Do the rates of repeated hospital visits differ between patients who were discharged following an emergency department (ED) visit and have in-person follow-up visits vs those who have telehealth follow-up visits?In this cohort study that included 16 987 ED visits, telehealth follow-up was associated with 28.3 more repeated ED encounters and 10.6 more return hospital admissions per 1000 patients compared with in-person follow-up.In this study, telehealth follow-up visits after ED encounters were associated with higher rates of repeated hospital visits even after controlling for presentation acuity, comorbidities, and sociodemographic factors. This cohort study evaluates whether the rates of emergency department (ED) return visits and hospitalization differ between patients who obtain in-person vs telehealth encounters for post-ED follow-up care. For patients discharged from the emergency department (ED), timely outpatient in-person follow-up is associated with improved mortality, but the effectiveness of telehealth as follow-up modality is unknown.To evaluate whether the rates of ED return visits and hospitalization differ between patients who obtain in-person vs telehealth encounters for post-ED follow-up care.This retrospective cohort study included adult patients who presented to either of 2 in-system EDs of a single integrated urban academic health system from April 1, 2020, to September 30, 2021; were discharged home; and obtained a follow-up appointment with a primary care physician within 14 days of their index ED visit .In-person vs telehealth post–ED discharge follow-up within 14 days.Multivariable logistic regression was used to estimate the odds of ED return visits (primary outcome) or hospitalization (secondary outcome) within 30 days of an ED visit based on the modality of post–ED discharge follow-up. Models were adjusted for age, sex, primary language, race, ethnicity, Social Vulnerability Index, insurance type, distance to the ED, ambulatory billing codes for the index visit, and the time from ED discharge to follow-up.Overall, 12 848 patients with 16 987 ED encounters  were included; 11 818 (70%) obtained in-person follow-up, and 5169 (30%) obtained telehealth follow-up. Overall, 2802 initial ED encounters (17%) led to returns to the ED, and 676 (4%) led to subsequent hospitalization. In adjusted analyses, telehealth vs in-person follow-up visits were associated with increased rates of ED returns  and hospitalizations .In this cohort study of patients in an urban integrated health care system, those with telehealth follow-up visits after an ED encounter were more likely to return to the ED and be hospitalized than patients with in-person follow-up. The use of telehealth warrants further evaluation to examine its effectiveness as a modality for continuing care after an initial ED presentation for acute illness. Current efforts to improve care coordination following ED encounters is an active area of policy interest: ensuring patients receive appropriate follow-up while also preventing unnecessary hospitalizations and improving health care value.8Nearly 1 in 5 US residents visit the emergency department (ED) annually.10 While telehealth may increase availability of follow-up appointments and decrease risk of exposure to communicable diseases, it is possible that telehealth visits may provide suboptimal evaluation in certain scenarios and paradoxically increase the rate that patients return to the hospital.14Telehealth—the use of synchronous telephone and video technologies and services to provide health care from a distance—underwent rapid adoption since 2020 and now represents 30% of all outpatient care and 34% of all primary care visits.As a first step toward understanding the effectiveness of post–ED discharge follow-up by telehealth, we examined the association between in-person and telehealth post–ED discharge follow-up visits with subsequent 30-day ED return (primary outcome) and hospitalization (secondary outcome). We hypothesized that the limitations of telemedicine may create challenges for the care of many patients recently discharged from the ED and that telemedicine would be associated with greater subsequent acute hospital utilization compared with patients who obtain in-person follow-up visits.STROBE) reporting guideline and was approved as minimal risk and exempt from the requirement for informed consent by the UCLA institutional review board due to its sole use of deidentified and coded data.This retrospective cohort study used electronic health record (EHR) data from an urban integrated academic health system in Los Angeles, California, consisting of 2 EDs that provide approximately 150 000 total visits annually. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology . We selected a 14-day follow-up period given that many acute illnesses would be expected to resolve within that period, with subsequent primary care visits likely related to other issues. We excluded patients who did not have records of a completed follow-up visit within 14 days, returned to the ED before having a follow-up visit, and were not discharged home at the index ED visit . We also excluded all patients enrolled in hospice. For patients with multiple ED visits during the study period, each ED encounter was treated as a unique encounter. For example, a patient who was discharged from the ED and had a follow-up visit day 7, then returned day 8 and was again discharged, would count as having only 1 index ED encounter (day 1) and 1 ED return (day 8). If there were a follow-up visit on day 9, they would have 2 index ED encounters (with day 8 serving as both an ED return and a new index ED visit).18 At this health system, race and ethnicity are self-reported by patients and entered into the EHR at the time of profile creation. Ethnic categories included Hispanic or Latinx or not. Racial categories included American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Pacific Islander, White, and other (including unknown and decline to state). To adjust for clinically relevant factors we extracted the Risk Adjustment Factor (RAF) score, a previously tested and widely implemented measure used by the Centers for Medicare & Medicaid Services to calculate risk adjustment, and ambulatory billing  codes at the index ED visit to adjust for acuity of the initial ED presentation.20 Ambulatory billing codes were categorized into low acuity , medium acuity (level 3), and high acuity .To adjust for sociodemographic factors that influence telehealth and ED utilization, we extracted the following patient characteristics from the EHR: age, sex, primary language, self-reported race and ethnicity, Social Vulnerability Index (SVI), insurance type, and distance to the ED.18 RAF scores had the largest odds of missingness for the uninsured population , average marginal probabilities, and average marginal effects per 1000 patients.22 to estimate the minimum strength of association that an unmeasured confounder (such as the pandemic) would need to have with both the treatment and the outcome to fully explain away a specific treatment-outcome association.To examine whether secular changes in health care utilization over time could affect our findings, we conducted a sensitivity analysis that used the same regression models from the primary analyses but also included an interaction term between encounter type and time. To assess whether COVID-19 cases were contributing substantially to ED returns or hospitalizations, we also conducted a sensitivity analysis that excluded all patients with COVID-19 at the time of their ED presentation. We calculated E-valuesTo further examine the potential impact of missing RAF scores, we (1) examined sample characteristics within the subgroup of patients with missing RAF scores vs those with RAF scores and (2) measured RAF score missingness by follow-up visit modality across all covariates. To assess whether treating return visits within the 30-day window as independent affected findings, we conducted a sensitivity analysis limiting our analytic sample to 1 index encounter per patient.P ≤ .05 was considered statistically significant. All analyses were performed in Stata version 15.1 (StataCorp).A 2-sided In the analysis that was conducted to examine whether there was a prepandemic trend, we found that post–ED discharge telehealth follow-up visits increased after March 2020 compared with the prepandemic baseline rate . TeleheaAmong in-person postdischarge follow-up visits, 1865 (16%) were followed by an ED return visit and 438 (4%) with a hospital admission within 30 days. Among telehealth postdischarge follow-up visits, 937 (18%) were followed by an ED return and 238 (5%) with a hospital admission within 30 days.In the primary analyses, telehealth follow-up was significantly associated with both increased rates of ED returns and hospitalizations. For patients who had a telehealth post–ED discharge follow-up visit compared with those who had an in-person post–ED discharge follow-up visit, the adjusted OR (AOR) for an ED return visit was 1.23  and for hospitalization, 1.31 . As average marginal effects, this equates to 28.3  more ED returns per 1000 encounters and 10.6  more hospitalizations per 1000 encounters compared with in-person follow-up visits  and 3.There was temporal variability with in-person and telehealth follow-up visits that corresponded to surges in local COVID-19 cases . In our In the sensitivity analyses that adjusted for RAF scores in the smaller sample , telehealth follow-up remained associated with greater rates of ED returns, although with a smaller effect size   compared with the RAF nonmissing group (17% and 4%). RAF scores were missing for 15% of patients with in-person and 10% of patients with telehealth follow-up visits; across all variables, RAF score missing rates were grossly similar between follow-up visit modality  and telephone visit . The observed effect size on the outcome of hospitalizations was qualitatively larger for video  than for telephone  .Patients with telehealth visits lived farther from the ED in this study than those with in-person visits. From the patient’s perspective, the remote nature of the encounter may cause them to seek further care for questions or concerns that they were not able to address via telehealth.32 While this could skew our results due to inequitable access to and use of telehealth, we attempted to adjust for these effects by controlling for various sociodemographic factors.15 As policy makers, health systems, and patients consider how to use telehealth to increase access to care, these findings suggest that telehealth may not be the best modality for all types of encounters, including many post–ED discharge follow-up visits. These findings may have particular relevance for rural health.While telehealth is a relatively new modality of care that allows patients more timely and increased access to care, our study found the even when adjusting for time to follow-up, post–follow-up health care utilization was still higher for patients with telehealth visits. In addition, with the rapid adoption of telehealth, there remain concerns of a growing digital divide.Interestingly, the exploratory analyses examining telehealth by modality (video vs telephone) suggested that both video and telephone visits are associated with return to the ED (with similar effect sizes) compared with in-person visits, but for that for the outcome of hospitalizations, video visits have an especially large association compared with in-person visits. These analyses strengthen support for the hypothesis that video visits may be inadequate for acute care follow-up and warrant further investigation.This study has several limitations. Due to the observational study design, there may be unmeasured factors determining who received in-person vs telehealth visits that could bias our results. For example, discrete EHR data do not contain many of the complex social determinants of health that could have affected our results . Similarly, while we adjusted for illness acuity, this does not capture how unwell a patient feels or whether the patient has social support and other resources needed for an in-person visit. Second, although we limited the sample to patients who saw a primary care physician, we could not account for patients who followed up outside of this integrated health system, and it is possible that these outside ED visits were unevenly distributed. Third, RAF scores were missing largely in the uninsured population, skewing the sample in the fully adjusted models. Fourth, this study was done in a single academic medical center. Future studies from multiple health systems are needed to determine the generalizability of these findings.In this retrospective cohort study, we found that after being discharged from the ED, patients with telehealth post–ED discharge follow-up visits were more likely to return to the ED, even after adjustment for sociodemographic characteristics, insurance type, distance to the ED, severity of illness at the index visit, the time from ED discharge to follow-up, and medical complexity (RAF scores). There were numerically increased subsequent hospitalizations as well, but the difference was not statistically significant. The association of telehealth with increased health care utilization warrants further study to evaluate its appropriateness as modality for post-ED follow-up.


