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At least 73 records · Page 4

Project: Corbomite - Product: ConsoleWorks REACT

TDi Technologies presents ConsoleWorks REACT, an advanced platform designed to tackle the complexities of cyber and operational risk assessment. This comprehensive solution goes beyond asset-focused approaches by considering the impact of both assets and people have on the security and operation of critical infrastructure, specifically targeting preventing gird mis-operation by evaluating real-time human interaction or commands with critical assets. The hypothesis suggests that by integrating the assessment of user commands into the overall risk assessment process, organizations can make more informed decisions, prioritize resources effectively, and respond promptly to potential threats. This hypothesis forms the basis for the development of a proactive and holistic risk management approach that is more comprehensive and context aware than traditional models which only look at assets, patch levels, configuration and threat intel by collecting that information off the network vs directly from the asset, human, and human interaction all in real-time. ConsoleWorks' unique man-in-the-middle architecture is a key feature that sets it apart in the cybersecurity landscape. This architecture enables the real-time observation, enforcement, and commands or interaction risk transparency of user interaction with critical infrastructure to be risk mitigated and audited as they are aggregated with device and human risk factors for a more comprehensive risk threat score across a device or group of devices. This architecture allows ConsoleWorks to act as a secure intermediary between users and critical assets, monitoring all interactions and ensuring that only authorized commands are sent to the asset to be executed. This not only enhances security but also provides a comprehensive audit trail of all user activities, contributing to compliance efforts and facilitating incident investigation and risk management. By integrating this unique architecture with our comprehensive risk assessment methodology, ConsoleWorks REACT provides a powerful solution for managing cyber and operational risks, enabling organizations to maintain a robust security posture and effectively mitigate potential threats. To that end, the primary objective of this project was to research and develop a robust solution that enables the energy industry to mitigate the risks associated with human actions that can compromise the security or operations of assets critical to energy delivery, generation, transmission and operation. ConsoleWorks REACT plays a pivotal role in achieving this goal by leveraging its unique capabilities to monitor and track all user activity. Through its Zero Trust approach, which emphasizes continuous verification, the platform ensures secure access to assets and serves as the centralized human response and notification platform for addressing cyber and operational issues.

97 MATHEMATICS AND COMPUTING↗

Lung cancer mortality among construction workers: implications for early detection

Objectives This study examined predictors of lung cancer mortality, beyond age and smoking, among construction workers employed at US Department of Energy (DOE) sites to better define eligibility for low-dose CT (LDCT) lung cancer screening. Methods Predictive models were based on 17 069 workers and 352 lung cancer deaths. Risk factors included age, gender, race/ethnicity, cigarette smoking, years of trade or DOE work, body mass index (BMI), chest X-ray results, spirometry results, respiratory symptoms, beryllium sensitisation and personal history of cancer. Competing risk Cox models were used to obtain HRs and to predict 5-year risks. Results Factors beyond age and smoking included in the final predictive model were chest X-ray changes, abnormal lung function, chronic obstructive pulmonary disease (COPD), respiratory symptoms, BMI, personal history of cancer and having worked 5 or more years at a DOE site or in construction. Risk-based LDCT eligibility demonstrated improved sensitivity, specificity and positive predictive value compared with current US Preventive Services Task Force guidelines. The risk of lung cancer death from 5 years of work in the construction industry or at a DOE site was comparable with the risk from a personal cancer history, a family history of cancer or a diagnosis of COPD. LDCT eligibility criteria used for DOE construction workers, which includes factors beyond age and smoking, identified 86% of participants who eventually would die from lung cancer compared with 51% based on age and smoking alone. Conclusions Results support inclusion of risk from occupational exposures and non-malignant respiratory clinical findings in LDCT clinical guidelines.

