Human migration facilitates the spread of infectious disease. However, little is known about the contribution of migration to the spread of tuberculosis in South Africa. We analyzed longitudinal data on all tuberculosis test results recorded by South Africa’s National Health Laboratory Service (NHLS), January 2011–July 2017, alongside municipality-level migration flows estimated from the 2016 South African Community Survey. We first assessed migration patterns in people with laboratory-diagnosed tuberculosis and analyzed demographic predictors. We then quantified the impact of cross-municipality migration on tuberculosis incidence in municipality-level regression models. The NHLS database included 921,888 patients with multiple clinic visits with TB tests. Of these, 147,513 (16%) had tests in different municipalities. The median (IQR) distance travelled was 304 (163 to 536) km. Migration was most common at ages 20–39 years and rates were similar for men and women. In municipality-level regression models, each 1% increase in migration-adjusted tuberculosis prevalence was associated with a 0.47% (95% CI: 0.03% to 0.90%) increase in the incidence of drug-susceptible tuberculosis two years later, even after controlling for baseline prevalence. Similar results were found for rifampicin-resistant tuberculosis. Accounting for migration improved our ability to predict future incidence of tuberculosis. Like many infectious diseases, internal migration of infected people may contribute to the spread of TB and emergence of new hotspots via TB introduction and increased encounters between infectious and susceptible individuals7. In low-TB-burden countries, migrants from high-burden countries represent a large share of new infections and a focus population for treatment and preventive interventions11. As such, understanding internal migration patterns in people with TB in high-burden settings is key to preventing TB and drug-resistant TB spread13.Tuberculosis (TB) prevalence varies geographically in South Africa, but the drivers of this spatial heterogeneity are poorly understood20. Existing evidence on migration and TB spread comes from genetic studies. In a study of 344 people with extensively drug-resistant (XDR) TB in KwaZulu-Natal province, South Africa, Nelson and colleagues21 found that 84% of genetically linked TB transmissions occurred between people living in different districts, suggesting an important role of cross-district migration in XDR-TB transmission.Previous studies have used census data, Global Positioning System (GPS) data, mobile phone call records and public transit passenger data to demonstrate increased mobility being associated with increased risk of infectious disease spreadHere, we aimed to (1) characterize cross-municipality migration patterns in people with laboratory-diagnosed TB, and (2) quantify the contribution of cross-municipality migration in people with TB in the spread of drug-susceptible (DS-TB) and rifampicin-resistant TB  in South Africa. We analyzed TB laboratory test results from South Africa’s National Health Laboratory Service (NHLS) database, which we linked to individuals, enabling longitudinal follow-up of people with laboratory-diagnosed TB. We identified people with laboratory-diagnosed TB who had more than one clinic visit during the study period, and we assumed that people who visited clinics located in more than one municipality are migrants. Combining laboratory-diagnosed TB results by municipality from the NHLS data, the notification:prevalence ratio from the 2018 South African TB prevalence survey, and cross-municipality migration rates from the 2016 household survey, we estimated “migration-adjusted” TB prevalence and assessed the contribution of migration to the spread of DS-TB and RR-TB.P≤ 0.01 for all tests; Figure The NHLS database included 921,888 people with laboratory-diagnosed TB with at least two clinic visits. Of these, 147,513 (16%) people submitted TB test samples to clinics located in more than one municipality, which, for this study, we assume indicates that they migrated between municipalities. Migration was slightly higher than average in females less than 20 years, and both males and females between 20–40 years respectively  baseline TB prevalence by municipality was 13.93 (9.00 to 18.83) per 1000 for DS-TB and 0.64 (0.44 to 0.97) per 1000 for RR-TB. The residual, i.e. the difference between migration-adjusted and baseline TB prevalence by municipality ranged from −4.15 to 6.78 per 1000 for DS-TB and −0.23 to 0.35 per 1,000 for RR-TB  prevalence was significantly associated with DS-TB (RR-TB) incidence two years later, even after controlling for unadjusted DS-TB (RR-TB) prevalence Table . After cWe characterized and quantified the role of cross-municipality migration patterns in people with laboratory-diagnosed TB in TB spread. We found that 16% of people with at least two clinic visits submitted TB test samples in different municipalities (which was defined as migration), and most people migrated between nearby municipalities. Migration was higher in females less than 20 years and males and females between 20–40 years  prevalence was associated with DS-TB (RR-TB) incidence two years later  and Boston University Institutional Review Board (no. H-38441) for use of deidentified data with a waiver of consent. All methods were carried out in accordance with relevant guidelines and regulations.29. RR-TB was estimated to be 3.4% and 7.1% among new and previously treated TB cases respectively23. Until the August 2016 redistricting, South Africa was divided into nine provinces, 52 districts, and 234 metropolitan and local municipalities; we used these boundaries as most of our data were pre-August 2016.South Africa is a high TB/HIV burden country, with an estimated TB incidence of 554/100,000 in 2020Mycobacterium tuberculosis (M.tb) or detect resistance to a TB drug  respectively, but the treatment guideline varies by province34.We developed and validated a record linkage algorithm to identify TB tests belonging to the same individualWe excluded TB test samples that were taken in hospital settings to separate mobility due to migration from mobility due to hospital referral because people may attend clinics near to their home but might travel longer distances for specialized in-hospital care. All the tests submitted within 30 days were considered as part of the same clinic visit, and we identified people with laboratory-diagnosed TB who had more than one clinic visit in the study period 35.The NHLS migration cohort enables us to describe migration patterns in people with laboratory-diagnosed TB. However, estimates of the cross-municipality migration rate using the NHLS migration cohort could be biased and less precise. First, some municipalities have small cohort size, and as such, estimates of migration rate for those municipalities are less precise .We described migration patterns among people with laboratory-diagnosed TB with at least two clinic visits in the NHLS migration cohort. We defined migration as a person with laboratory-diagnosed TB who submitted samples in more than one municipality. To quantify migration rates by municipality, we identified the two most visited municipalities by each person with laboratory-diagnosed TB with at least two clinic visits in the NHLS dataset. We assumed that the municipality that was first visited among the two most visited municipalities is the person’s origin municipality, and the other municipality is the destination municipality. We calculated (1) the percentage of people with laboratory-diagnosed TB who moved, (2) the median distance travelled among people who moved , (3) emigration ratio , (4) immigration ratio  by municipality.To test our hypothesis that cross-municipality migration and TB spread are associated, we formulated a basic regression model, where future TB incidence depends on TB prevalence today. In the presence of migration, future incidence in a locality depends not just on local baseline TB prevalence but the number of people moving into that locality and TB prevalence in their locality of origin. We formalized this concept by constructing a measure of “migration-adjusted” TB prevalence and assessed whether migration is associated with future incidence after controlling for unadjusted baseline prevalence.36. We then estimated baseline TB prevalence by municipality as the average prevalence over 2013 and 2014. The prevalence:notification ratio may also vary by municipality because the different health districts in South Africa may not have the same health infrastructure for TB detection. As estimates of prevalence:notification ratios by municipality are not available, we conducted a sensitivity analysis to investigate the impact of differential TB detection at the municipality-level on our results.We defined municipality i incidence in 2015 and 2016 as total number of people starting a TB care episode in that municipality in 2015 and 2016 in the NHLS database . The coefficient of interest, Municipality population size (Supplementary Information.


