Complete dentures: an update on clinical assessment and management: part 2.

The ability to provide high quality complete dentures remains an important skill for general dental practitioners. The prevalence of edentulism is increasingly concentrated within an older patient cohort and general dental practitioners may face challenges associated with providing care for these patients. This two-part series explores various aspects of complete denture provision and is designed to act as a refresher on the management of edentulous patients. This second part focuses on the copy denture technique as well as discussing strategies for assessing and managing gag reflexes, prominent palatal and lingual tori and microstomia.

Complete dentures: an update on clinical assessment and management: part 1.

The ability to provide high-quality complete dentures has been a key skill for general dental practitioners throughout the history of dental care. The prevalence of edentulism is becoming increasingly concentrated in an older patient cohort and general dental practitioners may more commonly face challenges associated with providing care for these patients. This two-part series explores various aspects of complete denture provision and is designed to act as a refresher on core aspects of managing these patients, while also covering common challenges associated with anatomical or patient factors. This first part will explore changes in the provision and teaching of complete denture care in the UK and will describe important aspects of patient examination. It will discuss the management of unstable lower dentures and fibrous replacement ridges. Part two will cover management of the gag reflex, tori, microstomia and copy dentures.

The preferences of young adults with Type 1 diabetes at clinics using a discrete choice experiment approach: the D1 Now Study.

AIM: Attending routine outpatient clinic appointments is a central self-management behaviour of individuals living with Type 1 diabetes. A large number of young adults with Type 1 diabetes disengage from diabetes services, which may contribute to poor psychosocial and diabetes outcomes. The aim of this study is to elicit preferences from young adults with Type 1 diabetes regarding clinic-related services to inform service delivery. METHODS: A discrete choice experiment was developed to understand the preferences of young adults with Type 1 diabetes for clinic-related services. RESULTS: Young adults recruited from young adult Type 1 diabetes clinics in 2016 completed the experiment (n = 105). Young adults with Type 1 diabetes showed a preference for shorter waiting times, seeing a nurse and a consultant, relative to a nurse alone, and a flexible booking system compared with fixed appointment times. Results suggest no preference for a nurse and a doctor, relative to a nurse alone, or other optional services (e.g. seeing dietitians or psychologists), type of HbA1c test and digital blood glucose diaries over paper-based diaries. CONCLUSION: This study highlights aspects of routine clinic appointments that are valued by young adults living with Type 1 diabetes, namely shorter waiting times at clinic, the option to see both a nurse and consultant at each visit and a flexible clinic appointment booking system. These findings suggest young adults with Type 1 diabetes value convenience and should help services to restructure their clinics to be more responsive to the needs of young adults.

The Effect of Complete Denture Occlusion on Function and Patient Quality of Life: Systematic Review.

Edentulism presents an ongoing challenge for prosthodontic dentistry. Many aspects of complete denture construction lack contemporary evidence. One such aspect is denture occlusion. Balanced occlusion (BO) has become the prevailing occlusal scheme. It has been suggested that canine guidance (CG) is unsuitable for complete denture occlusion due to an increased risk for tipping of the prostheses. However it may be indicated in patients with minimal alveolus resorption. There has been limited evidence suggesting the superiority of either occlusal scheme over another. This article investigates the available literature assessing complete denture occlusion by means of clinical trials or reviews of evidence. We utilised PRISMA guidelines to investigate the effect of complete denture occlusal scheme (balance occlusion vs. canine guidance) on functional or quality of life. Seven studies were included for review. All studies were poor to moderate quality with the majority lacking randomisation, blinding and demographic data from the study sample. The available evidence suggests that the differences between occlusal schemes may be small, challenging the notion that BO may be the optimal occlusal scheme. There is a need for high-quality clinical research, investigating both chewing ability and quality of life in complete denture wearers in the long-term.

Leveraging a Clinical Phase Ib Proof-of-Concept Study for the GPR40 Agonist MK-8666 in Patients With Type 2 Diabetes for Model-Informed Phase II Dose Selection.