How have antiviral agents and monoclonal antibodies for mild to moderate COVID-19 been used in the Veterans Affairs health care system?In this cohort study of 111 717 outpatient US veterans with clinical risk factors for severe COVID-19 who tested positive for SARS-CoV-2 during January and February 2022, 4233 (3.8%) received outpatient pharmacotherapy. Black veterans and Hispanic veterans were less likely to receive treatment, whereas older veterans with a higher number of underlying conditions were more likely to receive treatment.These findings suggest that during a 2-month period when 4 anti–SARS-CoV-2 pharmacotherapies were authorized for use, few eligible veterans received treatment. This cohort study examines factors associated with receipt of outpatient COVID-19 pharmacotherapies in the Veterans Affairs (VA) health care system among veterans with increased risk for severe COVID-19. Older adults and individuals with medical comorbidities are at increased risk for severe COVID-19. Several pharmacotherapies demonstrated to reduce the risk of COVID-19–related hospitalization and death have been authorized for use.To describe factors associated with receipt of outpatient COVID-19 pharmacotherapies in the Veterans Affairs (VA) health care system.This cohort study assessed outpatient veterans with risk factors for severe COVID-19 who tested positive for SARS-CoV-2 during January and February 2022. The setting was the VA health care system, the largest integrated health care system in the US.Demographic characteristics, place of residence, underlying medical conditions, and COVID-19 vaccination.The odds of receipt of any COVID-19 pharmacotherapy, including sotrovimab, nirmatrelvir boosted with ritonavir, molnupiravir, or remdesivir were estimated using multivariable logistic regression.Among 111 717 veterans included in this study  who tested positive for SARS-CoV-2 during January to February 2022, 4233 (3.8%) received any COVID-19 pharmacotherapy, including 2870 of 92 396 (3.1%) in January and 1363 of 19 321 (7.1%) in February. Among a subset of 56 285 veterans with documented COVID-19–related symptoms in the 30 days preceding a positive SARS-CoV-2 test, 3079 (5.5%) received any COVID-19 pharmacotherapy. Untreated veterans had a median (IQR) age of 60 (46-71) years and a median (IQR) of 3 (2-5) underlying medical conditions. Veterans receiving any treatment were more likely to be older  and have a higher number of underlying conditions . Compared with White veterans, Black veterans  were less likely to receive treatment; and compared with non-Hispanic veterans, Hispanic veterans  were less likely to receive treatment. There were 16 546 courses of sotrovimab, nirmatrelvir, and molnupiravir allocated across the VA during this period.In this cohort study of veterans who tested positive for SARS-CoV-2 during January and February when supply of outpatient COVID-19 pharmacotherapies was limited, prescription of these pharmacotherapies was underused, and many veterans with risk factors for severe COVID-19 did not receive treatment. Veterans from minority racial and ethnic groups were less likely to receive any pharmacotherapy. Although these therapies have been demonstrated in clinical trials to be effective in reducing the short-term risk of hospitalization or death among unvaccinated individuals,12 early limited drug supply, the requirement for prompt recognition of symptomatic disease and linkage to treatment, logistical barriers to administration, and the need for clinician and public awareness of therapeutic options have hampered widespread use.14 To date, use of outpatient SARS-CoV-2 pharmacotherapies in the US has not been well described.During January 2022 when the incidence of COVID-19 in the United States was at its highest, 82% of intensive care unit hospital beds were occupied, and nearly 900 000 COVID–19-related deaths had occurred since the pandemic began.15 Within the VA, COVID-19 pharmacotherapies allocated by the federal government are distributed across 156 VA pharmacies by the Pharmacy Benefits Management Services (PBM). This national distribution system serving a population with a majority of older adults with a high burden of underlying conditions who are frequently at increased risk for severe COVID-1916 provides a unique opportunity to evaluate how these therapies have been allocated to at-risk patients infected with SARS-CoV-2, including among minority racial and ethnic groups for whom reach of novel pharmacotherapies in the general US population is often unequal.17 Thus, we sought to describe rates and factors associated with prescription of outpatient COVID-19 pharmacotherapies during January and February 2022 when sotrovimab, a monoclonal antibody active against circulating Omicron SARS-CoV-2 variants at the time and antivirals nirmatrelvir, molnupiravir, and remdesivir were authorized for use.8The Veterans Affairs health care system (VA) is the largest integrated health care system in the US, providing care to more than 9 million veterans at 171 VA medical centers (VAMCs) and 1113 outpatient sites of care.18 supported by the VA Informatics and Computing Infrastructure (VINCI) which integrates multiple data sources to provide patient-level COVID-19–related information on VA enrollees. CSDR includes information on first laboratory-confirmed SARS-CoV-2 tests (either by nucleic acid amplification or antigen testing) within the VA system as well as tests performed outside the VA but documented in VA clinical records. Positive tests are identified by the VA National Surveillance Tool19 and provisioned to the CSDR to support national VA research and operational needs. We also used the VA Corporate Data Warehouse (CDW), a nationally linked database of the VA electronic health records system (EHR), which contains medical and administrative data as well as pharmacy records. These data were supplemented with detailed claims data  from the VA Community Care program, which coordinates and reimburses local care provided outside the VA. We included linked data from the Centers for Medicare and Medicaid Services (CMS) to enhance capture of information on COVID-19 vaccination occurring in non–VA settings. We also integrated data from PBM surveillance on the allocation of sotrovimab, nirmatrelvir, and molnupiravir across VA pharmacies. Remdesivir was approved by the FDA in October 2020 for hospitalized patients with COVID-19 and therefore not part of the national PBM distribution of EUA pharmacotherapies.20 The study was approved by the VA Puget Sound and VA Portland institutional review boards and followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.We used the VA’s COVID-19 Shared Data Resource (CSDR),21We identified veterans aged 18 years or older with a first positive laboratory-confirmed SARS-CoV-2 test in CSDR between January 1 and February 28, 2022. We limited the study population to VA enrollees with an inpatient or outpatient encounter in the VA health care system in the 18 months preceding January 1, 2022, who were not hospitalized on or before the date of positive SARS-CoV-2 test (and hence considered to have mild to moderate COVID-19). We further limited test-positive patients to veterans with at least 1 risk factor for progression to severe COVID-19, including hospitalization or death, as defined by the FDA and the US Centers for Disease Control and Prevention (CDC)  codes, vital signs (temperature), and VINCI-generated natural language processing of admission diagnoses, COVID-19 symptom screening questionnaires, and relevant clinical notes.Using the date of the positive SARS-CoV-2 test as the index date, we ascertained baseline demographic characteristics including race and ethnicity (associated with COVID-19 care) as reported in the VA EHR and most recent ZIP code of residence documented in the year prior to the index date. The ZIP code was used to determine Veterans Integrated Services Network (VISN), rurality of residence based on the Rural-Urban Commuting Areas (RUCA) system, and distance to the nearest VAMC allocated COVID-19 pharmacotherapies.We determined receipt of 4 FDA authorized therapies in use between January 1 and February 28, 2022, which included sotrovimab, nirmatrelvir, molnupiravir, and remdesivir as captured by prescriptions within the VA as well as VA community care claims for reimbursed care provided outside of the VA. To distinguish outpatient from inpatient remdesivir use, we reviewed the date of first remdesivir dose relative to the date of hospital admission. Veterans who were not hospitalized after the index date, who received their first dose of remdesivir prior to any hospitalization, or who received their first dose while in the hospital where the length of stay lasted less than 1 day were classified as having received outpatient remdesivir.Among veterans included in our study, we described sociodemographic and clinical characteristics, stratified by receipt of sotrovimab, nirmatrelvir, molnupiravir, remdesivir, or no antiviral nor monoclonal antibody (no treatment). Among treated veterans, we also described the relative proportion of each of the 4 pharmacotherapies prescribed by VISN. We conducted binomial logistic regression to estimate odds ratios for receipt of any pharmacotherapy vs no treatment as well as multinomial and binomial logistic regression to estimate odds ratios for receipt of sotrovimab, nirmatrelvir, molnupiravir, or remdesivir vs no treatment. Base models for each factor of interest were adjusted for age, sex, and race and ethnicity. Additional covariates identified a priori as potential confounders based on clinical and organizational knowledge  were included for each comparison if they changed the adjusted odds ratio (aOR) by at least 5% when added individually to each base model. Final models were limited to veterans with complete data for all included covariates. Odds ratios were compared using 95% CIs. Analyses were conducted using SAS Enterprise Guide 8.2 (SAS Institute) from April to June 2022.During January and February 2022, 111 717 VA enrollees  with a first positive SARS-CoV-2 test were eligible to receive therapy for mild to moderate COVID-19 , of whomAmong untreated veterans, median (IQR) age was 60 (46-71) years, 22 740 (21.2%) were Black, 72 726 (67.7%) were White, 70 210 (65.3%) had completed primary or booster COVID-19 vaccination, and median (IQR) number of underlying conditions was 3 (2-5) . Among pVeterans receiving any of the 4 treatments were more likely to be older , live in rural areas , and have a higher number of underlying conditions  . ReceiptAmong veterans treated with anti–SARS-CoV-2 pharmacotherapies, the relative proportion of treatments varied across VISNs, from 3.5% to 37.3% for sotrovimab, 30.7% to 64.4% for nirmatrelvir, 6.5% to 44.7% for molnupiravir, and 2.4% to 30.5% for remdesivir .In a nationwide study of 111 717 outpatient US veterans seen in the VA health care system who tested positive for SARS-CoV-2 in January and February 2022, only 3.8% received any outpatient pharmacotherapy, including 5.5% of those with COVID-19–related symptoms and 3.4% of those who were unvaccinated or only partially vaccinated. Untreated veterans during this