However, it might carry potential risks derived of the limited experience of smaller centers and differences in accessibility to complex therapies including allogeneic hematopoietic cell transplantation  and chimeric antigen receptor (CAR) T-cells. These risks might be especially relevant in infrequent cancers as adult acute lymphoblastic leukemia (ALL).Diagnosis and treatment of hematological cancers is usually provided in many healthcare facilities including large but also middle size centers.4 Several patient and disease characteristics have been identified as prognostic factors for outcomes including age, white blood cell count (WBC) at diagnosis, central nervous system (CNS) infiltration, clearance of measurable residual disease (MRD),4 and disease genetics.7 The outcome of patients with ALL may also depend on external factors including center experience, access to cellular therapies and economic variables.10 The impact of these center-related and macroeconomic variables on the outcome of patients has been scarcely studied. Thus, the aim of this study was to analyze the potential impact of center-related and macroeconomic variables on the outcome of newly diagnosed adult ALL patients included in 4 consecutive trials of the Spanish Program for Treatment of Hematological Malignancies (PETHEMA) Group.In most European countries, ALL treatment protocols are based on pediatric-inspired regimens which include a large number of immune-chemotherapeutic agents and several key decision points to allocate patients to distinctive treatment arms based on genetics and treatment response.13 Centralized analysis of MRD was performed in 5 centers in the ALL-AR-03 and in a single institution in the ALL-HR-11 trial. The PH-08 protocol included adults with newly diagnosed Ph-positive ALL up to the age of 60 years. Patients received an induction therapy with daunorubicin, vincristine, and steroids in combination with imatinib 600 mg/d followed by a 12-week consolidation chemotherapy based on alternated cycles of high-dose methotrexate and cytarabine in combination with imatinib. Allo-HCT was offered to all fit patients with a suitable donor.Patients with Philadelphia chromosome (Ph) positive or negative ALL enrolled in one of the 4 consecutive protocols of the PETHEMA group by Spanish institutions adhered to the public health system from 2003 to 2018 were included in this study. The 4 protocols have been closed and reported elsewhere.13 The ALL-RE-2008 trial included intermediate risk patients based on age (<30 years), WBC count , and cytogenetics. The ALL-AR-03 and ALL-HR-11 protocols included high-risk patients up to the age of 60 years diagnosed from 2003 to 2011 and 2011 to 2019, respectively. In both trials, bone marrow MRD assessment by flow cytometry was performed at the end of induction (week 5) and at the end of the third consolidation cycle (weeks 16–18). Only patients with slow clearance of MRD in both trials were allocated to allo-HCT, while patients with good MRD clearance continued with chemotherapy for up to 2 years.Treatment protocols used in the ALL-RE-2008, ALL-AR-03, and ALL-HR-11 trials were pediatric-inspired.Clinical variables analyzed in this study included age, gender, ECOG performance status, WBC, CNS infiltration, precursor lineage (B or T) presence or absence of Ph and treatment period (2003–2010 versus 2011–2018). The Allo-HCT center was defined as centers having authorization by the Spanish government to perform allo-HCT in the same institution where the patient was treated for the ALL. The Allo-HCT center in the same province was defined as having a designated allo-HCT center in the same province where the patient was treated. Reported ALL referred to the number of ALL patients reported to the PETHEMA database by a particular center and served as a surrogate marker of center experience in treating ALL. Nine centers reporting at least 30 ALL patients each and around half of the patients together in this data set were considered as “experienced centers.” Protocol deviation center referred to centers with identified protocol deviations in key treatment decisions  in at least 5% of the patients.Other demographic and macroeconomic variables are self-explanatory and listed in Table 1. Demographic and economic variables were obtained from the Spanish Government  was considered an exploratory endpoint and was defined as patients after the first CR dying of infectious causes during ALL treatment or after allo-HCT without previous ALL relapse.Clinical endpoints included overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse (CIR), and nonrelapse mortality (NRM) were defined as previously described.14 The effects of center-related and macroeconomic indicators on OS and DFS were analyzed using Cox proportional hazards regression models, and the Fine and Gray model was used for analyzing these effects on CIR and NRM.15 For each main effect, a separate multivariable model was built, adjusted for other potential risk factors (listed in table 1). All statistical analyses were performed using SPSS (v.24) and R (v.4.1.0). Two-sided values of P < 0.05 were considered statistically significant.All numerical variables were summarized and categorized by medians. Spearman’s rank coefficient or median test was used to analyze correlations between factors. OS and DFS curves were plotted by the Kaplan–Meier method and compared by the log-rank test. CIR, NRM, and IRM were estimated using cumulative incidence functions by competing risks analysis, and the Gray test was used for comparisons.Eight hundred sixteen patients were included in the study. Main characteristics at diagnosis appear in Table experienced centers for this study. Patient characteristics were similar between experienced and less-experienced centers, except for treatment period (Suppl.Table S1). Twenty centers (36%) had at least a major deviation in more than 5% of their reported patients. Details on center-related and macroeconomic variables are summarized in Table Fifty-five centers in 40 different cities located in 15 Spanish Autonomous Communities included at least 1 patient in one of the 4 protocols. Twenty-three (42%) centers were accredited for allo-HCT and 47% of nontransplant institution had an allo-HCT center in the same province. Median number of ALL reported by center to PETHEMA database during the study period was 10 (interquatile range 4–20). Approximately half of the patients  were reported by ten centers which were considered P = 0.002), the number of beds in the hospital (P < 0.001), and with major protocol deviations (P = 0.039). Health investment relative to GDP was inversely correlated with the number of inhabitants in the Autonomous Community (P = 0.032) and directly associated with its GDP per capita (P = 0.001). Other explored associations are listed in Suppl. Table S2.As expected, there were some associations among center-related and macroeconomic variables. Hence, being a transplant center was correlated with the number of ALL cases reported . Probability of DFS at 5 years for the whole cohort was 43% (95% CI: 38-47). In the univariable analysis, ECOG PS > 1, higher WBC at diagnosis, Ph-negative ALL, and earlier diagnosis were associated with worse DFS (Suppl. Table S3). In the multivariable model adjusted for macroeconomic variables, none of the center-, region- and economic-related variables was associated with lower OS or DFS .Probability of OS at 5 years for the whole cohort was 46% . Variables associated with lower OS in the univariable analysis were older age, higher ECOG PS score, higher WBC at diagnosis, Ph-negative ALL and diagnosis in the earlier period (P = 0.01)  achieved CR after one or two induction cycles. Cumulative incidence of relapse among them was 41% (95% CI: 36-45). In the univariable analysis, factors associated with an increased risk of relapse were older age, higher WBC at diagnosis, Ph-negative ALL, and T-cell phenotype. The only center-, region- and economic-related variable associated with a higher CIR in the multivariable model was a higher number of inhabitants in the city where the treatment center was located hazard ratio (HR) 1.399  Table .One hundred ten patients died of non-relapsing causes, 49 of them (45%) after allo-HCT. Cumulative incidence of NRM at 5 years was 17% (95% CI: 14-20). In the univariable analysis, older age, higher EOCG PS score at diagnosis, Ph-negative ALL, and diagnosis in the earlier period were associated with higher NRM. In the multivariable adjusted model, none of the center-, region- and economic-related variables were associated with higher NRM (Table P = 0.001) and earlier treatment period . Again, none of the center-related and macroeconomic variables were associated with higher IRM (not shown).Finally, of the 738 patients achieving CR, 110 died without previous ALL relapse. Of them, causes of death could be identified in 104 (94.5%). Seventy-three patients (70%) died of infectious causes  and were considered to have IRM. Factors associated with higher IRM in the univariable analysis were older age  or have not included well known clinical and genetic factors in their analyses.18 Noteworthy, none of the variables associated with the experience of the center or size of the city or region where the patient was treated associated with DFS or OS. Patients treated in larger cities had a higher CIR which did not translated into lower OS or DFS. Reasons for this finding are uncertain and might reflect early referrals of more complex cases at diagnosis to larger centers located in highly populated cities.Regarding efficacy, we did not observe differences across centers in terms of center-related and macroeconomic variables. The only variables associated with DFS and OS were those dependent on patient and disease characteristics including age, ECOG performance status and WBC at diagnosis, all of them being previously identified as prognostic factors for ALL patients.19 However, we did not find any impact of center experience on the outcome of patients. Transplantation is probably a more complex and less well standardized procedure than first-line therapy for ALL, in which physician’s expertise might be more relevant on patient outcomes. Conversely, PETHEMA ALL protocols include very detailed information in terms of dosing and modification of chemotherapeutic agents and transplant indications which might have contributed to mitigate the potential impact of center experience and assure the equity and access to complex therapies to all the population.Center experience has been identified as a prognostic factor in other high-risk procedures performed in hematological patients such as allo-HCT.Limitations of our study include a local diagnosis of ALL in most patients, a relatively limited sample size and the fact that our results are based on data reported to our cooperative group database. Prospective reporting of data to a cooperative group might indicate certain commitment on scientific studies of these centers. While using data prospectively reported to a cooperative group might harbor a selection bias toward well structured and organized centers, the use of national cancer statistics including all patients diagnosed with ALL in our country would not have allowed us to include homogeneous population of patients treated under the same protocols and with centralized MRD determination, which constitutes a strength of our study.In summary, center-related and macroeconomic variables do not seem to have an impact on outcomes in newly diagnosed adult patients with ALL in the setting of a public health system with clearly defined and structured treatment protocols. Based on our results, these protocols can be safely administered to ALL patients in all hospitals adhered to a national cooperative ALL group. These data should be considered for nation-wide planning of healthcare infrastructures for cancer patients.Conception and Design: PB, JMR. Collection of data: All authors. Data analysis and interpretation: PB, MM, JMR. Manuscript writing: All authors. Final approval of manuscript: All authors.PB declares having received honoraria from Allogene, Amgen, BMS, Gilead, Incyte, Jazz Pharmaceuticals, Miltenyi Biomedicine, Novartis and Roche. J.M.R. has received honoraria and grants from Amgen, Pfizer, Incyte, Servier, Takeda and Novartis. All the other authors have no conflicts of interest to disclose.PB received research funding from the Carlos III Health Institute , Asociación Española contra el Cáncer (Ideas Semilla 2019) and a PERIS 2018-2020 grant from the Generalitat de Catalunya (BDNS357800). J.M.R. has received grants from Asociacion Española contra el Cáncer (GC16173697BIGA) and HARMONY Alliance .