GPR40 mediates free fatty acid-induced insulin secretion in beta cells. We investigated the safety, pharmacokinetics, and glucose response of MK-8666, a partial GPR40 agonist, after once-daily multiple dosing in type 2 diabetes patients. This double-blind, multisite, parallel-group study randomized 63 patients (placebo, n = 18; 50 mg, n = 9; 150 mg, n = 18; 500 mg, n = 18) for 14-day treatment. The results showed no serious adverse effects or treatment-related hypoglycemia. One patient (150-mg group) showed mild-to-moderate transaminitis at the end of dosing. Median MK-8666 Tmax was 2.0-2.5 h and mean apparent terminal half-life was 22-32 h. On Day 15, MK-8666 reduced fasting plasma glucose by 54.1 mg/dL (500 mg), 36.0 mg/dL (150 mg), and 30.8 mg/dL (50 mg) more than placebo, consistent with translational pharmacokinetic/pharmacodynamic model predictions. Maximal efficacy for longer-term assessment is projected at 500 mg based on exposure-response analysis. In conclusion, MK-8666 was generally well tolerated with robust glucose-lowering efficacy.

The accuracy of nurse performance of the triage process in a tertiary hospital emergency department in Gauteng Province, South Africa.

BACKGROUND: Triage in the emergency department (ED) is necessary to prioritise management according to the severity of a patient's condition.The South African Triage Scale (SATS) is a hospital-based triage tool that has been adopted by numerous EDs countrywide.Many factors can influence the outcome of a patient's triage result, and evaluation of performance is therefore pivotal. OBJECTIVES: To determine how often patients were allocated to the correct triage category and the extent to which they were incorrectly promoted or demoted, and to determine the main reasons for errors in a nurse-led triage system. METHODS: Triage forms from a tertiary hospital ED in Gauteng Province, South Africa, were collected over a 1-week period and reviewed retrospectively. RESULTS: A total of 1 091 triage forms were reviewed. Triage category allocations were correct 68.3% of the time. Of the incorrect category assignments, 44.4% of patients were promoted and 55.6% demoted. Patients in the green category were most commonly promoted (29.4%) and patients who should have been in orange were most commonly demoted (35.0%). Trauma patients were more likely to be incorrectly promoted and non-trauma patients to be incorrectly demoted. Mistakes were mainly due to discriminator errors (57.8%), followed by numerical miscalculations (21.5%). The leading omitted discriminators were 'abdominal pain', 'chest pain' and 'shortness of breath'. CONCLUSIONS: Mis-triaging using the SATS can be attributed to incorrect or lack of discriminator use, numerical miscalculations and other human errors. Quality control and quality assurance measures must target training in these areas to minimise mis-triage in the ED.

Perceived barriers towards healthy eating and their association with fruit and vegetable consumption.

Background: Improving dietary intakes is a key public health target. Perceived barriers to healthy eating (PBHE) are an important component of the Health Belief Model which aims to understand why individuals do not adopt preventive health measures. This study investigates the relationship between PBHE and reported fruit and vegetable (F&V) consumption. Methods: Data from the Scottish Health Survey 2008-11 (n = 8319) for PBHE and self-reported F&V consumption were used in Probit regression models to test the association between meeting the 400 g per day F&V recommendation and PBHE. Results: Regression models show women who reported a lack of cooking skills were 10.4% less likely to meet the F&V recommendations (P = 0.001). Not liking the taste of healthy foods or finding them too boring (10.2%, P = 0.022), preparation time (5.6%, P = 0.020) or willpower (3.0%, P = 0.021) were also significant. For men, reporting not liking the taste of healthy foods or finding them too boring (6.8%, P = 0.02) was the only significant result. Price, a commonly reported PBHE, was not significantly associated with F&V consumption. Conclusions: Not all commonly reported perceived barriers to healthy eating are significantly associated with meeting the recommended F&V intake.

Creating a Healthy Ship.

In 2015 HMS DUNCAN was chosen as the intervention ship for an Institute of Naval Medicine (INM)-led project entitled Second Sea Lord (2SL)'s Feeding the Fleet Initiative. During her nine-month maiden deployment on Operation KIPION, a healthy lifestyle intervention was initiated, encompassing executive health, catering services, medical services and physical training. The key enabler of the success of the intervention was the formation of an effective Unit Health Committee. This article presents the lessons identified and provides useful examples from the intervention, which aimed to create a healthy lifestyle culture on board a deployed ship.

Glucodynamics of long-acting basal insulin peglispro compared with insulin glargine at steady state in patients with type 1 diabetes: substudy of a randomized crossover trial.

