Edoxaban versus placebo, aspirin, or aspirin plus clopidogrel for stroke prevention in atrial fibrillation. An indirect comparison analysis.

As non-valvular atrial fibrillation (AF) brings a risk of stroke, oral anticoagulants (OAC) are recommended. In 'real world' clinical practice, many patients (who may be, or perceived to be, intolerant of OACs) are either untreated or are treated with anti-platelet agents. We hypothesised that edoxaban has a better net clinical benefit (NCB, balancing the reduction in stroke risk vs increased risk of haemorrhage) than no treatment or anti-platelet agents. We performed a network meta-analysis of published data from 24 studies of 203,394 AF patients to indirectly compare edoxaban with aspirin alone, aspirin plus clopidogrel, and placebo. Edoxaban 30 mg once daily significantly reduced the risk of all stroke, ischaemic stroke and mortality compared to placebo and aspirin. Compared to aspirin plus clopidogrel, there was a lower risk of intra-cranial haemorrhage (ICH). Edoxaban 60 mg once-daily had a reduced risk of any stroke and systemic embolism compared to placebo, aspirin, and aspirin plus clopidogrel. Mortality rates for both edoxaban doses were estimated to be lower compared to any anti-platelet, and significantly lower compared to placebo. With overall reduced risk of ischemic stroke and ICH, both edoxaban doses bring a NCB of mean (SD) 1.68 (0.15) saved events per 100 patients per year compared to anti-platelet drugs in a clinical trial population. The NCB was demonstrated to be lower, at 0.77 (0.12) events saved (p< 0.01) when modeled to data from a 'real world' cohort of AF patients. In conclusion, edoxaban is likely to provide even better protection from stroke and ICH than placebo, aspirin alone, or aspirin plus clopidogrel in both clinical trial populations and unselected community populations. Both edoxaban doses would also bring a positive NCB compared to anti-platelet drugs or placebo/non-treatment based on 'real world' data.

Dabigatran adherence in atrial fibrillation patients during the first year after diagnosis: a nationwide cohort study.

BACKGROUND: There is a perception among physicians that lack of routine monitoring with non-vitamin K antagonist oral anticoagulants (NOACs) may lead to poor adherence to medication. We studied adherence during the first year of usage in a cohort of patients with newly diagnosed non-valvular atrial fibrillation (AF) started on the NOAC, dabigatran etexilate. METHODS AND RESULTS: Nationwide Danish patient and prescription purchase registries were used to identify newly diagnosed AF patients taking dabigatran, comorbidities, and refill patterns under a twice-daily, one pill regimen. Adherence was characterized among remaining users (N = 2960) after 1 year using the proportion of days covered (PDC), gap rates and restart rates. The overall 1-year PDC was 83.9%, with 76.8% of patients having a 1-year PDC in excess of 80%. Patients with a CHA2 DS2 -VASc score ≥ 2 were more adherent to medication regimes than patients with a CHA2 DS2 -VASc score of 1 (PDC ratio, 1.12; 95% confidence interval [CI], 1.08-1.17) and generally patients with higher morbidity showed more adherence. Patients with prior bleeding were not less adherent to medication regimes than patients with no prior bleeding (PDC ratio, 1.02; 95% CI, 0.98-1.06). The overall gap rate was 1.4 gaps per year. There were no clear tendencies in gap rates among subgroups, although patients with higher morbidity tended to have slightly more, but shorter, gap periods. CONCLUSIONS: More than 75% of patients were showed > 80% adherence to medication regimes during the first year. Patients with higher morbidity, including patients with a higher risk of stroke or bleeding, exhibited better adherence. This improvement may be attributable to more regular contact with the healthcare system.

Short communication: Changes in gait symmetry in healthy and lame dairy cows based on 3-dimensional ground reaction force curves following claw trimming.

Lameness is a frequent health problem in dairy cows. This preliminary study aimed to detect gait differences between healthy and lame walking cows using 3-dimensional force plates. We examined left-right leg symmetry changes of healthy and lame Holstein dairy cows following claw trimming. Gait scoring (GS) was performed on d -5, 0, 1, and 7 relative to claw trimming. Before the experiment, 5 cows walked normally (initial GS=1) and 4 cows limped moderately on a hind leg (initial GS=3). Gait was measured on d -2, -1, 0, 1, and 7 relative to trimming by obtaining ground reaction forces as cows walked repeatedly across 2 parallel 3-dimensional force plates. From the ground reaction forces, stance phase data were derived using computerized procedures. Left-right leg symmetries of entire curves in the 3 force directions were calculated. Effects of lameness and trimming were analyzed in a mixed model, using a low lameness threshold (GS>1). One week after claw trimming, only one cow was mildly lame. In addition, the symmetries of all 3 dimensions were significantly improved shortly after trimming. Importantly, lameness significantly worsened vertical symmetry. Lame cows walked significantly more slowly than healthy cows. In conclusion, all force symmetries seemed capable of detecting gait responses to claw trimming. Although our results are based on a small number of animals, vertical leg symmetry was affected by lameness.

