Global access to affordable direct oral anticoagulants

Poor control of cardiovascular disease accounts for a substantial proportion of the disease burden in developing countries, but often essential anticoagulant medicines for preventing strokes and embolisms are not widely available. In 2019, direct oral anticoagulants were added to the World Health Organization's WHO Model list of essential medicines. The aims of this paper are to summarize the benefits of direct oral anticoagulants for patients with cardiovascular disease and to discuss ways of increasing their usage internationally. Although the cost of direct oral anticoagulants has provoked debate, the affordability of introducing these drugs into clinical practice could be increased by: price negotiation; pooled procurement; competitive tendering; the use of patent pools; and expanded use of generics. In 2017, only 14 of 137 countries that had adopted national essential medicines lists included a direct oral anticoagulant on their lists. This number could increase rapidly if problems with availability and affordability can be tackled. Once the types of patient likely to benefit from direct oral anticoagulants have been clearly defined in clinical practice guidelines, coverage can be more accurately determined and associated costs can be better managed. Government action is required to ensure that direct oral anticoagulants are covered by national budgets because the absence of reimbursement remains an impediment to achieving universal coverage. Tackling cardiovascular disease with the aid of direct oral anticoagulants is an essential component of efforts to achieve the World Health Organization's target of reducing premature deaths due to noncommunicable disease by 25% by 2025

Improving the use of research evidence in guideline development: 9. Grading evidence and recommendations

BACKGROUND: The World Health Organization (WHO), like many other organisations around the world, has recognised the need to use more rigorous processes to ensure that health care recommendations are informed by the best available research evidence. This is the ninth of a series of 16 reviews that have been prepared as background for advice from the WHO Advisory Committee on Health Research to WHO on how to achieve this. OBJECTIVES: We reviewed the literature on grading evidence and recommendations in guidelines. METHODS: We searched PubMed and three databases of methodological studies for existing systematic reviews and relevant methodological research. We did not conduct a full systematic review ourselves. Our conclusions are based on the available evidence, consideration of what WHO and other organisations are doing and logical arguments. KEY QUESTIONS AND ANSWERS: Should WHO grade the quality of evidence and the strength of recommendations? • Users of recommendations need to know how much confidence they can place in the underlying evidence and the recommendations. The degree of confidence depends on a number of factors and requires complex judgments. These judgments should be made explicitly in WHO recommendations. A systematic and explicit approach to making judgments about the quality of evidence and the strength of recommendations can help to prevent errors, facilitate critical appraisal of these judgments, and can help to improve communication of this information. What criteria should be used to grade evidence and recommendations? • Both the quality of evidence and the strength of recommendations should be graded. The criteria used to grade the strength of recommendations should include the quality of the underlying evidence, but should not be limited to that. • The approach to grading should be one that has wide international support and is suitable for a wide range of different types of recommendations. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, which is currently suggested in the Guidelines for WHO Guidelines, is being used by an increasing number of other organizations internationally. It should be used more consistently by WHO. Further developments of this approach should ensure its wide applicability. Should WHO use the same grading system for all of its recommendations? • Although there are arguments for and against using the same grading system across a wide range of different types of recommendations, WHO should use a uniform grading system to prevent confusion for developers and users of recommendations

Interpreting the results of patient reported outcome measures in clinical trials: The clinician's perspective

This article deals with the problem of interpreting health-related quality of life (HRQL) outcomes in clinical trials. First, we will briefly describe how dichotomization and item response theory can facilitate interpretation. Based on examples from the medical literature for the interpretation of HRQL scores we will show that dichotomies may help clinicians understand information provided by HRQL instruments in RCTs. They can choose thresholds to calculate proportions of patients benefiting based on absolute scores or change scores. For example, clinicians interpreting clinical trial results could consider the difference in the proportion of patients who achieve a mean score of 50 before and after an intervention on a scale from 1 to 100. For the change score approach, they could consider the proportion of patients who have changed by a score of 5 or more. Finally, they can calculate the proportion of patients benefiting and transform these numbers into a number needed to treat or natural frequencies. Second, we will describe in more detail an approach to the interpretation of HRQL scores based on the minimal important difference (MID) and proportions. The MID is the smallest difference in score in the outcome of interest that informed patients or informed proxies perceive as important, either beneficial or harmful, and that would lead the patient or clinician to consider a change in the management. Any change in management will depend on the downsides, including cost and inconvenience, associated with the intervention. Investigators can help with the interpretation of HRQL scores by determining the MID of an HRQL instrument and provide mean differences in relation to the MID. For instance, for an MID of 0.5 on a seven point scale investigators could provide the mean change on the instrument as well as the proportion of patients with scores greater than the MID. Thus, there are several steps investigators can take to facilitate this process to help bringing HRQL information closer to the bedside

A thylakoid membrane-bound and redox-active rubredoxin (RBD1) functions in de novo assembly and repair of photosystem II.