Public, Environmental & Occupational Health↗

Optimizing Information Automation Using a New Method Based on System-Theoretic Process Analysis: Tool Development and Method Evaluation

This report is an update to a prior report that describes progress and findings for a program of research supporting the design and optimization of information automation systems for nuclear power plants. Much of the domestic nuclear fleet is currently focused on modernizing technologies and processes, including transitioning toward digitalization in the control room and throughout the plant, along with a greater interest in the use of automation, artificial intelligence, robotics, and other emerging technologies. While there are significant opportunities to apply these technologies toward greater plant safety, efficiency, and overall cost-effectiveness, optimizing their design and avoiding potential safety and performance risks depends on ensuring that human performance-related organizational and technical design issues are identified and addressed early in the design process. This report describes modeling tools and techniques, based on sociotechnical systems theory, to support these design goals and their application in the current research effort. The report is primarily intended for senior nuclear energy stakeholders, including regulators, corporate management, and senior plant management. We have developed and employed a method to design an optimized information automation ecosystem (IAE) based on the systems-theoretic constructs underlying sociotechnical systems theory in general and the Systems-Theoretic Accident Modeling and Processes (STAMP) approach in particular. We argue that an IAE can be modeled as an interactive information control system whose behavior can be understood in terms of dynamic control, feedback, and communication relationships amongst the system’s technical and organizational components. We have employed two STAMP-based tools in this effort. The first is Causal Analysis based on STAMP (CAST), an accident and incident analysis technique that was used to examine a performance- and safety-related incident at an industry partner’s plant involving the unintentional activation of an emergency diesel generator. This analysis provided insight into the behavior of the plant’s current information control structure within the context of a specific, significant event. The second tool is Systems Theoretic Process Analysis (STPA) which is a proactive risk analysis tool used to examine existing and potential, planned sociotechnical systems. STPA was used to identify risk factors in the current design of a generic nuclear power plant (NPP) preventive maintenance system. Our analyses focused on identifying near-term system improvements and longer-term design requirements for an optimized IAE system. CAST analysis findings indicate an important underlying contributor to the incident under investigation, and a significant risk to information automation system performance, was perceived time and schedule pressure, which exposed weaknesses in interdepartmental coordination between and within responsible plant organizations and challenged the resilience of established plant processes, until a human caused the eventual event. These findings are discussed in terms of their risk to overall system performance and their implications for information automation system resilience and brittleness. STPA findings exposed several areas of concern in the design of current preventive maintenance systems. We also present two preliminary information automation models. The proactive issue resolution (PIR) model is a test case of an information automation concept with significant near-term potential for application and subsequent reduction in significant plant events. The IAE model is a more general representation of a broader, plantwide information automation system and represents an end-state vision for our work. From our results, we have generated an initial set of preliminary system-level requirements and safety constraints for these models. We have also focused on early development of easy to learn, easy to use “transportable” tools for sociotechnical systems analysis. We intend these to be used by NPP personnel as a means of gaining reliable and relatively quick insight into (1) sociotechnical systems factors impacting incidents and accidents, (2) potential sociotechnical risk factors in existing or planned system designs, and (3) potential weaknesses in a system’s safety and/or information control structure. We conclude the report with a set of summary recommendations, a discussion of planned and potential follow-on research and development, and a draft list of system-level requirements and safety constraints for optimized information automation systems.

99 GENERAL AND MISCELLANEOUS↗

Lung Cancer and Heart Disease Risks Associated With Low-Dose Pulmonary Radiotherapy to COVID-19 Patients With Different Background Risks

The respiratory disease COVID-19 reached global pandemic status in 2020. Excessive inflammation is believed to result in the most severe symptoms and death from this disease. Because treatment options for patients with severe COVID-19 related pulmonary symptoms remain limited, whole-lung low-dose radiation therapy is being evaluated as an anti-inflammatory modality. However, there is concern about the long-term risks associated with low-dose pulmonary irradiation. To help quantify the benefit-risk balance of low-dose radiation therapy for COVID-19, we estimated radiation-induced lifetime risks of both lung cancer and heart disease (major coronary events) for patients of different sexes, treated at ages 50 to 85, with and without other relevant risk factors (cigarette smoking and baseline heart disease risk).