Positive attitudes, perceived subjective norm, and perceived behavioral control were associated with higher parental acceptability in both rounds of surveys . A negative association of negative attitudes with parental acceptability was observed in the second round (p = 0.02). No significant associations of exposure to information related to COVID-19 vaccination on social media with parental acceptability was found in either round of survey. Expanding the existing COVID-19 vaccination programs to cover children aged 6–35 months is necessary in China. Future programs should focus on modifying perceptions among parents to promote COVID-19 vaccination for children in this age group.China is considering to offer COVID-19 vaccination for children aged 6–35 months. This study investigated the changes in COVID-19 vaccine acceptability and associated factors among parents with children aged 6–35 months in 2020 and 2021. Two rounds of cross-sectional online surveys were conducted among adult factory workers in Shenzhen, China. A subset of 208 (first round) and 229 (second round) parents with at least one child aged 6–35 months was included in the study. Parental acceptability of COVID-19 vaccination increased significantly from 66.8% in the first round to 79.5% in the second round ( Coronavirus diseases 2019 (COVID-19) is one of the major challenges in the 21st century ,4, but aCOVID-19 vaccination is highly effective in preventing COVID-19 and its equality should be guaranteed in populations and communities at risk of infection ,13,14. VSufficient vaccination coverage is conditioned by the people’s acceptance of these vaccines. However, providing children with COVID-19 vaccination is challenging due to low parental acceptability, especially for those of younger age . StudiesThe objectives of this study included: (1) to investigate the changes in parental acceptability of COVID-19 vaccination for children aged 6–35 months in 2020 and 2021 among factory workers in Shenzhen, China, and (2) to investigate factors associated with parental acceptability of COVID-19 vaccination at each time point. In the first round of survey, COVID-19 vaccination was not yet available in China. In the second round of survey, COVID-19 vaccination was available for children aged three years or above but was not yet available for children under three years. We hypothesized that parental vaccine acceptability would increase over time, and associated factors would differ at these two-time points.Two rounds of cross-sectional online surveys were conducted to explore COVID-19 vaccine acceptability among adult factory workers in Shenzhen Municipality, China from 1 to 7 September 2020 and 26 to 31 October 2021, respectively ,43,44. TFull-time factory workers aged 18 years or above in Shenzhen Municipality were recruited in the two rounds of surveys. We extracted data of participants having children aged 6–35 months for this study. Details of data collection have been described previously ,43,44. FA common encrypted online survey platform, Questionnaire Star, was used to collect information. Quick response (QR) codes were provided to access the online questionnaire and each mobile device was only allowed once for the questionnaire response to avoid duplication. The survey included about 20 items and took around 20 min to complete. A completeness check was performed before participants submitted their questionnaires. An e-coupon with 10 RMB (1.5 USD) was sent to participants once completion. All data was stored on the online survey platform server, and only the corresponding author had access to the database. Longhua District CDC provided the ethics approval (references 2020001 and 2021015).A panel, including one member of CDC staff, two public health researchers, a health psychologist, and a factory worker, developed the questionnaire. A pilot test was conducted to assess the clarity and readability among 10 factory workers, who did not participate in the actual survey. The questionnaire was revised and finalized based on the workers’ comments.Demographic information, including age, sex, relationship status, education, monthly personal income, type of work, and age of the child were collected. Compliance with personal preventive behaviors was estimated using validated tools ,47,48, iVaccine acceptability in both rounds of surveys was assessed by asking, “What is your likelihood of having your child take up free COVID-19 vaccination provided by the government?” . Parental acceptability was defined as “very likely” or “likely” in both rounds. The same definition of parental acceptability was used in other published studies ,49.In both rounds, parents who had not received COVID-19 vaccination were asked about their likelihood to take up such vaccination in future . Unvaccinated parents who were very unlikely/unlikely/neutral to take up COVID-19 vaccination future were defined as having parental vaccine hesitancy.Items/scales on attitudes toward COVID-19 vaccination were constructed in our previous study, which was one of the first studies looking at parental attitudes toward COVID-19 vaccination. Since there was no validated questionnaires on this topic in early 2020, the items and scales were self-constructed based on those from previous studies on parental acceptability of human papillomavirus vaccination in China . PositivIn both rounds, participants were asked about the frequency of exposure to experiences related to COVID-19 vaccination on social media (such as WeChat and Weibo), shared by recipients in the last month. In the second round, four other types of information on social media were collected, including (1) the COVID-19 pandemic is not under control in some countries after scaling up COVID-19 vaccination, (2) infectiousness and harms of the variants concern of COVID-19, (3) outbreak caused by variants concern of COVID-19 in some places of China, and (4) people contract COVID-19 after receiving primary series of COVID-19 vaccines. Each item was rated from 1 = almost never, 2 = seldom, 3 = sometimes, to 4 = always.n = 200), we estimated about 60–70% of parents showed vaccine acceptability for their children in the first round. The smallest between-round difference in vaccine acceptability of 9.9% could be detected .The original study had two rounds of cross-sectional online surveys looking at COVID-19 vaccination uptake and attitudes among adult factory workers in Shenzhen, China. The target sample size was 2000 for the original study in both rounds, which has been explained in previous papers ,44. Thisp values were obtained. Using parental acceptability, attitudes toward COVID-19 vaccination, and social media influence as dependent variables, round of survey as independent variable (second versus first), and adjusting for significant background characteristics with between-group differences, adjusted p values were obtained by logistic regression models (for binary dependent variables) or linear regression models (for continuous dependent variables). Regarding the effect sizes of the between-round comparisons, Cohen’s d was calculated for continuous variables and Cohen’s h was calculated for proportions. For parents in the same round of the survey, Logistic regression models were used to assess the association of vaccine acceptability with background characteristics, attitudes toward COVID-19 vaccination, and influence of social media, giving odds ratio (ORs) and 95% confidence interval (CI). Statistical analyses were conducted using R software . All tests were two-sided with p < 0.05 as statistically significant.Differences in background characteristics, parental acceptability, attitudes toward COVID-19 vaccination and social media influence between participants in the first and second round of survey were compared using Chi-square tests  or independent-sample t-tests (for continuous variables). Unadjusted A total of 2653 and 3060 eligible factory workers were approached in the first and second rounds of surveys, 600 and 434 refused to join the study due to a lack of time or other logistical reasons, and 2053 and 2626 completed the surveys with the response rate being 77.3% and 85.8%, respectively. Among these participants, 208 and 229 with at least one child aged 6–35 months were included in the analyses.p < 0.001) and had higher education levels (p = 0.02).p = 0.01). Significant increases were also found in positive attitudes, negative attitudes, perceived subjective norm, and perceived behavioral control related to children’s COVID-19 vaccination . More parents in the second round were exposed to testimonials given by recipients of COVID-19 vaccination on social media compared to those in the first round (p < 0.001)  .In the first round, better compliance with physical distancing behaviors was associated with higher parental acceptability. In the second round, being female, and having better compliance in terms of face mask wearing in the workplace and hand hygiene were associated with higher parental acceptability. Higher education level was negatively associated with parental acceptability .p < 0.001), perceived subjective norm , and perceived behavioral control  were associated with higher parental acceptability for children in the first and second rounds, respectively. Parental hesitancy to receive COVID-19 vaccination was negatively associated with vaccine acceptability for children in the first round . In the second round, negative attitude was associated with lower parental acceptability . The association between frequency of information exposure on social media and the dependent variable was not statistically significant in either round : 1.86 and 1.99, er round . Regardier round .To our knowledge, this was the first study to monitor the changes in COVID-19 vaccine acceptability among parents with children aged 6–35 months. Factors at both individual and interpersonal levels were considered, which provided a more comprehensive understanding about the determinants of parental acceptability. The findings enriched international literature about parental acceptability of COVID-19 vaccination for children under the age of three years. The findings also had some practical implications to inform development of vaccination programs and related health promotion for this group of children. Currently, the risk of COVID-19 infection under the age of three years increased dramatically after the country changed its zero COVID policy. It was expected that the fear about COVID-19 and its consequences would be a major stressor for parents of young children [Parental acceptability of COVID-19 vaccination for children increased from 66.8% in the first round to 79.5% in the second round, possibly due to the increasing coverage of COVID-19 vaccination in adults. Most parents had already received the vaccine when the second round of survey was conducted. As of 3 December 2022, 90.7% of the entire population in China had received primary series of COVID-19 vaccine . In addiCompared to the first round, significant increases were observed in attitudes favoring COVID-19 vaccination for children, including positive attitudes, perceived subjective norm, and perceived behavioral control in the second round. The health promotion conducted by governments, availability of COVID-19 vaccine for children aged 3–17 years, and associated vaccination experiences from older children may explain the observed changes. Positive attitudes were associated with higher parental COVID-19 vaccine acceptability for children, which was consistent with previous studies ,31,33,41Some non-significant findings also provided insights for planning future interventions. In contrast to our hypothesis, exposure to information related to COVID-19 vaccination on social media was not a significant determinant of parental acceptability in either round of survey. Therefore, future programs promoting COVID-19 vaccination among children aged 6–35 months should focus on modifying perceptions among parents.Our study had several limitations. First, our findings are most applicable to the time when zero COVID policy was implemented in China. When China started to relieve its strict COVID-19 control measures in December 2022, the number of new cases increased dramatically. Parents may perceive a much stronger need to vaccinate their children against COVID-19. Second, participants referred to the child whose birthday was closest to the survey date when answering questions related to parental acceptability if they had more than one child under the age of 18 years. Therefore, we did not collect information about their other children’s COVID-19 vaccination status. Other children’s vaccination status may represent an important determinant of parental acceptability for their younger children. Third, the history of COVID-19 infection was not collected in our surveys, and an Italian study showed that parents with children previously experiencing COVID-19 were more likely to support the vaccination . HoweverThis study compared parental COVID-19 vaccination acceptability for children aged 6–35 months in 2020 and 2021 among factory workers in Shenzhen, which is one of four most developed cities in China. The prevalence of parental acceptability was relatively high and had been increasing over time. Expanding the existing COVID-19 vaccination programs to cover this age group of young children is necessary in China. Future programs promoting COVID-19 vaccination for children in this age group should focus on modifying perceptions among parents, such as increasing positive attitudes, perceived subjective and perceived behavioral control, and reducing negative attitudes related to children’s vaccination.