early period included many persons at high risk for progression to severe COVID-19. Persons of Black race and Hispanic ethnicity were less likely to receive treatment whereas older veterans with a higher number of underlying conditions were more likely to receive treatment. There were notable geographic differences in the distribution of selected pharmacotherapies.8 has not been well described. As reported here, even among at-risk patients engaged in care in a system with national distribution across 156 sites, use remained low. Because oral antivirals were authorized just before the start of the study period, it is expected for initial uptake to be low and increase with time as clinical familiarity and infrastructures develop; in fact, the proportion of veterans testing positive for SARS-CoV-2 who were treated more than doubled from 3.1% in January to 7.1% in February. Nonetheless, there was still a relative surplus in drug supply during this period. Low use is not unique to the VA25 and has been observed in the US and other countries28 reflecting widespread, complex barriers to optimal use.Prescription of outpatient SARS-CoV-2 pharmacotherapies following FDA EUA of oral antivirals in December 202129 also likely contributed to variability in prescribing across VISNs.Across VISNs, there were notable differences in the percentage of veterans receiving any COVID-19 pharmacotherapy as well the relative use of different pharmacotherapies, likely reflecting differences in local infrastructure and clinician education. Furthermore, in the absence of head-to-head clinical trials or observational study evidence for the effectiveness of authorized therapies during this early period, clinical practice varied. Local and regional differences in patient awareness of therapies, particularly during the period of this study before the launch of the nationwide COVID-19 Test to Treat Initiative,30 many VA facilities allocated anti–SARS-CoV-2 pharmacotherapies are also located in rural areas. Rural veterans in our study, in addition to being older, male, and non-Hispanic White, also had more underlying conditions than their urban counterparts (data not shown). Veterans testing positive for SARS-CoV-2 lived within a relatively close distance of a dispensing facility, and we did not observe a meaningful difference between treated and untreated persons, suggesting that relative to other factors, physical distance may not have been a substantial barrier to treatment. However, veterans living farther from VA facilities are more likely to engage in VA care, which may have contributed to better ascertainment of prescriptions in this group and a higher observed likelihood of treatment among rural veterans.31Differences in treatment by rurality were also observed, with veterans in rural areas somewhat more likely to receive treatment. Although US Veterans are a highly rural population,25 While demographic differences in access to care, including lower use of COVID-19 monoclonal antibody treatments among people from minority racial and ethnic groups have been well-described in non–veteran populations,25 disparities in COVID-19–related care within the VA system have been less pronounced.32 Possible reasons for observed racial and ethnic differences in the treatment of mild to moderate COVID-19 include lower awareness of COVID-19 therapy efficacy and eligibility, differences in care-seeking and access to primary care, transportation challenges, potential clinician biases, and lower trust in the health care system impacting acceptance of recommended investigational therapies.35Consistent with findings in other studies, Black veterans were less likely to receive outpatient treatments for COVID-19; Hispanic veterans in our study were also slightly less likely to receive treatment, whereas other studies have been mixed.24 NIH guidance also prioritizes unvaccinated individuals, however, we did not observe a consistent pattern between likelihood of treatment and COVID-19 vaccination; despite the early emphasis on treating unvaccinated individuals, we did not observe any differences in the likelihood of treatment in this group compared with fully vaccinated or boosted veterans. On the other hand, partially vaccinated veterans were more likely to be treated. These findings may reflect differences in patient behaviors, with veterans willing to seek vaccination also more likely to accept recommended investigational therapies. Differences in clinician practice may also affect observed results; because the demonstrated benefit of COVID-19 pharmacotherapies in clinical trials was among unvaccinated participants, clinicians may have differing perspectives on the potential of these therapies to reduce the risk of severe COVID-19 among vaccinated persons. With nearly two-thirds of veterans in our study fully vaccinated or boosted, evidence from observational studies for the effectiveness of current used therapies will be essential to inform best practices.The association between increasing age and higher number of underlying conditions with receipt of pharmacotherapy is consistent with NIH patient prioritization recommendations, which include age, immune status, and clinical risk factors as key determinants for assessing risk for progression to severe COVID-19.This study has several important limitations. Eligibility for treatment of mild to moderate COVID-19 under FDA EUA requires symptomatic disease, and we were not able to fully ascertain COVID-19–related symptoms. National surveillance is conducted by VA PBM to ensure eligibility among veterans receiving treatment in the VA; however, determination of symptom eligibility among untreated veterans is limited to use of natural language processing supplementation of structured data. Nonetheless, even with the study population restricted to symptomatic individuals, the percentage of veterans (5.5%) receiving treatment was still small. Although we augmented data from the VA EHR with multiple sources of information, including receipt of COVID-19 monoclonal antibodies through the VA Community Care program, it is still possible that veterans were treated for COVID-19 outside of the VA. However, this study was conducted during a time when treatments were still very limited. We also restricted the study population to veterans engaged in VA care to increase the likelihood that treatment would occur within the VA system. Although CSDR captures laboratory-based SARS-CoV-2 tests performed in the VA as well as non-VA testing documented in clinical notes, we did not identify all veterans testing positive for SARS-CoV-2, particularly those who did not report non-VA or home-based testing to their clinician. Thus, we may have underestimated the true number of untreated veterans. Furthermore, our estimates of prescribed pharmacotherapies do not account for veterans who were offered but declined treatment. Additionally, veterans are older and have more underlying conditions than persons in the general US population, and care delivery in the VA is very different from non–VA systems; therefore, usage findings may not be generalizable to other groups.In this nationwide study of US veterans using the VA health care system who tested positive for SARS-CoV-2 during January and February 2022, most eligible persons were not prescribed treatment for mild to moderate COVID-19. Demographic, clinical, and facility-level factors were associated with the likelihood of being prescribed treatment. These findings suggest the need for improved infrastructure and education to support treatment of persons at risk for progression to severe COVID-19. Studies of the effectiveness and comparative effectiveness of outpatient COVID-19 pharmacotherapies will also be critical to inform clinical care.


At multivariate analysis, only treatment with MMF  and active neoplasia  were independent predictors of seroconversion failure. These findings suggest that MMF dose reduction or suspension may be required to optimize vaccine response in these patients.Vaccines are the most effective means to prevent the potentially deadly effects of SARS-CoV-2 infection, but not all vaccinated individuals gain the same degree of protection. Patients undergoing chronic immunosuppressive therapy due to autoimmune diseases or liver transplants, for example, may show impaired anti-SARS-CoV-2 antibody response after vaccination. We performed a prospective observational study with parallel arms, aiming to (a) evaluate seroconversion after anti-SARS-CoV-2 mRNA vaccine administration in different subgroups of patients receiving immunosuppressive treatment for rheumatological or autoimmune diseases or to prevent organ rejection after liver transplantation and (b) identify negative predictors of IgG anti-SARS-CoV-2 development. Out of 437 eligible patients, 183 individuals were enrolled at the Rheumatology and Hepatology Tertiary Units of “Maggiore della Carità” University Hospital in Novara: of those, 52 were healthy subjects, while among the remaining 131 patients, 30 had a diagnosis of spondyloarthritis, 25 had autoimmune hepatitis, 10 were liver transplantation recipients, 23 suffered from connective tissue diseases (including 10 cases that overlapped with other diseases), 40 were treated for rheumatoid arthritis, and 5 had vasculitis. Moreover, all patients were receiving chronic immunosuppressive therapy. The immunogenicity of mRNA COVID-19 vaccines was evaluated by measuring IgG anti-SARS-CoV-2 antibody titers before vaccination and after 10, 30, and 90 days since the first dose administration. Of the selected cohort of patients, 24.0% did not develop any detectable anti-SARS-CoV-2 IgG after a complete mRNA-based two doses primary vaccination cycle. At univariate analysis, independent predictors of an absent antibody response to vaccine were a history of liver transplantation (OR 11.5, 95% CI 2.5–53.7,  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a coronavirus responsible for coronavirus disease 2019 (COVID-19), a very heterogeneous disease ranging from a nearly asymptomatic state to a life-threatening condition with high in-hospital mortality, with the highest toll among the elderly or those with chronic diseases and cancer ,4. COVIDSince 2020, more than 50 vaccines against COVID-19 have been developed and tested in phase II and III trials ,9,10,11.Patients affected by chronic immune-mediated inflammatory diseases have high rates of morbidity and mortality due to infections that rely on immunodeficiency, related to either the autoimmune diseases themselves or to the immunosuppressive drugs used to treat these illnesses . Thus, tTo date, few data are available on the efficacy of anti-COVID-19 vaccination in patients with inflammatory autoimmune diseases or in transplanted patients receiving immunosuppressive treatments. To fill this gap, we performed a prospective observational study to assess seroconversion rates after vaccine administration in different subgroups of patients undergoing chronic immunosuppressive treatment due to autoimmune diseases or liver transplantation.We performed a prospective observational study (acronym RIVALSA) with parallel arms including healthy subjects and autoimmune/liver-transplanted