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Quantifying mean, variability, and uncertainty in indoor radon exposure in Pennsylvania using random forest and quantile regression forest models

Radon is a naturally occurring radioactive gas that poses a serious health risk as the primary cause of lung cancer in non-smokers. Despite the well-known adverse association with health outcomes, current radon exposure assessments are limited to county-level or average-level estimates, which fail to capture regional variability. This study uses Machine Learning models, including Random Forest (RF) and Quantile Regression Forest (QRF), to estimate the indoor radon concentrations at the ZCTA (Zip code tabulation area)-level and characterize uncertainties in model estimates. Incorporating geological, meteorological, and building-specific data, the models aim to improve radon risk assessment by capturing mean exposure, variability, and extreme concentration levels. Processed radon test data (n = 718,111) were analyzed using average, variability, and quantile prediction methods. Models that estimate the average radon exposure at the ZCTA-level can yield promising model-fit results, but they do not capture the underlying variability of indoor radon exposure within a ZCTA. We utilize volatility analyses to identify characteristics indicative of high variability of indoor radon exposure. We also show that a QRF model can be used to estimate upper quantiles of residential radon exposure, thereby uncovering localized areas of elevated exposure that were not apparent in mean estimates. The results highlighted the need for a deep characterization of exposure risk and show that regions with moderate average exposure levels could still harbor extreme outliers with implications for evaluating health risks. Utilizing multiple radon exposure models allows for a deeper characterization of radon risk within a geographic area and can better identify high-risk areas. The results from this study provide a foundation for developing mitigation strategies and examining associations between radon exposure and health outcomes at fine scales. Future research should extend the geographic scope and incorporate additional environmental risk factors to establish a comprehensive framework for risk assessment.

Lee, Heechan [ORNL]↗

Staged progression epidemic models for the transmission of invasive nontyphoidal Salmonella (iNTS) with treatment

We develop and analyze a stage-progression compartmental model to study the emerging invasive nontyphoidal Salmonella (iNTS) epidemic in sub-Saharan Africa. iNTS bloodstream infections are often fatal, and the diverse and non-specific clinical features of iNTS make it difficult to diagnose. We focus our study on identifying approaches that can reduce the incidence of new infections. In sub-Saharan Africa, transmission and mortality are correlated with the ongoing HIV epidemic and severe malnutrition. We use our model to quantify the impact that increasing antiretroviral therapy (ART) for HIV infected adults and reducing malnutrition in children would have on mortality from iNTS in the population. We consider immunocompromised subpopulations in the region with major risk factors for mortality, such as malaria and malnutrition among children and HIV infection and ART coverage in both children and adults. We parameterize the progression rates between infection stages using the branching probabilities and estimated time spent at each stage. We interpret the basic reproduction number R 0 as the total contribution from an infinite infection loop produced by the asymptomatic carriers in the infection chain. The results indicate that the asymptomatic HIV+ adults without ART serve as the driving force of infection for the iNTS epidemic. We conclude that the worst disease outcome is among the pediatric population, which has the highest infection rates and death counts. Our sensitivity analysis indicates that the most effective strategies to reduce iNTS mortality in the studied population are to improve the ART coverage among high-risk HIV+ adults and reduce malnutrition among children.

59 BASIC BIOLOGICAL SCIENCES↗

Multi-Site Observational Study to Assess Biomarkers for Susceptibility or Resilience to Chronic Pain: The Acute to Chronic Pain Signatures (A2CPS) Study Protocol

Chronic pain has become a global health problem contributing to years lived with disability and reduced quality of life. Advances in the clinical management of chronic pain have been limited due to incomplete understanding of the multiple risk factors and molecular mechanisms that contribute to the development of chronic pain. The Acute to Chronic Pain Signatures (A2CPS) Program aims to characterize the predictive nature of biomarkers (brain imaging, high-throughput molecular screening techniques, or “omics,” quantitative sensory testing, patient-reported outcome assessments and functional assessments) to identify individuals who will develop chronic pain following surgical intervention. The A2CPS is a multisite observational study investigating biomarkers and collective biosignatures (a combination of several individual biomarkers) that predict susceptibility or resilience to the development of chronic pain following knee arthroplasty and thoracic surgery. This manuscript provides an overview of data collection methods and procedures designed to standardize data collection across multiple clinical sites and institutions. Pain-related biomarkers are evaluated before surgery and up to 3 months after surgery for use as predictors of patient reported outcomes 6 months after surgery. The dataset from this prospective observational study will be available for researchers internal and external to the A2CPS Consortium to advance understanding of the transition from acute to chronic postsurgical pain.

