In this international multicenter study, we aimed to determine the independent risk factors associated with increased 30 day mortality and the impact of cancer and novel treatment modalities in a large group of patients with and without cancer with COVID-19 from multiple countries.We retrospectively collected de-identified data on a cohort of patients with and without cancer diagnosed with COVID-19 between January and November 2020 from 16 international centers.We analyzed 3966 COVID-19 confirmed patients, 1115 with cancer and 2851 without cancer patients. Patients with cancer were more likely to be pancytopenic and have a smoking history, pulmonary disorders, hypertension, diabetes mellitus, and corticosteroid use in the preceding 2 wk (p≤0.01). In addition, they were more likely to present with higher inflammatory biomarkers  but were less likely to present with clinical symptoms (p≤0.01). By country-adjusted multivariable logistic regression analyses, cancer was not found to be an independent risk factor for 30 day mortality (p=0.18), whereas lymphopenia was independently associated with increased mortality in all patients and in patients with cancer. Older age (≥65y) was the strongest predictor of 30 day mortality in all patients . Remdesivir was the only therapeutic agent independently associated with decreased 30 day mortality . Among patients on low-flow oxygen at admission, patients who received remdesivir had a lower 30 day mortality rate than those who did not .Increased 30 day all-cause mortality from COVID-19 was not independently associated with cancer but was independently associated with lymphopenia often observed in hematolgic malignancy. Remdesivir, particularly in patients with cancer receiving low-flow oxygen, can reduce 30 day all-cause mortality.National Cancer Institute and National Institutes of Health. The COVID-19 pandemic has challenged the health care system worldwide and has spread to more than 200 countries, causing hundreds of millions confirmed cases and several million deaths .Data from multiple studies have shown consistently that older age and comorbidities such as cardiovascular disease, diabetes mellitus (DM), hypertension, and chronic obstructive pulmonary disease (COPD) have been associated with severe illness and increased mortality .Several studies on COVID-19 mortality suggested that patients with cancer had poor outcomes . Many ofGiven that many of the therapeutic studies on COVID-19 were conducted in patients without cancer and given the poor outcomes of COVID-19 reported in patients with cancer , we aimeTherefore, given the global spread of the COVID-19 pandemic and the worldwide prevalence of cancer, we undertook this international initiative that included 16 centers from five continents to study and compare the clinical course, risk factors, and treatment modalities impact on outcomes of COVID-19 in patients with cancer vs patients without cancer on a worldwide basis.This was a retrospective international multicenter study that included all patients diagnosed with COVID-19 by RT-PCR for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the site or an outside facility between January 4, 2020 and November 15, 2020.The study involved 16 centers from 9 countries, 8 centers in the United States and 1 each in Australia, Brazil, France, Japan, Lebanon, Singapore, South Korea, and Spain. Patients were divided into two groups: patients without cancer and those with cancer diagnosed or treated within a year before the diagnosis of COVID-19.The University of Texas MD Anderson Cancer Center was the coordinating center that designed the study, built the electronic case report form, and collected de-identified patient information from all participating centers using the secure Research Electronic Data Capture platform. We reviewed each patient’s electronic hospital record and collected all needed data. This study was approved by the institutional review board at MD Anderson Cancer Center (Protocol# 2020–0437) and the institutional review boards of the collaborating centers. A patient waiver of informed consent was obtained.The follow-up period was defined as 30 days after a diagnosis of COVID-19.Neutropenia was defined as an absolute neutrophil count <500 cells/mL. Lymphopenia was defined as an absolute lymphocyte count (ALC) <500 cells/mL.For each patient, data were collected on COVID-19 treatments, including antimicrobial therapy and potential antiviral therapy. We evaluated patient’s oxygen requirement: low flow was defined as oxygen supplementation of ≤6 l/min through a nasal cannula or facemask and high flow included all other modalities of oxygen supplementation, including mechanical ventilation.The primary outcome of interest was 30 day mortality. Any death that occurred within 30 days after COVID-19 diagnosis was considered to be COVID-19-related, irrespective of other comorbidities that could have contributed to death. The secondary outcomes included mechanical ventilation, progression to lower respiratory tract infection, co-infection, and hospital readmissions within 30 days after COVID-19 diagnosis.2 or Fisher’s exact test, and continuous variables were compared using Wilcoxon rank sum test. Logistic regression model was used to identify the factors that were independently associated with 30 day mortality, and the following factors were included in the analysis in addition to cancer status: patients’ demographic (including country) and clinical characteristics, medical history, and laboratory findings at diagnosis and treatment. First, univariable analysis of each factor was performed, but factors were not considered if more than 40% of the data were missing. Next all the factors with p-values≤0.15 on their univariable analyses were included in a full logistic regression model and then the full model was reduced to the final model by backward elimination procedure so that all the factors remaining in the final model had p-values≤0.05 except cancer and country. Cancer was kept in the final model despite its p-value in order to evaluate its independent impact on mortality. The final model was country-adjusted to account for the treatment differences among the countries. For the above complete cases analysis, only patients with no missing data in any of the variables retained for the final regression model were included in the final model analysis. To investigate the impact of missing data on our primary data analysis, we performed a sensitivity analysis. We first estimated missing values using multiple imputation technique and then performed a similar multivariable analysis based on the imputed datasets. Lastly, the analysis results were compared between the complete-case and multiple imputation analyses. Logistic regression model was also used to identify the independent predictors of mortality among patients with and without cancer, respectively, and similar sensitivity analysis was performed for each group as well. In cancer patients, the mortality rates of four different cancers were estimated and compared: hematological malignancy, lung cancer, and non-lung solid tumors with and without metastasis. χ2 or Fisher’s exact test was used for comparisons. If a significant result (p<0.05) was detected, pairwise comparisons were performed with α levels adjusted using Holm’s sequential Bonferroni adjustment to control type I error. In addition, the associations between mortality and certain therapeutic agents including remdesivir, steroids, and convalescent plasma, as well as the impact of their treatment timing on mortality, were also evaluated using χ2 or Fisher’s exact test. All statistical tests were two-sided with a significance level of 0.05, except the pairwise comparisons with the α adjustment. Statistical analyses were performed using SAS version 9.4 .Patient characteristics and outcomes were compared between COVID-19 patients with and without cancer. Categorical variables were compared using χA total of 4015patients diagnosed with COVID-19 by PCR were included in the study. After excluding 18 patients who had missing demographics and 31 patients younger than 18y, we evaluated 3966 COVID-19 patients: 2851 without cancer and 1115 with cancer , lymphocytopenia , thrombocytopenia , and anemia  and had higher median levels of inflammatory biomarkers, including D-dimer , ferritin , and procalcitonin . On imaging studies (CT), patients with cancer were less likely than patients without cancer to be present with ground-glass opacities  or peripheral distribution of the infiltrates .For most treatments for COVID-19 infection, patients without cancer were more likely to receive them than patients with cancer, including hydroxychloroquine , azithromycin , remdesivir , convalescent plasma , and steroids . However, patients with cancer were more likely to receive tocilizumab . In addition, the treatments patients received for COVID-19 infection significantly differed among the countries (data not shown). The rate of COVID-related hospital admission was higher in the patients without cancer . Co-infections occurred more frequently in patients with cancer . Among hospitalized patients, patients with cancer were more likely than patients without cancer to be discharged on supplemental oxygen . Likewise, the rate of hospital readmission within 30 days was higher in patients with cancer . Furthermore, the mortality rate within 30 days was also significantly higher in patients with cancer by univariable analyses , need for mechanical ventilation , and presence of co-infection  than in patients with non-lung cancer solid tumors , including those with lung metastases . However, among patients on high-flow oxygen at admission, there was no difference in the mortality rate between patients who received remdesivir and those who did not .Since 85% of patients treated with remdesivir also received corticosteroids, we evaluated the impact of their combination therapy on 30 day mortality. Among patients on low-flow oxygen at admission, the mortality rates among those who received remdesivir alone or in combination with corticosteroids (6% [3 of 51]) was significantly lower than the mortality rate of those who received corticosteroids alone . However, mortality rates were similar for remdesivir alone and combination therapy among various patients’ groups .Giving convalescent plasma to patients later than 3d after diagnosis did not make any difference in mortality (data not shown). In contrast to what was observed for