On an interpretation of safe recursion in light affine logic

AbstractWe introduce a subalgebra BC− of Bellantoni and Cook's safe-recursion function algebra BC. Functions of the subalgebra have safe arguments that are non-contractible (i.e non-duplicable). We propose a definition of safe and normal variables in light affine logic (LAL), and show that BC− is the largest subalgebra that is interpretable in LAL, relative to that definition. Though BC− itself is not PF complete, there are extensions of it (by additional schemes for defining functions with safe arguments) that are, and are still interpretable in LAL and so preserve PF closure. We focus on one such which is BC− augmented by a definition-by-cases construct and a restricted form of definition-by-recursion scheme over safe arguments. As a corollary we obtain a new proof of the PF completeness of LAL

Symbolic Backwards-Reachability Analysis for Higher-Order Pushdown Systems

Higher-order pushdown systems (PDSs) generalise pushdown systems through the use of higher-order stacks, that is, a nested "stack of stacks" structure. These systems may be used to model higher-order programs and are closely related to the Caucal hierarchy of infinite graphs and safe higher-order recursion schemes. We consider the backwards-reachability problem over higher-order Alternating PDSs (APDSs), a generalisation of higher-order PDSs. This builds on and extends previous work on pushdown systems and context-free higher-order processes in a non-trivial manner. In particular, we show that the set of configurations from which a regular set of higher-order APDS configurations is reachable is regular and computable in n-EXPTIME. In fact, the problem is n-EXPTIME-complete. We show that this work has several applications in the verification of higher-order PDSs, such as linear-time model-checking, alternation-free mu-calculus model-checking and the computation of winning regions of reachability games

Digital Cognitive Behavioral Therapy for Insomnia in Women With Chronic Migraines

Objective/Background: Insomnia commonly co-occurs with chronic migraines (CM). Non-pharmacological treatments for insomnia in CM patients remain understudied. This is a proof-of-concept study, which aims to evaluate the feasibility, acceptability, and preliminary efficacy of a digital cognitive behavioral therapy for insomnia (dCBT-I) for individuals with CM and insomnia (CM-I) in the United States. Methods: We recruited 42 females with CM-I symptoms from a U.S.-based observational cohort and from the general population via advertisements. Within a multiple baseline design, participants were randomized to receive dCBT-I after 2, 4, or 6 weeks of completing baseline sleep diaries. DCBT-I was scrutinized against benchmarks for completion rates (≥90% to complete dCBT-I), acceptability (≥80% to find dCBT-I acceptable), and posttreatment changes in insomnia symptoms (≥50% indicating a clinically relevant improvement in their insomnia symptoms). As a secondary measure, we also reported percentage of individuals reverting to episodic migraines. Results: Out of 42 randomized, 35 (83.3%) completed dCBT-I within the 12 weeks provided. Of these completers, 33 (94.3%) reported being satisfied (n = 16) or very satisfied (n = 17) with treatment. Additionally, 65.7% of completers responded to treatment as per universally accepted criteria for insomnia. Lastly, 34% of completers reverted from CM to episodic migraine. Conclusion: This study provides evidence for the feasibility and acceptability of dCBT-I in patients with CM-I complaints. Effects of improving insomnia and migraines were suggested. These results indicate that a randomized controlled trial is needed to determine the efficacy of dCBT-I in CM patients

Towards a canonical classical natural deduction system

This paper studies a new classical natural deduction system, presented as a typed calculus named \lml. It is designed to be isomorphic to Curien-Herbelin's calculus, both at the level of proofs and reduction, and the isomorphism is based on the correct correspondence between cut (resp. left-introduction) in sequent calculus, and substitution (resp. elimination) in natural deduction. It is a combination of Parigot's $\lambda\mu$-calculus with the idea of ``coercion calculus'' due to Cervesato-Pfenning, accommodating let-expressions in a surprising way: they expand Parigot's syntactic class of named terms. This calculus aims to be the simultaneous answer to three problems. The first problem is the lack of a canonical natural deduction system for classical logic. \lml is not yet another classical calculus, but rather a canonical reflection in natural deduction of the impeccable treatment of classical logic by sequent calculus. The second problem is the lack of a formalization of the usual semantics of Curien-Herbelin's calculus, that explains co-terms and cuts as, respectively, contexts and hole-filling instructions. The mentioned isomorphism is the required formalization, based on the precise notions of context and hole-expression offered by \lml. The third problem is the lack of a robust process of ``read-back'' into natural deduction syntax of calculi in the sequent calculus format, that affects mainly the recent proof-theoretic efforts of derivation of $\lambda$-calculi for call-by-value. An isomorphic counterpart to the $Q$-subsystem of Curien-Herbelin's-calculus is derived, obtaining a new $\lambda$-calculus for call-by-value, combining control and let-expressions.Fundação para a Ciência e a Tecnologia (FCT

Untyped Recursion Schemes and Infinite Intersection Types

Abstract. A new framework for higher-order program verification has been recently proposed, in which higher-order functional programs are modelled as higher-order recursion schemes and then model-checked. As recursion schemes are essentially terms of the simply-typed lambda-calculus with recursion and tree constructors, however, it was not clear how the new framework applies to programs written in languages with more advanced type systems. To circumvent the limitation, this paper introduces an untyped version of recursion schemes and develops an in-finite intersection type system that is equivalent to the model checking of untyped recursion schemes, so that the model checking can be re-duced to type checking as in recent work by Kobayashi and Ong for typed recursion schemes. The type system is undecidable but we can obtain decidable subsets of the type system by restricting the shapes of intersection types, yielding a sound (but incomplete in general) model checking algorithm.