60 APPLIED LIFE SCIENCES↗

Post-Combat-Injury Opioid Prescription and Alcohol Use Disorder in the Military

Previous studies have identified combat exposure and combat traumatic experience as problematic drinking risk factors. Increasing evidence suggests that opioid use increases the risk of alcohol use disorder. This study investigated the association between opioid prescription use after injury and (1) alcohol use disorder and (2) severity of alcohol use disorder among deployed military servicemembers. Deidentified health records data of 9,029 deployed servicemembers from a retrospective cohort study were analyzed. Data were randomly selected from the Department of Defense Trauma Registry and included servicemembers with combat injuries during deployment in Iraq or Afghanistan (2002–2016). Pharmacy records and International Classification of Diseases, Ninth and Tenth Revision diagnosis codes were used. Three groups were identified (no opioid prescription use, nonpersistent opioid prescription use, and persistent opioid prescription use) and were compared on the basis of alcohol use disorder risk using Cox proportional hazard models. Data analyses were performed in 2021. Of the 9,029 servicemembers with combat injury, 2,262 developed alcohol use disorder (1,322 developed severe alcohol use disorder). Compared with no opioid prescription use, increased alcohol use disorder risk was associated with persistent opioid prescription use, with a hazard ratio of 1.13 (95% CI=1.02, 1.26). After covariate adjustment, increased risk remained statistically significant (hazards ratio=1.24; 95% CI=1.10, 1.39). There was no significant difference in alcohol use disorder risk between no opioid prescription use and nonpersistent opioid prescription use. The risk of severe alcohol use disorder did not vary by opioid use among servicemembers with alcohol use disorder diagnosis. Furthermore, the findings of the study suggest that the incidence of alcohol use disorder was higher among injured servicemembers with persistent opioid prescription use than among those without opioid use. If replicated in prospective studies, the findings highlight the need for clinicians to consider the current and history of alcohol use of patients in initiating treatment involving opioids.

60 APPLIED LIFE SCIENCES↗

Scaling Up: Demonstrating Risk Reduction and Cost Compression for Commercial Heat Pump Water Heaters (CRADA 625) (Final Report)

This report is a final deliverable for project 81966: Scaling Up: Demonstrating Risk Reduction and Cost Compression for Commercial Heat Pump Water Heaters (CRADA 625) Commercial heat pump water heater (CHPWH) systems can significantly improve the energy efficiency of service water heating (SWH), aka domestic hot water (DHW), in commercial and multifamily buildings but have not yet achieved widespread adoption due to pricing, complexity, and perceived risk factors. The goal of this project – Scaling Up: Demonstrating Risk Reduction and Cost Compression for Commercial HPWHs (Scaling Up) – was to demonstrate and validate a holistic systems approach for CHPWHs that de-risks the technology, creating a reliable, cost-effective, and repeatable approach to CHPWH deployment.

32 ENERGY CONSERVATION, CONSUMPTION, AND UTILIZATI↗

The impact of adjusting for hysterectomy prevalence on cervical cancer incidence rates and trends among women aged 30 years or older—United States, 2001-2019