convalescent plasma, the later corticosteroids were administered, the greater the benefit. There was a trend toward a greater reduction in 30 day mortality in patients who received corticosteroids later (>5d after diagnosis), whereas no difference was observed in patients who received corticosteroids earlier .Lastly, sensitivity analyses were performed to evaluate the impact of missing data on our primary analyses. The multivariable logistic regression models of mortality predictors based on the complete-case analysis and multiple imputation analysis were compared for all patients  and for Unlike the previously published studies that compared patients with COVID-19 with and without cancer, our study included a large number of patients with cancer from five different continents. Our findings demonstrate that cancer is not an independent risk factor for increased 30 day all-cause mortality in a multivariable logistic regression analyses that accounted for the treatment differences among the countries, which is inconsistent with a recent large study in the US that showed that patients recently receiving cancer treatment had a worse outcome . The higMost of the other independent risk factors that we identified for 30 day mortality after a diagnosis of COVID-19 have also been commonly reported as risk factors for mortality in previous studies of COVID-19 in patients with and without cancer with older age (≥65y) being the strongest independent predictor of 30 day mortality in our study . In our The presentation pattern of COVID-19 in patients with cancer was different to that of patients without cancer. Patients with cancer seemed to be less symptomatic. This could be related to the fact that patients with cancer tended to be older, with fewer inflammatory cells (neutrophils and lymphocytes), and more often on corticosteroids. Levels of inflammatory biomarkers were also higher in patients with cancer, particularly D-dimer, ferritin, and procalcitonin.On multivariable analysis, the only therapeutic agent that independently decreased 30 day all-cause mortality among all patients and in patients with cancer was remdesivir, even after accounting for treatment diffrences among countries. Upon further analysis, remdesivir was found to further decrease mortality in patients with pneumonia and mild hypoxia who were receiving low-flow oxygen (≤6l/min) and not in patients with severe advanced pneumonia who were receiving high-flow oxygen and/or ventilatory support. This is consistent with a large multicenter prospective randomized placebo-controlled trial - Adaptive COVID-19 Treatment Trial-1 (ACTT-1), that found that remdesivir significantly reduced the time to recovery and 28d mortality in patients who were on low-flow oxygen at baseline but not in patients who were on mechanical ventilation or extracorporeal membrane oxygenation at baseline .In a meta-analysis that examined four large prospective randomized trials, remdesivir was shown to be associated with reduced 14 d mortality and reduced need for mechanical ventilation , which aIn contrast, the WHO-sponsored multinational Solidarity Trial of COVID-19 hospitalized patients who were randomly assigned to either remdesivir (2750patients) or standard of care (2708patients) showed no difference in overall 28d mortality . HoweverTherefore, the cumulative data in the literature do support our findings that remdesivir in all patients particularly in patients with cancer improves outcome and may reduce mortality especially if started early in COVID-19 patients with moderate pneumonia who are receiving low-flow oxygen who fit into the stage II of the three-stage COVID-19 classification previously proposed by The use of corticosteroids (dexamethasone 6mg/d) was shown in a large randomized open-label study conducted in the United Kingdom to be associated with reduced 28d mortality, particularly in patients requiring oxygen supplementation and invasive ventilation who receive corticosteroids after 7d from the onset of symptoms . SubsequOur study has several limitations. First, the retrospective design precluded complete assessment of disease progression in the outpatients, which limited their input into the general study. Second, some non-cancer centers contributed data only on their hospitalized patients who were likely sicker. This may have biased the data toward a higher rate of hospitalization among patients without cancer and made the data more heterogeneous. In addition, the predominance of symptomatic patients (87%) might also limit our evaluation of the impact of cancer in the whole picture of the disease. Third, our data contained a lot of missing values due to the nature of data collection. However, we performed sensitivity analyses to evaluate its impact on our primary analyses, and it showed that overall this impact was limited. Most independent predictors were identified by both complete-case and multiple imputation analyses with similar effects. The differences between the two analysis methods in identifying a few independent mortality predictors were probably due to the sample size changes from complete-case analyses to multiple imputation analyses. Last, this study was conducted prior to the introduction of COVID vaccines and included patients who were not vaccinated and who were infected by early variants which limits the generalizability of our results to contemporary COVID-19 patients. A multinational European registry showed that severity of COVID-19 and mortality in cancer patients have improved since 2020. This could be multifactorial related to earlier diagnosis, improved management including current antivirals, monoclonal antibodies, vaccination, as well as different circulating variants of the virus that could be associated with less severe disease than the earlier strains . HoweverIn conclusion, this is the largest multicenter worldwide study comparing COVID-19 in patients with cancer to those without. In this study, although the limited effect size, underlying malignancy was not found to be an independent risk factor for a higher 30 day all-cause COVID-19 mortality. However, lymphopenia and anemia were frequently observed in patients with hematological malignancies, and patients with lung cancer were associated with the highest risks for poor outcome. Finally, remdesivir stood out as the only therapeutic agent independently associated with decreased 30 day mortality, particularly in patients with cancer on low-flow oxygen. Corticosteroids tended to be most useful if given more than 5d after COVID-19 diagnosis. The role of these therapeutics and their timing of administration should be verified in larger studies, especially in patients with cancer, who tend to have a higher degree of immunosuppression, which may lead to prolongation of the viral phase. This study addresses the important subject of correlates of COVID-19 mortality in patients with cancer. It is a large multinational cohort of patients. The authors provide solid evidence based on careful multivariate analysis for the finding that cancer is not an independent risk factor for COVID-19 death. public reviews designed to be posted alongside the preprint for the benefit of readers; (ii) feedback on the manuscript for the authors, including requests for revisions, shown below. We also include an acceptance summary that explains what the editors found interesting or important about the work.Our editorial process produces two outputs: (i) Decision letter after peer review:eLife. Your article has been reviewed by 2 peer reviewers, and the evaluation has been overseen by a Reviewing Editor and Eduardo Franco as the Senior Editor. The following individual involved in the review of your submission has agreed to reveal their identity: Annika Fendler (Reviewer #1).Thank you for submitting your article "International Multicenter Study Comparing Cancer to Non-Cancer Patients with COVID-19: Impact of Risk Factors and Treatment Modalities on Survivorship" for consideration by eLife, the reviewers have discussed their critiques with one another and with the editors. What follows below is our edited compilation of the essential and ancillary points provided by reviewers in their critiques and in their interaction post-review. Please submit a revised version that addresses these concerns directly. Although we expect that you will address these comments in your response letter, we also need to see the corresponding revision clearly marked in the text of the manuscript. Some of the reviewers' comments may seem to be simple queries or challenges that do not prompt revisions to the text. Please keep in mind, however, that readers may have the same perspective as the reviewers. Therefore, it is essential that you attempt to amend or expand the text to clarify the narrative accordingly.As is customary in Essential revisions:(1) Consort diagram to explain attrition.(2) Sensitivity analysis to evaluate the impact of data missingness.(3) Justify clearly the choice of multivariate models.4) Detail the cause of death as per reviewer 1.(5) Discuss the fact this is an unvaccinated cohort and how that has implications in the context of vaccination.Reviewer #1 (Recommendations for the authors):– The data contain a lot of missing values, likely due to the nature of data collection. The authors should perform a sensitivity analysis to explore how this affects their results.– The authors mention that patients were lost to follow-up especially those not hospitalised. I'm not clear how many patients are in both groups. I also can't see how many patients were censored in the Kaplan-Meyer Analysis. A consort diagram would be helpful to understand how many patients the primary endpoint could be investigated.– The authors present several multivariate models. It is not clear how they chose which data to include and on what basis the variables were selected.– The authors describe that 348 patients died, and 93% of death are COVID-related. How was this split between patients with cancer and those without? Was there a difference in the proportion of death that was COVID-19-related?– An overview of all treatments that patients received is missing. Were these similar between patients with cancer and those without? Did they differ by country? Did this impact outcome?– The discussion is very long and includes a detailed description of published studies. The authors should summarise the findings of previously published studies in a concise way and restrict this discussion only to the direct results presented in the paper. For example, the authors discuss in length which treatment should be given at a certain stage of COVID-19, which is not directly relevant to the data they present.