| 1. |
- Abdulla, Salim, et al.
(författare)
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Baseline data of parasite clearance in patients with falciparum malaria treated with an artemisinin derivative : an individual patient data meta-analysis
- 2015
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Ingår i: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Background: Artemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This study collated data from clinical trials of artemisinin derivatives in falciparum malaria with frequent parasite counts to provide reference parasite clearance estimates stratified by location, treatment and time, to examine host factors affecting parasite clearance, and to assess the relationships between parasite clearance and risk of recrudescence during follow-up. Methods: Data from 24 studies, conducted from 1996 to 2013, with frequent parasite counts were pooled. Parasite clearance half-life (PC1/2) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC1/2 and risk of recrudescence within areas with reported delayed parasite clearance (western Cambodia, western Thailand after 2000, southern Vietnam, southern Myanmar) and in all other areas where parasite populations are artemisinin sensitive. Results: PC1/2 was estimated in 6975 patients, 3288 of whom also had treatment outcomes evaluate d during 28-63 days follow-up, with 93 (2.8 %) PCR-confirmed recrudescences. In areas with artemisinin-sensitive parasites, the median PC1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC1/2 > 5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC1/2 by 8.1 % (95 % CI 3.2-12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC1/2 (HR = 2.91, 95 % CI 1.95-4.34 for twofold increase, p < 0.001) and high initial parasitaemia (HR = 2.23, 95 % CI 1.44-3.45 for tenfold increase, p < 0.001) were associated independently with an increased risk of recrudescence. In western Cambodia, the region with the highest prevalence of artemisinin resistance, there was no evidence for increasing PC1/2 since 2007. Conclusions: Several factors affect PC1/2. As substantial heterogeneity in parasite clearance exists between locations, early detection of artemisinin resistance requires reference PC1/2 data. Studies with frequent parasite count measurements to characterize PC1/2 should be encouraged. In western Cambodia, where PC1/2 values are longest, there is no evidence for recent emergence of higher levels of artemisinin resistance.
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| 2. |
- Bozakov, Zdravko, et al.
(författare)
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Deliverable D2.1 - First Version of Low-Level Core Transport System
- 2016
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Rapport (refereegranskat)abstract
- This document presents the first version of the low-level Core Transport System in NEAT, to be used for development of a reference implementation of the NEAT System. The design of this core transport system takes into consideration the Transport Services and the API defined in Task 1.3 and in close coordination with the overall architecture (Task 1.2). To realise the basic Transport Services provided by the API, a set of low-level transport functionalities has to be provided by the NEAT core transport system. These functionalities take the formof several building blocks, or NEAT Components, each representing an associated implementation activity. Some of the components are needed to ensure the basic operation of the NEAT System—e.g., a NEAT Flow Endpoint, a callback-based NEAT API Framework, the NEAT Logic and the functionality to Connect to a name. Some other components are needed to ensure connectivity usingMiddlebox Traversal techniques (e.g., TURN), discovery of path support for different transport protocols using Happy Eyeballs mechanisms, offering end-to end Security (e.g., (D)TLS over transport), gather statistics for the users or system administrators, and the ability to apply different policies in order to influence the decision-making process of the transport system. This document describes each of these building blocks and related design choices.
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| 3. |
- Fairhurst, Gorry, et al.
(författare)
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Deliverable D1.1 - NEAT Architecture
- 2016
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Rapport (refereegranskat)abstract
- Ossification of the Internet transport-layer architecture is a significant barrier to innovation of the Internet. Such innovation is desirable for many reasons. Current applications often need to implement their own mechanisms to receive the transport service they need, but many do not have the breadth of adapting to all possible network characteristics. An updated transport architecture can do much to make the Internet more flexible and extensible. New ground-breaking services often require different or updated transport protocols, could benefit from better signalling between application and network, or desire a more flexible choice of which network path is used for which traffic. This document therefore proposes a new transport architecture. Such architecture lowers the barrier to service innovation by proposing a “transport system”, the NEAT System, that can leverage the rich set of available transport protocols. It paves the way for an architectural change of the Internet where new transport-layer services can seamlessly be integrated and quickly made available, minimising deployment difficulties, and allowing Internet innovators to take advantage of them wherever possible. The document provides a survey of the state-of-the-art to identify the architectural obstacles to, and opportunities for, evolution of the transport layer. It also details a set of general requirements for a new transport architecture. This new architecture is motivated by a set of use-cases, followed by a description of the NEAT architecture for a transport system, designed to permit applications to select appropriate transports based on their needs and the available transport services.
