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The CakeML compiler is, to the best of our knowledge, the most realistic verified compiler for a functional programming language to date. The architecture of the compiler, a sequence of intermediate languages through which high-level features are compiled away incrementally, enables verification of each compilation pass at an appropriate level of semantic detail. Parts of the compiler’s implementation resemble mainstream (unverified) compilers for strict functional languages, and it supports several important features and optimisations. These include efficient curried multi-argument functions, configurable data representations, efficient exceptions, register allocation, and more. The compiler produces machine code for five architectures: x86-64, ARMv6, ARMv8, MIPS-64, and RISC-V. The generated machine code contains the verified runtime system which includes a verified generational copying garbage collector and a verified arbitrary precision arithmetic (bignum) library. In this paper, we present the overall design of the compiler backend, including its 12 intermediate languages. We explain how the semantics and proofs fit together and provide detail on how the compiler has been bootstrapped inside the logic of a theorem prover. The entire development has been carried out within the HOL4 theorem prover.
Building on the recent advances in next-generation sequencing, the integration of genomics, proteomics, metabolomics, and other approaches hold tremendous promise for precision medicine. The approval and adoption of these rapidly advancing technologies and methods presents several regulatory science considerations that need to be addressed. To better understand and address these regulatory science issues, a Clinical and Translational Science Award Working Group convened the Regulatory Science to Advance Precision Medicine Forum. The Forum identified an initial set of regulatory science gaps. The final set of key findings and recommendations provided here address issues related to the lack of standardization of complex tests, preclinical issues, establishing clinical validity and utility, pharmacogenomics considerations, and knowledge gaps.
Wheat stem sawfly, Cephus cinctus Norton (Hymenoptera: Cephidae), indigenous to North America, quickly adapted from host native grasses to wheat crops (Triticum Linnaeus (Poaceae)) with expansion of agriculture on the Great Plains of North America. Bioclimatic simulation tools, such as Climex, predict the potential geographic distribution and establishment of insects in ecosystems, based on climate. The ecoclimatic index, a measure of ecological suitability, integrates potential population growth with stresses to produce estimates of relative abundance. This simulation software was used to develop a bioclimate model for C. cinctus in western Canada. Results fostered a better understanding of how C. cinctus responded to selected climate variables. Two general circulation models were then applied to assess the response of C. cinctus populations to future climate. Relative to current climate, predicted changes in C. cinctus distribution and relative abundance were greatest for 2030, with a small further increase for 2070. Across the Prairies and Boreal Plains Ecozones, changes in ecoclimatic index were greater than in geographic distribution. Both general circulation models indicated most of this area would be categorised as very favourable. This suggests that the potential for pest populations could expand into areas that do not currently experience economic losses associated with C. cinctus.
Needle thoracostomy (NT) is a common prehospital intervention for patients in extremis or cardiac arrest due to trauma. The purpose of this study is to compare outcomes, efficacy, and complications after a change in policy related to NT in a four-county Emergency Medical Services (EMS) system with a catchment area of greater than 1.6 million people.
This is a before and after observational study of all patients who had NT performed in the Central California (USA) EMS system. The before, anterior midclavicular line (MCL) group consisted of all patients who underwent NT from May 7, 2007 through February 28, 2013. The after, midaxillary line (MAL) axillary group consisted of all patients who underwent NT from March 1, 2013 through January 30, 2016, after policy revisions changed the timing, needle size, and placement location for NT. All prehospital and hospital records where NT was performed were queried for demographics, mechanism of injury, initial status and post-NT clinical change, reported complications, and final outcome. The trauma registry was accessed to obtain Injury Severity Scores (ISS). Information was manually abstracted by study investigators and examined utilizing univariate and multivariate analyses.