– The authors only briefly discuss that this study was conducted in an unvaccinated cohort. They should include a more detailed discussion of and how their data apply to the current situation.Reviewer #2 (Recommendations for the authors):Suggestions to the authors before considering this paper for publication:(1) Replace the term "cancer patients and non-cancer patients" with "patients with and without cancer".(2) It is unclear what tables 2 and 3 add to the manuscript and the authors might want to consider moving them to the supplement.(3) The table of patients at risk shown in Figure 1 should be adjusted to include data at some, but not all time points.4) The authors may want to cite PMID: 34958894 to discuss the impact of cancer on patients with COVID-19 in the era of COVID-19 vaccines. Essential revisions:1) Consort diagram to explain attrition.We have added a consort diagram to explain patient attrition as shown in figure 1.2) Sensitivity analysis to evaluate the impact of data missingness.We performed a sensitivity analysis to evaluate the impact of data missingness on our primary data analysis. Please see below the detailed response to the reviewer.3) Justify clearly the choice of multivariate models.We have provided a detailed description of the performance of our multivariable logistic regression analyses including variable selection, univariable analysis, multivariable analysis and the final models. Please see below the detailed response to the reviewer’s comment.(4) Detail the cause of death as per reviewer 1.We have revised the manuscript to reflect that any death that occurred within 30 days after COVID-19 diagnosis was considered to be COVID-related, irrespective of other comorbidities that could have contributed to death.(5) Discuss the fact this is an unvaccinated cohort and how that has implications in the context of vaccination.We agree with the reviewer and have acknowledged this limitation in the Discussion section as follows: “Last, this study was conducted prior to the introduction of COVID vaccines and included patients who were not vaccinated and who were infected by early variants which limits the generalizability of our results to contemporary COVID-19 patients”. We have added in the Discussion section the results of a recent study on the impact of vaccination in cancer patients.Reviewer #1 (Recommendations for the authors):– The data contain a lot of missing values, likely due to the nature of data collection. The authors should perform a sensitivity analysis to explore how this affects their results.We totally agree with the reviewer. This study aimed to identify risk factors for 30-day mortality of COVID-19 patients and the data had a lot of missing values. Following this advice, we performed a sensitivity analysis to evaluate the impact of missing data on our primary data analysis. We first estimated missing values using multiple imputation technique and then performed a multivariable analysis based on the imputed datasets. Lastly, the analysis results were compared between our initial primary analysis based on the complete cases  and the analysis based on the imputed datasets. We have added the sensitivity analyses results in the revised manuscript in Table 3  and Table 4 (for patients with (A) and without cancer (B)) and summarized the main findings in Results section. We also included a description of the sensitivity analysis in the revised Statistical analysis section.– The authors mention that patients were lost to follow-up especially those not hospitalised. I'm not clear how many patients are in both groups. I also can't see how many patients were censored in the Kaplan-Meyer Analysis. A consort diagram would be helpful to understand how many patients the primary endpoint could be investigated.We are sorry, we did not make a statement about loss to follow-up in the manuscript and there might be a misunderstanding about it. We mentioned “some non-cancer centers contributed data only on their hospitalized patients who were likely sicker” because some non-cancer centers provided only hospitalized (non-cancer) patients to this study. We considered it a study limitation in Discussion section because of a possible imbalance in COVID-19 infection severity between patients with and without cancer in our study population. Regarding loss to follow up, although our data had a lot of missing values for many variables, the data for the primary endpoint 30-day mortality were relatively complete, and there were only 10 patients excluded from the Kaplan-Meier analysis due to their missing death dates, including 8 patients with cancer and 2 patients without cancer. However, after redoing multivariable analysis adjusting for country as advised by another comment, we found that cancer was no longer independently associated with 30-day mortality. Therefore, the Kaplan-Meier showing a significant impact of cancer on mortality has been no longer appropriate for this manuscript and therefore, we have removed this figure form the revised manuscript. As advised, a consort diagram of patient attrition has been added to the manuscript .– The authors present several multivariate models. It is not clear how they chose which data to include and on what basis the variables were selected.We thank the reviewer for this comment and have modified the Statistical Analysis section by providing a detailed description of the performance of our multivariable logistic regression analyses including variable selection, univariable analysis, multivariable analysis and the final models.– The authors describe that 348 patients died, and 93% of death are COVID-related. How was this split between patients with cancer and those without? Was there a difference in the proportion of death that was COVID-19-related?We have revised the manuscript to reflect that any death that occurred within 30 days after COVID-19 diagnosis was considered to be COVID-19-related, irrespective of other comorbidities that could have contributed to death. We have revised the manuscript accordingly.– An overview of all treatments that patients received is missing. Were these similar between patients with cancer and those without? Did they differ by country? Did this impact outcome?Treatment data are an important part of this study and we apologize for missing to provide them. We have added the treatment data in Table 1. As we can see, there was a significant difference in every treatment received between patients with and without cancer. Treatments that patients received also significantly differed by country and we have added this finding in Results section. In addition, to account for the treatment differences among the countries, we redid multivariable logistic regression analyses on mortality with adjusting for the country effect. Compared to our previous analysis, a main change in the new analyses is that cancer was no longer an independent risk factor for 30-day mortality after adjusting for country in multivariable analysis. We believe that lymphopenia and possibly anemia which occurred more frequently in cancer patients (Table 1) might be the confounding independent variables that made cancer appear to be associated with higher mortality by univariate analysis. Another change is that among patients without cancer, remdesivir was no longer independently associated with 30-day mortality, while it still had a similar significant impact on reducing mortality among all patients and among patients with cancer. We have updated the analyses results in the revised manuscript.– The discussion is very long and includes a detailed description of published studies. The authors should summarise the findings of previously published studies in a concise way and restrict this discussion only to the direct results presented in the paper. For example, the authors discuss in length which treatment should be given at a certain stage of COVID-19, which is not directly relevant to the data they present.– The authors only briefly discuss that this study was conducted in an unvaccinated cohort. They should include a more detailed discussion of and how their data apply to the current situation.We have shortened our discussion to mainly focus on our results. We agree with the reviewer that this study was conducted in an unvaccinated cohort before the introduction of COVID vaccines and have acknowledged this limitation in the Discussion section as follows: “Last, this study was conducted prior to the introduction of COVID vaccines and included patients who were not vaccinated and who were infected by early variants which limits the generalizability of our results to contemporary COVID-19 patients”. We have added in the Discussion section the results of a recent study on the impact of vaccination in cancer patients.Reviewer #2 (Recommendations for the authors):Suggestions to the authors before considering this paper for publication:(1) Replace the term "cancer patients and non-cancer patients" with "patients with and without cancer".We have replaced the term “cancer patients and non-cancer patients” with “patients with and without cancer” as requested throughout the manuscript.(2) It is unclear what tables 2 and 3 add to the manuscript and the authors might want to consider moving them to the supplement.We thank the reviewer for their comments. We have shortened table 2 and moved table 3 to supplement Table 1. We have added additional tables and a new figure to address the other comments.(3) The table of patients at risk shown in Figure 1 should be adjusted to include data at some, but not all time points.We agree and thank the reviewer for the advice. However, after redoing multivariable analysis adjusting for country as advised in another comment, we found that cancer was no longer independently associated with 30-day mortality. Therefore, the Kaplan-Meier showing a significant impact of cancer on mortality has been no longer appropriate for this manuscript and therefore, we have removed this figure form the revised manuscript.(4) The authors may want to cite PMID: 34958894 to discuss the impact of cancer on patients with COVID-19 in the era of COVID-19 vaccines.We have cited this reference and added the findings of the impact of vaccination in patients with cancer in the Discussion section.