patients receiving immunosuppressive drugs with planned COVID-19 vaccination between March and July 2021. Inclusion and exclusion criteria are reported in The study protocol was approved by the local ethical committee (CE 72/21), and the study was conducted in strict accordance with the Declaration of Helsinki. Among all the patients attending either the Rheumatology or Hepatology Unit of “Maggiore della Carità” University Hospital in Novara , eligible subjects (patients receiving immunosuppressive drugs to treat autoimmune diseases or to prevent organ rejection after liver transplantation) were asked to participate in the study; from the 437 subjects screened, 131 patients were included in the study together with 52 healthy subjects selected among the healthcare professionals of these units and/or their relatives. (1)Assessment of the IgG anti-SARS-CoV-2 titer in response to vaccination in patients who completed the primary vaccination cycle receiving immunosuppressive therapy due to inflammatory autoimmune diseases or organ rejection prevention after liver transplantation and proportion of the failure of IgG seroconversion relative to healthy subjects in patients who completed the primary vaccination cycle, 90 days after the first vaccine dose;(2)Identification of predictors of the absence of an IgG anti-SARS-CoV-2 seroconversion 90 days after the first vaccine dose in patients who completed the primary vaccination cycle.The predefined endpoints of the cohort study were as follows:All individuals enrolled in the study underwent blood sampling before anti-SARS-CoV-2 vaccination (t0) and after 10, 30, and 90 days from the first vaccination dose . Blood samples were collected using EDTA as an anticoagulant, and blood fractions were immediately separated via centrifugation and stored at −80 °C until the time of analysis.IgG anti-spike protein antibodies were determined by performing an ELISA test, using a CE-IVD commercial kit (EUROIMMUN Medizinische Labordiagnostika AG Anti-SARS-CoV-2 QuantiVac ELISA (IgG), Lübeck, Germany) ,26, foll2 test or Fisher’s exact test when appropriate, while continuous variables were compared with the Mann-Whitney U test. Odds ratios (ORs) with confidence intervals (CIs) were calculated at univariate analysis. A set of variables associated with seroconversion failure at univariate analysis were used to build multivariate stepwise logistic regression models. The statistical significance threshold was set at 0.05 (two-tailed). Statistical analyses were performed with Statistica for Windows release 12  and MedCalc® Statistical Software version 20.014 .The relevant clinical and experimental data of each subject  were collected from clinical records or during an ad hoc interview and stored in a dedicated database (REDCap). Categorical variables were expressed as frequencies (percentage), while the measures of central tendency and dispersion of continuous variables were, respectively, expressed as medians and interquartile range (IQR). Categorical variables were compared with Pearson’s χAmong the 131 patients, 69.5% were women with a median age of 58 years (IQR 49–67). Healthy controls had a median age of 32 years (IQR 29–45) and were mainly women (65.4%). Most of them were healthcare professionals and had no comorbidities.The baseline population features (patients and controls) are shown in Comparing the two groups, we observed a significant difference in the median antibody titers between healthy subjects and patients at 10, 30, and 90 days since the first vaccine dose .This difference was also confirmed after the exclusion of those subjects with baseline antibody positivity for any time with the exception of the assessment at 90 days after vaccination .p = 0.0010).Interestingly, 50 out of the 50 healthy individuals with complete follow-up (100%) developed anti-SARS-CoV-2 IgG antibodies; by contrast, only 100 out of 119 patients with complete follow-up (84.0%) showed a detectable antibody response to vaccination at 90 days  was built. Treatment with MMF and active cancer as comorbidity were independent predictors of the absence of vaccine response in this model  nor with b-DMARDs  was associated with the absence of IgG anti-spike antibody detection. These results are even more interesting when compared with the existing literature about DMARDs and immune response to vaccines. Indeed, previous studies assessing antirheumatic drug effects on vaccine immunogenicity were mainly focused on seasonal influenza and pneumococcal vaccines. These showed reduced humoral responses in methotrexate-, abatacept-, and rituximab-treated patients and a minimal or absent response in patients treated with anti-cytokine drugs. Such data thus raise the question about the effectiveness of anti-SARS-CoV-2 vaccination in DMARD-treated patients and foster new studies aimed to evaluate immunomodulatory drug effect on COVID-19 vaccination in rheumatologic patients ,33,34,35+ T cells in a third of patients treated with methotrexate [With the aim to evaluate the immunogenicity of a single dose BNT162b2 mRNA vaccine, Bugatti et al., studied 140 chronic inflammatory arthritis patients and observed that anti-cytokine drugs had a low impact on vaccination (>80% response), while the treatment with methotrexate and/or glucocorticoids had a greater effect in reducing the IgG seroconversion, even after methotrexate withholding before and after vaccination . In a laotrexate . On the otrexate , a resulInterestingly, studying a cohort of 404 rheumatic patients, Ruddy et al., showed that anti-TNF-α therapy did not influence antibody response (100%), while only 82% of patients receiving glucocorticoids and 73% receiving MMF had IgG seroconversion . In our Notably, MMF and calcineurin inhibitors impaired immunogenicity to vaccination in our population as well. Indeed, the present study provided evidence of a perdurable absence of antibody response up to 3 months after the first dose administration and the following second one, suggesting a definitive absence of seroconversion. Such interesting results are in agreement not only with those of Furer et al., on autoimmune inflammatory rheumatic patients  but alsoIn univariate analysis, being affected by SLE, undergoing liver transplantation, and being treated with MMF or calcineurin inhibitors were all predictors of the lack of response to vaccination. When all of these predictors were analyzed together in a comprehensive multivariate model, only MMF treatment remained associated with an increased risk of vaccination failure. Such observation is of great interest, as MMF is a common treatment used in either SLE or liver transplantation and may account for the principal lack of immunogenicity observed in these patients. The observed impaired humoral response to mRNA-based vaccines in patients treated with MMF and calcineurin inhibitors could be explained by their pharmacological mechanism of action. Both classes of drugs, in fact, are known to impair T-cell proliferation and activation processes, especially by suppressing follicular T helper cells, thus reducing B-cell-mediated antibody production ,46,47,48As an additional point of interest, we observed that the concomitant diagnosis of neoplasia was a negative predictor of antibody response in all the analyses. This result is not surprising if we consider that, due to their therapeutic regimen, these patients show an increased risk to develop severe COVID-19 manifestations. To date, oncological patients have been generally excluded from anti-SARS-CoV-2 efficacy clinical trials, and studies assessing vaccine immunogenicity in these individuals are still few. The emerging literature on this topic highlights that seroconversion in oncological patients is significantly reduced compared with a healthy population ,50,51.Recently, Mitchell et al.  observedDue to the ongoing pandemic situation, and according to recent lines of evidence highlighting that vaccine efficacy decreases over time ,54, manyAs the pandemic situation evolved, different SARS-CoV-2 variants emerged, acquiring new mutations that could account for immune escape properties. Such lines of evidence foster studies aimed to investigate the ability of vaccine-elicited immunity to neutralize these new threats. According to the “Istituto Superiore di Sanità” , at the time of the present study, the prevalent variant in Italy was the lineage B.1.1.7 (Alpha variant). Different research groups investigated the ability of post-immunization sera to neutralize circulating variants, highlighting that the Alpha variant is unlikely to escape neutralization through both BNT162b2- and mRNA-1273-elicited antibodies and to increase reinfection risk ,60,61,62The present study has some limitations. First of all, the sample size was relatively small, and the population of patients was heterogeneous in terms of diseases, limiting the possibility to identify predictors of vaccination failure with smaller effects than those evidenced due to eventual biases. Additionally, control cohort heterogeneity could, to some extent, limit the possibility to elaborate conclusions stronger than those proposed. Furthermore, we focused only on people receiving mRNA-based vaccines, as only few of our patients received adenoviral vaccines, thus precluding the evaluation of this kind of vaccine immunogenicity. In addition, the chosen assay detected only IgG and not IgM or IgA against SARS-CoV-2 spike protein. Therefore, we cannot exclude that other antibodies targeted to other viral antigens may be present. Moreover, we did not evaluate T-cell-mediated response; thus, a deeper investigation of the cell-mediated response to viral infection would be necessary to better elucidate the role of MMF in vaccination failure. Due to the local COVID-19 infection recording protocol, not establishing a routine identification of viral variants, it was not possible to draw any conclusion about the possible role of the timely prevalent variants of concern in determining vaccination failure. Furthermore, the adopted study setting and the healthcare data availability did not allow a deeper investigation of vaccine efficacy in protecting against symptomatic infection. Finally, the monocentric design of the study may have led to some bias due to the clinical practice of our center.In this prospective, observational study, we showed that a limited but relevant proportion of patients receiving immunosuppressive therapy for inflammatory autoimmune diseases or prevention of solid organ rejection after liver transplantation did not develop detectable anti-SARS-CoV-2 IgG three months after a complete, two-dose mRNA vaccine schedule. The principal predictors of the lack of seroconversion were ongoing treatment with MMF and the compresence of active neoplasia as comorbidity. Individuals under treatment with calcineurin inhibitors or those affected by SLE or undergoing liver transplantation also had a high risk of a failure of vaccine response, but the risk may be biased by concomitant MMF treatment. Our study suggests that MMF treatment modification, its temporary suspension, or a different vaccine regimen may be required in these populations to enhance immune responses.