Cardiovascular events are common in COVID-19. While the use of anticoagulation during hospitalization has been established in current guidelines, recommendations regarding antithrombotic therapy in the post-discharge period are conflicting.n = 1,002) or dipyridamole (n = 304), or, no post-discharge antithrombotic treatment . All-cause mortality, as well as cardiovascular mortality (CVM) and further cardiovascular outcomes (CVO) resulting in hospitalization due to pulmonary embolism (PE), myocardial infarction (MI) and stroke were investigated during the follow-up period.To investigate this issue, we conducted a retrospective follow-up (393 ± 87 days) of 1,746 consecutive patients, hospitalized with and surviving COVID-19 pneumonia at a single tertiary medical center between April and December 2020. Survivors received either 30-day post-discharge antithrombotic treatment regime using prophylactic direct oral anticoagulation  and dipyridamole . This effect was also evident for both therapies after propensity score analyses using weighted binary logistic regression . While both treatment groups displayed a reduced rate of CVM , the effect in the DOAC group was driven by reduction of both PE  and stroke . Dipyridamole significantly reduced rates of PE alone .While no major bleeding events occured during follow-up in the treatment groups, Ctrl showed a high but evenly distributed rate all-cause mortality. All-cause mortality (CVM) was attenuated by prophylactic DOAC (0.6%, Late cardiovascular events and all-cause mortality were high in the year following hospitalization for COVID-19. Application of prophylactic DOAC or dipyridamole in the early post-discharge period improved mid- and long-term CVO and all-cause mortality in COVID-19 survivors. Cardiovascular events including thromboembolisms due to coagulopathy represent frequent and serious complications in COVID-19 patients. Accordingly, high rates of stroke, pulmonary embolism and venous thromboembolisms have been reported in the context of COVID-19 disease. These events seem primarily driven by the profound inflammatory response, along with endothelial inflammation and dysfunction  which caIn hospitalized patients, no beneficial effects of therapeutic anticoagulation was observed in critically ill COVID-19 , 9, whilIn mid-2020, dipyridamole or prophylactic direct anticoagulation (DOAC) were routinely prescribed in the early post-discharge period (30-days post-discharge) in several medical centers based on experts' recommendations. This approach was subsequently adopted in a nationwide class C guideline recommendation for prophylactic DOAC in September 2020 . The useThe study was performed in accordance with the standards of good clinical practice and the principles of the Declaration of Helsinki, receiving approval by the ethics commission of the Bashkir State Medical University .For this single-center, retrospective study, 2,294 COVID-19 survivors were consecutively screened at discharge following hospitalization for COVID-19 disease at a tertiary medical center  between April 2020 and December 2020 for moderate COVID-19 associated pneumonia, defined according to current WHO recommendations .All included patients were 18 years or older and suffered from moderate COVID-19-related pneumonia requiring hospitalization. Exclusion criteria were defined as: requirement for therapeutic anticoagulation using Vitamin K antagonists or therapeutic DOAC therapy before or/and after enrollment, history of relevant thrombotic disorders requiring anticoagulation therapy. Furthermore, with respect to potential bleeding complication, according to our hospital standard of clinical care procedures, patients with requirement for combination therapy of DOAC and/or dipyridamole and/or any other additional antiplatelet therapies including acetylsalicylic acid, ticagrelor, prasugrel or clopidogrel were not considered for the investigated post-discharge antithrombotic regimes. Consequently, to avoid any bias, which might be associated with the described patients' selection, patients in Ctrl treated with antiplatelet medications including acetylsalicylic acid, ticagrelor, prasugrel or clopidogrel were also excluded from further analyses. In addition, to account for disease severity and associated potential thrombotic risk, patients requiring mechanical ventilation during their hospitalization were also excluded from further analyses .Based on the primary inclusion and exclusion criteria, 2,073 qualifying COVID-19 patients were further stratified based upon the recommended anticoagulation post-discharge regime: anticoagulation using dipyridamole 75 mg TID or prophylactic DOAC (DOAC) for 30-days post hospital discharge  or a no anticoagulation therapy group as the control group . Choice n = 327). Follow-up outcomes in the remaining 1,002 patients with confirmed prophylactic Direct Oral Anticoagualtion (DOAC) intake and 304 patients with confirmed dipyridamole therapy intake was propensity-matched to the control group, in whom no anticoagulation regime was prescribed at hospital discharge (At the time point of data collection (after October 1st 2021), all patients with confirmed recommendation for post-discharge anticoagulation were further contacted by phone. A standardized telephone interview was performed to verify the applied antithrombotic substance use and to confirm compliance to the DOAC or dipyridamole regime in the post-discharge setting . If a patient was deceased by the time of scheduled contact, a standardized telephone interview was performed with a close relative. Patients were excluded from further analyses, if the recommended anticoagulation regime was not taken by the patient or if collection of sufficient information about the therapy regime was not possible . Distribution of continuous data was assessed visually and using the Kolmogorov-Smirnov-test, kurtosis and skew were assessed visually. Since data were not normally distributed, median ± interquartile-range (IQR) are depicted. Medians were compared by Kruskal-Wallis test, whereas categorical data was analyzed using Fisher's exact test. Survival probability is depicted using the Kaplan-Meier method, Cox proportional hazards analysis was performed to assess the association of applied therapies with mortality. To account for imbalances in baseline covariates with possible influence on outcome, standardized differences between the three groups were calculated. Covariates with statistically significant differences or standardized differences >0.25 between the groups , R Foundation for Statistical Computing, Vienna, Austria; oups see . Prior tn = 1,002) received DOAC , 7.1% apixaban  1.3% dabigatran , and 17.4% (n = 304) received dipyridamole. The control group consisted of 25.2% (n = 440) of the study population. Baseline characteristics and laboratory values at the time of enrollment are depicted in In total, 1,746 patients (100% Caucasian) were included in the final statistical analysis. As illustrated in n = 0), dipyridamole: 0% (n = 0), Ctrl.: 0.9% (n = 4), p = 0.005], 3-month all-cause mortality , 6-month all-cause mortality  and all-cause mortality at the end of follow-up  than patients treated with DOAC or dipyridamole , dipyridamole: 0.3% (n = 1), Ctrl.: 1.6% (n = 7), p = 0.014] during follow-up. A trend toward higher prevalence of pulmonary embolisms was also observed in the control group .In univariate Cox proportional hazards analysis, both treatment with DOAC or dipyridamole was associated with a reduced risk of mortality . In addition, weighted logistic regression revealed protective effects of treatment with DOAC or dipyridamole for cardiovascular mortality  as well as for pulmonary embolism . Treatment with DOAC was furthermore protective for stroke .We performed Generalized Boosted Models (GBM) using the Average Treatment Effect on Treated (ATT) estimate for propensity score weighting of groups to account for covariate imbalances between the three groups, which might affect outcome. Covariates included were those with statistically significant differences and/or standardized differences >0.25 between the groups  data capturing extended post-discharge thromboprophylaxis in COVID-19 patients, including different anticoagulatory treatment regimens.With respect to baseline characteristics, thromboembolic risk as indicated by the IMPROVE score was similar between groups. The control group however showed significantly lower rates of in-hospital corticosteroids, IL-6-inhibitors and therapeutic anticoagulation. This might be due in part to the comparably lower inflammatory burden, indicated by significantly lower baseline CRP-levels in the control group. With regards to concomitant disease, control patients were younger and had lower rates of arterial hypertension . HoweverOverall mortality in patients not receiving thromboprophylaxis was high reaching 5.9% during the total follow-up period . Thus, mWhile the treatment regime was only applied in the early phase after hospitalization, differences in relevant clinical outcomes were also observed after a longer follow-up. Therefore, it can be speculated that even after survived hospitalization, medical intervention might be crucial to minimize disease progression and improve cardiovascular outcomes as well as mortality rates. Our speculations are further supported by publications indicating an increase in the incidence of cardiovascular events even after mild COVID-19 disease  as well Despite their comparable effects on all-cause mortality and, also cardiovascular mortality, different pathophysiologic effects of DOAC and dipyridamole therapy on predefined cardiovascular events have to be considered with regards to our findings and are potentially in part reflected in our study results.in vitro  of different thromboprophylactic treatment regimens after hospitalization for COVID-19. Mortality rates were significantly reduced by both 30-day regimes of dipyridamole and prophylactic DOAC treatment, emphasizing the ongoing thromboembolic and inflammatory burden in COVID-19 in the early post-discharge period following the acute phase of the disease. Accordingly, thromboprophylactic treatment might offer beneficial effects in the long-term treatment of COVID-19 patients. Therefore, further randomized trials are necessary to investigate the effects of these regimes in COVID-19 survivors.The present study has by design its limitations, mainly due to its single-center and retrospective design as well as lack of randomization and treatment arm blinding. Among others, this could bias the results due to hospital-specific standards of patient care. The overstrained medical system amidst the pandemic may have exacerbated cardiovascular events rates and mortality leading to an overestimation of the effects of the investigated medical regimes. On the other hand, rates of cardiovascular outcomes were based on hospitalized events only. Therefore, an underestimation of events is possible. This may be further aggravated by the unwillingness of patients to be hospitalized during the pandemic. While anticoagulatory regimes in the investigated center were used as the pandemic progressed, a large number of patients enrolled in the control group were treated in the very early stage. Therefore, limited accumulated clinical experience, the implementation of novel therapy regimes and the evolution of the viral genome could have affected disease management and therefore long-term outcomes. Nevertheless, to adjust for this bias, propensity score weighting of groups was performed, which did not significantly affect our results. Furthermore, since the first novel viral variants, B.1.1.7 and B.1.351 were declared a variant of concern on December 18th, 2020, followed by P.1 on January 11th, 2021  differenThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Bashkir State Medical University . Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.This study was supported by grant of Russian Science Foundation No. 22-18-20123.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.


