Bayer (Netherlands)

KEY MESSAGE: Thermotolerant crop research. Global warming has become a serious worldwide threat. High temperature is a major environmental factor limiting crop productivity. Current adaptations to high temperature via alterations to technical and management systems are insufficient to sustain yield. For this reason, breeding for heat-tolerant crops is in high demand. This review provides an overview of the effects of high temperature on plant physiology, fertility and crop yield and discusses the strategies for breeding heat-tolerant cultivars. Generating thermotolerant crops seems to be a challenging task as heat sensitivity is highly variable across developmental stages and processes. In response to heat, plants trigger a cascade of events, switching on numerous genes. Although breeding has made substantial advances in developing heat-tolerant lines, the genetic basis and diversity of heat tolerance in plants remain largely unknown. The development of new varieties is expensive and time-consuming, and knowledge of heat tolerance mechanisms would aid the design of strategies to screen germplasm for heat tolerance traits. However, gains in heat tolerance are limited by the often narrow genetic diversity. Exploration and use of wild relatives and landraces in breeding can increase useful genetic diversity in current crops. Due to the complex nature of plant heat tolerance and its immediate global concern, it is essential to face this breeding challenge in a multidisciplinary holistic approach involving governmental agencies, private companies and academic institutions.

IMPORTANCE: Combined anticoagulant and aspirin therapy is associated with increased bleeding risk in patients with atrial fibrillation, but the bleeding risk of combined use of anticoagulant and nonsteroidal anti-inflammatory drugs (NSAIDs) is poorly documented. OBJECTIVE: To estimate the bleeding risk of combined anticoagulant (rivaroxaban or enoxaparin-vitamin K antagonist [VKA]) and NSAID or aspirin therapy in patients with venous thromboembolism. DESIGN, SETTING, AND PARTICIPANTS: Prospective analysis of observational data from the EINSTEIN deep vein thrombosis and pulmonary embolism clinical trials comparing rivaroxaban with enoxaparin-VKA treatment, trials performed in hospitals and clinics in 8246 patients enrolled from 2007 to 2009. EXPOSURE: Bleeding event rates during exposure to NSAID and aspirin therapy were compared to time without exposure. MAIN OUTCOMES AND MEASURES: Days of NSAID or aspirin use and nonuse, clinically relevant bleeding event and major bleeding event rates by patient-years, and hazard ratios. RESULTS: During NSAID-anticoagulant concomitant treatment, clinically relevant bleeding occurred with an event rate of 37.5 per 100 patient-years vs 16.6 per 100 patient-years during anticoagulant use only (hazard ratio [HR], 1.77 [95% CI, 1.46-2.14]). Major bleeding during NSAID-anticoagulant treatment occurred with an event rate of 6.5 per 100 patient-years, compared to 2.0 per 100 patient-years during nonuse (HR, 2.37 [95% CI, 1.51-3.75]). For aspirin-anticoagulant concomitant treatment, clinically relevant bleeding occurred with an event rate of 36.6 per 100 patient-years, compared to 16.9 per 100 patient-years during aspirin nonuse (HR, 1.70 [95% CI, 1.38-2.11]). Major bleeding in aspirin-anticoagulant-treated patients occurred with an event rate of 4.8 per 100 patient-years, compared to 2.2 per 100 patient-years during aspirin nonuse (HR, 1.50 [95% CI, 0.86-2.62]). Increases in risk for clinically relevant and major bleeding were similar for rivaroxaban and enoxaparin-VKA anticoagulation regimens. CONCLUSIONS AND RELEVANCE: Among patients with venous thromboembolism receiving anticoagulant therapy, concomitant use of an NSAID or aspirin is associated with an increased risk of clinically relevant and major bleeding.

Global warming has become a worldwide concern due to its adverse effects on agricultural output. In particular, long-term mildly high temperatures interfere with sexual reproduction and thus fruit and seed set. To uncover the genetic basis of observed variation in tolerance against heat, a bi-parental F2 mapping population from two contrasting cultivars, i.e. Nagcarlang and NCHS-1, was generated and phenotyped under continuous mild heat conditions for a number of traits underlying reproductive success, i.e. pollen viability, pollen number, style length, anther length, style protrusion, female fertility and flowering characteristics, i.e. inflorescence number and flowers per inflorescence. Quantitative trait loci (QTLs) were identified for most of these traits, including a single, highly significant one for pollen viability, which accounted for 36% of phenotypic variation in the population and modified pollen viability under high temperature with around 20%. QTLs for some traits colocalised, indicating trait dependency or pleiotropic-effect loci. We conclude that a limited set of major genes determines differences in performance of reproductive traits under continuous mild heat in tomato. The results contribute to our fundamental understanding of pollen thermotolerance and may support development of more heat-tolerant tomato varieties.

