Risk factors for severe outcomes of coronavirus disease 2019 through the waves of the pandemic: Comparing patients with and without solid organ transplantation.

BACKGROUND: While coronavirus disease 2019 (COVID-19) is no longer a public health emergency, certain patients remain at risk of severe outcomes. To better understand changing risk profiles, we studied the risk factors for patients with and without solid organ transplantation (SOT) through the various waves of the pandemic. METHODS: Using the National COVID Cohort Collaborative we studied a cohort of adult patients testing positive for COVID-19 between January 1, 2020, and May 2, 2022. We separated the data into waves of COVID-19 as defined by the Centers for Disease Control. In our primary outcome, we used multivariable survival analysis to look at various risk factors for hospitalization in those with and without SOT. RESULTS: A total of 3,570,032 patients were captured. We found an overall risk attenuation of adverse COVID-19-associated outcomes over time. In both non-SOT and SOT populations, diabetes, chronic kidney disease, and congestive heart failure were risk factors for hospitalization. For SOT specifically, longer time periods between transplant and COVID-19 were protective and age was a risk factor. Notably, asthma was not a risk factor for major adverse renal cardiovascular events, hospitalization, or mortality in either group. CONCLUSIONS: Our study provides a longitudinal view of the risks associated with adverse COVID-related outcomes amongst SOT and non-SOT patients, and how these risk factors evolved over time. Our work will help inform providers and policymakers to better target high-risk patients.

Preexisting Autoimmunity Is Associated With Increased Severity of Coronavirus Disease 2019: A Retrospective Cohort Study Using Data From the National COVID Cohort Collaborative (N3C).

BACKGROUND: Identifying individuals with a higher risk of developing severe coronavirus disease 2019 (COVID-19) outcomes will inform targeted and more intensive clinical monitoring and management. To date, there is mixed evidence regarding the impact of preexisting autoimmune disease (AID) diagnosis and/or immunosuppressant (IS) exposure on developing severe COVID-19 outcomes. METHODS: A retrospective cohort of adults diagnosed with COVID-19 was created in the National COVID Cohort Collaborative enclave. Two outcomes, life-threatening disease and hospitalization, were evaluated by using logistic regression models with and without adjustment for demographics and comorbidities. RESULTS: Of the 2 453 799 adults diagnosed with COVID-19, 191 520 (7.81%) had a preexisting AID diagnosis and 278 095 (11.33%) had a preexisting IS exposure. Logistic regression models adjusted for demographics and comorbidities demonstrated that individuals with a preexisting AID (odds ratio [OR], 1.13; 95% confidence interval [CI]: 1.09-1.17; P < .001), IS exposure (OR, 1.27; 95% CI: 1.24-1.30; P < .001), or both (OR, 1.35; 95% CI: 1.29-1.40; P < .001) were more likely to have a life-threatening disease. These results were consistent when hospitalization was evaluated. A sensitivity analysis evaluating specific IS revealed that tumor necrosis factor inhibitors were protective against life-threatening disease (OR, 0.80; 95% CI: .66-.96; P = .017) and hospitalization (OR, 0.80; 95% CI: .73-.89; P < .001). CONCLUSIONS: Patients with preexisting AID, IS exposure, or both are more likely to have a life-threatening disease or hospitalization. These patients may thus require tailored monitoring and preventative measures to minimize negative consequences of COVID-19.

Outcomes of SARS-CoV-2 Infection in Patients With Chronic Liver Disease and Cirrhosis: A National COVID Cohort Collaborative Study.

