The method of fundamental solutions (MFS) is a popular tool to solve Laplace and Helmholtz boundary value problems. Its main drawback is that it often leads to ill-conditioned systems of equations. ...In this paper, we investigate for the interior Helmholtz problem on analytic domains how the singularities (charge points) of the MFS basis functions have to be chosen such that approximate solutions can be represented by the MFS basis in a numerically stable way. For Helmholtz problems on the unit disc we give a full analysis which includes the high frequency (short wavelength) limit. For more difficult and nonconvex domains such as crescents we demonstrate how the right choice of charge points is connected to how far into the complex plane the solution of the boundary value problem can be analytically continued, which in turn depends on both domain shape and boundary data. Using this we develop a recipe for locating charge points which allows us to reach error norms of typically
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on a wide variety of analytic domains. At high frequencies of order only 3 points per wavelength are needed, which compares very favorably to boundary integral methods.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Diabet. Med. 29, 682–689 (2012)
Aims To examine patient and physician beliefs regarding insulin therapy and the degree to which patients adhere to their insulin regimens.
Methods Internet survey of ...1250 physicians (600 specialists, 650 primary care physicians) who treat patients with diabetes and telephone survey of 1530 insulin‐treated patients (180 with Type 1 diabetes, 1350 with Type 2 diabetes) in China, France, Japan, Germany, Spain, Turkey, the UK or the USA.
Results One third (33.2%) of patients reported insulin omission/non‐adherence at least 1 day in the last month, with an average of 3.3 days. Three quarters (72.5%) of physicians report that their typical patient does not take their insulin as prescribed, with a mean of 4.3 days per month of basal insulin omission/non‐adherence and 5.7 days per month of prandial insulin omission/non‐adherence. Patients and providers indicated the same five most common reasons for insulin omission/non‐adherence: too busy; travelling; skipped meals; stress/emotional problems; public embarrassment. Physicians reported low patient success at initiating insulin in a timely fashion and adjusting insulin doses. Most physicians report that many insulin‐treated patients do not have adequate glucose control (87.6%) and that they would treat more aggressively if not for concern about hypoglycaemia (75.5%). Although a majority of patients (and physicians) regard insulin treatment as restrictive, more patients see insulin treatment as having positive than negative impacts on their lives.
Conclusions Glucose control is inadequate among insulin‐treated patients, in part attributable to insulin omission/non‐adherence and lack of dose adjustment. There is a need for insulin regimens that are less restrictive and burdensome with lower risk of hypoglycaemia.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Treatment algorithms for type 2 diabetes call for intensification of therapy over time as the disease progresses and glycaemic control worsens. If diet, exercise and oral antihyperglycaemic ...medications (OAMs) fail to maintain glycaemic control then basal insulin is added and ultimately prandial insulin may be required. However, such an intensification strategy carries risk of increased hypoglycaemia and weight gain, both of which are associated with worse long‐term outcomes. An alternative strategy is to intensify therapy by the addition of a short‐acting glucagon‐like peptide‐1 receptor agonist (GLP‐1 RA) rather than prandial insulin. Short‐acting GLP‐1 RAs such as exenatide twice daily are particularly effective at reducing postprandial glucose while basal insulin has a greater effect on fasting glucose, providing a physiological rationale for this complementary approach. This review analyzes the latest randomized controlled clinical trials of insulin/GLP‐1 RA combination therapy and examines results from ‘real‐world’ use of the combinations as reported through observational and clinical practice studies. The most common finding across all types of studies was that combination therapy improved glycaemic control without weight gain or an increased risk of hypoglycaemia. Many studies reported weight loss and a reduction in insulin use when a GLP‐1 RA was added to existing insulin therapy. Overall, the relative degree of benefit to glycaemic control and weight was influenced by the insulin titration employed in conjunction with the GLP‐1 RA. The greatest glycaemic benefits were observed in studies with structured titration of insulin to glycaemic targets while the greatest weight benefits were observed in studies with a protocol‐specified focus on insulin sparing. The adverse event profile of GLP‐1 RAs in the reviewed trials was similar to that reported with GLP‐1 RAs as monotherapy or in combination with OAMs with gastrointestinal events being the most commonly reported.