Abstract Hysterectomy protects against cervical cancer when the cervix is removed. However, measures of cervical cancer incidence often fail to exclude women with a hysterectomy from the population-at-risk denominator, underestimating and distorting disease burden. In this study, we estimated hysterectomy prevalence from the Behavioral Risk Factor Surveillance System surveys to remove the women who were not at risk of cervical cancer from the denominator and combined these estimates with the US Cancer Statistics data. From these data, we calculated age-specific and age-standardized incidence rates for women aged >30 years from 2001-2019, adjusted for hysterectomy prevalence. We calculated the difference between unadjusted and adjusted incidence rates and examined trends by histology, age, race and ethnicity, and geographic region using joinpoint regression. The hysterectomy-adjusted cervical cancer incidence rate from 2001-2019 was 16.7 per 100 000 women—34.6% higher than the unadjusted rate. After adjustment, incidence rates were higher by approximately 55% among Black women, 56% among those living in the East South Central division, and 90% among women aged 70-79 and ≥80 years. These findings underscore the importance of adjusting for hysterectomy prevalence to avoid underestimating cervical cancer incidence rates and masking disparities by age, race, and geographic region. This article is part of a Special Collection on Gynecological Cancers.

Public, Environmental & Occupational Health↗

MVP-CTL Fellowship for Suicide Intervention (CRADA Final Report)

Research conducted with Crisis Text Line (CTL) served as an important stepping stone in the group’s ongoing work of developing natural language processing (NLP) methodologies to discover indicators of suicide factors in the U.S. veteran population. With rising cases of suicide, detecting risk factors among veterans is of growing concern. Socio-economic factors are often under-reported along structured medical variables, and extracting information through NLP methods may improve the sensitivity of suicide prediction models. The research explored through the CTL collaboration provided insights on suicide crisis detection and de-escalation, experience in applying scalable data analysis on real world datasets, contributions to study designs for detecting rare-event and produced transferable methods applicable to the domain of veteran suicide mitigation. Tools developed during this research directly benefits ongoing work on the Million Veteran Project (MVP) collaboration with the Department of Veteran Affairs (VA).

99 GENERAL AND MISCELLANEOUS↗

Enhancing Nuclear and Radiological Security in Polarized Times: Safeguarding Against Extremist Insider Threats

Domestic violent extremism has been on the rise in recent years, fueled by growing political polarization, the COVID-19 pandemic, and the spread of misinformation online. This concerning trend raises an important question: has this increase in extremist violence manifested in more incidents involving radioactive or nuclear (RN) materials and a corresponding security concern? To explore this question, we analyzed existing data on events involving chemical, biological, radiological, or nuclear materials over time. Specifically, we examined the rate of RN-related incidents, the targets of these events, and the ideologies motivating the perpetrators by using the Violent Non-State Actor Chemical, Biological, Radiological, and Nuclear Event Database from the National Consortium for the Study of Terrorism and Responses to Terrorism. Our analysis aimed to determine whether the broader rise of violent extremism has translated to an elevated risk of attacks involving RN materials. Results of the analysis revealed that there was no clear increase in events involving RN material in the dataset. However, given the rarity of these events, this conclusion does not indicate that such a trend might not appear in coming years if violent extremism continues to rise. To address the potential risk presented by violent extremism, in addition to quantifying the frequency of RN events, we also reviewed traits that could make organizations more susceptible to insider threats from radicalized employees. Focusing on the literature around counterproductive workplace behavior, we identified organizational characteristics that might increase the risk of malicious acts committed by radicalized insiders. These risk factors include abusive leadership, situational constraints, and organizational injustice. Finally, using these organizational risk characteristics, we discuss interventions that organizations with RN material can take to reduce their risk of attacks stemming from violent extremism while still protecting individual rights to privacy and civil liberties. Overall, this article provides an overview of the intersections between rising domestic extremism, insider threats, and risks posed by RN materials. We present current data on trends and patterns in this space as well as practical guidance for organizational resilience.

98 NUCLEAR DISARMAMENT, SAFEGUARDS, AND PHYSICAL P↗

Interactions Between Diabetes Mellitus and Osteoarthritis: From Animal Studies to Clinical Data

Diabetes mellitus (DM) and osteoarthritis (OA) are commonly known metabolic diseases that affect a large segment of the world population. These two conditions share several risk factors such as obesity and aging; however, there is still no consensus regarding the direct role of DM on OA development and progression. Interestingly, both animal and human studies have yielded conflicting results, with some showing a significant role for DM in promoting OA, while others found no significant interactions between these conditions. In this review, we will discuss preclinical and clinical data that assessed the interaction between DM and OA. We will also discuss possible mechanisms associated with the effect of high glucose on the articular cartilage and chondrocytes. An emerging theme dominates the breath of published work in this area: most of the studies discussed in this review do not take into consideration the role of other factors such as the type of diabetes, age, biological sex, type of animal model, body mass index, and the use of pain medications when analyzing and interpreting data. Therefore, future studies should be more rigorous when designing experiments looking at DM and its effects on OA and should carefully account for these confounding factors, so that better approaches can be developed for monitoring and treating patients at risk of OA and DM.

