Modeling high-performance wormhole NoCs for critical real-time embedded systems

Manycore chips are a promising computing platform to cope with the increasing performance needs of critical real-time embedded systems (CRTES). However, manycores adoption by CRTES industry requires understanding task's timing behavior when their requests use manycore's network-on-chip (NoC) to access hardware shared resources. This paper analyzes the contention in wormhole-based NoC (wNoC) designs - widely implemented in the high-performance domain - for which we introduce a new metric: worst-contention delay (WCD) that captures wNoC impact on worst-case execution time (WCET) in a tighter manner than the existing metric, worst-case traversal time (WCTT). Moreover, we provide an analytical model of the WCD that requests can suffer in a wNoC and we validate it against wNoC designs resembling those in the Tilera-Gx36 and the Intel-SCC 48-core processors. Building on top of our WCD analytical model, we analyze the impact on WCD that different design parameters such as the number of virtual channels, and we make a set of recommendations on what wNoC setups to use in the context of CRTES.Peer ReviewedPostprint (author's final draft

Improving performance guarantees in wormhole mesh NoC designs

Wormhole-based mesh Networks-on-Chip (wNoC) are deployed in high-performance many-core processors due to their physical scalability and low-cost. Delivering tight and time composable Worst-Case Execution Time (WCET) estimates for applications as needed in safety-critical real-time embedded systems is challenged by wNoCs due to their distributed nature. We propose a bandwidth control mechanism for wNoCs that enables the computation of tight time-composable WCET estimates with low average performance degradation and high scalability. Our evaluation with the EEMBC automotive suite and an industrial real-time parallel avionics application confirms so.The research leading to these results is funded by the European Union Seventh Framework Programme under grant agreement no. 287519 (parMERASA) and by the Ministry of Science and Technology of Spain under contract TIN2012-34557. Milos Panic is funded by the Spanish Ministry of Education under the FPU grant FPU12/05966. Carles Hernández is jointly funded by the Spanish Ministry of Economy and Competitiveness and FEDER funds through grant TIN2014-60404-JIN. Jaume Abella is partially supported by the Ministry of Economy and Competitiveness under Ramon y Cajal postdoctoral fellowship number RYC-2013-14717.Peer ReviewedPostprint (author's final draft

pTNoC: Probabilistically time-analyzable tree-based NoC for mixed-criticality systems

The use of networks-on-chip (NoC) in real-time safety-critical multicore systems challenges deriving tight worst-case execution time (WCET) estimates. This is due to the complexities in tightly upper-bounding the contention in the access to the NoC among running tasks. Probabilistic Timing Analysis (PTA) is a powerful approach to derive WCET estimates on relatively complex processors. However, so far it has only been tested on small multicores comprising an on-chip bus as communication means, which intrinsically does not scale to high core counts. In this paper we propose pTNoC, a new tree-based NoC design compatible with PTA requirements and delivering scalability towards medium/large core counts. pTNoC provides tight WCET estimates by means of asymmetric bandwidth guarantees for mixed-criticality systems with negligible impact on average performance. Finally, our implementation results show the reduced area and power costs of the pTNoC.The research leading to these results has received funding from the European Community’s Seventh Framework Programme [FP7/2007-2013] under the PROXIMA Project (www.proxima-project.eu), grant agreement no 611085. This work has also been partially supported by the Spanish Ministry of Science and Innovation under grant TIN2015-65316-P and the HiPEAC Network of Excellence. Mladen Slijepcevic is funded by the Obra Social Fundación la Caixa under grant Doctorado “la Caixa” - Severo Ochoa. Carles Hern´andez is jointly funded by the Spanish Ministry of Economy and Competitiveness (MINECO) and FEDER funds through grant TIN2014-60404-JIN. Jaume Abella has been partially supported by the MINECO under Ramon y Cajal postdoctoral fellowship number RYC-2013-14717.Peer ReviewedPostprint (author's final draft

Adapting TDMA arbitration for measurement-based probabilistic timing analysis

Critical Real-Time Embedded Systems require functional and timing validation to prove that they will perform their functionalities correctly and in time. For timing validation, a bound to the Worst-Case Execution Time (WCET) for each task is derived and passed as an input to the scheduling algorithm to ensure that tasks execute timely. Bounds to WCET can be derived with deterministic timing analysis (DTA) and probabilistic timing analysis (PTA), each of which relies upon certain predictability properties coming from the hardware/software platform beneath. In particular, specific hardware designs are needed for both DTA and PTA, which challenges their adoption by hardware vendors. This paper makes a step towards reconciling the hardware needs of DTA and PTA timing analyses to increase the likelihood of those hardware designs to be adopted by hardware vendors. In particular, we show how Time Division Multiple Access (TDMA), which has been regarded as one of the main DTA-compliant arbitration policies, can be used in the context of PTA and, in particular, of the industrially-friendly Measurement-Based PTA (MBPTA). We show how the execution time measurements taken as input for MBPTA need to be padded to obtain reliable and tight WCET estimates on top of TDMA-arbitrated hardware resources with no further hardware support. Our results show that TDMA delivers tighter WCET estimates than MBPTA-friendly arbitration policies, whereas MBPTA-friendly policies provide higher average performance. Thus, the best policy to choose depends on the particular needs of the end user.The research leading to these results has been funded by the EU FP7 under grant agreement no. 611085 (PROXIMA) and 287519 (parMERASA). This work has also been partially supported by the Spanish Ministry of Economy and Competitiveness (MINECO) under grant TIN2015-65316-P and the HiPEAC Network of Excellence. Miloˇs Pani´c is funded by the Spanish Ministry of Education under the FPU grant FPU12/05966. Jaume Abella has been partially supported by the MINECO under Ramon y Cajal postdoctoral fellowship number RYC-2013-14717.Peer ReviewedPostprint (author's final draft