The COVID-19 pandemic impacted workers globally during 2020–2022 and it has had major psychological implications for workers’ wellbeing. This longitudinal study analyzed risk and protective factors predicting COVID-19 anxiety among workers in Finland. Longitudinal national sample of Finnish workers (n = 685) participated in a five-wave study conducted in 2020–2022, covering multiple waves of the COVID-19 pandemic and its aftermath. Our outcome measure was COVID-19 anxiety. Predictors were psychological distress, work exhaustion, technostress, and loneliness. Models also controlled for self-regulation; social support at work and remote working; and socio-demographic background factors. Both within-person and between-person effects were analyzed using multilevel hybrid regression models. COVID-19 anxiety varied between time points which is explained by changes in circumstances during the pandemic. Highest anxiety was expressed in the middle of the Delta variant surge and lockdown in spring 2021. Within-person changes in psychological distress, work exhaustion, technostress, self-regulation, and perceived loneliness were all associated with COVID-19 anxiety. Between-person results showed that distressed, exhausted, technostressed, and lonely workers expressed more anxiety than others. Remote workers reported higher anxiety over time than others. Those who had reported high self-regulation reported lower anxiety than others. Female gender and younger age were associated with higher anxiety. COVID-19 anxiety continues to be an important phenomenon with a magnitude of consequences on people and numerous industries. This study showed that general mental health and work stressors predict COVID-19 anxiety. Promoting social support and workers’ self-regulation skills can be beneficial for overcoming anxiety during and after the pandemic. The spread of the SARS-CoV-2 virus and COVID-19 disease impacted work conditions fundamentally in 2020–2022. Employees were forced to adapt rapidly to unexpected changes in ways of working and work settings which have also put a strain on the mental health of various professionals . UncertaAnxiety is a normal response under a stressful situation, such as the COVID-19 pandemic. State anxiety is an emotional state characterized by feelings of dread and tension and physiological arousal . A meta-COVID-19 is considered an acute crisis that has similarities to large-scale catastrophes . TheoretExisting psychological problems are a major risk factor in any crisis. People with existing or increasing psychological distress are at a higher risk for experiencing COVID-19 anxiety as well ,36,37. CProlonged remote work increased social isolation, and it led to technostress  especially during the first phase of the pandemic in spring 2020 . NeverthThe presence of protective factors can help mitigate the negative impact of stressors and lower COVID-19 anxiety among workers. COVID-19 coping skills are found to buffer the negative effects of COVID-19 anxiety and support general health . Social Stressors of the COVID-19 pandemic have affected a large portion of the world population, but recent research indicates that there are socio-demographic differences in mental health outcomes. For instance, younger age, lower income, and female gender have been associated with higher COVID-19 anxiety ,35,39,56The COVID-19 pandemic provides a unique research setting to investigate wellbeing at work longitudinally. Circumstances varied a lot during the pandemic in 2020–2022, and these changing circumstances are also likely to have an impact on the perceptions people have had. For example, in Finland—the focus country of our study—the pandemic was handled very well in the first phases of the pandemic and mortality rate remained low . A GermaThis longitudinal study analyzed risk and protective factors predicting COVID-19 anxiety among workers in Finland in 2020–2022. Building on COR theory and research on stress factors under COVID-19, we hypothesized that risk factors for mental health and occupational wellbeing predict higher COVID-19 anxiety over time (H1) and protective factors at work predict lower COVID-19 anxiety over time (H2). Additional analyses aimed to show whether any of these effects were stronger at a certain time point.Participants of this study included employees from mainland Finland. Participants took part in the longitudinal Social Media at Work in Finland Survey study, which targeted the Finnish working population. The response rate for the baseline survey collected in March–April 2019 was 28.31% ,64. MeasParticipants included in the study were 41.62% female and aged 20 to 66 . Out of the participants, 47.45% were married or in a registered relationship, 22.71% had a university degree, and 11.28% had a high individual income (at least 5000 Euros per month) at T1. Out of the participants, 14.63% were working in the social and welfare sector, 13.72% in raw materials and manufacturing, 5.34% in construction, 11.13% in retail and transportation, 16.16% in the service sector, 14.33% in business, communication and technology, 7.93% in public administration, 9.45% in education, and 7.32% in other sectors. Geographically, they came from all the regions of mainland Finland: 37.96% from the Helsinki–Uusimaa area, 20.43% from Southern Finland, 23.78% from Western Finland, and 17.84% from Eastern and Northern Finland. Sample characteristics generally match the working population in Finland, and no major biases have been found during the longitudinal study. Drop-out analysis has shown that participants responding to all survey waves are slightly older, include more males, and have a higher education than the average working population in Finland according to the official statistics of Finland . AnalytiThe Academic Ethics Committee of the Tampere region in Finland stated that the study does not pose ethical problems (decision number 90/2018). Participation was voluntary. Participants were informed of the study’s purpose, and they gave their consent for participation. Data collection was administrated by Norstat, and all respondents answered the survey online. Participants were drawn from Norstat’s web-based panel. Data included only respondents who completed the whole survey. Separate data integrity checks involving attention checks, patterned responses, and nonsensical responses checks were conducted for each time point. Open-ended comments were also checked to further evaluate possible biased motives in response patterns.COVID-19 anxiety was measured using a scale based on the 6-item Spielberger State–Trait Anxiety Inventory, STAI-6 . The meaPsychological distress was measured using the 12-item General Health Questionnaire to assess psychological distress at each time point . The meaWork exhaustion was measured using the five-item exhaustion subscale of Maslach Burnout Indicator . The scaTechnostress measure was based on six items from techno-overload and techno-invasion subscales of Ragu-Nathan and collagues’ technostress scale . Items wSelf-regulation was measured with a 2-item scale based on the self-determination theory ,54. ItemLoneliness was measured with a three-item loneliness scale adapted from the standard Revised UCLA Loneliness Scale (R-UCLA) . The scaSocial support at work was measured with four questions on supportive working environment and support received from colleagues and supervisors. The items derived from the Copenhagen Psychosocial Questionnaire (CPSQII) . The scaRemote work was measured at each time point with questions on whether respondents had worked remotely and how often they worked remotely. For our analyses, we created a dummy variable showing those working remotely at least three days a week.Socio-demographic and occupational information were used as controls. These included age, gender, marital status, education, occupational area, and income. For education level, we used a dummy variable categorizing those having a university degree (22.71% at T1). Those working in the social and welfare sector (14.63% at T1), with an income of at least 5000 euros per month (11.28% at T1), and married (47.45% at T1) were also dichotomized.All analyses were conducted using Stata 17 software. Descriptive results of the study are reported in We ran the main analyses on longitudinal predictors of COVID-19 anxiety using linear multilevel hybrid models. Hybrid models enable simultaneous estimation of within-person effects and between-person effects. Such models combine the strengths of random-effects and fixed-effects approaches and solve their shortcomings ,75. For p-values for statistical significance. Within-person effects show how changes over time in predictors are associated with the change in the outcome variable. Between-person variables show group differences between individuals. The final model also included between-person control variables.All our main time-varying variables had both within-person and between-person effects. We first ran zero models (model 0) by including only one independent variable while adjusting for age and gender. The full model included all main variables and control variables in the same model. All variables were standardized for the regression models. Models report regression coefficients (B) and their robust standard errors (SE). We also report 95% confidence intervals (95% CI) of B, Z-statistics, and The last part of the analysis involved checking interactions with time points to see whether some effects of the key within person effects were stronger during different time points. These fixed effects multilevel models were run separately for all main independent variables. Also, the directionality of effects was checked separately with standardized variables and the effects were significantly stronger when independent variables were predicting COVID-19 anxiety than vice versa. The only exception was self-regulation which had a slightly bigger effect when COVID-19 anxiety was predicting it.p < 0.001). p < 0.001, see The results showed that anxiety was highest at T2, representing spring 2021 see . Within-p < 0.001) indicating that an increase in psychological distress is associated with an increase in COVID-19 anxiety. Work exhaustion and perceived loneliness also had relatively strong effects. Between-person effects of the same variables were all statistically significant, except for remote work. Psychological distress had the strongest between-person association with COVID-19 anxiety.Hybrid models reported in p < 0.001). The between person-effects part of the model showed that those reporting higher psychological distress, work exhaustion, technostress, and loneliness had a higher score in COVID-19 anxiety. Higher self-regulation was associated with lower COVID-19 anxiety. Remote workers, women, and younger people reported higher levels of anxiety. The last part of the analysis investigated whether any of the within-person effects were stronger at certain time points. We found no statistically significant differences in this analysis.The full model included all the variables and control variables in the same model. The results showed statistically significant within-person effects: an increase in psychological distress, technostress, and perceived loneliness were associated with an increase in COVID-19 anxiety. An increase in self-regulation was associated with a decrease in COVID-19 anxiety. A within-person effect of psychological distress was strongest out of all risk and protective factors included in the model  and those working in the frontline of the pandemic  experience higher levels of COVID-19 anxiety and other mental health consequences ,24,25,29Overall, our results underline that stressors at work and life in general have led to anxiety during uncertain times of the COVID-19 pandemic. Moreover, this effect on anxiety seems to hold for some workers, even though the pandemic itself has become largely accepted and treated more as an endemic toward the end of 2022. This is also shown in our results with declining COVID-19 anxiety rates despite the high mortality rate in 2022. However, given its exhaustive aftermath and new potential variants, COVID-19 can continue to cause anxiety and mental health consequences among people worldwide.Our results suggest the existence of protective factors that can help protect workers from experiencing COVID-19 anxiety. Higher self-regulation was associated with lower COVID-19 anxiety, which is in line with previous results regarding positive outcomes of self-efficacy in relation to COVID-19 anxiety . MoreoveOur results show that women and younger employees report stronger COVID-19 anxiety. These results are in line with findings from past research ,28,35. IOur results provide essential insights for organizations regarding work life during pandemics and these findings can be used to develop strategies to cope with COVID-19 anxiety in workplaces. Employees’ psychological distress, work exhaustion, technostress, and perceived loneliness are important factors to be considered when finding ways to relieve COVID-19 anxiety. Fostering opportunities for social support and self-regulation is essential for sustaining resilience and mental wellbeing and alleviating the anxiety of employees during unpredictable, stressful times of pandemics. This can mean creating employee assistance programs or simply organizing a dedicated space and time in the online working sphere for social interaction and encouraging workers to reach out to their supervisors or designated human resources specialists if they need support. Workers’ self-regulation skills can be promoted by allowing them to influence their tasks and organization of their work time when possible. Educating employees to deal with the challenges that stem from remote work and technology use at work in general, can help raise awareness and protect them from the potential negative consequences, such as