59 BASIC BIOLOGICAL SCIENCES↗

Restrictive spirometry pattern among construction trade workers

Spirometry-based studies of occupational lung disease have mostly focused on obstructive or mixed obstructive/restrictive outcomes. We wanted to determine if restrictive spirometry pattern (RSP) is associated with occupation and increased mortality. Study participants included 18,145 workers with demographic and smoking data and repeatable spirometry. The mortality analysis cohort included 15,445 workers with known vital status and cause of death through December 31, 2016. Stratified analyses explored RSP prevalence by demographic and clinical variables and trade. Log-binomial regression models explored RSP risk factors while controlling for important confounders such as smoking, obesity, and comorbidities. Cox regression models explored mortality risk by spirometry category. Prevalence of RSP was very high (28.6%). Mortality hazard ratios for RSP were 1.50 for all causes, 1.86 for cardiovascular diseases, 2.31 for respiratory diseases, and 1.66 for lung cancer. All construction trades except painters, machinists, and roofers had significantly elevated risk for RSP compared to our internal reference group. RSP was significantly associated with both parenchymal and pleural changes seen by chest X-ray. Construction trade workers are at significantly increased risk for RSP independent of obesity. Individuals with RSP are at increased risk for all-cause mortality as well as mortality attributable to respiratory diseases, cardiovascular diseases, and lung cancer. RSP deserves greater attention in occupational medicine and epidemiology.

60 APPLIED LIFE SCIENCES↗

Night shift schedule causes circadian dysregulation of DNA repair genes and elevated DNA damage in humans

Circadian disruption has been identified as a risk factor for health disorders such as obesity, cardiovascular disease, and cancer. Although epidemiological studies suggest an increased risk of various cancers associated with circadian misalignment due to night shift work, the underlying mechanisms have yet to be elucidated. Here, we sought to investigate the potential mechanistic role that circadian disruption of cancer hallmark pathway genes may play in the increased cancer risk in shift workers. In a controlled laboratory study, we investigated the circadian transcriptome of cancer hallmark pathway genes and associated biological pathways in circulating leukocytes obtained from healthy young adults during a 24‐hour constant routine protocol following 3 days of simulated day shift or night shift. The simulated night shift schedule significantly altered the normal circadian rhythmicity of genes involved in cancer hallmark pathways. A DNA repair pathway showed significant enrichment of rhythmic genes following the simulated day shift schedule, but not following the simulated night shift schedule. In functional assessments, we demonstrated that there was an increased sensitivity to both endogenous and exogenous sources of DNA damage after exposure to simulated night shift. Our results suggest that circadian dysregulation of DNA repair may increase DNA damage and potentiate elevated cancer risk in night shift workers.

circadian misalignment↗

Chemical Impacts of Potential CO2 and Brine Leakage on Groundwater Quality with Quantitative Risk Assessment: A Case Study of the Farnsworth Unit

Potential leakage of reservoir fluids is considered a key risk factor for geologic CO2 sequestration (GCS), with concerns of their chemical impacts on the quality of overlying underground sources of drinking water (USDWs). Effective risk assessment provides useful information to guide GCS activities for protecting USDWs. In this study, we present a quantified risk assessment case study of an active commercial-scale CO2-enhanced oil recovery (CO2-EOR) and sequestration field, the Farnsworth Unit (FWU). Specific objectives of this study include: (1) to quantify potential risks of CO2 and brine leakage to the overlying USDW quality with response surface methodology (RSM); and (2) to identify water chemistry indicators for early detection criteria. Results suggest that trace metals (e.g., arsenic and selenium) are less likely to become a risk due to their adsorption onto clay minerals; no-impact thresholds based on site monitoring data could be a preferable reference for early groundwater quality evaluation; and pH is suggested as an indicator for early detection of a leakage. This study may provide quantitative insight for monitoring strategies on GCS sites to enhance the safety of long-term CO2 sequestration.