A Burkholderia pseudomallei toxin inhibits helicase activity of translation factor eIF4A

The structure of BPSL1549, a protein of unknown function from Burkholderia pseudomallei, reveals a similarity to Escherichia coli cytotoxic necrotizing factor 1. We found that BPSL1549 acted as a potent cytotoxin against eukaryotic cells and was lethal when administered to mice. Expression levels of bpsl1549 correlate with conditions expected to promote or suppress pathogenicity. BPSL1549 promotes deamidation of glutamine-339 of the translation initiation factor eIF4A, abolishing its helicase activity and inhibiting translation. We propose to name BPSL1549 Burkholderia lethal factor 1

Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial

Background: Oral semaglutide is the first oral formulation of a glucagon-like peptide-1 (GLP-1) receptor agonist developed for the treatment of type 2 diabetes. We aimed to compare the efficacy and safety of flexible dose adjustments of oral semaglutide with sitagliptin 100 mg. Methods: In this 52-week, multicentre, randomised, open-label, phase 3a trial, we recruited patients with type 2 diabetes from 81 sites in ten countries. Patients were eligible if they were aged 18 years or older (19 years or older in South Korea), had type 2 diabetes (diagnosed ≥90 days before screening), HbA1c of 7·5–9·5% (58–80 mmol/mol), and were inadequately controlled on stable daily doses of one or two oral glucose-lowering drugs (for 90 days or more before screening). Participants were randomly assigned (1:1) by use of an interactive web-response system, stratified by background glucose-lowering medication at screening, to oral semaglutide with flexible dose adjustments to 3, 7, or 14 mg once daily or sitagliptin 100 mg once daily. To approximate treatment individualisation in clinical practice, oral semaglutide dose could be adjusted on the basis of prespecified HbA1c and tolerability criteria. Two efficacy-related estimands were prespecified: treatment policy (regardless of treatment discontinuation or use of rescue medication) and trial product (on treatment and without use of rescue medication) for participants randomly assigned to treatment. The primary endpoint was achievement of HbA1c of less than 7% (53 mmol/mol) at week 52 and the confirmatory secondary efficacy endpoint was change in bodyweight from baseline to week 52. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02849080, and European Clinical Trials Database, EudraCT number 2015-005593-38, and an open-label extension is ongoing. Findings: Between Sept 20, 2016, and Feb 7, 2017, of 804 patients assessed for eligibility, 504 were eligible and randomly assigned to oral semaglutide (n=253) or sitagliptin (n=251). Most participants were male (285 [57%] of 504) with a mean age of 57·4 years (SD 9·9). All participants were given at least one dose of their allocated study drug except for one participant in the sitagliptin group. From a mean baseline HbA1c of 8·3% (SD 0·6%; 67 mmol/mol [SD 6·4]), a greater proportion of participants achieved an HbA1c of less than 7% with oral semaglutide than did with sitagliptin (treatment policy estimand: 58% [134 of 230] vs 25% [60 of 238]; and trial product estimand: 63% [123 of 196] vs 28% [52 of 184]). The odds of achieving an HbA1c of less than 7% was significantly better with oral semaglutide than sitagliptin (treatment policy estimand: odds ratio [OR] 4·40, 95% CI 2·89–6·70, p<0·0001; and trial product estimand: 5·54, 3·54–8·68, p<0·0001). The odds of decreasing mean bodyweight from baseline to week 52 were higher with oral semaglutide than with sitagliptin (estimated mean change in bodyweight, treatment policy estimand: −2·6 kg [SE 0·3] vs −0·7 kg [SE 0·2], estimated treatment difference [ETD] −1·9 kg, 95% CI −2·6 to −1·2; p<0·0001; and trial product estimand: −2·9 kg [SE 0·3] vs −0·8 kg [SE 0·3], ETD −2·2 kg, −2·9 to −1·5; p<0·0001). Adverse events occurred in 197 (78%) of 253 participants in the oral semaglutide group versus 172 (69%) of 250 in the sitagliptin group, and nausea was the most common adverse event with oral semaglutide (53 [21%]). Two deaths occurred in the sitagliptin group during the trial. Interpretation: Oral semaglutide, with flexible dose adjustment, based on efficacy and tolerability, provided superior glycaemic control and weight loss compared with sitagliptin, and with a safety profile consistent with subcutaneous GLP-1 receptor agonists. Funding: Novo Nordisk A/S

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries