Journal articles on the topic 'Alcor Life Extension Foundation'

As special equipment, long-distance pipeline is widely used in petroleum, chemistry and other fields. However, with the extension of its running time, some problems have arisen with parts of the pipeline. The detection and repair technology is the foundation for assurance of the safe operation of pipelines; therefore, in order to avoid or reduce pipeline accidents as well as to protect people's lives and property safety, periodic detection and designed reasonable repair of the pipeline has naturally become an important part of pipeline industry today. Several commonly used inspection techniques of pipeline were introduced in this paper and related repair measures were described in view of problems emerging during the service life of long-distance pipeline in the practical engineering.

AbstractFor the Kasena, life finds in death both its measure and its renewal. Indeed, the dead survive through their descendants and in the world of ancestors. Funeral practices are very elaborate. They not only reflect the social, cultural, religious and psychological values and preoccupations shared by the group but are also a way of elaborating upon them. Social and cultural life is re-invigorated through a person's death and funerals, while the dead person is himself the foundation of his descendants' life.This article, drawing from fieldwork in the author's native area, focuses, in particular, on first funerals for adults. Detailed description is followed by the analysis of surprising similarities between birth and funeral rites. It then examines the ‘house’ or the ‘bedroom’ built in the ground – either in the maternal bedroom itself, or in a neighbouring field towards the east – in order to welcome death as an extension, as a founder in the depths of the survivors' dwelling.

Building information modelling (BIM) is increasingly appropriate for infrastructure projects, and in particular for transport infrastructure. It is a digital solution that integrates the practices of the construction industry in facility management during the whole life cycle. This integration is possible through a single tool, which is the 3D digital model. Nevertheless, BIM standards, such as industry foundation classes, are still in the pipeline for infrastructure management. These standards do not fully meet the requirements of operation and maintenance of transport infrastructure. This paper shows how BIM could be implemented to address issues related to the operation and maintenance phase for transport infrastructure management. For this purpose, a new ontological approach, called Industry Foundation Classes for Operation and Maintenance of Infrastructures (IFCInfra4OM), is detailed. This ontology aims to standardise the use of building information modelling for operation and maintenance in road infrastructures. To highlight the interest of the proposed ontological approach, a building information model of a section on the A7 Agadir–Marrakech Highway in Morocco is produced according to IFCInfra4OM. The methodology is presented. The results obtained, including the IFCInfra4OM data model, are submitted. In the last section, an overview of the IFC extension approach is submitted.

The aim of this study is to demonstrate the influence of the stress parallel to the crack plane on subcritical crack growth in brittle materials by using a numerical code MFPA2D. The mechanism of this influence is also discussed. The curves of subcritical crack extension vs. strain of brittle materials under uniaxial and biaxial stress were obtained through numerical tests with acoustic emission consideration. The results showed that the tensile stress parallel to the crack plane has the effect on crack arrest, while the compressive stress parallel to the crack plane plays important role in crack opening process. The numerical results were consistent with experimental observed result, which shows the reliability of the numerical method, and provides theoretic foundation for failure analysis and life estimation of brittle materials.

Abstract It has become clear that nutrient regulatory pathways are the major determinants of lifespan. From early studies on caloric restriction to genetic ablation studies in yeast, worms, flies, and more recently mice, a unifying theme has emerged that suppressing nutrient sensing pathways and neuroendocrine networks results in lifespan extension. This work has laid the foundation for interventions designed to ameliorate late-life dysfunction. Inhibition of the mechanistic target of rapamycin (mTOR) pathway using rapamycin, an FDA-approved drug used clinically to inhibit solid organ rejection, is one of the most promising of these interventions. It has been demonstrated that rapamycin enhances longevity in mice, even when initiated in relatively old animals. We will discuss the development of anti-aging therapies, the potential for emerging therapies, and pitfalls associated with clinical trials designed to test these therapies.

Life cycle assessment (LCA) methodology has been used to evaluate the performance of the following lighting systems: compact fluorescent lamps (CFL), light-emitting diode (LED) lamps, and fluorescent tubes (T5 type). This work covers the singularity of the French electricity mix for indoor workplaces lighting and describes the best strategy for lamp replacement. We have defined the light loss factor to integrate the following additional parameters: lumen depreciation, dirt accumulation, and risks of failure. Therefore, we propose a new definition of the functional unit (maintained megalumen hour), and we conduct this assessment to be compliant with the standards of lighting system equipment (NF EN 12464-1). Unlike previous studies, we observed that the manufacturing phase is the most impacting over the whole life cycle, thus making the extension of LED lamps’ lifetime a more effective strategy to reduce the potential environmental impacts than increasing their efficacy. This paper highlights how the light loss factor affects the LCA results and proves that it should be taken into account for subsequent assessments. Finally, this new approach includes the real usage of the lamps in the study and contributes to lay the foundation for life cycle sustainability assessment to also evaluate the economic, social, and human impacts of lighting.

This study focuses on a safety evaluation method for underground gas storage. Gas storage is usually constructed underground in complex environments, and the service life of such facilities is limited. To ensure the secure and long-term operation of gas storage facilities, safety evaluation has become the focus of management. The present paper provides an effective method for safety evaluation. An index system was established as the foundation of the analysis for this evaluation, and the matter-element extension method was applied to obtain a quantitative evaluation result. For the weight values of each index in the matter-element extension method, this paper presents a comprehensive weight computation method based on vague sets and entropy. By application of this method, the safety level of a gas storage facility in the Jintan salt mines (in Jiangsu, China) was calculated, and the evaluation result was 4.6433, which meant the safety level was V and the underground gas storage was slightly at risk. It indicated that the influence on the overall safety and tightness of this gas storage could be ignored in the operation process, but the frequency of regular monitoring should be increased. The defective indexes were also obtained, such as salt rock cohesion, the roof thickness, the volume contraction ratio, the interlayer content, the height of the casing shoe and the adjacent cavity pressure difference, which need to be monitored and modified. This paper evaluated the safety of the underground gas storage from a unique perspective. It is expected that the results of this research will contribute to the maintenance and operational decisions, and provide a reference for management in the energy industry.

The story of the rural Chinese family household in the post-Mao period is generally told in one of three ways, which might be labelled modernization, tradition restored, and demographic determinism. Modernization parallels the family theories of classical sociology: economic development and education tend to undermine extended family living arrangements by instilling nuclear family preferences, while the relaxation of migration restrictions allows young men to seek their fortune away from home. “Tradition restored” sees collectivization as having undermined the foundation of the extended family household, the family economy. The return of family farming has, in this view, restored the conditions under which the extended family can flourish. The demographic determinisi view assumes that family preferences persist but that demographic structures change. Rising life expectancies and declining fertility should increase rates of family extension, since smaller families mean that there will be fewer brothers available to live with a surviving parent. Thus as the birth control cohorts come of age, the prevalence of extended households should increase.

This study was carried out with the objective of describing the evolution and importance of andragogical processes in the search of rural profiles committed to the university work in the development and implementation of programs and projects. Among its main contributions, the importance of knowing and teaching processes applied strictly for adults by university coordinators of programs and projects stands out. The relevance of applying this kind of knowledge will allow efficient use of institutional financial resources, particularly for the real commitment of the rural adult community towards the implementation of field activities and accomplishing, in a shorter term, the expected academic achievement. A successful project experience is described in which some andragogical strategies were applied through extension, and which produced a better participation and engagement from rural people with the projects developed by the University. Consequently, applicability of these concepts in the programs and projects of rural development promoted through universities must lay the foundation for regional rural development strategies with the ultimate goal of finding ways to improve the quality of life of people in particular scenarios.

Background: BAY 94‐9027 is a B-domain deleted recombinant factor VIII (FVIII) that is site-specifically PEGylated with a 60 kDa (2×30 kDa) polyethylene glycol to extend its half-life. Efficacy and safety of BAY 94-9027 as prophylactic (PPX) and on-demand (OD) therapy for patients with severe hemophilia A (HemA) were demonstrated in the phase II/III PROTECT VIII trial (NCT01580293) and its Extension. BAY 94-9027 has been approved in the US, EU, Japan and Canada for previously treated patients ≥12 years old. Extended dosing (e.g. once-weekly PPX) is an attractive therapeutic approach for patients previously treated OD. This post hoc analysis was conducted to confirm the anticipated bleeding and quality of life (QoL) outcomes among patients who were previously treated with OD FVIII and switched to BAY 94-9027 PPX in PROTECT VIII. Patients/Methods: PROTECT VIII was a partially randomized, open-label trial of 134 males aged 12-65 years with HemA (FVIII <1%) and ≥150 FVIII exposure days. At enrolment, prior OD patients could select PPX or continue OD therapy. PPX patients received BAY 94-9027 25 IU/kg twice weekly (2×W) for a 10-week run-in period. Patients with ≤1 spontaneous joint or muscle bleeds during this period were randomized to 45‒60 IU/kg every 5 days (E5D) or 60 IU/kg every 7 days (E7D) for the main 26-week study period. Patients enrolling after the randomization arms were full, or with ≥2 bleeds in the run-in period, received 30-40 IU/kg 2×W. Patients completing the main study could enter an extension and continue, or switch regimens. Patients switching after Extension start were evaluated as a 'variable' group (VAR). The primary efficacy outcome was annualized bleeding rate (ABR). QoL was assessed using the hemophilia-specific health-related quality of life questionnaire for adults (Hemo-QoL-A) and the Work Productivity and Activity Impairment (WPAI) questionnaire. All analyses were descriptive and reported outcomes by pre-study treatment regimen. Results: Of 43 patients on prior OD therapy, 20 selected OD BAY 94-9027 [OD→OD] and 23 selected PPX BAY 94-9027 [OD→PPX] in the main PROTECT study. Of 39 patients on prior OD therapy who continued into the Extension, 14 continued OD, and 25 switched to PPX [OD→PPX], including 3 patients who switched from OD at the Extension start. A total of 89 patients on prior PPX therapy received PPX during the main study [PPX→PPX] and 82 continued to receive PPX during the Extension. At data cut-off (Feb 2017), median time in the study was 3.9 years (3.2 years in the Extension). See Table for baseline characteristics. At the end of the main study, median ABR was 23.4, 2.1, and 2.1 in the OD→OD, OD→PPX and PPX→PPX groups, respectively. During the Extension, median ABR was 33.5, 1.3 and 1.6 in the OD→OD, OD→PPX and PPX→PPX groups, respectively. Robust improvements in median ABR were observed for patients previously on OD treatment in both the main study and Extension, irrespective of which PPX regimen they received (Figure). Hemo-QoL-A total score was maintained or improved from baseline during the main study all PPX regimens with greater benefit among OD→PPX (median change from baseline: 2.5 for all PPX and 4.3 for OD→PPX), and greatest improvement in OD→E7D PPX (median change from baseline: 13.8; almost twice the minimal clinically important difference [7-8]). OD patients prior to study entry also saw higher benefit in WPAI activity and work impairment sub-scores compared with prior PPX patients (mean changes from baseline: -15.9 vs -4.9 and -16.4 vs -1.7, respectively). As of August 2018, E7D PPX had a similar number of infusions per year to OD treatment (52 vs 47) and double median consumption (3048 vs 1394 IU/kg/year for E7D and OD, respectively). Conclusions: Despite entering PROTECT VIII with higher ABR than PPX→PPX patients, OD→PPX patients experienced a major decrease in ABR with BAY 94-9027 treatment during the first 6 months, achieving a similar rate to that observed in patients who received PPX before the trial. OD→PPX patients experienced larger improvements in QoL and WPAI sub-scores from baseline compared with PPX→PPX patients. Prior OD patients who switched to BAY 94‐9027 E7D had the greatest improvement in QoL. Further, the number of infusions/year was only slightly higher with E7D dosing than with OD treatment, and the difference in median consumption between PPX and OD was smaller than seen in previous studies. Disclosures Ducore: BioMarin: Research Funding; HEMA Biologics: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Octapharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Research Funding; Spark Therapeutics: Research Funding; Bayer: Consultancy, Honoraria, Other: speaker (not bureau). Lalezari:Bayer: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Teva: Consultancy, Honoraria; Bayer: Speakers Bureau; Pfizer: Speakers Bureau. Santagostino:CSL Behring: Speakers Bureau; Bayer: Speakers Bureau; Grifols: Speakers Bureau; Bioverativ Sanofi: Speakers Bureau; Kedrion: Speakers Bureau; Novo Nordisk: Speakers Bureau; Octapharma: Speakers Bureau; Pfizer: Speakers Bureau; Shire/Takeda: Speakers Bureau; Sobi: Speakers Bureau; UniQure: Speakers Bureau; Roche: Speakers Bureau; Spark: Speakers Bureau. Ahuja:XaTexk Inc.: Consultancy, Patents & Royalties, Research Funding; Rainbow Children's Foundation: Research Funding; Genentech: Consultancy; Biovertiv Sanofi: Consultancy; Bayer: Consultancy. Maas Enriquez:Bayer AG: Employment. Tueckmantel:Bayer: Employment. Reding:Takeda: Consultancy, Honoraria, Speakers Bureau; Biomarin: Research Funding; Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Speakers Bureau.

The Univ. of Florida's College of Agricultural and Life Sciences and Institute of Food and Agricultural Sciences have taken a bold step in teaching crop health management with the creation of the Plant Medicine Program. This innovative program offers students a multidisciplinary approach to solving the challenges of crop production that leads to the Doctor of Plant Medicine (DPM) degree. Extensive coursework in the Plant and Soil Sciences, Entomology, Plant Pathology, and Nematology provides students with the fundamental knowledge needed to be successful problem solvers and decision makers. Students apply their expertise to practical situations during multiple internships with a wide array of professionals. Interns have worked nationally and internationally on a wide variety of crops with private corporations, public institutions, and government and non-government agencies, in research, regulatory, and extension capacities. Students have the opportunity to tailor their program to reflect specific interests while maintaining a strong foundation in the discipline of Plant Medicine through the core courses. Since its inception in 1999, enrollment in the Plant Medicine Program has grown to over 40 students, and beginning in 2003, graduates have become valued members of the global agricultural community.

This paper presents distance measure between two complex Atanassov's intuitionistic fuzzy sets (CAIFSs). This distance measure is used to illustrate an application of CAIFSs in solving one of the most core application areas of fuzzy set theory, which is multiattributes decision-making (MADM) problems, in complex Atanassov's intuitionistic fuzzy realm. A new structure of relation between two CAIFSs, called complex Atanassov's intuitionistic fuzzy relation (CAIFR), is obtained. This relation is formally generalised from a conventional Atanassov's intuitionistic fuzzy relation, based on complex Atanassov's intuitionistic fuzzy sets, in which the ranges of values of CAIFR are extended to the unit circle in complex plane for both membership and nonmembership functions instead of [0, 1] as in the conventional Atanassov's intuitionistic fuzzy functions. Definition and some mathematical concepts of CAIFS, which serve as a foundation for the creation of complex Atanassov's intuitionistic fuzzy relation, are recalled. We also introduce the Cartesian product of CAIFSs and derive two properties of the product space. The concept of projection and cylindric extension of CAIFRs are also introduced. An example of CAIFR in real-life situation is illustrated in this paper. Finally, we introduce the concept of composition of CAIFRs.

Abstract The development of artificial intelligence, e. g. for Computer Vision, through supervised learning requires the input of large amounts of annotated or labeled data objects as training data. Usually, the creation of high-quality training data is done manually which can be repetitive and tiring. Gamification, the use of game elements in a non-game context, is one method to make such tedious tasks more interesting. We propose a multi-step process for gamifying the manual creation of training data for machine learning purposes. In this article, we give an overview of related concepts and existing implementations and present a user-centered approach for a real-life use case. Based on a survey within the target user group we identified annotation use cases and dominant player characteristics. The results served as a foundation for designing the gamification concepts which were then discussed with the participants. The final concept includes levels of increasing difficulty, tutorials, progress indicators and a narrative built around a robot character which at the same time is a user assistant. The implemented prototype is an extension of an existing annotation tool at an AI product company and serves as a basis for further observations.

