens. Reducing unnecessary medication regimen complexity (eg, by consolidating the number of administration times or using alternative formulations) may benefit residents and staff. Objective: To develop and validate an implicit tool to facilitate medication regimen simplification in aged care facilities. Method: A purposively selected multidisciplinary expert panel used modified nominal group technique to identify and prioritize factors important in determining whether a medication regimen can be simplified. The five prioritized factors were formulated as questions, pilot-tested using non-identifiable medication charts and refined by panel members. The final tool was validated by two clinical pharmacists who independently applied the tool to a random sample of 50 residents of aged care facilities to identify opportunities for medication regimen simplification. Inter-rater agreement was calculated using Cohen’s kappa. Results: The Medication Regimen Simplification Guide for Residential Aged CarE (MRS GRACE) was developed as an implicit tool comprising of five questions about 1) the resident; 2) regulatory and safety requirements; 3) drug interactions; 4) formulation; and 5) facility and follow-up considerations. Using MRS GRACE, two pharmacists independently simplified medication regimens for 29/50 and 30/50 residents (Cohen’s kappa=0.38, 95% CI 0.12–0.64), respectively. Simplification was possible for all residents with five or more administration times. Changing an administration time comprised 75% of the two pharmacists’ recommendations. Conclusions: Using MRS GRACE, two clinical pharmacists independently simplified over half of residents’ medication regimens with fair agreement. MRS GRACE is a promising new tool to guide medication regimen simplification in aged care.Esa YH Chen, Janet K Sluggett, Jenni Ilomäki, Sarah N Hilmer, Megan Corlis, Leonie J Picton, Laura Dean, Christopher P Alderman, Nicholas Farinola, Joy Gailer, Jane Grigson, Andrew R Kellie, Peter JC Putsey, Solomon Yu, J Simon Bel

Conditional and Reversible Activation of Class A and B G Protein-Coupled Receptors Using Tethered Pharmacology

Understanding the activation and internalization of G protein-coupled receptors (GPCRs) using conditional approaches is paramount to developing new therapeutic strategies. Here, we describe the design, synthesis, and testing of ExONatide, a benzylguanine-linked peptide agonist of the glucagon-like peptide-1 receptor (GLP-1R), a class B GPCR required for maintenance of glucose levels in humans. ExONatide covalently binds to SNAP-tagged GLP-1R-expressing cells, leading to prolonged cAMP generation, Ca2+ rises, and intracellular retention of the receptor. These effects were readily switched OFF following cleavage of the introduced disulfide bridge using the cell-permeable reducing agent beta-mercaptoethanol (BME). A similar approach could be extended to a class A GPCR using GhrelON, a benzylguanine-linked peptide agonist of the growth hormone secretagogue receptor 1a (GHS-R1a), which is involved in food intake and growth. Thus, ExONatide and GhrelON allow SNAP-tag-directed activation of class A and B GPCRs involved in gut hormone signaling in a reversible manner. This tactic, termed reductively cleavable agONist (RECON), may be useful for understanding GLP-1R and GHS-R1a function both in vitro and in vivo, with applicability across GPCRs