An efficient asynchronous multiplier

An efficient asynchronous serial-parallel multiplier architecture is presented. If offers significant advantages over conventional clocked versions, without some of the drawbacks normally associated with similar asynchronous techniques, such as excessive area. It is shown how a general asynchronous communication element can be designed and illustrated with the CMOS multiplier chip implementation. It is also shown how the multiplier could form the basis for a faster and more robust implementation of the Rivest-Sharmir-Adleman (RSA) public-key cryptosystem

An efficient asynchronous multiplier

An efficient asynchronous serial-parallel multiplier architecture is presented. If offers significant advantages over conventional clocked versions, without some of the drawbacks normally associated with similar asynchronous techniques, such as excessive area. It is shown how a general asynchronous communication element can be designed and illustrated with the CMOS multiplier chip implementation. It is also shown how the multiplier could form the basis for a faster and more robust implementation of the Rivest-Sharmir-Adleman (RSA) public-key cryptosystem

RATE OF DEGRADATION OF CENTRALIZED OPTIMIZATION SOLUTIONS AND ITS APPLICATION TO HIGH PERFORMANCE DOMAIN FORMATION IN AD HOC NETWORKS

Future military systems such a FCS require a robust and flexible network that supports thousands of ad hoc nodes; therefore, we must ensure the scalability of networking protocols (e.g., rout-ing, security and QoS). The use of hierarchy is a powerful solu-tion to the scaling problem, since it allows networking protocols to operate on a limited number of nodes, as opposed to the entire network. We have proposed an automated solution to dynami-cally create and maintain such hierarchy based on a combina-tion of global optimization algorithms [1] and local distributed maintenance protocols [2]. Global optimization clearly im-proves performance in a static network but, it is unclear how effective it is in a dynamic ad hoc environment. As network and node characteristics change, the optimization algorithm may use incomplete, stale, or even inaccurate metrics. In this paper, we analyze how the hierarchy created deteriorates from the optimal as network conditions change. We show that the fragility of the optimization depends on the particular cost function and the number of metrics that change. More important, we show, for the first time, that global optimization can remain effective for long periods with good cost functions, even in large dynamic ad hoc networks (where metrics may change rapidly due to node mobility and links making and breaking). This result shows that, with fast optimization algorithms such as modified Simulated Annealing [1], future military systems can use global optimiza-tion to autoconfigure domains to significantly improve perform-ance. We also show that local maintenance protocols support the global optimization mechanisms by extending the time the hierarchy remains feasible

A Framework for Scalable Hierarchical Routing in Mobile Ad Hoc Networks

The theoretical performance advantages of dividing a network into independent routing domains is well known; however, the actual benefits are hard to quantify and are often not sufficient to outweigh the added complexity. Justification of domains is especially hard in mobile ad hoc networks (MANETS), because reconfiguration overhead increases and use of single interface routers. Nevertheless, we believe that with the right domain configuration and inter-domain routing protocol we can get better performance using hierarchy than flat routing, especially in heterogeneous and dynamic networks. This paper proposes a framework for scalable routing in MANETs based on auto-configured optimized routing domains and an enhanced inter-domain routing scheme. To minimize overall overhead, the inter-domain routing protocol exploits existing messages needed for domain maintenance. The framework allows different routing protocols to run in each domain. OPNET simulations show the benefits of the proposed approach using OLSR for intra-domain routing. Results show significant reduction in protocol overhead, increased route stability and increased route availability in a dynamic heterogeneous network

A natural product compound inhibits coronaviral replication in vitro by binding to the conserved Nsp9 SARS-CoV-2 protein

The Nsp9 replicase is a conserved coronaviral protein that acts as an essential accessory component of the multi-subunit viral replication/transcription complex. Nsp9 is the predominant substrate for the essential nucleotidylation activity of Nsp12. Compounds specifically interfering with this viral activity would facilitate its study. Using a native mass-spectrometry-based approach to screen a natural product library for Nsp9 binders, we identified an ent-kaurane natural product, oridonin, capable of binding to purified SARS-CoV-2 Nsp9 with micromolar affinities. By determining the crystal structure of the Nsp9-oridonin complex, we showed that oridonin binds through a conserved site near Nsp9’s C-terminal GxxxG-helix. In enzymatic assays, oridonin’s binding to Nsp9 reduces its potential to act as substrate for Nsp12’s Nidovirus RdRp-Associated Nucleotidyl transferase (NiRAN) domain. We also showed using in vitro cellular assays oridonin, while cytotoxic at higher doses has broad antiviral activity, reducing viral titer following infection with either SARS-CoV-2 or, to a lesser extent, MERS-CoV. Accordingly, these preliminary findings suggest that the oridonin molecular scaffold may have the potential to be developed into an antiviral compound to inhibit the function of Nsp9 during coronaviral replication