Effects of hunger level and tube diameter on the feeding behavior of teat-fed dairy calves.

Behavioral changes caused by variation in hunger have a great potential in health monitoring in dairy cattle. The present experiment used 48 Danish Holstein bull calves with a median age of 33 d. We examined the effect of different levels of hunger (reduced, in which calves were fed 1.5L of milk via esophageal tube before feeding; increased, in which calves were fed half milk ration at the previous feeding, or control, in which calves were fed normal ration at the previous feeding) on feeding behavior of calves fed via different tube diameters (6.0, 3.0, or 1.5mm). Behavior observed during a 40-min period after morning milk feeding on d 7, 9, and 11 of testing is reported. No significant interactions between tube diameter and hunger level on behavior were found. Reduced tube diameter led to increased latency to empty the teat bucket, increased duration of nutritive sucking, and decreased duration of nonnutritive sucking for calves fed via 1.5-mm tubes compared with calves in the 2 other treatments. The duration of nonnutritive sucking increased with increasing level of hunger. Furthermore, calves with reduced hunger showed a lower frequency of butting than calves at the 2 other hunger levels. The present results show that only a rather high reduction in tube diameter led to reduced drinking rate. Neither reduced nor increased hunger levels led to changes in drinking rate, but calves showed reduced nonnutritive sucking and butting when they were less hungry and increased nonnutritive sucking and butting when hunger was increased. The results suggest that nonnutritive sucking is a more sensitive indicator than drinking rate of changes in feeding motivation. Consequently, reduction in nonnutritive sucking might be a new candidate in the search for behavioral indicators of disease in dairy calves.

Technical note: Quantifying and characterizing behavior in dairy calves using the IceTag automatic recording device.

The objectives of the current study were 1) to validate the IceTag (http://www.icerobotics.com) automatic recording device for measuring lying, standing, and moving behavior in dairy calves, and 2) to improve the information yield from this device by applying a filtering procedure allowing for the detection of lying versus upright. The IceTag device provides measures of intensity (I) of lying, standing, and activity measured as percent lying, percent standing, and percent active, but does not directly measure lying, standing, and moving behavior because body movements occurring while lying (e.g., shifts in lying position) and while upright (e.g., grooming) are recorded as activity. Therefore, the following 3-step procedure was applied. First, thresholds for I were determined by choosing the cutoff that maximized the sum of sensitivity (Se) and specificity (Sp). Second, a lying period criterion (LPC) was established empirically, and IceTag data were filtered according to the LPC, providing information on the posture of the animal as lying versus being upright. Third, a new threshold of I was estimated for moving activity conditional on the animal being upright. IceTag recordings from 9 calves were compared with video recordings during a 12-h period and analyzed using 2 x 2 contingency tables. Data from the first 4 calves were used to determine an LPC, whereas the remaining 5 calves served for validation of the procedure. An optimal LPC was found by modeling the deviance between IceTag and video recordings as a function of the LPC and choosing the LPC threshold that minimized the deviance. The IceTag device was found to accurately measure the high-prevalence behaviors (lying and standing; Se+Sp >1.90) and less accurately measure the low-prevalence behavior (moving; Se+Sp = 1.39). Application of the 3-step procedure using an optimal LPC estimate of 24.8 s resulted in an improved description of calf behavior, yielding a valid representation of the number and duration of lying and upright periods (Se+Sp = 2.00) within a precision of 0 to 49 s (95% confidence interval). In group-housed dairy calves, valid measures of the number and duration of lying and upright periods may be obtained from the IceTag device when applying the presented filtering procedure to the data. Measures regarding locomotion, on the other hand, should be used with caution.

Estimating transfer of bovine virus-diarrhoea virus in Danish cattle by use of register data.

To study how routinely recorded data (also called "register data") might be used in disease monitoring on a regional or national level, a database for bovine virus-diarrhoea virus (BVDV) was made from existing databases, covering the period January 1995-November 1999. This paper includes a general description of the database, including basic statistics for selected variables. Information was largely complete for cattle herds in the milk-recording scheme (MRS), but only partly available for other herds. A methodology was developed to identify when and how a herd initially was infected. For most herds, it was possible to determine when and how BVDV first was introduced. Among the infected herds, most were already infected by the start of the study. BVDV had been present in 40% of the MRS herds and in 9% of the non-MRS herds. In the MRS herds, most new infections were associated with a dam that had been present in the same herd during gestation. Among the non-MRS herds, most new infections were associated with movement of a persistently infected animal. The monthly number of newly infected herds is presented; it is seen that the incidence declined substantially during the study period.

The effect of increasing levels of insoluble dietary fibre on the establishment and persistence of Oesophagostomum dentatum in pigs.

