Epistaxis in anticoagulated patients: Fewer hospital admissions and shorter hospital stays on rivaroxaban compared to phenprocoumon.

OBJECTIVES: Treatment of epistaxis in patients on anticoagulants is challenging and associated with higher admission rates and longer hospital stays compared with patients without anticoagulation. However, there is little information about epistaxis in patients taking new direct oral anticoagulants such as rivaroxaban compared with patients on traditional vitamin K antagonists such as phenprocoumon. DESIGN: Retrospective cohort study. SETTING: The study was conducted at the emergency department of the University Hospital Inselspital, Bern, Switzerland. PARTICIPANTS: All admissions to the emergency department of the University Hospital Inselspital, Bern, Switzerland from 1st July 2012 to 30th June 2016 with non-traumatic epistaxis on anticoagulant therapy with phenprocoumon or rivaroxaban were included. MAIN OUTCOME MEASURES: We compared clinical outcome parameters (admission rates, length of hospital stay and mortality) for both anticoagulant groups. RESULTS: We included 440 patients with epistaxis, 123 (28%) on rivaroxaban and 317 (72%) on phenprocoumon. Fewer hospital admissions and shorter hospital stays were found in patients under rivaroxaban (12 (10.4%) vs 57 (18.0%) patients, P=.033; 0.7±2.2 vs 1.5±3.7 days, P=.011) compared with phenprocoumon. Anterior epistaxis was more common in the rivaroxaban group in contrast to posterior epistaxis in patients on phenprocoumon (74 (60.2%) vs 139 (43.8%) patients, P=.002; 7 (5.7%) vs 39 (12.3%) patients, P=.042). CONCLUSIONS: Our data suggests that epistaxis on direct oral anticoagulation with rivaroxaban is associated with shorter hospital stays and fewer hospital admissions than epistaxis on vitamin K antagonist phenprocoumon.

Long-term outcomes of elderly patients with CYP2C9 and VKORC1 variants treated with vitamin K antagonists.

Essentials The long-term effects of VKORC1 and CYP2C9 variants on clinical outcomes remains unclear. We followed 774 patients ≥65 years with venous thromboembolism for a median duration of 30 months. Patients with CYP2C9 variants are at increased risk of death and non-major bleeding. Patients with genetic variants have a slightly lower anticoagulation quality only. SUMMARY: Background The long-term effect of polymorphisms of the vitamin K-epoxide reductase (VKORC1) and the cytochrome P450 enzyme gene (CYP2C9) on clinical outcomes remains unclear. Objectives We examined the association between CYP2C9/VKORC1 variants and long-term clinical outcomes in a prospective cohort study of elderly patients treated with vitamin K antagonists for venous thromboembolism (VTE). Methods We followed 774 consecutive patients aged ≥ 65 years with acute VTE from nine Swiss hospitals for a median duration of 30 months. The median duration of initial anticoagulant treatment was 9.4 months. The primary outcome was the time to any clinical event (i.e. the composite endpoint of overall mortality, major and non-major bleeding, and recurrent VTE. Results Overall, 604 (78%) patients had a CYP2C9 or VKORC1 variant. Three hundred and thirty-four patients (43.2%) had any clinical event, 119 (15.4%) died, 100 (12.9%) had major and 167 (21.6%) non-major bleeding, and 100 had (12.9%) recurrent VTE. After adjustment, CYP2C9 (but not VKORC1) variants were associated with any clinical event (hazard ratio [HR], 1.34; 95% confidence interval [CI], 1.08-1.66), death (HR, 1.74; 95% CI, 1.19-2.52) and clinically relevant non-major bleeding (sub-hazard ratio [SHR], 1.39; 95% CI, 1.02-1.89), but not with major bleeding (SHR, 1.03; 95% CI, 0.69-1.55) or recurrent VTE (SHR, 0.95; 95% CI, 0.62-1.44). Patients with genetic variants had a slightly lower anticoagulation quality. Conclusions CYP2C9 was associated with long-term overall mortality and non-major bleeding. Although genetic variants were associated with a slightly lower anticoagulation quality, there was no relationship between genetic variants and major bleeding or VTE recurrence.

Accuracy and consistency of anti-Xa activity measurement for determination of rivaroxaban plasma levels.