Pulmonary hypertension (PH) is a serious and life-threatening disease characterized by elevated mean arterial pressure and pulmonary vascular resistance. COVID-19 may exacerbate PH, as evidenced by higher mortality rates among those with PH. The objective of this study was to understand the unique burdens that the COVID-19 pandemic has placed upon families of children living with PH.Participants were recruited online through the “Families of children with pulmonary hypertension” Facebook group and asked to complete a survey about their experiences during the COVID-19 pandemic.A total of 139 parents/caregivers of children living with PH completed the online survey. Almost all (85.6%) of parents/caregivers had received the COVID-19 vaccine, though only 59.7% reported a willingness to vaccinate their child with PH against COVID-19. Over 75% of parents/caregivers felt that they practiced preventative measures  more than those in the community where they live. They also reported several hardships related to caring for their child with PH during the pandemic such as financial duress, loss of work, and affording treatment costs.These findings indicate that parents/caregivers of children at higher risk for COVID-19 complications may be more willing to act on clinical recommendations themselves as proxy for protecting those at high risk. The economic, emotional and social impacts of COVID-19 are significantly greater for high-risk individuals. Pulmonary hypertension (PH) is rare but a serious and potentially life-threatening disease characterized by an elevation in mean pulmonary artery pressure and pulmonary vascular resistance . In seveSince the onset of the coronavirus disease-19 (COVID-19) pandemic, millions of people have been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and millions have lost their lives as a result , 21. ThoThe COVID-19 pandemic has negatively influenced infants and newborns with chronic conditions (such as PH) and their parents/caregivers, especially when clinics were temporarily closed during the pandemic leaving parents/caregivers with only telehealth/telemedicine visits to monitor their child’s condition(s) , 28. BefThe goal of the current study was to understand the unique burdens that the COVID-19 pandemic has placed upon parents/caregivers of children living with PH. The focus of the study was to better understand the experiences of parents/caregivers accessing care, undertaking preventative practices against SARS-CoV-2 infection, beliefs towards COVID-19 vaccination, and disruptions such as education, doctor availability, prescription dispensing that impacted their ability to care for their child living with PH.n = 934) also received a personal invitation via the internal Facebook messaging system (Facebook Messenger). To maximize study participation and to provide each group member an opportunity to participate, we posted the invitation on the Facebook group homepage 3 times over a 5-week period during December 2021 to January 2022. Participants who clicked on the invitation link were redirected to a secure study website and provided with study information, asked to convey consent to participate, and then immediately prompted to begin the survey using the Qualtrics™ survey platform. Eligible individuals who completed the survey were compensated for their participation and emailed a $20 gift card to Amazon.com®. The study protocol was approved by the Institutional Review Board at Brigham Young University (#IRB2021–371).Participants were recruited online via Facebook™ invitations posted on the “Families of children with pulmonary hypertension” Facebook page. A random sample of group members , many of whom routinely (daily) interact with others to learn more about existing PH therapies, to cope, and to share experiences of caring for a child with PH.strongly disagree/never) to 5 . In addition, we assessed specific familial hardships due to the COVID-19 pandemic including job loss (yes/no), loss of financial stability (yes/no), financial aid receipt to offset PH therapy costs (yes/no), and difficulty covering PH treatment costs (yes/no). Finally, we queried family sociodemographics including race (white/other), relationship to child living with PH , U.S. citizenship (yes/no), respondents’ educational attainment , employment status , household income , health insurance status (yes/no). The average survey completion time was 19.5 minutes (range: 8 to 56 minutes).We developed a questionnaire containing questions intended to be answered by the parent of a child living with PH. The survey assessed participants’ knowledge, attitudes, perceptions, and burdens related to COVID-19 and caring for a child living with PH. Survey questions related to COVID-19 threat appraisal, vulnerability and anxiety were adapted from published studies for our study population , 29–31. We calculated the frequency of actions undertaken by parents/caregivers and their child living with PH to prevent SARS-CoV-2 infection, reasons for not taking actions to prevent SARS-CoV-2 infection, attitudes and perceptions regarding COVID-19 vaccination for themselves and their child living with PH, sources from which parents/caregivers would seek COVID-19-related news and information, and financial, medical, and other impacts  imposed by the COVID-19 pandemic. We report the counts and frequencies (percentages) of each of the aforementioned actions. Statistical analysis was conducted in R version 4.1.0 .Characteristics of the 139 parents/caregivers of children living with PH who responded to the online survey are presented in Table Parents/caregivers engaged in a variety of preventative practices to prevent infection with SARS-CoV-2 see Fig. . For exaParents/caregivers reported several financial hardships related to caring for their child with PH during the COVID-19 pandemic  . This fiParents/caregivers of children living with PH were also engaged in several recommended prevention practices and at higher rates than most adults in the U.S. , 42. In The large majority (71.9%) of parents/caregivers of children living with PH reported that the quality of their child’s education has decreased due to the COVID-19 pandemic. This educational deficit is not unique to children living with PH, though this may further isolate children with PH as they are at greater risk of serious complications from SARS-CoV-2 infection. For example, since many children with PH are not able to participate in common childhood activities  and now must maintain social distance, they may experience disproportionate social development and educational setbacks . Apart fThis study has some limitations. First, parents/caregivers were recruited from an online Facebook group and are a convenience sample  of all parents/caregivers of children living with PH. However, this is also a strength as this is the largest group worldwide of individuals with children living with PH. Second, survey responses were self-reported by parents/caregivers over the Internet and may be subject to under or overreporting. However, other Internet-based studies have shown increased self-disclosure and reporting with online surveys, which may reduce potential response biases  , 53. FinThis study enhances our understanding of how parents/caregivers of children living with PH have responded to the COVID-19 pandemic, including preventative practices and vaccination uptake. The results demonstrate how parents/caregivers may respond differently to COVID-19 recommendations and practices in order to protect high-risk individuals under their care and supervision. Learning about the experience of these individuals living through the COVID-19 crisis can help empower public health and healthcare professionals to continue to protect the health of this population.


Biological sex may play a large role in cigarette use and cessation outcomes and neuroimaging studies have demonstrated that cigarette smoking is associated with sex-related differences in brain structure and function. However, less is known about sex-specific alterations in spontaneous brain activity in cigarette smokers. In this study, we investigated the sex-related effects of cigarette smoking on local spontaneous brain activity using regional homogeneity (ReHo) based on resting-state fMRI. Fifty-six smokers  and sixty-three  healthy non-smoking controls were recruited. Whole-brain voxelwise 2-way analysis of covariance of ReHo was performed to detect brain regions with sex-dependent alterations on the spontaneous brain activity. Compared to non-smokers, smokers exhibited significant ReHo differences in several brain regions, including the right medial orbitofrontal cortex extended to the ventral striatum/amygdala/parahippocampus, left precuneus, and bilateral cerebellum crus. Smoking and sex interaction analysis revealed that male smokers showed significantly lower ReHo in the right ventral striatum, left cerebellum crus1, and left fusiform gyrus compared to male non-smokers, whereas there are no significant differences between female smokers and non-smokers. Furthermore, the ReHo within the left cerebellum crus1 was negatively correlated with craving scores in male smokers but not in female smokers. Such sex-dependent differences in spontaneous brain activity lays a foundation for further understanding the neural pathophysiology of sex-specific effects of nicotine addiction and promoting more effective health management of quitting smoking. Tobacco smoking, the leading cause of preventable death worldwide, is associated with many serious health problems including cardiovascular disease and lung cancer . DespiteNeuroimaging studies showed that cigarette smoking is associated with sex-specific alterations in brain structure and function. Compared to sex-matched non-smokers, male rather than female nicotine-dependent subjects had a larger volume in the left putamen and a smaller volume in the left caudate, whereas female but not male smokers showed a smaller volume in the right amygdala . ExposurResting-state fMRI (rs-fMRI) provides a non-invasive method of assessing changes in resting-state brain activity and functional connectivity across the whole-brain . ReHo meTo test our hypothesis, we employed ReHo method to depict spontaneous brain activity and then performed a voxel-wise analysis to examine the intrinsic brain activity differences between smokers and non-smokers, and to further explore the sex interaction on smoking dependency. Such sex-dependent differences in spontaneous brain activity lays a foundation for further understanding the neural pathophysiology nicotine addiction and promoting more effective health management of quitting smoking.Sixty cigarette smokers  and 67 healthy nonsmoking controls  aged 18–29 years participated in this study. The Mini International Neuropsychiatric Interview was used to exclude participants who had substance use disorder other than nicotine dependence, current Axis 1 DSM V psychiatric diagnoses, or significant medical conditions. Exclusion criteria for both smokers and non-smokers were a history of head trauma or injury causing loss of consciousness lasting >3 min or associated with skull fracture or intracranial bleeding, or had irremovable magnetically active objects on or within their body. Smokers were defined as those who smoked at least 10 cigarettes/day on any given day during the last year. The severity of nicotine addiction was determined from the Fagerström Test for Nicotine Dependence (FTND) , and theThe current study adhered to the Declaration of Helsinki and was approved by the Research Ethics Committee of Renji Hospital, School of Medicine of Shanghai Jiaotong University. All participants were informed of the measurements and the experimental procedures of the study before their MRI examinations. Each participant provided written informed consent.Images were obtained using a 3.0-T GE Signa HDx  scanner with a standard 8-channel head coil. Restraining foam pads were used to reduce head motion, and earplugs were used to reduce scanner noise. Before MRI scanning, all subjects were instructed to relax with their eyes closed while refraining from falling asleep and without engaging in any directed, systematic thought. The physiological state of the smokers when they were in the scanner as spontaneous, rather than abstinence or satiety, that was, none of the smokers felt the acute urge to smoke or experience any withdrawal symptoms confirmed by a self-report completed by each participant immediately after the scan.2, thickness = 4 mm with no gap, 34 slices). For each participant, the rs-fMRI scan lasted 7 min and 20 s and a total of 220 volumes were acquired. The axial T1-weighted and T2-weighted images were also performed to confirm the absence of structural lesions. All images were evaluated by two experienced neuroradiologists and no participants were excluded on this basis.Rs-fMRI data were acquired using a gradient-echo echo-planar imaging sequence . After removing the first 10 volumes for each subject, the remaining 210 volumes were corrected for slice timing and realigned to the first volume for head-motion correction. The Friston 24-parameter model  was performed to regress out the head motion effects. The scrubbing strategy was further carried out to correct the head motion effects. Time points with framewise displacement larger than 0.2 mm were identified and removed along with 1 back and 2 forward neighbors (p = 0.17). Afterward, the functional images were normalized to the standard Montreal Neurological Institute (MNI) space and resampled to a 3-mm isotropic voxel. Then, linear and quadratic trends as well as white matter and corticospinal fluid signals were removed. Finally, temporal bandpass filtering (0.01–0.1 Hz) was performed to reduce the effects of high-frequency physiological noise.Rs-fMRI data were preprocessed using the Data Processing Assistant for Resting-State fMRI  on ReHo. We extracted the averaged ReHo from significant clusters showing group effects, and then performed the 1-way ANCOVA controlling for age and education level to determine the specific smoking effects on ReHo. When the group-by-sex interaction effects occurred, the sex-specific effects of smoking on ReHo were investigated. The mean ReHo values from clusters showing group-by-sex interaction effects were extracted, and then the 1-way ANCOVAs controlling for age and education level were conducted to compare male smokers vs. male non-smokers and female smokers vs. female non-smokers separately.A 2-way analysis of variance (ANOVA) was used to identify differences among groups in age, education level, SAS, SDS and BIS scores. A voxelwise 2-way analysis of covariance (ANCOVA) with age and education level as covariates was performed to evaluate the main effects of group (smokers vs. non-smokers) and sex  as well as the interaction between group and sex. A false discovery rate (FDR) corrected p-value of < 0.05 was considered significant.For smokers, Pearson correlation analysis was performed to investigate whether there were correlations between the altered ReHo and the smoking-related variables . A p = 0.77) or group by sex interaction (p = 0.83) were found, while there was a significant main effect of sex (p = 0.002). For years of education, significant main effect of group (p < 0.001) and group by sex interaction (p < 0.001) were revealed, while there was no main effect of sex (p = 0.35). Specifically, male smokers had higher education level than female smokers (p = 0.006), while male non-smokers had lower education level than female non-smokers (p = 0.005).p = 0.09), FTND (p = 0.42) or craving scores (p = 0.88) between male and female smokers, while male smokers had an earlier age at first smoking (p < 0.001) than female smokers. Smokers as a whole had higher scores than non-smokers on SAS (p < 0.001), SDS (p < 0.001) and BIS (p = 0.003), which is consistent with prior studies showing that smoking has often been associated with increased depression, anxiety and impulsivity (p = 0.07), SDS (p = 0.03) and BIS (p = 0.003) than men. Although the SAS, SDS and BIS scores of smokers were higher than those of non-smokers, they did not meet the criteria for comorbid mood or attention disorders.There were no significant differences in duration of smoking , whereas there was no significant correlation between the ReHo and the craving scores in female smokers  (p = 0.03).We also found that the lower ReHo in the left cerebellum crus1 exhibited higher craving scores in male smokers (= 0.608) . The ReHIn this study, we investigated sex-specific differences in local spontaneous brain activity between smokers and healthy non-smoking subjects using rs-fMRI and ReHo analysis. Our findings demonstrated that both male and female smokers showed higher ReHo in the left precuneus compared to sex-matched non-smokers while only male smokers had greater ReHo value in the cerebellum crus 1/2. However, male smokers had lower ReHo in the right medial OFC extending to the ventral staiatum/amygdala/parahippocampal gyrus, right lateral OFC, left cerebellum crus 1 extending to the inferior temporal gyrus, and left fusiform gyrus. Moreover, the ReHo in the left cerebellum crus1 was negatively correlated with craving scores in male smokers but not in female smokers. Taken together, these findings suggest that cigarette smoking may have differential effects on the spontaneous brain activity between men and women, especially in regions that are associated with reward and motivation functions, which are known to be affected by nicotine dependence.One of the main results of this study using smoking by sex interaction, was found to reduce ReHo in several regions, such as the right ventral striatum/putamen, left fusiform gyrus, and left cerebellum crus 1 extending to the inferior temporal gyrus . The venr = −0.402; p = 0.022) in male smokers. This may be explained by the significant differences in smoking duration , and the complex mechanisms of chronic smoking, such as early dysfunction and late compensation Interestingly, female smokers did not show the same pattern of brain activity as male smokers. This finding may be partially explained by circulations in the menstrual cycle phase that modulates the reward-related regions in females  and the Frontier Scientific Significant Breakthrough Project of CAS (Grant No. QYZDB-SSW-SLH046), the Shanghai Science and Technology Committee Project , and the Explorer Project in Shanghai (Grant No. 21TS1400700).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.


