To evaluate the association between carotid intima-media thickness (CIMT) at hospital admission and unfavorable outcomes in adults without advanced vascular diseases presenting with non-severe COVID-19 pneumonia to assess the feasibility of evaluating CIMT as a risk stratification aid in this setting.This proof-of-concept nested case-control study enrolled consecutive non-vaccinated adults free of advanced vascular diseases presenting with verified non-severe COVID-19 pneumonia between December 2020 and June 2021. CIMT was measured at admission, and patients were managed in line with the national Ministry of Health guidelines. Those who died or required mechanical ventilation (MV) during the index hospital stay were considered cases and were matched  on a set of covariates to survivors not requiring MV (controls). Frequentist and Bayesian logistic models were fitted to the case status.The study enrolled 207 patients: 27 (13%) cases and 180 controls. All were retained in the analysis after entropy balancing, while 27 cases were exactly matched to 99 controls. Higher CIMT at the proximal internal carotid artery (both left and right) was consistently associated with higher odds of being a case: all odds ratio point-estimates were ≥1.50 with lower limits of the 99% confidence intervals/credibility intervals ≥1.00 with two-sided probabilities of OR>1.00 greater than 99.5%. The susceptibility of the estimates to unmeasured confounding was low.This study supports the feasibility of CIMT as a risk stratification aid in adults free of advanced vascular disease presenting with non-severe COVID-19 pneumonia. COVID-19, an infectious disease caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), in up to 20% of symptomatic patients induces viral pneumonia leading to acute respiratory failure . TherefoAll of the well-known clinically obvious risk factors for severe forms of COVID-19, ie, intertwined metabolic disorders  and closely accompanying cardiovascular diseases (particularly hypertension) are characterized by endothelial dysfunction . EndotheThis nested case-control study enrolled consecutive adults free of advanced vascular diseases and presenting with non-severe COVID-19 pneumonia at the Dubrava University Hospital Respiratory Center between December 2020 and June 2021. The study was approved by the Institutional Review Board of Dubrava University Hospital (2O21/ 2202-02). All patients provided signed informed consent for study inclusion and were managed in line with standard in-house procedures. The only difference was the ultrasound CIMT measurements, which were otherwise not routinely performed. This also included early assessment of the risk of disease deterioration with the MEWS  and asseThe study enrolled non-vaccinated adults (≥18 years of age) with confirmed SARS-CoV-2 infection (polymerase chain reaction test) presenting with clinical/radiological signs of pneumonia requiring low-flow oxygen treatment with a nasal cannula at <5 L/min  who provided informed consent. Patients not requiring oxygen treatment or patients requiring more intense immediate oxygen treatment, patients with clinically manifest or known atherosclerotic cardiovascular diseases (or a history of such a condition), including acute coronary syndrome, myocardial infarction, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral artery diseases , were not enrolled.In November 2020, the national Ministry of Health published a second version of the guidelines for the management of patients with COVID-19 . These gRemdesivir was recommended for the treatment of COVID-19 patients with a severe course of disease and illness duration of fewer than 15 days and normal renal function. The use was justified in immunocompromised patients after the 15th day of illness. Patients received 200 mg of remdesivir on day 1, followed by 100 mg once daily for the subsequent 4 to 9 days, depending on their clinical condition. Systemic corticosteroid therapy was recommended in patients with severe and critical COVID-19 after the seventh day of illness. Patients were treated with dexamethasone 10 mg once daily for 10 days. Tocilizumab was considered in patients with clinical worsening and in those at high risk of the cytokine storm syndrome.Patients were treated with prophylactic enoxaparin (4000 IU subcutaneously) once or twice daily, depending on body weight and renal function . Those warteria carotis interna). It corresponds to the space between the two hyperechoic lines on each acquired ultrasound image . CIMT was measured at the posterior wall: 1 cm proximally from the most distal part of the right and left main common carotid arteries (CCA); at the carotid bifurcation; and 2 cm distally from the most proximal part of the internal carotid arteries  exactly on a set of covariates, and then uses optimal full matching based on Mahalanobis distance to further minimize the distance between the matched units regarding covariates not included in exact matching (a priori hypothesis of no association (assigns 95% probability to an odds ratio [OR] between 0.50 and 2.00), a vaguely informative normal prior for the intercept , and vaguely informative priors on the terms of a decomposition of the covariance matrices . We used SAS for Windows 9.4  and the packages WeightIt  entropy balancing , a form matching ,22. For matching ,17,23. TWeightIt , MatchiIMatchiIt , and rstrstanarm  in the Rrstanarm .We planned to enroll 200 patients based on the assumptions that around 12% (24 patients) would be cases and that we would be able to match each case to an average of five controls in an exact matching procedure combined with optimal full matching, that is, that there would be 120 controls . An odds ratio of 2.00 or higher was considered to indicate a reasonably strong association between CIMT indicators and the case status. Under the assumption of successful matching, and a relative standard deviation of the CIMT measures of 20%-25%, such a sample would provide 87% to 98% power to detect the targeted odds ratio at two-sided alpha = 0.01.Evalue  needed to explain the observed associations between the CIMT indicators and the case status , ie, to Evalue  and episepisensr  in R.The cohort comprised 207 patients: 27 (13.0%) cases  and 180 controls . Cases wConsidering raw covariate data, irrelevant-to-moderate (d = 0.036 to 0.442) and large standardized differences (d = 0.749 for age) were observed between cases and controls , and entHigher values of all CIMT measures tended to be associated with higher odds of being a case  – based on raw data, after entropy balancing, and after matching . HoweverIn the present proof-of-concept study, CIMT measurements were shown to be candidates for a more comprehensive evaluation of their utility in the risk stratification of patients with milder forms of COVID-19 pneumonia but free of advanced clinically obvious vascular diseases. To the best of our knowledge, this is the first study to address this issue. The rationale behind it comprises several elements: i) COVID-19 is characterized by a highly unpredictable course and outcomes , which cOverall, the present findings document an independent association between higher IMT  at the proximal part of the internal carotid arteries and higher odds of death or need for MV in adult COVID-19 patients presenting with non-severe pneumonia who are not burdened with clinically explicit advanced cardio- or cerebrovascular diseases. Consequently, it appears feasible to evaluate CIMT measurements as aids in risk stratification in these patients, and, potentially, in other COVID-19 patient subsets. One practical obstacle in this effort is easily envisaged: despite the fact that CIMT has been long investigated in cardiovascular pathology settings, the cut-off value of “abnormal” CIMT is debatable because the reference ranges are age- and sex-dependent, with significantly higher values in men and an age-related increase in all carotid segments -51. ProfIn conclusion, the present study supports the feasibility of evaluating CIMT as a risk stratification aid in adult COVID-19 patients presenting with milder COVID-19-related pneumonia.