58 GEOSCIENCES↗

Longitudinal Plasma Proteomic Profiling Reveals Divergent Immune Responses in Durably Cured and Relapsed Pulmonary Tuberculosis

Background: Predicting the risk of tuberculosis (TB) relapse is vital to improving treatment outcomes. Although clinical risk factors of relapse are well characterized, the biological mechanisms driving relapse, particularly host immune responses, remain poorly understood. Elucidating these mechanisms is necessary to better predict relapse risk. Methods: We conducted a longitudinal, global proteomic study on 60 participants with active pulmonary TB, half who were durably cured and half who relapsed. Plasma was collected at seven time-points: at treatment initiation (baseline), during therapy, and 52 weeks post-baseline. Samples were analyzed by high-resolution LC-MS/MS. Results: 2,418 proteins were identified across all samples, with 1,756 being differentially expressed relative to baseline (unadjusted p < 0.05). 956 proteins were differentially abundant between cured and relapsed participants. Relapsed participants showed heightened humoral immunity throughout treatment, as well as upregulated complement activation and HDL particles. Cured participants exhibited elevated recovery-related pathways by week 4, including downregulated epithelial invasion and upregulated oxygen transport. Conclusions: Heightened humoral and innate immune responses were associated with relapse, whereas recovery signatures were associated with durable cure. These findings advance our understanding of host responses to treatment and provide a basis for developing blood-based biomarkers to identify patients at increased risk of relapse.

LC-MS/MS↗

A Phenome-Wide Association Study of genes associated with COVID-19 severity reveals shared genetics with complex diseases in the Million Veteran Program

The study aims to determine the shared genetic architecture between COVID-19 severity with existing medical conditions using electronic health record (EHR) data. We conducted a Phenome-Wide Association Study (PheWAS) of genetic variants associated with critical illness (n = 35) or hospitalization (n = 42) due to severe COVID-19 using genome-wide association summary data from the Host Genetics Initiative. PheWAS analysis was performed using genotype-phenotype data from the Veterans Affairs Million Veteran Program (MVP). Phenotypes were defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods. Among 658,582 Veterans, variants associated with severe COVID-19 were tested for association across 1,559 phenotypes. Variants at the ABO locus (rs495828, rs505922) associated with the largest number of phenotypes (n rs495828 = 53 and n rs505922 = 59); strongest association with venous embolism, odds ratio (OR rs495828 1.33 (p = 1.32 x 10 –199 ), and thrombosis OR rs505922 1.33, p = 2.2 x10 -265 . Among 67 respiratory conditions tested, 11 had significant associations including MUC5B locus (rs35705950) with increased risk of idiopathic fibrosing alveolitis OR 2.83, p = 4.12 × 10 –191 ; CRHR1 (rs61667602) associated with reduced risk of pulmonary fibrosis, OR 0.84, p = 2.26× 10 –12 . The TYK2 locus (rs11085727) associated with reduced risk for autoimmune conditions, e.g., psoriasis OR 0.88, p = 6.48 x10 -23 , lupus OR 0.84, p = 3.97 x 10 –06 . PheWAS stratified by ancestry demonstrated differences in genotype-phenotype associations. LMNA (rs581342) associated with neutropenia OR 1.29 p = 4.1 x 10 –13 among Veterans of African and Hispanic ancestry but not European. Overall, we observed a shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes. Differing associations between genotype-phenotype across ancestries may inform heterogenous outcomes observed with COVID-19. Divergent associations between risk for severe COVID-19 with autoimmune inflammatory conditions both respiratory and non-respiratory highlights the shared pathways and fine balance of immune host response and autoimmunity and caution required when considering treatment targets.

59 BASIC BIOLOGICAL SCIENCES↗