Photosystem II (PSII) undergoes frequent photooxidative damage that, if not repaired, impairs photosynthetic activity and growth. How photosynthetic organisms protect vulnerable PSII intermediate complexes during de novo assembly and repair remains poorly understood. Here, we report the genetic and biochemical characterization of chloroplast-located rubredoxin 1 (RBD1), a PSII assembly factor containing a redox-active rubredoxin domain and a single C-terminal transmembrane α-helix (TMH) domain. RBD1 is an integral thylakoid membrane protein that is enriched in stroma lamellae fractions with the rubredoxin domain exposed on the stromal side. RBD1 also interacts with PSII intermediate complexes containing cytochrome b 559 Complementation of the Chlamydomonas reinhardtii (hereafter Chlamydomonas) RBD1-deficient 2pac mutant with constructs encoding RBD1 protein truncations and site-directed mutations demonstrated that the TMH domain is essential for de novo PSII assembly, whereas the rubredoxin domain is involved in PSII repair. The rubredoxin domain exhibits a redox midpoint potential of +114 mV and is proficient in 1-electron transfers to a surrogate cytochrome c in vitro. Reduction of oxidized RBD1 is NADPH dependent and can be mediated by ferredoxin-NADP+ reductase (FNR) in vitro. We propose that RBD1 participates, together with the cytochrome b 559, in the protection of PSII intermediate complexes from photooxidative damage during de novo assembly and repair. This role of RBD1 is consistent with its evolutionary conservation among photosynthetic organisms and the fact that it is essential in photosynthetic eukaryotes

A systematic review on randomized controlled trials : Coaching elements of digital services to support chronically ill adolescents during transition of care

Aims To define digital health services that have been studied among chronically ill adolescents and to describe e-health coaching elements that may have an impact on transition outcomes. Design Systematic review without meta-analysis. Data sources MEDLINE (Ovid), Pub Med, Scopus and CINAHL on 28 May 2018. Review methods Peer-reviewed articles published between January 2008-May 2018 were reviewed following the Cochrane Handbook for Systematic Reviews of Interventions and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. Results Twelve randomized controlled trials were included. The interventions varied significantly in duration and content. E-coaching that included human and social support showed positive impact on transition outcomes. Digital health services incorporated into usual care provide efficient and accessible care. Conclusion E-coaching elements enable tailoring and personalization and present a tool for supporting and motivating chronically ill adolescents during transition of care. Future research should evaluate the effectiveness of e-coaching elements. Impact Digital services are considered a means for increasing adolescents' motivation for self-care and for increasing their accessibility to health care. The coaching elements in digital services consist of a theoretical basis, human support, interactive means and social support. Included interventions varied in terms of duration, dose, content and design. Our results may serve the development of digital health services for adolescents in transition. E-coaching can be used to engage and motivate chronically ill adolescents to improve health behaviour and self-management during transition of care.Peer reviewe

Improving the use of research evidence in guideline development: 14. Reporting guidelines

BACKGROUND: The World Health Organization (WHO), like many other organisations around the world, has recognised the need to use more rigorous processes to ensure that health care recommendations are informed by the best available research evidence. This is the 14(th )of a series of 16 reviews that have been prepared as background for advice from the WHO Advisory Committee on Health Research to WHO on how to achieve this. OBJECTIVES: We reviewed the literature on reporting guidelines and recommendations. METHODS: We searched PubMed and three databases of methodological studies for existing systematic reviews and relevant methodological research. We did not conduct systematic reviews ourselves. Our conclusions are based on the available evidence, consideration of what WHO and other organisations are doing and logical arguments. KEY QUESTIONS AND ANSWERS: There is little empirical evidence that addresses these questions. Our answers are based on logical arguments and standards put forward by other groups. What standard types of recommendations or reports should WHO use? • WHO should develop standard formats for reporting recommendations to facilitate recognition and use by decision makers for whom the recommendations are intended, and to ensure that all the information needed to judge the quality of a guideline, determine its applicability and, if needed, adapt it, is reported. • WHO should develop standard formats for full systematically developed guidelines that are sponsored by WHO, rapid assessments, and guidelines that are endorsed by WHO. • All three formats should include the same information as full guidelines, indicating explicitly what the group preparing the guideline did not do, as well as the methods that were used. • These formats should be used across clinical, public health and health systems recommendations. How should recommendations be formulated and reported? • Reports should be structured, using headings that correspond to those suggested by the Conference on Guideline Standardization or similar headings. • The quality of evidence and strength of recommendations should be reported explicitly using a standard approach. • The way in which recommendations are formulated should be adapted to the specific characteristics of a specific guideline. • Urgent attention should be given to developing a template that provides decision makers with the relevant global evidence that is needed to inform a decision and offers practical methods for incorporating the context specific evidence and judgements that are needed