With Norwegian national registry data, we assessed the prevalence of post-COVID-19 symptoms at least 3 months after confirmed infection, and whether sociodemographic factors and pre-pandemic health problems were risk factors for these symptoms.All persons with a positive SARS-CoV-2 PCR test from February 2020 to February 2021 (exposed) were compared to a group without a positive test (unexposed) matched on age, sex, and country of origin. We used Cox regression to estimate hazard ratios (HR) for 18 outcome symptoms commonly described as post-COVID-19 related, registered by GPs. We compared relative risks (RR) for fatigue, memory disturbance, or shortness of breath among exposed and unexposed using Poisson regression models, assessing sex, age, education, country of origin, and pre-pandemic presence of the same symptom and comorbidity as possible risk factors, with additional analyses to assess hospitalisation for COVID-19 as a risk factor among exposed.The exposed group (N = 53 846) had a higher prevalence of most outcome symptoms compared to the unexposed (N = 485 757), with the highest risk for shortness of breath , fatigue  and memory disturbance . High HRs were also found for disturbance of smell/taste and hair loss, but frequencies were low. Concerning risk factors, sociodemographic factors were at large similarly associated with outcome symptoms in both groups. Registration of the outcome symptom before the pandemic increased the risk for fatigue, memory disturbance and shortness of breath after COVID-19, but these associations were weaker among exposed. Comorbidity was not associated with fatigue and shortness of breath in the COVID-19 group. For memory disturbance, the RR was slightly increased with the higher comorbidity score both among exposed and unexposed.COVID-19 was associated with a range of symptoms lasting more than three months after the infection.The online version contains supplementary material available at 10.1186/s12879-023-08727-6. Since the start of the COVID-19 pandemic in 2020, patients have reported various long-term symptoms after infection, and the term “Long-COVID” was introduced in May 2020 by patients’ initiatives –6.Several terms and definitions have been proposed for health problems following COVID-19 . The WHOPost-infectious health problems are well-documented for a variety of infectious diseases, but the mechanisms by which the acute infection leads to later symptoms are unclear . A partiEarly reviews on symptoms following COVID-19 reported that the most frequent persistent symptoms occurring one to six months after COVID-19 were fatigue, dyspnoea, arthralgia, headache, sleep disturbance and mental health problems, concentration difficulties, and memory loss. A meta-analysis in 2022 including 43 studies of hospitalized and non-hospitalized patients with follow-up time ranging from 30 to 120 days found the pooled prevalence of persistent symptoms to be 43%, with moderate variations between geographic regions . Higher Symptoms currently identified as post-COVID-19 are frequent in the general population without prior infection. There is a lack of studies from primary care addressing whether such symptoms occur more frequently among people who have had COVID-19 than in the general population. Also, we do not know whether risk factors for these common symptoms differ between people who have had COVID-19 compared to those without a positive SARS-CoV-2 PCR test.We used nationwide data from Norwegian primary care and designed a study with the following aims: (1) To compare the prevalence of possible post-COVID-19 symptoms (outcome symptoms) registered by primary care physicians at least 3 months after confirmed COVID-19 (exposed) to the prevalence in a matched control population without positive SARS-CoV-2 PCR test (unexposed). (2) To investigate if risk factors such as sociodemographic factors, prior illness/comorbidity, or pre-pandemic presence of symptoms acted differently for selected outcome symptoms after COVID-19 as compared to an unexposed group.This is a prospective population-based cohort study based on nationwide registry data from Norway in the period 2019–2021. The population at risk included all residents in Norway 18 years and above in 2020 who were not living in a nursing home before February 2020 (N = 4 278 768). Exposure-density sampling is used to sample unexposed controls for each exposed persons from the population at risk.Norway has a public health care system with universal health coverage. All citizens are assigned to a specific general practitioner (GP), who is responsible for the management of acute and chronic disease including follow-up of symptoms after acute illness. Emergency out-of-hours services are run by the municipalities and staffed with GPs on rotation. Specialist care and hospitalization require referral from a primary care physician or direct admission by ambulance. During the pandemic public test-centres were set up where people could get tested free of charge. In Norway most COVID-19 patients were evaluated and treated in primary care.All SARS-CoV-2 PCR test results were mandatorily reported to a registry run by the Norwegian Surveillance System for Infectious Diseases (MSIS) , and froUsing the national identifier that is unique for all residents, information from all registries were linked at an individual level. New project specific identifiers for each person were generated and personal identification numbers were removed before the datafiles were sent to the researchers.All persons with a positive PCR test for SARS-CoV-2 between 21 February 2020 and 20 February 2021 were included in a COVID-19 group and denoted as “exposed” , highest fulfilled education in 2019 , country of origin , pre-pandemic registration (21 February 2019 to 20 February 2020) of the same symptom as the outcome symptom, the number of pre-pandemic chronic conditions selected among a list of diagnoses defined by ICPC-2 codes as shown in Supplementary file Table Hospitalization due to COVID-19 was defined as registration of one of ICD-10 codes U071, U072, B342, B972 in NPR with more than 5 h of hospital stay during the exposure period.To investigate the risk for different outcome symptoms after COVID-19 we applied Cox regression models with a positive SARS-CoV-2 PCR test as a time-dependent exposure variable to obtain hazard ratios (HRs) with 95% confidence interval (CI) for each outcome symptom. Cluster robust standard errors were used to account for clustering of individuals who were included in the study population first as unexposed but later had a positive PCR test and included as exposed. Other covariates were education, pre-pandemic registration of the same symptom as the outcome symptom, pre-pandemic registration comorbidities, and pre-pandemic number of consultations.The follow-up periods were calculated separately for each of the 18 diagnoses listed in Tables An unexposed control was censored at the time of the PCR test if he/she had a positive test. If the positive PCR test was before 20 February 2021, which is the latest test date to be included in as exposed, the person was transferred to the exposed group, contributing with time as unexposed from sampling time to a positive test, and with time as exposed from 3 months after the positive test.Persons were also censored 12 months after their sampling date or at end of follow-up on 31 December 2021, at day of emigration or death, or if they moved to a nursing home during the study period. Patients treated for severe COVID-19 in intensive care were censored at their date of entry to intensive care unit due to an overlap between symptoms commonly found after intensive care in general and possible post-COVID-19 symptoms.HRs were calculated by using above explained models including the adjustment variables and are presented with their 95% confidence intervals in the tables and in the text.Secondly, to investigate possible risk factors for the post-COVID-19 symptoms fatigue, memory disturbance and shortness of breath we used separate Poisson regression models with robust standard errors to estimate RRs. The three outcome symptoms were chosen as markers for different clusters of previously described post-COVID symptoms such as fatigue (with bodily pain or mood swings), cognitive problems and ongoing respiratory problems . We usedFurther, we investigated whether the possible risk factors acted differently for those with COVID-19 compared to the unexposed control, and tested whether there was an interaction between the exposure (COVID-19) and each predictor variable (risk factor). We applied multivariable modified Poisson models  with an interaction term between COVID-19 yes/no and the predictor (one-by-one) for each outcome. The p-values of interaction terms are presented in Supplementary file Tables We identified 53 846 persons aged 18 to 102 years with a positive SARS-CoV-2 PCR test in the study period. The mean age was 41 years and 51.6% were male , shortness of breath , memory disturbance  and headache . Disturbance of smell and taste  and hair loss  was also more frequent in the exposed, but both groups had very low frequencies of registration before the pandemic. The likelihood for sleep disturbance, anxiety and depression were lower among exposed compared to the unexposed. However, the prevalence of anxiety and depression increased in both groups from 2019 to the follow-up period.Fatigue, memory disturbance and shortness of breath are outcome symptoms that represent different organ systems or possible mechanisms for post-COVID-19 symptoms, and these were used in analyses of demographic factors and prior illness as risk factors.In Fig. To assess whether association with risk factors varied between the exposed COVID-19 group and the unexposed control group, we did stratified analyses of adjusted relative risks (RRs) for these two groups. These results are shown in Supplementary file Tables Sex was a risk factor for fatigue and shortness of breath both for exposed and unexposed  increased with the number of comorbidities and appeared to be higher in the COVID-19 group for those with three or more comorbidities. However, the difference did not reach statistical significance in the interaction analyses.Conversely, for shortness of breath a higher number of comorbidities was associated with an increased RR for this symptom among the unexposed group, but this association was not observed among the exposed group.The differences in impact of the risk factors were supported by interaction analyses , only 7.5% of the Norwegian population had had a first dose and 3.7% of the population had two doses vaccinated [A limitation of our study is that for GPs, it is common to register only one or two ICPC-2 diagnosis codes, while