AIMS: To compare, in an open-label, randomized, crossover phase II substudy, the glucodynamics of insulin glargine and those of basal insulin peglispro (BIL) in patients with type 1 diabetes. METHODS: Patients (n = 23) underwent 24-h euglycaemic clamps after 8 weeks of treatment with glargine or with BIL. Clinically-titrated basal insulin doses (BIL group 16-64 U; glargine group 19-60 U) were administered on the morning of the clamp. RESULTS: At baseline, the patients' mean ± standard deviation (s.d.) body mass index was 26.78 ± 4.20 kg/m2 and glycated haemoglobin was 7.69 ± 0.99%. The mean ± s.d. endpoint dose for the BIL group was 0.42 ± 0.13 U/kg and for the glargine group was 0.42 ± 0.10. The daily mean ± s.d. blood glucose concentration was 7.7 ± 1.2 in the BIL group and 7.9 ± 1.2 mmol/l in the glargine group (p = 0.641). The mean ± s.d. total and nocturnal hypoglycaemia rates/30 days were 2.7 ± 2.3 and 0.5 ± 0.8, respectively, for the BIL group, and 3.0 ± 2.4 and 0.7 ± 1.1, respectively, for the glargine group (p = 0.112 and 0.428). The mean glucose infusion rate (GIR) normalized to insulin unit was lower for BIL than for glargine. One patient in the glargine group and eight patients in the BIL group had minimal (<0.8 g/kg) GIRs over 24 h. The mean ± s.d. total glucose infused over 24 h (GTOT(0-24) ) was 1.22 ± 0.82 g/kg in the BIL group and 1.90 ± 1.01 g/kg in the glargine group (p = 0.002). The mean ± s.d. total glucose infused during hours 0-6 (GTOT(0-6) ) was 0.21 ± 0.22 in the BIL group and 0.41 ± 0.22 g/kg in the glargine group (p < 0.001), while the mean total glucose infused during hours 18-24 (GTOT(18-24) ) in the BIL group was 0.28 ± 0.18 g/kg and in the glargine group was 0.35 ± 0.23 g/kg (p = 0.198). The peak-to-trough ratio was 1.41 for BIL versus 2.22 for glargine. CONCLUSIONS: BIL has a flatter profile than glargine, with potentially more stable metabolic control. The lower GTOT(0-24) observed in the BIL group is consistent with BIL's reduced peripheral action.

Albiglutide does not impair the counter-regulatory hormone response to hypoglycaemia: a randomized, double-blind, placebo-controlled, stepped glucose clamp study in subjects with type 2 diabetes mellitus.

AIM: To determine if the glucagon-like peptide-1 (GLP-1) receptor agonist albiglutide, once weekly, impairs counter-regulatory responses during hypoglycaemia. METHODS: We conducted a randomized, double-blind, parallel, placebo-controlled study in subjects with type 2 diabetes mellitus. A single dose of albiglutide 50 mg (n = 22) or placebo (n = 22) was administered on day 1. Glucose was clamped on day 4 (to coincide with the approximate albiglutide maximum plasma concentration) at 9.0, 5.0, 4.0, 3.3 and 2.8 mmol/l (162, 90, 72, 59.4 and 50.4 mg/dl), with a post-clamp recovery period to 3.9 mmol/l (70 mg/dl). Hormone measurements were made at each plateau and adverse events (AEs) were recorded. RESULTS: The counter-regulatory hormones glucagon, epinephrine, norepinephrine, growth hormone and cortisol were appropriately suppressed when plasma glucose levels were >4.0 mmol/l (>72 mg/dl), but increased in the albiglutide and placebo groups with glucose levels <3.3 mmol/l (<59.4 mg/dl) in response to hypoglycaemia. The area under the curve geometric mean ratios (albiglutide : placebo), calculated from the clamped plateau of 4.0 mmol/l (72 mg/dl) to the glucose recovery point, were not significantly different for any of the counter-regulatory hormones. When plasma glucose levels were >5.0 mmol/l (>90 mg/dl), albiglutide increased pancreatic ß-cell secretion of C-peptide in a glucose-dependent manner to a greater extent than did placebo, and it was suppressed in each group when levels were <4.0 mmol/l (<72 mg/dl). No significant difference between groups was observed in the recovery time to glucose level ≥3.9 mmol/l (≥70 mg/dl). There were no clinically relevant differences in AEs or other safety variables. CONCLUSIONS: A single 50-mg dose of albiglutide was well tolerated and did not impair the counter-regulatory response to hypoglycaemia. These data provide mechanistic evidence supporting the low intrinsic hypoglycaemic potential of albiglutide.