Essentials Accurate determination of anticoagulant plasma concentration is important in clinical practice. We studied the accuracy and consistency of anti-Xa assays for rivaroxaban in a multicentre study. In a range between 50 and 200 µg L-1 , anti-Xa activity correlated well with plasma concentrations. The clinical value might be limited by overestimation and intra- and inter-individual variation. SUMMARY: Background Determining the plasma level of direct oral anticoagulants reliably is important in the work-up of complex clinical situations. Objectives To study the accuracy and consistency of anti-Xa assays for rivaroxaban plasma concentration in a prospective, multicenter evaluation study employing different reagents and analytical platforms. Methods Rivaroxaban 20 mg was administered once daily to 20 healthy volunteers and blood samples were taken at peak and trough levels (clinicaltrials.gov NCT01710267). Anti-Xa activity was determined in 10 major laboratories using different reagents and analyzers; corresponding rivaroxaban plasma concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS). Findings Overall Pearson's correlation coefficient of anti-Xa levels and HPLC-MS results was 0.99 for Biophen® Heparin (95% CI, 0.99, 0.99), Biophen® DiXaI (95% CI, 0.99, 0.99) and STA® anti-Xa liquid (95% CI, 0.99, 1.00). Correlation was lower in rivaroxaban concentrations below 50 µg L-1 and above 200 µg L-1 . The overall bias of the Bland-Altman difference plot was 14.7 µg L-1 for Biophen Heparin, 17.9 µg L-1 for Biophen DiXal and 19.0 µg L-1 for STA anti-Xa liquid. Agreement between laboratories was high at peak level but limited at trough level. Conclusions Anti-Xa activity correlated well with rivaroxaban plasma concentrations, especially in a range between 50 and 200 µg L-1 . However, anti-Xa assays systematically overestimated rivaroxaban concentration as compared with HPLC-MS, particularly at higher concentrations. This overestimation, coupled with an apparent interindividual variation, might affect the interpretation of results in some situations.

Impact of a product-specific reference standard for the measurement of a PEGylated rFVIII activity: the Swiss Multicentre Field Study.

INTRODUCTION: Measuring factor VIII (FVIII) activity can be challenging when it has been modified, such as when FVIII is pegylated to increase its circulating half-life. Use of a product-specific reference standard may help avoid this issue. AIM: Evaluate the impact of using a product-specific reference standard for measuring the FVIII activity of BAX 855 - a pegylated FVIII - in eight of Switzerland's main laboratories. METHODS: Factor VIII-deficient plasma, spiked with five different concentrations of BAX 855, plus a control FVIII sample, was sent to the participating laboratories. They measured FVIII activity by using either with a one-stage (OSA) or the chromogenic assay (CA) against their local or a product-specific reference standard. RESULTS: When using a local reference standard, there was an overestimation of BAX 855 activity compared to the target concentrations, both with the OSA and CA. The use of a product-specific reference standard reduced this effect: mean recovery ranged from 127.7% to 213.5% using the OSA with local reference standards, compared to 110% to 183.8% with a product-specific reference standard, and from 146.3% to 182.4% using the CA with local reference standards compared to 72.7% to 103.7% with a product-specific reference standard. CONCLUSION: In this in vitro study, the type of reference standard had a major impact on the measurement of BAX 855 activity. Evaluation was more accurate and precise when using a product-specific reference standard.

SF6(-) photodetachment near the adiabatic limit.

High sensitivity photodetachment cross-section measurements of SF6(-) are performed near the adiabatic threshold limit. The extraction of adiabatic detachment energy (ADE) from the high sensitivity measurement of the cross-section change as a function of photon energy is discussed. Below the vertical detachment energy a steep 4 orders of magnitude cross-section drop is observed, with cross sections as low as 2 × 10(-6) Å(2) measured for photon energies below 2 eV. The cross-section is fitted with both the expected spectral shape based on recently calculated Frank-Condon overlaps and a phenomenological threshold function. The resulting 1.7 ± 0.02 eV ADE values are significantly higher than previously recommended experimental ADE values obtained based on kinetics modeling, and possible differences between the experimental approaches are discussed.

[New oral anticoagulants - influence on coagulation tests]. / Neue orale Antikoagulanzien - Einfluss auf Gerinnungstests.