The Rise of Adaptive Platform Trials in Critical Care

As durable learning research systems, adaptive platform trials represent a transformative new approach to accelerating clinical evaluation and discovery in critical care. This Perspective provides a brief introduction to the concept of adaptive platform trials, describes several established and emerging platforms in critical care, and surveys some opportunities and challenges for their implementation and impact.<br/

Repair of Acute Respiratory Distress Syndrome in COVID-19 by Stromal Cells (REALIST-COVID Trial):A Multicentre, Randomised, Controlled Trial

RationaleMesenchymal stromal cells (MSCs) may modulate inflammation, promoting repair in COVID-19-related Acute Respiratory Distress Syndrome (ARDS).ObjectivesWe investigated safety and efficacy of ORBCEL-C (CD362-enriched, umbilical cord-derived MSCs) in COVID-related ARDS.MethodsThis multicentre, randomised, double-blind, allocation concealed, placebo-controlled trial (NCT03042143) randomised patients with moderate-to-severe COVID-related ARDS to receive ORBCEL-C (400million cells) or placebo (Plasma-Lyte148).MeasurementsThe primary safety and efficacy outcomes were incidence of serious adverse events and oxygenation index at day 7 respectively. Secondary outcomes included respiratory compliance, driving pressure, PaO2/FiO2 ratio and SOFA score. Clinical outcomes relating to duration of ventilation, length of intensive care unit and hospital stays, and mortality were collected. Long-term follow up included diagnosis of interstitial lung disease at 1 year, and significant medical events and mortality at 2 years. Transcriptomic analysis was performed on whole blood at day 0, 4 and 7.Main results60 participants were recruited (final analysis n=30 ORBCEL-C, n=29 placebo: 1 in placebo group withdrew consent). 6 serious adverse events occurred in the ORBCEL-C and 3 in the placebo group, RR 2.9(0.6-13.2)p=0.25. Day 7 mean[SD] oxygenation index did not differ (ORBCEL-C 98.357.2], placebo 96.667.3). There were no differences in secondary surrogate outcomes, nor mortality at day 28, day 90, 1 or 2 years. There was no difference in prevalence of interstitial lung disease at 1year nor significant medical events up to 2 years. ORBCEL-C modulated the peripheral blood transcriptome.ConclusionORBCEL-C MSCs were safe in moderate-to-severe COVID-related ARDS, but did not improve surrogates of pulmonary organ dysfunction. Clinical trial registration available at www.Clinicaltrialsgov, ID: NCT03042143. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/)

Long-term impact of COVID-19 hospitalisation among individuals with pre-existing airway diseases in the UK:a multicentre, longitudinal cohort study - PHOSP-COVID

BACKGROUND: The long-term outcomes of COVID-19 hospitalisation in individuals with pre-existing airway diseases are unknown.METHODS: Adult participants hospitalised for confirmed or clinically suspected COVID-19 and discharged between 5 March 2020 and 31 March 2021 were recruited to the Post-hospitalisation COVID-19 (PHOSP-COVID) study. Participants attended research visits at 5 months and 1 year post discharge. Clinical characteristics, perceived recovery, burden of symptoms and health-related quality of life (HRQoL) of individuals with pre-existing airway disease (i.e., asthma, COPD or bronchiectasis) were compared to the non-airways group.RESULTS: A total of 615 out of 2697 (22.8%) participants had a history of pre-existing airway diseases (72.0% diagnosed with asthma, 22.9% COPD and 5.1% bronchiectasis). At 1 year, the airways group participants were less likely to feel fully recovered (20.4% versus 33.2%, p&lt;0.001), had higher burden of anxiety (29.1% versus 22.0%, p=0.002), depression (31.2% versus 24.7%, p=0.006), higher percentage of impaired mobility using short physical performance battery ≤10 (57.4% versus 45.2%, p&lt;0.001) and 27% had a new disability (assessed by the Washington Group Short Set on Functioning) versus 16.6%, p=0.014. HRQoL assessed using EQ-5D-5L Utility Index was lower in the airways group (mean±SD 0.64±0.27 versus 0.73±0.25, p&lt;0.001). Burden of breathlessness, fatigue and cough measured using a study-specific tool was higher in the airways group.CONCLUSION: Individuals with pre-existing airway diseases hospitalised due to COVID-19 were less likely to feel fully recovered, had lower physiological performance measurements, more burden of symptoms and reduced HRQoL up to 1 year post-hospital discharge.</p