Effect of exogenously administered glucagon versus spontaneous endogenous counter-regulation on glycaemic recovery from insulin-induced hypoglycaemia in patients with type 2 diabetes treated with a novel glucokinase activator, AZD1656, and metformin.

AIMS: To study the effect of exogenous i.m. glucagon on recovery from controlled insulin-induced hypoglycaemia in patients with type 2 diabetes treated with the novel glucokinase activator AZD1656, in combination with metformin. METHODS: This was a single-centre randomized, open, two-way crossover phase I, automated glucose clamp (Biostator(®); Life Science Instruments, Elkhart, MD, USA) study (NCT00817271) in eight patients (seven men and one woman, mean age 58.6 years, body mass index 28.1 kg/m(2)). All patients received a stable dose of metformin twice daily, ranging from 1000 to 2250 mg. A 2-day titration phase commenced with 40 mg AZD1656 twice daily, escalating to 80 mg twice daily if tolerated. This was followed by a single dose of 80 or 160 mg AZD1656, administered on days 5 and 8 when metabolic studies were performed. After an overnight fast on days 5 and 8, controlled hypoglycaemia was induced using an exogenous i.v. infusion of insulin. Plasma glucose was lowered in a stepwise fashion over 3 h to attain a target nadir of 2.7 mmol/l. This was sustained for 30 min, at the end of which the hypoglycaemic clamp was released. In random sequence, patients either received an i.m. injection of 1 mg glucagon or were allowed to recover from hypoglycaemia by endogenous counter-regulation. To avoid prolonged hypoglycaemia, a reverse glucose clamp was applied from 4 to 6 h post-dose. RESULTS: Three patients received 40 mg AZD1656 twice daily and five patients 80 mg twice daily. Mean plasma glucose at 20 min after release of the hypoglycaemic clamp was significantly lower (3.1 ± 0.3 mmol/l) for AZD1656 alone than for AZD1656 + glucagon (4.9 ± 0.8 mmol/l; p < 0.001 between the groups). Catecholamine and cortisol responses were similar on the AZD1656 + glucagon and AZD alone study days. Growth hormone response was 18% lower for AZD1656 alone (p = 0.01), consistent with the effect of a pharmacological dose of glucagon on growth hormone secretion. No safety or tolerability concerns were observed during treatment with AZ1656. CONCLUSIONS: Exogenous glucagon was effective as a rescue treatment for hypoglycaemia induced during treatment with AZD1656, given in combination with metformin in patients with type 2 diabetes.

Safety, efficacy and weight effect of two 11ß-HSD1 inhibitors in metformin-treated patients with type 2 diabetes.

AIMS: We assessed safety and efficacy of two selective 11ß-HSD1 inhibitors (RO5093151/RO-151 and RO5027383/RO-838) in this randomized, controlled study in metformin-treated patients with type 2 diabetes. METHODS: Patients either received placebo (N = 21), RO-151 BID 5 mg (N = 24) or 200 mg (N = 20) or RO-838 QD 50 mg (N = 21) or 200 mg (N = 24) for 28 days. Metabolic assessments comprising of nine-point plasma glucose profiles, oral glucose tolerance tests and determination of metabolic biomarkers including insulin, C-peptide, glucagon, HbA1c and lipids were done at baseline and end of treatment. RESULTS: Despite the short treatment duration, both RO-151 and RO-838 showed trends for improved HbA1c and consistent reductions in body weight (-0.86 to -1.67 kg) exceeding those observed with placebo (-0.28 kg, p = 0.019 for 200 mg RO-151 vs. placebo). Insulin sensitivity parameters (e.g. HOMA-IR and Matsuda-Index) improved non-significantly with 200 mg RO-151. Lipid parameters did not consistently improve with either compound, but RO-838 led to non-significant increases in triglycerides and VLDL-cholesterol versus placebo. Both compounds were well tolerated and showed inhibitory effects on 11ß-HSD1 activity based on urinary corticosteroid excretion. As reported for other 11ß-HSD1-inhibitors increased concentrations of ACTH and adrenal androgen precursors were found with RO-151, but not with RO-838. CONCLUSIONS: Slight metabolic improvements were seen, in particular with RO-151 high dose, however, the observed changes often did not reach statistical significance and were not clearly dose dependent. Studies of longer duration are needed to further investigate potential benefits and risks of these compounds.