Three-hundred and five trauma patients treated with NT were included in this study, of which, 169 patients (the MCL group) were treated with a 14-guage intravenous (IV) catheter at least 5.0-cm long at the second intercostal space (ICS), MCL after being placed in the ambulance; and 136 patients (the MAL group) were treated with a 10-guage IV catheter at least 9.5-cm long at the fifth ICS, MAL on scene. The mean ISS was lower in the MAL cohort (64.5 versus 69.2; P=.007). The mortality rate was 79% in both groups. The multivariate model with regard to survival supported that a lower ISS (P<.001) and reported clinical change after NT (P=.003) were significant indicators of survival. No complications from NT were reported.
Changing the timing, length of needle, and location of placement did not change mortality in patients requiring NT. Needle thoracostomy was used more frequently after the change in policy, and the MAL cohort was less injured. No increase in reported complications was noted.
WeichenthalLA, OwenS, StrohG, RamosJ. Needle Thoracostomy: Does Changing Needle Length and Location Change Patient Outcome?Prehosp Disaster Med. 2018;33(3):237–244.
Chemical-biological-radio-nuclear (CBRN) gas masks are the standard means for protecting the general population from inhalation of toxic industrial compounds (TICs), for example after industrial accidents or terrorist attacks. However, such gas masks would not protect patients on home mechanical ventilation, as ventilator airflow would bypass the CBRN filter. We therefore evaluated in vivo the safety of adding a standard-issue CBRN filter to the air-outflow port of a home ventilator, as a method for providing TIC protection to such patients.
Eight adult patients were included in the study. All had been on stable, chronic ventilation via a tracheostomy for at least 3 months before the study. Each patient was ventilated for a period of 1 hour with a standard-issue CBRN filter canister attached to the air-outflow port of their ventilator. Physiological and airflow measurements were made before, during, and after using the filter, and the patients reported their subjective sensation of ventilation continuously during the trial.
For all patients, and throughout the entire study, no deterioration in any of the measured physiological parameters and no changes in measured airflow parameters were detected. All patients felt no subjective difference in the sensation of ventilation with the CBRN filter canister in situ, as compared with ventilation without it. This was true even for those patients who were breathing spontaneously and thus activating the ventilator’s trigger/sensitivity function. No technical malfunctions of the ventilators occurred after addition of the CBRN filter canister to the air-outflow ports of the ventilators.
A CBRN filter canister can be added to the air-outflow port of chronically ventilated patients, without causing an objective or subjective deterioration in the quality of the patients’ mechanical ventilation. (Disaster Med Public Health Preparedness. 2018;12:739-743)
The higher-order logic found in proof assistants such as Coq and various HOL systems provides a convenient setting for the development and verification of functional programs. However, to efficiently run these programs, they must be converted (or ‘extracted’) to functional programs in a programming language such as ML or Haskell. With current techniques, this step, which must be trusted, relates similar looking objects that have very different semantic definitions, such as the set-theoretic model of a logic and the operational semantics of a programming language. In this paper, we show how to increase the trustworthiness of this step with an automated technique. Given a functional program expressed in higher-order logic, our technique provides the corresponding program for a functional language defined with an operational semantics, and it provides a mechanically checked theorem relating the two. This theorem can then be used to transfer verified properties of the logical function to the program. We have implemented our technique in the HOL4 theorem prover, translating functions to a subset of Standard ML, and have applied the implementation to examples including functional data structures, a parser generator, cryptographic algorithms, a garbage collector and the 500-line kernel of the HOL light theorem prover. This paper extends our previous conference publication with new material that shows how functions defined in terms of a state-and-exception monad can be translated, with proofs, into stateful ML code. The HOL light example is also new.
Galileo's stunning discovery of the four largest satellites of Jupiter forced the over throw of the Earth-centered cosmology that had dominated astronomy for centuries. Such a fundamental transformation of the Western World's view of its importance in the cosmos could be expected to produce some humility in society. However, the deep desire for our uniqueness continues to struggle with the astronomical evidence.
