The cost-effectiveness of dapagliflozin compared to DPP-4 inhibitors in the treatment of type 2 diabetes mellitus in the Netherlands.

AIM: When glycaemic control for people with type 2 diabetes is not achieved with metformin and sulfonylurea alone, adding another oral anti-diabetes drug, such as a sodium-glucose co-transporter 2 (SGLT2) or dipeptidyl peptidase-4 (DPP-4) inhibitor, is an alternative to starting insulin. The aim of this study is to determine the cost-effectiveness of dapagliflozin (an SGLT2 inhibitor) compared with DPP-4 inhibitors when added to metformin and sulfonylurea in people with type 2 diabetes in the Netherlands. METHODS: A cost-utility analysis is performed using the Cardiff diabetes model, a fixed-time increment stochastic simulation model informed by 'United Kingdom Prospective Diabetes Study 68' risk equations. The base-case analysis uses a 40-year time horizon, a Dutch societal perspective and differential discounting (4% for costs, 1.5% for effects). Inputs are obtained from the literature and Dutch price lists. Univariate and probabilistic sensitivity analysis are performed. RESULTS: Dapagliflozin is dominant compared with DPP-4 inhibitors, resulting in a €990 cost saving and a 0.28 quality-adjusted life year gain over 40 years. Cost savings are associated mainly with treatment costs and a reduced incidence of micro- and macrovascular complications, among others nephropathy, myocardial infarction and stroke. Results are robust to changes in input parameters. CONCLUSIONS: Dapagliflozin is a cost-saving alternative to DPP-4 inhibitors when added to metformin and sulfonylurea. The incidence of micro- and macrovascular complications is lower for people treated with dapagliflozin. Uncertainty around this outcome is low.

Reducing the level of nutrition of twin-bearing ewes during mid to late pregnancy produces leaner prime lambs at slaughter.

The Australian prime lamb industry is seeking to improve lean meat yield (LMY) as a means to increasing efficiency and profitability across the whole value chain. The LMY of prime lambs is affected by genetics and on-farm nutrition from birth to slaughter and is the total muscle weight relative to the total carcass weight. Under the production conditions of south eastern Australia, many ewe flocks experience a moderate reduction in nutrition in mid to late pregnancy due to a decrease in pasture availability and quality. Correcting nutritional deficits throughout gestation requires the feeding of supplements. This enables the pregnant ewe to meet condition score (CS) targets at lambing. However, limited resources on farm often mean it is difficult to effectively manage nutritional supplementation of the pregnant ewe flock. The impact of reduced ewe nutrition in mid to late pregnancy on the body composition of finishing lambs and subsequent carcass composition remains unknown. This study investigated the effect of moderately reducing ewe nutrition in mid to late gestation on the body composition of finishing lambs and carcass composition at slaughter on a commercial scale. Multiple born lambs to CS2.5 target ewes were lighter at birth and weaning, had lower feedlot entry and exit weights with lower pre-slaughter and carcass weights compared with CS3.0 and CS3.5 target ewes. These lambs also had significantly lower eye muscle and fat depth when measured by ultrasound prior to slaughter and carcass subcutaneous fat depth measured 110 mm from the spine along the 12th rib (GR 12th) and at the C-site (C-fat). Although carcasses were ~5% lighter, results showed that male progeny born to ewes with reduced nutrition from day 50 gestation to a target CS2.5 at lambing had a higher percentage of lean tissue mass as measured by dual energy X-ray absorptiometry and a lower percentage of fat during finishing and at slaughter, with the multiple born progeny from CS3.0 and CS3.5 target ewes being similar. These data suggest lambs produced from multiple bearing ewes that have had a moderate reduction in nutrition during pregnancy are less mature. This effect was also independent of lamb finishing system. The 5% reduction in carcass weight observed in this study would have commercially relevant consequences for prime lamb producers, despite a small gain in LMY.

The impact of a multimodal intervention on emergency department crowding and patient flow.