Purpose The purpose of this paper is to review and provide recommendations to extend the current open standard data models for describing monitoring systems and circular economy precepts for built assets. Open standard data models enable robust and efficient data exchange which underpins the successful implementation of a circular economy. One of the largest opportunities to reduce the total life cycle cost of a built asset is to use the building information modelling (BIM) approach during the operational phase because it represents the largest share of the entire cost. BIM models that represent the actual conditions and performance of the constructed assets can boost the benefits of the installed monitoring systems and reduce maintenance and operational costs. Design/methodology/approach This paper presents a horizontal investigation of current BIM data models and their use for describing circular economy principles and performance monitoring of built assets. Based on the investigation, an extension to the industry foundation classes (IFC) specification, recommendations and guidelines are presented which enable to describe circular economy principles and asset monitoring using IFC. Findings Current open BIM data models are not sufficiently mature yet. This limits the interoperability of the BIM approach and the implementation of circular economy principles. An overarching approach to extend the current standards is necessary, which considers aspects related to not only modelling the monitoring system but also data management and analysis. Originality/value To the authors’ best knowledge, this is the first study that identifies requirements for data model standards in the context current linear economic model of making, using and disposing is growing unsustainably far beyond the finite limits of planet of a circular economy. The results of this study set the basis for the extension of current standards required to apply the circular economy precepts.

The developmental paradigm in the software engineering industry has transformed from a programming-oriented approach to model-oriented development. At present, model-based development is becoming an emerging method for enterprises for constructing software systems and services most proficiently. In Capability Maturity Model Integration (CMMI) Level 2, i.e., Managed, we need to sustain the bi-directional trace of the transformed models for the administration of user requirements and demands. This goal is achieved by the organization after applying the particular practices suggested by CMMI level 2 process area of Requirements Management (RM). It is very challenging for software developers and testers to maintain trace, particularly during the evaluation and upgrading phases of development. In our previous research work, we proposed a traceability framework for model-based development of applications for software enterprises. This work is the extension of our previously presented research work in which we have anticipated the meta-model transformations according to the Software Development Life Cycle (SDLC). These meta-models are capable of maintaining the trace information through relations. The proposed technique is also verified using a generalized illustration of an application. This transformation practice will give a foundation to software designers to maintain traceability links in model-driven development

The global burden of children and young people (CYP) with bronchiectasis is being recognised increasingly. They experience a poor quality of life and recurrent respiratory exacerbations requiring additional treatment, including hospitalisation. However, there are no published data on patient-driven clinical needs and/or research priorities for paediatric bronchiectasis.Parent/patient-driven views are required to understand the clinical needs and research priorities to inform changes that benefit CYP with bronchiectasis and reduce their disease burden. The European Lung Foundation and the European Respiratory Society Task Force for paediatric bronchiectasis created an international roadmap of clinical and research priorities to guide, and as an extension of, the clinical practice guideline.This roadmap was based on two global web-based surveys. The first survey (10 languages) was completed by 225 respondents (parents of CYP with bronchiectasis and adults with bronchiectasis diagnosed in childhood) from 21 countries. The parent/patient survey encompassed both clinical and research priorities. The second survey, completed by 258 health practitioners from 54 countries, was limited to research priorities.The two highest clinical needs expressed by parents/patients were: having an action management plan for flare-ups/exacerbations and access to physiotherapists. The two highest health practitioners’ research priorities related to eradication of airway pathogens and optimal airway clearance techniques. Based on both surveys, the top 10 research priorities were derived, and unanimous consensus statements were formulated from these priorities.This document addresses parents'/patients' clinical and research priorities from both the parents'/patients' and clinicians' perspectives and will help guide research and clinical efforts to improve the lives of people with bronchiectasis.

The article discusses some features of planning solutions of apartments in the architecture of Yerevan, which are typical to different periods, since the turn of 19-20th centuries to the present day. Housing is the chief determinant of human activity. In the process of societal development the house is the foundation of a family, and the family, on its turn, is the key to the stable state. Nevertheless, the time influences the residential architecture. Societal progress periodically affects the living environment. Therefore, housing formation process never reaches the stage of completion: it is always in an endless process of development. The above mentioned primarily concerns the evolution of the planning structure of the apartment. In this context, the dynamics of evolution of housing in Yerevan has accelerated in the second half of the 19th century. The centuries-generated space-planning system of apartment begins to develop in accordance with the rapid changes of social, urban planning and life processes of the time (extension of industry, formation of new socio-economic relations, rapid growth of population, acceleration of construction processes). The impetuous transformation of the dwelling structure is reflected in the complex process of evolution - starting from the traditional houses and ending with the apartments in high-rise buildings. The research of the problems of the traditional dwelling structure, its transformation in the first apartment buildings and diverse improvements of apartment planning solutions contributes to the definition of the main development stages of the dwelling units during the last century, which are observed in the article. Identification of the characteristics of each stage and the multilateral evaluation of different qualities of spatial-planning arrangement of apartments allow working out proper solutions for dwelling units in the future.

Human beings impose subjective, time-related interpretations on their existence, and the experience of time is a major aspect of lifespan development. In this mini-review, we understand subjective time as the way individuals subjectively perceive and evaluate the passing of their personal “objective” lifetime. A broad range of constructs and operationalizations has been developed in (gero-) psychology to capture subjective time, including future time perspective, personal goals, or autobiographical memories. In order to theoretically integrate this yet loosely connected body of literature, we propose a conceptual model of subjective time concepts according to 2 dimensions: temporal direction (past, present, future) and thematic field (duration/expansion, time-ordered life content, and time-related evaluations, attitudes, and mindsets). This conceptual model of subjective time perceptions builds the foundation for a review of the empirical literature regarding associations of subjective time with developmental outcomes (i.e., subjective well-being and physical health) in middle and late adulthood. Empirical findings establish subjective time concepts as a consistent predictor of well-being and health. Positive subjective time perceptions (i.e., an expanded view of the future, a focus on positive past and future life content, and favorable time-related evaluations) were associated with higher well-being and better physical health, while negative subjective time perceptions in general were linked to lower levels of health and well-being. Contrasting past- and future-oriented subjective time perceptions, it appears that past-oriented subjective time perceptions have been studied primarily in relation to subjective well-being, while future-oriented time perceptions play a key role both with regard to physical health and well-being. In conclusion, we argue that a stronger integration of subjective time constructs into developmental regulation models may deepen our understanding of human development across the lifespan. To this end, we call for theoretical and empirical interlinkages between yet loosely connected conceptual developments related to subjective time. These endeavors should be paralleled by an extension of methodological procedures (e.g., implementation of longitudinal research designs as well as a focus on the oldest-old) in order to inform a “lifespan theory of subjective time.”

Background:Studies have reported the association between overweight or obesity and ankylosing spondylitis (AS), but their relation is still unclear in China.Objectives:To explore the prevalence of overweight or obesity and its effect on other indicators and their relationships in Chinese AS patients.Methods:Demographic and clinical variables were collected from 207 AS patients. Patients were categorized to normal BMI group (BMI < 23kg/m2) and overweight group (BMI ≥ 23kg/m2). We used Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Metrology Index (BASMI), Health Assessment Questionnaire (HAQ), Ankylosing Spondylitis Quality of Life (ASQoL) and Medical Outcomes Study Short Form 36 (SF-36) to evaluate disease activity, physical function, spinal mobility, functional limitation and health-related quality of life, respectively. Statistical analysis used independent t test, Mann-Whitney U test, Chi-square test and Spearman’s rank correlation test.Results:56.5% (117) AS patients were overweight or obese, among which 80.3% (94) were male. In the overweight group, patients were older, more being married, and have higher BMI, higher waist circumference, higher waist-to-hip ratio, longer disease duration, higher BASMI score, higher white blood cell count (WBC), higher lymphocyte and higher platelet count compared to the non-overweight group (P≤ 0.038). However, there was no distinct difference in BASDAI score between the two groups (P= 0.891). In the correlation analyses, gender and marital status (P≤ 0.036) were correlated negatively with BMI; while age, waist circumference, waist-to-hip ratio, WBC, lymphocyte count and red blood cell (P≤ 0.036) were correlated positively with BMI.Conclusion:Overweight or obesity is common in Chinese AS patients. Increased BMI affects not disease activity but spinal mobility, which indicates that patients with high BMI are more likely to have limitations in flexion, extension, lateral bending and torsion of spine.References:[1]Bowness P. Hla-B27. Annu Rev Immunol. 2015;33:29-48.[2]de Araújo TA, Mota MC, Crispim CA. Obesity and sleepiness in women with fibromyalgia. Rheumatology International. 2014;35(2):281-7.Acknowledgments:This study was funded by Science and technology Project of Nantong City (Grant/Award Number: MSZ18217), Postgraduate Research & Practice Innovation Program of Jiangsu Province (Grant/Award number: KYCX19_2071 and KYCX18_2410), National Natural Science Foundation of China (Grant/Award number: 81671616 and 81871278), Science and technology Project of Jiangsu Province (Grant/Award number: BE2018671) and Clinical Research Center of Stem Cells, Affiliated Hospital of Nantong University, Nantong (Grant/Award number: HS2018001).Disclosure of Interests:None declared

Introduction BAY 94-9027 (damoctocog alfa pegol) is an extended-half-life PEGylated recombinant factor VIII approved for use in patients with hemophilia A aged ≥12 years (USPI; https://www.fda.gov/). Due to age-related pharmacokinetic and other differences to adult patients, there is a need to assess FVIII replacement products in pediatric populations (Shah et al, Haemophilia 2018, 24(5):733-40). In the PROTECT VIII Kids main study (NCT01775618), BAY 94-9027 was efficacious for the prevention and treatment of bleeds in previously treated patients (PTPs) aged <12 years with severe hemophilia A. We report long-term efficacy and safety data from the PROTECT VIII Kids extension in patients aged <6 and 6 to <12 years at study entry. Methods In PROTECT VIII Kids, male PTPs aged <12 years with severe hemophilia A were enrolled in two age cohorts: <6 and 6 to <12 years. Patients received BAY 94-9027 prophylaxis twice weekly (25-60 IU/kg), every 5 days (E5D, 45-60 IU/kg), or every 7 days (E7D, 60 IU/kg) at the investigator's discretion. Patients completing ≥50 exposure days and ≥6 months in the main study, or a 12-week safety expansion study that enrolled additional PTPs aged <6 years, could continue in the optional extension phase. Patients recorded bleeds and BAY 94-9027 usage in an electronic diary and were followed for safety assessments every 6 months. Analyses were based on age group at enrollment (<6 or 6 to <12 years). The study complied with the principles found in the Declaration of Helsinki. Results Of the 73 PTPs enrolled in the main or expansion study, 59 continued in the extension phase (n=32 aged <6 years; n=27 aged 6 to <12 years). Median age at enrollment was 5.0 years and median age at the end of the extension was 12.0 years. Median time in the extension study was 4.7 years in patients aged <6 years and 5.5 years in those aged 6 to <12 years; median exposure was 354.5 and 424.0 days, respectively (Table 1). Fifty-two patients completed ≥3 years of treatment and 39 patients completed ≥5 years. At the end of the extension, 29 patients were treated twice weekly, 20 patients were treated E5D and 10 patients were treated E7D. The median number of infusions per year was 78. Median annualized bleeding rate (ABR) for total bleeds was 1.54 for all patients aged <6 years and 1.89 for those aged 6 to <12 years. Total ABR improved compared to the main study and was maintained during the extension. In the last 12 months of treatment, median spontaneous ABR was 0.0 in both age groups, however, trauma ABR was higher in patients aged <6 years (Figure 1). In the last 12 months, 19 patients (33.3%) had zero bleeds and 27 patients (47.4%) had zero joint bleeds. Overall, joint bleeds comprised 49.2% and 46.5% of total bleeds in younger and older patients, respectively, and predominantly affected ankle, knee and elbow joints. The majority of bleeds were mild (<6 years, 52.9%; 6 to <12 years, 30.8%) or moderate (<6 years, 39.3%; 6 to <12 years, aged <6; 55.5%) in severity. During the extension, 4 patients (6.8%) experienced study-drug-related adverse events (AEs): 1 patient (<6 years) had suspected FVIII inhibitors; 1 patient (<6 years) had severe muscle spasms; 1 patient (6 to <12 years) had suspected FVIII inhibitors; and 1 patient (6 to <12 years) had both suspected FVIII inhibitors and mild arthralgia. Two patients in the older group reported study-drug-related serious AEs (SAEs) of suspected FVIII inhibitors, neither of which was confirmed. Two patients aged <6 years discontinued, one due to an AE and one due to a non-study-drug-related SAE. No safety signals related to hypersensitivity or loss-of-efficacy were detected. A total of 11 patients (18.6%) had detectable PEG in plasma during the extension (n=6 aged <6 years; n=5 aged 6 to <12 years). PEG was detected at only a single time point in 6 patients and at repeated time points in 5 patients; in all cases, PEG levels were just above the detection limit (0.1 mg/L) and did not change over time, indicating steady-state was reached. Levels of renal biomarkers (Albumin, Beta-2 Microglobulin, Cystatin C, Kidney Injury Molecule-1, Lipocalin-2, proteinuria) were consistent over time, demonstrating normal renal function. Conclusion In both younger and older pediatric patients with severe hemophilia A, long-term treatment (median 5.8 years) with BAY 94-9027 prophylaxis was efficacious and well-tolerated. Financial support: Study funded by Bayer. Disclosures Ahuja: Genentech: Consultancy; Sanofi-Genzyme: Consultancy; XaTec Inc.: Consultancy; Sanofi-Genzyme: Honoraria; Genentech: Honoraria; XaTec Inc.: Research Funding; XaTec Inc.: Divested equity in a private or publicly-traded company in the past 24 months. Fischer:Bayer, Baxter/Shire, SOBI/Biogen, CSL Behring, Octapharma, Pfizer, NovoNordisk: Research Funding; Bayer, Biogen, Pfizer, Baxter/Shire, and Novo Nordisk: Research Funding; Bayer, Baxter, Biogen, CSL Behring, Freeline, Novo Nordisk, Pfizer, Roche, and Sobi: Consultancy. Biss:Bayer, Boehringer Ingelheim: Honoraria. Maas Enriquez:Bayer: Current Employment. Mancuso:Bayer, CSL Behring, Novo Nordisk, Roche, Sobi, Octapharma, Kedrion, Pfizer, Shire/Takeda, Biomarin, Grifols: Speakers Bureau; Bayer, CSL Behring, Novo Nordisk, Roche, Sobi, Octapharma, Kedrion, Shire/Takeda, Biomarin, Grifols, Catalyst: Honoraria; Bayer, CSL Behring, Novo Nordisk, Roche, Sobi, Octapharma, Kedrion, Pfizer, Shire/Takeda, PedNet Foundation: Consultancy. Wang:Bayer: Current Employment. Kenet:Bayer, Pfizer, Takeda, BioMarin, Novo Nordisk: Speakers Bureau; PI Healthcare, CSL Behring: Honoraria; Bayer, Pfizer, Roche, Alnylam (Sanofi), Shire: Research Funding; Bayer, Pfizer, BioMarin, Takeda, Roche, Novo Nordisk, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: BAY 94-9027 (damoctocog alfa pegol), current indication for patients with hemophilia A aged >12 years. We report efficacy and safety data in patients aged <12 years.