Adverse Event Assessment of Antimuscarinics for Treating Overactive Bladder: A Network Meta-Analytic Approach

BACKGROUND: Overactive bladder (OAB) affects the lives of millions of people worldwide and antimuscarinics are the pharmacological treatment of choice. Meta-analyses of all currently used antimuscarinics for treating OAB found similar efficacy, making the choice dependent on their adverse event profiles. However, conventional meta-analyses often fail to quantify and compare adverse events across different drugs, dosages, formulations, and routes of administration. In addition, the assessment of the broad variety of adverse events is dissatisfying. Our aim was to compare adverse events of antimuscarinics using a network meta-analytic approach that overcomes shortcomings of conventional analyses. METHODS: Cochrane Incontinence Group Specialized Trials Register, previous systematic reviews, conference abstracts, book chapters, and reference lists of relevant articles were searched. Eligible studies included randomized controlled trials comparing at least one antimuscarinic for treating OAB with placebo or with another antimuscarinic, and adverse events as outcome measures. Two authors independently extracted data. A network meta-analytic approach was applied allowing for joint assessment of all adverse events of all currently used antimuscarinics while fully maintaining randomization. RESULTS: 69 trials enrolling 26'229 patients were included. Similar overall adverse event profiles were found for darifenacin, fesoterodine, transdermal oxybutynin, propiverine, solifenacin, tolterodine, and trospium chloride but not for oxybutynin orally administered when currently used starting dosages were compared. CONCLUSIONS: The proposed generally applicable transparent network meta-analytic approach summarizes adverse events in an easy to grasp way allowing straightforward benchmarking of antimuscarinics for treating OAB in clinical practice. Most currently used antimuscarinics seem to be equivalent first choice drugs to start the treatment of OAB except for oral oxybutynin dosages of ≥ 10 mg/d which may have more unfavorable adverse event profiles

Criminal liability of autonomous agents: from the unthinkable to the plausible

Series : Lecture notes in computer science, ISSN 0302-9743, vol. 8929The evolution of information technologies have brought us to a point where we are confronted with the existence of agents - computational entities - which are able to act autonomously with little or no human intervention. And their behavior can damage individual or collective interests that are protected by criminal law. Based on the analysis of different models of criminal responsibility of legal persons - which constituted an interesting advance in the criminal law in rela-tion to what was hitherto traditionally accepted -, we will appraise whether the necessary legal elements to have direct criminal liability of artificial entities are present.This work is part-funded by CROWDSOURCING project (Reference: DER2012-39492-C02-01)

Two-species mixture of quantum degenerate Bose and Fermi gases

We have produced a macroscopic quantum system in which a Li-6 Fermi sea coexists with a large and stable Na-23 Bose-Einstein condensate. This was accomplished using inter-species sympathetic cooling of fermionic Li-6 in a thermal bath of bosonic Na-23

Ultra-cold atoms in an optical cavity: two-mode laser locking to the cavity avoiding radiation pressure

The combination of ultra-cold atomic clouds with the light fields of optical cavities provides a powerful model system for the development of new types of laser cooling and for studying cooperative phenomena. These experiments critically depend on the precise tuning of an incident pump laser with respect to a cavity resonance. Here, we present a simple and reliable experimental tuning scheme based on a two-mode laser spectrometer. The scheme uses a first laser for probing higher-order transversal modes of the cavity having an intensity minimum near the cavity's optical axis, where the atoms are confined by a magnetic trap. In this way the cavity resonance is observed without exposing the atoms to unwanted radiation pressure. A second laser, which is phase-locked to the first one and tuned close to a fundamental cavity mode drives the coherent atom-field dynamics.Comment: 7 pages, 7 figure