Refinement Reflection:Complete Verification with SMT

We introduce Refinement Reflection, a new framework for building SMT-based deductive verifiers. The key idea is to reflect the code implementing a user-defined function into the function's (output) refinement type. As a consequence, at uses of the function, the function definition is instantiated in the SMT logic in a precise fashion that permits decidable verification. Reflection allows the user to write equational proofs of programs just by writing other programs using pattern-matching and recursion to perform case-splitting and induction. Thus, via the propositions-as-types principle, we show that reflection permits the specification of arbitrary functional correctness properties. Finally, we introduce a proof-search algorithm called Proof by Logical Evaluation that uses techniques from model checking and abstract interpretation, to completely automate equational reasoning. We have implemented reflection in Liquid Haskell and used it to verify that the widely used instances of the Monoid, Applicative, Functor, and Monad typeclasses actually satisfy key algebraic laws required to make the clients safe, and have used reflection to build the first library that actually verifies assumptions about associativity and ordering that are crucial for safe deterministic parallelism.Comment: 29 pages plus appendices, to appear in POPL 2018. arXiv admin note: text overlap with arXiv:1610.0464

Identifying molecular mediators of the relationship between body mass index and endometrial cancer risk:a Mendelian randomization analysis

Endometrial cancer is the most common gynaecological cancer in high-income countries. Elevated body mass index (BMI) is an established modifiable risk factor for this condition and is estimated to confer a larger effect on endometrial cancer risk than any other cancer site. However, the molecular mechanisms underpinning this association remain unclear. We used Mendelian randomization (MR) to evaluate the causal role of 14 molecular risk factors (hormonal, metabolic and inflammatory markers) in endometrial cancer risk. We then evaluated and quantified the potential mediating role of these molecular traits in the relationship between BMI and endometrial cancer using multivariable MR. Methods Genetic instruments to proxy 14 molecular risk factors and BMI were constructed by identifying single-nucleotide polymorphisms (SNPs) reliably associated (P < 5.0 × 10−8) with each respective risk factor in previous genome-wide association studies (GWAS). Summary statistics for the association of these SNPs with overall and subtype-specific endometrial cancer risk (12,906 cases and 108,979 controls) were obtained from a GWAS meta-analysis of the Endometrial Cancer Association Consortium (ECAC), Epidemiology of Endometrial Cancer Consortium (E2C2) and UK Biobank. SNPs were combined into multi-allelic models and odds ratios (ORs) and 95% confidence intervals (95% CIs) were generated using inverse-variance weighted random-effects models. The mediating roles of the molecular risk factors in the relationship between BMI and endometrial cancer were then estimated using multivariable MR

The design, launch and assessment of a new volunteer-based plant monitoring scheme for the United Kingdom

Volunteer-based plant monitoring in the UK has focused mainly on distribution mapping; there has been less emphasis on the collection of data on plant communities and habitats. Abundance data provide different insights into ecological pattern and allow for more powerful inference when considering environmental change. Abundance monitoring for other groups of organisms is well-established in the UK, e.g. for birds and butterflies, and conservation agencies have long desired comparable schemes for plants. We describe a new citizen science scheme for the UK (the ‘National Plant Monitoring Scheme’; NPMS), with the primary aim of monitoring the abundance of plants at small scales. Scheme development emphasised volunteer flexibility through scheme co-creation and feedback, whilst retaining a rigorous approach to design. Sampling frameworks, target habitats and species, field methods and power are all described. We also evaluate several outcomes of the scheme design process, including: (i) landscape-context bias in the first two years of the scheme; (ii) the ability of different sets of indicator species to capture the main ecological gradients of UK vegetation; and, (iii) species richness bias in returns relative to a professional survey. Survey rates have been promising (over 60% of squares released have been surveyed), although upland squares are under-represented. Ecological gradients present in an ordination of an independent, unbiased, national survey were well-represented by NPMS indicator species, although further filtering to an entry-level set of easily identifiable species degraded signal in an ordination axis representing succession and disturbance. Comparison with another professional survey indicated that different biases might be present at different levels of participation within the scheme. Understanding the strengths and limitations of the NPMS will guide development, increase trust in outputs, and direct efforts for maintaining volunteer interest, as well as providing a set of ideas for other countries to experiment with

Digitally deployed, GP remote consultation video intervention that aims to reduce opioid prescribing in primary care: protocol for a mixed-methods evaluation

INTRODUCTION: Opioid prescribing rates are disproportionately high in the North of England. In addition to patients' complex health needs, clinician prescribing behaviour is also a key driver. Although strategies have been initiated to reduce opioid prescribing nationally, the COVID-19 pandemic has interrupted service provision and created challenges for the system and health professionals to tackle this complex issue. A pilot intervention using smartphone video messaging has been developed to remotely explain the rationale for opioid reduction and facilitate self-initiation of support. The aim of this study is to evaluate the potential benefits, risks and economic consequences of 'at scale' implementation. METHODS AND ANALYSIS: This will be a mixed-methods study comprising a quasi-experimental non-randomised before-and-after study and qualitative interviews. The intervention arm will comprise 50 General Practitioner (GP) Practices using System 1 (a clinical computer system hosting the intervention) who will deliver the video to their patients via text message. The control arm will comprise 50 practices using EMIS (a different computer system) who will continue usual care. Monthly practice level prescribing and consultation data will be observed for 6 months postintervention. A general linear model will be used to estimate the association between the exposure and the main outcome (opioid prescribing; average daily quantity (ADQ)/1000 specific therapeutic group age-sex related prescribing unit). Semi-structured interviews will be undertaken remotely with purposively selected participants including patients who received the video, and health professionals involved in sending out the videos and providing additional support. Interviews will be audio recorded, transcribed and analysed thematically. ETHICS AND DISSEMINATION: Ethics approval has been granted by the NHS Health Research Authority Research Ethics Committee (22/PR/0296). Findings will be disseminated to the participating sites, participants, and commissioners, and in peer-reviewed journals and academic conferences. TRIAL REGISTRATION NUMBER: NCT05276089