The Gy14 cucumber (Cucumis sativus) is resistant to oomyceteous downy mildew (DM), bacterial angular leaf spot (ALS) and fungal anthracnose (AR) pathogens, but the underlying molecular mechanisms are unknown. Quantitative trait locus (QTL) mapping for the disease resistances in Gy14 and further map-based cloning identified a candidate gene for the resistant loci, which was validated and functionally characterized by spatial-temporal gene expression profiling, allelic diversity and phylogenetic analysis, as well as local association studies. We showed that the triple-disease resistances in Gy14 were controlled by the cucumber STAYGREEN (CsSGR) gene. A single nucleotide polymorphism (SNP) in the coding region resulted in a nonsynonymous amino acid substitution in the CsSGR protein, and thus disease resistance. Genes in the chlorophyll degradation pathway showed differential expression between resistant and susceptible lines in response to pathogen inoculation. The causal SNP was significantly associated with disease resistances in natural and breeding populations. The resistance allele has undergone selection in cucumber breeding. The durable, broad-spectrum disease resistance is caused by a loss-of-susceptibility mutation of CsSGR. Probably, this is achieved through the inhibition of reactive oxygen species over-accumulation and phytotoxic catabolite over-buildup in the chlorophyll degradation pathway. The CsSGR-mediated host resistance represents a novel function of this highly conserved gene in plants.

Abstract Climate change has become a serious threat for crop productivity worldwide. The increased frequency of heat waves strongly affects reproductive success and thus yield for many crop species, implying that breeding for thermotolerant cultivars is critical for food security. Insight into the genetic architecture of reproductive heat tolerance contributes to our fundamental understanding of the stress sensitivity of this process and at the same time may have applied value. In the case of tomato ( Solanum lycopersicum ), germplasm screenings for thermotolerance have often used yield as the main measured trait. However, due to the complex nature of yield and the relatively narrow genetic variation present in the cultivated germplasm screened, there has been limited progress in understanding the genetic basis of reproductive heat tolerance. Extending the screening to wild accessions of related species that cover a range of climatic conditions might be an effective approach to find novel, more tolerant genetic resources. The purpose of this study was to provide insight into the sensitivity of individual reproductive key traits (i.e. the number of pollen per flower, pollen viability and style protrusion) to heat-wave like long-term mild heat (LTMH), and determine the extent to which genetic variation exists for these traits among wild tomato species. We found that these traits were highly variable among the screened accessions. Although no overall thermotolerant species were identified, several S. pimpinellifolium individuals outperformed the best performing cultivar in terms of pollen viability under LTMH. Furthermore, we reveal that there has been local adaptation of reproductive heat tolerance, as accessions from lower elevations and higher annual temperature are more likely to show high pollen viability under LTMH.

Characterization of a new tomato (Solanum lycopersicum) T-DNA mutant allowed for the isolation of the CALCINEURIN B-LIKE PROTEIN 10 (SlCBL10) gene whose lack of function was responsible for the severe alterations observed in the shoot apex and reproductive organs under salinity conditions. Physiological studies proved that SlCBL10 gene is required to maintain a proper low Na+/Ca2+ ratio in growing tissues allowing tomato growth under salt stress. Expression analysis of the main responsible genes for Na+ compartmentalization (i.e. Na+/H+ EXCHANGERs, SALT OVERLY SENSITIVE, HIGH-AFFINITY K+ TRANSPORTER 1;2, H+-pyrophosphatase AVP1 [SlAVP1] and V-ATPase [SlVHA-A1]) supported a reduced capacity to accumulate Na+ in Slcbl10 mutant leaves, which resulted in a lower uploading of Na+ from xylem, allowing the toxic ion to reach apex and flowers. Likewise, the tomato CATION EXCHANGER 1 and TWO-PORE CHANNEL 1 (SlTPC1), key genes for Ca2+ fluxes to the vacuole, showed abnormal expression in Slcbl10 plants indicating an impaired Ca2+ release from vacuole. Additionally, complementation assay revealed that SlCBL10 is a true ortholog of the Arabidopsis (Arabidopsis thaliana) CBL10 gene, supporting that the essential function of CBL10 is conserved in Arabidopsis and tomato. Together, the findings obtained in this study provide new insights into the function of SlCBL10 in salt stress tolerance. Thus, it is proposed that SlCBL10 mediates salt tolerance by regulating Na+ and Ca2+ fluxes in the vacuole, cooperating with the vacuolar cation channel SlTPC1 and the two vacuolar H+-pumps, SlAVP1 and SlVHA-A1, which in turn are revealed as potential targets of SlCBL10.

