P. aeruginosa bacteremia and whether follow-up blood cultures in this context are associated with short- and long-term survival.Evidence supporting collection of follow-up blood cultures for Gram-negative bacteremia is mixed. We sought to understand why providers order follow-up blood cultures when managing P. aeruginosa bacteremia at the University of Maryland Medical Center in 2015–2020. Kaplan-Meier survival curves and Cox regression with time-varying covariates were used to evaluate the association between follow-up blood cultures and time to mortality within 30 days of first positive blood culture. Provider justifications for follow-up blood cultures were identified through chart review.We conducted a retrospective cohort study of adult inpatients with P. aeruginosa and 10 (8%) that were positive for other organisms. Follow-up blood cultures were typically collected “to ensure clearance” or “to guide antibiotic therapy.” Overall, 30-day mortality was 25.2%. After risk adjustment for patient characteristics, follow-up blood cultures were associated with a nonsignificant reduction in mortality risk . In exploratory analyses, the potential mortality reduction from follow-up blood cultures was driven by their use in patients with Pitt bacteremia scores >0.Of 159 eligible patients, 127 (80%) had follow-up blood cultures, including 9 (7%) that were positive for P. aeruginosa bacteremia but infrequently identify persistent bacteremia. Targeted use of follow-up blood cultures based on severity of illness may reduce unnecessary culturing.Follow-up blood cultures are commonly collected for  Although follow-up blood cultures are recommended in the management of bacteremia due to Gram-positive organisms such as Staphylococcus aureus, our understanding of their role in Gram-negative bacteremia is evolving. Early studies of Gram-negative bacteremia caused predominantly by Escherichia coli suggested that follow-up blood cultures are rarely positive and do not correlate well with clinical outcomes. Subsequent studies including larger samples of patients with bacteremia due to other Gram-negative organisms have demonstrated higher rates of persistent bacteremia and a potential mortality benefit when follow-up blood cultures are collected. No studies have focused exclusively on Pseudomonas aeruginosa.Gram-negative bacteremia is associated with high mortality.P. aeruginosa are associated with higher mortality than infections due to other Gram-negative organisms,P. aeruginosa may be less likely than other Gram-negative organisms, such as Serratia spp or Stenotrophomonas maltophilia, to be associated with persistent bacteremia. With adequate source control, follow-up blood cultures may be unnecessary. To support diagnostic stewardship of blood cultures at our institution, we evaluated the utility of follow-up blood cultures in cases of P. aeruginosa bacteremia by determining their positivity rate and association with 30-day mortality. In secondary analyses, we explored which patient groups were most likely to benefit from follow-up blood cultures.Our institution has recently begun an initiative related to diagnostic stewardship of blood cultures, including implementation of an algorithm to guide when culturing is appropriate for fever in the intensive care unit. Although infections due to P. aeruginosa. Patients who died or were discharged within 24 hours of the initial blood culture were excluded. For patients who had >1 hospital stay in which they had a positive P. aeruginosa blood culture, only the first hospital stay was included. This study was deemed exempt from review by the University of Maryland Baltimore Institutional Review Board.The cohort included all adult patients admitted to the University of Maryland Medical Center between November 1, 2015, and January 1, 2020, with a blood culture positive for  The primary outcome was time in days from the first positive blood culture to all-cause mortality for up to 30 days of follow-up. A 30-day follow-up period was chosen to capture clinical outcomes during the acute phase of illness which might occur after hospital discharge. Mortality events were identified through review of connected electronic health records available on the Care Everywhere Network provided by Epic and review of records from CRISP, the designated health information exchange for the state of Maryland. Individuals who did not have documented follow-up at least 30 days after the index positive blood culture were censored at the time of last documented living interaction with healthcare. Individuals who had documented living interaction 30 days after the index positive blood culture were censored at 30 days. A sensitivity analysis was performed using time from the first positive blood culture to mortality within a 90-day follow-up period as the outcome.Data were extracted from the electronic medical records