Using Flow Specifications of Parameterized Cache Coherence Protocols for Verifying Deadlock Freedom

We consider the problem of verifying deadlock freedom for symmetric cache coherence protocols. In particular, we focus on a specific form of deadlock which is useful for the cache coherence protocol domain and consistent with the internal definition of deadlock in the Murphi model checker: we refer to this deadlock as a system- wide deadlock (s-deadlock). In s-deadlock, the entire system gets blocked and is unable to make any transition. Cache coherence protocols consist of N symmetric cache agents, where N is an unbounded parameter; thus the verification of s-deadlock freedom is naturally a parameterized verification problem. Parametrized verification techniques work by using sound abstractions to reduce the unbounded model to a bounded model. Efficient abstractions which work well for industrial scale protocols typically bound the model by replacing the state of most of the agents by an abstract environment, while keeping just one or two agents as is. However, leveraging such efficient abstractions becomes a challenge for s-deadlock: a violation of s-deadlock is a state in which the transitions of all of the unbounded number of agents cannot occur and so a simple abstraction like the one above will not preserve this violation. In this work we address this challenge by presenting a technique which leverages high-level information about the protocols, in the form of message sequence dia- grams referred to as flows, for constructing invariants that are collectively stronger than s-deadlock. Efficient abstractions can be constructed to verify these invariants. We successfully verify the German and Flash protocols using our technique

Dynamic Cutoff Detection in Parameterized Concurrent Programs

Abstract. We consider the class of finite-state programs executed by an unbounded number of replicated threads communicating via shared variables. The thread-state reachability problem for this class is essential in software verification using predicate abstraction. While this problem is decidable via Petri net coverability analysis, techniques solely based on coverability suffer from the problem’s exponential-space complexity. In this paper, we present an alternative method based on a thread-state cutoff: a number n of threads that suffice to generate all reachable thread states. We give a condition, verifiable dynamically during reachability analysis for increasing n, that is sufficient to conclude that n is a cutoff. We then make the method complete, via a coverability query that is of low cost in practice. We demonstrate the efficiency of the approach on Petri net encodings of communication protocols, as well as on non-recursive Boolean programs run by arbitrarily many parallel threads.

Validation of the NANA (Novel Assessment of Nutrition and Ageing) touch screen system for use at home by older adults

Prospective measurement of nutrition, cognition, and physical activity in later life would facilitate early detection of detrimental change and early intervention but is hard to achieve in community settings. Technology can simplify the task and facilitate daily data collection. The Novel Assessment of Nutrition and Ageing (NANA) toolkit was developed to provide a holistic picture of an individual's function including diet, cognition and activity levels. This study aimed to validate the NANA toolkit for data collection in the community. Forty participants aged 65 years and over trialled the NANA toolkit in their homes for three 7-day periods at four-week intervals. Data collected using the NANA toolkit were compared with standard measures of diet (four-day food diary), cognitive ability (processing speed) and physical activity (self-report). Bland–Altman analysis of dietary intake (energy, carbohydrates, protein fat) found a good relationship with the food diary and cognitive processing speed and physical activity (hours) were significantly correlated with their standard counterparts. The NANA toolkit enables daily reporting of data that would otherwise be collected sporadically while reducing demands on participants; older adults can complete the daily reporting at home without a researcher being present; and it enables prospective investigation of several domains at onc

Levetiracetam versus phenytoin for second-line treatment of paediatric convulsive status epilepticus (EcLiPSE): a multicentre, open-label, randomised trial

Background Phenytoin is the recommended second-line intravenous anticonvulsant for treatment of paediatric convulsive status epilepticus in the UK; however, some evidence suggests that levetiracetam could be an effective and safer alternative. This trial compared the efficacy and safety of phenytoin and levetiracetam for second-line management of paediatric convulsive status epilepticus.Methods This open-label, randomised clinical trial was undertaken at 30 UK emergency departments at secondary and tertiary care centres. Participants aged 6 months to under 18 years, with convulsive status epilepticus requiring second-line treatment, were randomly assigned (1:1) using a computer-generated randomisation schedule to receive levetiracetam (40 mg/kg over 5 min) or phenytoin (20 mg/kg over at least 20 min), stratified by centre. The primary outcome was time from randomisation to cessation of convulsive status epilepticus, analysed in the modified intention-to-treat population (excluding those who did not require second-line treatment after randomisation and those who did not provide consent). This trial is registered with ISRCTN, number ISRCTN22567894.Findings Between July 17, 2015, and April 7, 2018, 1432 patients were assessed for eligibility. After exclusion of ineligible patients, 404 patients were randomly assigned. After exclusion of those who did not require second-line treatment and those who did not consent, 286 randomised participants were treated and had available data: 152 allocated to levetiracetam, and 134 to phenytoin. Convulsive status epilepticus was terminated in 106 (70%) children in the levetiracetam group and in 86 (64%) in the phenytoin group. Median time from randomisation to cessation of convulsive status epilepticus was 35 min (IQR 20 to not assessable) in the levetiracetam group and 45 min (24 to not assessable) in the phenytoin group (hazard ratio 1·20, 95% CI 0·91–1·60; p=0·20). One participant who received levetiracetam followed by phenytoin died as a result of catastrophic cerebral oedema unrelated to either treatment. One participant who received phenytoin had serious adverse reactions related to study treatment (hypotension considered to be immediately life-threatening [a serious adverse reaction] and increased focal seizures and decreased consciousness considered to be medically significant [a suspected unexpected serious adverse reaction]). Interpretation Although levetiracetam was not significantly superior to phenytoin, the results, together with previously reported safety profiles and comparative ease of administration of levetiracetam, suggest it could be an appropriate alternative to phenytoin as the first-choice, second-line anticonvulsant in the treatment of paediatric convulsive status epilepticus

SARS-CoV-2-specific nasal IgA wanes 9 months after hospitalisation with COVID-19 and is not induced by subsequent vaccination

BACKGROUND: Most studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced. METHODS: In this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data. FINDINGS: Strong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal and plasma anti-S IgG remained elevated for at least 12 months (p < 0.0001) with plasma neutralising titres that were raised against all variants compared to controls (p < 0.0001). Of 323 with complete data, 307 were vaccinated between 6 and 12 months; coinciding with rises in nasal and plasma IgA and IgG anti-S titres for all SARS-CoV-2 variants, although the change in nasal IgA was minimal (1.46-fold change after 10 months, p = 0.011) and the median remained below the positive threshold determined by pre-pandemic controls. Samples 12 months after admission showed no association between nasal IgA and plasma IgG anti-S responses (R = 0.05, p = 0.18), indicating that nasal IgA responses are distinct from those in plasma and minimally boosted by vaccination. INTERPRETATION: The decline in nasal IgA responses 9 months after infection and minimal impact of subsequent vaccination may explain the lack of long-lasting nasal defence against reinfection and the limited effects of vaccination on transmission. These findings highlight the need to develop vaccines that enhance nasal immunity. FUNDING: This study has been supported by ISARIC4C and PHOSP-COVID consortia. ISARIC4C is supported by grants from the National Institute for Health and Care Research and the Medical Research Council. Liverpool Experimental Cancer Medicine Centre provided infrastructure support for this research. The PHOSP-COVD study is jointly funded by UK Research and Innovation and National Institute of Health and Care Research. The funders were not involved in the study design, interpretation of data or the writing of this manuscript

Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain–gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials