Synthesising Labelled Transitions and Operational Congruences in Reactive Systems, Part 1

The dynamics of process calculi, e.g. CCS, have often been defined using a labelled transition system (LTS). More recently it has become common when defining dynamics to use reaction rules ---i.e. unlabelled transition rules--- together with a structural congruence. This form, which I call a reactive system, is highly expressive but is limited in an important way: LTSs lead more naturally to operational equivalences and preorders. This paper shows how to synthesise an LTS for a wide range of reactive systems. A label for an agent (process) `a' is defined to be any context `F' which intuitively is just large enough so that the agent `Fa' (`a' in context `F') is able to perform a reaction step. The key contribution of my work is the precise definition of ``just large enough'' in terms of the categorical notion of relative pushout (RPO). I then prove that several operational equivalences and preorders (strong bisimulation, weak bisimulation, the traces preorder, and the failures preorder) are congruences when sufficient RPOs exist

Acute: high-level programming language design for distributed computation

Existing languages provide good support for typeful programming of standalone programs. In a distributed system, however, there may be interaction between multiple instances of many distinct programs, sharing some (but not necessarily all) of their module structure, and with some instances rebuilt with new versions of certain modules as time goes on. In this paper we discuss programming language support for such systems, focussing on their typing and naming issues. We describe an experimental language, Acute, which extends an ML core to support distributed development, deployment, and execution, allowing type-safe interaction between separately-built programs. The main features are: (1) type-safe marshalling of arbitrary values; (2) type names that are generated (freshly and by hashing) to ensure that type equality tests suffice to protect the invariants of abstract types, across the entire distributed system; (3) expression-level names generated to ensure that name equality tests suffice for type-safety of associated values, e.g. values carried on named channels; (4) controlled dynamic rebinding of marshalled values to local resources; and (5) thunkification of threads and mutexes to support computation mobility. These features are a large part of what is needed for typeful distributed programming. They are a relatively lightweight extension of ML, should be efficiently implementable, and are expressive enough to enable a wide variety of distributed infrastructure layers to be written as simple library code above the byte-string network and persistent store APIs. This disentangles the language runtime from communication intricacies. This paper highlights the main design choices in Acute. It is supported by a full language definition (of typing, compilation, and operational semantics), by a prototype implementation, and by example distribution libraries

Rationale and design of the GUIDE-IT study: Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure.

OBJECTIVES: The GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) study is designed to determine the safety, efficacy, and cost-effectiveness of a strategy of adjusting therapy with the goal of achieving and maintaining a target N-terminal pro-B-type natriuretic peptide (NT-proBNP) level of BACKGROUND: Elevations in natriuretic peptide (NP) levels provide key prognostic information in patients with HF. Therapies proven to improve outcomes in patients with HF are generally associated with decreasing levels of NPs, and observational data show that decreases in NP levels over time are associated with favorable outcomes. Results from smaller prospective, randomized studies of this strategy thus far have been mixed, and current guidelines do not recommend serial measurement of NP levels to guide therapy in patients with HF. METHODS: GUIDE-IT is a prospective, randomized, controlled, unblinded, multicenter clinical trial designed to randomize approximately 1,100 high-risk subjects with systolic HF (left ventricular ejection fraction ≤40%) to either usual care (optimized guideline-recommended therapy) or a strategy of adjusting therapy with the goal of achieving and maintaining a target NT-proBNP level of CONCLUSIONS: The GUIDE-IT study is designed to definitively assess the effects of an NP-guided strategy in high-risk patients with systolic HF on clinically relevant endpoints of mortality, hospitalization, quality of life, and medical resource use. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure [GUIDE-IT]; NCT01685840)

Effect of Natriuretic Peptide-Guided Therapy on Hospitalization or Cardiovascular Mortality in High-Risk Patients With Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial.