Abstract The long history of exploration and mining of mineral resources on Earth provides the foundation for the extension of the human footprint to space. Resources in space share some features with the better-known resources on Earth but also present some unique challenges. Foremost among these are the energy cost of escaping Earth’s gravity and the need to develop in situ resources that can be processed robotically, to the extent possible, because of the supplies (air, food, and water) necessary to support long-term human space travel and habitation. Despite popular imagination, it is unlikely that space resources can or will be brought back to Earth, due to the high energy cost of overcoming gravity. The most likely commodity for in situ resource utilization (ISRU) is water, which has multiple and indispensable uses as propellant and life support for agriculture and respiration. The need for propellant to be available in space reflects the fact that fuel constitutes ~80% of the mass of a rocket that can travel beyond Earth orbit. Thus, water will be the first and most important space resource to be developed. Water is known to be present on the moon, Mars, and in C-type asteroids. It is relatively straightforward to separate water into hydrogen and oxygen by electrolysis, and solar energy provides abundant and uninterrupted power in space. Water combined with carbon in asteroids or carbon dioxide in the Martian atmosphere provides the basis for agriculture and the production of methane as a practical and easily handled propellant. In addition to structural materials for buildings or spacecraft, the other resource needed for long-term space exploration or colonization is bulk material for radiation shielding. This could be any of the loose regolith materials known to exist on the lunar and Martian surfaces and on some asteroids. Such regolith could be used as is, or manufactured into blocks or other structural materials. All of these space resources need to be assessed and characterized to provide the equivalent of a bankable feasibility study in order to prove the business case for their future development.

Background Multiple sclerosis (MS) is a chronic, neurodegenerative disease that causes a range of motor, sensory, and cognitive symptoms. Due to these symptoms, people with MS are at a high risk for falls, fall-related injuries, and reductions in quality of life. There is no cure for MS, and managing symptoms and disease progression is important to maintain a high quality of life. Mobile health (mHealth) apps are commonly used by people with MS to help manage their health. However, there are limited health apps for people with MS designed to evaluate fall risk. A fall risk app can increase access to fall risk assessments and improve self-management. When designing mHealth apps, a user-centered approach is critical for improving use and adoption. Objective The purpose of this study is to undergo a user-centered approach to test and refine the usability of the app through an iterative design process. Methods The fall risk app Steady-MS is an extension of Steady, a fall risk app for older adults. Steady-MS consists of 2 components: a 25-item questionnaire about demographics and MS symptoms and 5 standing balance tasks. Data from the questionnaire and balance tasks were inputted into an algorithm to compute a fall risk score. Two iterations of semistructured interviews (n=5 participants per iteration) were performed to evaluate usability. People with MS used Steady-MS on a smartphone, thinking out loud. Interviews were recorded, transcribed, and developed into codes and themes. People with MS also completed the System Usability Scale. Results A total of 3 themes were identified: intuitive navigation, efficiency of use, and perceived value. Overall, the participants found Steady-MS efficient to use and useful to learn their fall risk score. There were challenges related to cognitive overload during the balance tasks. Modifications were made, and after the second iteration, people with MS reported that the app was intuitive and efficient. Average System Usability Scale scores were 95.5 in both iterations, representing excellent usability. Conclusions Steady-MS is the first mHealth app for people with MS to assess their overall risk of falling and is usable by a subset of people with MS. People with MS found Steady-MS to be usable and useful for understanding their risk of falling. When developing future mHealth apps for people with MS, it is important to prevent cognitive overload through simple and clear instructions and present scores that are understood and interpreted correctly through visuals and text. These findings underscore the importance of user-centered design and provide a foundation for the future development of tools to assess and prevent scalable falls for people with MS. Future steps include understanding the validity of the fall risk algorithm and evaluating the clinical utility of the app.

Introduction: Replacement factor VIII (FVIII) products have been administered to achieve desired FVIII levels for bleed treatment, perioperative management, or routine prophylaxis. Individual variability in pharmacokinetics (PK) has resulted in dosing ranges, rather than fixed doses. N8-GP (ESPEROCT®) is an extended half-life recombinant FVIII product. The pathfinder trials evaluated routine prophylaxis and bleed treatment in previously treated adolescents/adults (pathfinder 2) and children (pathfinder 5) with severe hemophilia A and perioperative management of major surgery (pathfinder 3). Methods: Adolescents/adults (aged ≥12 y) were administered 50 IU/kg N8-GP every 4 days (Q4D) as routine prophylaxis in the main phase; alternative weekly dosing was explored in 2 extension phases. For the on-demand treatment arm, patients were to be given 20 to 70 IU/kg, depending on bleed severity and desired FVIII levels. Children (aged <12 y) on prophylaxis were administered a target of 60 (50-75) IU/kg N8-GP twice weekly. For surgery, a pre-trial test dose of 50 IU/kg was administered with PK assessment and then dosing in the study was to achieve desired FVIII suggested by World Federation of Hemophilia guidelines. Results: Pathfinder 2 enrolled 186 patients (46 from the US) with 128 (69%) completing the second extension phase encompassing 785 patient-years (66,577 exposure days) with 2,758 treated bleeds. On-demand patients (n=12) treated for a total of 37 patient-years of exposure reported 1,270 (46%) bleeds. In the main phase, 105 of 175 adolescents/adults on prophylaxis (50 IU/kg Q4D) experienced 436 bleeds with a median annualized bleeding rate (ABR) of 1.2. Through the study (mean 3.5 years), 177 adolescents/adults on doses of ~52 IU/kg Q4D had a median ABR of 0.99 and mean (95% CI) FVIII trough levels of 3.1 (2.6-3.4) IU/dL. Treatment of bleeding through extension 1 is described in Table; the median dose for mild/moderate bleeds was 42 IU/kg. For participants who were in the on-demand arm, the median initial dose was 28 IU/kg, with 88.4% of bleeds treated with a single dose. In subjects receiving prophylaxis, the median initial dose matched the prophylaxis dose (52 IU/kg), and 76% of bleeds received a single dose. For 15 severe bleeds, the median total dose was 111 IU/kg per episode. Pathfinder 5 enrolled 68 children (34 aged 0-5 y, 34 aged 6-11 y), 95% previously on prophylaxis; 62 completed the extension, amounting to 306 patient-years (32,138 exposure days) with mean exposure of 4.5 years. Overall, 55 patients (81%) reported 330 bleeds; most were traumatic (67%). Median ABR in the main phase (0.48 years) was 2.0 and through the entire study was 0.8 with mean (95% CI) FVIII trough activity of 1.9 (1.6-2.5) IU/dL. The mean prophylaxis dose was 64.7 IU/kg at a mean interval of 3.5 days, likely reflecting rounding the targeted 60 IU/kg twice weekly dose. For 70 bleeds in the main phase, 88% of bleeds were treated with 1 to 2 injections; median utilization for bleeds was 68 IU/kg (Table). Pathfinder 3 evaluated 45 surgeries in 33 adolescents/adults; 96% were reported as excellent/good efficacy. Median preoperative dose mirrored test dose (52 IU/kg) with median total dose per surgery of 702 IU/kg (until 14 days post-surgery). Postoperative dosing was at ~24-hour intervals with the number of doses and treatment duration dependent on procedure (Table). Conclusion: The pathfinder trials demonstrate effective prophylaxis was achieved with very consistent prophylaxis dosing for both adolescents/adults (~50 IU/kg Q4D) and children (~65 IU/kg twice weekly). Bleeds were generally treated for patients on prophylaxis with a single prophylactic dose (~50 or ~65 IU/kg). Dosing intervals in severe bleeding and surgery were ~24 hours, including in children. Disclosures Escobar: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; National Hemophilia Foundation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wheeler:uniQure: Membership on an entity's Board of Directors or advisory committees; BioMarin: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk Inc: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees. Lentz:Novo Nordisk Inc.: Consultancy, Honoraria, Research Funding. Clausen:Novo Nordisk A/S: Employment. Cooper:Novo Nordisk Inc.: Employment.

ABSTRACT: 2017-226 Fa’a-Samoa (the Samoan way) is a living tradition and continues to define the Samoan way of life. It is the foundation of Polynesia’s oldest culture - dating back some 3,000 years. Fa’a-Samoa is interconnected with Samoan lands and waters and by sharing the intact and vibrant traditions, values, and legends that connect the Samoan people to the land and sea, the local community plays an INTEGRAL role in the protection and preservation of natural and cultural resources of the area. Fa’a-Samoa places great importance on the dignity and achievements of the group rather than individuals. On April 14, 2016, the 62 ft. FV NO1 JI HYUN lost the main engines and grounded off the west side of Aunu’u Island in the National Marine Sanctuary of American Samoa (NMSAS). This area is of ecological and cultural significance for the local residents using hook-and-line, casting nets, spearfishing (non-scuba assisted) and other non-destructive fishing methods including those traditionally used for sustenance and cultural purposes such as gleaning, ‘enu and ola. The village on Aunu’u was extremely wary of inclusion of the waters of Aunu’u in the expansion of the sanctuary being concerned about loss of control of their traditional uses of the nearshore environment. In what became an extension of Fa’a-Samoa, the United States Coast Guard (USCG), the National Oceanic and Atmospheric Administration (NOAA) and the American Samoa Territorial government worked, together to address both the pollution hazards from the incident and the impact to the coral reef ecosystem even after the fuel was removed. While a relatively straight forward response were it to happen in the continental U.S., severe weather (Tropical Cyclone Amos), high winds and swells, limitations on site access, daylight high tides, and availability of resources to include tugs, tow lines and trained personnel made this quite challenging. Three removal attempts occurred under Oil Pollution Act (OPA) authorization and three efforts occurred under the National Marine Sanctuaries Act (NMSA), with guidance from a professional salvage master. This prolonged 4-month response has prompted some new dialogue and hopefully new commitment to increase preparedness and spill response capabilities within the territory. The designation of the NMSAS allowed for the use of the combined authorities of OPA and the NMSA, forging new path that protects and preserves both the natural and cultural resources of the region from the impacts of pollution and from future groundings whether large or small.

In a previous work, we proposed an algorithm to select a subset of discriminant morphokinetical parameters within a larger predefined set (116 parameters) and to predict 6 major bovine embryo profiles of in vitro development. The algorithm relies on flexible combinations of the discriminant parameters selected within the four first cleavage cycles. The retained profiles were arrested embryos (embryos without mitotic activity, showing signs of life); dead embryos (embryos with all cells dead); anarchic embryos (embryos with abnormal morphological and/or kinetical development: some of these embryos can result in a blastocyst); not hatched blastocysts (blastocysts not hatching by 8 dpi); hatching blastocysts (blastocysts hatching in vitro from 7.3 to 8 dpi); and early hatching blastocysts (blastocysts hatching from 6 to 7.2 dpi) (Reis et al. 2018 Anim. Reprod.). The aim of the present work was to develop a ready-to-use software (EasyPickAndPredict) allowing the extension of this methodology to other embryologists. The software of high portability was built with the JAVA language and embedded with the classifier (R language, R Foundation for Statistical Computing, Vienna, Austria) and a user’s help for annotation (Adobe Premiere Pro CS5, San Jose, CA, USA). The predictive software is easy to handle, fast to load, and has high portability. The “manual annotation” function is based on click actions to annotate the discriminant parameters. The “prediction” function calls the embedded classifier. The “report” function creates customised reports including the embryo classification, the summary of the measures, and the accuracy of the prediction (vote system). The “help” function calls an audiovisual guideline with annotation specifications for all the morphokinetic parameters currently described (including the discriminant subset of parameters). This document includes help to produce a good time-lapse video (16min 51s); annotation specifications for the cleavage cycles 1 to 4 (36 min 26s); and a summary with examples of the 6 major embryonic morphokinetical profiles (16min 47s). The predictive graphical interface is easy to manipulate and automatically extracts the value of each discriminant parameter on the time-lapse picture as validated by the user click. The functions “manual annotation”, “automatic prediction”, “help”, and “report” supply embryologists with a standard approach to predict and analyse morphokinetical profiles of their embryos. This standardised approach is necessary to improve the capacity of comparison of morphokinetical works in different laboratories and enhance knowledge about in vitro-produced bovine embryos.

Grundtvig in Politic until 1830-1831By Vagn WåhlinVagn Wåhlin discusses the Grundtvig text, .Political Considerations., re-printed above, which was written in the year of the 1930 revolution. In the Danish United Monarchy the European revolutions gave rise to a demand for a wider citizen participation in politics through parliamentary institutions and a demand for a solution to the national problem of the position of Schleswig between the Kingdom and Holstein. In addition, the debate led to a discussion of and a demand for an extension of the civil rights, including in particular a specification of the character and extent of the freedom of the press. The present article discusses Grundtvig’s treatment of these and other political subjects in the pamphlet mentioned.In the article, the concept of politics is defined as the attempt by an individual or a group to influence the authoritative distribution of the material and spiritual wealth of the society, a definition that comes close to Grundtvig’s own view. The article does not intend an exhaustive account of Grundtvig’s political views, but aims to show how Grundtvig’s attitude in a number of earlier writings has emerged through his occupation with current events and considerable social philosophers. The decisive thing for Grundtvig, before and especially around and after the time of the pamphlet discussed here, was to present and promote a form of government, on a historical and pragmatic basis, for the benefit and welfare of the whole people, where freedom and power balanced each other, where the rulers were responsive to the voice of an enlightened citizenry, and where confidence, love and responsibility rather than selfishness prevailed among the members of the society and determined the purposeful actions of the whole people - all under Divine Providence. It is pointed out how Grundtvig takes account of the character of the Danish society as an agrarian society by emphasizing the peasantry as ideally the fundamental and stabilizing element in the state. Consequently Grundtvig stresses the primary production as the foundation of society, structured through the mutual love in freedom and the folk culture of the people - traits common to the nation - as the basis of the interaction of the citizens and hence the balance between their equality and freedom. Grundtvig doubts the general possibility or desirability of equality, and is of the opinion that inequality is a natural condition of life, but that this condition is counterbalanced by the mutual fellow feeling of the citizens. Grundtvig uses the social pact idea in his definition of the distribution of power between the consultative function of the people, expressing the general will of the public, and the executive power of the King. The consultative power of the citizens finds its expression through the public media, dependent on freedom of the press, and Grundtvig brings up the concrete proposal that the Schleswig question should be solved by letting the Schleswigers give expression to the general public will in the public press. Grundtvig defends the right of the citizens to revolt the moment their rights, for example their right of property, are violated, but he dissociates himself from revolutions which, in his opinion, lead to tyranny, the opposite of freedom. The article explains how trust in God’s Providence together with love is the condition of the King’s and the people’s trust in the viability of the above-mentioned relationship. Grundtvig’s political views have their foundation in his emphasis on the importance of Christianity for the universal-historical development and for a people’s fulfillment of its own destiny in it.