Semantic definitions of full-scale programming languages are rarely given, despite the many potential benefits. Partly this is because the available metalanguages for expressing semantics – usually either for informal mathematics or the formal mathematics of a proof assistant – make it much harder than necessary to work with large definitions. We present a metalanguage specifically designed for this problem, and a tool, Ott, that sanity-checks such definitions and compiles them into proof assistant code for Coq, HOL, and Isabelle/HOL, together with code for production-quality typesetting, and OCaml boilerplate. The main innovations are (1) metalanguage design to make definitions concise, and easy to read and edit; (2) an expressive but intuitive metalanguage for specifying binding structures; and (3) compilation to proof assistant code. This has been tested in substantial case studies, including modular specifications of calculi from the TAPL text, a Lightweight Java with Java JSR 277/294 module system proposals, and a large fragment of OCaml (OCamllight, 310 rules), with mechanised proofs of various soundness results. Our aim with this work is to enable a phase change: making it feasible to work routinely, without heroic effort, with rigorous semantic definitions of realistic languages.
Regular-expression derivatives are an old, but elegant, technique for compiling regular expressions to deterministic finite-state machines. It easily supports extending the regular-expression operators with boolean operations, such as intersection and complement. Unfortunately, this technique has been lost in the sands of time and few computer scientists are aware of it. In this paper, we reexamine regular-expression derivatives and report on our experiences in the context of two different functional-language implementations. The basic implementation is simple and we show how to extend it to handle large character sets (e.g., Unicode). We also show that the derivatives approach leads to smaller state machines than the traditional algorithm given by McNaughton and Yamada.
Atomic scale molecular dynamics simulations have been used to predict the location of glass modifying Na, Li and Mg species in a borosilicate Magnox type waste glass adjacent to interfaces with the (100) and (110) surfaces of MgO, CaO and SrO crystals. These simulations show a considerable increase in alkali and alkali earth concentration adjacent to specific interfaces. In particular, there are significant, systematic changes in Na, Li and Mg position and concentration as a function of both the crystal's terminating surface and composition.
In a previous publication the order–disorder pyrochlore to fluorite transformation temperatures for a series of A2Hf2O7 pyrochlores were predicted [C.R. Stanek and R.W. Grimes: Prediction of rare-earth A2Hf2O7 pyrochlore phases. J. Am. Ceram. Soc. 2002, 85, p. 2139]. This was facilitated by establishing a relationship between these temperatures and the energy required to introduce a specific defect structure into the perfect pyrochlore lattice. Here an equivalent relationship for A2Zr2O7 pyrochlores was generated, and from this the disorder temperatures for a number of compositions including Eu2Zr2O7 were predicted.
Psychological measures have little sensitivity in the prediction of postnatal depression. We report the development
of a questionnaire of beliefs about pregnancy and motherhood. Information from a literature review, staff working
with women with postnatal depression and interviews with recently ill patients was used to develop a questionnaire
called the PRBQ. The PRBQ was piloted on 42 pregnant women and achieved a Cronbach alpha of 0.85. Scores
significantly correlated with scores on the Dysfunctional Attitude Scale (DAS), Beck Depression Inventory (BDI) and
the Cognitive Adaptation to Stressful Events questionnaire (CASE), measuring adaptation to pregnancy. DAS and
CASE scores did not correlate. The PRBQ and the CASE differentiated between those with (n = 5) and those without
moderate depression. The PRBQ has been validated against established psychological measures. It may be a helpful
tool contributing to the identification of women specifically at risk of postnatal depression. Further basic research is
Phenotypic variation of Fucus spiralis was examined in terms of morphology and chemical composition, as determined by pyrolysis mass spectrometry (PyMS). After discriminant analysis both techniques revealed the existence of two morphotypes which were subsequently designated as F. spiralis and F. spiralis forma nanus. The nanus plants differed from the nominate spiralis in that they were shorter, narrower and had fewer branches, but had more units of growth from a single holdfast. F. spiralis f. nanus was consistently higher on the shore than F. spiralis, but the two morphotypes overlapped in terms of shore exposure level. We suggest that the formae exist within a mosaic of stable phenotypes representing populations specifically adapted to the local environment. PyMS data were in agreement with morphological descriptions showing that gross morphology can be correlated with chemical composition.