patients may have presented several problems in one consultation. This is likely to limit the number of symptoms that we identified from registered codes, resulting in underestimation of the symptom burden. Since the data are from GP consultations which do not capture all symptoms in the population, the present study cannot be interpreted as prevalence study of post-COVID-19 symptoms in the general population.Also, under-registration of COVID-19 is likely, as not all infected persons were tested. This was particular the case in the first 2–3 months of the pandemic due to a shortage of test kits. However, during the first phase in 2020 the incidence of COVID-19 in Norway was low due to lockdowns. This is supported by a study among 27 700 randomly selected persons at the end of 2020 detecting antibodies against SARS-CoV-2 only among 0.9% of the sample, which is close to the prevalence in the population with a positive PCR test at that time at 0.8% . TherefoHaving had COVID-19 may alter the utilisation of healthcare, but according to a Norwegian study the increased use of GP services related to COVID-19 gradually decreased to a normal level during the first three months after COVID-19 .The lack of a specific diagnostic code for post-COVID-19 makes it difficult to assess the epidemiology of post-COVID-19 health issues. Walker et al.  found liStill, those who have undergone COVID-19 may be more alert to symptoms reported as post-COVID-19 and present them to their GP. GPs may also have altered their coding practice, being more attentive to and record symptoms that could be related to prior COVID-19. This could result in confirmation and detection bias in our study. If so, the differences between exposed and unexposed may be overestimated in the current study. However, this is a challenge in all studies on registered symptoms that may be related to a certain disease.The number of individuals with positive PCR test for SARS-CoV-2 was not very high during the exposure period used in this study. This leads to a small number of individuals in some of the risk factor strata within the COVID-19 group, and this is also reflected in the wide confidence intervals for some RRs in Fig. Determining the prevalence of post-COVID-19 symptoms in the population is methodologically challenging, including confirmation of infection  and approaches to define post-COVID-19.The prevalence of symptoms reported in meta-analyses published early during the pandemic were generally much higher than our findings , 18, 19.Unlike previous studies, particularly those relying on self-reported symptoms , 19, we A Dutch study, using data from a large population-based cohort study initiated before the pandemic, was able to establish a control group like we did . The diaRecently, based on 9764 tested persons in the US, an attempt was made to develop a definition on post-acute sequelae of SARS-CoV-2 infection (PASC) . HoweverIn general, after various infections a minority of patients experience long term post-acute health problems . Such syFemale sex, higher age, belonging to an ethnic minority group and a high disease burden prior to infection are documented risk factors for post-COVID syndrome , 13, 30.In the literature, comorbid conditions are found to increase the risk for post-COVID-19 symptoms , 5. HoweOutcome symptoms such as fatigue, memory disturbance and shortness of breath are common in the general population, and having had the same symptom before the pandemic markedly increased the risk for having an outcome symptom in the observation period. In clinical practice it is difficult or impossible to determine in each case whether a symptom actually was present prior to the infection, whether it is caused or aggravated by the infection or whether it appears by chance. This underlines the challenge using “post-COVID-19” as diagnosis in primary care, as shown by low-frequent use of such a code when introduced in the UK  and alsoIn this study of a predominantly unvaccinated population, we found a higher prevalence of commonly defined post-COVID-19 symptoms 3 to 12 months after acute COVID-19 compared to an unexposed control group. This was particularly evident for fatigue and shortness of breath. The sociodemographic risk factors for outcome symptoms were generally similar for the exposed and the unexposed control group. However, having had a symptom previously represented a lower relative risk for a new encounter with the same symptom in the exposed COVID-19 group compared to the unexposed. This indicates that COVID-19 itself inflicted a stronger risk for a symptom in this group. In conclusion, COVID-19 was associated with a range of symptoms lasting more than three months after the infection.Below is the link to the electronic supplementary material.Supplementary Material 1


The Itaovid-19) . HoweverWe utilized an existing database containing data on all Swedish individuals together with information on relevant Covid-19 outcomes (the SCIFI-PEARL project database), with information on all positive Covid-19 tests (PCR-based testing) as well as all Covid-19-related hospital and intensive care unit (ICU) admissions, deaths, and national vaccination data . This daWe defined two separate CML cohorts. The first, main cohort, consisted of individuals diagnosed with TKI-treated CML in chronic phase (CP-CML) before March 1st 2020, defined here as the start of the pandemic in Sweden. A secondary cohort consisted of individuals diagnosed during the pandemic, after this index date. We excluded individuals born outside of Europe, as it is documented that they suffered increased susceptibility to severe Covid-19 outcomes in the Swedish population [We performed multiple sets of analyses, comparing the incidence rate ratios (IRRs) between the CML and control cohorts. In the first main analysis, elucidating the inherent risk of Covid-19 in an unvaccinated CML population, patients were additionally censored at the time of first vaccination. Four separate outcomes were investigated: the risk of testing positive for Covid-19, hospital or ICU admission, respectively, related to Covid-19  or death (defined as death with Covid-19 as underlying or contributing cause of death during follow-up).In several secondary analyses, we investigated the same four outcomes. First by initiating follow-up at the time of vaccine protection (defined as 14 days after the 2nd dose of any vaccine used), comparing the CML cohort to their control cohort. To reduce the impact of the knowledge gap regarding the management of Covid-19 disease early in the pandemic and the potential for less adequate management, we also performed analyses limiting the population to CML patients and their respective controls who were alive and without any of the outcomes after the first 6 months of the pandemic. We also compared the cohort consisting of patients diagnosed during the pandemic to their matched control cohort to elucidate the impact of a more active, recent leukemic disease. Furthermore, we investigated the effect of the first-line TKI imatinib as compared to the later generations TKIs  at the time of Covid-19-infection, limiting the analysis to the CML population. IRRs were calculated using a quasi-Poisson regression model incorporating sex  and age , in the main analysis to model the events comparing the CML cohort with the matched control cohort. In the analysis within the CML cohort, the model incorporated the same covariates with the addition of TKI treatment as a categorical time-dependent variable (imatinib or any other TKI). A total of 1146 CP-CML patients were identified and 5,730 matched controls were selected. Among them, 83% of the CML patients were diagnosed before the index date March 1st 2020. The characteristics of patients and controls are outlined in Table P = 0.01). Among the 24 unvaccinated CML patients admitted to the hospital due to Covid-19, all had comorbid conditions. The most common comorbid conditions were cardiovascular diseases (N = 15), renal disease (N = 12), diabetes (N = 10), and chronic lung disease (N = 8). A similar point estimate, but due to lower statistical power, non-significant trend was observed for mortality with IRRs for Covid-19-related death 2.04 . This corresponds to a case fatality-rate of 1.9% (N = 2) and 1.1% (N = 5) for CML patients and controls, respectively. None of the CML patients who tested Covid-19 positive were admitted to an ICU.The risk of Covid-19 infection and severe Covid-19 disease among CML patients is summarized in Table In the analysis where we delayed entry with 6 months, to account for incomplete testing and a high mortality rate early in the pandemic phase, the effect of increased Covid-19 hospital admission disappeared.The vaccination rate during the follow-up was high among both CML patients and controls; 94% and 92%, respectively. Initiating follow-up at the time of vaccination for each subject, there was no significant difference between the CML and the control cohorts regarding any of the outcomes, likely due partly to fewer events, although point estimates were consistent with the ones for unvaccinated individuals.Focusing on the 198 CML patients diagnosed after the index date March 1st 2020  we identified no increased risk vs. their 948 matched controls for any of the listed outcomes Studying the effect of imatinib vs. later generation TKIs we detected no significant differences related to any of the Covid-19 outcomes. In a sensitivity analyses relaxing the definition of hospital admission and/or ICU admission to not require a previous positive PCR test, we did not see any altered findings.In summary, in this register-based matched cohort study utilizing high-quality nationwide data from a large number of individuals, we investigated the risk of developing Covid-19 and suffering more severe Covid-19 outcomes between CML patients and carefully matched population controls. The overall risks for developing Covid-19 positivity, ICU admission, and case-related mortality were comparable and relatively low. However, in CML patients with no Covid-19 vaccination, we observed an increased risk of hospitalization, as compared to controls. In this study, however, we cannot accurately describe the association between CML and Covid-19 death due to the low number of deaths that occurred. Still, the few deaths observed suggest that if there is an increased risk of death, this increased risk is moderate.We did not observe any distinct differences regarding Covid-19 outcome comparing CML patients on 1st generation TKI (imatinib) vs. later generations TKI. Moreover, patients diagnosed with CML after the onset of the Covid-19 pandemic , and thus with a higher leukemic burden, did not display any increased risk of suffering more severe outcomes.