technostress. Special attention should be given to women and young workers as it is shown that they are more likely to suffer from anxiety during the coronavirus pandemic.Our study was limited to workers in Finland and other studies should continue to investigate COVID-19 anxiety as reactions to COVID-19 have varied quite a lot between European countries alone. Future studies should investigate the observed associations in cross-cultural contexts. We are also limited by self-reported measures. Although our focus was on risk and protective factors of COVID-anxiety, we do recognize that COVID-19 anxiety itself could have an impact on our predictors. This was most obvious with the case of COVID-19 anxiety having a larger effect on self-regulation than vice versa. Future studies could also investigate how COVID-19 anxiety impacts well-being in general. Furthermore, our study did not inquire the respondents about their perceived vulnerability to COVID-19 which could have been expected to relate to COVID-19 anxiety. Future research should consider this measure. Lastly, our analyses are based on workers between ages 20 to 66. Age is an important factor in the mental health outcomes of pandemics, and older adults were the most vulnerable age group to COVID-19 infection. Anxiety among older adults should be analyzed in future studies. We also recommend future longitudinal studies to include additional relevant predictors of anxiety, such as comorbidities, pre-existing mental health or psychological disorders, and COVID-19 infection. Despite these limitations, the current study also has significant strengths. The primary one is its longitudinal design with repeated measurements during various points of the COVID-19 crisis.The COVID-19 pandemic continued longer than expected as new variants of the virus emerged and increased the number of cases periodically. At the same time, the pandemic changed the everyday lives of people and permanently reshaped the world. Under these circumstances, the pandemic may still cause anxiety. Considering the high likelihood of similar pandemics and subsequent events in the future, it is of the utmost importance to support workers’ mental wellbeing. Our longitudinal study found that stressors in work and private life can contribute to COVID-19 anxiety as it tends to increase with other added stressors. The risk factors for COVID-19 anxiety identified in this study included psychological distress, work exhaustion, technostress at work, perceived loneliness, and remote work. Self-regulation served as a protective factor, and it is increasingly important as remote work has become commonplace in many occupational sectors. These results suggest that stressors at work and life in general make adapting to prolonged crises, like the COVID-19 pandemic, more difficult. Efforts to promote self-regulation and social support at work are needed to protect workers’ mental wellbeing.


Lysyl oxidase (LOX) is a secretory protein that catalyzes elastin and collagen cross-linking. Lowering LOX expression and activity in endothelial cells is associated with a high risk of aneurysms and vascular malformation. Interleukin-6 (IL-6), elevated in hypertension, is known to suppress LOX expression. The influence of anti-hypertensive medication on the plasma LOX concentration is currently unknown. In a cohort of 34 patients diagnosed with resistant hypertension and treated with up to nine different drugs, blood concentration of LOX was analyzed to identify drugs that have an impact on plasma LOX concentration. Key findings were confirmed in a second independent patient cohort of 37 patients diagnosed with dilated cardiomyopathy. Blood concentrations of aldosterone and IL-6 were analyzed. In vitro, the effect of IL-6 on LOX expression was analyzed in endothelial cells. Patients receiving aldosterone antagonists had the highest plasma LOX concentration in both cohorts. This effect was independent of sex, age, blood pressure, body mass index, and co-medication. Blood aldosterone concentration correlates with plasma IL-6 concentration. In vitro, IL-6 decreased the expression of LOX in endothelial cells but not fibroblasts. Aldosterone was identified as a factor that affects blood concentration of LOX in an IL-6-dependent manner.  Lysyl oxidase (LOX) is a secreted copper-containing amine oxidase that catalyzes elastin and collagen cross-linking and thereby helps to maintain the supporting architecture of the extracellular matrix in different organs and in the vasculature. Strong activation of LOX has been linked to cardiac dysfunction in animal models and is associated with diastolic heart failure and liver fibrosis in clinical settings ,2,3. ExpLOX is strongly expressed in the endothelium of healthy subjects, but down-regulation is associated with endothelial dysfunction (reviewed by ). Pro-inLOX activity and local concentration can be regulated on various levels, mainly by changes in local expression and proteolytic cleavage. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring endogenous bioactive tetrapeptide that is generated from thymosine β4 by prolyl-oligopeptidase and suppresses the angiotensin II-dependent up-regulation of LOX mRNA expression . WhereasTo determine whether anti-hypertensive medication affects the plasma concentration of LOX, we assessed the LOX plasma concentration of hypertensive patients. We chose a cohort of patients with resistant hypertension whose blood pressure remained elevated despite intensive medical treatment with at least three different anti-hypertensive medications of different classes, including diuretics, at the maximally tolerated doses. This initial screening test was performed to detect potential candidates for involvement in the regulation of LOX secretion. As aldosterone antagonism showed the best correlation with LOX levels in this patient cohort, we subsequently verified the effect of aldosterone blockade on the plasma concentration of LOX in an independent second patient cohort. Here, patients with dilated cardiomyopathy (DCM) were chosen because a large proportion of them received aldosterone antagonists. Patients with known hypertension were excluded from this second cohort in order to examine whether the effect of aldosterone antagonism could be reproduced in a completely independent cohort. Finally, the observed relationship between aldosterone, IL-6, and LOX was confirmed by association studies of plasma concentrations and in vitro studies using isolated endothelial cells.In this study, we analyzed blood samples from patients of the subproject 9a of the German Competence Network Heart Failure. Blood samples were taken at the time of inclusion. The investigation conforms to the principles outlined in the Declaration of Helsinki. All participants provided written informed consent. The study was approved by the ethic boards of the universities of Gießen and Marburg ; patient cohort 2: approval code 115/04ff (6 September 2004)).This study was conducted to analyze the effect of anti-hypertensive medication on circulating concentrations of LOX. Two different prospective cohorts were used. In cohort 1, patients (n = 34) were initially enrolled for classification of resistant hypertension. Physical examination and laboratory tests were assessed for all patients. Patient data contain information about clinical history, age, sex, body mass index, blood pressure, and current medication. Office and 24 h ambulatory blood pressure measurements (ABPM) were performed in accordance with the current guidelines of the European Society of Cardiology for the management of arterial hypertension . PatientThe LOX concentration in plasma and serum samples was analyzed using a human LOX ELISA kit  according to the manufacturer’s protocol. The limit of detection of the assay was 0.63 ng/mL. Aldosterone concentration in samples was analyzed using a human aldosterone ELISA kit  according to the manufacturer’s protocol. The limit of the detection assay was 4.7 pg/mL. IL-6 concentration in samples was analyzed using a human IL-6 ELISA kit . The limit of the detection assay was 3 pg/mL. All measurements were carried out batch-wise on thawed samples by experienced staff blinded to patient characteristics.Male Wistar rats were used for the isolation of coronary endothelial cells. Cells were isolated as described before and grown for 2 days before use . The purThe mRNA levels of LOX were quantified by real-time RT-PCR using iQ-SYBR Green Supermix . Beta-2-Microglobulin (B2M) was used as a housekeeping gene to normalize samples. Total RNA was isolated from cells using peqGOLD TriFast  according to the manufacturer’s protocol. To remove genomic DNA contamination, isolated RNA samples were treated with 1 U DNAse/µg RNA . Then, 1 µg of RNA was used to synthesize cDNA using Superscript RNase H Reverse Transcriptase and oligo (dTs) as primers. The sequences of primers used for determination had the following sequences: LOX: forward: ACA ACC GCA CTG CCT CTG CC; reverse: GCC TTG AGG CTC CAT CGC CG; B2M: forward: GCC GTC GTG CTT GCC ATT C; reverse: CTG AGG TGG GTG GAA CTG AGA C. Quantification was performed by the ΔΔt-method, as described before .t-tests or the Welch test, as appropriate. Exact p-values are given, and differences having p-values < 0.05 are considered to be significant. Association studies were performed by linear regression analysis (Pearson correlation). The Shapiro–Wilk test was used to determine whether the data obtained in each group are normally distributed, and Levene’s test was used to assess whether data in two groups have a comparable variance. Group comparisons were made with either two-sided p-value of < 0.05. With this definition, the null hypothesis was rejected only for patients on aldosterone antagonists. In these patients, plasma concentrations of LOX were increased with aldosterone blockade (p = 0.027).The plasma concentration of LOX was quantified in 34 samples from patients diagnosed with resistant hypertension . These pp < 0.05, the effect sizes were large (ACE/AT1), or at least medium-sized . Therefore, we analyzed the data again but removed patients receiving aldosterone blockade  for 24 h. As outlined in p = 0.021, n = 14 patients). Our data suggest that aldosterone induces the release of IL-6 that then down-regulates vascular expression of LOX, leading to lower blood concentration of LOX. Finally, we proved this suggestion by correlating the blood concentrations of aldosterone with that of IL-6 in the patients of cohort 2 without aldosterone inhibition . Both coThe main finding of this study is that aldosterone blockade is associated with normalized blood LOX concentration. This finding was validated in two totally independent patient cohorts diagnosed with hypertension or DCM. This suggests that aldosterone down-regulates vascular expression of LOX. There is no evidence in the literature that aldosterone directly modifies the expression of LOX. However, aldosterone can activate the NFκB pathway  that is Paradoxically, cardiac induction of LOX may be stimulated by aldosterone via activation of the RhoA GTPase pathway in cardiac fibroblasts . HoweverIL-6 down-regulates the expression of LOX in other tissues as well. In lathyrism, a disease characterized by LOX inhibition, oxidative stress induces cytokines such as IL-6 . MechaniAlthough our study identifies aldosterone as a key player in the regulation of plasma LOX concentration, it has some limitations. It is a cross-sectional study that is not normalized to the duration of aldosterone treatment, use of spironolactone or eplerenone, or dosage of the medication. Nevertheless, a common finding in two completely different patient cohorts is that the effect of aldosterone antagonism is completely independent of co-medication, sex, blood pressure, body mass index, or the additive effect of ACE/AT1 treatment. In addition, mechanistic insights from previous experimental studies suggest that aldosterone is an important regulator of vascular LOX expression .We describe that ACE/AT1 blockade appears to elevate plasma LOX concentration . However, the effect was less clear, restricted to men, and associated with more intensive co-medication. The different responsiveness of male and female patients was surprising, but taking into account that IL-6 is a key player in the vascular expression of LOX, this may be a relevant finding. Sex-dependent differences in IL-6 plasma concentrations have been reported previously . In addip-value did not allow us to reject the null hypothesis). Statins have been shown to directly affect vascular LOX expression in pigs, and the data in our present study are consistent with the idea that statins can also increase the plasma LOX concentration in men and women [Another potential candidate identified in our study that might affect blood LOX levels are statins  was validated in a completely different patient collectives, there are, of course, differences in age, sample generation (plasma vs. serum), and storage time. It is therefore not surprising that the absolute levels differed between both cohorts. However, in the context of our study, it was more important to compare the individual samples within the cohorts.p-value does not allow us to reject the null hypothesis). In contrast to statins and ACE/AT1 blockade, there are no possible mechanisms related to this effect available in the literature.Finally, ASA increased the blood concentration of LOX (again, the None of the other treatment regimens, including beta-blockers, calcium antagonists, diuretics, or alpha-adrenergic antagonists, were associated with differences in the plasma concentration of LOX, indicating that the effect of aldosterone antagonism is rather specific. Our study provides evidence that aldosterone induces IL-6 that is responsible for a reduction in blood concentration of LOX. Furthermore, aldosterone antagonism is efficient to normalize LOX values.