BACKGROUND & AIMS: In patients with chronic liver disease (CLD) with or without cirrhosis, existing studies on the outcomes with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have limited generalizability. We used the National COVID Cohort Collaborative (N3C), a harmonized electronic health record dataset of 6.4 million, to describe SARS-CoV-2 outcomes in patients with CLD and cirrhosis. METHODS: We identified all patients with CLD with or without cirrhosis who had SARS-CoV-2 testing in the N3C Data Enclave as of July 1, 2021. We used survival analyses to associate SARS-CoV-2 infection, presence of cirrhosis, and clinical factors with the primary outcome of 30-day mortality. RESULTS: We isolated 220,727 patients with CLD and SARS-CoV-2 test status: 128,864 (58%) were noncirrhosis/negative, 29,446 (13%) were noncirrhosis/positive, 53,476 (24%) were cirrhosis/negative, and 8941 (4%) were cirrhosis/positive patients. Thirty-day all-cause mortality rates were 3.9% in cirrhosis/negative and 8.9% in cirrhosis/positive patients. Compared to cirrhosis/negative patients, cirrhosis/positive patients had 2.38 times adjusted hazard of death at 30 days. Compared to noncirrhosis/positive patients, cirrhosis/positive patients had 3.31 times adjusted hazard of death at 30 days. In stratified analyses among patients with cirrhosis with increased age, obesity, and comorbid conditions (ie, diabetes, heart failure, and pulmonary disease), SARS-CoV-2 infection was associated with increased adjusted hazard of death. CONCLUSIONS: In this study of approximately 221,000 nationally representative, diverse, and sex-balanced patients with CLD; we found SARS-CoV-2 infection in patients with cirrhosis was associated with 2.38 times mortality hazard, and the presence of cirrhosis among patients with CLD infected with SARS-CoV-2 was associated with 3.31 times mortality hazard. These results provide an additional impetus for increasing vaccination uptake and further research regarding immune responses to vaccines in patients with severe liver disease.

A Bayesian Survival Analysis on Long COVID and non Long COVID patients: A Cohort Study Using National COVID Cohort Collaborative (N3C) Data.

Since the outbreak of COVID-19 pandemic in 2020, numerous researches and studies have focused on the long-term effects of COVID infection. The Centers for Disease Control (CDC) implemented an additional code into the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) for reporting 'Post COVID-19 condition, unspecified (U09.9)' effective on October 1st 2021, representing that Long COVID is a real illness with potential chronic conditions. The National COVID Cohort Collaborative (N3C) provides researchers with abundant electronic health records (EHR) data by aggregating and harmonizing EHR data across different clinical organizations in the United States, making it convenient to build up a survival analysis on Long COVID patients and non Long COVID patients among large amounts of COVID positive patients.

Associations between COVID-19 therapies and outcomes in rural and urban America: A multisite, temporal analysis from the Alpha to Omicron SARS-CoV-2 variants.

PURPOSE: To investigate the enduring disparities in adverse COVID-19 events between urban and rural communities in the United States, focusing on the effects of SARS-CoV-2 vaccination and therapeutic advances on patient outcomes. METHODS: Using National COVID Cohort Collaborative (N3C) data from 2021 to 2023, this retrospective cohort study examined COVID-19 hospitalization, inpatient death, and other adverse events. Populations were categorized into urban, urban-adjacent rural (UAR), and nonurban-adjacent rural (NAR). Adjustments included demographics, variant-dominant waves, comorbidities, region, and SARS-CoV-2 treatment and vaccination. Statistical methods included Kaplan-Meier survival estimates, multivariable logistic, and Cox regression. FINDINGS: The study included 3,018,646 patients, with rural residents constituting 506,204. These rural dwellers were older, had more comorbidities, and were less vaccinated than their urban counterparts. Adjusted analyses revealed higher hospitalization odds in UAR and NAR (aOR 1.07 [1.05-1.08] and 1.06 [1.03-1.08]), greater inpatient death hazard (aHR 1.30 [1.26-1.35] UAR and 1.37 [1.30-1.45] NAR), and greater risk of other adverse events compared to urban dwellers. Delta increased, while Omicron decreased, inpatient adverse events relative to pre-Delta, with rural disparities persisting throughout. Treatment effectiveness and vaccination were similarly protective across all cohorts, but dexamethasone post-ventilation was effective only in urban areas. Nirmatrelvir/ritonavir and molnupiravir better protected rural residents against hospitalization. CONCLUSIONS: Despite advancements in treatment and vaccinations, disparities in adverse COVID-19 outcomes persist between urban and rural communities. The effectiveness of some therapeutic agents appears to vary based on rurality, suggesting a nuanced relationship between treatment and geographic location while highlighting the need for targeted rural health care strategies.

Association of Premorbid GLP-1RA and SGLT-2i Prescription Alone and in Combination with COVID-19 Severity.