OBJECTIVE: The objective of this study is to assess the impact of a multimodal intervention on emergency department (ED) crowding and patient flow in a Dutch level 1 trauma center. METHODS: In this cross-sectional study, we compare ED crowding and patient flow between a 9-month pre-intervention period and a 9-month intervention period, during peak hours and overall (24/7). The multimodal intervention included (1) adding an emergency nurse practitioner (ENP) and (2) five medical specialists during peak hours to the 24/7 available emergency physicians (EPs), (3) a Lean programme to improve radiology turnaround times, and (4) extending the admission offices' openings hours. Crowding is measured with the modified National ED OverCrowding Score (mNEDOCS). Furthermore, radiology turnaround times, patients' length of stay (LOS), proportion of patients leaving without being seen (LWBS) by a medical provider, and unscheduled representations are assessed. RESULTS: The number of ED visits were grossly similar in the two periods during peak hours (15,558 ED visits in the pre-intervention period and 15,550 in the intervention period) and overall (31,891 ED visits in the pre-intervention period vs. 32,121 in the intervention period). During peak hours, ED crowding fell from 18.6% (pre-intervention period) to 3.5% (intervention period), radiology turnaround times decreased from an average of 91 min (interquartile range 45-256 min) to 50 min (IQR 30-106 min., p < 0.001) and LOS reduced with 13 min per patient from 167 to 154 min (p < 0.001). For surgery, neurology and cardiology patients, LOS reduced significantly (with 17 min, 25 min, and 8 min. respectively), while not changing for internal medicine patients. Overall, crowding, radiology turnaround times and LOS also decreased. Less patients LWBS in the intervention period (270 patients vs. 348 patients, p < 0.001) and less patients represented unscheduled within 1 week after the initial ED visit: 864 (2.7%) in the pre-intervention period vs. 645 (2.0%) patients in the intervention period, p < 0.001. CONCLUSIONS: In this hospital, a multimodal intervention successfully reduces crowding, radiology turnaround times, patients' LOS, number of patients LWBS and the number of unscheduled return visits, suggesting improved ED processes. Further research is required on total costs of care and long-term effects.

Comparison of a grain-based diet supplemented with synthetic vitamin E versus a lucerne (alfalfa) hay-based diet fed to lambs in terms of carcass traits, muscle vitamin E, fatty acid content, lipid oxidation, and retail colour of meat.

Dietary supplementation of vitamin E (VitE) in a synthetic or natural form was examined. Forty-eight lambs were assigned (n = 16) to either a grain-based diet at moderate (MOD, 42 mg∙kg-1 VitE as all-rac α-tocopheryl acetate) or supranutritional (SUP, 285 mg∙kg-1 of vitE) levels of synthetic VitE or a lucerne hay-based diet (LUC; 37 mg∙kg-1 VitE) for 8 weeks. Meat from the LUC group had lower muscle n-6 and PUFA levels compared to meat from the MOD and SUP groups. Despite a similar VitE intake, muscle VitE was higher for LUC compared to MOD, while SUP lambs showed the highest VitE. Lipid oxidation did not differ between groups. For fresh meat, redness tended to be higher in LUC fed lambs than the other two groups, but brownness formation was only lower than the SUP group. For aged meat colour stability, redness tended to be higher in lambs fed SUP and LUC, whereas highest browning occurred in the MOD group.

Costs of non-small cell lung cancer in the Netherlands.