Hereditary angioedema is a rare and commonly misdiagnosed disease characterized by recurrent, painful, nonurticarial, and nonpruritic deep tissue swelling attacks, including potentially life-threatening asphyxiation. Nurses can assist in identifying disease hallmarks and provide emergency care, patient support, and education about injectable or infused medications. Hereditary angioedema is a rare and commonly misdiagnosed disease. This article discusses how nurses can assist in identifying disease hallmarks and provide emergency care, patient support, and education. RJ, a 13-year-old high school student presents to her primary care provider complaining of very swollen hands and forearms, which have worsened over the past 18 hours to the point where she could not go to school. She has no history of food or contact allergies and is taking no medications. Her mother had given her 50 mg of diphenhydramine when she woke up, but this did not confer any apparent improvement. The patient believes her face was starting to swell as well, but there was no evidence of hoarseness or trouble breathing. She denies pruritus and there is no evidence of urticaria .A thorough history revealed that a similar, albeit less severe, event had occurred about a year prior soon after the onset of menses. RJ also admitted to occasional episodes of gastrointestinal pain that each lasted for a few days with no determined cause and resolved without treatment. Based on this history, which seemed indicative of hereditary angioedema, and the risks of asphyxiation with laryngeal swelling, she was sent to a nearby ED where plasma-derived C1 esterase inhibitor (pdC1-INH) was administered I.V. and RJ was monitored for several hours in the ED until the facial and peripheral swelling resolved. Follow-up lab testing revealed low levels of complement component 4 (C4), C1-INH antigen, and C1-INH function, confirming a diagnosis of type 1 hereditary angioedema (HAE).HAE is an autosomal dominant disease characterized by recurrent, generally unpredictable episodes of localized angioedema.HAE attacks result from localized production of excess bradykinin, a potent vasodilatory mediator with vascular permeability-enhancing effects, following activation of the plasma kallikrein-kinin system, which is normally regulated by the C1-INH enzyme. Most patients with HAE have genetic mutations resulting in either deficient levels of normally functioning C1-INH  or C1-INH proteins that are dysfunctional, even though levels may be normal .Erythema marginatum). Other reported prodrome symptoms include tingling, discomfort, fatigue, weakness, or lack of energy.2Patients often report experiencing a “prodrome” or aura shortly before the onset of an HAE attack. The most common prodrome event is erythema marginatum, a distinctive, pale pink rash caused by injured or inflamed capillaries that spreads over the limbs or torso (see Angioedema of lip). They can also occur in the submucosal tissues of the oropharynx and larynx, or abdomen, and occasionally, in the genitals.4Angioedema attacks, which can be painful and disfiguring, typically affect subcutaneous tissues of the extremities  or the face and lips  and a family history of recurrent angioedema are other indicators suggestive of HAE.2Confirmation of an HAE diagnosis and determination of HAE type may be obtained by lab evaluation of plasma levels and function of C1-INH and C4, which is a complement protein that is consumed upon uncontrolled activation of the complement pathway in the absence of normal C1-INH function.6A low C4 level is highly suggestive of either HAE-1 or HAE-2. A C4 level can be used as an initial screening test for HAE. HAE can be definitively diagnosed by an abnormally low level of C1-INH function even if levels are normal.3Because HAE attacks are mediated by excess bradykinin and are not related to mast cell activation and histamine release, they require HAE-specific therapy and do not respond to treatment with antihistamines, epinephrine, or corticosteroids.Recommended therapies for HAE):There are three main HAE management strategies (see Management of HAE attacks requires promptly administered on-demand therapies to limit attack progression and severity I.V. Human plasma-derived C1-INH concentrate (pdC1-INH)Recombinant human C1-INH (rhC1-INH)2-receptor antagonistIcatibant, a bradykinin BFDA-approved medications for on-demand treatment of HAE attacks).Ecallantide, a kallikrein inhibitor  should consider factors, such as the level of disease activity, frequency of attacks, the patient's quality of life, availability of healthcare resources, and failure to achieve adequate control with appropriate on-demand therapy.FDA-approved medications for LTP of HAE attacks).The most recently updated HAE guidelines (United States Hereditary Angioedema Association [US HAEA] and the WAO/EAACI) recommend either I.V. or SUBQ pdC1-INH, or the SUBQ plasma kallikrein inhibitor  lanadelumab-flyo, as preferred first-line agents for LTP  is strongly recommended whenever a patient with HAE is preparing to undergo an invasive dental or medical procedure or is facing a stressful life event. Short-term prophylaxis can be a single dose of I.V. pdC1-INH 1-12 hours before the stressor, or anabolic androgen started 5 to 7 days before the stressor and continued for 2 to 5 days afterward. In a large, retrospective study, facial swelling or laryngeal attacks occurred in 20.8% of patients who received STP with I.V. pdC1-INH 1 hour before a dental extraction; in comparison, 37.2% of patients who did not receive STP experienced facial or laryngeal edema. On a per-patient basis, STP led to a 44.1% reduction in angioedema attacks.22C1-INH products are recommended as first-line options for STP; a course of oral anabolic androgens is a second-line option. If none of these agents are available or there is no time for a course of anabolic androgen, fresh frozen plasma may be used as it contains C1-INH.1While there are no HAE treatments that are FDA-approved for use during pregnancy, the 2020 US HAEA guidelines recommend C1-INH for attack treatment in women who are pregnant or breastfeeding, a recommendation based on case reports and observational study data; prophylaxis is recommended for pregnant women before medical procedures, such as amniocentesis, chorionic villus sampling, and also before planned cesarean delivery and deliveries requiring vacuum or forceps. Attacks are uncommon during normal vaginal deliveries, but on-demand treatment should be available as a precaution. The guidelines also recommend C1-INH products for on-demand treatment or prophylaxis in women who are breastfeeding. Anabolic androgens are contraindicated in those who are pregnant or lactating.3HAE commonly manifests during childhood. The mean age of onset is 10 years, and signs and symptoms usually worsen around the time of puberty.3HAE is not a common diagnosis, yet one that requires awareness and vigilance. The unique pathophysiology and treatment requirements of HAE demand accurate diagnosis to avoid potentially life-threatening consequences and improve the patient's quality of life.Low initial suspicion has been deemed the most significant hurdle to the diagnosis of HAE in primary care clinics and EDs.The awareness of potentially fatal laryngeal swelling is also very important. Patients who present with any facial or laryngeal swelling should be managed as an emergency. If they have any swelling above the shoulders, patients can be counseled to administer on-demand treatment and then go to a local ED or call 911 in case of the rare event that the swelling progresses into potentially fatal laryngeal edema, which can happen relatively quickly (within hours).Finally, almost all of the currently approved medications for HAE are injectable, either I.V. or SUBQ. Nurses can play a valuable role in teaching patients to self-administer these medications and offering regular follow-up appointments. Follow-up frequency, for new patients, is about every 3 months to monitor attack frequency and make any necessary adjustments to the treatment regimen. Once stabilized on a given treatment regimen, patients are generally seen every 6 to 12 months for routine follow-up.The potential adverse reactions of each prescribed medication should be reviewed with the patient. They should be educated on how to differentiate between the adverse reactions of drugs and HAE signs and symptoms. Patient information material, part of drug labeling supplied as a paper copy within the drug packaging and also available online, can be a helpful resource for patients. While HAE attacks are often spontaneous, patients should be made aware of the potential for attacks to be precipitated by dental work, invasive medical procedures, or stressful events. Female patients should be alerted to the potential effects of estrogen-containing medications such as oral contraceptives on HAE attack frequency.HAE resources).The information presented here is far from an exhaustive review of HAE and its treatments. Further, it should be noted that several non-HAE types of angioedema are also mediated by excess bradykinin production, including angioedema induced by angiotensin-converting enzyme-inhibitor therapy in susceptible individuals, and acquired angioedema that may be associated with an autoimmune mechanism. Nurses should consult more detailed HAE and HAE management guidelines and other resources to assist with patient care if referral to an HAE specialist is not an option (see US Hereditary Angioedema Associationwww.haea.org(866) 798-5598Hereditary Angioedema International (HAEi)www.haei.orgAmerican Academy of Asthma and Immunologywww.aaaai.org