of each patient and supplemented with chart review. All data elements extracted electronically were validated by chart review in a random sample of 20 charts. The variables we investigated included demographic information , clinical characteristics , and components of the Pitt bacteremia score .Source of bacteremia was determined by review of progress notes from the infectious disease consultant or primary team. Charts were independently reviewed by 2 members of the study team (A.G. and J.B.) in sets of 10, with a third team member available for adjudication (A.H.). Once agreement between the 2 reviewers reached >90%, remaining charts were reviewed by a single individual (A.G.). Documented justification for follow-up blood culture was collected from the progress note of the infectious disease consultant or primary team. In time-to-event analysis, the exposure of interest was a time-varying binary variable representing the presence of follow-up blood culture at a given time after the index positive blood culture (time 0). Physician justification for follow-up blood culture was defined by documentation of a reason for follow-up blood cultures on the day before, day of, or day after collection. Baseline health was represented using the sum of conditions present from the Elixhauser comorbidity index as defined using International Classification of Disease, Tenth Revision (ICD-10) codes. Hospital-onset bacteremia was defined by the index positive blood culture occurring after hospital day 3. The Pitt bacteremia score was calculated using the most abnormal values for each contributing element from the calendar day of the index positive blood culture. In multivariable analyses, Pitt bacteremia scores were categorized as low (a score of 0), moderate (scores 1–4), and high (scores ≥5) based on thresholds from the literature used to indicate severe infection. Antimicrobial resistance, selection of antibiotic coverage, and use of empiric therapy were captured in a single variable representing the number of days from collection of the index positive blood culture to administration of effective antibiotic therapy. Antibiotics administered >24 hours before collection of the index positive blood culture were excluded. In multivariable analyses, days to effective antibiotic therapy was categorized into 4 levels based on whether effective antibiotics were started concurrently with the index blood culture (from 24 hours before until 3 hours after), within 1 day (3–24 hours after the index blood culture), within 2 days (24–48 hours after the index blood culture), or after a delay of >48 hours.Blood cultures were categorized as follow-up if collected >24 hours and ≤7 days after the index positive, in accordance with the literature.t test or Wilcoxon rank-sum test for continuous variables and Pearson χ test or Fisher exact test for categorical variables. Logistic regression was used to evaluate associations between predictors and binary outcomes, such as positivity of follow-up blood culture.Patient demographics and clinical characteristics were described using means and standard deviations or frequencies and proportions, as appropriate. Comparisons between patients who underwent follow-up blood culture and those who did not were performed using the Student The cumulative incidence of mortality for each time-varying follow-up blood culture group was presented using Kaplan-Meier survival curves. The association between follow-up blood culture collection and time to mortality within the period of follow-up (30 days or 90 days) was modeled using Cox proportional hazards regression while adjusting for confounding variables. To explore the potential impact of follow-up blood cultures in patients with different levels of severity of illness, heterogeneity of treatment effect analyses were performed by including an interaction term between follow-up blood cultures and Pitt bacteremia scores in the Cox model. We estimated 95% confidence intervals (CIs) for hazard ratios (HRs) using robust standard errors. Covariates included in the Cox model for risk adjustment included age, baseline health in terms of number of conditions from the Elixhauser comorbidity index, Pitt bacteremia score, presence of immunosuppression, hospital-onset of index bacteremia, and days from index positive blood culture collection to administration of effective antibiotics. Statistical analyses were performed with SAS version 9.4 software  and Stata/SE version 16 software .In all time-to-event analyses, the presence of follow-up blood culture was defined as a time-varying binary variable to account for immortal time bias.This study was determined to be exempt from requirements for patient consent by the Institutional Review Board of the University of Maryland School of Medicine. A waiver of HIPAA authorization for release of the private health information was