Importance: The natriuretic peptides are biochemical markers of heart failure (HF) severity and predictors of adverse outcomes. Smaller studies have evaluated adjusting HF therapy based on natriuretic peptide levels ( guided therapy ) with inconsistent results. Objective: To determine whether an amino-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided treatment strategy improves clinical outcomes vs usual care in high-risk patients with HF and reduced ejection fraction (HFrEF). Design, Settings, and Participants: The Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) study was a randomized multicenter clinical trial conducted between January 16, 2013, and September 20, 2016, at 45 clinical sites in the United States and Canada. This study planned to randomize 1100 patients with HFrEF (ejection fraction ≤40%), elevated natriuretic peptide levels within the prior 30 days, and a history of a prior HF event (HF hospitalization or equivalent) to either an NT-proBNP-guided strategy or usual care. Interventions: Patients were randomized to either an NT-proBNP-guided strategy or usual care. Patients randomized to the guided strategy (n = 446) had HF therapy titrated with the goal of achieving a target NT-proBNP of less than 1000 pg/mL. Patients randomized to usual care (n = 448) had HF care in accordance with published guidelines, with emphasis on titration of proven neurohormonal therapies for HF. Serial measurement of NT-proBNP testing was discouraged in the usual care group. Main Outcomes and Measures: The primary end point was the composite of time-to-first HF hospitalization or cardiovascular mortality. Prespecified secondary end points included all-cause mortality, total hospitalizations for HF, days alive and not hospitalized for cardiovascular reasons, the individual components on the primary end point, and adverse events. Results: The data and safety monitoring board recommended stopping the study for futility when 894 (median age, 63 years; 286 [32%] women) of the planned 1100 patients had been enrolled with follow-up for a median of 15 months. The primary end point occurred in 164 patients (37%) in the biomarker-guided group and 164 patients (37%) in the usual care group (adjusted hazard ratio [HR], 0.98; 95% CI, 0.79-1.22; P = .88). Cardiovascular mortality was 12% (n = 53) in the biomarker-guided group and 13% (n = 57) in the usual care group (HR, 0.94; 95% CI; 0.65-1.37; P = .75). None of the secondary end points nor the decreases in the NT-proBNP levels achieved differed significantly between groups. Conclusions and Relevance: In high-risk patients with HFrEF, a strategy of NT-proBNP-guided therapy was not more effective than a usual care strategy in improving outcomes. Trial Registration: clinicaltrials.gov Identifier: NCT01685840

Acute: High-level programming language design for distributed computation : Design rationale and language definition

This paper studies key issues for distributed programming in high-level languages. We discuss the design space and describe an experimental language, Acute, which we have defined and implemented. Acute extends an OCaml core to support distributed development, deployment, and execution, allowing type-safe interaction between separately-built programs. It is expressive enough to enable a wide variety of distributed infrastructure layers to be written as simple library code above the byte-string network and persistent store APIs, disentangling the language runtime from communication. This requires a synthesis of novel and existing features: (1) type-safe marshalling of values between programs; (2) dynamic loading and controlled rebinding to local resources; (3) modules and abstract types with abstraction boundaries that are respected by interaction; (4) global names, generated either freshly or based on module hashes: at the type level, as runtime names for abstract types; and at the term level, as channel names and other interaction handles; (5) versions and version constraints, integrated with type identity; (6) local concurrency and thread thunkification; and (7) second-order polymorphism with a namecase construct. We deal with the interplay among these features and the core, and develop a semantic definition that tracks abstraction boundaries, global names, and hashes throughout compilation and execution, but which still admits an efficient implementation strategy