We present the first systematic literature review on stress and burnout in K−12 teachers during the COVID-19 pandemic. Based on a systematic literature search, we identified 17 studies that included 9,874 K−12 teachers from around the world. These studies showed some indication that burnout did increase during the COVID-19 pandemic. There were, however, almost no differences in the levels of stress and burnout experienced by K−12 teachers compared to individuals employed in other occupational fields. School principals' leadership styles emerged as an organizational characteristic that is highly relevant for K−12 teachers' levels of stress and burnout. Individual teacher characteristics associated with burnout were K−12 teachers' personality, self-efficacy in online teaching, and perceived vulnerability to COVID-19. In order to reduce stress, there was an indication that stress-management training in combination with training in technology use for teaching may be superior to stress-management training alone. Future research needs to adopt more longitudinal designs and examine the interplay between individual and organizational characteristics in the development of teacher stress and burnout during the COVID-19 pandemic and beyond. Between spring 2020 and summer 2021, teachers and students around the world experienced school closures as a result of the COVID-19 pandemic. Although school closures are not unknown historically—occurring, for instance, during the polio pandemic in 1916  had to have measured teacher burnout or stress during the COVID-19 pandemic (2) in quantitative terms and (3) had to focus on K−12 teachers. They had to be published (4) in English (5) between 2020 (when the pandemic began) and 2021 (when we conducted the literature search). For inclusion in our review on research question 1—which focuses on the effects of the COVID-19 pandemic on teacher stress and burnout—the studies also had to have a longitudinal design with one measurement before and one measurement during the COVID-19 pandemic. For inclusion in our review based on research question 2, the studies had to report differences between K−12 teachers and individuals working in other professions. For inclusion in our review based on research questions 3 and 4, the studies had to report the association with another construct (that was not teacher stress or burnout). We did not include intervention studies without control groups, reviews, or non-empirical studies, e.g., opinion papers.When searching for relevant studies, we used a multistep process see . In a fid = 0.89. In case of disagreement, the authors discussed the studies in question until they reached consensus. During this first step, 41 studies were identified as being potentially eligible for our review. Nearly all of the studies that we excluded in this first step did either not focus on K−12 teachers, did not apply a quantitative research design or were not written in English. We subsequently read the full texts of all of the 41 eligible studies and decided upon inclusion based on our inclusion criteria.The titles and abstracts of all 157 studies identified were thoroughly examined by the authors on the basis of the inclusion criteria. To test for interrater agreement, the first and second author each rated a subset of 20 studies. Inter-rater reliability was Cohen's To find additional relevant work, we conducted a backward reference search in the articles selected; that is to say, we examined whether other potentially relevant studies were cited in these articles. The selection process was repeated on the nine additional studies identified during this search. In total, 17 studies were selected for inclusion in our review during full-text screening. These studies were then coded by the first and second author and the coding was checked by a research assistant see . Most ofThe quality of the studies included in the review was independently rated by two of the authors based on eight quality indicators for non-intervention studies and 14 quality indicators for intervention studies  the measures of K−12 teacher stress and burnout (3.2), the research designs, and (3.3) the teacher samples used in the studies. We then report (3.4) the study findings on changes in K−12 teachers' levels of stress and burnout during the COVID-19 pandemic and (3.5) differences in stress and burnout between K−12 teachers and individuals employed in other occupational fields. Finally, we outline findings on the relevance of (3.6.1) job and organizational characteristics and (3.6.2) individual characteristics. In Of the 17 studies included in our review, three studies assessed both teacher stress and burnout, nine studies just assessed teacher burnout, and five studies focused only on teacher stress. Of the 12 studies examining burnout, eight relied on Maslach's operationalization of burnout, applying the original Maslach Burnout Inventory  included in our review applied a cross-sectional and non-experimental study design, surveying teachers once during the pandemic. One study . Overall, 33.9% were primary school teachers . Five studies reported they recruited teachers from both primary and secondary schools ,Two studies reported changes in teachers' stress and burnout levels during the pandemic compared to burnout levels prior to the pandemic ,Two studies examined differences between K−12 teachers' stress levels and stress levels in other professions. Ozamiz-Etxebarria et al.  found noWhen presenting the study findings in the following, we will only include findings pertaining to teacher stress and burnout, although some studies reported additional results.via workplace buoyancy.One study examined the role of leadership Collie,  and showTwo studies examined associations between teacher burnout and reduced work (hours per week) or self-reported workload  - Projekt nummer 491466077.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The use of telemedicine has become a fundamental tool in healthcare in recent years, especially at times of Covid-19 pandemic. Currently, there are several telemedicine tools that are simple, inexpensive, and effective means of communication. This article aims to describe indicators of feasibility including patient recruitment, attendance, discomfort (internet connection issues and/or noncompliant patient behavior), satisfaction, and travel time and cost savings of virtual telemedicine consultations for patients with dementia.st and December 31, 2020. The eligibility criteria included previous diagnosis of dementia syndrome and receiving care at the hospital’s dementia outpatient clinic in face-to-face consultations in the preceding 12 months. Patients were excluded if they did not feel comfortable with virtual consultations, did not have the required communication technology available or their caregiver was not available to attend the remote consultation. The patients were recruited from the outpatient dementia clinic’s medical appointment scheduling list. The intervention was designed as a one-time consultation and it included treatment approaches and health promotion recommendations.The study was conducted at the Geriatrics Department of Hospital Universitário Walter Cantídio (HUWC) in Fortaleza, Brazil, between May 1Patient recruitment, attendance and discomfort rates were 85.5%, 97.7% and 9.4%, respectively. To attend face-to-face visits, they reported an average travel time (including the consultation) of 233.21 minutes and average total cost of 60.61 reais (around USD 11). The study intervention was well accepted among the patients and their caregivers with 97.6% being satisfied. Many were happy to avoid long waits in crowded medical waiting rooms and the risk of covid-19 contagion.We found good recruitment, attendance, and acceptance rates of remote care for the follow-up of dementia patients as well as low discomfort rates.RBR-9xs978.Brazilian Trial Registry (REBEC)  On March 18, 2020 government’s authorities imposed social distancing measures and public gathering restrictions in the state of Ceará, Northeast Brazil, in response to the COVID-19 pandemic [The workup, diagnosis, and clinical follow-up of elderly with neurodegenerative diseases such as dementia may have been harmed by a shift in resources and professionals to combat the pandemic. Besides those living alone in community felt lonely due to social isolation and the absence of group activities . BehavioThe use of telemedicine has become a fundamental tool in healthcare in recent years, especially at times of Covid-19 pandemic . CurrentOnline social networking appears to have a rising number of advantages, including increases in cognitive, social, and emotional well-being in the elderly. Executive functioning, working memory, episodic memory, perceived quality of life, social support, and engagement, as well as decreased depressive symptoms and feelings of loneliness, are all advantages ,15.To the best of our knowledge, no study has assessed the feasibility of using telemedicine for delivering care to patients with dementia in Brazil’s public health system ,11,13. OTelegeriatric is a term that derives from the junction of Tele  and Geriatrics . In our study, it represents the act of attending elderly patients using video calls by mobile devices.We performed a single-center one-arm study to describe indicators of feasibility  of virtual medical consultations.st and December 31, 2020. It was approved by HUWC Ethics Committee (registration number 31779920.1.0000.5045) and the Brazilian Trial Registry (REBEC) RBR-9xs978. All patients or their caregivers signed an online informed consent form.The study was conducted at the Geriatrics Department of Hospital Universitário Walter Cantídio (HUWC) in Fortaleza, Brazil, between May 1Participants were consecutively drawn from the dementia outpatient clinic’s medical appointment scheduling platform at HUWC. Those who met the inclusion criteria were selected until the required recruitment period  was achieved. The patients were invited in a phone call to participate in the feasibility study. Those who agreed to participate were screened for eligibility and, if eligible, they were asked to attend a remote medical consultation. The WhatsApp-based intervention included video and text messages. Recent studies have emphasized broad opportunities of WhatsApp messenger as an adjunctive tool for telemedicine . We chosThe eligibility criteria included previous diagnosis of dementia by our outpatient clinic’s geriatric staff according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) and receiving care at the hospital’s dementia outpatient clinic in face-to-face consultations in the preceding 12 months. Patients were excluded if they did not feel comfortable with virtual consultations, did not have the required communication technology available or their caregiver was not available to attend the remote consultation. If the patient did not have a brain image to confirm the etiological diagnosis of the dementia syndrome, he or she was identified as dementia under evaluation.We reviewed medical charts before and during the consultation to check for comorbidities and medication use. The remote consultations were held once a week during the morning hours and followed an interview approach similar to the face-to-face consultations. Since the study setting was a public teaching hospital, consultations were carried out by medical residents and interns during their rotation in this service under the supervision of one geriatrician who is a hospital employee.The remote consultations involved treatment approaches, health promotion recommendations, drug prescription, complementary diagnostic tests, and referral to other health providers. Patients were sent education materials with health recommendations and medication use schedules to improve their adherence (supplementary files 1 and 2). We developed two different education materials (PDF files), one for patients with preserved mobility and other for those with limited mobility.The intervention was designed as a one-time consultation (see flowchart in We used the Research Electronic Data Capture (REDCap) software for data collection and management.The feasibility criteria that were set apriori to the trial were: recruitment and attendance rates, sense of safety and satisfaction and travel time and cost savings. The study sample was drawn consecutively among those meeting the eligibility criteria during the recruitment period from May to December 2020. The period of recruitment was established based on logistics. The HUWC coordination permitted virtual visits from May to December 2020, considering the pandemic’s social constraints and staff availability. The purpose of this study was not to assess the effectiveness of the intervention, but rather to decide whether the virtual consultations are viable in our outpatient clinic. All studies should have a sample size justification. Not all studies however need to have a sample size calculation. For pilot and feasibility trials, while a sample size justification is important, a formal sample size calculation may not be appropriate . We usedData was collected through medical chart review and patient questionnaires. Baseline and demographic data included age; gender; type of caregiver ; dementia duration; presence of chronic comorbidities; medication use; rehabilitation care; fall events; neuropsychiatric symptoms; sleep disturbance complaints; constipation; dysphagia; and urinary incontinence. The participants were also asked about functional decline due to social restrictions during the pandemic. Duration of dementia was defined as the number of years that the patient received the diagnosis of dementia by a physician. The duration from onset of dementia symptoms was defined as