In an open study 28 patients were treated for complicated UTI with ciprofloxacin 250 mg every 12 h for 10 days. The most frequently isolated species were Escherichia coli and Klebsiella pneumoniae. All pathogens were sensitive to ciprofloxacin in vitro. Twenty-three of the 28 patients (82%) were free of infection 5-9 days after therapy. A persistent infection was noted in two patients (7%) and a reinfection in three patients (11%). Four to six weeks after the end of therapy, 18 patients (64%) were still totally free of infection. Clinical resolution of symptoms and signs occurred in 27 patients (96%). Adverse reactions were spontaneously reported by four of the 28 patients (14%) and by 11 (39%) after detailed inquiry. Most side effects were of gastrointestinal or neurological nature. This small open study supports the view, that ciprofloxacin may be useful in the treatment of complicated UTI.

Vegetable crops in general, and specifically tomato, are economically very important crops in Israel. In June 2014, 20% of plants from a tomato (Solanum lycopersicum) greenhouse in Northern Israel showed severe mosaic symptoms and fern-like leaf deformations that reduced production from infected plants. Two of these plants were sampled and mechanical inoculation was done on Nicotiana tabacum cv. White Burley causing local necrotic lesions. Two isolates, each from distinct lesions were deposited in the PLAVIT (Plant Virus of Italy) collection with accession numbers VE493 and VE494. Tomato plants mechanically infected with single local lesions from N. tabacum cv. White Burley from isolate VE493 showed strong leaf deformation and their growth was stunted compared to mock-inoculated tomato plants (Fig. 1). Observation of leaf dip extracts by electron microscopy (Brandes, 1) showed the presence of abundant viral particles with a rigid rod shape and calculated length of c. 300 nm, consistent with the presence of a possible tobamovirus. RNA was extracted and RT-PCR was done using generic tobamovirus primers Tob-Uni1 and Tob-Uni2 (Heinze et al., 6). The amplified 797 bp PCR product was cloned, and two clones for each sample were sequenced. Consensus sequences were deposited in GenBank with accession numbers KP861747 and KP861748 for VE493 and VE494, respectively. BLAST searches of the GenBank database resulted in an almost perfect match (99% identity at the nucleotide level) to strain MX5 of Tomato mottle mosaic virus (ToMMV), a recently described tobamovirus (Li et al., 3). DAS-ELISA using polyclonal antisera for Tomato mosaic virus (ToMV) and Tobacco mosaic virus (TMV) from the CNR collection (A128 and A25, respectively) detected the ToMMV isolates from Israel. A specific RT-PCR assay was also done using primers ToMMV-F (5'-AAAAGGGCGGTCTAATTTC-3') and ToMMV-Rev (5'-TAATTTCGTCCTTTATTAC-3') which were designed to bind to regions of the ToMMV genome which shared limited homology with ToMV, the closest virus species to ToMMV. A band of c. 600 bp was obtained from the ToMMV-infected samples but not from ToMV isolate IFA9 or TMV isolate Ta9 (PLAVIT collection) which were included in the assay. In late 2014, tobamovirus-positive seed extract samples from the same area in Northern Israel were detected by DAS-ELISA using the previously described antisera for ToMV and TMV. Leaf extracts were subsequently inoculated to N. tabacum cv. Xanthi NN, and lesions were tested by RT-PCR using the ToMMV-specific primers. Sequences of the amplified segments confirmed the presence of ToMMV. ToMMV is present in Mexico (Li et al., 6), USA (Webster et al., 6), China (Li et al., 6), Iran and Brazil. The report from Brazil is the first linked to a sequence in the GenBank database corresponding to ToMMV (Moreira et al., 5); the sequences from Iran corresponding to ToMMV were deposited in GenBank before the characterisation of the virus as a new tobamovirus species. To the best of our knowledge this is the first report of ToMMV in Israel. The authors would like to thank Riccardo Lenzi and Caterina Perrone for their excellent technical assistance.