The new oral anticoagulants (NOACs) represent alternative antithrombotic agents for prophylaxis and therapy of thromboembolic diseases. They act either by inhibition of the clotting factor Xa or IIa (thrombin). As a consequence, they influence several coagulation assays (for example prothrombin time, activated partial thromboplastin time). Because of the short half-life of these new agents, these changes show great variations in the course of 24 hours. Furthermore, there are significant differences of laboratory results depending on the used reagents. We explain the influence of apixaban, rivaroxaban (factor Xa inhibitors) and dabigatran (thrombin inhibitor) on the most commonly used coagulation assays. Besides we show that this influence depends on the way of action of the drug as well as on the principle of the coagulation assay. Being aware of this relationships helps to interpret the results of coagulation assays under influence of NOACs correctly.

[Laboratory diagnostic with regard to new anticoagulants - monitoring and influence on coagulation tests]. / Labordiagnostik neuer Antikoagulantien - Einfluss auf Hämostaseparameter und Monitoring.

New oral anticoagulants promise to overcome essential drawbacks of traditional substances. They have a predictable therapeutic effect, a wide therapeutic window, only limited interaction with food and drugs and can be administered p.o. with a fixed dose. On the other hand, knowledge on the laboratory management of new anticoagulants is limited. In the present article we discuss possible indications and available assays for monitoring of Rivaroxaban, Apixaban and Dabigatran. Furthermore, we discuss interpretation of routine coagulation tests during therapy with these new drugs.

A case of Ohtahara syndrome with olivary-dentate dysplasia and agenesis of mamillary bodies.

We report a patient with early infantile epileptic encephalopathy (EIEE) with suppression-burst (Ohtahara syndrome) associated with olivary-dentate dysplasia and agenesis of mamillary bodies is reported. Although those with Ohtahara syndrome are a heterogeneous group, virtually all reported cases are secondary to neuronal migrational disorders, sometimes only identified by detailed neuropathologic examination, as in this case report, which describes mamillary body agenesis as a not-yet-recognized anomaly associated with Ohtahara syndrome. All children with Ohtahara syndrome should have high-resolution magnetic resonance imaging (MRI) and detailed postmortem neuropathologic examinations.

Genotoxicity testing of extracts from aflatoxin-contaminated peanut meal, following chemical decontamination.

One of the most important concerns in the decontamination of aflatoxin-containing feed commodities is the safety of the products for food-producing animals and for human consumption of products derived from these animals. A new method, based on the use of florisil and C18 solid phase extraction columns, was developed for the preparation of extracts from decontaminated peanut meal, which allowed testing with in vitro genotoxicity assays without interference of the residual aflatoxin B1. Recovery of degradation products in the extracts was evaluated by the use of radiolabelled [14C]-aflatoxin B1 (AFB1) added to naturally-contaminated peanut meal (3.5 mg AFB1/kg). The meal was treated by a small-scale version of an industrial decontamination process based on ammoniation. Following decontamination, more than 90% of the label could not be extracted from the meal. AFB1 accounted for about 10% of the radiolabel present in the extractable fraction, indicating a total AFB1 reduction of more than 99%. Decontamination of the meal by a number of other small- and industrial-scale ammonia-based processes resulted in similar efficiencies. Application of the extraction procedure resulted in AFB1-rich and AFB1-poor fractions, the latter containing half of the extractable decontamination products but less than 1% of the residual AFB1. Testing in the Salmonella/microsome mutagenicity assay (TA 100, with S9-mix) of the original crude extracts and AFB1-rich fractions prepared from non-treated and decontaminated meal, showed the positive results expected from the AFB1 contents as determined by HPLC analysis. Analysis and testing of the AFB1-poor fractions showed that the various decontamination processes not only resulted in a successful degradation of AFB1 but also did not produce other potent mutagenic compounds. Slight positive results obtained with these extracts were similar for the untreated and treated meals and may be due to unknown compounds originally present in the meal. Results obtained with an unscheduled DNA synthesis (UDS) and Comet assay with rat hepatocytes supported this conclusion. Positive results obtained with the micronucleus assay, using immortalized mouse hepatocytes (GKB), did not clearly reflect the mycotoxin levels and require further examination. It is concluded that the newly developed extraction procedure yields highly reproducible fractions and hence is very suitable for examining the possible formation of less potent degradation products of aflatoxins in short-term genotoxicity tests.

Differences detected in vivo between samples of aflatoxin-contaminated peanut meal, following decontamination by two ammonia-based processes.