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Aim: To assess the safety and efficacy of the potent and selective dipeptidyl peptidase-4 inhibitor linagliptin 5 mg when given for 24 weeks to patients with type 2 diabetes who were either ...treatment-naive or who had received one oral antidiabetes drug (OAD). Methods: This multicentre, randomized, parallel group, phase III study compared linagliptin treatment (5 mg once daily, n = 336) with placebo (n = 167) for 24 weeks in type 2 diabetes patients. Before randomization, patients pretreated with one OAD underwent a washout period of 6 weeks, which included a placebo run-in period during the last 2 weeks. Patients previously untreated with an OAD underwent a 2-week placebo run-in period. The primary endpoint was the change in HbA1c from baseline after 24 weeks of treatment. Results: Linagliptin treatment resulted in a placebo-corrected change in HbA1c from baseline of −0.69% (p < 0.0001) at 24 weeks. In patients with baseline HbA1c ≥ 9.0%, the adjusted reduction in HbA1c was 1.01% (p < 0.0001). Patients treated with linagliptin were more likely to achieve a reduction in HbA1c of ≥0.5% at 24 weeks than those in the placebo arm (47.1 and 19.0%, respectively; odds ratio, OR = 4.2, p < 0.0001). Fasting plasma glucose improved by −1.3 mmol/l (p < 0.0001) with linagliptin vs. placebo, and linagliptin produced an adjusted mean reduction from baseline after 24 weeks in 2-h postprandial glucose of −3.2 mmol/l (p < 0.0001). Statistically significant and relevant treatment differences were observed for proinsulin/insulin ratio (p = 0.025), Homeostasis Model Assessment-%B (p = 0.049) and disposition index (p = 0.0005). There was no excess of hypoglycaemic episodes with linagliptin vs. placebo and no patient required third-party intervention. Mild or moderate renal impairment did not influence the trough plasma levels of linagliptin. Conclusions: Monotherapy with linagliptin produced a significant, clinically meaningful and sustained improvement in glycaemic control, accompanied by enhanced parameters of β-cell function. The safety profile of linagliptin was comparable with that of placebo.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
People with schizophrenia are at greater risk of obesity, Type 2 diabetes, dyslipidaemia and hypertension than the general population. This results in an increased incidence of cardiovascuLar disease ...(CVD) and reduced Life expectancy, over and above that imposed by their mentaL illness through suicide. Several Levels of evidence from data Linkage analyses to clinical trials demonstrate that treatment-related metabolic disturbances are commonplace in this patient group, and that the use of certain second-generation antipsychotics may compound the risk of developing the metabolic syndrome and CVD. In addition, smoking, poor diet, reduced physical activity and alcohol or drug abuse are prevalent in people with schizophrenia and contribute to the overall CVD risk. Management and minimization of metaboLic risk factors are pertinent when providing optimal care to patients with schizophrenia. This review recommends a framework for the assessment, monitoring and management of patients with schizophrenia in the UK clinical setting.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Aims
To characterize the incidence of type 2 diabetes in the UK over the previous 20 years; and determine if there has been an increase in people aged 40 years or less at diagnosis.
Methods
For this ...retrospective cohort study, patients newly diagnosed with type 2 diabetes between 1991 and 2010 were identified from the UK Clinical Practice Research Datalink (CPRD). Patient data were grouped into 5‐year intervals by year of diagnosis and age at diagnosis. A standardized incidence ratio (SIR) was determined (1991–1995 = 100). The percentage of newly diagnosed patients for each age group and aged ≤40 years was calculated for each 5‐year calendar period. The incidence rate by age and 5‐year calendar period was also determined.
Results
In 2010, the crude incidence rate of type 2 diabetes was 515 per 100,000 population. The overall SIR increased to 158 (95% CI 157–160, p < 0.001), 237 (235–238, p < 0.001) and 275 (273–276, p < 0.001) for 1996–2000, 2001–2005 and 2006–2010, respectively. For those ≤40, the respective values were 217 (209–226, p < 0.001), 327 (320–335, p < 0.001) and 598 (589–608, p < 0.001). An increase in incidence occurred with increasing 5‐year calendar period. The incidence of type 2 diabetes was higher for males after the age of 40 and higher for females aged ≤40. The percentage of patients aged ≤40 years at diagnosis increased with each increasing 5‐year calendar period (5.9, 8.4, 8.5 and 12.4%, respectively).