In an effort to minimize positive margins and subsequent re-excision after breast conserving surgery (BCS), many providers and facilities have implemented either a Full Cavity Shave (FCS) approach or adding the MarginProbe Radiofrequency Spectroscopy System.We sought to create a functioning Pro-Forma for use by facilities and payers to evaluate and compare the cost savings of implementing FCS or MarginProbe based on personalized variable inputs.A decision tree demonstrating three possible surgical pathways, BCS, BCS + FCS, and BCS + MarginProbe was developed with clinical inputs for re-excision rate, mastectomy as 2nd surgery, rate of reconstruction, and rate of 3rd surgery derived by a literature review. A surgical pathway cost formula was created using the decision tree and financial inputs derived by utilizing the nation’s largest database of privately billed health insurance claims and Medicare claims data . Using the surgical pathway formula and financial inputs, a customizable Pro-Forma was created for immediate cost savings analysis of BCS + FCS and BCS + Marginprobe using variable inputs. Costs are from the perspective of third-party payers.Utilizing MarginProbe to reduce re-excisions for positive margins can be associated with better cost-savings than FCS due to the increased pathology processing costs by using an FCS approach. The reduction in re-excision provided by both FCS and MarginProbe offset their increased expense to various degrees with cost savings of each method improving as baseline re-excisions rates increase, until ultimately each may become cost-neutral or cost-prohibitive when compared to BCS alone. Our data suggest that in the privately insured population, MarginProbe provides a cost-savings over BCS alone when baseline re-excision rates are over 20% and that FCS becomes cost-saving when baseline re-excision rates are over 29%. For Medicare patients, MarginProbe provides a cost-savings when baseline re-excision rates exceed 34%, and FCS becomes cost-saving for re-excision rates over 52%. Our Pro-Forma allows an individual provider or institution to evaluate the cost savings of the FCS approach and/or utilization of the MarginProbe device such that the additional cost or cost-savings of utilizing one or both of these methods can be quickly calculated based on their facility’s volume and baseline re-excision rate.Our data suggest that utilizing either an FCS approach or the MarginProbe radiofrequency spectroscopy system may be a cost-saving solution to reducing the rate of re-excisions depending on a facility or practice’s surgical volume and baseline re-excision rate. The degree to which each of these interventions provides an added cost or cost-savings to healthcare payers can be evaluated by utilizing the Pro-Forma outlined herein with customizable variable inputs. The American Cancer Society estimates that in 2023, over 350,000 women will be diagnosed with either invasive breast cancer or DCIS . The maj8Pathologically involved margins after lumpectomy double the risk of breast cancer recurrence, , 6 and tAlthough breast re-excision is standard procedure in the setting of positive surgical margins, the additional surgery poses several risks for the patient, including increased incidence of complications, greater psychological and emotional burden, a decline in cosmetic outcomes secondary to larger tissue volume removal, and delays initiating adjuvant therapy. In addition, after partial mastectomy with oncoplastic reconstruction, a mastectomy is required if margins are found to be positive on final surgical pathology. Re-operations also lead to increased healthcare spending, adding additional financial burden to the patient and the healthcare system as a whole.In an effort to reduce the need for reoperation, Full Cavity Shave (FCS) has emerged as an accepted approach for mitigating positive margins at the time of initial surgery. Surgeons utilizing FCS systematically remove additional margins from all aspects of the lumpectomy cavity at the time of BCS. Some studies have shown that rates of positive margins are substantially lower when additional cavity shaves are removed during initial surgery, leading to a decrease in re-excisions by up to 50% or more –13.Alternatively, surgeons may choose to utilize the MarginProbe Radiofrequency Spectroscopy System  as an adjunctive tool for intraoperative margin assessment. MarginProbe utilizes radiofrequency spectroscopy to algorithmically analyze and detect cancerous tissue at the margins of excised lumpectomy specimens in real-time. By providing immediate feedback at the time of surgery, surgeons can take directed shavings, removing additional tissue from only the areas of concern. Like FCS, MarginProbe clinical trials report reduction in re-excision by 50% or more –21.Although the clinical importance of minimizing the need for breast re-excision is clear, the cost savings in doing so is less understood. Few studies have directly compared the financial impact of re-excision after BCS or the cost savings of FCS, and to our knowledge none have performed a cost analysis of MarginProbe in comparison to BCS or BCS + FCS. We conducted a cost savings comparison of utilizing FCS or MarginProbe during BCS and examined the costs including the associated downstream resource utilization of each, presented as a customizable Pro-Forma for individual economic evaluation by third-party payers.For the purpose of this study, cost saving is reported from the perspective of third-party payers including commercial insurers and Medicare, as opposed to facility or patient perspective. The emotional and financial toll of reoperation on patients is known and acknowledged. Any additional cost to facility or payer due to reoperation or the prevention or reoperation may also impact the patient. Facilities must balance the clinical need to reduce re-excisions with the reality of adding additional procedural cost for a medical device without reimbursement, while conversely receiving payment for re-excision by third-party payers. Therefore, the least biased method to evaluate cost saving of methods to reduce re-excision will be from the perspective of the third-party payer , 23.We searched the PubMed MEDLINE database for BCS outcomes related to average (invasive and DCIS) re-excision rates in the United States, published since 2014 , 25–36. Using these clinical inputs, a decision tree was created illustrating the surgical care pathway for BCS alone, BCS + FCS or BCS + MarginProbe. Fig. Fairhealth.org was used to gather commercial cost data. Medicare data was collected from CMS.gov. To complement this comparison, we gathered data on the number of people who have healthcare insurance from the most recent U.S. Census Bureau report on healthcare coverage in the United States  which inAlthough CPT codes for BCS and BCS + FCS are identical, pathology CPT code 88,307 is paid on each specimen analyzed. Therefore, a FCS operation with multiple specimens incurs additional cost for payers than a BCS with fewer specimens for pathology analysis.MarginProbe costs were provided directly by the device manufacturer. A one-time cost for the MarginProbe is priced at $50,000. The list price for the disposable probe is $995 per procedure. Actual pricing for console and disposable probes may be lower based on IDN contract pricing and negotiated procedure volume discounts. All cost savings analyses use device list price unless stated otherwise.Using the clinical and financial inputs in combination with the Decision Tree, a cost formula was created for each surgical pathway Fig.  for inpuWe referenced the Cost Savings Economic Evaluation framework provided by the Office of the Associate Director for Policy and Strategy on the cdc.gov website  to perfoRe-excision rate reduction as a result of implementing either MarginProbe or FCS to BCS alone were set by default to 50%. The rate of reduction can be adjusted in the Pro-Forma. The MarginProbe console and disposable probe costs are set at list price by default but can be adjusted in the Pro-Forma.Net costs/net savings were calculated by subtracting the formula-calculated pathway cost from the pathway cost of its comparator. i.e., the net cost of adding FCS to BCS is the pathway cost of FCS minus the pathway cost of BCS alone. Net costs/net savings are presented on both a per patient basis and total annual basis based on BCS volume inputs in the Pro-Forma. When the intervention improves re-excision rates but is more costly, the cost savings is also presented as a ratio, reported as “cost per re-excision prevented.”All surgical pathway costs are dependent on multiple factors, including the patient’s insurance coverage, the provider’s current rate of re-excision, and the final rate of re-excision after adding FCS or MarginProbe to BCS. BCS + FCS pathway costs begin higher than BCS alone due to pathology charges for each of the additional shave specimens from the six anatomical faces of the lumpectomy cavity. BCS + MP costs begin higher than BCS alone due to an average two additional shave margins and device cost. The reduction in re-excision provided by adding FCS or MarginProbe to BCS may offset the increased spending to various degrees based on baseline re-excision rate, until ultimately, each may become cost-neutral or provide a cost-savings.In the commercially insured population, MarginProbe provides added cost to standard of care BCS when re-excision rates are below 20%, where it then becomes cost-neutral. Using an FCS approach adds additional cost when re-excision rates are below 29%, where it then becomes cost-neutral. For uninsured patients, MarginProbe becomes