Abstract Introduction: The completed Phase 3 A-LONG (NCT01181128) and Kids A-LONG (NCT01458106) studies established the safety and efficacy of rFVIIIFc among adults/adolescents and children with severe hemophilia A, respectively. Long-term safety and efficacy of rFVIIIFc are being evaluated in the ongoing ASPIRE extension study (NCT01454739). For people with hemophilia, frequent bleeding into the same joint (a target joint) may contribute to hemophilic arthropathy (chronic joint disease). Here we report longitudinal data from subjects with target joints at entry into A-LONG and Kids A-LONG throughout ASPIRE. Methods: Subjects with ≥1 target joint (major joint with ≥3 bleeding episodes in a 6-mo period) at entry into the parent study (A-LONG or Kids A-LONG) with available prestudy (pre-parent study) and on-study data were evaluated. There are 4 treatment groups in ASPIRE for subjects ≥12 y: individualized prophylaxis (IP), weekly prophylaxis (WP), modified prophylaxis (MP; for subjects not achieving optimal prophylaxis, as intended by treating physician, with IP or WP), or episodic treatment. Subjects <12 y can participate in IP or MP. Outcomes evaluated included: annualized bleeding rate (ABR), number and resolution of target joint bleeding episodes, and prophylactic dose and dosing interval. Quality of life measures were assessed by Haem-A-QOL for prophylaxis subjects who were ≥17 y and had ≥1 resolved target joint during the study, with Haem-A-QOL scores both at A-LONG baseline and ASPIRE Year 2. Outcomes were analyzed over the cumulative duration of the parent study through the second ASPIRE interim data cut (8 Dec 2014). Results: 113 subjects from A-LONG had target joints at baseline; 111 had prestudy and on-study data. These 111 subjects had 287 target joints at baseline (elbow [n=100; 34.8%], ankle [n=92; 32.1%], knee [n=63; 22.0%], shoulder [n=17; 5.9%], wrist [n=9; 3.1%], hip [n=6; 2.1%]). 13 subjects from Kids A-LONG had 15 target joints at baseline (ankle [n=10; 66.7%], elbow [n=4; 26.7%], knee [n=1; 6.7%]). Cumulative median (interquartile range [IQR]) duration of rFVIIIFc exposure was 157.2 (145.9-161.0) and 98.8 (26.3-103.9) weeks for subjects from A-LONG/ASPIRE and Kids A-LONG/ASPIRE, respectively. Median (IQR) on-study overall ABRs with rFVIIIFc prophylaxis were lower than bleeding rates with prestudy prophylaxis for adults/adolescents; on-study target joint and spontaneous target joint ABRs were low for adults/adolescents and children on prophylaxis (Figure). 46.3% of IP, 40.7% of WP, and 21.4% of MP A-LONG subjects had no target joint bleeding episodes; 53.8% of IP Kids A-LONG subjects had no target joint bleeding episodes. Among prophylaxis subjects with target joints at baseline and 12 months of follow-up, 100% (93/93) of A-LONG and 100% (7/7) of Kids A-LONG subjects had ≥1 target joint resolved (ie, ≤2 spontaneous bleeding episodes 12 consecutive mo); 98.3% (231/235) and 100% (9/9) of target joints (based on all bleeds) in A-LONG and Kids A-LONG subjects were resolved, respectively.Overall, median (IQR) prophylactic dose among prophylaxis subjects with target joints at baseline was similar to overall study populations (A-LONG: target joint, 76.0 [68.0-90.9] IU/kg; overall, 75.0 [70.0-113.8] IU/kg; Kids A-LONG: target joint, 83.5 [79.9-111.6] IU/kg; overall, 95.0 [75.0, 113.0] IU/kg). Median (IQR) dosing intervals were comparable (A-LONG: target joint, 3.8 [3.5-5.6] days and overall, 3.5 [3.0-5.0] days; Kids A-LONG: target joint, 3.5 [3.5-3.5] days and overall, 3.5 [3.5-3.5] days). Among the 48 subjects included in the Haem-A-QOL analysis, quality of life improved at ASPIRE Year 2 compared with A-LONG baseline (18% or 5.4 point reduction in total Haem-A-QOL score [P <0.05]). Domains reduced ≥6 points and ≥20% from baseline (P <0.05) included Feeling (toward hemophilia), Physical Health, Sports & Leisure, and Work & School. Conclusion: Efficacy data from the phase 3 and extension trials show low target joint ABRs and effective target joint resolution in pediatric, adolescent, and adult subjects on long-term rFVIIIFc prophylaxis. Improvement in quality of life was seen in subjects with target joint resolution with rFVIIIFc prophylaxis. This research was funded by Biogen and Sobi. Biogen and Sobi reviewed and approved feedback on the abstract. The authors had full editorial control of the abstract and provided their final approval of all content. Disclosures Wang: CSL Behring: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees; LFB: Membership on an entity's Board of Directors or advisory committees; HEMA Biologics: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees. Pasi:Biogen: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; SOBI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria. Kerlin:Bayer Healthcare US: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; CSL Behring Foundation: Research Funding. Kulkarni:Baxter: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Research Funding, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; BPL: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees. Nolan:Sobi: Research Funding; Biogen: Research Funding. Liesner:Grifols: Consultancy, Honoraria; SOBI: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding; Biogen: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Cangene: Research Funding; BPL: Consultancy, Honoraria, Research Funding; Baxalta Innovations GmbH, now a part of Shire: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Speakers Bureau; Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau. Brown:Baxter: Consultancy; Novo Nordisk: Consultancy; Biogen: Consultancy. Hanabusa:Bayer: Honoraria; KaketsuKen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Tsao:Biogen: Employment, Equity Ownership. Winding:Sobi: Employment. Lethagen:Sobi: Employment. Jain:Biogen: Employment, Equity Ownership.

Since the founding of the Missouri Botanical Garden (MBG) in 1859, the emphasis on research and the distribution of research findings in botany has been, and will remain, one of the central components of the garden’s mission. Likewise, Washington University in St. Louis (WUSTL), the MBG’s partner in graduate programs since 1885, has had a continuous and similarly strong emphasis on research and the dissemination of research findings in plant science through publications. Since the beginning of this partnership, the ongoing extension of common research themes has been critical, through the early focus on traditional botanical studies (1885–1930) at the MBG, the move toward a focus on physiology and the emerging field of ecology (1930–1960), and eventually the shift to the study of biochemistry, molecular biology, and genomic studies in plant science (1960–present), primarily at WUSTL. For more than 135 years (1885–2020), this St. Louis–based collaboration has had a prominent place in the region’s rich history in plant science. In recent years, collaboration with and contributions from other St. Louis–area degree-granting institutions in the field (such as Saint Louis University [SLU] and the University of Missouri–St. Louis [UMSL]) have steadily increased. Couple this with the addition of the Donald Danforth Plant Science Center (Danforth Center) in 2000, which, like the MBG, has undertaken research and training in plant science, and you now have impressive depth and diversity within St. Louis’s plant science offerings. As a result, both organizations train students and carry out peer-reviewed research funded by the same agencies (i.e., National Institutes of Health, National Science Foundation, U.S. Department of Agriculture) as the region’s degree-granting institutions. Every year, a significant number of master’s degree and Ph.D. graduates in this consortium comprise an impressive pool of talent available for postdoctoral training, research, and teaching positions, as well as employment in government entities and private and public life science corporations. To this end, St. Louis has one of the largest concentrations of plant science Ph.D.’s in the world (with more than 1,000 such individuals residing in the region [BioSTL, 2018]), as well as a broad diversity of disciplines represented. In addition, the faculties at both the Danforth Center and MBG frequently serve as adjunct members of university departments and as advisors to graduate students, and greatly increase the breadth of topics offered in the St. Louis plant science community, particularly in areas not directly supported by the universities. Both organizations contribute to an increasingly important part of this ecosystem. Below is a short history of the relationship between the MBG and WUSTL, and how this collaboration, primarily through graduate research education, has been foundational for the St. Louis area’s impressive plant science ecosystem. This is not a detailed review of the science generated by these organizations, but rather an account of the initial events and leaders that led to the region becoming the present-day hub for plant science.

Diffuse interstitial lung diseases (ILDs) include more than hundreds of diseases which have different causes or underlying, target groups, signs and symptoms, clinical courses, radiographic appearances, treatments, and prognosis. Among them, idiopathic pulmonary fibrosis (IPF) is the most fatal, with prognosis worse than many cancers. After decades of no specific treatment, new medications that may help slow the progression of the fibrosis have been introduced and approved in some countries. Similar to corticosteroid, anti-inflammatory and immunosuppressive drugs which are used to treat some ILDs; these antifibrotic medications could cause certain side effects. In contrast, the cost of treatment is much higher.
 To monitor ILDs in terms of incidence, demographic and geographic distributions, and life expectancy; T.S.T. is developing a national ILD database. To ensure that this data base will provide the most accurate information, diagnosis should be as much precise as possible.
 However, the diagnoses of most ILDs are multidisciplinary. With the facts that surgical lung biopsies are available in patients fewer than 20% in most countries1, HRCT plays important role in showing disease characters and extension. Certain HRCT patterns are accepted to replace surgical lung biopsies (SLB) in some diseases.
 Unfortunately typical diagnostic HRCT patterns to replace SLB are not possible in all cases; for example, only about half of usual interstitial pneumonia2. Initially, diagnosis could not be made in some cases whose HRCT patterns are not specific and other clinical information is not sufficient. Longitudinal study by following up HRCTs and adding subsequently exhibited clinical data, or even surgical lung biopsy, could eventually establish the diagnosis. These patients need a system that provide regular clinical and HRCT follow up, also the multidisciplinary team to evaluate those newly acquired clinical and radiographic information .
 As an important role in managing patients with ILDs, standard HRCT is required to ensure that the initial examination will provide sufficient radiographic information, both the initial and follow-up examinations could be compared, the interpretation of all examinations is reproducible, and it could be performed in most institutes.
 To develop national standard HRCT protocol; current situation of interstitial lung diseases in Thailand,the purpose to develop the protocol, and a probable draft of the standard protocol (made by the committee from RCRT) were presented to a panel consisted of thoracic radiologist experts from all parts of Thailand in a meeting held on 11 January 2019 by Foundation of Orphan and Rare Lung Disease (FORD) and Imaging Academic Outreach Center (iAOC). Knowledge sharing, benefits and disadvantages of the drafted protocol were discussed. Adjustment was done based on feasibility, coverage of all lung diseases, diagnostic accuracy, and radiation safety.
 The panel provided a standard protocol describing scan coverage, technique, collimation, rotation time, pitch, radiation dose, and reconstruction images. The standard protocol recommends a mandatory acquisition for the first HRCT and optional or additional ones for the follow-up or particular cases.

Abstract Abstract 1260 Background: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, progressive and life-threatening hematopoietic stem cell disorder. It is characterized by uncontrolled activation of the complement system leading to chronic intravascular hemolysis. Chronic hemolysis is the underlying cause of the thromboembolism (TE), renal insufficiency and other end organ damage, and early mortality associated with PNH. It has been demonstrated that long-term eculizumab treatment has a favorable efficacy profile due to continuous suppression of the terminal complement system. Objective: To analyze the long-term safety of patients on continuous eculizumab treatment. Methods: Patients receiving continuous eculizumab treatment (mean duration: 30.3 months) who were enrolled in the eculizumab PNH clinical development trials and associated extension studies were assessed for the incidence of adverse events (AEs). The incidence of AEs, irrespective of relation to treatment, reported during the first 26 weeks of eculizumab treatment was compared with the last 26 weeks of treatment. In patients with treatment duration <52 weeks, the incidence of AEs reported during the first 26 weeks of treatment was compared with the incidence of AEs from 26 weeks + 1 day until the patient's last dose of eculizumab. Results: The analysis included 192/195 patients enrolled in the trials; 3 patients were excluded because of treatment duration <26 weeks. Significantly fewer patients reported an AE in the last 26 weeks (n=145) compared with the first 26 weeks (n=189) of treatment (P<0.001); this included the most commonly reported AEs such as headache (P<0.001), nasopharyngitis (P=0.029), back pain (P=0.031), nausea (P=0.029), and fatigue (P=0.029). Results by system organ class revealed significantly fewer patients experienced infections and infestations (P=0.005); infusion site reactions (P=0.018); gastrointestinal, musculoskeletal and connective tissue and nervous systems (all P<0.001); and skin and subcutaneous tissue (P=0.006), metabolism and nutrition (P=0.008), psychiatric (P=0.014), vascular (P=0.025), or respiratory thoracic and mediastinal (P=0.030) disorders. None of the individual AEs reported increased significantly over time. In addition, the probability of a patient experiencing an AE decreased significantly with time (P<0.001). All patients are required to be vaccinated against Neisseria meningitidis because suppression of terminal complement activity by eculizumab increases the risk of meningococcal infections. Patients were vaccinated at least 2 weeks before the first dose of eculizumab and were educated on the early signs and symptoms of these infections. Two cases of meningococcal sepsis were reported with a time to onset of 353 and 416 days. Both patients developed a strain of meningococcal infection that was not covered by their vaccination. The infections were successfully treated: 1 patient received ceftriaxone and ciprofloxacin, and the other imipenem, rocephin, vancomycin, ceftriaxone and penicillin. Both infections resolved without sequelae: 1 patient remained in the extension study and continued to receive eculizumab; the second patient withdrew from the study. Five (5/195) patients discontinued from the study due to an AE, which included the development of myelodysplastic syndrome, meningococcal sepsis, worsening of PNH and 2 pregnancies. Over the course of the study, 4 patient deaths were reported; no deaths were considered related to eculizumab treatment. Conclusions: PNH patients receiving long-term eculizumab treatment (up to 5.5 years) did not experience signs of cumulative toxicity. In fact, patients showed a significantly decreased incidence of AEs with continuous eculizumab treatment, suggesting a favorable risk-to-benefit ratio over the long term. The low discontinuation rate due to an AE suggests long-term treatment with eculizumab is well tolerated. Disclosures: Off Label Use: The use of romiplostim in MDS was examined in this trial. Muus:Alexion Pharmaceuticals.: Sat on advisory board of Alexion Pharmaceuticals. Other. Roeth:Alexion: Honoraria, Research Funding. Elebute:Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Risitano:Alexion: Membership on an entity's Board of Directors or advisory committees, Research Funding. Maciejewski:NIH: Research Funding; Aplastic Anemia&MDS International Foundation: Research Funding. Urbano-Ispizua:Alexion Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees. de Castro:Alexion Pharmaceuticals, Inc: Speakers Bureau.

Introduction: Patient-derived data can increase breadth of knowledge in rare cancers like Waldenström's Macroglobulinemia (WM), including patient-reported outcomes (PROs). WhiMSICAL (Waldenström's Macroglobulinemia Study Involving CArt-wheeL) is the only global registry capturing patient-derived data for hypothesis generation in WM. Rapidly adaptable, it has been amended to capture Coronavirus Disease 2019 (COVID-19) data. Methods: An ethically-approved WM-specific extension to www.cart-wheel.org, an online rare cancer database for patient-derived data, was developed by clinician and patient investigators. Participants complete consent, and enter symptom, pathology, treatment and PRO (EORTC-QLQ-C30, Impact of Event Scale-6) data online. Recruitment strategies utilizing social media tools are driven by the International Waldenström's Macroglobulinemia Foundation investigators. A validation study compared patient-entered data with data-manager-entered data in the Australia & New Zealand Lymphoma & Related Diseases Registry (LaRDR). To capture the impact of COVID-19, additional questions on COVID-19 testing, symptoms and therapy, as well as effect on WM management in those without COVID-19, were included in April 2020. Results: 453 patients from 19 countries have been recruited, predominantly from USA (46%) and Australia (25%), with male predominance (62%). At diagnosis, median age was 61 (range 24-83), median IgM 2620 mg/dL (IQR 1320-3850 mg/dL, n=175) and median hemoglobin 11.4 g/dL (IQR 9.5-12.9 g/dL, n=181). Of the 365 (81%) patients providing symptoms at diagnosis, fatigue/muscle weakness was most common (46%) and 30% were asymptomatic. Using the Impact of Event Scale for symptoms of post-traumatic stress disorder (PTSD) resulting from a cancer diagnosis, the mean score among 387 patients was 5.9 (no stress=0, maximal stress=24), with 39/387 (10%) scoring >13 (PPV 94% for PTSD, Thoresen et al, 2010). This proportion did not increase for scores entered after March 1st, 2020 - 12/123 (10%) - when the COVID-19 pandemic became a global crisis. Marked treatment variation was noted, with 47 different first-line therapeutic combinations documented by 302 patients. Median time from diagnosis to first treatment for USA patients was 48 days (IQR 13-404, n=133) vs Rest of World (ROW) 176 days (IQR 20-885, n=163), (p=0.01). At median follow up of 38.5 months, first-line bendamustine rituximab had superior time to next treatment outcomes compared to other first-line therapies: rituximab monotherapy, dexamethasone-rituximab-cyclophosphamide and Bruton tyrosine kinase inhibitors (BTKi, Figure 1). 51 patients exposed to BTKi had a trend to higher EORTC QLQ-C30 global scales, mean 78.6±17.7, compared to 148 not exposed: mean 73.4±22.6 (p=0.13), despite higher treatment burden: median lines of treatment 2 (IQR 1-4) and 1 (IQR 1-2), respectively (p<0.0001). Paired analysis of global scales entered by patients prior to and after March 1 2020 demonstrated no impact of COVID-19 on quality of life: mean scores 74.4±18.8 and 76.0±17.1, respectively (n=69, p=0.45). Validation of patient-entered data with data-manager-entered data for 31 patients also in LaRDR demonstrated high concordance of >83%. 188/453 (42%) participants responded to the impact of COVID-19 questions; 75/188 (40%) had reduced face-to-face reviews, 4/188 (2%) had delays to starting treatment and 57/188 (30%) documented no impact. Of the 188 respondents, 23 (12%) had COVID-19 testing, with two returning a positive result and neither requiring hospitalization. Conclusion: WhiMSICAL is a robust, rapidly adaptable, global patient-derived data platform, providing insight into patient symptoms, real-world therapies and PROs. It is a scientific, ethically-approved portal for contributing the patients' voice in this rare lymphoma. Disclosures Warden: Janssen Cilag: Other: Personal fees for photoshoot event. Opat:CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Epizyme: Research Funding. D'Sa:Sanofi: Honoraria; BeiGene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Kersten:Takeda: Research Funding; Roche: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Kite/Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Miltenyi Biotech: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen/Cilag: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); BMS: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); MSD: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Olszewski:Genentech, Inc.: Research Funding; Adaptive Biotechnologies: Research Funding; TG Therapeutics: Research Funding; Spectrum Pharmaceuticals: Research Funding. Harrington:Calithera Biosciences: Current equity holder in publicly-traded company; Bristol-Myers Squibb: Current equity holder in publicly-traded company; BeiGene: Current equity holder in publicly-traded company; Gilead: Current equity holder in publicly-traded company; Idera Pharmaceuticals: Current equity holder in publicly-traded company; AbbVie: Current equity holder in publicly-traded company. Trotman:Takeda: Research Funding; PCYC: Research Funding; F. Hoffmann-La Roche: Research Funding; Celgene: Research Funding; BeiGene: Research Funding.