Conclusions
There was a significant increase in the incidence of diagnosed type 2 diabetes between 1991 and 2010 and the proportion of people diagnosed at a relatively early age has increased markedly.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Insulin resistance (IR) plays an important role in the pathogenesis of type 2 diabetes (T2D) and cardiovascular disease. Hence improving IR is a major target of treatment in patients with T2D. ...Obesity and lack of exercise are major causes of IR. However, recent evidence implicates sleep disorders and disorders of the circadian rhythm in the pathogenesis of IR. Weight loss and lifestyle changes are the cornerstone and most effective treatments of IR, but adherence and patient's acceptability are poor. Bariatric surgery results in significant and sustainable long‐term weight loss associated with beneficial impact on IR and glucose metabolism, making this an attractive treatment option for patients with T2D. Currently available pharmacological options targeting IR (such as metformin and thiazolidinediones) do not maintain glycaemic measures within targets long term and can be associated with significant side effects. Over the last two decades, many pharmacological agents targeting different aspects of the insulin signalling pathway were developed to improve IR, but only a minority reached clinical trials. Such treatments need to be specific and reversible as many of the components of the insulin signalling pathway are involved in other cellular functions such as apoptosis. Recent evidence highlighted the role of circadian rhythm and sleep‐related disorders in the pathogenesis of IR. In this article, we review the latest developments in the pharmacological and non‐pharmacological interventions targeting IR including bariatric surgery. We will also review the role of circadian rhythm and sleep‐related disorders in the development and treatment of IR.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The infant gut microbiota affects childhood health. This pioneer microbiota may be vulnerable to antibiotic exposures, but could be supported by prebiotic oligosaccharides found in breast milk and ...some infant formulas. We sought to characterize the effects of several exposures on the neonatal gut microbiota, including human milk oligosaccharides (HMOs), galacto-oligosaccharides (GOS), and infant/maternal antimicrobial exposures. We profiled the stool microbiota of 1023 one-month-old infants from the KOALA Birth Cohort using 16S rRNA gene amplicon sequencing. We quantified 15 HMOs in breast milk from the mothers of 220 infants, using high-performance liquid chromatography-mass spectrometry. Both breastfeeding and antibiotic exposure decreased gut microbial diversity, but each was associated with contrasting shifts in microbiota composition. Other factors associated with microbiota composition included C-section, homebirth, siblings, and exposure to animals. Neither infant exposure to oral antifungals nor maternal exposure to antibiotics during pregnancy were associated with infant microbiota composition. Four distinct groups of breast milk HMO compositions were evident, corresponding to maternal Secretor status and Lewis group combinations defined by the presence/absence of certain fucosylated HMOs. However, we found the strongest evidence for microbiota composition associations between two non-fucosylated HMOs: 6'-sialyllactose (6'-SL) and lacto-N-hexaose (LNH). Among 111 exclusively formula-fed infants, the GOS-supplemented formula was associated with a lower relative abundance of Clostridium perfringens. In conclusion, the gut microbiota is sensitive to some prebiotic and antibiotic exposures during early infancy and understanding their effects could inform future strategies for safeguarding a health-promoting infant gut microbiota.
Bromocriptine is an ergot alkaloid dopamine D₂ receptor agonist that has been used extensively in the past to treat hyperprolactinaemia, galactorrhoea and Parkinsonism. It is known that hypothalamic ...hypodopaminergic states and disturbed circadian rhythm are associated with the development of insulin resistance, obesity and diabetes in animals and humans. When administered in the early morning at the start of the light phase, a new quick release (QR) formulation of bromocriptine appears to act centrally to reset circadian rhythms of hypothalamic dopamine and serotonin and improve insulin resistance and other metabolic abnormalities. Phase II and III clinical studies show that QR‐bromocriptine lowers glycated haemoglobin by 0.6-1.2% (7-13 mmol/mol) either as monotherapy or in combination with other antidiabetes medications. Apart from nausea, the drug is well tolerated. The doses used to treat diabetes (up to 4.8 mg daily) are much lower than those used to treat Parkinson's disease and have not been associated with retroperitoneal fibrosis or heart valve abnormalities. QR‐bromocriptine (Cycloset™) has recently been approved in the USA for the treatment of type 2 diabetes mellitus (T2DM). Thus, a QR formulation of bromocriptine timed for peak delivery in the early morning may provide a novel neurally mediated approach to the control of hyperglycaemia in T2DM.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In people with type 2 diabetes mellitus (T2DM), the incretin effect is reduced, but the recent advent of dipeptidyl peptidase‐4 inhibitors and glucagon‐like peptide (GLP)‐1 agonists/analogues has ...enabled restoration of at least some of the function of the incretin system, with accompanying improvements in glycaemic control. Two GLP‐1 receptor agonists/analogues are currently approved for the treatment of T2DM—exenatide (Byetta®, Eli Lilly & Co., Indianapolis, IN, US) and liraglutide (Victoza®, Novo Nordisk, Bagsvaerd, Denmark); a once‐weekly formulation of exenatide (Bydureon®, Eli Lilly & Co.) has also been approved by the European Medicines Agency. The National Institute for Health and Clinical Excellence (NICE) has recently published guidance on the use of liraglutide in T2DM, based on evidence from the Liraglutide Effect and Action in Diabetes (LEAD) Phase III trial programme, which compared liraglutide with existing glucose‐lowering therapies, such as exenatide and insulin glargine. The LEAD programme reported HbA1c reductions from 0.8 to 1.5% with liraglutide (1.2 and 1.8 mg), accompanied by low rates of hypoglycaemia and some weight loss; side effects were primarily gastrointestinal in nature (e.g. nausea and diarrhoea). Based on the findings of the LEAD studies and the NICE recommendation, liraglutide now represents an important therapy widely available in the UK for certain patient groups, including those with a body mass index (BMI) ≥35.0 kg/m2, and patients with a BMI <35 kg/m2 who are considered unsuitable for insulin and are failing to meet targets for glycaemic control with oral agents. NICE guidelines still suggest that most patients without considerable obesity (BMI <35 kg/m2) are probably best managed using insulin therapy. Evidence also suggests a future role for GLP‐1 mimetics in combination with basal insulin.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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