INTRODUCTION: People with type 2 diabetes are at heightened risk for severe outcomes related to COVID-19 infection, including hospitalization, intensive care unit admission, and mortality. This study was designed to examine the impact of premorbid use of glucagon-like peptide-1 receptor agonist (GLP-1RA) monotherapy, sodium-glucose cotransporter-2 inhibitor (SGLT-2i) monotherapy, and concomitant GLP1-RA/SGLT-2i therapy on the severity of outcomes in individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: Utilizing observational data from the National COVID Cohort Collaborative through September 2022, we compared outcomes in 78,806 individuals with a prescription of GLP-1RA and SGLT-2i versus a prescription of dipeptidyl peptidase 4 inhibitors (DPP-4i) within 24 months of a positive SARS-CoV-2 PCR test. We also compared concomitant GLP-1RA/SGLT-2i therapy to GLP-1RA and SGLT-2i monotherapy. The primary outcome was 60-day mortality, measured from the positive test date. Secondary outcomes included emergency room (ER) visits, hospitalization, and mechanical ventilation within 14 days. Using a super learner approach and accounting for baseline characteristics, associations were quantified with odds ratios (OR) estimated with targeted maximum likelihood estimation (TMLE). RESULTS: Use of GLP-1RA (OR 0.64, 95% confidence interval [CI] 0.56-0.72) and SGLT-2i (OR 0.62, 95% CI 0.57-0.68) were associated with lower odds of 60-day mortality compared to DPP-4i use. Additionally, the OR of ER visits and hospitalizations were similarly reduced with GLP1-RA and SGLT-2i use. Concomitant GLP-1RA/SGLT-2i use showed similar odds of 60-day mortality when compared to GLP-1RA or SGLT-2i use alone (OR 0.92, 95% CI 0.81-1.05 and OR 0.88, 95% CI 0.76-1.01, respectively). However, lower OR of all secondary outcomes were associated with concomitant GLP-1RA/SGLT-2i use when compared to SGLT-2i use alone. CONCLUSION: Among adults who tested positive for SARS-CoV-2, premorbid use of either GLP-1RA or SGLT-2i is associated with lower odds of mortality compared to DPP-4i. Furthermore, concomitant use of GLP-1RA and SGLT-2i is linked to lower odds of other severe COVID-19 outcomes, including ER visits, hospitalizations, and mechanical ventilation, compared to SGLT-2i use alone. Graphical abstract available for this article.

Guanosine-derived atomically dispersed Cu-N3-C sites for efficient electroreduction of carbon dioxide.

Single-atom copper (Cu) embedded within carbon catalysts have demonstrated significant potential in the electrochemical reduction of carbon dioxide (CO2) into valuable chemicals and fuels. Herein, we develop a straightforward and template-free strategy for synthesizing atomically dispersed CuNC catalysts (CuG) by annealing the self-assembled guanosine. The CuG catalysts display two-dimensional morphology, tunable pore size and large surface areas that can be adjusted by changing carbonization temperature. Spherical aberration-corrected transmission electron microscopy reveals that single-atom Cu are homogeneously dispersed on the surface of carbon nanosheets. The optimum CuG-1000 catalysts achieve a high CO Faradaic efficiency (FEco) up to 99% and a high CO current density of 6.53 mA cm-2 (-0.65 V vs. RHE). Besides, the flow cell test of CuG-1000 shows a high current density up to 25.2 mA cm-2 and the FEco still exceeded 91% after more than 20 h of testing. Specifically, the existence of Cu-N3-C active sites was proved by extended X-ray absorption fine structure (EXAFS). Density functional theory evidences that tricoordinated copper with N can largely regulate the adsorption and desorption of key intermediates by transferring electrons to *COOH through Cu atoms, thereby improving selectivity toward CO. This work demonstrates the active origin of CuNC catalysts in CO2 electroreduction and offers a blueprint to construct atomically dispersed transition site catalysts by supramolecular self-assembly strategy.

Effectiveness of various COVID-19 vaccine regimens among 10.4 million patients from the National COVID Cohort Collaborative during Pre-Delta to Omicron periods - United States, 11 December 2020 to 30 June 2022.