The management of lower back pain.

Lower back pain (LBP) is one of the most common musculoskeletal conditions, with an estimated 60-70% of the adult population experiencing a back problem at some point in their lives. It can have a significant social and occupational impact on a patient, and therefore is a major concern to both civilian and military populations. The impact of low back pain in the military setting, regardless of chronicity, can result in considerable restrictions on a patient's ability to perform his or her job. This may have important ramifications for deployability, medical category and, potentially, a patient's future career. This article will consider the diagnosis and classification of lower back pain (LBP) in the pre-shore, pre-hospital and hospital settings. It will detail management options including investigations, pain management and referral options; furthermore, the potential occupational implications of lower back pain will be detailed.

Effects of sulfur and acidity on performance and digestibility in feedlot lambs fed dried distillers grains with solubles.

Negative interactions of the acidity and S content of dried distillers grains with solubles (DDGS) have not been quantified. The objectives of this study were to determine the effects of dietary S, dietary acidity, and their interactions on growth, feed efficiency, ruminal H2S concentration, and apparent nutrient digestibility in lambs fed DDGS-based diets. To neutralize acidity, the DDGS was untreated or treated with 2% NaOH. Dietary S content was adjusted with Na2SO4 to achieve a 0.2 percentage unit difference in dietary S. Experiment 1 included 72 ewe and wether lambs (BW = 24.9 ± 0.4 kg) penned by sex in 24 pens, blocked by BW, and allotted in a 2 × 2 factorial arrangement of treatments for a 60 d feeding trial. On a DM basis, diets were: i) 60% DDGS + 0% Na2SO4, ii) 60% DDGS + 0.88% Na2SO4, iii) 62% NaOH-treated DDGS + 0% Na2SO4, and iv) 62% NaOH-treated DDGS + 0.83% Na2SO4. There were no interactions (P ≥ 0.19) of dietary S concentration and NaOH treatment. Lambs fed DDGS treated with 2% NaOH had 4% greater (P = 0.05) final BW and tended (P ≤ 0.07) to have greater DMI and ADG than lambs fed untreated DDGS; however, NaOH treatment did not affect (P = 0.42) G:F. Increasing dietary S with Na2SO4 tended (P = 0.07) to reduce DMI; however, dietary S did not affect (P > 0.17) ADG, G:F, or final BW. Rumen H2S concentration in gas samples collected on d 32 and 60 were not (P > 0.17) affected by dietary S or NaOH treatment. Experiment 2 included 24 lambs (initial BW = 43.0 ± 4.4 kg) used to determine the effects of NaOH treatment of DDGS and sulfur (Na2SO4) supplementation on N retention and the apparent digestibility of NDF, ADF, and OM. Treatments were similar to those used in Exp. 1, except that dietary DDGS was reduced to 45% of DM. Intake of DM, NDF, ADF, and N was not affected (P > 0.16) by NaOH treatment of DDGS or dietary S (Na2SO4) content. Treating DDGS with 2% NaOH reduced (P = 0.05) NDF digestibility by 10% compared with lambs fed untreated DDGS. Urine pH for lambs consuming DDGS treated with 2% NaOH was increased (P = 0.01) 1.74 pH units compared with urine from lambs fed untreated DDGS. Nitrogen intake and retention were not affected (P > 0.35) by dietary S concentration or NaOH treatment of DDGS. For feedlot lambs, treating DDGS with 2% NaOH did not lower ruminal H2S concentrations, but tended to increase ADG and DMI. Although treating DDGS with 2% NaOH was an effective way to neutralize the acidity in DDGS, this treatment reduced NDF digestibility.

Safety, pharmacokinetics and pharmacodynamics of multiple-ascending doses of the novel glucokinase activator AZD1656 in patients with type 2 diabetes mellitus.