A sample of peanut meal, highly contaminated with aflatoxins, has been subjected to decontamination by two commercial ammonia-based processes. The original contaminated and the two decontaminated meals were fed to rats for 90 days. No lesions associated with aflatoxin-induced hepatocarcinogenesis were detected histologically following feeding with the two detoxified meals. There were, however, clear differences between the two meals in respect of growth rates of the rats. In addition, feeding one of the detoxified meals resulted in hepatic abnormalities detected using novel immunohistochemical reagents. Differences between the two detoxified meals were also indicated by the results of studies using meals 'spiked' with [14C]-aflatoxin B1 prior to being subjected to the detoxification processes. The meals differed in the bioavailability of the label. It was concluded that peanut meal where an initial, unacceptable level of contamination with aflatoxins had been reduced by two ammonia-based processes to comparable, acceptable levels, may still have different effects in vivo when incorporated into animal diets.

Absorption, distribution and excretion of aflatoxin-derived ammoniation products in lactating cows.

Peanut meal naturally contaminated with 3.5 mg/kg aflatoxin B1 (AFB1) was spiked with radiolabelled AFB1 (meal 14C-I0) and decontaminated by a small-scale copy of an industrial ammoniation process (meal 14C-I1). During the process 15% of the radioactivity was lost, whereas 90% of the remaining radiolabel could not be extracted from the meal. In the extractable part, AFB1 accounted for 10% of the radiolabel, consistent with a total AFB1 reduction of more than 99%. No degradation products were observed in the extracts. Four lactating cows were fed with a diet containing 15% of either meal 14C-I0 or 14C-I1 for 10 days. On day 9 of this treatment, respectively 23 and 67% of the radiolabel was excreted in the urine and faeces of cows fed meal 14C-I0, as compared with 2 and 101% in the case of cows fed meal 14C-I1. Milk contained respectively 1.35 (meal 14C-I0) and 0.25% (meal 14C-I1) of the radiolabel. Milk samples taken during the equilibrium stage contained respectively 5 and 0.5 ng/ml of AFB1-derived compounds. Aflatoxin M1 (AFM1) accounted for 50-80% of these compounds in the case of milk from cows fed 14C-I0, as compared with 6-20% in the case of 14C-I1. AFB1 to AFM1 carry-over rates for 14C-I0 or 14C-I1 were estimated to be respectively 0.5 and 5.9%. Only liver and kidney samples contained detectable levels of the radiolabel, being respectively 260 and 37 micrograms/kg for cows fed meal 14C-I0, and 10 and 3 micrograms/kg for those fed meal 14C-I1. In the latter case, more than 55% of the radiolabel in the liver could not be extracted, as compared with 90% in the group fed meal 14C-I1. A small part of the extractable radiolabel in the livers of cows fed meal 14C-I0 could be attributed to AFB1 and AFM1 (less than 1% of total radioactivity). In the case of the animals fed 14C-I1 there were indications for the presence of AFB1 and AFM1 (6% of total radioactivity). Decontamination of the highly contaminated (non-radiolabelled) peanut meal by two different industrial ammoniation processes, resulted in a similar reduction of the initial AFB1 levels of 3.5 mg/kg to 15 micrograms/kg. Feeding of diets containing 15% of the non-treated and two treated peanut meals to cows for a period of 10 days, resulted in AFM1 levels in milk of respectively 2.1, 0.04 and 0.07 ng/ml. AFB1 to AFM1 carry-over rates were calculated to be respectively 0.5, 2.0, and 3.6%. It is concluded that the efficient reduction of aflatoxin levels by ammoniation of contaminated peanut meal results in a strong reduction of aflatoxin-related residues in milk and meat of cows, most likely caused by a decreased bioavailability of the degradation products.

Sampling plans for the determination of aflatoxin B1 in large shipments of animal feedstuffs.

Incremental samples (50, 100, and 500 g) were systematically collected from large shipments of copra meal pellets, copra cake, and palm kernel cake to study the distribution of aflatoxin B1 and evaluate adherence of distribution to the model, CV(2)is (EQ) = A + B/Mis (where CVis = coefficient of variation of the true concentration of aflatoxin B1 within the incremental samples; Mis = mass of the incremental samples; and A and B are constants). Also evaluated was the distribution of aflatoxin B1 among 1 kg composite samples, produced both by random combination of existing incremental samples and by collection of 1 kg composite samples (composed of 10 x 100 g increments) from additional batches of copra meal pellets and cottonseed cake. The efficiency of selected sample preparation (grinding and subdivision) procedures was compared, culminating in the development and description of a variety of sampling plans. The coefficient of variation (CV) among incremental samples varied from 0 to 38%, and was independent of incremental sample size. No significant difference (F-test, 5% significance level) was found between the efficacy of 4 sample preparation methods when these methods were applied to the commodities described above. Various sampling plans were evaluated with estimated CVs from 4.0 to 12.5%, for the aflatoxin B1 content of the composite samples.