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| 4. |
- Grinnemo, Karl-Johan, 1968-, et al.
(författare)
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Deliverable D3.2 - Final Report on Transport Protocol Enhancements
- 2017
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Rapport (refereegranskat)abstract
- This deliverable provides a final report on the work on transport protocol enhancements done inWork Package 3. First, we report on the extensions made to the SCTP protocol that turn it into a viable alternative to TCP and allow to deliver a lower-latency transport service. Next, we describe our work to develop a framework for providing a deadline-aware, less-than-best-effort transport service, targeting background traffic and thus addressing requirements on NEAT from the EMC use case. We also present our efforts to design and implement a latency-aware scheduler for MPTCP, which enables NEAT to offer a transport service that meets the needs of latency-sensitive applications, and that efficiently utilises available network resources. Lastly, this document informs on our work on coupled congestion control for TCP, a mechanism that treats a bundle of parallel TCP flows between the same pair of hosts as a single unit. By efficiently multiplexing concurrent TCP flows, our coupled congestion control alleviates the effects of queueing, and tends to result in a more efficient usage of available bandwidth, where the flows’ aggregate capacity share can be apportioned based on application preferences.
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| 5. |
- Khademi, Naeem, et al.
(författare)
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Deliverable D2.2 - Core Transport System, with both Low-level and High-level Components
- 2017
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Rapport (refereegranskat)abstract
- This document presents the core transport system in NEAT, as used for development of thereference implementation of the NEAT System. The document describes the componentsnecessary to realise the basic Transport Services provided by the NEAT User API, with thedescription of a set of NEAT building blocks and their related design choices. The designof this core transport system takes into consideration the Transport Services and the API(defined in Task 1.3) and in close coordination with the overall architecture (Task 1.2).To realise the Transport Services provided by the API, a set of transport functionalitieshas to be provided by the NEAT Core Transport System. These functionalities take the formof several building blocks, or NEAT Components, each representing an associated implementationactivity. Some of the components are needed to ensure the basic operation ofthe NEAT System—e.g., a NEAT Flow Endpoint, a callback-based NEAT API Framework, theNEAT Logic and the functionality to Connect to a name. Additional components are neededfor: (a) ensuring connectivity, by means of mechanisms for discovery of path support fordifferent protocols; (b) supporting end-to-end security; (c) the ability to apply differentpolicies to influence the decision-making process of the transport system; (d) providingother important functionalities (e.g., a user-space SCTP stack, or gathering statistics forusers or system administrators).This document updates Deliverable D2.1; in particular, the descriptions of NEAT componentspresented here correspond to the implementation status at the time of writing,and as such they replace those in D2.1.
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| 6. |
- Khademi, Naeem, et al.
(författare)
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Deliverable D2.3 - Final Version of Core Transport System
- 2017
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Rapport (refereegranskat)abstract
- This document presents the core transport system in NEAT, as used for development of the reference implementation of the NEAT System. The document describes the components necessary to realise the basic Transport Services provided by the NEAT User API, with the description of a set of NEAT building blocks and their related design choices. The design of this core transport system, which is the final product ofWork Package 2, is driven by the Transport Services and API design from Task 1.4, and in close coordination with the overall NEAT architecture defined in Task 1.2. To realise the Transport Services provided by the API, a set of transport functions has to be provided by the NEAT Core Transport System. These functions take the form of several building blocks, or NEAT Components, each representing an associated implementation activity. Some components are needed to ensure the basic operation of the NEAT System—e.g., a NEAT Flow Endpoint, a callback-based NEAT API Framework, the NEAT Logic and the functionality to Connect to a name. Additional components are needed for: (a) ensuring connectivity, by means of mechanisms for discovery of path support for different protocols; (b) supporting end-to-end security; (c) the ability to apply different policies to influence the decision-making process of the transport system; (d) providing other important functionalities (e.g., a user-space SCTP stack, or gathering statistics for users or system administrators). This document updates Deliverable D2.2; in particular, the descriptions of NEAT components presented here correspond to their implementation status by the end of WP2, and as such they supersede those in D2.2.