the number of years that the relatives noticed the patient’s trouble in cognition.We administered three dementia-related geriatric questionnaires: The Functional Assessment Staging Tool (FAST); the Katz Activities of Daily Living (ADL) scale; and the Abbreviated Mental Test 4 (AMT4). The FAST is easy to administer and has excellent validity for assessing functional capacity over the course of Alzheimer’s disease and it is also used in other dementias .We used the AMT-4 to assess cognitive function, which is a brief cognitive test widely used, with good specificity (88%) and good reliability . The fouThe Katz scale is widely used to assess activities of daily living (ADLs) rated on a scale of 0 to 6. We administered a version of the Katz scale that was translated and culturally adapted to Brazilian Portuguese by Lino et al. (2008), where higher scores indicate more dependence .Eligible patients were asked to sign an informed consent form through an online permission form and an appointment was scheduled using WhatsApp messenger or via telephone. They were given some instructions to optimize the remote consultation: choose an adequate room with strong wi-fi signal; have their caregiver or a family member present during the entire appointment; and have their most recent test results and list of medications at hand.The recruitment rate for telemedicine consultations was calculated as the number of patients agreeing to participate in the study divided by total number of patients which we have attempted to contact.The attendance rate was calculated as the proportion of virtual medical consultations completed as scheduled. The intervention was considered feasible if at least 80% of the consultations could be completed .A self-administered questionnaire was used to evaluate whether our telemedicine intervention was feasible, safe, satisfying, and well-accepted for future use. This questionnaire was answered with the help of the caregiver for patients with early dementia and by the caregivers themselves for patients with moderate to severe dementia. They were asked to state the identity of the respondent. The questionnaire consisted of 12 questions with a visual analogue scale (VAS) to evaluate satisfaction (worst on the left end and best on the right end) and one additional open-ended question. The participants were asked to mark the point (face) on a horizontal line that was representative of their level of satisfaction. For each question, they could select only one option.The questionnaire has five domains: feasibility (items 1–2); sense of safety (items 3–5); appreciation and satisfaction (items 6–7); effectiveness (items 8–9); acceptance and future use of the intervention (items 10–12). Lower scores indicated lower perceived interest, safety, satisfaction, acceptance, and benefits of telemedicine. We also included an open-ended question for suggestions and comments. The VAS scale was sent on WhatsApp as a Google Drive link. This same questionnaire has been administered by other authors ,25. If tPatient discomfort during consultation was assessed by the number of consultations with internet connection issues and/or the interviewer’s perception of noncompliant patient behavior divided by the number of consultations.Information on travel time and costs was collected during the interview to capture both time and financial burden of face-to-face consultations. They were asked about transportation, average travel time from the clinic to their home, and travel expenses.For numerical variables, data was presented as means, standard deviations and medians. For categorical variables, data were described as frequencies.We recruited a total of 104 patients from the geriatric outpatient clinic’s medical appointment scheduling platform; 89 agreed to participate in the study. The recruitment rate was 89/104 x 100, i.e., 85.5%. The attendance rate was 87/89 x 100, i.e., 97.7%. We had two dropouts because two patients were not able to attend the scheduled consultation, one due to internet connection issues and the other one was hospitalized.The telemedicine team evaluated a total of 4 patients every Tuesday morning, except holidays. Remote reassessments were requested for 20 (12.9%) patients. The reasons for reassessment included medical complications (2 patients); behavior disturbances (4 patients); both clinical and behavior reasons (1 patient); medication withdrawal (1 patient); complementary test results (1 patient); and family request (2). Six (7.0%) patients were advised to come to the clinic as early as possible for a face-to-face consultation as they required physical examination.Discomfort was evidenced during the telemedicine consultation for 8 (9.4%) patients due to internet connection issues (7 patients) and noncompliant behavior (1 patient). Eighty-seven patients attended remote geriatric consultations in this study; however, two were excluded from the analysis because they had not had any consultations in the 12 months preceding the study. The final sample included 85 participants. The mean age was 81 ± 12 years old, mean dementia duration of 5.3 ± 3.2 years and mean duration from onset of dementia-related symptoms of 7.5 ± 3.8 years. Most participants were female (71.8%), 37.6% had Alzheimer’s disease and 14.1% mixed dementia (Alzheimer’s disease and vascular dementia). The main comorbidities included systemic arterial hypertension (72.9%); dyslipidemia (50.6%); osteoporosis (36.4%); and diabetes mellitus (34.1%). The most used classes of drugs were antihypertensive drugs (67%); antidepressants (51.8%); vitamin D supplements (49.4%); statins (40%); calcium supplementation (31.8%); oral antidiabetic drugs (30.6%); and atypical antipsychotic drugs (27.1%).Over half of the participants  had less than 8 years of schooling and the caregiving role was played by a family member for the large majority (90.4%). The average number of medications used was 7 ± 3.19. Thirty-seven (44%) patients showed behavior changes complaints and 33 (39.8%) had sleep disturbance complaints. Functional decline during the pandemic was reported for 23 (28.4%) patients. The median disability index of ADLs assessed by the Katz scale was 4. The most frequently medical prescriptions were for the treatment of osteoporosis and osteopenia including bisphosphonates; denosumab; vitamin D and calcium supplements (71.4%); requests of laboratory tests (60.7%); physical rehabilitation care (33.3%); bone densitometry (26.2%); laxative drugs (17.9%); and medication for controlling behavior changes (17.9%). The average duration of WhatsApp video call including medical consultation, health promotion recommendations and questionnaire administration was 46 minutes (SD 18).For attending face-to-face consultations, the most common types of transportation used were the patient’s own car (54.1%); Uber (27.1%); taxi (11.8%); and bus (8.2%). Most patients lived in the metropolitan area of Fortaleza (91.8%) and only 7 patients (8.2%) traveled from other cities within the state of Ceará. Regarding the caregiver’s social burden, 34.5% missed work to attend face-to-face consultations. Overall, the telemedicine approach was well-accepted among the participants as assessed by the acceptance domain of VAS for satisfaction, which was greater than 90% (satisfaction was the top-rated item). The worst rated question was that related to improvement of dementia symptoms with the intervention, with about 45% of the respondents stating that they believed remote consultations could help improve dementia symptoms .The answers to an open-ended question for suggestions, claims and comments of the VAS are described in We found that 51.7% of the study participants had Alzheimer’s dementia, either alone or mixed dementia with cerebrovascular disease. The large proportion of patients with dementia under evaluation in our sample is because we were not able to assess brain imaging studies and/or laboratory tests to confirm the etiological diagnosis. Public patients endure long delays for diagnostic tests and imaging studies.The participants were mostly female and this finding is likely due to women’s greater longevity as risk of developing dementia increases with age . They weFunctional decline was perceived by 28.4% of the caregivers. Only 14.1% of the sample was attending physical therapy rehabilitation sessions during the COVID-19 pandemic; and 93% were not engaging in any physical activity for at least 30 minutes 3 times per week.Older people are most vulnerable to the impact of confinement and they experience worsening of their medical conditions . The WorIn contrast with large studies –36. carrThe study had a small qualitative part in the satisfaction questionnaire. The responses to the one open-ended question were evaluated individually and grouped using repeated meanings. We examined the answers to the open-ended question in the satisfaction survey to better understand our sample’s experience with this new approach. The main disadvantage of telemedicine was inability to perform physical examinations. In later face-to-face encounters some caregivers admitted giving lower satisfaction ratings for fear the clinic will stop face-to-face consultations. Their main suggestion was to schedule video consultations more frequently with more convenient flexible hours because video consultations in the study were limited to one shift per week.The main advantage of the telemedicine intervention was to deliver care to the patient at home. Our hospital (study site) is in a busy area providing service to a broad population, so caregivers often encounter heavy traffic and difficult transport conditions to bring their patients (bedridden or in a wheelchair) for consultations, which is costly and time-consuming. Given the high prevalence of neuropsychiatric symptoms in patients with dementia syndrome, they usually experience distress when removed from familiar environments. Another important advantage stressed is avoiding exposure of older patients to the coronavirus in crowded waiting rooms as they are most vulnerable to severe forms of COVID-19.The question that ranked the lowest was: “Do you think video consultations can help improve dementia symptoms?” A possible explanation is that it was not understood as originally intended. This question was designed to assess additional dementia symptoms such as agitation, insomnia, or depression. However, the question was vague and gave rise to a different interpretation, i.e., full resolution of symptoms after a single video consultation. Another possible reason is that rehabilitation care prescribed during the remote consultation was often not provided to the patients due to few public rehabilitation centers being available as well as mobility constraints requiring home care. Home care rehabilitation services are seldom provided in a public setting in Northeast Brazil . In addiWe chose to deliver care through telemedicine only to patients who attended our outpatient clinic in the preceding year. First, to ensure the patients underwent thorough assessment and proper diagnosis, and that caregivers and family members knew how to handle test requests and prescriptions of costly medication such as anticholinesterase drugs available through the hospital.Recruitment and attendance rates in our study were high and are consistent with the findings of previous studies that showed that telemedicine consultations for monitoring chronic conditions are a convenient approach because patients avoid traveling to the medical facility for routine follow-up appointments and they are more convenient and safer for patients and less burdensome to caregivers –39. TeleMost previous studies of telemedicine consultations involved patients who were more educated and familiar with the use of internet than those in our sample ,23,34,43To the best of our knowledge this is the first study conducted in Brazil to assess the feasibility and acceptance of a telemedicine approach for patients with dementia using WhatsApp. Management of patients with dementia is quite challenging as it involves several multidisciplinary providers and dedicated caregivers  Health cThis study showed good patient satisfaction with telemedicine consultations for patients with dementia, reduced travel and financial burden and increased patient safety as caregivers do not have to deal with stressful situations in waiting rooms for face-to-face consultations and the risk of coronavirus contagion during the COVID-19 pandemic. The participating resident doctors were also satisfied that a telemedicine approach is feasible for geriatric monitoring of patients in a public setting during a challenging period of social distancing restrictions.The main limitations of this study were the small sample size and the absence of a control group attending face-to-face consultations. The main purpose of our study was to describe indicators of feasibility, patient satisfaction, benefit impression, and travel time and cost savings, so we did not collect data on effectiveness. A large multicenter study is needed to further examine the application and effectiveness of this intervention. We studied a sample that was mostly urban, but underserved populations  may benefit more from this intervention. Feasibility indicators should be assessed for patients in remote localities and rural areas.Our research found that, despite serving in a region with low education rates and per capita income, there is good acceptance and appreciation of distance care for the follow-up of dementia patients in our sample. However, the efficacy and safety of telemedicine treatments for dementia patients must be studied further in big prospective trials.S1 Checklist(DOCX)Click here for additional data file.S1 File(DOCX)Click here for additional data file.


