The consequences of delaying insulin initiation in UK type 2 diabetes patients failing oral hyperglycaemic agents: a modelling study

<p>Abstract</p> <p>Background</p> <p>Recent data have shown that type 2 diabetes patients in the UK delay initiating insulin on average for over 11 years after first being prescribed an oral medication. Using a published computer simulation model of diabetes we used UK-specific data to estimate the clinical consequences of immediately initiating insulin versus delaying initiation for periods in line with published estimates.</p> <p>Methods</p> <p>In the base case scenario simulated patients, with characteristics based on published UK data, were modelled as either initiating insulin immediately or delaying for 8 years. Clinical outcomes in terms of both life expectancy and quality-adjusted life expectancy and also diabetes-related complications (cumulative incidence and time to onset) were projected over a 35 year time horizon. Treatment effects associated with insulin use were taken from published studies and sensitivity analyses were performed around time to initiation of insulin, insulin efficacies and hypoglycaemia utilities.</p> <p>Results</p> <p>For patients immediately initiating insulin there were increases in (undiscounted) life expectancy of 0.61 years and quality-adjusted life expectancy of 0.34 quality-adjusted life years versus delaying initiation for 8 years. There were also substantial reductions in cumulative incidence and time to onset of all diabetes-related complications with immediate versus delayed insulin initiation. Sensitivity analyses showed that a reduced delay in insulin initiation or change in insulin efficacy still demonstrated clinical benefits for immediate versus delayed initiation.</p> <p>Conclusion</p> <p>UK type 2 diabetes patients are at increased risk of a large number of diabetes-related complications due to an unnecessary delay in insulin initiation. Despite clear guidelines recommending tight glycaemic control this failure to begin insulin therapy promptly is likely to result in needlessly reduced life expectancy and compromised quality of life.</p

The Optokinetic Reflex as a Tool for Quantitative Analyses of Nervous System Function in Mice: Application to Genetic and Drug-Induced Variation

The optokinetic reflex (OKR), which serves to stabilize a moving image on the retina, is a behavioral response that has many favorable attributes as a test of CNS function. The OKR requires no training, assesses the function of diverse CNS circuits, can be induced repeatedly with minimal fatigue or adaptation, and produces an electronic record that is readily and objectively quantifiable

Tikhonov adaptively regularized gamma variate fitting to assess plasma clearance of inert renal markers

The Tk-GV model fits Gamma Variates (GV) to data by Tikhonov regularization (Tk) with shrinkage constant, λ, chosen to minimize the relative error in plasma clearance, CL (ml/min). Using 169Yb-DTPA and 99mTc-DTPA (n = 46, 8–9 samples, 5–240 min) bolus-dilution curves, results were obtained for fit methods: (1) Ordinary Least Squares (OLS) one and two exponential term (E1 and E2), (2) OLS-GV and (3) Tk-GV. Four tests examined the fit results for: (1) physicality of ranges of model parameters, (2) effects on parameter values when different data subsets are fit, (3) characterization of residuals, and (4) extrapolative error and agreement with published correction factors. Test 1 showed physical Tk-GV results, where OLS-GV fits sometimes-produced nonphysical CL. Test 2 showed the Tk-GV model produced good results with 4 or more samples drawn between 10 and 240 min. Test 3 showed that E1 and E2 failed goodness-of-fit testing whereas GV fits for t > 20 min were acceptably good. Test 4 showed CLTk-GV clearance values agreed with published CL corrections with the general result that CLE1 > CLE2 > CLTk-GV and finally that CLTk-GV were considerably more robust, precise and accurate than CLE2, and should replace the use of CLE2 for these renal markers

Seasonal variations in the nitrogen isotopic composition of settling particles at station K2 in the western subarctic North Pacific

Intensive observations using hydrographical cruises and moored sediment trap deployments during 2010 and 2012 at station K2 in the North Pacific western subarctic gyre (WSG) revealed seasonal changes in δ15N of both suspended and settling particles. Suspended particles (SUS) were collected from depths between the surface and 200 m; settling particles by drifting traps (DST; 100-200 m) and moored traps (MST; 200 and 500 m). All particles showed higher δ15N values in winter and lower in summer, contrary to the expected by isotopic fractionation during phytoplankton nitrate consumption. We suggest that these observed isotopic patterns are due to ammonium consumption via light-controlled nitrification, which could induce variations in δ15N(SUS) of 0.4-3.1 ‰ in the euphotic zone (EZ). The δ15N(SUS) signature was reflected by δ15 N(DST) despite modifications during biogenic transformation from suspended particles in the EZ. δ15 N enrichment (average: 3.6 ‰) and the increase in C:N ratio (by 1.6) in settling particles suggests year-round contributions of metabolites from herbivorous zooplankton as well as TEPs produced by diatoms. Accordingly, seasonal δ15 N(DST) variations of 2.4-7.0 ‰ showed a significant correlation with primary productivity (PP) at K2. By applying the observed δ15 N(DST) vs. PP regression to δ15 N(MST) of 1.9-8.0 ‰, we constructed the first annual time-series of PP changes in the WSG. Moreover, the monthly export ratio at 500 m was calculated using both estimated PP and measured organic carbon fluxes. Results suggest a 1.6 to 1.8 times more efficient transport of photosynthetically-fixed carbon to the intermediate layers occurs in summer/autumn rather than winter/spring

Pigeon fanciers' lung: effects of smoking on serum and salivary antibody responses to pigeon antigens

A reduced prevalence of pigeon fanciers' lung has been reported in pigeon breeders who smoke cigarettes. Serum and salivary antibodies to pigeon intestinal mucin and pigeon serum proteins were investigated in 227 pigeon fanciers, subdivided according to smoking habit and clinical status. Smokers had a lower incidence of precipitating antibodies to pigeon antigens and lower titres of serum IgG and IgA antibodies to mucin and to pigeon serum proteins in ELISA compared with non-smokers and ex-smokers. In contrast, IgG antibody titres to tetanus toxoid were similar in smoking and non-smoking groups. In contrast to serum antibodies, salivary IgA antibody titres to pigeon antigens were similar in smokers and non- or ex-smokers. Approximately one third of the smokers reported symptoms consistent with pigeon fanciers' lung but did not have precipitating antibodies. Only some individuals with precipitating antibodies had disease symptoms, and IgG antibody titres in these individuals were not significantly higher than in many asymptomatic individuals. Salivary IgA titres against pigeon mucin were significantly higher in asymptomatic individuals, consistent with a protective role for these antibodies. The results confirm that smoking is associated with a decreased serum antibody response to inhaled pigeon antigens, affecting IgG1, IgG2 and IgA responses, but this impairment does not extend to salivary IgA or to antibody responses to a parenterally administered protein antigen. The fact that responses to pigeon serum proteins and to pigeon intestinal mucin were similarly affected suggests that cigarette smoking depresses both T-independent and T-dependent responses to inhaled antigens