Abstract Introduction: Recombinant factor IX Fc fusion protein (rFIXFc) is an extended half-life therapy for severe hemophilia B. The safety, efficacy, and prolonged half-life of rFIXFc were demonstrated in previously treated pediatric, adolescent, and adult subjects with severe hemophilia B in the Phase 3 B-LONG and Kids B-LONG trials (NCT01027364 and NCT01440946, respectively) (Fischer et al, Lancet Haematol, 2017; Powell et al, N Engl J Med, 2013). Here, the final results are reported from B-YOND (NCT01425723), the long-term extension of those 2 studies. Methods: This was an open-label, multicenter, long-term trial of previously treated subjects of all ages with severe hemophilia B. Dosing regimens included weekly prophylaxis (WP; 20-100 IU/kg every 7 days), individualized prophylaxis (IP; 100 IU/kg every 8-16 days or twice monthly), modified prophylaxis (MP; for subjects not achieving optimal dosing on IP or WP), or episodic treatment (ET; on-demand dosing based on type and severity of bleeding episodes). Subjects <12 years of age could only enroll in the prophylactic groups (WP, IP, or MP). Investigators were permitted to change treatment groups for a subject at any point in B-YOND; thus, subjects may be included in >1 group for analyses. The primary endpoint was development of inhibitors. Other endpoints included annualized bleeding rates (ABRs), joint ABRs, spontaneous joint ABRs, exposure days (ED), and factor consumption. Descriptive statistics were used for analysis. Analyses were performed separately based on parent study. Results: A total of 120 subjects (93 from B-LONG and 27 from Kids B-LONG) enrolled in B-YOND, and 98 subjects (75 from B-LONG and 23 from Kids B-LONG) completed the study. Of the 93 subjects from B-LONG, the median (range) age was 29 (13‒63) years and most were prescribed WP (WP, n=51; IP, n=31; MP, n=17; ET, n=15). Subjects from Kids B-LONG had a median (range) age of 7 (3‒12) years. Among subjects <6 years of age, 13 were prescribed WP and 1 MP. Ten subjects 6 to <12 years of age received WP, 5 received IP, and 1 received MP. No subject developed an inhibitor during B-YOND. The overall safety profile of rFIXFc was consistent with the parent studies and prior interim analyses. ABRs remained low and stable throughout B-YOND (Table 1). The overall median (range) number of ED in B-YOND for subjects from B-LONG was 146.0 (8.0-462.0) days, with an overall median (range) duration of 208 (4 years; 13.9-280.0) weeks. For subjects from the Kids B-LONG study, the median (range) number of ED was 55.0 (8.0-204.0) days and 149.0 (53.0-202.0) days for those aged <6 years and 6 to <12 years, respectively. Median (range) exposure to rFIXFc was 55.0 (1.1 years; 7.9‒177.0) weeks for subjects <6 years of age and 175.66 (3.4 years; 47.0‒201.1) weeks for subjects 6 to <12 years of age. The median dosing interval ranged from 7 to 14 days for B-LONG subjects and 7 to 10 days for Kids B-LONG subjects (Table 1). Most subjects (79% and 78% from B-LONG and Kids B-LONG, respectively) had maintained their dosing interval during the extension trial (Table 2), although the dosing interval was lengthened for 6% of B-LONG subjects and 15% of Kids B-LONG subjects. Median weekly dose was low (Table 1) and ranged from 48.46 IU/kg to 68.23 IU/kg for B-LONG subjects and 59.96 IU/kg to 67.70 IU/kg for Kids B-LONG subjects. There was no change in median weekly factor consumption from the end of either parent study through the B-YOND extension. Conclusions: During up to 4 years of treatment with rFIXFc in the B-YOND study, no inhibitors were reported. The low ABRs, low consumption, and extended dosing intervals of up to 14 days that were observed during the parent studies were sustained for the duration of the long-term extension trial. These data confirm the consistent, well-characterized safety profile, and durable efficacy of rFIXFc prophylaxis in subjects of all ages with severe hemophilia B. Disclosures Ragni: Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; American Academy of CME: Honoraria; Baxalta/ Shire: Research Funding; Baxter Bioscience: Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen/Bioverativ: Consultancy, Research Funding; Biomarin: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Research Funding; Foundation for Women and Girls with Blood Disorders: Membership on an entity's Board of Directors or advisory committees; Institute for Cost Effectiveness Research (ICER): Consultancy; NovoNordisk: Research Funding; OPKO Biologics: Research Funding; Pfizer: Research Funding; Shire Development LL: Consultancy, Other: Non-financial support (study Drug); SPARK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; MOGAM(Green Cross Corporation: Membership on an entity's Board of Directors or advisory committees. Kulkarni:Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octa Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kedrion: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genetech: Honoraria, Membership on an entity's Board of Directors or advisory committees; BPL: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pasi:Biomarin: Honoraria, Research Funding; NovoNordisk: Speakers Bureau; Alnylam: Honoraria, Research Funding; Catalyst Bio: Honoraria; Shire: Speakers Bureau; Octapharma: Honoraria; Pfizer: Speakers Bureau; Apcintex: Honoraria; Bioverativ: Honoraria, Research Funding; Sobi: Honoraria; Bayer: Speakers Bureau. Mahlangu:Sanofi: Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; LFB: Consultancy; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; Chugai: Consultancy; Catalyst Biosciences: Consultancy, Research Funding; Biomarin: Research Funding, Speakers Bureau; Biogen: Research Funding, Speakers Bureau; Bayer: Research Funding; Amgen: Consultancy; Alnylam: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau; Spark: Consultancy, Research Funding. Shapiro:Bioverativ, a Sanofi Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Research Funding; BioMarin: Research Funding; Bayer Healthcare: Other: International Network of Pediatric Hemophilia; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Prometic Life Sciences: Consultancy, Research Funding; Octapharma: Research Funding; Kedrion Biopharma: Consultancy, Research Funding; Sangamo Biosciences: Consultancy; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; OPKO: Research Funding; Bio Products Laboratory: Consultancy; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Nolan:Bayer: Research Funding; CSL Behring: Research Funding; Sobi: Research Funding. Oldenburg:Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Swedish Orphan Biovitrum: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Matsushita:Bioverativ: Honoraria; Bayer: Honoraria, Research Funding; NovoNordisk: Honoraria, Research Funding; JB: Honoraria, Research Funding; Shire: Honoraria; CSL: Honoraria. Willemze:SOBI: Employment. Rudin:Bioverativ: Employment, Equity Ownership.

The purpose of this paper is to identify factors and methods enhancing the quality of learning in a university setting. It is pointed out that an overcritical attitude towards learners’ incompetent public performance may cause anxiety and hinder their learning. However, group participation facilitates developing students’ self-expression and life skills. Traditional views on teaching are evaluated with regard to the latest pedagogical trends.The methodology of the paper relies on observation of the educational process, theoretical analysis of common and emerging frameworks for teaching English as a second language in a university setting, as well as synthesis, and generalization of research literature findings.The paper demonstrates how a traditional framework for teaching English as a second language can be modified to accommodate learners’ needs and investigates how innovative methods and technologies affect teaching of a foreign language and development of students’ foreign language competence. It is shown that lessons incorporating pre-communicative and communicative activities can be structured differently. The key to successful learning by a group of students is to take into consideration the quality of tasks and to present materials in a flexible manner to the learners.Our examples are based on fundamental principles, such as a variety of tasks, repetition and internationalization of the content. For warm-up or pre-communicative activities, we choose tasks preparing students for speaking and building their language competence. A number of “silent” activities enable learners to perform more or less simultaneously in order to lay the foundation for their internal language representation in an atmosphere free from anxiety and distraction. After completing exercises, students are expected to utilize previously learned grammar and vocabulary in their speech.In conclusion, we reiterate that successful learning takes place when external and internal factors are accounted for. Modern technologies are an effective extension of in-class learning for improving students’ pronunciation, enriching their vocabulary, and developing their speaking and writing skills.Key words: foreign and second language learning, principles of learning, approaches, technology-enhanced learning, the sequence of tasks. Метою статті є визначення факторів і підходів, які сприяють підвищенню якості університетської освіти. Зазначено, що занадто критичне ставлення до неправильних відповідей студентів в аудиторії може спричинити бентежність та сповільнити навчання. Проте групова діяльність уможливлює розвиток самовираження та життєво важливих навиків. Традиційні погляди на навчання оцінюються з огляду на новітні тенденції.Методологія роботи ґрунтується на спостереженнях за навчальним процесом, теоретичному аналізі загальних та новітніх моделей навчання англійської мови як іноземної в університеті, а також на синтезі та узагальненні матеріалу.У статті показано, як можна модифікувати традиційну модель для вивчення англійської мови як іноземної, щоб задовольнити потреби здобувачів, та досліджено, як інноваційні методи та технології впливають на викладання іноземної мови та розвиток іншомовної компетенції студентів. Заняття, яке включає домовленнєвий етап та власне мовленнєвий етап, можна структурувати по-різному. Ключовий момент полягає у врахуванні характеру завдань та гнучкості у навчанні здобувачів.Наші приклади ґрунтуються на фундаментальних засадах, таких як різноманітність завдань, повторення та індивідуальне осмислення змісту. Для домовленнєвого епапу ми дібрали завдання, які готують студентів до мовленнєвої діяльності та формують їхню мовну компетентність. Низка завдань, які виконуються мовчки, має на меті відносно одночасне їх завершення, закладає основи внутрішньої мовної репрезентації в умовах, позбавлених бентежності та відволікання уваги. Очікується, що після виконання завдань студенти використовуватимуть засвоєну граматику та лексику у власному мовленні.У висновках наголошується на тому, що навчання є успішним, коли до уваги беруться зовнішні та внутрішні фактори. Сучасні технології є ефективним продовженням аудиторної роботи, яка дає змогу покращувати вимову, збільшувати словниковий запас, а також розвивати навики усного та письмового мовлення.Ключові слова: вивчення другої мови як іноземної, принципи навчання, підходи, цифрові технології навчання, послідовність завдань

Introduction: Thrombin plays a central role in hemostasis: in the initiation, amplification, and propagation phases of coagulation and in the formation of a stable fibrin clot. Normal hemostatic function requires a balance between procoagulant and anticoagulant proteins that regulate thrombin generation (Negrier et al. Blood Reviews. 2019). Co-inheritance of antithrombin deficiency in people with hemophilia is associated with a milder bleeding phenotype (Shetty et al. Br J Haematol. 2007; Bolliger et al. Thromb Haemost. 2010), supporting the hypothesis that a reduction in antithrombin levels will increase thrombin generation and thus normalize hemostasis in people with hemophilia. Fitusiran is a subcutaneously administered investigational RNA interference therapeutic targeting antithrombin for prophylactic treatment of patients with hemophilia A and B, with or without inhibitors. In a completed Phase I study, monthly subcutaneous administration of fitusiran was found to lower antithrombin levels, increase thrombin generation, and was generally well tolerated (Pasi et al. Blood. 2016; Pasi et al. New Engl J Med. 2017). The aim of this abstract is to describe the longitudinal assessment of thrombin generation with fitusiran in the Phase I/II open-label extension study (NCT02554773). Methods: The fitusiran Phase I dose-escalation study (NCT02035605) was followed by the Phase II open-label extension study (NCT02554773), which included male patients, >18 years of age, with moderate or severe hemophilia A and B, with or without inhibitors, who were eligible to continue dosing with monthly subcutaneous fixed doses of fitusiran 50 mg or 80 mg. Thrombin generation was assessed monthly for the first 2 years and every 6 months thereafter using the calibrated automated thrombogram (CAT) assay. Results: Thirty-four patients aged 19-61 with hemophilia A (n=27; 13 with inhibitors and 14 without inhibitors) or hemophilia B (n=7; 2 with inhibitors and 5 without inhibitors) were treated for up to 4.7 years with a median exposure of approximately 2.6 years at the time of the data cut (March 10, 2020). Peak thrombin generation was assessed over the length of the study for each patient. Once-monthly subcutaneous dosing of 50 mg or 80 mg fitusiran prophylaxis over a period of 48 months resulted in sustained antithrombin lowering (a reduction of between 85% to 72% from baseline), which led to peak thrombin levels and an endogenous thrombin potential approaching the normal range seen in healthy volunteers (see figure). Additional subgroup analyses (hemophilia A and B, with or without inhibitor) will be conducted for presentation at the congress. Conclusions: Monthly fitusiran prophylaxis resulted in consistent peak thrombin generation levels in patients with hemophilia A and B, with or without inhibitors over an extended period of time. With the thrombin generation levels in people with hemophilia on fitusiran approaching that of normal healthy adults, this sustained lowering of thrombin has the potential to provide consistent bleed protection in patients over time. Disclosures Négrier: CSL, F. Hoffmann-La Roche Ltd, Sobi: Other: Travel support; CSL Behring, Octapharma, Shire/Takeda, Sobi: Research Funding; Bayer, Biomarin, CSL Behring, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche Ltd, Sanofi, Shire/Takeda, Sobi, Spark: Consultancy. Ragni:Alnylam Pharmaceuticals Inc., Baxalta/Takeda, BioMarin, Bioverativ, and Spark Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sangamo: Consultancy, Research Funding; Takeda: Research Funding; Bioverativ: Consultancy, Research Funding; Spark: Consultancy, Research Funding; BioMarin: Consultancy, Research Funding; Alnylam/Sanofi, ATHN, BioMarin, Bioverativ, Sangamo, Spark: Research Funding; Alnylam/Sanofi, BioMarin, Bioverativ, Spark: Consultancy; American Thrombosis Hemostasis Network: Other: Committee work; Baxalta/Takeda, CSL Behring, Genentech, a member of the Roche Group, OPKO Biologics, and Vascular Medicine Institute: Research Funding. Pasi:BioMarin: Consultancy, Honoraria, Other: Grants, personal fees, and nonfinancial support; honoraria as member of scientific advisory boards and symposia; Sanofi: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia, Research Funding; Roche: Honoraria, Other; Pfizer: Other; Octapharma: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia , Speakers Bureau; Novo Nordisk: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia ; Catalyst Biosciences: Consultancy, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia; Biotest: Consultancy, Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia; Alnylam (Sanofi): Other: Personal fees and nonfinancial support ; Takeda: Consultancy, Honoraria, Other: Personal fees; honoraria as member of scientific advisory boards and symposia ; ApcinteX: Consultancy, Other: Personal fees ; uniQure: Other: Grants and nonfinancial support , Research Funding; Sigilon: Research Funding; Tremeau: Research Funding; Sobi: Consultancy, Honoraria, Other. Pipe:Apcintex, Bayer, BioMarin, Catalyst Biosciences, CSL Behring, HEMA Biologics, Freeline, Novo Nordisk, Pfizer, F. Hoffmann-La Roche Ltd/Genentech, Inc., Sangamo Therapeutics, Sanofi, Takeda, Spark Therapeutics, uniQure: Consultancy; Siemens: Research Funding; Medical and Scientific Advisory Council to the National Hemophilia Foundation; Medical Advisory Board to World Federation of Hemophilia: Membership on an entity's Board of Directors or advisory committees. Kenet:PI Healthcare, CSL Behring: Honoraria; Bayer, Pfizer, Takeda, BioMarin, Novo Nordisk: Speakers Bureau; Bayer, Pfizer, Roche, Alnylam (Sanofi), Shire: Research Funding; Bayer, Pfizer, BioMarin, Takeda, Roche, Novo Nordisk, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Rangarajan:Sangamo: Research Funding; Takeda, Grifols, Roche, Reliance Life Sciences: Other: Conference support, Speakers Bureau. Kichou:Sanofi: Current Employment. Mei:Sanofi: Current Employment, Current equity holder in publicly-traded company. Andersson:Sanofi: Current Employment, Current equity holder in publicly-traded company.