Seventy patients performed the 6MWT. Step time, step symmetry, stride time and stride symmetry in both analyses showed high AUC values (>0.75). More significant differences in velocity and acceleration in the maximum Y axis or vertical movements. Three pure kinematic parameters obtained good discriminant capacity (AUC > 0.75). The new methodology proved differences in gait and pure kinematic parameters that can distinguish two groups according to the performance in the 6MWT and they had discriminant capacity.It is a challenge to manage and assess heart failure with preserved left ventricular ejection fraction (HFpEF) patients. Six-Minute Walk Test (6MWT) is used in this clinical population as a functional test. The objective of the study was to assess gait and kinematic parameters in HFpEF patients during the 6MWT with an inertial sensor and to discriminate patients according to their performance in the 6MWT: (1) walk more or less than 300 m, (2) finish or stop the test, (3) women or men and (4) fallen or did not fall in the last year. A cross-sectional study was performed in patients with HFpEF older than 70 years. 6MWT was carried out in a closed corridor larger than 30 m. Two Shimmer3 inertial sensors were used in the chest and lumbar region. Pure kinematic parameters analysed were angular velocity and linear acceleration in the three axes. Using these data, an algorithm calculated gait kinematic parameters: total distance, lap time, gait speed and step and stride variables. Two analyses were done according to the performance. Student’s  Heart failure is not a single pathological diagnosis but a clinical syndrome consisting of cardinal symptoms due to a structural and/or functional abnormality of the heart that may be accompanied by signs and results in elevated intracardiac pressures and/or inadequate cardiac output at rest and/or during exercise . The HF Patients with HF have reduced functional aerobic capacity, decreased muscle strength, tiredness, low weekly physical activity, increased time to recover after exercise, fatigue, dyspnea and exercise intolerance ,3,4. FurFunctional symptoms, like accentuated muscle dysfunction, appear in patients with HFpEF and not in patients with HFrEF . FunctioRegarding the gait parameters, there are discrepancies in which ones are useful to assess limitations in functional aerobic capacity in HF . KinematA cross-sectional study was carried out between April 2019 and March 2020 in the Heart Failure Unit of the Internal Medicine Department at the Regional University Hospital of Malaga . The study was registered on the ClinicalTrial.gov database as NCT03909919.The study included the participants according to the following criteria: (1) patients diagnosed with HFpEF according to the European Society of Cardiology Consensus Statement ; (2) oldEthical approval was obtained from the Provincial Ethics Committee of Malaga, Malaga, Spain (26032020). The study was carried out following the Helsinki Declaration , and theThe Six-Minute Walk Test (6MWT) was carried out in a closed corridor. Two marks were placed on the ground at 30 m, and patients walked from one end to the other for 6 minutes (min). Patients were instructed to walk as quickly as possible and informed of the time elapsed on each lap. The distance from which patients walked for 6 min was recorded [2) were assessed using the gyroscope and the accelerometer included in the Shimmer3 IMUs. The Shimmer3 IMU can measure kinematically along three orthogonal axes . A sensor was placed snugly secured to the lower back, specifically at the L3–L4 level, and fixed with adhesive tape to reduce error due to the movement of the sensor on the skin. The other sensor was placed in the same way but in the medial third of the sternum in the dorsal area  inertial measurement units (IMUs). Kinematic parameters such as the trunk’s angular velocity (°/s) and linear acceleration  recruited and assessed the eligibility of the participants during consultation. If participants met the eligibility criteria, they would be invited to participate in this study. The measurement was all done on the same day. While performing the 6MWT, participants also wore two inertial sensors, one on the back at the L3–L4 level and the other on the sternum, to assess kinematic parameters . PatientThe software used to assess and record kinematic parameters was Consensys v1.6 , a specific and paid software developed for kinematic analysis with Shimmer3. This software allows users to assess and record kinematic parameters, create a CSV file with recorded data, and export it. After each trial, the created CSV were processed and analysed using MATLAB software . An own MATLAB code was created specifically for this project to process and analyse the kinematic parameters. The first function of this code is to allow the researcher to select the beginning and the end of the functional test. Once the beginning and the end of the 6MWT are selected, the code analyses the angular velocity and the linear acceleration of both Shimmer3 IMUs, and the code calculates the following gait kinematic parameters from the Y-axis linear acceleration of the shimmer located at the L3–L4 level: total 6MWT distance (m), lap time (s), gait speed (m/s), number of steps and strides (n), step and stride time (s), step and stride length (m), step and stride velocity (m/s), step and stride cadence (steps or strides/min), and finally, step and stride symmetry ratio (higher step or stride time/lower step or stride time). Additionally, the pure kinematic parameters of both inertial sensors were extracted in the three dimensions: mean, maximum, and minimum peak. The interface of the processing code was shown in t-test (t-test) was used to measure kinematic differences between patients with HFpEF who walked more than 300 m and those patients who could not walk more than 300 m. The t-test assessed the kinematic differences between patients with HFpEF who stopped during the 6MWT and those who did not stop. This test was also used to assess the kinematic differences between women and men in the 6MWT, and between patients who had fallen in the last year and those who did not fall. 95% confidence intervals (95%CI) of the kinematic differences were also reported. Levene’s test assessed the variance heterogeneity (significance < 0.15). Four discriminant analyses using a receiver operating characteristic (ROC) curve were performed to assess the discriminant ability of kinematic parameters: (1) between patients who walked less than 300 m [p-value of p < 0.05 was considered to be statistically significant. All statistical analyses were conducted using the Statistical Package for the Social Sciences (SPSS) 22.0  for Windows.Descriptive, inferential and discriminant analyses were carried out. An absolute frequency and a percentage are described as qualitative measures. Quantitative measures were reported using the mean, the standard deviation (SD), the maximum, and the minimum. Distribution and normality were determined by one-sample Kolmogorov-Smirnov tests (significance < 0.05). The Student’s an 300 m , (2) peoan 300 m . The kinSeventy patients with HFpEF were voluntarily included in the study. Participants’ descriptive, anthropometric and clinical variables, as well as blood and urinary biomarkers, are shown in . Pure kinematic outcomes differences in the three dimensions between women and men in the 6MWT were reported in Lumbar and chest linear pure kinematic analysis with acceleration and angular velocity in the three dimensions during the 6MWT were shown in Table 5The objective of this study was achieved, and a new methodology could be presented to analyze the 6MWT test with inertial sensors in patients with HFpEF, which can help to stratify patients with HF based on the functional performance according to the impairment level. There was a difference between groups in all gait kinematic outcomes besides seven parameters with high discriminant values in both classifications.Patients with HFpEF who walked more than 300 m showed a higher gait speed (1.0 m/s) than patients with HFpEF who walked less than 300 m (0.54 m/s). Similar results in the other analysis between people who completed the test (0.80 m/s) and people who did not (0.51 m/s). Our results also showed that patients with HFpEF who could not finish the 6MWT walked 105.10 m less than patients with HFpEF who finished the test. The mechanisms that walking gets slowed down have had clinical and functional relevance , so theiAnother aspect associated with worse results is the physical capacity of the subjects. Patients with HFpEF have worse muscle function and more atrophy than HFrEF . RegardiThe relationship between 6WMT and gait speed is very close because both have similar abilities to predict mortality prognosis in cardiovascular diseases , so gaitThe step time, step symmetry, stride time and stride symmetry were the gait kinematic parameters that best discriminated in the two-discriminant analysis: (1) between patients with HFpEF who walked more or less than 300 m in the 6MWT and (2) patients with HFpEF who could not complete the 6MWT. These facts per the previous insight about the contribution of a short-stepping gait in the limitation of exercise capacity in patients with HF and the different responses between healthy subjects . The exeAll the gait parameters were significantly different regarding the analysis of the variables between the two groups previously mentioned. More differences in cadence and steps/breath between patients with HF and healthy subjects were shown by Clark et al. . HoweverFinally, only stride length was lower in women than in men. This stride length has been associated with the severity of HF, so the women included could have a more severe pathology . No kine2) that would correspond to the vertical movement was greater than the acceleration in the Z axis (3.28 m/s2), which corresponds to the person’s anteroposterior movement. If the movement is walking forward, more acceleration can be expected in the Z axis than in the Y axis, but this may be important to elicit future kinematic biomarkers that facilitate assessment. This fact agrees with the study by Galan-Mercant et al. [More pure kinematics differences were found in people that completed the test in ≥300 m and <300 m. The maximum acceleration and velocity in Y always differed significantly in all the analyses. Although these variables have not been different between patients with chronic heart failure and healthy people, it is known that there are important factors in biomechanics and kinematics that can classify them . The acct et al.  on frailt et al. . Regardit et al. . In contt et al. . A possiOn the other hand, angular velocity results have also been helpful in other pathologies, such as LBP . Three mRegarding the performance of the 6MWT, only 58.60% of patients with HFpEF could finish the test. Older adults with HFpEF with limited functional aerobic capacity have difficulty completing the test due to fatigue and other symptoms such as dyspnea. According to the presented results, kinematic assessment is another option that involves fewer space-time resources than the 6MWT. It allows clinicians to stratify their patients functionally.In addition, this large sample size of recruited patients with HFpEF could reduce any risk of selection or performance bias. The cross-sectional design could reduce any risk of detection and attrition bias as it reduces the possibility of missing data in outcomes. The results with statistically significant differences and statistically non-significant results were presented in this study to avoid publication bias.Although these strengths, this study presented some limitations. One of these limitations was that the results were not compared to an HFrEF or healthy control group. An analysis of these gait and kinematic variables with other physiological outcomes during the 6MWT could be recommended to complete the clinical assessment. It will consider outcomes such as oxygen consumption, perceived exertion or heart rate because these variables correlated during walking . Thus, tThe results of this study presented descriptive data on the development of the 6MWT test in HFpEF with an inertial sensor-based methodology. Gait kinematic outcomes can be useful to assess HFpEF patients during a different performance of 6MWT. Regarding the pure kinematics results, higher accelerations were observed more times in the vertical movement. Future studies should relate these results with other parameters and look for the stratification of this subtype among the other HF.