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ABSTRACT Several antibiotics have been reported to lessen the ovarian suppression produced by oral contraceptive agents, as a result of drug interactions. The present investigation was designed to study the likelihood of the occurrence of any such interaction between the fluoroquinolone antibiotic ciprofloxacin (Ciproxin) at a dosage of 500 mg twice a day and the “low-dose” oral contraceptive Marvelon (30 μg of ethinyl estradiol [EE] plus 150 μg of desogestrel). Twenty-four healthy female volunteers were studied in a double-blind, placebo-controlled, randomized crossover trial. There were no significant differences between measurements of the area under the concentration-time curve of EE up to 24 h after oral contraceptive intake during placebo and ciprofloxacin administration on days 11 and 16 of the cycles, indicating the absence of pharmacokinetic interaction. Similarly, no clinically significant differences in the levels of sex hormone binding globulin were found between the placebo and ciprofloxacin cycles, indicating no major variation in EE levels during ciprofloxacin and placebo treatment. Ten subjects in each of the placebo and ciprofloxacin groups had early-follicular-phase levels of 17-β estradiol (<184 ng/liter) at one or more points during their cycles, but none had values above the early-follicular-phase range, indicating no significant ovarian activity. In addition, all subjects had progesterone levels of <2 ng/ml, indicating the absence of ovulation. Only two subjects, who received the placebo, had evidence of sustained follicular growth to a potentially ovulatory follicle (∼18 mm). We conclude that ciprofloxacin does not interfere with the ovarian suppression produced by the low-dose oral contraceptive Marvelon.

BACKGROUND: The engagement of companion animal owners into the process of collecting epidemiological data can be facilitated through smartphone applications. In April 2018, the "tekenscanner" (Dutch for tick scanner) app was launched with the aim of engaging pet owners and veterinarians to record ticks removed from their pets and submit these ticks for identification and pathogen testing. Tick-borne pathogens identified in ticks removed from dogs and cats during the first 6 months after the app was launched in the Netherlands are reported. METHODS: The tekenscanner app was used to record the geographical coordinates of ticks removed from dogs or cats onto a map of the Netherlands. A barcode was assigned to each tick for the easy tracking of each submission to our laboratory for taxonomic identification. Thereafter, DNA extracted from the ticks was PCR amplified, subjected to reverse line blot hybridization (RLB) and screened for a broad range of tick-borne pathogens. Results were added to the same app, usually within 2 weeks after the submission of each tick. RESULTS: The app was downloaded 5591 times and resulted in the collection of 1273 georeferenced and barcoded ticks, with a peak submission in May and June of 2018. There were 1005 ticks collected from 406 dogs and 268 ticks collected from 111 cats. Ixodes ricinus was the predominant species (90.0%), with all stages found on dogs as well as on cats. Ixodes hexagonus (7.3%) female and nymphal ticks were also identified on both hosts, whereas adults of Dermacentor reticulatus (2.4%) and Rhipicephalus sanguineus (0.2%) were exclusively found on dogs. Nearly 15% of the ticks recovered from dogs carried one or more pathogens, whereas 13.8% of the ticks removed from cats were infected. Ixodes ricinus collected from dogs contained Borrelia spp. (1.9%), Babesia spp. (0.7%), Anaplasma phagocytophilum (1.3%), "Candidatus Neoehrlichia mikurensis" (2.9%) and Rickettsia helvetica (7.3%). Ixodes ricinus recovered from cats were infected with Borrelia spp. (1.9%), Babesia spp. (0.4%), A. phagocytophilum (1.9%), "Ca. Neoehrlichia mikurensis" (2.6%) and R. helvetica (6.7%). Ixodes hexagonus ticks (n = 93) were not infected. Dermacentor reticulatus ticks, found only in autumn, were infected with Rickettsia raoultii (16 %) and A. phagocytophilum. Three R. sanguineus, on dogs from France and the USA imported into the Netherlands, were all negative. CONCLUSIONS: The tekenscanner app is a versatile tool to use for submission of ticks and facilitated the fast feedback of test results. Community engagement through the app is suitable for identifying hotspots for ticks and tick-borne pathogens and provided an early warning system for exotic ticks invading the Netherlands.