OBJECTIVE: This study reports the vaccine effectiveness (VE) of COVID-19 vaccine regimens in the United States, based on the National COVID Cohort Collaborative (N3C) database. METHODS: Data from 10.4 million adults, enrolled in the N3C from 11 December 2020 to 30 June 2022, were analyzed. VE against infection and death outcomes were evaluated across 13 vaccine regimens in recipient cohorts during the Pre-Delta, Delta, and Omicron periods. VE was estimated as (1-odds ratio) × 100% by multivariate logistic regression, using the unvaccinated cohort as reference. RESULTS: Natural immunity showed a highly protective effect (70.33%) against re-infection, but the mortality risk among the unvaccinated population was increased after re-infection; vaccination following infection reduced the risk of re-infection and death. mRNA-1273 full vaccination plus mRNA-1273 booster showed the highest anti-infection effectiveness (47.59%) (95% CI, 46.72-48.45) in the overall cohort. In the type 2 diabetes cohort, VE against infection was highest with BNT162b2 full vaccination plus mRNA-1273 booster (61.19%) (95% CI, 53.73-67.75). VE against death was also highest with BNT162b2 full vaccination plus mRNA-1273 booster (89.56%) (95% CI, 85.75-92.61). During the Pre-Delta period, all vaccination regimens showed an anti-infection effect; during the Delta period, only boosters, mixed vaccines, and Ad26.COV2.S vaccination exhibited an anti-infection effect; during the Omicron period, none of the vaccine regimens demonstrated an anti-infection effect. Irrespective of the variant period, even a single dose of mRNA vaccine offered protection against death, thus demonstrating survival benefit, even in the presence of infection or re-infection. Similar patterns were observed in patients with type 2 diabetes. CONCLUSIONS: Although the anti-infection effect declined as SARS-CoV-2 variants evolved, all COVID-19 mRNA vaccines had sustained effectiveness against death. Vaccination was crucial for preventing re-infection and reducing the risk of death following SARS-CoV-2 infection.

An ordinal severity scale for COVID-19 retrospective studies using Electronic Health Record data.

Objectives: Although the World Health Organization (WHO) Clinical Progression Scale for COVID-19 is useful in prospective clinical trials, it cannot be effectively used with retrospective Electronic Health Record (EHR) datasets. Modifying the existing WHO Clinical Progression Scale, we developed an ordinal severity scale (OS) and assessed its usefulness in the analyses of COVID-19 patient outcomes using retrospective EHR data. Materials and Methods: An OS was developed to assign COVID-19 disease severity using the Observational Medical Outcomes Partnership common data model within the National COVID Cohort Collaborative (N3C) data enclave. We then evaluated usefulness of the developed OS using heterogenous EHR data from January 2020 to October 2021 submitted to N3C by 63 healthcare organizations across the United States. Principal component analysis (PCA) was employed to characterize changes in disease severity among patients during the 28-day period following COVID-19 diagnosis. Results: The data set used in this analysis consists of 2 880 456 patients. PCA of the day-to-day variation in OS levels over the totality of the 28-day period revealed contrasting patterns of variation in disease severity within the first and second 14 days and illustrated the importance of evaluation over the full 28-day period. Discussion: An OS with well-defined, robust features, based on discrete EHR data elements, is useful for assessments of COVID-19 patient outcomes, providing insights on the progression of COVID-19 disease severity over time. Conclusions: The OS provides a framework that can facilitate better understanding of the course of acute COVID-19, informing clinical decision-making and resource allocation.

Research informatics and the COVID-19 pandemic: Challenges, innovations, lessons learned, and recommendations.

The recipients of NIH's Clinical and Translational Science Awards (CTSA) have worked for over a decade to build informatics infrastructure in support of clinical and translational research. This infrastructure has proved invaluable for supporting responses to the current COVID-19 pandemic through direct patient care, clinical decision support, training researchers and practitioners, as well as public health surveillance and clinical research to levels that could not have been accomplished without the years of ground-laying work by the CTSAs. In this paper, we provide a perspective on our COVID-19 work and present relevant results of a survey of CTSA sites to broaden our understanding of the key features of their informatics programs, the informatics-related challenges they have experienced under COVID-19, and some of the innovations and solutions they developed in response to the pandemic. Responses demonstrated increased reliance by healthcare providers and researchers on access to electronic health record (EHR) data, both for local needs and for sharing with other institutions and national consortia. The initial work of the CTSAs on data capture, standards, interchange, and sharing policies all contributed to solutions, best illustrated by the creation, in record time, of a national clinical data repository in the National COVID-19 Cohort Collaborative (N3C). The survey data support seven recommendations for areas of informatics and public health investment and further study to support clinical and translational research in the post-COVID-19 era.

Outcomes of SARS-CoV-2 Infection in Patients with Chronic Liver Disease and Cirrhosis: a N3C Study.