OBJECTIVES: Real-world resource use and cost data on non-small cell lung cancer (NSCLC) are scarce. This data is needed to inform health-economic modelling to assess the impact of new diagnostic and/or treatment technologies. This study provides detailed insight into real-world medical resource use and costs of stage I-IV NSCLC in the Netherlands. MATERIALS AND METHODS: A random sample of patients newly diagnosed with NSCLC (2009-2011) was selected from four Dutch hospitals. Data was retrospectively collected from patient charts. This data included patient characteristics, tumour characteristics, treatment details, adverse events, survival and resource use. Resource use was multiplied by Dutch unit costs expressed in EUR 2012. Total mean costs were corrected for censoring using the Bang and Tsiatis weighted complete-case estimator. Furthermore, costs of adverse events, costs per phase of NSCLC management and costs of second opinions are presented. RESULTS: Data was collected on 1067 patients. Total mean costs for NSCLC diagnosis, treatment and follow-up are €28,468 during the study period and €33,143 when corrected for censoring. Adverse events were recorded in the patient charts for 369 patients (41%) and 82 patients (9%) experienced an adverse event of grade III or higher. For these patients, adverse event-related hospital admissions cost on average €2,091. Mean total costs are €1,725 for the diagnostic period, €17,296 for first treatment line, and €13,236 for each later treatment line. Costs of providing a second opinion are €2,580 per patient. CONCLUSIONS: Total mean hospital costs per NSCLC patient are €33,143 for the total duration of the disease. Ignoring censoring in our data underestimates these costs by 14%. Main limitations of the study relate to the short follow-up time, staging difficulties and missing data. Its main strength is that it provides highly detailed, real-world data on the costs of NSCLC.

Real-world cost-effectiveness of cetuximab in locally advanced squamous cell carcinoma of the head and neck.

Clinical trial EMR 62202-006 demonstrates prolonged median locoregional control (24.4 vs. 14.9 months), progression-free survival (17.1 vs. 12.4 months) and overall survival (49.0 vs. 29.3 months) for patients who receive cetuximab added to the comparator radiotherapy for locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). In the Netherlands, hospitals receive reimbursement for cetuximab conditional on cost-effectiveness in daily practice. To estimate the real-world incremental cost per quality adjusted life-year (QALY) gained for radiotherapy + cetuximab over radiotherapy alone in first line treatment of LA SCCHN, a Markov model is constructed with health states "alive without progression", "alive following progression" and "death". Transition probabilities per month are estimated from clinical trial data and retrospectively collected real-world data from two Dutch head and neck cancer treatment centres (2007-2010, n = 141). 5-year, 10-year and lifetime horizons are used, without and with discounting (4 % costs, 1.5 % effects) to calculate incremental cost-effectiveness ratios. Two scenarios explore different assumptions on prognosis of real-world versus trial patients. Adding cetuximab to radiotherapy results in increased costs and health gains in both scenarios and across each of the time horizons. Incremental costs per QALY gained range between 14,624 and 38,543 in the base-case. For a willingness to pay of 80,000 per QALY, the acceptability curves for the different scenarios show probabilities between 0.76 and 0.87 of radiotherapy + cetuximab being cost-effective compared to radiotherapy alone. Current results show the combined treatment of radiotherapy + cetuximab to be a cost-effective treatment option for patients with LA SCCHN.

Arrhenius plot for a reaction catalyzed by a single molecule of ß-galactosidase.

The activity of a single enzyme molecule of Escherichia coli ß-galactosidase was measured using a capillary electrophoresis continuous flow assay. As the enzyme molecule traversed the capillary the incubation temperature was increased from 27 to 37 °C, providing a continuous record of the change in rate with temperature. This data was used to develop a single enzyme molecule Arrhenius plot, from which the activation energy of the reaction was determined to be 31 kJ mol(-1).

Neurally adjusted ventilatory assist vs. pressure support ventilation in critically ill patients: an observational study.