Spinach (Spinacia oleracea L.) is a highly nutritious leafy vegetable and an economically important food crop. The wild species S. turkestanica Iljin and S. tetrandra Steven ex M. Bieb. are inter-fertile with cultivated spinach and constitute important sources of novel characters to improve spinach varieties, such as for their resistance to pests and diseases. Despite their relevance in plant breeding, S. turkestanica and S. tetrandra are poorly represented in genetic resources collections. Among the reasons for these collection gaps are the difficulties in propagating these species ex situ. Here we report on the results of collecting expeditions for S. turkestanica in Central Asia and for S. tetrandra in the Trans-Caucasus, which were organized by the Dutch gene bank in collaboration with several breeding companies. Furthermore, we also present efficient protocols for the ex situ regeneration of these species. These protocols were used to successfully regenerate 66 S. turkestanica and 36 S. tetrandra samples from the collecting expeditions. These new accessions fill up important collection gaps in ex situ conserved genetic resources of spinach and can be used for exploitation in crop improvement.

Peripheral neuropathy (PN) is a recognized side effect of microtubule-targeting agents and the most clinically relevant toxicity observed with the epothilone sagopilone (SAG). Studies suggest that acetyl-L-carnitine (ALC) may prevent chemotherapy-induced PN. We conducted a prospective, placebo (PBO)-controlled, double-blind, randomized trial to investigate the safety and efficacy of ALC for the prevention of SAG-induced PN. Methods. Patients with ovarian cancer (OC) or castration-resistant prostate cancer (CRPC) and no evidence of neuropathy received SAG (16 mg/m(2) intravenously over 3 hours every 3 weeks) with ALC (1,000 mg every 3 days) or placebo (PBO). The primary endpoint was incidence of PN within six or fewer cycles in both treatment groups. Results. Overall, 150 patients enrolled (98 OC patients, 52 CRPC patients), with 75 per treatment arm. No significant difference in overall PN incidence was observed between treatment arms. The incidence of grade ≥3 PN was significantly lower in the ALC arm in OC patients. Median duration of neuropathy was similar between treatment arms. The best overall response (according to the modified Response Evaluation Criteria in Solid Tumors), response according to tumor markers, time-to-event variables, and discontinuations because of adverse events (AEs) were comparable between treatment arms. Conclusion. Administration of ALC with SAG did not result in a significant difference in overall PN incidence compared with a PBO. OC patients in the SAG/ALC arm had a significantly lower incidence of grade 3 or 4 PN compared with OC patients in the SAG/PBO arm.

Penetration activities of ciprofloxacin into female genital tract tissues were studied following a single oral administration of 500 mg and an intravenous injection of 100 mg. Serum and tissue concentrations were within the same order of magnitude 1 and 3 h after oral administration; 3 h after intake of ciprofloxacin, however, tissue concentrations exceeded the corresponding serum levels twofold. Similarly, tissue concentrations following intravenous injection exceeded the corresponding serum levels by 60-190% 0.5 h after injection and were consistently higher throughout the study period of 2 h. These data confirm that ciprofloxacin disposition is characterized by a remarkably pronounced diffusion into the extravascular space, generating tissue levels exceeding the minimal inhibitory concentrations of most pathogens severalfold.