Measurements on the reality of the wavefunction

Quantum mechanics is an outstandingly successful description of nature, underpinning fields from biology through chemistry to physics. At its heart is the quantum wavefunction, the central tool for describing quantum systems. Yet it is still unclear what the wavefunction actually is: does it merely represent our limited knowledge of a system, or is it an element of reality? Recent no-go theorems argued that if there was any underlying reality to start with, the wavefunction must be real. However, that conclusion relied on debatable assumptions, without which a partial knowledge interpretation can be maintained to some extent. A different approach is to impose bounds on the degree to which knowledge interpretations can explain quantum phenomena, such as why we cannot perfectly distinguish non-orthogonal quantum states. Here we experimentally test this approach with single photons. We find that no knowledge interpretation can fully explain the indistinguishability of non-orthogonal quantum states in three and four dimensions. Assuming that some underlying reality exists, our results strengthen the view that the entire wavefunction should be real. The only alternative is to adopt more unorthodox concepts such as backwards-in-time causation, or to completely abandon any notion of objective reality.Comment: 7 pages, 4 figure

Differences in NT-proBNP Response and Prognosis in Men and Women With Heart Failure With Reduced Ejection Fraction.

Background NT-proBNP (N-terminal pro-B-type natriuretic peptide) is a prognostic biomarker in heart failure (HF) with reduced ejection fraction. However, it is unclear whether there is a sex difference in NT-proBNP response and whether the therapeutic goal of NT-proBNP ≤1000 pg/mL has equivalent prognostic value in men and women with HF with reduced ejection fraction. Methods and Results In a secondary analysis of the GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment) trial we analyzed trends in NT-proBNP and goal attainment by sex. Differences in clinical characteristics, HF treatment, and time to all-cause death or HF hospitalization were compared. Landmark analysis at 3 months determined the prognostic value of early NT-proBNP goal achievement in men and women. Of the 286 (32%) women and 608 (68%) men in the GUIDE-IT trial, women were more likely to have a nonischemic cause and shorter duration of HF. Guideline-directed medical therapy was less intense over time in women. The absolute NT-proBNP values were consistently lower in women; however, the change in NT-proBNP and clinical outcomes were similar. After adjustment, women achieving the NT-proBNP goal had an 82% reduction in death or HF hospitalization compared with a 59% reduction in men. Conclusions Men and women with HF with reduced ejection fraction had a similar NT-proBNP response despite less intensive HF treatment among women. However, compared with men, the early NT-proBNP goal of ≤1000 pg/mL had greater prognostic value in women. Future efforts should be aimed at intensifying guideline-directed medical therapy in women, which may result in greater NT-proBNP reductions and improved outcomes in women with HF with reduced ejection fraction. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01685840

Conduct of clinical trials in the era of COVID-19: JACC scientific expert panel

The coronavirus disease-2019 (COVID-19) pandemic has profoundly changed clinical care and research, including the conduct of clinical trials, and the clinical research ecosystem will need to adapt to this transformed environment. The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory and the Academic Research Consortium, composed of academic investigators from the United States and Europe, patients, the U.S. Food and Drug Administration, the National Institutes of Health, and industry members. A series of meetings were convened to address the challenges caused by the COVID-19 pandemic, review options for maintaining or altering best practices, and establish key recommendations for the conduct and analysis of clinical trials for cardiovascular disease and heart failure. This paper summarizes the discussions and expert consensus recommendations

Why protective measurement does not establish the reality of the quantum state

“Protective measurement” refers to two related schemes for finding the expectation value of an observable without disturbing the state of a quantum system, given a single copy of the system that is subject to a “protecting” operation. There have been several claims that these schemes support interpreting the quantum state as an objective property of a single quantum system. Here we provide three counter-arguments, each of which we present in two versions tailored to the two different schemes. Our first argument shows that the same resources used in protective measurement can be used to reconstruct the quantum state in a different way via process tomography. Our second argument is based on exact analyses of special cases of protective measurement, and our final argument is to construct explicit “휓-epistemic” toy models for protective measurement, which strongly suggest that protective measurement does not imply the reality of the quantum state. The common theme of the three arguments is that almost all of the information comes from the “protection” operation rather than the quantum state of the system, and hence the schemes have no implications for the reality of the quantum state