Clinical and EEG findings in complex partial status epilepticus with tiagabine.

A case of complex partial status epilepticus (CPSE) with high dose treatment of tiagabine (TGB) is reported. Seizure aggravation and CPSE developed after stepwise increase of TGB to a dose of 60 mg per day as add-on treatment to carbamazepine (CBZ) 1200 mg/day and vigabatrine (VGB) 1000 mg/day. The EEG during CPSE showed bilateral rhythmic slow activity. Clinical symptoms of CPSE and the EEG normalized after i.v. treatment with clonazepam. The literature and the possible mechanism of this paradoxical phenomenon are discussed.

Design of sampling plans for mycotoxins in foods and feeds.

The control of the occurrence of mycotoxins in foods and feeds requires effective surveillance and quality control procedures which facilitate the identification and control of the mycotoxin problem respectively. Surveillance and quality control procedures involve a sequence of sampling, sample preparation, and analysis steps; and the integrity of the data produced by these procedures will be determined by the effectiveness of these steps. It is imperative that the sampling step is performed as accurately as possible so that the sample collected is representative of the batch of food or feed under investigation. Needless to say, the collection of a biased sample will completely invalidate the resultant analytical data. Most attempts to develop effective sampling protocols have focused upon the aflatoxins, since the majority of current regulations are concerned specifically with this group of mycotoxins. However, the design of effective sampling protocols has been severely hindered by the highly skewed distribution of the aflatoxins in foods and feeds. Studies already performed indicate that representative samples of commodities, composed of large particles (e.g., corn and oilseed kernels) should be 10 kg in weight, at least, and composed of approximately one hundred incremental samples. Similar studies have indicated that samples of oilseed cakes and meal, however, should be composed of fifty incremental samples which afford a composite sample of approximately 5 kg in weight.

Spatial and temporal frequency selectivity of neurones in visual cortical areas V1 and V2 of the macaque monkey.

The spatial and temporal frequency selectivity of 148 neurones in the striate cortex, V1, and of 122 neurones in the second visual cortical area, V2, of the macaque monkey were studied using sine-wave gratings of suprathreshold contrast drifting over the receptive field at the preferred orientation and direction. Neurones in V1 and V2 were selective for different but partially overlapping ranges of the spatial frequency spectrum. At retinal eccentricities of 2-5 deg from the fovea, the spatial frequency preferences for neurones ranged from 0.5 to 8.0 cycles/deg in V1 and from 0.2 to 2.1 cycles/deg in V2 and were on average almost 2 octaves lower in V2 than in V1. Spatial frequency full band widths in the two cortical areas were in the range 0.8-3.0 octaves, with a mean value of 1.8 octaves, in the parafoveal representation of both V1 and V2, and 1.4 and 1.6 octaves respectively in the foveal representation of V1 and V2. Most neurones in V1 and some in V2 responded well at temporal frequencies up to 5.6-8.0 Hz before their responses dropped off at still higher frequencies. In V1, 68% of the neurones exhibited low-pass temporal tuning characteristics and 32% were very broadly tuned, with a mean temporal frequency full band width of 2.9 octaves. However, in V2 only 30% of the neurones showed low-pass temporal selectivity and 70% of the cells had bandpass temporal characteristics, with a mean full band width of 2.1 octaves. In V2 the minimal overlap of bandpass tuning curves across the temporal frequency spectrum suggests that there are at least two distinct bandpass temporal frequency mechanisms as well as neurones with low-pass temporal frequency tuning at each spatial frequency. A matrix of spatial and temporal frequency combinations was employed as stimuli for neurones with bandpass temporal frequency selectivity in both V1 and V2. The resultant spatio-temporal surfaces provided evidence that a neurone's preference for spatial frequency is essentially independent of the test temporal frequency; however, in V2 there was some tendency for temporal frequency peaks to shift slightly towards lower frequencies when non-optimum values of spatial frequency either above or below the preferred value were tested. Neurones with pronounced directional selectivity were encountered over a wide range of spatial frequencies, although in both cortical areas there was a tendency for an increased incidence of directional selectivity among neurones which were selective for lower spatial frequencies and higher temporal frequencies.