BACKGROUND: Hepatitis C virus (HCV) genotyping and accurate subtyping is becoming increasingly relevant to epidemiological studies, clinical management, pathogenicity, and vaccine development. METHODS: The TRUGENE HCV 5'NC Genotyping Kit, the new VERSANT HCV Genotype 2.0 Assay (LiPA), and a new laboratory-developed HCV NS5b sequencing assay designed for automated sequencing of the HCV NS5b region were used. Clinical samples and a molecular diagnostics HCV genotyping proficiency program panel were used to determine accuracy and differentiate performance characteristics of the three methods. RESULTS: All amplified samples from among the members of a HCV genotyping proficiency program panel that contained a single HCV genotype were subtyped correctly using all three HCV genotyping assays. With the TRUGENE HCV 5'NC Genotyping Kit, the HCV subtype was determined in 357 of 441 of routine clinical samples. When the 84 samples with only genotype results were retested with the VERSANT HCV Genotype 2.0 Assay (LiPA), 61 could be further subtyped accurately. With the new laboratory-developed HCV NS5b sequencing assay, all 84 could be subtyped accurately. CONCLUSIONS: The two new methods show advantages over the routinely used TRUGENE HCV 5'NC Genotyping Kit in terms of genotyping and subtyping accuracy by utilizing part of the HCV core region and NS5b region, respectively.

Sorafenib (twice daily [bid]) plus capecitabine (2 weeks on schedule/1 week off schedule) safety and pharmacokinetics were investigated in patients with advanced solid tumors (N = 35). Cohort 1 (n = 13) included sorafenib 200 mg bid and capecitabine 1050 mg/m(2) bid; cohort 2 (n = 4), sorafenib 400 mg bid and capecitabine 1050 mg/m(2) bid; cohort 3 (n = 6), sorafenib 200 mg bid and capecitabine 1050 mg/m(2) bid (cycles 1 and 2), then 400 mg bid and capecitabine 1050 mg/m(2) bid (cycle 3 onwards); and cohort 4 (n = 12), sorafenib 400 mg bid and capecitabine 850 mg/m(2) bid. The combination of sorafenib and capecitabine was generally well tolerated. Most frequent drug-related adverse events were hand-foot skin reaction (HFSR, 89%), diarrhea (71%), and fatigue (69%). The HFSR was dose-limiting toxicities in 6 patients. Sorafenib exposure (C(max) and AUC(0-12)) was unaffected by concomitant capecitabine. Concomitant sorafenib moderately increased capecitabine and 5-fluorouracil (metabolite) exposure when the capecitabine dose was 1050 mg/m(2) bid. Simultaneous administration of 400 mg bid sorafenib and 850 mg/m(2) bid capecitabine, however, had only minor effects on the exposure to capecitabine and 5-fluorouracil. Based on the overall toxicity profile and pharmacokinetic parameters, the recommended phase 2 doses were therefore sorafenib 400 mg bid and capecitabine 850 mg/m(2) bid, as scheduled above.

PURPOSE: Telatinib is an orally active small-molecule tyrosine kinase inhibitor of kinase insert domain receptor (KDR; VEGFR-2) and fms-related tyrosine kinase 4 (FLT4; VEGFR-3). This study aims at the identification of relationships between single nucleotide polymorphisms (SNPs) in genes encoding for transporter proteins and pharmacokinetic parameters in order to clarify the significant interpatient variability in drug exposure. In addition, the potential relationship between target receptor polymorphisms and toxicity of telatinib is explored. METHODS: Blood samples from 33 patients enrolled in a phase I dose-escalation study of telatinib were analyzed. For correlation with dose normalized AUC(0-12), ATP-binding cassette (ABC) B1 (ABCB1), ABCC1, and ABCG2 were the genes selected. For correlation with telatinib toxicity, selected genes were the drug target genes KDR and FLT4. RESULTS: No association between dose normalized AUC(0-12) and drug transporter protein polymorphisms was observed. In addition, no association between toxicity and KDR or FLT4 genotype or haplotype was seen. CONCLUSIONS: Our pharmacogenetic analysis could not reveal a correlation between relevant gene polymorphisms and clinical and pharmacokinetic observations of telatinib.