cost-neutral for a baseline re-excision rate of 25%, and FCS is cost-neutral when re-excisions reach 51%. Finally, in the Medicare population, MarginProbe was found to add additional cost up to a baseline re-excision rate of 34% where it becomes cost-neutral, and FCS provided added cost until a re-excision rate of 52% was reached. Pathway cost comparisons along the range of baseline re-excision rates in Commercially Insured, Uninsured, and Medicare patients are illustrated in Fig. Individualized analysis for consideration of surgical pathways across various patient populations, procedure volumes and current standard of care is made possible by utilizing the Pro-Forma. Examples A-B demonstrate its utility for evaluating the economic impact of adopting either method of margin management in additional to BCS, as well as comparing the effect of changing from one method to the other when it is already part of the facility standard of care.In this example of a typical 400 bed facility, inputs include an annual procedure volume of 45 lumpectomies of which 42% are Medicare and 58% are commercially insured. The re-excision rate is 19.6% and the analysis considers MarginProbe at list price.Implementing FCS would add an additional $1,458 per patient. It would cost $14,881 to prevent one re-excision. Alternatively, adding MarginProbe to BCS procedures would incur an initial capital expenditure of $50,000 and an additional $397 per patient preventing one re-excision for every $4,055 spent.Comparing the two interventions directly, implementing a MarginProbe program in lieu of FCS would be cost-neutral for the first year due to the initial capital cost of the MarginProbe console, and then would reduce healthcare spend by nearly $1,061 per patient and save nearly $48,000 per year while reducing re-excisions below 10%.  . ExampleFCS has also been recommended as a part of the toolbox, as a method to reduce the burden of positive margins . Cost-saOur Pro-Forma considers only the surgical phase of breast-cancer treatment, as the post-surgical treatment pathways would be the same for both FCS and MarginProbe patients. One shortcoming of the Pro-Forma is that it does not take into consideration radiation therapy costs, which does not impact a comparison of FCS and MarginProbe to each other but may alter the significance of the two methods in comparison to BCS alone, due to more conversion to mastectomy (and therefore less radiation) in a percentage of patients with positive margins undergoing standard BCS. It would not be difficult to adjust the Pro-Forma to consider radiation therapy costs based on a facility’s unique parameters.There are no known head-to-head studies of FCS versus MarginProbe. Therefore, although the Pro-Forma allows for variable inputs for the rate of re-excision reduction of each, the assumption of each reducing reoperations by 50% is based on published literature of each method and is a current limitation of the Pro-Forma cost savings example reported.Another way the Pro-Forma could be used is in only a subset of BCS patients at higher risk of positive margins and re-excision. For example, a facility utilizing intraoperative ultrasound for margin assessment during their 300 annual lumpectomies, with a re-excision rate of 4%, would see that although FCS and MarginProbe would lower re-excisions to 2%, it would be at an annual additional cost of nearly $850,000 for FCS or just over $500,000 for MarginProbe.Conversely, the same facility could determine that their 12 re-excisions were nearly exclusively in DCIS patients and use the Pro-Forma to determine that utilizing FCS or MarginProbe only for their 36 annual DCIS patients per year, they would reduce their re-excisions by half, while saving $3,000 per year if using FCS, or saving almost $37,000 per year if using MarginProbe.The personalization of the Pro-Forma enables exacting review and consideration to the cost and utility of the two surgical pathways. Any parameter can be attributed to a facility’s personalized input.https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/2023-cancer-facts-figures.htmlThe clinical importance of minimizing positive margins and subsequent re-excision after BCS is well known. MarginProbe Radiofrequency Spectroscopy is solution than reduce the positive margins and re-excisions by 50% or more. The degree to which each of these interventions provides an added cost or savings to healthcare payers is dependent on facility breast-conserving procedural volume and baseline re-excision rate. Comparison of the two interventions as well as overall cost savings to healthcare payers can be evaluated by utilizing the Pro-Forma with customized variable inputs.


In hospitalized patients with COVID-19, the dosing and timing of corticosteroids vary widely. Low-dose dexamethasone therapy reduces mortality in patients requiring respiratory support, but it remains unclear how to treat patients when this therapy fails. In critically ill patients, high-dose corticosteroids are often administered as salvage late in the disease course, whereas earlier administration may be more beneficial in preventing disease progression. Previous research has revealed that increased levels of various biomarkers are associated with mortality, and whole blood transcriptome sequencing has the ability to identify host factors predisposing to critical illness in patients with COVID-19.Our goal is to determine the most optimal dosing and timing of corticosteroid therapy and to provide a basis for personalized corticosteroid treatment regimens to reduce morbidity and mortality in hospitalized patients with COVID-19.This is a retrospective, observational, multicenter study that includes adult patients who were hospitalized due to COVID-19 in the Netherlands. We will use the differences in therapeutic strategies between hospitals (per protocol high-dose corticosteroids or not) over time to determine whether high-dose corticosteroids have an effect on the following outcome measures: mechanical ventilation or high-flow nasal cannula therapy, in-hospital mortality, and 28-day survival. We will also explore biomarker profiles in serum and bronchoalveolar lavage fluid and use whole blood transcriptome analysis to determine factors that influence the relationship between high-dose corticosteroids and outcome. Existing databases that contain routinely collected electronic data during ward and intensive care admissions, as well as existing biobanks, will be used. We will apply longitudinal modeling appropriate for each data structure to answer the research questions at hand.As of April 2023, data have been collected for a total of 1500 patients, with data collection anticipated to be completed by December 2023. We expect the first results to be available in early 2024.This study protocol presents a strategy to investigate the effect of high-dose corticosteroids throughout the entire clinical course of hospitalized patients with COVID-19, from hospital admission to the ward or intensive care unit until hospital discharge. Moreover, our exploration of biomarker and gene expression profiles for targeted corticosteroid therapy represents a first step towards personalized COVID-19 corticosteroid treatment.ClinicalTrials.gov NCT05403359; https://clinicaltrials.gov/ct2/show/NCT05403359DERR1-10.2196/48183 The emergence of SARS-CoV-2 in Wuhan caused a global COVID-19 pandemic, with a high mortality and morbidity rate worldwide [The main reason for hospitalization of patients with COVID-19 is the requirement of supplemental oxygen therapy because of hypoxemia. In some patients, ground glass opacification and the beginning of consolidations on pulmonary CT scan are observed , accompaFor decades, corticosteroids are given to treat patients with non–COVID-19 ARDS because of their strong anti-inflammatory effects . CurrentIn these dexamethasone-unresponsive patients with COVID-19, corticosteroid therapy is sometimes escalated to a much higher dose. However, large heterogeneity in the type, timing, and dosing of escalated corticosteroid therapy exists . High-doTreatment with high-dose corticosteroids may come at the cost of complications, such as secondary infections due to the immunosuppressive effects. To better predict the response to high-dose corticosteroids prior to therapy, additional diagnostic tools such as serum and BALF biomarker determination and whole blood transcriptome analysis could be helpful . ImplemeOverall, the optimal dosing and timing of high-dose corticosteroids in hospitalized patients with COVID-19 remains uncertain. Here, we present the study design and methodological considerations of the SELECT  study, a multicenter study that aims to study the most optimal dosing and timing of corticosteroid therapy to reduce the morbidity and mortality of hospitalized patients with COVID-19. In addition, we aim to provide a basis for personalized corticosteroid treatment regimens by exploring the predictive value of biomarkers and whole blood transcriptome analysis. We hypothesize that the effect of corticosteroid therapy on outcome is determined by the dosage and timing of administration, as well as the patient’s underlying inflammatory state.Work package 1A (WP1A) is used to investigate whether initial treatment with high-dose corticosteroids compared to treatment with 6 mg dexamethasone per day for 10 days, or an equivalent corticosteroid, improves patient outcomes in the ward .WP1B is used to investigate whether treatment with high-dose corticosteroids compared to no corticosteroids, after treatment with 6 mg dexamethasone per day for 10 days, improves patient outcomes in the ward.Work package 2 (WP2) is