The Son of the Widow from Nain.By Kaj ThaningThis article intends to elucidate the distinctions that Grundtvig made in his world of ideas in the course of the years from 1824 to 1834, first between spirit and letter, church and church-school (1826-1830), and then between natural life and Christian life (in 1832). In His "Literary Testament" (1827), Grundtvig himself admits that there was a "Chaos" in his writings, due to the youthful fervour that pervaded his literary works and his sermons in the years 1822-1824. But not until 1832 does he acknowledge that "when I speak or write as a citizen, or a bard, or a scholar, it is not the time nor the place to either preach or confess, so when I have done so, it was a mistake which can only be excused with the all too familiar disorder pertaining to our church, our civic life, and our scholarship...", as it says in a passage omitted from the manuscript for "Norse Mythology”, 1832. (The passage is printed in its entirety in ”A Human first...”, p. 259f.)The point of departure for Thaning’s article is a sermon on the Son of the Widow from Nain, delivered in 1834, which the editor, Christian Thodberg also found "singularly personal”, since Grundtvig keeps using the pronoun ”1”. In this sermon Grundtvig says that those who have heard him preaching on this text before, would remember that he regarded the mourning widow as ”an image of the same broken heart at all times”, and her comforter, Jesus, not only as a great prophet in Israel, but ”as the living Being who sees us and is with us always until the end of the world”. Thodberg is of the opinion that Grundtvig refers to his sermon from 1823. Thaning, however, thinks that the reference is to the sermon from 1824. But Grundtvig adds that one may now rightly ask him whether he ’’still regards the gospel for the day with the same eyes, the same hope and fear as before.” He wants to discuss this, among other things ’’because the best thing we can do when we grow old is ... to develop and explain what in the days of our youth .. sprang up before our eyes and echoes in our innermost mind.” In other words, he speaks as if he had grown old. So Thaning asks: "What happened on the way from Our Saviour’s Church to Frederick’s Church?"Thaning’s answer is that there was a change in Grundtvig’s view of life. Already in his first sermon in 1832, he says that his final and truly real hour as a pastor has now arrived. Thaning’s explanation is that Grundtvig has now passed from the time of strong emotions to that of calm reflections. Not until now does he realize "what is essential and what is not". And in 1834 he says that our Christian views, too, must go through a purgatorial fire when we grow older. This is not only true of the lofty views of human life which, naturally, go through this purgatory and most often lose themselves in it. Here Grundtvig distinguishes between natural and Christian life which is something new in a sermon. Thaning adds that this purgatorial fire pervades Grundtvig’s drafts for the Introduction to "Norse Mythology" in 1832. But then, Grundtvig’s lofty views did not lose themselves in purgatory. He got through it. His view of life changed. (Here Thaning refers to his dissertation, "A Human First...", p. 306ff).This is vaguely perceptible throughout the sermon in question. But according to Thaning Grundtvig slightly distorts the picture of his old sermon. In the latter he did not mix up natural and Christian life. It is Thaning’s view that Grundtvig is thinking of the distinct mixture of Christianity and Danish national feeling in the poem "New Year’s Morning" (1824). But he also refers to Grundtvig’s sermon on Easter Monday, 1824, printed in Helge Toldberg’s dissertation, "Grundtvig’s World of Symbols" (1950), p. 233ff, showing that he has been captured by imagery in a novel manner. He seems to want to impose himself upon his audience. In 1834 he knows he has changed. But 1832 is the dividing year. In the passage omitted from the manuscript for "Norse Mythology", Grundtvig states explicitly that faith is "a free matter": "Faith is a matter of its own, and truly each man’s own matter". Grundtvig could not say this before 1832. Thaning is of the opinion that this new insight lies behind the distinction that he makes in the sermon in 1834, where he says that he used to mix up Christian life with "the natural life of our people", which involved the risk that his Christian view might be misinterpreted and doubted. Now it has been through purgatory. And in the process it has only lost its "absurdity and obscurity, which did not come from the Lord, but from myself”.Later in the sermon he says: "The view is no more obscured by my Danish national feeling; I certainly do not by any means fail to appreciate the particularly friendly relationship that has prevailed through centuries between the Christian faith and the life of this people, and nor do I by any means renounce my hope that the rebirth of Christianity here will become apparent to the world, too, as a good deed, but yet this is only a dream, and the prophet will by no means tell us such dreams, but he bids us separate them sharply from the word of God, like the straw from the grain...". This cannot be polemically directed against his own sermons from 1824. It must necessarily reflect a reaction against the fundamental view expressed in "New Year’s Morning" and its vision of Christianity and Danishness in one. (Note that in his dissertation for the Degree of Divinity, Bent Christensen calls the poem "a dream", as Thaning adds).In his "Literary Testament" (1827) Grundtvig speaks about the "Chaos" caused by "the spirits of the Bible, of history, and of the Nordic countries, whom I serve and confuse in turn." But there is not yet any recognition of the same need for a distinction between Danishness and Christianity, which in the sermon he calls "the straw and the grain". Here he speaks of the distinction between "church and church-school, Christianity and theology, the spirit of the Bible and the letter of the Bible", as a consequence of his discovery in 1825. He still identifies the spirit of human history with the spirit of the Bible: "Here is the explanation over my chaos", Grundtvig says. But it is this chaos that resolves itself, leading to the insight and understanding in the sermon from 1834.In the year after "The Literary Testament", 1828, Grundtvig publishes the second part of his "Sunday Book", in which the only sermon on the Son of the Widow in this work appears. It is the last sermon in this volume, and it is an elaboration of the sermon from 1824. What is particularly characteristic of it is its talk about hope. "When the heart sees its hope at death’s door, where is comfort to be found for it, save in a divine voice, intoning Weep not!" Here Grundtvig quotes St. John 3:16 and says that when this "word of Life" is heard, when hope revives and rises from its bier, is it not then, and not until then, that we feel that God has visited his people...?" In the edition of this sermon in the "Sunday Book" a note of doubt has slipped in which did not occur in the original sermon from 1824. The conclusion of the sermon bears evidence that penitential Christianity has not yet been overcome: "What death would be too hard a transition to eternal life?" - "Then, in the march of time, let it stand, that great hope which is created by the Word ... like the son of the great woman from Nain."It is a strange transition to go from this sermon to the next one about the son of the widow, the sermon from 1832, where Christ is no longer called "hope". The faith has been moved to the present: "... only in the Word do we find him, the Word was the sign of life when we rose from the dead, and if we fell silent, it was the sign of death." - "Therefore, as the Lord has visited us and has opened our mouths, we shall speak about him always, in the certain knowledge that it is as necessary and as pleasurable as to breathe..." The emphasis of faith is no longer in words like longing and hope.In a sense this and other sermons in the 1830s anticipate the hymn "The Lord has visited his people" ("Hymn Book" (Sangv.rk) I, no. 23): the night has turned into morning, the sorrow has been removed. The gospel has become the present. As before the Church is compared with the widow who cried herself blind at the foot of the cross. Therefore the Saviour lay in the black earth, nights and days long. But now the Word of life has risen from the dead and shall no more taste death. The dismissal of the traditional Christianity, handed down from the past, is extended to include the destructive teaching in schools. The young man on the bier has been compared with the dead Christianity which Grundtvig now rejects. At an early stage Grundtvig was aware of its effects, such as in the Easter sermon in 1830 ("Sunday Book" III, p. 263) where Grundtvig speaks as if he had experienced a breakthrough to his new view. So, the discovery of the Apostles’ Creed in 1825 must have been an enormous feeling of liberation for him – from the worship of the letter that so pervaded his age. Grundtvig speaks about the "living, certain, oral, audible" word in contrast to the "dead, uncertain, written, mute" sign in the book. However, there is as yet no mention of the "Word from the Mouth of our Lord", which belongs to a much later time. Only then does he acquire the calm confidence that enables him to preach on the background of what has happened that the Word has risen from the dead. The question to ask then is what gave him this conviction."Personally I think that it came to him at the same time as life became a present reality for him through the journeys to England," Thaning says. By the same token, Christianity also became a present reality. The discovery of 1825 was readily at hand to grant him a means of expression to convey this present reality and the address to him "from the Lord’s own mouth", on which he was to live. It is no longer enough for him to speak about "the living, solemn evidence at baptism of the whole congregation, the faith we are all to share and confess" as much more certain than everything that is written in all the books of the world. The "Sunday Book" is far from containing the serene insight which, in spite of everything, the Easter sermon, written incidentally on Easter Day, bears witness to. But in 1830 he was not yet ready to sing "The Lord has visited his people", says Thaning.In the sermon from 1834 one meets, as so often in Grundtvig, his emphasis on the continuity in his preaching. In the mourning widow he has always seen an image of the Church, as it appears for the first time in an addition to the sermon on the text in the year 1821 ("Pr.st. Sermons", vol I, p. 296). It ends with a clue: "The Church of Christ now is the Widow of Nain". He will probably have elaborated that idea and concluded his sermon with it. Nevertheless, as it has appeared, the sermon in 1834 is polemically directed against his former view, the mixture of Christian and natural life. He recognizes that there is an element of "something fantastic" sticking to the "view of our youth".Already in a draft for a sermon from March 4,1832, Grundtvig says:"... this was truly a great error among us that we contented ourselves with an obscure and indefinite idea of the Spirit as well as the Truth, for as a consequence of that we were so doubtful and despondent, and we so often mistook the letter for the spirit, or the spirit of phantasy and delusion for that of God..." (vol. V, p. 79f).The heart-searchings which this sermon draft and the sermon on the 16th Sunday after Trinity are evidence of, provide enough argument to point to 1832 as a year of breakthrough. We, his readers, would not have been able to indicate the difference between before and now with stronger expressions than Grundtvig’s own. "He must really have turned into a different kind of person", Thaning says. At the conclusion of the article attention is drawn to the fact that the image of the Son of the Widow also appears in an entirely different context than that of the sermon, viz. in the article about Popular Life and Christianity that Grundtvig wrote in 1847. "What still remains alive of Danish national feeling is exactly like the disconsolate widow at the gate of Nain who follows her only begotten son to the grave" (US DC, p. 86f). The dead youth should not be spoken to about the way to eternal life, but a "Rise!" should be pronounced, and that apparently means: become a living person! On this occasion Grundtvig found an opportunity to clarify his ideas. His "popular life first" is an extension of his "a human being first" from 1837. He had progressed over the last ten years. But the foundation was laid with the distinction between Christian and natural life at the beginning of the 1830s.

Abstract INTRODUCTION Congenital FXIII A-subunit deficiency is a rare, autosomal recessive coagulation disorder with a high risk of life-threatening bleeding complications such as intracranial hemorrhages (Muszbek & Katona. Semin Thromb Hemost 2016;42:429-439). The true prevalence is estimated to be ~1 in 1 to 2 million people worldwide (Anwar R, et al. Pediatrics 2002;109:E32), however, there are only ~1300 diagnosed patients in the world (World Federation of Haemophilia. Report on the Annual Global Survey 2014), suggesting significant under-diagnosis. When severe congenital FXIII deficiency is confirmed, prophylactic replacement therapy is strongly recommended as without prophylaxis, FXIII deficiency places patients at high risk of spontaneous fatal or devastating intracranial bleeding, and because FXIII prophylaxis is reasonably easy and infrequent (once monthly) due to the long half-life of FXIII concentrates. Recombinant FXIII (rFXIII) is a new treatment possibility (Dorey E. Nat Biotechnol 2014;32:210), and here we report long-term safety and efficacy results from mentor™2, the largest clinical trial performed to date in patients with congenital FXIII A-subunit deficiency treated with rFXIII. METHODS The mentor™2 trial was a multinational, open-label, single-arm, multiple-dosing safety extension to the pivotal mentor™1 trial (Inbal A, et al. Blood 2012;119:5111-5117). The trial period was from September 2009 to October 2015. Eligible patients were aged ≥6 years, weighed ≥20 kg, and were diagnosed with congenital FXIII A-subunit deficiency. The Berichrom® FXIII activity assay was used to measure FXIII activity. The trial aimed to assess the long-term safety of replacement therapy with rFXIII (35 IU/kg once monthly) when used for the prevention of bleeding episodes and the treatment of breakthrough bleeds. RESULTS Sixty patients (64% male) were enrolled and exposed to rFXIII; 34 from the mentor™1 trial, and 26 newly recruited patients. Median age of patients at enrollment was 26.0 years (range 7.0-77.0) and 16 (27%) were <18 years old. Patients were exposed to a total of 2410 rFXIII doses and were followed for a total of 186.5 patient-years. Safety: a total of 920 treatment-emergent adverse events (AEs) were reported in 56 of the 60 (93.3%) patients: headache and nasopharyngitis occurred most commonly. No anti-rFXIII neutralizing or non-neutralizing antibodies were detected. In the mentor™1 trial 4 patients developed non-neutralizing antibodies, this was not seen in the current mentor™2 trial. There were no thromboembolic events, fatal AEs, or AEs leading to withdrawal, and no anaphylactic or allergic reactions to rFXIII. Serious AEs were few (19 events in 12 patients) and were evaluated as unlikely to be related to rFXIII. There were 7 AEs in 7 patients that were evaluated as possibly/probably related to the trial product (incorrect dose, overdose, arthralgia, leukopenia, limb injury, alanine aminotransferase increase, and blood alkaline phosphatase increase); all patients recovered. The case of overdose was 2.3 times the planned dose; the patient did not experience any adverse consequences. Efficacy: in all, 8 FXIII treatment-requiring bleeds occurred in 7 patients: 6 were trauma induced and 2 were spontaneous (Table). Three of the 8 bleeds occurred within the first 14 days post rFXIII infusion when FXIII levels would have been predicted to be >30% in all cases, while 5 bleeds occurred between days 17 and 24 post rFXIII infusion. No internal organ bleeds or severe gastrointestinal bleeds occurred. One trauma-induced muscular bleed was treated with rFXIII with an excellent response. The annual mean bleeding rate was 0.043 bleeds/patient/year, implying 1 bleed per patient, per ~23 years (0.032 for traumatic bleeds and 0.011 for spontaneous bleeds). The geometric mean FXIII trough level was 0.17 IU/mL (coefficient of variation of 0.37). CONCLUSION This is the largest dataset on congenital FXIII A-subunit deficiency, both in terms of number of patients and number of patient-years. Over the 6-year trial duration, no safety issues were identified and very few FXIII treatment-requiring bleeding episodes occurred, mainly trauma-related. These data all point to the safety and efficacy of a prophylactic regimen of 35 IU/kg of rFXIII given every 4 weeks to manage congenital deficiency of FXIII A subunit. Disclosures Carcao: Biogen/Idec/Sobi: Honoraria, Research Funding; Baxalta: Honoraria; Bayer: Honoraria; CSL Behring: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Octapharma: Honoraria. Altisent:Octapharma: Consultancy; CSL Behring: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Grifols: Consultancy; Novo Nordisk: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Baxalta: Consultancy, Research Funding. Castaman:Kedrion: Membership on an entity's Board of Directors or advisory committees; Baxalta-Shire: Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Fukutake:simic: Research Funding; Sekisui Medical: Consultancy, Honoraria, Speakers Bureau; Roche Diagnostics: Honoraria, Speakers Bureau; Biogen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbott: Honoraria, Speakers Bureau; Kaketsuken: Honoraria; Japan Blood Products Organization: Honoraria, Research Funding; Torii: Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; LSI Medience: Consultancy; SRL Inc: Consultancy; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxalta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Honoraria; EPS: Research Funding; Siemens: Speakers Bureau. Kerlin:Bayer Healthcare US: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; CSL Behring Foundation: Research Funding. Kessler:Pfizer: Consultancy; Octapharma: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; Grifols: Consultancy; Genentech: Consultancy, Research Funding; Biogen: Consultancy; Bayer: Consultancy, Research Funding; LFB: Other: Member of DSMB; Baxalta: Consultancy, Research Funding. Lassila:Aplagon Oy, Finland: Consultancy, Patents & Royalties. Rosholm:Novo Nordisk: Employment, Equity Ownership. Garly:Novo Nordisk: Employment, Equity Ownership.