approved.P. aeruginosa blood culture were identified, including 159 unique patients who met the inclusion criteria and 127 patients (80% of 159) with at least 1 follow-up blood culture , dependence on hemodialysis , Pitt bacteremia score , and days from index positive blood culture collection to administration of effective antibiotics  were not significantly associated with isolation of a pathogen from follow-up blood culture.The median number of follow-up blood cultures was 1 . The median time to first follow-up blood culture was 52.0 hours . Follow-up blood cultures were positive in 18 patients (14.2% of 127), including 9 cases of persistent Pseudomonal bacteremia (7.1%). Follow-up blood cultures were positive for P = .533, χ2 test).Among the 94 patients with a central line present before onset of bacteremia, 74 (79%) had their line removed during the 30-day follow-up period, and 32 (34%) had their line removed before completing inpatient antibiotics. The median time to line removal was 63 hours . Among 77 patients with follow-up blood cultures, 30 (39%) had their central lines removed before follow-up blood cultures were obtained. Of 30 patients with line removal prior to follow-up blood culture, 3 (10%) were still bacteremic at time of follow-up, compared with 7 (15%) of 47 patients whose line remained in place (A justification for follow-up blood cultures was documented in the charts of 58 (45.7%) of 127 eligible patients .Unfortunately, 7 patients provided incomplete follow-up data and were censored before 30 days of follow-up (see Supplementary Appendix online for the characteristics of these patients). Also, 40 patients (25.2%) died within 30 days of their index positive blood culture, including 24 (18.9%) of 127 patients who had follow-up blood cultures and 16 (50%) of 32 patients without follow-up blood cultures. Mortality rates within the 30-day follow-up period were similar between patients whose follow-up blood cultures were negative and positive . After adjusting for age, baseline health in terms of number of conditions from the Elixhauser comorbidity index, Pitt bacteremia score, presence of immunosuppression, hospital-onset of index bacteremia, and days from index positive blood culture collection to administration of effective antibiotics, follow-up blood cultures remained nonsignificantly associated with risk of mortality  (see Supplementary Appendix online for full model).Among those who died, median times from index positive blood culture to death in the overall sample, patients with follow-up blood culture, and patients without follow-up blood culture were 6 days IQR, 3–12), 9.5 days , and 3.5 , respectively. Kaplan-Meier survival curves for the 30-day follow-up period are displayed in Figure –12, 9.5 P = .014) and high  Pitt bacteremia scores were independently associated with increasing risk of mortality relative to a Pitt bacteremia score of 0 (see Supplementary Appendix online). The Kaplan-Meier survival curves for patients with low, medium, and high Pitt bacteremia scores are displayed in Figure P = .018)  of 46 patients with Pitt bacteremia scores of zero, 6 (11.1%) of 54 patients with Pitt bacteremia scores 1–4, and 2 (7.4%) of 27 patients with Pitt bacteremia scores >4. Sources of infection for patients with low, medium, and high Pitt scores are reported in the Supplementary Material (online). Follow-up blood cultures were positive for 2 of the 3 patients with low Pitt scores who died within 30 days of their index blood culture, 3 of 10 patients with medium Pitt scores who died within 30 days, and 1 of 11 with high Pitt scores who died within 30 days.P = .30). Follow-up blood cultures were not significantly associated with risk of mortality in unadjusted Cox regression  or adjusted Cox regression .Kaplan-Meier curves for an extended period of follow-up are displayed in Figure P. aeruginosa bacteremia were routine, but persistent bacteremia was infrequent. Follow-up blood cultures were not significantly associated with improved mortality, though exploratory analyses suggested a potential benefit when they were drawn for patients with elevated Pitt bacteremia scores.Unnecessary blood cultures can waste resources, complicate patient follow-up, and, when positive for a contaminant, adversely affect hospital quality metrics. In this cohort study of 5 years of clinical data from a large medical center, follow-up blood cultures for  When persistent bacteremia was found to be infrequent, we performed exploratory analyses to identify patients who might be most likely to benefit from follow-up blood cultures, and we investigated potential differences in impact associated with severity of illness. We also explored the reasons why follow-up blood cultures were being obtained and found that they were frequently reflexive, (“repeat until negative”) rather than ordered in response to the patient’s