BACKGROUND: Until recently, standard treatment of venous thromboembolism (VTE) concerned a combination of short-term low-molecular-weight heparin (LMWH) and long-term vitamin-K antagonist (VKA). Risk of bleeding and the requirement for regular anticoagulation monitoring are, however, limiting their use. Rivaroxaban is a novel oral anticoagulant associated with a significantly lower risk of major bleeds (hazard ratio = 0.54, 95% confidence interval = 0.37-0.79) compared to LMWH/VKA therapy, and does not require regular anticoagulation monitoring. AIMS: To evaluate the health economic consequences of treating acute VTE patients with rivaroxaban compared to treatment with LMWH/VKA, viewed from the Dutch societal perspective. METHODS: A life-time Markov model was populated with the findings of the EINSTEIN phase III clinical trial to analyze cost-effectiveness of rivaroxaban therapy in treatment and prevention of VTE from a Dutch societal perspective. Primary model outcomes were total and incremental quality-adjusted life years (QALYs), as well as life expectancy and costs. RESULTS: Over a patient's lifetime, rivaroxaban was shown to be dominant, with health gains of 0.047 QALYs and cost savings of €304 compared to LMWH/VKA therapy. Dominance was robustly present in all sensitivity analyses. Major drivers of the differences between the two treatment arms were related to anticoagulation monitoring (medical costs, travel costs, and loss of productivity) and the occurrence of major bleeds. CONCLUSION: Rivaroxaban treatment of patients with venous thromboembolism results in health gains and cost savings compared to LMWH/VKA therapy. This conclusion holds for the Dutch setting, both for the societal perspective, as well as the healthcare perspective.

The article contains sections titled: 1. Introduction 2. Information Structures in Process Control Engineering 2.1. Principles 2.2. Architectural Principles for Information Structuring 2.3. Applications in Process Control Engineering 3. Knowledge about the Process 3.1. Principles 3.2. Analysis Methods for Process Quantities 3.3. Process Models 3.4. Modeling 3.5. Management and Utilization of Information 4. From Process Knowledge to Process Control 4.1. Principles 4.2. Feedback Control 4.3. Optimal Control 4.4. Binary Control 4.5. Operational Control of Process Plants 5. The Process Control System and Its Elements: Process Sensor Systems 5.1. Principles 5.2. Process Sensor System Technology 5.3. Sensor Systems for Special Applications 5.4. The Market for Sensors and Sensor Systems 5.5. Field Installation and Cable Routing 6. The Process Control System and Its Elements: Process Actuator Systems 6.1. Principles 6.2. Actuator Systems for Material and Energy Streams 6.3. Electrical Drives in the Chemical Industry 6.4. Electric Power Supply Systems 7. The Process Control System and Its Elements: Distributed Control Systems 7.1. Principles 7.2. System and Component Structure 7.3. Process Control Operating System 7.4. General System Services 7.5. Design and Commissioning 8. The Process Control System and Its Elements: Information Logistics 8.1. Principles 8.2. Functional Structures and Information Flow in Production Companies 8.3. Computer Communications Between and Within Control Levels 8.4. Computer Communications in Industrial Production; Standards 8.5. MAP/TOP: Protocol Standards for Information Integration in Production Companies 8.6. Field Bus Systems 8.7. Quality Assurance: Conformance and Interoperability Tests 8.8. Methods and Tools for Protocol Specification 8.9. Steps toward Computer-Integrated Production 9. Computer-Aided Methods 9.1. Principles 9.2. System Analysis 9.3. CAE System for Process Control Engineering 9.4. Structure of a CAE System 9.5. Aids for Hardware Design 9.6. Aids for Software Design 9.7. Outlook 10. Design and Construction of Process Control Systems 10.1. Principles 10.2. Organizational Requirements 10.3. Decision Phase 10.4. Specifications 10.5. Execution Phase 10.6. Quality Assurance 10.7. Process Control Rooms 11. Operation 11.1. Principles 11.2. Human - Process Communications 11.3. Process Analysis and Process Optimization 11.4. Maintenance Strategies 12. Standards, Committees, and Associations 12.1. Principles 12.2. Standardization Bodies and Other Organizations Involved in Standardization 12.3. Technical and Scientific Bodies 12.4. Shows and Fairs 13. Integration of Knowledge-Based Systems in Process Control Engineering 13.1. Principles 13.2. Knowledge-Based Approach 13.3. Knowledge Engineering 14. Appendix 14.1. Glossary 14.2. Abbreviations

Seventeen women who met the criteria for bulimia nervosa (DSM-III-R) were treated for 4 weeks in an open trial with ipsapirone, a partial 5-HT1A agonist. Bulimic symptoms diminished in 66.6% of the patients after only 1 week of treatment, 93.3% showed a reduction of more than 50% of weekly binge eating attacks after 4 weeks. The mean frequency of binges was reduced by 81% at endpoint. Ipsapirone was well tolerated.