BACKGROUND: During neurally adjusted ventilatory assist (NAVA), the inspiratory support is controlled by the patients' respiratory drive influenced by an operator-controlled gain factor (NAVA level). The purpose of our observational study was to transfer patients from conventional pressure support ventilation (PSV) to NAVA safely. We compared two approaches to set the NAVA level and evaluated the effect of NAVA. METHODS: We studied mechanically ventilated patients capable of spontaneous breathing. For the change of the ventilator mode, we used a NAVA level calculated to generate a peak inspiratory pressure equal to PSV. We compared this NAVA level with a NAVA level determined by a NAVA level titration. Ventilatory and haemodynamic data were recorded during an observational period of 6 h. RESULTS: All 20 patients included in the study could be transferred from PSV to NAVA and completed the observation interval. Setting the NAVA level according to prior PSV settings proved to be a feasible approach, but in 75% of our patients, we modified the NAVA level according to the titration results. Gas exchange and ventilatory mechanics during the observation interval remained stable. CONCLUSIONS: The ventilator mode NAVA seems to be well tolerated in a heterogeneous group of critically ill patients. Pre-setting of the NAVA level during PSV can result in an overestimation of the required ventilator support. An additional titration of the NAVA level ads valuable information although difficult to interpret in some cases.

Variation in residual feed intake in Holstein-Friesian dairy heifers in southern Australia.

Feed conversion efficiency of dairy cattle is an important component of the profitability of dairying, given that the cost of feed accounts for much of total farm expenses. Residual feed intake (RFI) is a useful measure of feed conversion efficiency, as it can be used to compare individuals with the same or differing levels of production during the period of measurement. If genetic variation exists in RFI among dairy cattle, selection for lower RFI could improve profitability. In this experiment, RFI was defined as the difference between an animal's actual feed intake and its expected feed intake, which was determined by regression of dry matter (DM) intake against mean body weight (BW) and growth rate. Nine hundred and three Holstein-Friesian heifer calves, aged between 5 and 7 mo, were measured for RFI in 3 cohorts of approximately 300 animals. Calves were housed under feedlot style conditions in groups of 15 to 20 for 85 to 95 d and had ad libitum access to a cubed alfalfa hay. Intakes of individual animals were recorded via an electronic feed recording system and BW gain was determined by weighing animals once or twice weekly, over a period of 60 to 70 d. Calves had DM intake (mean ± SD) of 8.3±1.37 kg of DM/d over the measurement period with BW gains of 1.1±0.17 kg/d. In terms of converting feed energy for maintenance and growth, the 10% most efficient calves (lowest RFI) ate 1.7 kg of DM less each day than the 10% least efficient calves (highest RFI) for the same rate of growth. Low-RFI heifers also had a significantly lower rate of intake (g/min) than high-RFI heifers. The heritability estimate of RFI (mean ± SE) was 0.27 (±0.12). These results indicate that substantial genetic variation in RFI exists, and that the magnitude of this variation is large enough to enable this trait to be considered as a candidate trait for future dairy breeding goals. A primary focus of future research should be to ensure that calves that are efficient at converting feed energy for maintenance and growth also become efficient at converting feed energy to milk. Future research will also be necessary to identify the consequences of selection for RFI on other traits (especially fertility and other fitness traits) and if any interactions exist between RFI and feeding level.

Almost every pure state of three qubits is completely determined by its two-particle reduced density matrices.

In a system of n quantum particles, we define a measure of the degree of irreducible n-way correlation, by which we mean the correlation that cannot be accounted for by looking at the states of n-1 particles. In the case of almost all pure states of three qubits, we show that there is no such correlation: almost every pure state of three qubits is completely determined by its two-particle reduced density matrices.

The parts determine the whole in a generic pure quantum state.

We show that almost every pure state of multiparty quantum systems (each of whose local Hilbert space has the same dimension) is completely determined by the state's reduced density matrices of a fraction of the parties; this fraction is less than about two-thirds of the parties for states of large numbers of parties. In other words, once the reduced states of this fraction of the parties have been specified, there is no further freedom in the state.

Are all noisy quantum states obtained from pure ones?

We ask what type of mixed quantum states can arise when a number of separated parties start by sharing a pure quantum state and then this pure state becomes contaminated by noise. We show that not all mixed states arise in this way. This is even the case if the separated parties actively try to degrade their initial pure state by arbitrary local actions and classical communication.

Entanglement capabilities of nonlocal Hamiltonians.

