Stability of Articulated Revetments Against Wave Attack on Shallow Soft Soil Slopes

Continuously-connected, articulated revetment systems have potential to decrease the weight of armor cover in resisting wave attack, compared to traditional designs. Modes of instability for sloping revetments include uplift, sliding, and toe roll-up. Design methods are summarized by McDonnell (1998), Pilarczyk (1998), and Herbich (1999). Russo (2003) conducted a field prototype scale investigation on performance of Articulated Concrete Mattresses (ACMs) in coastal Louisiana, which demonstrated this structure’s ability to resist a range of wave loading conditions, and inspired scoping of further research to quantify structure performance beyond known limits. Present research expanded earlier works by examining fundamental physical processes of wave loading near the theoretical threshold of structure incipient motion. The motivation for further investigation and modeling modes of failure is to: (1) demonstrate a method to support the design selection process, (2) optimize revetment dimensions when articulated block is considered the most appropriate application, and (3) meet earthen slope protection requirements with relatively low ground pressures exerted by the armor layer for use in soft soil conditions. A new structure performance metric is derived as the physically dimensionless “hydromechanic potential,” which is used to quantify structure movement as an interconnected system under wave attack. Research involved using a spectral hydromechanics analytical approach, with instrumented physical model results, to demonstrate a capability for constraining uncertainty on the behavior of revetments in specified conditions. Physical modeling was conducted based on dimensional analysis and similitude criteria. Physical modeling and spectral analysis were based on principles of hydrodynamics and structure mechanics of articulated revetment system configurations at incipient motion under irregular wave conditions. Theoretical equilibrium exists when destabilizing wave loading forces are in balance with restoring gravitational forces of the structure. Tests of prior works, conducted through traditional methods, were generally able to measure structure performance under wave attack to between 3.7 and 8 of the ratio of destabilizing-to-restoring forces. Despite being the best available physical data measurable to-date, Herbich (1999) characterized structure performance in this range for design as “doubtful”. Results of this dissertation research indicated that a new lower limit is detectable at the threshold of equilibrium based on hydromechanic potential

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

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 hospitalization2–4 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

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

Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease

Quality Control of Mass-Produced GEM Detectors for the CMS GE1/1 Muon Upgrade

The series of upgrades to the Large Hadron Collider, culminating in the High Luminosity Large Hadron Collider, will enable a significant expansion of the physics program of the CMS experiment. However, the accelerator upgrades will also make the experimental conditions more challenging, with implications for detector operations, triggering, and data analysis. The luminosity of the proton-proton collisions is expected to exceed $2-3\times10^{34}$~cm$^{-2}$s$^{-1}$ for Run 3 (starting in 2022), and it will be at least $5\times10^{34}$~cm$^{-2}$s$^{-1}$ when the High Luminosity Large Hadron Collider is completed for Run 4. These conditions will affect muon triggering, identification, and measurement, which are critical capabilities of the experiment. To address these challenges, additional muon detectors are being installed in the CMS endcaps, based on Gas Electron Multiplier technology. For this purpose, 161 large triple-Gas Electron Multiplier detectors have been constructed and tested. Installation of these devices began in 2019 with the GE1/1 station and will be followed by two additional stations, GE2/1 and ME0, to be installed in 2023 and 2026, respectively. The assembly and quality control of the GE1/1 detectors were distributed across several production sites around the world. We motivate and discuss the quality control procedures that were developed to standardize the performance of the detectors, and we present the final results of the production. Out of 161 detectors produced, 156 detectors passed all tests, and 144 detectors are now installed in the CMS experiment. The various visual inspections, gas tightness tests, intrinsic noise rate characterizations, and effective gas gain and response uniformity tests allowed the project to achieve this high success rate

Production and validation of industrially produced large-sized GEM foils for the Phase-2 upgrade of the CMS muon spectrometer

The upgrade of the CMS detector for the high luminosity LHC (HL-LHC) will include gas electron multiplier (GEM) detectors in the end-cap muon spectrometer. Due to the limited supply of large area GEM detectors, the Korean CMS (KCMS) collaboration had formed a consortium with Mecaro Co., Ltd. to serve as a supplier of GEM foils with area of approximately 0.6 m$^{2}$. The consortium has developed a double-mask etching technique for production of these large-sized GEM foils. This article describes the production, quality control, and quality assessment (QA/QC) procedures and the mass production status for the GEM foils. Validation procedures indicate that the structure of the Korean foils are in the designed range. Detectors employing the Korean foils satisfy the requirements of the HL-LHC in terms of the effective gain, response uniformity, rate capability, discharge probability, and hardness against discharges. No aging phenomena were observed with a charge collection of 82 mC/cm$^{2}$. Mass production of KCMS GEM foils is currently in progress