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| 7. |
- Khademi, Naeem, et al.
(författare)
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NEAT: A Platform- and Protocol-Independent Internet Transport API
- 2017
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Ingår i: IEEE Communications Magazine. - : IEEE Communications Society. - 0163-6804 .- 1558-1896. ; 55:6, s. 46-54
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Tidskriftsartikel (refereegranskat)abstract
- The sockets Applications Programming Interface (API) has become the standard way that applications access the transport services offered by the Internet Protocol stack. This paper presents NEAT, a user-space library that can provide an alternate transport API. NEAT allows applications to request the service they need using a new design that is agnostic to the specific choice of transport protocol underneath. This not only allows applications to take advantage of common protocol machinery, but also eases introduction of new network mechanisms and transport protocols. The paper describes the components of the NEAT library and illustrates the important benefits that can be gained from this new approach. NEAT is a software platform for developing advanced network applications that was designed in accordance with the standardization efforts on Transport Services (TAPS) in the Internet Engineering Task Force (IETF), but its features exceed the envisioned functionality of a TAPS system.
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| 8. |
- Papastergiou, Giorgos, et al.
(författare)
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De-Ossifying the Internet Transport Layer: A Survey and Future Perspectives
- 2017
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Ingår i: IEEE Communications Surveys and Tutorials. - : IEEE. - 1553-877X. ; 19:1, s. 619-639
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Tidskriftsartikel (refereegranskat)abstract
- It is widely recognized that the Internet transport layer has become ossified, where further evolution has become hard or even impossible. This is a direct consequence of the ubiquitous deployment of middleboxes that hamper the deployment of new transports, aggravated further by the limited flexibility of the application programming interface (API) typically presented to applications. To tackle this problem, a wide range of solutions have been proposed in the literature, each aiming to address a particular aspect. Yet, no single proposal has emerged that is able to enable evolution of the transport layer. In this paper, after an overview of the main issues and reasons for transport-layer ossification, we survey proposed solutions and discuss their potential and limitations. The survey is divided into five parts, each covering a set of point solutions for a different facet of the problem space: (1) designing middlebox-proof transports; (2) signaling for facilitating middlebox traversal; (3) enhancing the API between the applications and the transport layer; (4) discovering and exploiting end-to-end capabilities; and (5) enabling user-space protocol stacks. Based on this analysis, we then identify further development needs toward an overall solution. We argue that the development of a comprehensive transport layer framework, able to facilitate the integration and cooperation of specialized solutions in an application-independent and flexible way, is a necessary step toward making the Internet transport architecture truly evolvable. To this end, we identify the requirements for such a framework and provide insights for its development
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| 9. |
- Schmidt, Amand F., et al.
(författare)
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PCSK9 genetic variants and risk of type 2 diabetes : a mendelian randomisation study
- 2017
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Ingår i: The Lancet Diabetes and Endocrinology. - : ELSEVIER SCIENCE INC. - 2213-8587 .- 2213-8595. ; 5:2, s. 97-105
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Tidskriftsartikel (refereegranskat)abstract
- Background Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way off sets their substantial benefi ts. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely eff ects of PCSK9 inhibitors on diabetes risk. Methods In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA 1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores. Findings Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0.09 mmol/L, 95% CI 0.02 to 0.15), bodyweight (1.03 kg, 0.24 to 1.82), waist-to-hip ratio (0.006, 0.003 to 0.010), and an odds ratio for type diabetes of 1.29 (1.11 to 1.50). Based on the collected data, we did not identify associations with HbA 1c (0.03%, -0.01 to 0.08), fasting insulin (0.00%, -0.06 to 0.07), and BMI (0.11 kg/m(2), -0.09 to 0.30). Interpretation PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefi ts of PCSK9 inhibitor treatment, as was previously done for statins.
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| 10. |
- Schmidt, Amand F., et al.
(författare)
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Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9
- 2019
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Ingår i: BMC Cardiovascular Disorders. - : BMC. - 1471-2261 .- 1471-2261. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
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