It is unclear if the impact of frailty on mortality differs between patients with viral pneumonitis due to COVID-19 or other causes. We aimed to determine if a difference exists between patients with and without COVID-19 pneumonitis.This multicentre, retrospective, cohort study using the Australian and New Zealand Intensive Care Society Adult Patient Database included patients aged ≥ 16 years admitted to 153 ICUs between 01/012020 and 12/31/2021 with admission diagnostic codes for viral pneumonia or acute respiratory distress syndrome, and Clinical Frailty Scale (CFS). The primary outcome was hospital mortality.p < 0.001) and less frail  than non-COVID-19 patients. The overall hospital mortality was similar between the patients with and without COVID-19 . Frailty alone as a predictor of mortality showed only moderate discrimination in differentiating survivors from those who died but was similar between patients with and without COVID-19 . Increasing frailty scores were associated with hospital mortality, after adjusting for Australian and New Zealand Risk of Death score and sex. However, the effect of frailty was similar in patients with and without COVID-19 .A total of 4620 patients were studied, and 3077 (66.6%) had COVID-19. The patients with COVID-19 were younger (median [IQR] 57.0 [44.7–68.3] vs. 66.1 [52.0–76.2]; The presence of frailty was an independent risk factor for mortality. However, the impact of frailty on outcomes was similar in COVID-19 patients compared to other causes of viral pneumonitis.The online version contains supplementary material available at 10.1186/s13054-022-04177-9. The coronavirus disease 2019 (COVID-19) pandemic has had a devastating global impact. The clinical spectrum ranges widely from asymptomatic to severe respiratory failure, multiorgan failure, and death , and thaHealthcare in many parts of the world has been severely strained due to insufficient intensive care unit (ICU) beds and workforce capacity . This prPre-pandemic, patients with frailty were also common among patients admitted to ICU. These patients had more than double the risk of death and functional dependence than patients without frailty –21. A stThis was a retrospective multicentre cohort study, which analysed ICU admissions reported to the Australian and New Zealand Intensive Care Society (ANZICS) Adult Patient Database (APD) between 1 January 2020 and 31 December 2021.The ANZICS-APD is a binational database that prospectively collects high-quality de-identified patient information, including demographics (such as age and sex), chronic health status, physiological and biochemical variables within the first 24 h of admission required for the Acute Physiology and Chronic Health Evaluation (APACHE)-III-j and IV illness severity scores and Australian and New Zealand Risk of Death (ANZROD), as well as ICU and hospital outcomes. Each patient is allocated a single diagnosis which reflects the primary cause of admission to ICU using the ANZICS modification of the APACHE-IV diagnosis coding system .Adult patients (age ≥ 16 years), with a documented CFS score, admitted to Australian and New Zealand ICUs with an ICU admission diagnosis of Viral Pneumonia or Acute Respiratory Distress Syndrome (ARDS) were included. Patients were further classified using a subcode of “suspected or confirmed pandemic infection” to indicate which were highly likely to have COVID-19  CFS, ICU organ supports , treatment limitation order, the incidence of delirium (developed during the current ICU admission), ICU and hospital mortality, and respective length of stays. Treatment limitation was defined as that medical treatment would be constrained by either patient wishes or medical futility but does not necessarily imply that the patient was expected to die during this ICU admission.Data included patient demographics , obesity status  or frail  . TerminaThe exposure variable was frailty status based on CFS categories in patients with and without COVID-19. The confounding variables were illness severity (measured with ANZROD), and sex.We aimed to investigate whether the impact of frailty on mortality differed between patients with COVID-19 pneumonia and other aetiologies of viral pneumonia. The primary outcome was hospital mortality. Secondary outcomes included ICU mortality, ICU, and hospital length of stays and discharge destination.Predefined subgroup analyses based on biological sex, age (≥ 65 years), and those needing mechanical ventilation were performed.t tests for normally distributed data, and Mann–Whitney U or Kruskal–Wallis tests for nonparametric data depending on the number of categories examined. Data are reported as frequencies (%), means (standard deviations [SD]), or medians (interquartile range [IQR] 25–75%), respectively. Illness severity was determined using ANZROD, a highly discriminatory, locally derived, and well-calibrated mortality prediction model used for benchmarking ICU performance in Australia and New Zealand which combines age, chronic illnesses, acute physiological disturbance, and diagnosis [p value of < 0.05 was used to indicate statistical significance.The group comparisons between patients with and without COVID-19 were made using chi-square tests for proportions, student iagnosis , 35. Theiagnosis . SensitiDuring the study period, a total of 5735 patients were admitted to 153 Australian and New Zealand ICUs with admission diagnoses of either viral pneumonia or ARDS that were reported to the ANZICS-APD. Of these, 4620 patients had a documented CFS and were included in the study. There were no differences in age, sex, the proportion of treatment limitations, or hospitalization prior to ICU or pre-ICU hours between the 4620 patients and 1115 patients without a documented CFS. However, a lower proportion of those with missing frailty data had COVID-19 and these patients had higher illness severity scores  and less frail , than patients without COVID-19. A higher proportion of patients with COVID-19 were male . Patients with COVID-19 had lower APACHE-III scores and less frequently had chronic comorbidities such as respiratory, cardiovascular, renal, liver, immunosuppressive conditions, and metastatic cancer, but were more likely to be obese and have delirium, than patients without COVID-19. Admissions to ICU following a rapid response team review were less frequent for patients with COVID-19 . More patients with COVID-19 were receipt of mechanical ventilation, tracheostomies, ECMO therapies, and vasoactive agents, whereas fewer patients were receipt of non-invasive ventilation or renal replacement therapy than patients without COVID-19 . Higher hospital mortality was observed in COVID-19 patients compared to those without COVID-19 at equivalent frailty levels  and CFS-4 , compared to patients without COVID-19  for CFS categories, than those without COVID-19 (p = 0.91). The ICU readmissions were lower in patients with COVID-19 for CFS categories CFS-1–3, CFS-4, and CFS-6, than in those without COVID-19 (p < 0.001). Overall, the patients with COVID-19 were less likely to be discharged home or to a nursing home, when compared to patients without COVID-19 (both p < 0.001) respectively.The unadjusted ICU mortality rates were higher only for non-frail patients with COVID-19 for CFS categories CFS-1–3 . Although the increasing frailty scores were associated with mortality, after adjusting for ANZROD, the effect of frailty was similar in both groups . A higher proportion of male patients had COVID-29 . In patients aged ≥ 65 years, although the increasing frailty scores were associated with mortality, after adjusting for ANZROD and sex, the effect of frailty was similar in patients with and without COVID-19 . Their median age was similar between the 2 groups . Although the increasing frailty scores were associated with mortality, after adjusting for ANZROD and sex, the effect of frailty was similar in patients with and without COVID-19  were mechanically ventilated. Although more patients with COVID-19 received mechanical ventilation overall,  had COVID-19 . Despite the increasing frailty scores were associated with mortality, after adjusting for ANZROD and sex, the effect of frailty was similar in both groups  admitted, 38.1% (5.2% admin = 2942) were patients with COVID-19 . Although the increasing frailty scores were associated with mortality, after adjusting for ANZROD and sex, the effect of frailty was similar in patients with and without COVID-19  admitted, 85.1% n = 942 were This multicentre retrospective observational study that compared viral pneumonia patients with and without COVID-19 admitted to ICU in Australia and New Zealand revealed that: firstly, the mortality increased with increasing frailty, but the impact of frailty was similar in patients with and without COVID-19 pneumonitis. Secondly, patients with COVID-19 were less frail and younger than patients without COVID-19. Thirdly, the CFS independently predicted hospital mortality in both patients with and without COVID-19 pneumonitis but had a low discriminatory capacity. Fourthly, only one in ten patients with frailty with COVID-19 received mechanical ventilation. Finally, the mortality was higher in patients ≥ 65 years of age and those requiring mechanical ventilation, especially with increasing frailty.There were few studies that compared outcomes of COVID-19 with influenza patients. These studies showed the overall hospital mortality; the need for ICU admission and mechanical ventilation was substantially higher in patients with COVID-19 –39. HoweOur key study finding was that although the risk of death increased with frailty, the impact of frailty on hospital mortality was comparable between patients with and without COVID-19 pneumonitis. It is important to note that the Australian experience of the COVID-19 pandemic has differed from that internationally . Our morIt is well established that higher degrees of frailty have been associated with poor outcomes and higher mortality rates during and after ICU admission , 43. SimPatients with frailty were associated with lower use of mechanical ventilation , 44. A rAustralia and New Zealand’s healthcare system was not as overwhelmed as other parts of the world in 2020. However, the impact was much greater in 2021. At the peak in October, 55% of all public ICU beds in Victoria and almost 40% of all public ICU beds in New South Wales were occupied by patients with COVID-19 . This caThe inclusion period of 2 years encompassed patients from several different waves that also witnessed changes in treatment and