Our aim was to map acquired peripheral and abdominal sarcopenia in mechanically ventilated adults with COVID-19 through ultrasound measurements. On Days 1, 3, 5 and 7 after admission to critical care, the muscle thickness and cross-sectional area of the quadriceps, rectus femoris, vastus intermedius, tibialis anterior, medial and lateral gastrocnemius, deltoid, biceps brachii, rectus abdominis, internal and external oblique, and transversus abdominis were measured using bedside ultrasound. A total of 5460 ultrasound images were analyzed from 30 patients . Muscle thickness loss was found in the bilateral anterior tibial and medial gastrocnemius muscles (range 11.5–14.6%) between Days 1 and 3; in the bilateral quadriceps, rectus femoris, lateral gastrocnemius, deltoid, and biceps brachii (range 16.3–39.1%) between Days 1 and 5; in the internal oblique abdominal (25.9%) between Days 1 and 5; and in the rectus and transversus abdominis (29%) between Days 1 and 7. The cross-sectional area was reduced in the bilateral tibialis anterior and left biceps brachii (range 24.6–25.6%) between Days 1 and 5 and in the bilateral rectus femoris and right biceps brachii (range 22.9–27.7%) between Days 1 and 7. These findings indicate that the peripheral and abdominal muscle loss is progressive during the first week of mechanical ventilation and is significantly higher in the lower limbs, left quadriceps and right rectus femoris muscles in critically ill patients with COVID-19. Studies show that prolonged bed rest is associated with multiple complications by inducing 25–33% muscle mass loss at an early stage of critical illness in the first week of hospitalization6. Furthermore, muscle impairment encompassing atrophy, weakness, or muscle function decrease has been widely reported (9–73%) in several studies and is persistent for approximately 6 months to 5 years after ICU discharge7.Sarcopenia is a progressive and generalized disorder that affects the musculoskeletal system and is characterized by muscle mass, strength, and function losses related to inactivity, malnutrition, and the presence of critical illness9. Although common, the use of neuromuscular blockade is associated with a high risk of developing polyneuropathy in critically ill patients, thus negatively affecting their functional status12. Critically ill patients affected by COVID-19 and under mechanical ventilation support may present with musculoskeletal impairments, with the main symptoms being myalgia, muscle fatigue, exercise intolerance, and myositis/rhabdomyolysis. symmetric neuropathy, critical illness myopathy and neuropathy15.Patients hospitalized with COVID-19 may require the use of mechanical ventilation, sedatives and/or neuromuscular blockers due to their illness severity, which would therefore require them to spend during their time in the ICU16, but volitional tests are not applicable in this acute disease phase18. Nonvolitional assessment tools such as computed tomography and magnetic resonance imaging and invasive techniques such as biopsy, electromyography and nerve conduction studies are highly accurate for the diagnosis of muscle changes; however, these resources are limited in this specialized COVID-19 ICU scenario because of high cost, radiation exposure, and aerosol transmission-related health hazards21.Early detection of muscle changes is necessary for appropriate management of rehabilitation strategies26. The literature is incipient on screening muscle damage, and there is no mapping of muscle mass loss to facilitate the tailoring of treatment28. Recently, published studies regarding ultrasonography assessment in patients with COVID-19 were limited in that these studies only reported data on quadriceps and diaphragm measurements30.From this perspective, the assessment of muscle mass using ultrasound (USG) has been proven to be an effective method for identifying peripheral and abdominal muscle changes during critical illness, in addition to being a low-cost, nonionizing, noninvasive bedside assessment in uncooperative or unconscious patients, enabling screening for alterations in skeletal muscle structure31, a broader overall assessment approach is necessary to elucidate the progression of muscle mass loss to direct strategies to minimize or revert the affected muscles. Therefore, this study aims to map peripheral and abdominal sarcopenia acquired in the acute phase of COVID-19 through ultrasound measurements of muscle thickness and cross-sectional area of multiple muscles in critically ill patients on invasive mechanical ventilation during the first week of hospitalization in the ICU.Thus, considering the impairment of the musculoskeletal system in these patientsThis observational and longitudinal study was carried out at a single center, COVID-ICU Hospital da Mulher do Recife, between March and October 2020. It was approved by the institutional Research Ethics Committee of the Federal University of Pernambuco (No. 5.180.364). It was conducted in accordance with the 1964 Helsinki Declaration. The informed consent statement was obtained by phone from the legal representatives of the participants.Patients 18 years and older who were mechanically ventilated for more than 48 h and had a confirmed diagnosis of COVID-19 by RT‒PCR were included. Patients with neurological impairment, known myopathies, limb amputation or bedridden prior to admission were excluded.The sample size calculation was performed using the G* Power version 3.1.9.4 statistical software program from the first ten medical data records included in the study. The means and standard deviations between D1 (first day) and D3 (third day) in the ICU were used, with α = 0.05 and β = 0.80 for muscle thickness and cross-sectional area of the muscle groups of interest , extubation, tracheostomy, ICU length of stay, and mortality. The Simplified Acute Physiology Score 3 (SAPS 3) and the Acute Physiology and Chronic Health Evaluation II (APACHE II) scale were also calculated within the first 24 h of the ICU stay.All patients with COVID-19 were under sedation and mechanically ventilated in the supine position, according to the routine hospital practice. The patients presenting with refractory hypoxemia, hypercapnia, or patient-ventilator asynchrony were elected to additionally receive neuromuscular blockade (rocuronium bromide), which was infused at a dose of 9–12 µg/kg/min intravenously.32.All ultrasonography of the peripheral and abdominal muscles was performed following the standard operating protocols (SOP) from the several references that are listed in Online Resource To ensure tracking and reliability of the measurements, the assessor performed the US measurements immediately on the ICU admission day by using a Philips ultrasound machine , with an 8.0 MHz linear probe . The patients’ ultrasound measurements were also registered on their medical records for further reassessments.2) in the brightness mode (B-mode) of the US. The scanning depth was set to 3.5 cm, and the selected region was set to include as much muscle as possible, excluding surrounding bone or fascia. Time gain and compensation were set to the neutral position. The focus number and area were maximally increased to remain consistent across all participants and to adjust for differences in muscle size between them. The following variables were analyzed:Muscle thickness of the lower limbs : quadriceps, rectus femoris, vastus intermedius, tibialis anterior, medial and lateral gastrocnemius muscles, for which imaging was achieved by flexion at the knee with the foot placed flat onto the patient’s bed.Muscle thickness of the upper limbs : deltoid and biceps brachii muscles;Abdominal muscle thickness: rectus abdominis, internal and external oblique, and transversus abdominis muscles;Cross-sectional area : rectus femoris, biceps brachii, and tibialis anterior musclesMuscle mass was determined by determining muscle thickness (mm) and cross-sectional area  program for Windows (version 26.0. Chicago. IL), and a significance level of p < 0.05 was established.The percentage change (Change%) for the values obtained for muscle thickness and the cross-sectional area between Days 1–3, 1–5, and 1–7 of MV were also calculated using the expression (Change%) = [/initial value] × 100 and the coefficient of variation (CV) given by the ratio between standard deviation/mean × 100 for all muscle groups. Thickness and cross-sectional area measurements for each muscle group between Days 1, 3, 5 and 7 were compared by analysis of variance of repeated measures .Considering the use of neuromuscular blockade as a presumed bias or confounding variable, a sensitivity analysis was performed comparing the sample divided into two groups by the use of neuromuscular blockade, 15 in each group. The baseline characteristics between the groups were compared using the t test for independent samples for variables with a normal distribution and the Mann‒Whitney test for variables with a nonnormal distribution. Chi-square Test was used to compare proportions and corrected by Fisher's exact test (if the number of cases < 5). An additional analysis was performed to verify the effect of NMB on muscle thickness and cross-sectional area alterations in a multivariate analysis of variance (MANOVA) test with NMB as a covariate in the model , and of a cross-sectional area decline marked by a cutoff higher than 12% (yes/no) between the observed and expected observations set with 0.50 in each category  and of a cross-sectional area decline marked by a cutoff higher than 12% (yes/no), and the categorical outcomes (ICU discharge/death), we used the chi-squared test corrected by Fisher's exact test and assessed the risk by determining the odds ratio.  