Analyses of mitochondrial (mt) DNA control region sequences from 175 leatherback turtles Dermochelys coriacea from 10 nesting colonies revealed shallow phylogenetic structuring of maternal lineages on a global scale. Eleven haplotypes were observed, and mean estimated sequence divergence, p = 0.00581, is much lower than the deepest nodes reported in global mtDNA surveys of the green turtle Chelonia mydas, loggerhead Caretta caretta, and ridley turtles Lepidochelys spp. The leatherback turtle is the product of an evolutionary trajectory originating at least 100 million years ago, yet the intraspecific phylogeny recorded in mitochondrial lineages may trace back less than 900 000 years. The gene genealogy and global distribution of mtDNA haplotypes indicate that leatherbacks may have radiated from a narrow refugium, possibly in the Indian–Pacific during the early Pleistocene glaciation. Analysis of haplotype frequencies revealed that nesting populations are strongly subdivided globally (FST = 0.415), and within ocean basins (FST = 0.203–0.253), despite the leatherback's highly migratory nature. Within the Atlantic significant differences in haplotype frequency distributions and Nm values < 2 are observed in pairwise comparisons between St. Croix (U.S. Virgin Islands) and mainland Caribbean populations, and between Trinidad and the same mainland populations. These findings provisionally support the natal homing hypothesis for leatherback turtles, although several proximal nesting populations were indistinguishable, suggesting recent colonization or less precise natal homing behaviour than documented for other marine turtle species. The evidence of natal homing, manifested on ecological time scales, may be erased in some populations by rapid rookery turnover resulting from climatic fluctuation and the ephemeral nature of nesting habitat on a geological time scale. The evolutionary effective population size (Ne) is estimated from mtDNA data to be between 45 000 and 60 000, a value that exceeds current global census estimates of 26 000 to 43 000 adult females.
Sediments of Balsam Meadow have produced a 11,000-yr pollen record from the southern Sierra Nevada of California. The Balsam Meadow diagram is divided into three zones. (1) The Artemisia zone (11,000–7000 yr B.P.) is characterized by percentages of sagebrush (Artemisia) and other nonarboreal pollen higher than can be found in the modern local vegetation. Vegetation during this interval was probably similar to the modern vegetation on the east slope of the Sierra Nevada and the climate was drier than that of today. (2) Pinus pollen exceeded 80% from 7000 to 3000 yr B.P. in the Pinus zone. The climate was moister than during the Artemisia zone. (3) Fir (Abies, Cupressaceae, and oak (Quercus) percentages increased after 3000 yr B.P. in the Abies zone as the modern vegetation at the site developed and the present cool-moist climatic regime was established. Decreased fire frequency after 1200 yr B.P. is reflected in decreased abundance of macroscopic charcoal and increased concentration of Abies magnifica and Pinus murrayana needles.
Chemically, trimipramine has an imino-benzyl nucleus and a side-chain resembling that of methotrimeprazine [5-(3-dimethyl-amino-2-methyl-propyl)-10, 11-dihydrodibenz (b, f,) azepine]. In “double blind” controlled comparisons of trimipramine and imipramine, Salzmann (1965) in 27 hospitalized depressed patients who did not require ECT, found the two drugs not significantly different in effect. Blumenthal and Seppala (1965) obtained similar results. Burns (1965), however, in 44 patients suffering from psychotic depression, found trimipramine to be significantly superior at the 5 per cent. level to imipramine in ratings of recovery from depression, anxiety and insomnia. No difference was found in the latency interval between the drugs.
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