the introduction of vaccinations. The rates of COVID-19 vaccine administration steadily increased since the rollout in February 2021. The vaccinations were initially prioritized in Victoria and New South Wales, which had the highest case numbers. At the end of the study period, > 90% of all eligible people had received the first dose Australia wide and > 84% received their second dose . FurtherOur study found that frailty independently predicted mortality in both patients with and without COVID-19 pneumonitis, but the impact of frailty was similar in patients with and without COVID-19 pneumonitis. This implies that, regardless of COVID-19 status, the patients’ care was no different. This may at least in part reflect that Australia and New Zealand have evaded the magnitude of the pandemic that has overwhelmed healthcare systems in many parts of the world. Moreover, the intensive care resource availability is owing to stringent public health measures in Australia and New Zealand. Our study has demonstrated that more patients with COVID-19 admitted to ICU had CFS scores between 1 and 3. It is possible that the intensive care teams were more selective in admitting frail patients with COVID-19 into their ICUs.Our study has several notable strengths. Firstly, the multicentre design, incorporating high-quality data Australia and New Zealand wide, as well as a larger sample size than many other studies. Secondly, the CFS, which is the most used frailty assessment tool for critically ill patients. Thirdly, we incorporated pre-specified several secondary analyses, to assess the impact of frailty on several important patient-centred ICU outcomes. To our knowledge, this is the only study to compare the impact of frailty among patients with and without COVID-19 pneumonitis. There are a few limitations to this study. Firstly, the retrospective study design meant that data collection was reliant on existing datasets and medical records. Secondly, despite the ANZICS-APD being recognized as a high-quality clinical registry dataset, the effect of data coding inaccuracy on the study findings could not be assessed. Thirdly, in the absence of having linkage to infection notification data and without site-based auditing of diagnostic coding over the pandemic, we cannot be certain about the degree of misclassification, if any. Fourthly, the CFS was adopted in the assessment of frailty in ICUs across Australia and New Zealand. Despite being an attractive tool to distinguish the different grades of frailty, the reliability of a single assessment tool may be inadequate, especially when it comes to justifying the rationing of medical treatment. Fifthly, the patients with COVID-19 admitted to the ICUs with an alternate diagnosis could have been missed. Sixthly, we do not have any information regarding the number of patients that were referred for ICU admission and denied ICU admission, or the COVID-19 pandemic may have led to an increased presentation of COVID-19 to the ICUs, while non-COVID-19 patients had a transient reduction in hospital presentations as well as ICU admissions. Seventhly, although some evidence suggests that CFS is a major determinant of long-term mortality in patients with COVID-19, we only reported on hospital mortality, as the ANZICS-APD only captured hospital-based outcomes. Finally, the Australia and New Zealand healthcare system has been very fortunate with the magnitude of COVID-19 infections being largely under control, and therefore, the results may not be generalizable in resource-constrained healthcare systems.This multicentre retrospective study that compared viral pneumonitis in patients with and without COVID-19 admitted to ICU in Australia and New Zealand found that patients with COVID-19 were younger and less frail than patients without COVID-19. The frailty independently predicted hospital mortality in both patients with and without COVID-19 pneumonitis but had low discriminatory capacity. The impact of frailty, however, was no different in patients with and without COVID-19.Additional file 1: Figure S1 ICU Supports among patients with COVID-19 (red lines) with patients without COVID-19 (black lines), based on CFS score. Standard error bars are 95%-CI. Figure S2 Age comparison based on CFS categories. The CFS categories are denoted by the different stacked colours starting with CFS 1–3 at the bottom up to CFS 7–8 at the top. Figure S3 ICU bed days stratified by Clinical Frailty Scale (CFS) categories for patients with and without COVID-19. The bottom panels demonstrate the median length of stay among ICU survivors and non-survivors. Figure S4 Hospital mortality according to Clinical Frailty Scale (CFS) categories for patients with (red) and without (black) COVID-19 for patients admitted in 2020 (a) and 2021 (b). The top panel is unadjusted hospital mortality, while the bottom panel is adjusted for ANZROD and sex.Additional file 2: Table S1 Diagnostic codes and subcodes for patients included in the study between 1st January 2020 and 31st December 2021. Table S2 Missing data comparison for patients with and without the CFS scores. Table S3a CFS-1–3, CFS-4, and CFS-5 for patients with COVID-19 admitted to ICU with an admission diagnosis of viral pneumonia or ARDS. Table S3b CFS-6 and CFS-7–8 for patients with COVID-19 admitted to ICU with an admission diagnosis of viral pneumonia or ARDS. Table S4 Comparison of unadjusted outcomes. Standard error bars are 95%-CI. Table S5 Exposure and raw outcomes for male patients . Table S6 Exposure and raw outcomes for female patients . Table S7 Exposure and raw outcomes for patients ≥ 65 years . Table S8 Exposure and raw outcomes in patients needing mechanical ventilation . Table S9 Exposure and raw outcomes for patients who were cared for in the year 2020 . Table S10 Exposure and raw outcomes for patients who were cared for in the year 2021 . Table S11 Predictors for hospital mortality with the Clinical Frailty Scale (CFS) categories, adjusted for ANZROD and sex.


Results: The study enrolled 101 patients, 36.6% of whom were female, with a median age of 74 years (30–92), and a median length of stay of 14.5 days in intensive care. A significant difference was observed in the estimation of GFR when comparing formulas based on SCrand CysC, resulting in large differences in the prediction of CKD. Three months after the AKI event, eGFRCysC < 25 mL/min/1.73 m2 was a predictive factor of mortality later on; however, this was not the case for eGFRSCr. Conclusion: The incidence of CKD was highly discrepant with eGFRCysC versus eGFRSCr during the follow-up period. CysC detects more CKD events compared to SCr in the follow-up phase and eGFRCysC is a predictor for mortality in follow-up but not eGFRSCr. Determining the proper marker to estimate GFR in the post-ICU period in AKI stage-3 populations needs further study to improve risk stratification.Background: Acute kidney injury (AKI) in critically ill patients is associated with a significant increase in mortality as well as long-term renal dysfunction and chronic kidney disease (CKD). Serum creatinine (SCr), the most widely used biomarker to evaluate kidney function, does not always accurately predict the glomerular filtration rate (GFR), since it is affected by some non-GFR determinants such as muscle mass and recent meat ingestion. Researchers and clinicians have gained interest in cystatin C (CysC), another biomarker of kidney function. The study objective was to compare GFR estimation using SCr and CysC in detecting CKD over a 1-year follow-up after an AKI stage-3 event in the ICU, as well as to analyze the association between eGFR (using SCr and CysC) and mortality after the AKI event. Method: This prospective observational study used the medical records of ICU patients diagnosed with AKI stage 3. SCr and CysC were measured twice during the ICU stay and four times following diagnosis of AKI. The eGFR was calculated using the EKFC equation for SCr and FAS equation for CysC in order to check the prevalence of CKD (defined as eGFR < 60 mL/min/1.73 m Acute kidney injury (AKI) is a common clinical syndrome characterized by a rapid decline in kidney function ,2,3,4. TCurrently, serum creatinine (SCr) is the most widely used biomarker to estimate glomerular filtration rate (GFR), which is the best overall index of kidney function . NeverthIn addition to SCr, cystatin C (CysC) is another biomarker of kidney function which has attracted the attention of researchers and clinicians in recent years. Even though CysC can also be affected by non-GFR determinants, the non-GFR determinants that affect CysC are distinct from those that affect SCr. Smoking status and serum C-reactive protein level are, for instance, independently associated with serum CysC levels . While SPredicting CKD following AKI is a highly important yet missing topic in the AKI research field. The earlier CKD is diagnosed after AKI, the less intensive utilization of resources and the better the prevention of morbidity and mortality . DelanayIn this study, we investigated whether the eGFR based on CysC differed from the eGFR based on SCr during the ICU stay and the follow-up period in adult ICU patients who had experienced an AKI stage-3 event. Additionally, we examined whether the eGFR determined by using the CysC-based FAS equation would further improve the correlation between eGFR and CKD diagnosis, as well as adjusted risks of death in the follow-up, compared to the use of an SCr-based eGFR. We hypothesized that CysC might provide additional benefits in post-ICU and be better-related to the outcomes , considering the inherent risk of muscle wasting that affects SCr.This study is a prospective observational study where we used medical records of ICU patients aged > 18 years who were diagnosed with AKI stage 3 during their ICU stay in AZ Groeninge Hospital in Kortrijk, Belgium, between September 2018, and October 2020.2 estimated by CKD-EPI [Exclusion criteria were patients with a baseline eGFR < 30 mL/min/1.73 m CKD-EPI , patientKDIGO criteria for AKI stage 3 have been used for the inclusion of patients based on SCr or urine output (UO). KDIGO defines stage 3 as an increase in SCr up to 3 times from baseline within a 7-day period or UO < 0.3 mL/kg/h for ≥24 h . In thisAll SCr measurements were performed with an Enzymatic method that is traceable to the isotope dilution mass spectrometric method (IDMS), which is the internationally approved reference method for measuring creatinine. In addition, CysC concentrations were measured by Liège University Hospital using a