Ovarian cancer is the leading cause of gynecological cancer related death in females worldwide. Our previous study demonstrated that decreased expression of microRNA (miR-126) promoted ovarian cancer angiogenesis and invasion by targeting VEGF-A. This study aimed to evaluate the clinical validity of miR-126 as a prognostic marker for epithelial ovarian cancer (EOC).The patients with EOC ranged in age from 27 to 79 years, with a mean age of 57 years.All patients had never had chemotherapy or biotherapy, and the diagnoses were confirmed pathologically in all casesMiR-126 levels in EOC tissue and normal ovaries were determined by qRT-PCR. Its prognostic value was analyzed using the Cox proportional hazards regression model. Survival curves were drawn using the Kaplan–Meier method.P = .044). Receiver operating characteristic analysis showed that the area under the curve of miR-126 was 0.806 .In this study, we found that compared to normal tissues, miR-126 expression was lower in EOC tissues, particularly in omental metastases. Though in our previous study we found that miR-126 may inhibit proliferation and invasion in EOC cell lines, but in this study patients with elevated miR-126 expression exhibited poor overall survival and relapse free survival. Multivariate Cox regression analysis showed that miRNA-126 was an independent prognostic factor for poor relapse-free survival (In this study, we established miR-126 as a potential independent biomarker for predicting recurrence in patients with EOC. It is estimated that 19,880 new cases of ovarian cancer will be diagnosed and 12,810 deaths due to ovarian cancer will occur in 2022 in United States. Even though the platinum-free interval (PFI) is considered as a major prognostic factor in guiding treatment selection in relapses, it is urgently needed to find a targeting marker in clinic to optimize the current diagnosis and treatment of ovarian cancer.Despite tremendous improvements in treatment strategies, epithelial ovarian cancer (EOC) remains to be the first leading cause of gynecological cancer death in the world.–7 microRNA (miR-126), originally identified as an endothelial-specific miRNA playing an essential role in angiogenesis and vascular integrity,,9 it has been shown to function as a critical tumor suppressor in various types of solid tumors.–13MicroRNAs are closely related to tumorigenesis and can act as oncogenes or tumor suppressor genes to influence the occurrence and development of tumor. Differentially expressed miRNA may be used as the indicator of early diagnosis, molecular typing and prognosis, including ovarian cancer. However, so far, the significance of miR-126 in the prognosis of ovarian cancer remains largely unclear. In this study, we identified miR-126 expression differences in 69 patients with primary EOC and 8 corresponding omental metastases. Our previous studies have indicated that the loss of expression of miR-126 contributes to the abnormal VEGF-A accumulation and subsequent unchecked cell invasion and cell proliferation in epithelial ovarian cancer. Interesting, in this study, we found that miR-126 was upregulated in the patients with resistant or refractory relapse (PFI < 6 months) compare to patients with partially sensitive or sensitive relapse (PFI > 6 months). We have indicated the potential of miR-126 to predict the risk of EOC recurrence. Our results demonstrate that miR-126 was an independent prognostic indicator in EOC.Overexpressed miR-126 can inhibit drug resistance cell proliferation and promote apoptosis of drug resistance cell, and invasion of cancer cells in various types of solid tumors.Tumor and normal specimens were obtained from the Gynecologic Tissue Bank of Wuhan Union Hospital with written informed consent and ethical approval from the ethical committee of the hospital. No patients had been subjected to previous chemotherapy. All diagnoses were pathologically confirmed.Samples of human ovarian tissues were obtained from patients who underwent surgery at Wuhan Union Hospital from 2004 through 2019.In total, 23 normal ovarian tissues , 15 benign cystadenomas (5 serous cystadenomas and 10 mucinous cystadenomas), 8 borderline cystadenomas (4 mucinous cystadenomas and 4 serous cystadenomas) and 69 malignant epithelial tumors  were analyzed. A total of 69 EOC patients .patients, no recurrence was found in 18 cases. Overall survival (OS) and relapse-free survival (RFS) time were measured from the date of the initial surgery to death and relapse, respectively.Clinical follow up was available for 50 patients . Mortality occurred in 26 patients during the follow up period. Among those 50 -∆∆CT method.Total RNA was extracted with Trizol reagent  according to the supplied protocol. miR-126 was amplified in triplicate using a Hairpin-it™ microRNAs qPCR Quantitation Kit  on a Step One Plus system  following the manufacturer’s instructions. Levels of gene expression were normalized to U6. The expression level of each gene was calculated using the 2P < .05 suggest a statistically significant different.The comparisons of means were assessed using independent-samples and paired-samples t tests. The median expression value of miR-126 in the EOC tissues was used to classify high and low miR-126 expression groups. The Fisher exact test was used to evaluate the association of miR-126 expression with EOC clinicopathological characteristics. The OS and RFS were analyzed by Kaplan–Meier survival curve and the log–rank test. Hazard ratios and 95% confidence intervals for miR-126 expression were calculated from univariate and multivariate Cox regression model. A receiver operating characteristic (ROC) curve was plotted to evaluate the validity of miR-126 levels to distinguish patients with resistant or refractory relapse (PFI < 6 months) from patients with partially sensitive or sensitive relapse (PFI > 6 months). Statistical analyses were performed using SPSS 13.0 software . The expression levels of miR-126 in 115 clinical samples were assessed by qRT-PCR. The results revealed miR-126 levels were significantly lower in primary ovarian lesions and omental metastases than in the normal ovarian epithelium, benign lesion, and borderline tumor  and relapse-free survival (P < .01)  (shown in Table P = .044)   to patients with partially sensitive or sensitive relapse (PFI > 6 months) was analyzed and a ROC curve was established. miR-126 level in the patients with <6 months of PFI recurrences was increased when compared to the patients with more than 6 months of PFI . The sensitivity was 77.8% and the specificity was 75%.at the cutoff value of 0.128, which represented highly predictive of tumor recurrence . Furthermore, miR-126 is found to be underrepresented in plasma exosomes from patients with EOC compared to healthy women. In concordance with this, we found that miR-126 was underrepresented in ovarian cancer (OC) samples. However, Resnick et al also observed a contradicting finding that miR-126 was overexpressed in sera from patients with OC. However, elevated serum levels of miRNA may not necessarily mean that these microRNAs are produced by cancers themselves.In ovarian cancer, previous studies show that miR-126 is down-regulated in ovarian cancer cells and can inhibit cancer cell growth, migration, and invasion by suppressing a range of gene targets such as PAK4, VEGF, PLXNB2, in vitro. we found that higher miR-126 levels was associated the shorter overall survival and elevated miR-126 levels was an independent predicative factor for EOC Recurrence. This finding may seem to be contradictory to the observation that miR-126 was down-regulated in OC specimens. However, a recent study shows that miR-126 confers platinum resistance in epithelial ovarian cancer through the activation of β-catenin/CBP signaling by targeting its negative regulators such as DKK3, AXIN1, BACH1, and NFAT5. Considering platinum resistant relapses account for most of the mortality, these findings may offer an explanation. That is, in the last stage, the development of chemoresistance may play a more important role in the mortality. However, whether this is the case, needs further studies.In concordance with another study,In addition, because our sample for the study came from only 1 medical center, our findings may not apply to all EOC populations. However, our research is consistent with existing published articles, and there may not be major deviations.In summary, in our study, we described the differential expression of miR-126 in the EOC patient cohort and demonstrate the potential utility of miR-126 as a prognostic marker in EOC.As far as we know, it is the first time we demonstrated that high expression of miR-126 was independent prognostic factors for OS and RFS. Therefore, miR-126 may serve as a molecular marker for early detection, postoperative monitoring recurrence, even targeted therapy for epithelial ovarian cancer in the future.Conceptualization: Jing Cai, Da Huang.Data curation: Lin Liu, Qing Han, Man Xiao, Jin Cao.Formal analysis: Lin Liu, Qing Han, Jing Cai, Jin Cao.Investigation: Lin Liu, Jing Cai, Man Xiao.Methodology: Lin Liu, Qing Han, Jing Cai, Man Xiao, Jin Cao.Project administration: Qing Han, Da Huang, Jin Cao.Supervision: Lin Liu, Jin Cao.Validation: Jin Cao.Writing – original draft: Lin Liu, Qing Han, Da Huang, Jin Cao.Writing – review & editing: Lin Liu, Qing Han, Jin Cao.