Background and Aims: In patients with chronic liver diseases (CLD) with or without cirrhosis, existing data on the risk of adverse outcomes with SARS-CoV-2 infection have been mixed or have limited generalizability. We used the National COVID Cohort Collaborative (N3C) Data Enclave, a harmonized electronic health record (EHR) dataset of 5.9 million nationally-representative, diverse, and gender-balanced patients, to describe outcomes in patients with CLD and cirrhosis with SARS-CoV-2. Methods: We identified all chronic liver diseases patients with and without cirrhosis who had SARS-CoV-2 testing documented in the N3C Data Enclave as of data release date 5/15/2021. The primary outcome was 30-day all-cause mortality. Survival analysis methods were used to estimate cumulative incidences of death, hospitalization, and mechanical ventilation, and to calculate the associations of SARS-CoV-2 infection, presence of cirrhosis, and demographic and clinical factors to 30-day mortality. Results: We isolated 217,143 patients with CLD: 129,097 (59%) without cirrhosis and SARS-CoV-2 negative, 25,844 (12%) without cirrhosis and SARS-CoV-2 positive, 54,065 (25%) with cirrhosis and SARS-CoV-2 negative, and 8,137 (4%) with cirrhosis and SARS-CoV-2 positive. Among CLD patients without cirrhosis, 30-day all-cause mortality rates were 0.4% in SARS-CoV-2 negative patients and 1.8% in positive patients. Among CLD patients with cirrhosis, 30-day all-cause mortality rates were 4.0% in SARS-CoV-2 negative patients and 9.7% in positive patients.Compared to those who tested SARS-CoV-2 negative, SARS-CoV-2 positivity was associated with more than two-fold (aHR 2.43, 95% CI 2.23-2.64) hazard of death at 30 days among patients with cirrhosis. Compared to patients without cirrhosis, the presence of cirrhosis was associated with a three-fold (aHR 3.39, 95% CI 2.96-3.89) hazard of death at 30 days among patients who tested SARS-CoV-2 positive. Age (aHR 1.03 per year, 95% CI 1.03-1.04) was associated with death at 30 days among patients with cirrhosis who were SARS-CoV-2 positive. Conclusions: In this study of nearly 220,000 CLD patients, we found SARS-CoV-2 infection in patients with cirrhosis was associated with 2.43-times mortality hazard, and the presence of cirrhosis among CLD patients infected with SARS-CoV-2 were associated with 3.39-times mortality hazard. Compared to previous studies, our use of a nationally-representative, diverse, and gender-balanced dataset enables wide generalizability of these findings.

Supraclavicular lymph node dissection with radiotherapy versus radiotherapy alone for operable breast cancer with synchronous ipsilateral supraclavicular lymph node metastases: a real-world cohort study.

BACKGROUND: The role of supraclavicular lymph node dissection (SCLD) in the treatment of breast cancer with ipsilateral supraclavicular lymph node metastasis (ISLM) remains controversial. We evaluated the role of SCLD in the treatment of breast cancer with ISLM and identified patients who may benefit from SCLD. METHODS: Data on patients presenting with breast cancer to the Breast Disease Center, Southwest Hospital, The Army Medical University from January 2004 and December 2017 were retrospectively screened. The median duration of follow-up was 36 months (2-175 months). 305 patients who were recently diagnosed with ISLM were eligible for the analysis. RESULTS: Overall, 9,236 women presented with breast cancer during the study period. Among the patients included, 146 and 159 received SCLD with radiotherapy (RT) and RT alone, respectively. Synchronous ISLM without distant metastases were present in 3.6% cases. The 3- and 5-year overall survival (OS) and disease-free survival (DFS) rates were 79.5% and 73.9%, respectively, and 67.5% and 54.8%, respectively. However, SCLD with RT was not associated with superior survival on both univariate and multivariate analyses. On stratified analyses, patients with non-luminal A tumors with 4-9 positive axillary lymph nodes who underwent SCLD with RT had both superior OS (HR =5.296; 95% CI: 1.857-15.107; P=0.001) and DFS (HR =5.331; 95% CI: 2.348-12.108; P<0.001) compared with those who received RT alone. CONCLUSIONS: SCLD may not beneficial in improving survival for unselected breast cancer patients with ISLNM. There is less of a tendency to perform SCLD in the luminal A group.