We quantify the capability of creating entanglement for a general physical interaction acting on two qubits. We give a procedure for optimizing the generation of entanglement. We also show that a Hamiltonian can create more entanglement if one uses auxiliary systems.

Good dynamics versus bad kinematics: is entanglement needed for quantum computation?

We study the role of entanglement in quantum computation. We consider the case of a pure state contaminated by "white noise." This framework arises, for example, in pseudopure state implementations of quantum computing using NMR. We analyze quantum computational protocols which aim to solve exponential classical problems with polynomial resources and ask whether or not entanglement of the pseudopure states is needed to achieve this aim. We show that, for a large class of such protocols, including Shor's factorization, entanglement is necessary. We also show that achieving entanglement is not sufficient: If the state is sufficiently noisy, exponential resources are needed even if entanglement is present.

Recurrent pancreatitis and chylomicronemia in an extended Dutch kindred is caused by a Gly154-->Ser substitution in lipoprotein lipase.

We report the molecular basis of familial chylomicronemia and recurrent pancreatitis in five members of a large Dutch family. All patients had normal plasma hepatic lipase and apoC-II levels, but absent lipoprotein lipase (LPL) catalytic activity and low LPL mass in postheparin plasma. The mutation in the LPL gene was characterized as a G715-->A substitution in the last nucleotide of exon 4, resulting in a substitution of Ser for Gly154. PCR amplification of exons 4 + 5 from the patients' mRNA, followed by direct sequencing, revealed normal splicing of intron 4. The mutation creates a BfaI restriction site that allows rapid screening of family members for the mutation. Reproduction of this mutation in LPL-cDNA by site-directed mutagenesis, followed by transient expression in COS-B cells, revealed production of a catalytically inactive enzyme. The Gly154-->Ser substitution appears in a conserved beta-sheet region, in close proximity to Asp156, which is part of the catalytic triad. These studies show that changes to residues close to Asp156 can have profound effects on catalytic activity of LPL.

Growth hormone and thyroxine affect lipoprotein metabolism in hypothyroid and hypophysectomized rats.

The aim of this study was to evaluate the effect of thyroxine (T4) and GH replacement therapy on serum lipoproteins in rats with primary and secondary hypothyroidism and to see whether recovery of GH activity was associated with normalization of serum lipoproteins. In both the primary and secondary hypoproteins. In both the primary and secondary hypothyroid rats, total cholesterol (TC) was higher than in normal controls, due to an increase in low-density lipoprotein cholesterol (LDL-c) and to a lesser extent also in high-density lipoprotein cholesterol (HDL-c). Treatment of hypophysectomized rats with GH induced a decrease in the concentration of TC, LDL-c and HDL-c, while liver lipase activity (LLA) increased. The effect of GH on HDL-c was correlated with the increase in LLA. T4 replacement therapy of hypophysectomized rats normalized LDL-c, but HDL-c and LLA were unaffected. During primary hypothyroidism, T4 treatment induced GH activity, increased LLA and reduced the HDL-c concentration. GH treatment of primary hypothyroid rats had a similar influence on the lipid levels and LLA as in hypophysectomized animals, although the lowering of HDL-c was less prominent. These results demonstrate that GH determines serum lipoproteins during both primary and secondary hypothyroidism.

Inhibition of carnitine palmitoyltransferase leads to induction of 3-hydroxymethylglutaryl coenzyme A reductase activity in rat liver.

The relation between carnitine palmitoyltransferase (CPT) activity and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity was investigated. Rats were treated with aminocarnitine or 1-carnitine overnight. In rats, in which CPT activity was inhibited by aminocarnitine, plasma and hepatic triacylglycerol contents were increased 5- to 6-fold. The plasma cholesterol concentration was unchanged, while the hepatic cholesterol content was lowered (-16%). Hepatic cholesterol synthesis, determined by following the incorporation of 14C-acetate and 3H2O into digitonin-precipitable sterols, in liver slices was increased 5- to 7-fold. HMG-CoA reductase activity in liver microsomes was increased to the same extent.