used to investigate whether initial treatment with high-dose corticosteroids compared to treatment with 6 mg dexamethasone per day for 10 days, or an equivalent corticosteroid, improves patient outcomes in the ICU.Work package 3 (WP3) is used to investigate whether treatment with high-dose corticosteroids compared to no corticosteroids, after treatment with 6 mg dexamethasone per day for 10 days, improves patient outcomes in the ICU.Work package 4a (WP4a) is used to investigate whether biomarker profiles in serum and BALF act as response predictors for high-dose corticosteroids on the outcome.WP4b is used to investigate whether whole blood transcriptome analysis acts as a response predictor for high-dose corticosteroids on the outcome.High-dose corticosteroids are defined as every treatment with dexamethasone >6 mg daily or an equivalent corticosteroid . RegardiThe SELECT study is a retrospective cohort study with data from 22 hospitals in the Netherlands, including 4 academic and 18 nonacademic hospitals . Other hAdult patients (≥18 years) hospitalized with polymerase chain reaction–confirmed COVID-19 or high clinical suspicion of COVID-19 will be included . PregnanThe study will be conducted according to the principles of the Declaration of Helsinki  and in accordance with Erasmus MC Research code, Netherlands Code of Conduct for Research Integrity, General Data Protection Regulation, Code of Conduct for Health Research , Code of Conduct for Responsible Use of Human Tissue (Non-WMO), and Medical Treatment Contracts Act. The study was approved by the Medical Research Ethics Committee from Erasmus University Medical Center (MEC-2022-0297) and the local review boards of all other participating centers. Regarding informed consent procedure: within the Erasmus MC, a consent waiver was provided by the Medical Research Ethics Committee for research including patients with COVID-19 due to the pandemic (exception due to emergency situation). Therefore, an opt-out informed consent procedure will be used in the participating centers, and subjects with registered objections to participate will be excluded from the study. This opt-out registration method was approved by the Medical Research Ethics Committee from Erasmus University Medical Center (MEC-2022-0297). Each center is responsible for appropriate informed consent procedures, which are covered in the data transfer agreements. Regarding the biobank data, only biobank material collected within the Collaboration on Identification, Understanding and Improved Management of patients with infectious diseases study of the Erasmus MC (METC number primary application: 2017-0417 and amendment 2020-0222) and samples collected at the Amsterdam UMC within the MERMAIDS-ARI (NL54834.018.15), VIS cohort study (NL73759.018.20), and the Amsterdam UMC COVID-19 biobank will be used.In WP1, variation in corticosteroid treatment protocols on the ward between centers is evaluated via questionnaires and extraction of data from the electronic patient record. The focus lies on collecting data from centers that use high-dose corticosteroids on the ward directly after admission and subsequently collecting data from centers with low-dose regimens as a comparison. For the data collection of ICU patients (WP2-3), a collaboration with 2 large COVID-19 study groups is started: the Practice of Ventilation in COVID-19 study  study and the “Practice of Adjunctive Treatments in Intensive Care Unit Patients with Coronavirus Disease 2019” (PROACT-COVID) study . The datPatients were administered with >6 mg dexamethasone or an equivalent corticosteroid for a minimum of 3 consecutive days . Our stuSeveral outcome parameters will be studied for the different work packages based on the available data. In WP1A, the primary outcome of interest is hospital mortality in patients who do not receive high-flow nasal canule or invasive mechanical ventilation due to restrictions in care, either on medical grounds or advance directives of the patient. In patients who do not have restrictions in care, the need for high-flow nasal canule or invasive mechanical ventilation will be the primary outcome of interest (WHO severity 6-9). In WP1B, WP2, and WP3, 28-day survival and 28-day need for invasive mechanical ventilation will be studied as primary outcomes. In WP4, we will study the response to corticosteroids using the same outcomes.Secondary outcomes for the ICU work packages include ICU mortality; in-hospital mortality; hospital length of stay (the number of days from the date of ICU admission to date of ICU discharge or death); mechanical ventilation duration ; and ventilator-free days, and alive at day 28. In all 4 work packages, we will evaluate the incidence of general systemic complications during the hospital stay as a secondary outcome, including myocardial infarction, deep venous thrombosis, pulmonary embolus, hyperglycemia, acute kidney injury, and sepsis. The definition of the various general systemic complications is shown in Table S1 in Data will be analyzed on a convenience sample. No sample size calculations are considered for the study nor will they be provided post hoc . The useTo study between-center variation in corticosteroid dosing strategy, the proportion of individuals who received high-dose corticosteroids will be compared across hospitals. Determinants of receiving high-dose corticosteroids will be evaluated using a multivariable logistic regression model with study center forced in the model. Whether the effects of significant determinants are different across centers will be tested through a determinant × center interaction term added for each determinant, separately.In WP1, WP2, and WP3, several statistical analysis approaches will be considered to determine the association between high-dose corticosteroids and outcome, and statistical analyses will depend on the structure of the available data. A multivariable logistic regression model will be used with high-dose corticosteroids as exposure and survival at day 28 as an outcome. Covariates used for adjustment will include age, gender, BMI, smoking status, prior administration of corticosteroids during admission, comorbidity, sequential organ failure assessment score, oxygen saturation, partial pressure of oxygen in arterial blood–fraction of inspiratory oxygen concentration ratio, C-reactive protein, procalcitonin, ferritin, interleukin 6, D-dimer, lactate dehydrogenase, platelet count, lymphopenia, and level of respiratory support. Covariates can be added or removed based on insights from the data set or from the literature. A model might be constructed in which patients are matched on a propensity score based on their probability to receive high-dose corticosteroid treatment. Propensity scores will be determined using a logistic regression model with high-dose corticosteroids as a dependent variable and determinants of high-dose corticosteroids as independent variables. After matching, survival and mortality at day 28 and other outcome parameters will be compared between matched groups using logistic regression. A Cox proportional hazards model might be performed to determine the effect of high-dose corticosteroids on time to death while taking into account the days of administration using time-dependent covariates. Other approaches involving censoring weights for differential loss to follow-up  or competing risks  might be explored.P value of <.05.Furthermore, we will use clinical and biological data to perform latent class analysis to search for subphenotypes, which respond more favorably to corticosteroid treatment. This heterogeneity of treatment effect will be evaluated by including the latent class analysis-derived subphenotype, corticosteroid exposure, and an interaction term of the 2 as c-variate in the above-described survival models. Heterogeneity of treatment effect is considered to be present if the interaction term has a Regarding WP4, patients are randomly selected and cases will be patients treated with high-dose corticosteroids, whereas controls will be patients who were not treated with high-dose corticosteroids. In WP4a, inverse probability treatment weighting and inverse probability of censoring weights will be used together in a marginal structural model. After we have analyzed the effect of high-dose corticosteroids on mortality and the other outcome measures, we will use this model to determine if the listed biomarkers modify the effect of high-dose corticosteroids on mortality.t-test and P values will be adjusted for false-discovery rate using the Benjamini-Hochberg procedure. The log2 mean fold change of levels between cases and controls will also be calculated for each transcriptome. We will define transcriptome features as those with an adjusted P value of <.05 and a >2.0 or <–2.0 log2 mean fold change in level.In WP4b, we will identify transcriptome features that are differentially altered between cases and controls. Mean transcriptome levels will be compared using an unpaired The study was funded in December 2021. As of April 2023, data have been collected for a total of 1500 patients, with data collection anticipated to be completed by December 2023. We expect the first results to be available in early 2024.The SELECT study is a retrospective multicenter observational cohort study that aims to determine the most optimal dosing and timing of high-dose corticosteroid therapy in hospitalized patients with COVID-19 and to provide a basis for personalized treatment regimens using biomarkers and whole transcriptome analyses. Increasing insight in the pathophysiological pathways that underlie SARS-CoV-2 infection and the efficacy of