BackgroundFor human immunodeficiency virus (HIV)-infected adolescents facing lifelong antiretroviral therapy (ART), short-cycle therapy (SCT) with long-acting agents offers the potential for drug-free weekends, less toxicity, better adherence and cost savings.ObjectivesTo determine whether or not efavirenz (EFV)-based ART in short cycles of 5 days on and 2 days off is as efficacious (in maintaining virological suppression) as continuous EFV-based ART (continuous therapy; CT). Secondary objectives included the occurrence of new clinical HIV events or death, changes in immunological status, emergence of HIV drug resistance, drug toxicity and changes in therapy.DesignOpen, randomised, non-inferiority trial.SettingEurope, Thailand, Uganda, Argentina and the USA.ParticipantsYoung people (aged 8–24 years) on EFV plus two nucleoside reverse transcriptase inhibitors and with a HIV-1 ribonucleic acid level [viral load (VL)] of < 50 copies/ml for > 12 months.InterventionsYoung people were randomised to continue daily ART (CT) or change to SCT (5 days on, 2 days off ART).Main outcome measuresFollow-up was for a minimum of 48 weeks (0, 4 and 12 weeks and then 12-weekly visits). The primary outcome was the difference between arms in the proportion with VL > 50 copies/ml (confirmed) by 48 weeks, estimated using the Kaplan–Meier method (12% non-inferiority margin) adjusted for region and age.ResultsIn total, 199 young people (11 countries) were randomised (n = 99 SCT group,n = 100 CT group) and followed for a median of 86 weeks. Overall, 53% were male; the median age was 14 years (21% ≥ 18 years); 13% were from the UK, 56% were black, 19% were Asian and 21% were Caucasian; and the median CD4% and CD4 count were 34% and 735 cells/mm3, respectively. By week 48, only one participant (CT) was lost to follow-up. The SCT arm had a 27% decreased drug exposure as measured by the adherence questionnaire and a MEMSCap™Medication Event Monitoring System (MEMSCap Inc., Durham, NC, USA) substudy (median cap openings per week: SCT group,n = 5; CT group,n = 7). By 48 weeks, six participants in the SCT group and seven in the CT group had a confirmed VL > 50 copies/ml [difference –1.2%, 90% confidence interval (CI) –7.3% to 4.9%] and two in the SCT group and four in the CT group had a confirmed VL > 400 copies/ml (difference –2.1%, 90% CI –6.2% to 1.9%). All six participants in the SCT group with a VL > 50 copies/ml resumed daily ART, of whom five were resuppressed, three were on the same regimen and two with a switch; two others on SCT resumed daily ART for other reasons. Overall, three participants in the SCT group and nine in the CT group (p = 0.1) changed ART regimen, five because of toxicity, four for simplification reasons, two because of compliance issues and one because of VL failure. Seven young people (SCT group,n = 2; CT group,n = 5) had major non-nucleoside reverse transcriptase inhibitor mutations at VL failure, of whom two (n = 1 SCT group,n = 1 CT group) had the M184V mutation. Two young people had new Centers for Disease Control B events (SCT group,n = 1; CT group,n = 1). There were no significant differences between SCT and CT in grade 3/4 adverse events (13 vs. 14) or in serious adverse events (7 vs. 6); there were fewer ART-related adverse events in the SCT arm (2 vs. 14;p = 0.02). At week 48 there was no evidence that SCT led to increased inflammation using an extensive panel of markers. Young people expressed a strong preference for SCT in a qualitative substudy and in pre- and post-trial questionnaires. In total, 98% of the young people are taking part in a 2-year follow-up extension of the trial.ConclusionsNon-inferiority of VL suppression in young people on EFV-based first-line ART with a VL of < 50 copies/ml was demonstrated for SCT compared with CT, with similar resistance, safety and inflammatory marker profiles. The SCT group had fewer ART-related adverse events. Further evaluation of the immunological and virological impact of SCT is ongoing. A limitation of the trial is that the results cannot be generalised to settings where VL monitoring is either not available or infrequent, nor to use of low-dose EFV. Two-year extended follow-up of the trial is ongoing to confirm the durability of the SCT strategy. Further trials of SCT in settings with infrequent VL monitoring and with other antiretroviral drugs such as tenofovir alafenamide, which has a long intracellular half-life, and/or dolutegravir, which has a higher barrier to resistance, are planned.Trial registrationCurrent Controlled Trials ISRCTN97755073; EUDRACT 2009-012947-40; and CTA 27505/0005/001–0001.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme (projects 08/53/25 and 11/136/108), the European Commission through EuroCoord (FP7/2007/2015), the Economic and Social Research Council, the PENTA Foundation, the Medical Research Council and INSERM SC10-US19, France, and will be published in full inHealth Technology Assessment; Vol. 20, No. 49. See the NIHR Journals Library website for further project information.

Polycythemia vera (PV) is the most common type of Philadelphia-negative myeloproliferative neoplasms (MPNs). PV is a long-term debilitating and life-threatening condition as it is associated with the risk of thrombosis, hemorrhage, and a long-term propensity to develop myelofibrosis and secondary acute myeloid leukemia. Early intervention with disease-modifying treatment that can eradicate the mutated clones is needed to prevent disease progression and transformation. To date, therapeutic options for PV are limited and no cure is available. Most low-risk patients with PV are treated with phlebotomy and low-dose aspirin to manage increased blood viscosity and reduce the risk of vascular events, whereas high-risk patients require cytoreductive treatment. Several cytoreductive agents are available and hydroxyurea (HU) is commonly used as a first-line therapy. Ruxolitinib, a JAK2 inhibitor, is approved as a second-line treatment of PV restricted to patients who are resistant to or intolerant of HU. While interferon alfa agents have reported efficacy in patients with PV, their use has been limited by tolerability concerns. Ropeginterferon alfa-2b (P1101), a long-acting, mono-PEGylated proline interferon, was developed for the treatment of PV. The novel formulation of P1101 improves its pharmacokinetic properties allowing once every 2 weeks administration and offering improved tolerability and convenience. P1101 was evaluated for the treatment of PV in the phase 3 PROUD-PV trial and its extension study CONTINUATION-PV. In CONTINUATION-PV, a significantly higher proportion of patients treated with P1101 achieved complete hematologic response (CHR) with improved disease burden at 36 months compared with patients treated with HU. P1101 has recently been approved by the European Medicines Agency and the Taiwan Food and Drug Administration as monotherapy in adults for the treatment of PV without symptomatic splenomegaly. Here, we describe a phase 2 study to evaluate the safety and efficacy of P1101 in Japanese patients with PV for whom the current standard of treatment is difficult to apply. This is an ongoing phase 2, open-label, multicenter, single-arm study. Eligible patients receive subcutaneous administration of P1101, starting at 100 μg with dose escalation by 50 μg every 2 weeks until stabilization of hematological parameters at the highest tolerated dose. The dose is maintained at the highest dose that can be tolerated and delivers the best disease response. The maximum recommended single dose is 500 μg every 2 weeks. Low-dose aspirin is administered during the 52 weeks of study treatment, unless contraindicated. At weeks 36 and 52, the primary study endpoint, phlebotomy-free CHR, is analyzed. Secondary endpoints include changes in hematocrit, white blood cell count, platelet count, and spleen size from baseline; time requiring no phlebotomy; time to first response; and duration of response maintenance. After completion of 52-weeks of treatment, collection of the long-term follow-up information (blood parameters, molecular and cytogenetic data, safety parameters, and optional bone marrow data) will be continued until the drug becomes commercially available for all patients. Key eligibility criteria include patients diagnosed with PV according to the WHO criteria, a total cumulative HU treatment duration < 3 years at screening, and patients where the current standard therapy is difficult to apply. The study population includes patients across a wide age range (26 to 72 years) with the median age of 54. Patients are 55% female, 48.3% received prior HU therapy, and 93.1% are JAK2 V617F mutation positive. Patients with a documented history of refractoriness to HU, previous use of interferon alfa, or symptomatic splenomegaly are not eligible. Additional baseline characteristics are shown in Table 1. This study addresses an unmet need for patients where standard therapy cannot be applied. The study population includes younger patients who would require treatment, patients who are classified as low risk of thrombosis, but are considered to be candidates for cytoreductive therapy based on disease-related symptoms, and patients who are intolerant to HU. Data from these patients will be used to demonstrate the safety and efficacy of P1101 and help patients for whom the standard of care is difficult to apply. Trial results are anticipated for Q3 2021. NCT04182100. Disclosures Kirito: Novartis Pharma KK: Honoraria; Shire Japan: Honoraria; Pharmaessential Japan: Honoraria. Shimoda:Otsuka Pharmaceutical: Research Funding; Asahi Kasei Medical: Research Funding; Japanese Society of Hematology: Research Funding; The Shinnihon Foundation of Advanced Medical Treatment Research: Research Funding; Pfizer Inc.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Merck & Co.: Research Funding; Astellas Pharma: Research Funding; AbbVie Inc.: Research Funding; PharmaEssentia Japan: Research Funding; Perseus Proteomics: Research Funding; Celgene: Honoraria; Shire plc: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceutical Company: Honoraria; Novartis: Honoraria, Research Funding. Komatsu:Otsuka Pharmaceutical Co., Ltd., Shire Japan KK, Novartis Pharma KK, PharmaEssentia Japan KK, Fuso Pharmaceutical Industries, Ltd., Fujifilm Wako Pure Chemical Corporation, Chugai Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Takeda Pharmaceutica: Research Funding; Meiji Seika Pharma Co., Ltd.: Patents & Royalties: PCT/JP2020/008434, Research Funding; Takeda Pharmaceutical Co., Ltd, Novartis Pharma KK, Shire Japan KK: Speakers Bureau; AbbVie: Other: member of safety assessment committee in M13-834 clinical trial.; PPMX: Consultancy, Research Funding; Otsuka Pharmaceutical Co., Ltd., PharmaEssentia Japan KK, AbbVie GK, Celgene KK, Novartis Pharma KK, Shire Japan KK, Japan Tobacco Inc: Consultancy.