condition.Strategies to improve use of follow-up blood cultures may focus on the underlying infectious syndrome, the pathogen, the adequacy of treatment, or the patient’s condition. In this study, we focused on a pathogen that has been identified as an independent risk factor for breakthrough bacteremia and for which the evidence is limited. At our medical center, follow-up blood cultures are collected in 4 of 5 cases of P. aeruginosa bacteremia. Although others have reported similar rates of repeated cultures, medical centers vary, suggesting that approaches may be cultural rather than evidence based. We suspect that follow-up blood cultures are not necessary in all cases of P. aeruginosa bacteremia but have been unable to reach a local consensus on how best to de-implement this process. Thus, when consulted, infectious disease physicians continue to encourage collection of follow-up blood cultures in many cases. Despite recent adoption of protocols to reduce unnecessary “pan-culturing” in the intensive care unit, these protocols explicitly permit repeat cultures to ensure clearance.Repeat blood cultures have been identified as a potentially unnecessary testing practice representing an opportunity for diagnostic stewardship.P. aeruginosa bacteremia. Positivity rate is often used as a proxy for clinical utility, but blood cultures may provide clinical utility when negative, particularly among the critically ill. Further investigation, including ideally a larger sample of severely ill patients with pseudomonal bacteremia, is needed before the optimal context for use of follow-up blood cultures can be identified.Surprisingly, follow-up blood cultures were less frequently positive for patients with elevated Pitt scores. This finding may reflect an increased frequency of line-related bacteremia among the patients with low Pitt scores (see Supplementary Appendix online). However, despite a lower positivity rate, follow-up blood cultures were associated with a trend toward improved survival among patients with Pitt scores >0. Although subgroups with medium and high Pitt scores were small and clinical courses were heterogeneous, we suspect that follow-up blood cultures may support effective clinical management of patients who are severely ill with P. aeruginosa as they were for unrelated but nonetheless clinically relevant pathogens. This finding may reflect the high rate of early effective antibiotic therapy or may indicate that P. aeruginosa bacteremia is a marker among hospitalized patients for underlying predisposition toward severe infections. Given that mortality was high (25.2%) regardless of whether persistent bacteremia was present, the poor prognosis associated with P. aeruginosa bacteremia may be attributable to host factors in addition to acute illness.Notably, follow-up blood cultures in our cohort were as frequently positive for This study has several limitations. First, we analyzed observational data from a single medical center, and our findings therefore may not be generalizable to other clinical settings. However, in the context of other single-center studies in the literature, these results are meaningful. Second, though we adjusted for severity of illness using the Pitt bacteremia score and baseline health using the Elixhauser comorbidity index, our results are likely still susceptible to residual confounding related to severity of illness. Third, most follow-up blood cultures in our cohort were drawn within 72 hours of the index positive blood culture. Thus, our results may not be generalizable to clinical protocols that emphasize collection of follow-up blood cultures later in the course of illness or at the conclusion of therapy. Finally, the retrospective design of this study did not permit an evaluation of causal pathways. Rather, we were limited to reporting associations only.In this retrospective observational study, follow-up blood cultures were not associated with clear or consistent benefit in either short- or long-term outcomes. Follow-up blood cultures were frequently drawn reflexively “to ensure clearance.” Diagnostic stewardship initiatives can potentially reduce unnecessary culturing by targeting follow-up blood cultures based on severity of illness.