particle-enhanced nephelometric immunoassay on the BNII nephelometer . The assay was calibrated against the international certified reference material ERM-DA471/IFCC for CysC.SCr) was calculated according to the EKFC equation introduced by Pottel et al. in 2021 [The SCr-based estimated glomerular filtration rate (eGFR in 2021 :(1)EKFC−The EKFC equation is based on normalized SCr (CysC) was calculated according to the full age spectrum (FAS) equation introduced by Pottel et al. in 2017 [The CysC-based estimated glomerular filtration rate FAThe FAS equation is based on normalized CysC  and categorical variables were expressed as percentages. Correlation between all measurements of the biomarkers was assessed using Pearson and Spearman’s correlation coefficient. The normality of the distributions was assessed with the Shapiro-Wilk test. A Mann-Whitney U test/Wilcoxon rank-sum test was used to compare continuous variables of independent subgroups.SCr and eGFRCysC with mortality were analyzed using Cox proportional hazard regression and logistic regression models, adjusted for covariates age, sex, length of stay (LoS), and dialysis in ICU.The associations of eGFR2 in the first follow-up measurement and compared using the log-rank test.Kaplan–Meier survival curves were plotted for SCr- or CysC-based eGFR < 25 and eGFR ≥ 25 mL/min/1.73 mSCr and eGFRCysC (only for the follow-up period), and compared the slopes and intercepts. For mixed-effect models, subjects and time (days in follow-up) were treated as random effects. p-value of p < 0.05 was considered statistically significant. Analyses were carried out using R Statistical Software (version 4.0.5) [Given the multiple visits per patient during follow-up, we used linear mixed models, derived slopes and intercepts for both eGFRn 4.0.5) .A total of 101 critically ill patients  age of 74 (30–92) years) who developed AKI stage 3 were included in this study. Characteristics of patients on ICU admission and after discharge are shown in In SCr against eGFRCysC during ICU stay and follow-up period are presented in p-value < 0.0001; Wilcoxon test). No significant deviation from the identity line was observed during the ICU stay . Furthermore, the Bland–Altman analysis for the ICU stay and follow-up phase is presented in SCr and eGFRCysC is near-zero; however, it is nearly 15 in the follow-up phase.Results of eGFRSCr levels are higher during each follow-up visit compared to eGFRCysC. Notably, the number of patients differs in each follow-up visit due to drop-out or death.The within-subject evolution of the eGFR for alive patients using both SCr and CysC from the first measurements in ICU until the last follow-up is shown in CysC increases steadily from the time AKI is diagnosed (time point 2) onward, whereas eGFRSCr plateaus at the first follow-up (time point f1).As shown in SCr in the mixed-effect model is much higher than the intercept for eGFRCysC and furthermore that the slope for eGFRSCr is not changing while the slope for eGFRCysC is increasing (regaining kidney function) confirms that according to the SCr, it seems as if the kidneys have already recovered at the first follow-up, while CysC-based eGFR still shows ongoing recovery during follow-up.Mixed-model analysis  during f2 and eGFR ≥ 60 mL/min/1.73 m2 based on SCr and CysC in each follow-up visit. We see large differences in the incidence of chronic kidney disease (defined as eGFR < 60 mL/min/1.73 m2) using the two biomarkers during follow-up visits. Specifically, in the first follow-up, as shown in CysC; however, eGFRSCr had classified them as having no CKD. The difference between the two biomarkers in detecting CKD in the first follow-up was statistically significant  as GFR category 2, on the other hand for eGFRCysC, the majority (n = 29) belong to class CKD3B (moderate to severely decreased).We also evaluated whether there were differences between those with CKD and those without CKD based on either eGFR SCr or CysC levels during each follow-up time . Stages There were 43 (42.6%) deaths during the study, of which 24 occurred during the ICU stay and 19 during the follow-up period. Univariate Cox proportional hazard regression models were performed to examine the risk factors associated with mortality in ICU with all patients included and mortality in follow-up with patients who survived ICU .CysC in ICU, and average eGFRSCr in ICU. The average eGFRCysC/SCr in ICU is the average over two eGFRs using SCr and CysC during ICU stay.The analysis of the association between eGFR and mortality in ICU was performed on the whole population (n = 101), and we considered variables of age, gender, average eGFRCysC and eGFRSCr in the first follow-up were considered in the model. Reduced eGFRCysC/SCr in the first follow-up was defined as eGFR < 25 mL/min/1.73 m2.In analyses of the association between eGFR and mortality in the follow-up phase, patients who survived the ICU and appeared at the first follow-up visit were included. Variables including age, gender, length of stay in ICU (LoS ICU), dialysis in ICU, and reduced eGFR2 at first follow-up, has a significantly increased risk for mortality compared to a patient who has eGFR based on SCr below 25 mL/min/1.73 m2. Kaplan–Meier curves using eGFR <25 and ≥25 as strata illustrate these findings  occurs in some patients, even after experiencing the most severe AKI Stage-3 event. Despite its relative non-specificity, SCr remains the gold-standard for defining AKI and for follow-up after an AKI event. However, less is known about CysC during the follow-up phase after experiencing an AKI episode. The present study investigates whether the use of CysC has advantages over SCr as a biomarker for renal function for adult ICU patients who had experienced such an AKI stage-3 event. First, by comparing the evolution of the two biomarkers and estimated GFR during the ICU stay and post-AKI follow-up, we discovered that they behave differently after the ICU discharge, and the correlation between the two GFR estimates drops during the follow-up period. Several articles suggest that SCr may result in an overestimation of recovery by ignoring the decrease in SCr due to the loss of muscle mass that occurs during critical illness ,21. The CysC increases steadily from the time the AKI is diagnosed onward, whereas eGFRSCr plateaus at the first follow-up, which may reflect the fact that kidney function improves (thus decreasing SCr) and muscle mass increases when patients are recovering from their ICU stay (thereby increasing SCr). The combined effect may be that SCr does not change much. Due to the fact that CysC is not affected by muscle mass, there is no double effect present for CysC.Using different statistical analyses, we compared creatinine- and cystatin C-based estimates of GFR during ICU stay and the follow-up period. On admission, we observed that both eGFRs are approximately the same, which strongly supports the hypothesis that the loss of muscle mass explains the differences observed over time in the follow-up phase. In the follow-up period, we found a significant difference in eGFR values between the two biomarkers. In particular, we saw that eGFRCysC in the follow-up after AKI was more frequent than the occurrence of low eGFRSCr, especially during the first visit, about 1 month after hospital discharge. Two phenomena might explain the high eGFRSCr values in the first follow-up. First, patients may not yet have recovered from ICU stay, leading to a lower SCr (higher eGFRSCr). Second, patients recovering from AKI have their kidney function improving, which consequently leads to a lower SCr value (higher eGFRSCr). It was suggested in [SCr and eGFRCysC [Moreover, the occurrence of low eGFRested in  that, aleGFRCysC ,23.SCr tends to classify more patients towards the less-severe stages compared to eGFRCysC. Both biomarkers give similar GFR estimates in the steady state, providing an acceptable correlation with measured GFR [Furthermore, according to our results, CKD incidence was far higher when GFR was estimated using CysC than with SCr, which was a confirmation of the findings in the study by Rimes-Stigare et al. . We obseured GFR ,25. It iured GFR .2 at first follow-up has a significantly increased risk for mortality compared to a patient who has eGFR based on SCr below 25 mL/min/1.73 m2; hence, clinicians should look at eGFRCysC instead of eGFRSCr at the first follow-up. After evaluating different cut-offs, 25 was chosen because it gave us the best ‘survival’ discrimination between the two eGFR equations. Other cut-offs failed to reach significance probably because there were few participants. Future studies should validate this cut-off.Since the surveillance of all patients would be expensive and impractical, we must establish how best to determine renal function during post-AKI follow-up. As in our results, we saw that a patient who has eGFR based on CysC below 25 mL/min/1.73 mEven though our findings are intriguing and may be clinically useful, there are some limitations to be considered. First of all, the number of patients in our study was limited, and loss of follow-up is present and was due in part to logistical difficulties. Additionally, we did not measure GFR using a gold-standard technique since this is not routinely available and is practically impossible in an ICU setting. Moreover, our study was conducted in Europe, and our patient population consisted only of Caucasian patients. Thus, our results cannot be generalized to countries with predominantly black, Asian, or mixed-race populations; moreover, differences in SCr should be taken into consideration due to racial factors.Furthermore, CysC is affected by inflammation and infection; however, we did not adjust CysC for this as CRP was not available in follow-up.CysC was a better predictor of mortality compared to eGFRSCr. Accordingly, our study demonstrated that using SCr alone at follow-up could lead to an underestimate of renal dysfunction (CKD) among AKI stage-3 survivors. Further follow-up is required to evaluate the validity of estimated GFR based on both biomarkers by comparing them to clinical assessment and progression to dialysis.Our prospective observational study demonstrated that the incidence of CKD defined with CysC-based eGFR versus SCr-based eGFR during the follow-up period of critically ill patients, recovering from AKI stage 3 in their intensive care unit stay, was highly discrepant. In the follow-up phase, CysC-based eGFR categorized significantly more patients in more severe CKD stages than SCr-based eGFR, and eGFR