This investigation compared the effect of diets with increasing content of insoluble dietary fibre (DF) on the establishment and persistence of Oesophagostomum dentatum in growing pigs. Twenty-eight worm-free pigs, from a specific pathogen-free farm were randomly divided to four groups of seven animals. The animals were assigned to the following diets: diet A, barley flour plus protein mixture (70%:30%); diet B, barley flour, oat husk meal plus protein mixture (65%:7%:28%); diet C, barley flour, oat husk meal plus protein mixture (60%:14%:26%) and diet D, barley flour, oat husk meal plus protein mixture (55%:21%:24%). The diets were formulated to provide increasing content of DF but constant levels of digestible protein per feeding unit for pigs. All pigs were experimentally inoculated with 6,000 infective O. dentatum larvae and followed coprologically for 11 weeks post infection, whereafter they were slaughtered. The experimental diets influenced the mean transit time and the metabolism in the large intestine significantly. Diets C and D, with highest content of insoluble DF, provided favourable conditions for establishment of O. dentatum, but diets A and B led to a significant lower worm numbers and fecundity.

The impact of diets varying in carbohydrates resistant to endogenous enzymes and lignin on populations of Ascaris suum and Oesophagostomum dentatum in pigs.

The impact of diets varying in type and level of carbohydrates resistant to endogenous enzymes and lignin on the establishment and location of Ascaris suum and Oesophagostomum dentatum was investigated experimentally. Fifty worm-free pigs, from a specific pathogen-free farm were used. The animals were assigned randomly to 5 diets and infected with 600 infective A. suum eggs and 6000 infective larvae of O. dentatum per pig. The diets consisted of a traditional ground barley plus protein feed (diet A), commercial full-constituent pelleted feed (diet B), barley flour plus protein (diet C), barley flour, inulin (Raftiline ST, ORAFTI, Tienen, Belgium), sugar beet fibre plus protein (diet D), and barley flour, wheat bran, and protein (diet E). The faecal egg excretion was followed and the pigs were slaughtered at 8 weeks p.i. and samples taken from the small and large intestine. Intestinal contents were analysed for worm burdens, worm location and female worm fecundity along with the concentration of insoluble (chromic oxide) and soluble (polyethylene glycol-4000) markers, lignin, non-starch polysaccharides (NSP) and organic acids. In all diet groups A. suum worm burdens were low and comparable, whereas the O. dentatum worm burdens were significantly higher in pigs fed the diets with high levels of NSP and lignin (diets A and E) than in pigs fed diets B, C, and D. The present study suggests that a diet rich in lignin and insoluble NSP's provides favourable conditions for the establishment of O. dentatum in the large intestine of pigs while it is unlikely that the concentration of short-chain fatty acids and pH plays and major role.

Effects of varying content of soluble dietary fibre from wheat flour and oat milling fractions on gastric emptying in pigs.

Four pigs fitted with a gastric cannula were fed on a wheat-flour-based diet (WF) and three oat-based diets, consisting mainly of oat flour (OF), rolled oats (RO) or oat bran (OB), for 1 week each. The stomach contents were collected quantitatively daily at 0.5, 1, 2, 3 or 5 h after feeding. The viscosity (mPa.s) of the liquid fraction of stomach contents 1 h after feeding was 1.7 with diet WF, 15 with diet OF, 30 with diet RO and approximately 400 with diet OB. The viscosity and the concentration of beta-glucan in the liquid phase was to some extent determined by the dietary level of beta-glucan in the diet. However, there was a trend towards a lower viscosity after longer exposure to the gastric juices. The correlation between logarithmic values for viscosity and concentration of beta-glucan in the liquid phase of digesta was r 0.45. On centrifugation of digesta there was a higher proportion present in the sediment phase when the pigs were fed on diets with a higher content of soluble dietary fibre (DF), suggesting that the digesta was more coherent. This possibility was supported by the higher water-holding capacity (WHC) of the sediment. Feeding diets with oats containing a higher soluble DF content led to lower recoveries of digesta, PEG 4000 (liquid-phase marker), and the DF components beta-glucan and arabinoxylan in the first hour after feeding. No effect related to the DF content of the diet was seen in the gastric emptying of starch and Cr2O3 (solid-phase marker). In conclusion, soluble DF from oats increased the viscosity of stomach contents and increased the ability of the dry matter to retain water. Higher levels of soluble DF led to higher recoveries of digesta, the liquid phase and DF itself in the initial stage of gastric emptying, whereas no effect was seen on the gastric emptying of starch.

Genetic models for the inheritance of the silver colour mutation of foxes.

We consider genetic models for the inheritance of the particular colour patterns of silver foxes. The models are evaluated by computation of statistical likelihoods based on observations of related foxes in extended pedigrees. Problems caused by incomplete paternity information are addressed by inferences based on phenotypic observations. The unreliability of subjective evaluations of fur colour also provides difficulty, in particular crossfoxes emerge as being difficult to differentiate. No evidence of linkage between Agouti locus and Extension locus is found in this dataset.