Tissue-specific genetic variation suggests distinct molecular pathways between body shape phenotypes and colorectal cancer

It remains unknown whether adiposity subtypes are differentially associated with colorectal cancer (CRC). To move beyond single-trait anthropometric indicators, we derived four multi-trait body shape phenotypes reflecting adiposity subtypes from principal components analysis on body mass index, height, weight, waist-to-hip ratio, and waist and hip circumference. A generally obese (PC1) and a tall, centrally obese (PC3) body shape were both positively associated with CRC risk in observational analyses in 329,828 UK Biobank participants (3728 cases). In genome-wide association studies in 460,198 UK Biobank participants, we identified 3414 genetic variants across four body shapes and Mendelian randomization analyses confirmed positive associations of PC1 and PC3 with CRC risk (52,775 cases/45,940 controls from GECCO/CORECT/CCFR). Brain tissue-specific genetic instruments, mapped to PC1 through enrichment analysis, were responsible for the relationship between PC1 and CRC, while the relationship between PC3 and CRC was predominantly driven by adipose tissue-specific genetic instruments. This study suggests distinct putative causal pathways between adiposity subtypes and CRC

Recessive <i>HYDIN</i> mutations cause primary ciliary dyskinesia without randomization of left-right body asymmetry

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder characterized by defective cilia and flagella motility. Chronic destructive-airway disease is caused by abnormal respiratory-tract mucociliary clearance. Abnormal propulsion of sperm flagella contributes to male infertility. Genetic defects in most individuals affected by PCD cause randomization of left-right body asymmetry; approximately half show situs inversus or situs ambiguous. Almost 70 years after the hy3 mouse possessing Hydin mutations was described as a recessive hydrocephalus model, we report HYDIN mutations in PCD- affected persons without hydrocephalus. By homozygosity mapping, we identified a PCD-associated locus, chromosomal region 16q21- q23, which contains HYDIN. However, a nearly identical 360 kb paralogous segment (HYDIN2) in chromosomal region 1q21.1 complicated mutational analysis. In three affected German siblings linked to HYDIN, we identified homozygous c.3985G>T mutations that affect an evolutionary conserved splice acceptor site and that subsequently cause aberrantly spliced transcripts predicting premature protein termination in respiratory cells. Parallel whole-exome sequencing identified a homozygous nonsense HYDIN mutation, c.922A>T (p.Lys307( *)), in six individuals from three Faroe Island PCD-affected families that all carried an 8.8 Mb shared haplotype across HYDIN, indicating an ancestral founder mutation in this isolated population. We demonstrate by electron microscopy tomography that, consistent with the effects of loss-of-function mutations, HYDIN mutant respiratory cilia lack the C2b projection of the central pair (CP) apparatus; similar findings were reported in Hydin-deficient Chlamydomonas and mice. High-speed videomicroscopy demonstrated markedly reduced beating amplitudes of respiratory cilia and stiff sperm flagella. Like the hy3 mouse model, all nine PCD-affected persons had normal body composition because nodal cilia function is apparently not dependent on the function of the CP apparatus

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

The role of ascorbate in antioxidant protection of biomembranes: Interaction with vitamin E and coenzyme Q

One of the vital roles of ascorbic acid (vitamin C) is to act as an antioxidant to protect cellular components from free radical damage. Ascorbic acid has been shown to scavenge free radicals directly in the aqueous phases of cells and the circulatory system. Ascorbic acid has also been proven to protect membrane and other hydrophobic compartments from such damage by regenerating the antioxidant form of vitamin E. In addition, reduced coenzyme Q, also a resident of hydrophobic compartments, interacts with vitamin E to regenerate its antioxidant form. The mechanism of vitamin C antioxidant function, the myriad of pathologies resulting from its clinical deficiency, and the many health benefits it provides, are reviewed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44796/1/10863_2004_Article_BF00762775.pd

Accelerating a green recovery of cities: Lessons from a scoping review and a proposal for mission-oriented recovery towards post-pandemic urban resilience

In the post-pandemic era, we must value our cities as cultural and economic centres, that are socially and environmentally diverse. This requires a transformation in the way we plan and govern our cities, but what can be learnt from the current crisis about how cities should be managed? In this article, we report on a scoping review to help identify seven lessons learnt for cities from the COVID-19 pandemic. We build on these lessons through a synthesis, outlining three urban missions that will chart a green urban recovery. The missions are to accelerate the urban mobility transition; to attain regenerative urban development; and create resilient urban infrastructure. We expand on what these missions entail, by defining six pathways that supports transition of urban mobility, energy, food, housing, health and nature. These pathways, when implemented in an integrated manner, provides a roadmap for green recovery in cities, that also builds resilience