AIMS: To assess the safety, pharmacokinetics and pharmacodynamics of multiple-ascending doses of the novel glucokinase activator AZD1656 in patients with type 2 diabetes mellitus (T2DM). METHODS: This randomized, single-blind, placebo-controlled, monotherapy study was carried out in two parts. In part A, 32 patients received AZD1656 (7, 20, 40 or 80 mg) twice daily or placebo for 8 days in hospital. In part B, another 20 patients received, as outpatients, individually titrated AZD1656 15-45 mg twice daily or placebo for 28 days. Safety, pharmacokinetics and pharmacodynamic variables were evaluated. RESULTS: AZD1656 was generally well tolerated. Pharmacokinetics of AZD1656 were virtually dose- and time-independent. AZD1656 was rapidly absorbed and eliminated. An active metabolite was formed which had a longer half-life than AZD1656, but showed ∼15% of the area under the plasma concentration versus time curve from 0 to 24 h compared with that of AZD1656. Renal excretion of AZD1656 and the metabolite was low. In part A, fasting plasma glucose (FPG) was reduced by up to 21% and mean 24-h plasma glucose was reduced by up to 24% with AZD1656 versus placebo, depending on dose. No dose-related changes in serum insulin or C-peptide were observed with AZD1656 at the end of treatment. Results in part B confirmed the glucose-lowering effect of AZD1656 versus placebo. CONCLUSIONS: AZD1656 was well tolerated with predictable pharmacokinetics in patients with T2DM. Dose-dependent reductions in plasma glucose were observed.

Canagliflozin improves glycaemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin.

AIM: Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor that is being investigated for the treatment of type 2 diabetes mellitus (T2DM). METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group, 28-day study conducted at two sites, in 29 subjects with T2DM not optimally controlled on insulin and up to one oral antihyperglycaemic agent. Subjects were treated with canagliflozin 100 mg QD or 300 mg twice daily (BID) or placebo. Safety, tolerability, pharmacokinetic characteristics and pharmacodynamic effects of canagliflozin were examined. Glucose malabsorption following a 75-g oral glucose challenge was also examined. RESULTS: Canagliflozin pharmacokinetics were dose-dependent, and the elimination half-life ranged from 12 to 15 h. After 28 days, the renal threshold for glucose excretion was reduced; urinary glucose excretion was increased; and A1C, fasting plasma glucose and body weight decreased in subjects administered canagliflozin (A1C reductions: 0.19% with placebo, 0.73% with 100 mg QD, 0.92% with 300 mg BID; body weight changes: 0.03 kg increase with placebo, 0.73 kg reduction with 100 mg QD, 1.19 kg reduction with 300 mg BID). Glucose malabsorption was not observed with canagliflozin treatment. There were no deaths, serious adverse events or severe hypoglycaemic episodes. The incidence of adverse events was similar across groups. There were no clinically meaningful changes in routine laboratory safety tests, vital signs or electrocardiograms. CONCLUSION: In subjects receiving insulin and oral antihyperglycaemic therapy, canagliflozin was well tolerated without evidence for glucose malabsorption, had pharmacokinetic characteristics consistent with once-daily dosing, and improved glycaemic control.

Short-term metabolic effects of prednisone administration in healthy subjects.

AIMS: Supraphysiologic glucocorticoid activity is well established to cause impaired glucose tolerance and insulin resistance, yet no study has evaluated dose-dependent effects of low-dose prednisone during short-term oral administration. METHODS: The objective of this study was to quantify the effects of daily 10 or 25 mg prednisone administration for one week on insulin sensitivity by employing a two-step hyperinsulinemic euglycemic glucose clamp (Step 1: insulin infusion = 20 mU/m²/min; Step 2: insulin infusion = 80 mU/m²/min) in healthy, lean males. The amount of glucose infused at steady-state to maintain stable blood glucose [90 mg/dl (4.95 mmol/l)] was used to calculate several indices of insulin sensitivity. RESULTS: During Step 1 of the clamp, whole body glucose disposal (M) was reduced by 35% (p = 0.003) and M/I was reduced by 29% (p = 0.025) for 25 mg prednisone compared to placebo. No appreciable effect of 10 mg prednisone was observed. During Step 2, M was reduced by 33% (p = 0.001) and 15% (p = 0.006) for 25 and 10 mg prednisone compared to placebo; and M/I ratio was reduced by 31% (p < 0.001) and 13% (p = 0.026), respectively. The insulin sensitivity index, Si, calculated as the quotient of augmentation of M/I between Step 1 and 2, was reduced by 35.3% (p < 0.01) and 23.5% (p < 0.05) for 25 and 10 mg prednisone, respectively. CONCLUSION: Administration of relatively low pharmacological doses of prednisone for one week impaired insulin sensitivity in a dose-dependent manner in healthy males. These observed changes in insulin sensitivity are likely to be clinically relevant, especially in individuals predisposed to develop glucose intolerance.