high-dose corticosteroid therapy could lead to more precise targeting of high-dose corticosteroid therapy, and as a result, could improve patient outcomes.The necessity of exploring this matter is underlined by the fact that there is currently no consensus regarding the administration of high-dose corticosteroid therapy in patients with COVID-19.This study design has several strengths. First, no studies have been performed that evaluate the effect of high-dose corticosteroids throughout the entire clinical course of hospitalized patients with COVID-19. Our study will evaluate the effect of high-dose corticosteroids from hospital admission to the ward or ICU, until hospital discharge. Furthermore, our exploration of biomarker and gene expression profiles for targeted corticosteroid therapy represents a first step toward personalized corticosteroid therapy in COVID-19. By using existing research databases and biobanks, successful data collection is assured, and we will be able to include a large number of patients, which increases the generalizability of the results.Due to the retrospective study design, some methodological considerations require further discussion. A major issue for any observational study is the fact that treatment modalities are not randomly assigned, but rather likely given based on specific patient characteristics or within-center protocols. This nonrandomized assignment is prone to bias by indication. To correct this bias, our initial analysis step will be the identification of factors that contribute to the allocation of corticosteroid treatment. Subsequently, we will examine several statistical approaches, such as the use of propensity scores at the patient level to minimize treatment indication bias.The findings of this study could support COVID-19 guidelines and hospital protocols regarding the management of hospitalized patients with COVID-19. Thus far, the translation of predictive biomarkers and whole transcriptome analysis into an applicable bedside tool is highly challenging. We expect to provide valuable tools to guide the dosing and timing of high-dose corticosteroid therapy. Furthermore, the answers to our research questions might be extrapolated to patients with non–COVID-19 ARDS, as the use of high-dose corticosteroids is still a matter of debate in this group of patients. The mortality rate of non–COVID-19 ARDS is even higher than that of COVID-19 ARDS , emphasiIn conclusion, our study protocol presents a strategy to gain a better understanding of the optimal dosing and timing of high-dose corticosteroid therapy in hospitalized patients with COVID-19 and thereby improve patient outcomes.


Psychological resilience is an indicator of mental health, but there has been no research to date on changes in psychological resilience among older adults with mild cognitive impairment (MCI) during the stress of the coronavirus disease 2019 (COVID-19) pandemic including factors related to those changes. To fill the gap, this study examined the factors and the changes in psychological resilience of older adults with MCI during the COVID-19 pandemic.One hundred thirty participants completed the 10-item version of the Connor-Davidson Resilience Scale (CD-RISC-10) between December 2020 and June 2021 as a baseline assessment and between December 2021 and February 2022 as a follow-up. Participants also answered questions on sleep quality, depression symptoms, activities in daily living (ADL), instrumental ADL and social participation to explore factors associated with changes.p < 0.05), indicating the improvement of psychological resilience. In multiple regression analyses, sleep quality was significantly correlated with change in CD-RISC-10 score .In this cohort, the mean CD-RISC-10 scores were significantly higher than the baseline at follow-up (Psychological resilience could improve even during the stress of the COVID-19 pandemic in older adults with MCI who were at risk of developing dementia. The factor associated with improved psychological resilience was good sleep quality. The coronavirus disease 2019 (COVID-19) pandemic began spreading in Japan in March 2020, and the Japanese government declared a state of emergency in April 2020 to mitigate the infection spread. People were strongly recommended to stay at home and were restricted from using facilities where people gather; public life faced social restrictions to enforce infection control measures. Research on mental health among older adults with mild cognitive impairment (MCI) during the COVID-19 pandemic is important because a large number of older adults with MCI or at risk of dementia developed increased anxiety and depression during the lockdown  and facePsychological resilience is the ability to recover one’s mental health following adversity or stressful experiences . This acWe conducted a longitudinal study during the COVID-19 pandemic as a substudy of the Japan-Multimodal Intervention Trial for Prevention of Dementia (J-MINT) . We condThe target participants were 150 older adults with MCI aged 65–85 years in the control group of J-MINT, where we considered a diagnosis of MCI if they fulfilled the following criteria: (1) having a cognitive decline in the National Center for Geriatrics and Gerontology (NCGG) Functional Assessment Tool , (2) MinWe administered a questionnaire to the participants that collected information on sociodemographic characteristics  as well as the Barthel Index , Lawton t-test to compare the baseline and follow-up CD-RISC-10 scores. We further used single and multivariate analyses to evaluate the relationships between changes in the CD-RISC-10 score  and explanatory variables. To develop a multivariate model, we included as moderator variables sociodemographic characteristics, which have been associated with psychological resilience in previous studies , for a median change of 3 points. In the single regression analysis, the only factor that was significantly associated with the change in the CD-RISC-10 score was the baseline CD-RISC-10 score ; the PSQI tended to be associated, but not statistically significant  (We received 136 responses from the 150 participants who received our questionnaire (90.7%). We excluded 6 participants who met the exclusion criteria, resulting in 130 participants. The mean age of the study participants was 73.1 ± 4.5 years; 42.3% were female; 80.0% were married; the mean number of years of education was 12.5 ± 2.3 . The meato 5.73) . In contWe investigated changes in psychological resilience in older adults with MCI during the COVID-19 restrictions; interestingly, the results showed a trend toward increased psychological resilience. In addition, we investigated the associations between changes in CD-RISC-10 score and factors that have been related to psychological resilience . Among tIt is necessary to understand the state of psychological resilience in this vulnerable population so that intervention measures are already in place in the event of future disasters or other emergencies. The results of our investigations could help in developing preventive measures against mental health deterioration in this population.In a previous examination of the psychological resilience of adolescents affected by a natural disaster, the young people’s median CD-RISC-10 score increased from 20 to 23 in 1 year , similarGood sleep quality was a factor associated with changes in psychological resilience. Psychological resilience entails high control of one’s emotions under stress , and pooThis present study has some limitations. First, Aichi and Gifu prefectures, where the study participants live, were placed under a state of emergency from mid-January to February 2021 (during the baseline), and participants responded to the questionnaires in different infection statuses, but we did not include these differences in our analyses. Second, our findings have limited generalizability to broader populations, because this is a substudy of the J-MINT and we did not perform random sampling. Third, the COVID-19 pandemic has been ongoing in Japan since March 2020, and people have faced social restrictions for a long time. Due to long-term social restrictions, people may have adjusted to restricted lifestyles, increasing their psychological resilience. Our analyses did not reflect this factor. Fourth, it was not possible to determine whether changes in psychological resilience differed by type of cognitive impairment, as the present study did not distinguish participants by type. Fifth, this study was unable to determine why resilience improved because sleep quality and depressive symptoms were not assessed with the follow-up in this study.This study showed that psychological resilience improved after some time even during the stress of the COVID-19 pandemic in a population of older adults with MCI who were at risk of declining mental health. For instance, good sleep quality was related to improvements in psychological resilience, which maintains mental health. However, further research may be needed to determine whether factors related to changes in psychological resilience contribute to the maintenance of mental health in older adults with MCI.The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by the National Center for Geriatrics and Gerontology Ethics Committee (No. 1468). The patients/participants provided their written informed consent to participate in this study.NM designed the study, performed the statistical analyses, and wrote the first draft. All authors contributed to the interpretation and discussion of the results and reviewed the manuscript and contributed to the article and approved the submitted version.