Risk factors for nosocomial bloodstream infections in COVID-19 affected patients : protocol for a case-control study

Nosocomial bloodstream infection (nBSI) is an important clinical concern among COVID-19 hospitalised patients. It can cause sepsis and septic shock leading to high morbidity, mortality, and the emergence of antibiotic resistance. The aim of this case-control study is to identify the risk factors associated with the nBSI development in COVID-19 hospitalised patients and its incidence. A retrospective case-control study will be performed. Cases will include nBSI episodes of adult patients (≥18 years) admitted to Hospital Universitari Germans Trias i Pujol, Barcelona, Spain, from April to December 2020 with a diagnosis of SARS-CoV-2 pneumonia. Patients transferred from other hospitals will be excluded. Controls will include hospitalisation episodes of COVID-19 patients without nBSI. We will recruit a minimum of 74 nBSI episodes (cases) and 74 controls (according to sample size calculation). We will collect data on sociodemographics, clinical status at admission, hospital admission, in-hospital mortality, and exposure data (use of antivirals, glucocorticoids or immunomodulatory agents, length of hospitalisation, and use of medical devices such as intravenous catheters). A bivariate and a subsequent multivariate regression analysis will be performed to assess the independent effect of the associated risk factors after adjusting for confounders. The nBSI incidence rate will be estimated according to the number of nBSI episodes in admitted COVID-19 patients among the total person-month of follow-up. The protocol of this study was approved by the Ethical Committee for Drug Investigation of the Hospital Universitari Germans Trias i Pujol. The results of this case-control study will be published in a peer reviewed journal

Probabilistic timing analysis on time-randomized platforms for the space domain

Timing Verification is a fundamental step in real-time embedded systems, with measurement-based timing analysis (MBTA) being the most common approach used to that end. We present a Space case study on a real platform that has been modified to support a probabilistic variant of MBTA called MBPTA. Our platform provides the properties required by MBPTA with the predicted WCET estimates with MBPTA being competitive to those with current MBTA practice while providing more solid evidence on their correctness for certification.The research leading to these results has received funding from the European Community’s FP7 [FP7/2007-2013] under the PROXIMA Project (www.proxima-project.eu), grant agreement no 611085. This work has also been partially supported by the Spanish Ministry of Science and Innovation under grant TIN2015-65316-P and the HiPEAC Network of Excellence. Jaume Abella has been partially supported by the Ministry of Economy and Competitiveness under Ramon y Cajal postdoctoral fellowship number RYC-2013-14717. Carles Hernandez is jointly funded by the Spanish Ministry of Economy and Competitiveness and FEDER funds through grant TIN2014-60404-JIN.Peer ReviewedPostprint (author's final draft

Identification of Plitidepsin as Potent Inhibitor of SARS-CoV-2-Induced Cytopathic Effect After a Drug Repurposing Screen

There is an urgent need to identify therapeutics for the treatment of Coronavirus disease 2019 (COVID-19). Although different antivirals are given for the clinical management of SARS-CoV-2 infection, their efficacy is still under evaluation. Here, we have screened existing drugs approved for human use in a variety of diseases, to compare how they counteract SARS-CoV-2-induced cytopathic effect and viral replication in vitro. Among the potential 72 antivirals tested herein that were previously proposed to inhibit SARS-CoV-2 infection, only 18 % had an IC50 below 25 µM or 102 IU/ml. These included plitidepsin, novel cathepsin inhibitors, nelfinavir mesylate hydrate, interferon 2-alpha, interferon-gamma, fenofibrate, camostat along the well-known remdesivir and chloroquine derivatives. Plitidepsin was the only clinically approved drug displaying nanomolar efficacy. Four of these families, including novel cathepsin inhibitors, blocked viral entry in a cell-type specific manner. Since the most effective antivirals usually combine therapies that tackle the virus at different steps of infection, we also assessed several drug combinations. Although no particular synergy was found, inhibitory combinations did not reduce their antiviral activity. Thus, these combinations could decrease the potential emergence of resistant viruses. Antivirals prioritized herein identify novel compounds and their mode of action, while independently replicating the activity of a reduced proportion of drugs which are mostly approved for clinical use. Combinations of these drugs should be tested in animal models to inform the design of fast track clinical trials.info:eu-repo/semantics/publishedVersio