muscle mass thickness loss (higher than 15%) and cross-sectional area decline (higher than 12%); (2) percentage change of muscle mass and cross-sectional area, and (3) risk factors. These automatic models were generated by employing the following settings: the selection method was “Forward Stepwise”, and the criteria for entry/removal: Information Criterion (AICC) including effects with p values less than 0.05 and the removal of effects with p values greater than 0.1. The model selected was the one with the highest adjusted RThis study followed the National Health Council (Resolution 466/2012) and the Declaration of Helsinki for research on human beings and was approved by the research ethics committee of the institution. The hospital also consented to the research.The sample consisted of 30 patients with 5,460 images analyzed. This total number of images corresponded to the following details: three measurements were performed on each body segment , 12 patients were assessed twice , 5 patients were assessed 3 times  and 13 patients were assessed four times . The lowest ICC was 0.97 with a confidence interval of 0.91–0.99 in biceps brachii thickness.The baseline characteristics of the patients included are shown in Table The muscle thickness and cross-sectional area data for all muscle groups and follow-up analyses are presented in the Supplementary material The other muscles of the lower limbs were affected from the 5th day in the ICU, with a more significant loss of muscle mass in the right  and left quadriceps muscles . On the fifth day, the impacts on the muscles were as follows: right  and left rectus femoris ; right  and left vastus intermedius ; and right  and left lateral gastrocnemius   and left deltoid  and the right  and left biceps  , as well as the internal oblique . The transversus abdominis muscle  only showed a decline in muscle thickness from the 7th day of evaluation, while the external oblique muscle showed a reduction in mass at the end of the 7 days of MV, but without a significant difference   and left anterior tibialis muscles  and left biceps brachii . This loss pattern for the other muscles that were evaluated was observed only from the 7th day of ICU stay Fig. .Figure 5MANOVA showed that there was an effect of neuromuscular blockade on the decline in muscle thickness  and on the reduction of the cross-sectional area . Details are presented in the supplementary material  and left (42.28%) rectus femoris, as well as in the thickness of the right (41.18%) and the left (45.44%) quadriceps.Muscle disuse is an important risk factor for critically ill patients with COVID-19 who require admission to the ICU and mechanical ventilation, as observed in the study by Andrade-Junior33. They may undergo a process of necrosis and be replaced by adipose tissue or fibrosis, directly compromising the activities of daily living performance, especially the power activities in which these fibers are most employed.35.Skeletal muscle disuse caused by prolonged bed rest leads to muscle fiber atrophy. Fast-twitch fibers (type II) are more sensitive to the inflammatory process from critical illness and are the most affected30. Furthermore, some authors claim that the COVID-19 virus binds to the angiotensin-converting enzyme 2 (ACE 2) receptor in human cells, and this virus has high expression in the musculoskeletal system, thus causing direct invasion by hematogenous dissemination36.Previous studies have reported that muscle tissue injury may be associated with damage regulated by proinflammatory cytokines in patients with COVID-1938.Evidence of body composition assessment in non-COVID-19 patients has demonstrated protein loss because of proteolysis. This alteration can be explained by the imbalance of protein metabolism since the skeletal muscle system is considered a protein reservoir. Protein synthesis in the critically ill is severely low and is equivalent to the levels found during fasting on the first day of illness, followed by an increase to normal levels by the end of the first week. However, a catabolic state that manifests clinically as weight loss, undernutrition and sarcopenia remains during the ICU stay despite nutritional support39. Our findings showed that this mass declination followed a caudal-cranial pattern that was detected on the 3rd day in the lower limbs and then was detected in the upper limbs on the 5th day, maintaining a progressive loss. The disparity in sarcopenia in the skeletal muscle of the upper and lower limbs has not been fully elucidated but is speculated to be the result of less physical activity42, especially lower-limb disuse, as the upper limbs are constantly utilized for activities of daily living across the patient’s lifespan43.To date, no study has tracked sarcopenia ultrasonographically in critically ill patients with COVID-19 in the acute phase. General studies have reported that muscle mass loss in the lower limbs of critically ill patients is prevalent44. Some authors report similarities between this infection pathophysiology and that of demyelinating diseases, such as Guillain‒Barré Syndrome and acute myelitis, which present as a pattern of muscle weakness starting from the lower to upper extremities46. We could not assess nerve conduction in our sample, thus limiting the ability to obtain stronger results.Another possible explanation is that SARS-CoV-2 infection affects neural tissue, therefore inducing neural cell apoptosis and consequently affecting muscle function47. In our study, this rectus femoris mass declination was observed even sooner (Day 5) and was observed bilaterally partially due to methodological reasons.A recent Italian study analyzing the quality of peripheral and respiratory muscle ultrasound characteristics in mechanically ventilated patients at Days 3 and 7 found a significant change in the rectus femoris and quadriceps by Day 749. In our study, it was observed that there was a statistically significant effect of the use of neuromuscular blockers in reducing muscle thickness and cross-sectional area.Neuromuscular blockade was used to facilitate oxygenation or mechanical ventilation coupling in patients with COVID-19. It is known that the use of this resource was associated with a 25% greater chance of developing ICU-acquired muscle weakness due to the deregulation of acetylcholine metabolism and upregulation of receptor subtypes that are less sensitive to acetylcholine50. This reduction can also be masked by fluid overload represented by positive fluid balance, as well as by metabolic alterations associated with inadequate nutritional support51 and by imbalances in calcium ion homeostasis (Ca + +)52.Other factors need to be considered in muscle thickness reduction, such as illness severity, age, sepsis and multiple organ failureUltrasound screening for muscle mass loss is a valuable asset to anticipate muscle dysfunction in critically ill patients with COVID-19 under mechanical ventilation and sedation. The diagnosis of ICU-acquired weakness and functional dysfunctions are usually detected late after individual awakening and cooperation with functionality assessments. By identifying individuals who may develop future deterioration of strength and functionality early, strategies can be set to prevent or attenuate the muscle damage induced by extended bed rest and the use of mechanical ventilation in the acute phase of COVID-19 critical illness.Some limitations that are present in this study need to be addressed. First, the single-centered feature can limit the generalization of our results. Second, unadjusted confounding variables such as age, gender, fluid balance and albumin may result in the over- or underestimation of the ultrasound-related outcomes, although we believe that they would not change the overall results obtained, which showed to be robust. Third, it was not possible to retrieve baseline assessments of the onset of COVID-19-related symptoms before the patients were admitted to the ICU, as this timing can have some influence on the outcomes.This is a pioneering study in tracking peripheral and abdominal muscle wasting via ultrasound in critically ill patients with COVID-19 and is thereby clinically relevant for guiding therapeutic interventions to promote functional recovery as early as possible through an individualized approach.Peripheral and abdominal muscle mass loss is progressive over the ICU time of mechanically ventilated patients with COVID-19. The lower limbs, left quadriceps and right rectus femoris muscles showed greater muscle wasting during the first week.Supplementary Information.