Retrospective analysis of post-mortem findings in 1,444 aged donkeys.

The aim of this study was to describe and report the prevalence of conditions found at necropsy examination of UK donkeys. Records from 1,444 donkeys over a 7-year period were included in the analysis. Sixty-one categories of post-mortem finding were identified from 9,744 observations. The four most prevalent conditions noted were dental disorder (78.7%), vascular disease other than aneurysm (60.9%), arthritis (55.4%) and foot disorder (44.8%). Gastric ulceration was found in 42% of the donkeys and gastrointestinal impaction in 18.6%. The most frequent combination of two post-mortem findings in the same animal was arthritis and dental disorder. The most common disorders were associated with age, body weight and/or body condition post mortem and, for some disorders, gender. For many of the post-mortem findings, crude associations were found between the presence of one finding and the odds of also having certain other post-mortem findings. This study is the first to summarize all conditions noted at necropsy examination for a large group of donkeys. The findings increase knowledge of diseases and conditions of this species and may be useful when investigating the relevance of various pathological conditions in the live animal.

Co-administration of liraglutide with insulin detemir demonstrates additive pharmacodynamic effects with no pharmacokinetic interaction.

AIM: To compare the pharmacokinetic (PK) [area under the curve (AUC0(-)24 (h), C(max))] and pharmacodynamic (PD) (AUC(GIR) 0(-)24 (h), GIR(max)) properties of single-dose insulin detemir in the presence or absence of steady-state liraglutide (1.8 mg dose) in subjects with type 2 diabetes to determine whether co-administration affected the PK and PD profiles of either therapeutic agent. METHODS: Following a 3-week washout of oral antidiabetic agents (OADs) other than metformin, PK and PD assessments during three euglycaemia clamps were conducted: day 1 following a single dose of insulin detemir alone (0.5 U/kg), day 22 after 3 weeks of once-daily liraglutide with weekly dose escalation to 1.8 mg daily, and day 36 after 2 weeks of steady-state liraglutide maintenance at the 1.8 mg dose following co-administration with a single dose of insulin detemir (0.5 U/kg). RESULTS: The study population (N = 33; age 49.6 (±8.5) years) had diabetes for an average of 6.5 (±4.1) years, BMI 33 (±6.4) kg/m², FPG 9.7 (±1.6) mmol/l and HbA1c 8.3% (±0.9). PK: The PK profiles of insulin detemir were similar with and without steady-state liraglutide. Liraglutide did not affect AUC or C(max) of insulin detemir and vice versa. The 90% confidence intervals (CIs) for ratios of insulin detemir AUC [1.03; CI (0.97, 1.09)] and C(max) [1.05; CI (0.98, 1.13)] and liraglutide AUC [0.97; CI (0.87, 1.08)] and C(max) [1.03, CI (0.93, 1.13)] were all within the no-effect boundary (0.80, 1.25) (bioequivalence criterion). A stable mean insulin detemir concentration with and without liraglutide was maintained at the end of the 24-h PK sampling period. PD: The sum of AUC(GIR) for liraglutide (1982 mg/kg) and insulin detemir (1058 mg/kg) when given alone was similar to that obtained when the two were co-administered (2947 mg/kg). No serious adverse events were reported and no adverse events led to study withdrawal. CONCLUSION: Co-administration of liraglutide 1.8 mg at steady state and insulin detemir produces an additive glucose-lowering effect without affecting the PK profile of either therapeutic agent suggesting that the addition of insulin detemir to patients treated with liraglutide will not require titration algorithms different from when insulin is added to OADs. The co-administration of insulin detemir and liraglutide was well tolerated.