Improving Measurement-Based Timing Analysis through Randomisation and Probabilistic Analysis

The use of increasingly complex hardware and software platforms in response to the ever rising performance demands of modern real-time systems complicates the verification and validation of their timing behaviour, which form a time-and-effort-intensive step of system qualification or certification. In this paper we relate the current state of practice in measurement-based timing analysis, the predominant choice for industrial developers, to the proceedings of the PROXIMA project in that very field. We recall the difficulties that the shift towards more complex computing platforms causes in that regard. Then we discuss the probabilistic approach proposed by PROXIMA to overcome some of those limitations. We present the main principles behind the PROXIMA approach as well as the changes it requires at hardware or software level underneath the application. We also present the current status of the project against its overall goals, and highlight some of the principal confidence-building results achieved so far

A cluster-randomized trial of hydroxychloroquine for prevention of Covid-19

Background: current strategies for preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are limited to nonpharmacologic interventions. Hydroxychloroquine has been proposed as a postexposure therapy to prevent coronavirus disease 2019 (Covid-19), but definitive evidence is lacking. Methods: we conducted an open-label, cluster-randomized trial involving asymptomatic contacts of patients with polymerase-chain-reaction (PCR)-confirmed Covid-19 in Catalonia, Spain. We randomly assigned clusters of contacts to the hydroxychloroquine group (which received the drug at a dose of 800 mg once, followed by 400 mg daily for 6 days) or to the usual-care group (which received no specific therapy). The primary outcome was PCR-confirmed, symptomatic Covid-19 within 14 days. The secondary outcome was SARS-CoV-2 infection, defined by symptoms compatible with Covid-19 or a positive PCR test regardless of symptoms. Adverse events were assessed for up to 28 days. Results: the analysis included 2314 healthy contacts of 672 index case patients with Covid-19 who were identified between March 17 and April 28, 2020. A total of 1116 contacts were randomly assigned to receive hydroxychloroquine and 1198 to receive usual care. Results were similar in the hydroxychloroquine and usual-care groups with respect to the incidence of PCR-confirmed, symptomatic Covid-19 (5.7% and 6.2%, respectively; risk ratio, 0.86 [95% confidence interval, 0.52 to 1.42]). In addition, hydroxychloroquine was not associated with a lower incidence of SARS-CoV-2 transmission than usual care (18.7% and 17.8%, respectively). The incidence of adverse events was higher in the hydroxychloroquine group than in the usual-care group (56.1% vs. 5.9%), but no treatment-related serious adverse events were reported. Conclusions: postexposure therapy with hydroxychloroquine did not prevent SARS-CoV-2 infection or symptomatic Covid-19 in healthy persons exposed to a PCR-positive case patient. (Funded by the crowdfunding campaign YoMeCorono and others; BCN-PEP-CoV2 ClinicalTrials.gov number, NCT04304053.)

Hydroxychloroquine for Early Treatment of Adults With Mild Coronavirus Disease 2019: A Randomized, Controlled Trial

No effective treatments for coronavirus disease 2019 (COVID-19) exist. We aimed to determine whether early treatment with hydroxychloroquine (HCQ) would be efficacious for outpatients with COVID-19.The authors thank Gerard Carot-Sans, PhD, for providing medical writing support during the revisions of the subsequent drafts of the manuscript; the personnel from the Fights Aids and Infectious Diseases Foundation for their support in administration, human resources and supply chain management; Eric Ubals (Pierce AB) and Òscar Palao (Opentic) for website and database management; Óscar Camps and OpenArms nongovernmental organization for nursing home operations; and Anna Valentí and the Hospital Germans Trias i Pujol Human Resources Department for telephone monitoring. We thank Consorci Sanitari del Maresme, Centre Sociosanitari El Carme, l'Hospital General de Granollers and occupational hazards department of Hospital Germans Trias i Pujol for their contribution with patient enrollment. We are very grateful to Marc Clotet and Natalia Sánchez who coordinated the JoEmCorono crowd-funding campaign. We thank the Hospital Germans Trias Pujol Institutional Review Board and the Spanish Agency of Medicines and Medical Devices for their prompt action for consideration and approvals to the protocol. Financial support. This work was mainly supported by the crowd-funding campaign JoEmCorono (https://www.yomecorono.com/) with contributions from more than 72 000 citizens and corporations. The study also received financial support from Laboratorios Rubió, Laboratorios Gebro Pharma, Zurich Seguros, SYNLAB Barcelona, and Generalitat de Catalunya. Laboratorios Rubió also contributed to the study with the required doses of hydroxychloroquine (Dolquine®). Foundation Dorneur partly funded lab equipment at Irsi-Caixa.Peer reviewe