The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or “Long COVID”) in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults.REsearching COVID to Enhance Recovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of five cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study . The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments ; 2) longitudinal follow-up for up to 4 years ; and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology . Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science.We describe the protocol for the Pediatric Observational Cohort Study of the NIH’s RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions. The coronavirus disease 2019 (COVID-19) pandemic has significantly impacted child health. Nearly 100 million people have been diagnosed with COVID-19 in the United States (US), with nearly 16 million children , 4. As aUnique challenges in understanding PASC symptoms in children have likely contributed to the limited evidence. Given that young children might not be able to articulate symptoms, studies must rely on caregiver interpretation. In addition, manifestation of symptoms may vary substantively across stages of physiological, emotional, and cognitive development . As the The pandemic began with a misconception that children were spared . We now RECOVER has established the Pediatric Observational Cohort Study (RECOVER-Pediatrics), which is a combined retrospective and prospective longitudinal study, including five distinct cohorts, integrated together as a meta-cohort . The oveRECOVER-Pediatrics scientific aims are to:Characterize the prevalence and incidence of new onset or worsening symptoms related to PASCCharacterize the spectrum of clinical symptoms of PASC, including distinct phenotypes, and describe the clinical course and recovery.Identify risk and resiliency factors for developing PASC and recovering from PASC.Define the pathophysiology of PASC, including subclinical organ dysfunction, and identify biological mechanisms underlying the pathogenesis of PASC.with and without a history of a SAR-CoV-2 infection are included. For those 17 years or younger, data are collected by caregiver report and child direct assessments, and for those 18 through 25 years old by self-report. The study is being conducted from March 2022 to March 2026.RECOVER-Pediatrics is a longitudinal, observational meta-cohort study of children and young adults (ages birth through 25 years) and their caregivers, recruited from healthcare- and community-based settings in more than 100 sites throughout the US, including Puerto Rico. Those de novo RECOVER prospective cohort including children and young adults ages birth through 25 years, with or without a known history of infection, and their caregivers; 2) Adolescent Brain Cognitive Development (ABCD) extant cohort, the largest long-term US study of brain development in adolescence ). Young adults, aged 18 through 25 years old, sign their own informed consent. Tier 3 consent forms will only be completed when testing is offered.In ABCD, 11,880 children aged 9–10 years old were recruited from community and school sites to participate in a 10-year study with the goal of understanding neurocognitive development during adolescence , 25, 30.de novo cohort, regardless of history of SARS CoV-2 infection. Enrolled participants are then categorized as either “infected” or “uninfected”: Infected participants have history of suspected, probable, or confirmed SARS-CoV-2 infection, defined by the World Health Organization (WHO) criteria [Children and young adults from birth through 25 years old are eligible to be enrolled in the criteria , evidencA primary caregiver, defined as an individual responsible for the enrolled child or young adult who resides in the same household, such as biological or nonbiological family member, is invited to enroll.The primary exclusion criterion is any child or young adult with co-morbid illness with expected survival of less than 2 years. There is no limit to the number of children or young adults who can be enrolled from a single household. See supplemental tables for detailed eligibility criteria, definitions of analytic groups, and the World Health Organization Criteria , based on their history of SARS-CoV-2 infection and infection dates. The acute arm includes 800 children and young adults whose most recent SARS-CoV-2 infection was 30 days or less prior to enrollment. The post-acute arm includes 4,000 children and young adults whose most recent SARS-CoV-2 infection was greater than 30 days prior to enrollment. In the group without a history of infection, 1,200 children and young adults will be randomly assigned to follow either the acute  or post-acute  arm of the protocol. Additional children and young adults will be recruited from Long COVID clinics and other subspecialty services in order to achieve Tier 2 sample size targets  includes a single visit that is completed either via self-administration (remote and electronic) or research staff-assisted collection .Tier 2 (follow-up visits) includes five longitudinal in-person visits at 2 to 6-, 12-, 24-, 36- and 48-months post-enrollment. The children and young adults followed longitudinally in Tier 2 are selected based on a sampling scheme that prioritizes the acute arm as well as children and youth in the post-acute arm with a greater likelihood of having PASC. Promotion to Tier 2 occurs as follows: 1) All children/young adults in the acute arm with or without history of infection will be promoted; 2) children/young adults in the post-acute arm with a history of infection will be promoted at a rate dependent on their likelihood of PASC based on prior Long COVID diagnoses, Tier 1 PROMIS global health measure responses [esponses –34, and esponses , 35  and whole blood collections. All post-acute Tier 2 biospecimens consist of whole blood. The maximum amount of blood drawn at a single visit is age dependent. Whole blood is collected using serum separator tube (SST) and Ethylenediaminetetraacetic tube acid (EDTA) across all ages above 24 months and an additional cell preparation tube (CPT) is included at participants 6 years of age and older.Tier 3 biospecimens consist of whole blood, sputum, swabs , urine and stool. Collection of Tier 3 biospecimens is limited to children ages 3 years and older .We will estimate the proportion of children and young adults experiencing new onset or worsening of each symptom (incidence), stratified by age , over time. Prevalence within the recruited population will be estimated by calculating the point prevalence of each symptom at each 3-month interval since infection by calculating the proportion of children and young adults who are currently experiencing each symptom at each study visit. The excess burden of each symptom due to infection will be assessed by calculating differences in incidence and prevalence between children and young adults with and without an infection history. Odds ratios and relative risks for the association between infection and onset of each symptom will also be calculated, adjusting for sex in each age strata.A preliminary case definition of PASC will be informed by using variable selection methods to identify which symptoms best differentiate children and young adults with and without an infection. The estimated associations obtained from regression models will be used to define a PASC score, with a cutoff for PASC defined based on clinical expertise while ensuring that the rate of those with no history of infection who are diagnosed as having PASC is reasonably low. This preliminary symptom-based case definition will be modified and augmented by clinical and subclinical findings as they become available. To identify PASC phenotypes among children and young adults who are classified as having PASC defined by symptom patterns, we will use unsupervised learning methods to discover symptom clusters within each age strata , assuming the sample has 400 with PASC and 200 without PASC, for a marker with 10% prevalence in the PASC- group, we have 90% power to detect an odds ratio as small as 2.60 for PASC.In Tier 2, given the sampling and promotion framework described in The overall goal of RECOVER-Pediatrics is to improve our understanding of recovery after SARS-CoV-2 infection, with a focus on the prevalence, natural history, and pathogenesis of PASC in children and young adults. Successful completion should lead to formal characterization of pediatric PASC as its own syndrome. This is essential to develop diagnostic, treatment, and preventive strategies tailored to children’s unique physiology.RECOVER-Pediatrics is well positioned to ascertain the epidemiology, four-year clinical course, and sociodemographic contributions to pediatric PASC, with rich data and biosamples available to readily test further mechanistic hypotheses, establish biomarkers, and provide insights into potential therapies. The meta-cohort is designed to provide details that are not available in other large epidemiologic or electronic health records queries, including a dynamic study design that can be flexible and responsive as new variants arise, and as our understanding of the long-term effects of SARS-CoV-2 evolves. RECOVER-Pediatrics was designed to include a wide range of ages, and diverse socioeconomic, racial, ethnic and geographic populations to ensure that findings are generalizable, and provide equitable benefit for all.The generation-defining nature of the COVID-19 pandemic will impact the life course of children in ways that we have yet to fully understand. The unprecedented scope of RECOVER-Pediatrics sets the stage for not only characterizing a new disorder that will impact children for years to come, but also for identifying and deploying solutions through its collaborations with investigators and communities across the country.RECOVER-Pediatrics is expected to gather a rich data set that can be used to develop treatments for persons with Long COVID and provide guidelines for how to respond more quickly to prevent, reduce the consequences, and treat complications of future coronavirus outbreaks which are likely to emerge.Supplement 1