Verified lifting of stencil computations

This paper demonstrates a novel combination of program synthesis and verification to lift stencil computations from low-level Fortran code to a high-level summary expressed using a predicate language. The technique is sound and mostly automated, and leverages counter-example guided inductive synthesis (CEGIS) to find provably correct translations. Lifting existing code to a high-performance description language has a number of benefits, including maintainability and performance portability. For example, our experiments show that the lifted summaries can enable domain specific compilers to do a better job of parallelization as compared to an off-the-shelf compiler working on the original code, and can even support fully automatic migration to hardware accelerators such as GPUs. We have implemented verified lifting in a system called STNG and have evaluated it using microbenchmarks, mini-apps, and real-world applications. We demonstrate the benefits of verified lifting by first automatically summarizing Fortran source code into a high-level predicate language, and subsequently translating the lifted summaries into Halide, with the translated code achieving median performance speedups of 4.1X and up to 24X for non-trivial stencils as compared to the original implementation.United States. Department of Energy. Office of Science (Award DE-SC0008923)United States. Department of Energy. Office of Science (Award DE-SC0005288

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

The flow fields involved in hydrodynamic imaging by blind Mexican cave fish (Astyanax fasciatus). Part II: gliding parallel to a wall

SUMMARY Blind Mexican cave fish (Astyanax fasciatus) are able to sense detailed information about objects by gliding alongside them and sensing changes in the flow field around their body using their lateral line sensory system. Hence the fish are able to build hydrodynamic images of their surroundings. This study measured the flow fields around blind cave fish using particle image velocimetry (PIV) as they swam parallel to a wall. Computational fluid dynamics models were also used to calculate the flow fields and the stimuli to the lateral line sensory system. Our results showed that characteristic changes in the form of the flow field occurred when the fish were within approximately 0.20 body lengths (BL) of a wall. The magnitude of these changes increased steadily as the distance between the fish and the wall was reduced. When the fish were within 0.02 BL of the wall there was a change in the form of the flow field owing to the merging of the boundary layers on the body of the fish and the wall. The stimuli to the lateral line appears to be sufficient for fish to detect walls when they are 0.10 BL away (the mean distance at which they normally swim from a wall), but insufficient for the fish to detect a wall when 0.25 BL away. This suggests that the nature of the flow fields surrounding the fish are such that hydrodynamic imaging can only be used by fish to detect surfaces at short range.</jats:p

The flow fields involved in hydrodynamic imaging by blind Mexican cave fish (Astyanax fasciatus). Part I: open water and heading towards a wall

SUMMARY Blind Mexican cave fish (Astyanax fasciatus) sense the presence of nearby objects by sensing changes in the water flow around their body. The information available to the fish using this hydrodynamic imaging ability depends on the properties of the flow field it generates while gliding and how this flow field is altered by the presence of objects. Here, we used particle image velocimetry to measure the flow fields around gliding blind cave fish as they moved through open water and when heading towards a wall. These measurements, combined with computational fluid dynamics models, were used to estimate the stimulus to the lateral line system of the fish. Our results showed that there was a high-pressure region around the nose of the fish, low-pressure regions corresponding to accelerated flow around the widest part of the body and a thick laminar boundary layer down the body. When approaching a wall head-on, the changes in the stimulus to the lateral line were confined to approximately the first 20% of the body. Assuming that the fish are sensitive to a certain relative change in lateral line stimuli, it was found that swimming at higher Reynolds numbers slightly decreased the distance at which the fish could detect a wall when approaching head-on, which is the opposite to what has previously been expected. However, when the effects of environmental noise are considered, swimming at higher speed may improve the signal to noise ratio of the stimulus to the lateral line.</jats:p

Misunderstanding the Female Athlete Triad: Refuting the IOC Consensus Statement on Relative Energy Deficiency in Sport (RED-S)

We are concerned that readers of the IOC paper will be confused and misled by the poorly referenced statements and frank (and sometimes dangerous) errors in the paper. The IOC authors should publish a correction of these and other errors noted. Broadening research of low energy availability in other groups, such as the male athlete, athletes of diverse ethnicities and the disabled athlete may help to advance science and may one day warrant introduction of a specific term for whatever serious clinical sequelae of energy deficiency may be discovered in future research on men. Research on the “Female Athlete Triad” has forged a platform from which a broad array of healthcare providers (e.g., physicians, sport dietitians, mental health professionals and athletic trainers) have made great strides in learning how to manage and treat affected women. Research on the “Female Athlete Triad” has also been translated to the lay public such that more and more affected female athletes and exercising women willingly seek education, prevention and treatment. Meanwhile, subsuming the term “Female Athlete Triad” under the umbrella of the term RED-S has the potential to confuse rather than enlighten, and undo decades of work educating and advocating for awareness, prevention and treatment for the Triad. The individual most impacted by the de-emphasis on the Triad will be the female athlete herself. The overwhelming clinical importance of the Female Athlete Triad compared with other conditions under the proposed RED-S umbrella will continue to make a specific reference for the Triad useful for those who deal with it, including physicians, coaches, sport dietitians, athletics trainers, parents and, most importantly, female athletes. As such, efforts promoting awareness, prevention and treatment of the Female Athlete Triad remain critically important and should not be overshadowed by an ill-conceived and poorly defended new construct