Abstract. 1. The conference The third conference on "Nonlinear VAriability in Geophysics: scaling and multifractal processes" (NVAG 3) was held in Cargese, Corsica, Sept. 10-17, 1993. NVAG3 was joint American Geophysical Union Chapman and European Geophysical Society Richardson Memorial conference, the first specialist conference jointly sponsored by the two organizations. It followed NVAG1 (Montreal, Aug. 1986), NVAG2 (Paris, June 1988; Schertzer and Lovejoy, 1991), five consecutive annual sessions at EGS general assemblies and two consecutive spring AGU meeting sessions. As with the other conferences and workshops mentioned above, the aim was to develop confrontation between theories and experiments on scaling/multifractal behaviour of geophysical fields. Subjects covered included climate, clouds, earthquakes, atmospheric and ocean dynamics, tectonics, precipitation, hydrology, the solar cycle and volcanoes. Areas of focus included new methods of data analysis (especially those used for the reliable estimation of multifractal and scaling exponents), as well as their application to rapidly growing data bases from in situ networks and remote sensing. The corresponding modelling, prediction and estimation techniques were also emphasized as were the current debates about stochastic and deterministic dynamics, fractal geometry and multifractals, self-organized criticality and multifractal fields, each of which was the subject of a specific general discussion. The conference started with a one day short course of multifractals featuring four lectures on a) Fundamentals of multifractals: dimension, codimensions, codimension formalism, b) Multifractal estimation techniques: (PDMS, DTM), c) Numerical simulations, Generalized Scale Invariance analysis, d) Advanced multifractals, singular statistics, phase transitions, self-organized criticality and Lie cascades (given by D. Schertzer and S. Lovejoy, detailed course notes were sent to participants shortly after the conference). This was followed by five days with 8 oral sessions and one poster session. Overall, there were 65 papers involving 74 authors. In general, the main topics covered are reflected in this special issue: geophysical turbulence, clouds and climate, hydrology and solid earth geophysics. In addition to AGU and EGS, the conference was supported by the International Science Foundation, the Centre Nationale de Recherche Scientifique, Meteo-France, the Department of Energy (US), the Commission of European Communities (DG XII), the Comite National Francais pour le Programme Hydrologique International, the Ministere de l'Enseignement Superieur et de la Recherche (France). We thank P. Hubert, Y. Kagan, Ph. Ladoy, A. Lazarev, S.S. Moiseev, R. Pierrehumbert, F. Schmitt and Y. Tessier, for help with the organization of the conference. However special thanks goes to A. Richter and the EGS office, B. Weaver and the AGU without whom this would have been impossible. We also thank the Institut d' Etudes Scientifiques de Cargese whose beautiful site was much appreciated, as well as the Bar des Amis whose ambiance stimulated so many discussions. 2. Tribute to L.F. Richardson With NVAG3, the European geophysical community paid tribute to Lewis Fry Richardson (1881-1953) on the 40th anniversary of his death. Richardson was one of the founding fathers of the idea of scaling and fractality, and his life reflects the European geophysical community and its history in many ways. Although many of Richardson's numerous, outstanding scientific contributions to geophysics have been recognized, perhaps his main contribution concerning the importance of scaling and cascades has still not received the attention it deserves. Richardson was the first not only to suggest numerical integration of the equations of motion of the atmosphere, but also to attempt to do so by hand, during the First World War. This work, as well as a presentation of a broad vision of future developments in the field, appeared in his famous, pioneering book "Weather prediction by numerical processes" (1922). As a consequence of his atmospheric studies, the nondimensional number associated with fluid convective stability has been called the "Richardson number". In addition, his book presents a study of the limitations of numerical integration of these equations, it was in this book that - through a celebrated poem - that the suggestion that turbulent cascades were the fundamental driving mechanism of the atmosphere was first made. In these cascades, large eddies break up into smaller eddies in a manner which involves no characteristic scales, all the way from the planetary scale down to the viscous scale. This led to the Richardson law of turbulent diffusion (1926) and tot he suggestion that particles trajectories might not be describable by smooth curves, but that such trajectories might instead require highly convoluted curves such as the Peano or Weierstrass (fractal) curves for their description. As a founder of the cascade and scaling theories of atmospheric dynamics, he more or less anticipated the Kolmogorov law (1941). He also used scaling ideas to invent the "Richardson dividers method" of successively increasing the resolution of fractal curves and tested out the method on geographical boundaries (as part of his wartime studies). In the latter work he anticipated recent efforts to study scale invariance in rivers and topography. His complex life typifies some of the hardships that the European scientific community has had to face. His educational career is unusual: he received a B.A. degree in physics, mathematics, chemistry, biology and zoology at Cambridge University, and he finally obtained his Ph.D. in mathematical psychology at the age of 47 from the University of London. As a conscientious objector he was compelled to quit the United Kingdom Meteorological Office in 1920 when the latter was militarized by integration into the Air Ministry. He subsequently became the head of a physics department and the principal of a college. In 1940, he retired to do research on war, which was published posthumously in book form (Richardson, 1963). This latter work is testimony to the trauma caused by the two World Wars and which led some scientists including Richardson to use their skills in rational attempts to eradicate the source of conflict. Unfortunately, this remains an open field of research. 3. The contributions in this special issue Perhaps the area of geophysics where scaling ideas have the longest history, and where they have made the largest impact in the last few years, is turbulence. The paper by Tsinober is an example where geometric fractal ideas are used to deduce corrections to standard dimensional analysis results for turbulence. Based on local spontaneous breaking of isotropy of turbulent flows, the fractal notion is used in order to deduce diffusion laws (anomalous with respect to the Richardson law). It is argued that his law is ubiquitous from the atmospheric boundary layer to the stratosphere. The asymptotic intermittency exponent i hypothesized to be not only finite but to be determined by the angular momentum flux. Schmitt et al., Chigirinskaya et al. and Lazarev et al. apply statistical multifractal notions to atmospheric turbulence. In the former, the formal analogy between multifractals and thermodynamics is exploited, in particular to confirm theoretical predictions that sample-size dependent multifractal phase transitions occur. While this quantitatively explains the behavior of the most extreme turbulent events, it suggests that - contrary to the type of multifractals most commonly discussed in the literature which are bounded - more violent (unbounded) multifractals are indeed present in the atmospheric wind field. Chigirinskaya et al. use a tropical rather than mid-latitude set to study the extreme fluctuations form yet another angle: That of coherent structures, which, in the multifractal framework, are identified with singularities of various orders. The existence of a critical order of singularity which distinguishes violent "self-organized critical structures" was theoretically predicted ten years ago; here it is directly estimated. The second of this two part series (Lazarev et al.) investigates yet another aspect of tropical atmospheric dynamics: the strong multiscaling anisotropy. Beyond the determination of universal multifractal indices and critical singularities in the vertical, this enables a comparison to be made with Chigirinskaya et al.'s horizontal results, requiring an extension of the unified scaling model of atmospheric dynamics. Other approaches to the problem of geophysical turbulence are followed in the papers by Pavlos et al., Vassiliadis et al., Voros et al. All of them share a common assumption that a very small number of degrees of freedom (deterministic chaos) might be sufficient for characterizing/modelling the systems under consideration. Pavlos et al. consider the magnetospheric response to solar wind, showing that scaling occurs both in real space (using spectra), and also in phase space; the latter being characterized by a correlation dimension. The paper by Vassiliadis et al. follows on directly by investigating the phase space properties of power-law filtered and rectified gaussian noise; the results further quantify how low phase space correlation dimensions can occur even with very large number of degrees of freedom (stochastic) processes. Voros et al. analyze time series of geomagnetic storms and magnetosphere pulsations, also estimating their correlation dimensions and Lyapounov exponents taking special care of the stability of the estimates. They discriminate low dimensional events from others, which are for instance attributed to incoherent waves. While clouds and climate were the subject of several talks at the conference (including several contributions on multifractal clouds), Cahalan's contribution is the only one in this special issue. Addressing the fundamental problem of the relationship of horizontal cloud heterogeneity and the related radiation fields, he first summarizes some recent numerical results showing that even for comparatively thin clouds that fractal heterogeneity will significantly reduce the albedo. The model used for the distribution of cloud liquid water is the monofractal "bounded cascade" model, whose properties are also outlined. The paper by Falkovich addresses another problem concerning the general circulation: the nonlinear interaction of waves. By assuming the existence of a peak (i.e. scale break) at the inertial oscillation frequency, it is argued that due to remarkable cancellations, the interactions between long inertio-gravity waves and Rossby waves are anomalously weak, producing a "wave condensate" of large amplitude so that wave breaking with front creation can occur. Kagan et al., Eneva and Hooge et al. consider fractal and multifractal behaviour in seismic events. Eneva estimates multifractal exponents of the density of micro-earthquakes induced by mining activity. The effects of sample limitations are discussed, especially in order to distinguish between genuine from spurious multifractal behaviour. With the help of an analysis of the CALNET catalogue, Hooge et al. points out, that the origin of the celebrated Gutenberg-Richter law could be related to a non-classical Self-Organized Criticality generated by a first order phase transition in a multifractal earthquake process. They also analyze multifractal seismic fields which are obtained by raising earthquake amplitudes to various powers and summing them on a grid. In contrast, Kagan, analyzing several earthquake catalogues discussed the various laws associated with earthquakes. Giving theoretical and empirical arguments, he proposes an additive (monofractal) model of earthquake stress, emphasizing the relevance of (asymmetric) stable Cauchy probability distributions to describe earthquake stress distributions. This would yield a linear model for self-organized critical earthquakes. References: Kolmogorov, A.N.: Local structure of turbulence in an incompressible liquid for very large Reynolds number, Proc. Acad. Sci. URSS Geochem. Sect., 30, 299-303, 1941. Perrin, J.: Les Atomes, NRF-Gallimard, Paris, 1913. Richardson, L.F.: Weather prediction by numerical process. Cambridge Univ. Press 1922 (republished by Dover, 1965). Richardson, L.F.: Atmospheric diffusion on a distance neighbour graph. Proc. Roy. of London A110, 709-737, 1923. Richardson, L.F.: The problem of contiguity: an appendix of deadly quarrels. General Systems Yearbook, 6, 139-187, 1963. Schertzer, D., Lovejoy, S.: Nonlinear Variability in Geophysics, Kluwer, 252 pp, 1991.

This article reconstructs the theoretical premises of Tom Regan’s animal ethics, the American philosopher recently disappeared who has given a fundamental contribution to this area of practical ethics, by developing a theory of rights based on the extension to all subjects-of-a-life of Kantian notions such as inherent value and respect. Regan’s theory still remains the most rigorous foundation of an animal ethics alternative to the utilitarian approach of Peter Singer, but it is not without unresolved problems or not entirely satisfactory solutions. To remedy some of them, in the final part the author tries to insert into the Reganian theoretical framework elements of gradualism.

In 2020, we began developing software components for an Application Programming Interface (API)-based integration architecture (the “Specify Network”) to leverage the global footprint of the Specify 7 collections management platform (www.specifysoftware.org) and the analytical services of the Lifemapper (lifemapper.org) and Biotaphy (biotaphy.org) Projects. The University of Kansas Lifemapper Project is a community gateway for species distribution and macroecological modeling. The Biotaphy Project, an extension of Lifemapper, is the product of a six-year, U.S. National Science Foundation-funded collaboration among researchers at the Universities of Michigan, Florida, and Kansas. Biotaphy's primary scope is to use big data methods and high-performance computing to integrate species occurrence data with phylogenetic and biogeographic data sets for large taxonomic and spatial scale analyses. Our initial integrations between Biotaphy and the Specify Network enable Specify users to easily discover remote information related to the specimens in their collection. The widely-discussed, digital specimen architecture being championed by DiSSCo (Distributed System of Scientific Collections www.dissco.eu) and others (https://bit.ly/3jfsAgz) will change data communications between biodiversity collections and the broader biodiversity data community. Those network interactions will evolve from being predominantly one-way, batch-oriented transfers of information from museums to aggregators, to an n-way communications topology that will make specimen record discovery, updates and usage much easier to accomplish. But museum specimens and their catalogs will no longer be an intellectual endpoint of species documentation. Rather, records in collections management systems will increasingly serve as a point of departure for data synthesis, which takes place outside of institutional data domains, and which will overlay the legacy role of museums as authoritative sources of information about the diversity and distribution of life on Earth. Biological museum institutions will continue to play a vital role as the foundation of a global data infrastructure connecting aggregators, collaborative databases, analysis engines, journal publishers, and data set archives. In this presentation, we will provide an update on the components and capabilities that make up integrations in the Specify Network as an exemplar of the global architecture envisaged by the biodiversity research community.

The phenomenon of corruption has no doubt become monstrous and pervasive in the Nigerian state, such that it has threatened the very foundation for her rapid development in socio-economic and political trajectory. Given its innumerable manifestations, corruption has permeated all spheres of life and institutions of governance. More worrisome is the fact that successive governments continue to battle with this endemic scourge, all to no avail as it keeps increasing by leaps and bounds. This paper, therefore, argues that corruption is responsible for the state of underdevelopment in Nigeria and Africa by extension because there exists, a clear nexus between corruption and underdevelopment. The paper further imports the basic tenets of prebendalism as a theoretical construct to understanding corruption and the reasons why it is prevalent. Complementing this theoretical analysis is the utilization of the documentary and desktop analytical approach and/or information cum personal experiences in the articulation of the causes and effects of corruption on the society. The paper therefore concludes that though corruption is pervasive and global, it is antithetical to development in all facets. Hence, it requires a holistic and an unsentimental approach to conquer it, the paper recommends institutionalization of legal frameworks, stringent punishment like capital punishment as well as improvement in salary and wage structures of bureaucratic officials as probable and workable solutions to minimize corruption to its barest minimum.
 
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ABSTRACTMetagenomics of marine sediments has uncovered a broad diversity of new uncultured taxa and provided insights into their metabolic capabilities. Here, we detected microbial lineages from a sediment core near the Jiulong methane reef of the northern South China Sea (at 1,100-m depth). Assembly and binning of the metagenomes resulted in 11 genomes (>85% complete) that represented nine distinct phyla, including candidate phyla TA06 and LCP-89,Lokiarchaeota,Heimdallarchaeota, and a newly described globally distributed phylum (B38). The genome of LCP-89 has pathways for nitrate, selenate, and sulfate reduction, suggesting that they may be involved in mediating these important processes. B38 are able to participate in the cycling of hydrogen and selenocompounds. Many of these uncultured microbes may also be capable of autotrophic CO2fixation, as exemplified by identification of the Wood-Ljungdahl (W-L) pathway. Genes encoding carbohydrate degradation, W-L pathway, Rnf-dependent energy conservation, and Ni/Fe hydrogenases were detected in the transcriptomes of these novel members. Characterization of these new lineages provides insight to the undescribed branches in the tree of life.IMPORTANCESedimentary microorganisms in the South China Sea (SCS) remain largely unknown due to the complexity of sediment communities impacted by continent rifting and extension. Distinct geochemical environments may breed special microbial communities including microbes that are still enigmatic. Functional inference of their metabolisms and transcriptional activity provides insight in the ecological roles and substrate-based interactivity of these unculturedArchaeaandBacteria. These microorganisms play different roles in utilizing inorganic carbon and scavenging diverse organic compounds involved in the deep-sea carbon cycle. The genomes recovered here contributed undescribed species to the tree of life and laid the foundation for future study on these novel phyla persisting in marginal sediments of the SCS.

Zammit, Marisa, and Erica Dornbusch. A Friend In Hope: a Story About Hope's Journey with a Brain Tumour. Brain Tumor Foundation of Canada, 2008.Zammit, Marisa, Erica Dornbusch, and Carole Baillargeon. Mon amie Claire: L'histoire de Claire et de sa tumeur cérébrale. Foundation canadienne des tumeurs cérébrales, 2009.Zammit, Marisa, Erica Dornbusch, and Rocco Speranza. La mia amica Speranza : Speranza e il suo tumore cerebrale. Fondazione canadese del tumore cerebrale, 2008.In an interview with Daytime television, available on YouTube, author Marisa Zammit explains how the Brain Tumour Foundation of Canada contacted her as an established freelance copy writer to come up with a positive story of hope for and about children with brain tumours. According to Susan Marshall, executive director of the Foundation, no other storybook existed for elementary school aged children in Canada before 2008, when the book was published. It is the personal connection, having a child diagnosed with a brain tumour at the age of 4,that motivated Sharon to commission the publication of A Friend in Hope. Marisa had worked previously with illustrator Erica Dornbusch, who had published other storybooks (e.g. Finding Kate's shoes , Mrs. Goodstory) in the past. Marisa is now a school teacher librarian at Holy Cross Catholic Secondary School in Strathroy, Ontario and she has read the book to her students.A Friend in Hope has definitely accomplished its main objective of giving children, parents, and friends a positive and hopeful outlook on the brain tumour journey. Amy Mathias, the Online Community Engagement Coordinator of the Foundation, indicated that 15,000 copies of the book had been distributed in time for the organization’s 30th Anniversary in 2012. It is thanks to the Ronald McDonald House Charities that printing and distribution of the book were possible. The book addresses a very real need not only in alleviating young patients’ fears, but also in explaining brain tumours and their medical implications to children’s teachers and classmates. In turn, adults diagnosed with brain tumours may also use the storybook to approach the subject with their children.As for the translated versions of the book, Pia di Bacco helped translate from English into French by enlisting the support of youth and staff at her school in Montreal. Similarly, her godson Rocco Speranza commissioned grades 4, 5, and 6 youth and staff at the École East Hill School’s Italian program to translate the storybook from English and French into Italian. The motivation in both translation cases was a result of a family member or a student being diagnosed with a brain tumour and the belief in educating youth about brain tumours. Schools across the English Montreal School Board and beyond in Italy, Australia, Argentina, and the USA have also benefited from the storybook.The story is written from the perspective of a young brain tumour patient’s best friend, Danny, Daniel, or Daniele in English, French, and Italian respectively. Danny is trying to understand and, most of all, support his “best buddy,” Hope, who begins her brain tumour journey. As the author Marisa Zammit expressed in the Daytime interview, Hope, or in Italian Speranza, received that name because “it is hope [speranza] that buoys the character through the hardships of the story.” In French, the character’s name is Claire, whose Latin origin “clarus” means “clear, bright, celebrated” and by extension the word “clear”. The French name too, therefore, is representative of her personality and journey.Part of the story involves references to some of the medical treatments that Hope undergoes: MRI, pharmaceutical drugs, radiation therapy, a special helmet and mouthguard, a hospital’s child life centre, and the effects of various treatments on Hope. In every instance, the story uses the narrator’s voice and point of view to express Hope’s various experiences, Danny’s reactions to them, and his own fears. It is a child’s imagination which makes this topic bearable and allows the illustrations to become particularly powerful, when, for example, Danny sees Hope take some medication, which she says will help her “feel well enough to play with [him].” The illustration, in this case, represents a mountain scape and the children’s game of climbing pillows and cushions as if they were mountain climbers, because as Hope says the medication she takes is the “same medicine mountain climbers use,” (ie. dexamethasone). Another exceptional illustration is the one representing an oceanic world with an octopus and fish, which is how Hope faces the MRI machine and transforms it into a submarine. The illustrations are identical across the translations and the English source text, except for one image representing a hockey player in what appears to be Toronto Maple Leafs colours; however, in the French and Italian translations, which originated in Montreal, the team colours were changed to those of the Montreal Canadiens. Habs fans will no doubt appreciate the sensitivity of the illustrator.All in all the story is very well written and the language is suitable for children from grades 2 to 4; however the concepts that are addressed also make this book relevant to higher grade levels. That said, some grammatical inaccuracies exist within the French translation. Public and school libraries would benefit from access to this book, as would hospital library patrons and those who use Faculty of Education libraries. The health education elements of the story are presented in a very appropriate yet realistic manner for the target audience, who will appreciate having access to such a unique resource.Highly Recommended: 4 out of 4 stars Reviewer: Denis LacroixDenis Lacroix has worked at the University of Alberta Libraries since 2003. He is the romance languages and classics librarian and enjoys reading in French, Spanish, and Italian.