For people with chronic DM complications, a perception of higher risk and severer consequences of COVID-19 infection, a belief that doctors would suggest they receive COVID-19 vaccination, and a belief that relatives’ vaccination uptake would influence their own decision to receive a COVID-19 vaccination were all associated with higher COVID-19 vaccination uptake. For their counterparts without chronic complications, a perception of severer consequences of COVID-19 infection, a belief that receiving COVID-19 vaccination could reduce the risk of infection, and a belief that relatives’ vaccination uptake would influence their own decision to receive a COVID-19 vaccination were all associated with higher COVID-19 vaccination uptake. Concerns about the safety and the side effects of vaccination were negatively associated with COVID-19 vaccination uptake in both groups of DM patients. Different strategies might be applied to promote COVID-19 vaccination uptake in DM patients with and without chronic complications.The health of people with chronic diabetes mellitus (DM) complications will worsen following coronavirus disease 2019 (COVID-19) infection. This cross-sectional study compared perceptions and factors related to COVID-19 vaccination uptake between subgroups of DM inpatients with and without chronic complications in China. A multivariate logistic regression model was used for data analysis. Of the 645 participants, those without any complications reported significantly higher uptake of at least one dose of COVID-19 vaccination (43.2% versus 11.2%,  Globally, diabetes mellitus (DM) affects approximately 537 million people . China hDM can affect many different organ systems and lead to serious chronic complications over time. Chronic DM complications include microvascular complications  and macrovascular complications  . In ChinFew published studies have investigated COVID-19 vaccine hesitancy among people with DM. The prevalence of vaccine hesitancy ranged from 14.2% in Italy  to 29% iThis study used the Health Belief Model (HBM) as a theoretical framework . PreviouTo address the knowledge gaps, this study compared COVID-19 vaccination uptake and levels of perceptions related to COVID-19 vaccination between subgroups of DM inpatients with and without chronic complications. This study also investigated factors associated with COVID-19 vaccination uptake in each subgroup. We hypothesized that there would be significant between-group differences affecting COVID-19 vaccination uptake and levels of perceptions related to COVID-19/COVID-19 vaccination. The associated factors of COVID-19 vaccination uptake would also be different between participants with and without chronic DM complications.This study was a cross-sectional study conducted among inpatients diagnosed with DM which was carried out at the endocrinology departments of Heping and Heji Hospitals, Changzhi Medical College  between April and August 2021. This study was a continuation of our published studies ,24. Inclusion criteria applied to patients (1) diagnosed with type 1 or type 2 DM who were hospitalized in the two participating hospitals throughout the study period, (2) aged at least 18 years, and (3) willing to provide written informed consent to complete the survey. Exclusion criteria applied to patients (1) with a diagnosis of mental illness or who had taken medication for a mental illness in the previous 3 months, or (2) who had apparent dementia symptoms or were unable to communicate verbally with the investigators. Physicians confirmed the first two inclusion and exclusion criteria based on their medical records.The participating hospitals’ medical staff approached all inpatients diagnosed with DM in the endocrinology departments, screened their eligibility, briefed them about the study, and invited them to complete a face-to-face interview. The medical staff informed prospective eligible participants that their responses would be anonymous. They had the right to withdraw from the study, and refusal to participate would not affect their access to any services. Written informed consent was sought. Among 717 eligible inpatients with DM, 72 refused to participate, and 645 provided written informed consent and completed the face-to-face interview, as shown in A panel of epidemiologists, statisticians, and endocrinologists developed and finalized the questionnaire before the study implementation. Sociodemographic information was collected, including gender, age, ethnicity, highest educational level, relationship status, employment status, monthly personal income, types of medical insurance, and lifestyles. The medical staff extracted characteristics of DM and other chronic diseases from participants’ medical records, such as type of DM, family history of DM, presence of chronic DM complications, glycemic control, and diagnosis of other chronic diseases that were not considered as chronic DM complications.The number of doses of COVID-19 vaccination taken up by the participants was extracted from their vaccination records. This study used uptake of at least one dose of COVID-19 vaccination as the dependent variable. A checklist was used to assess local adverse events  and systematic adverse events  within one month of receiving COVID-19 vaccination. The same checklist was used to measure self-reported adverse events following COVID-19 vaccination among the general population in China .We defined chronic DM complications such as neuropathy, nephropathy, eye damage, cardiovascular and cerebrovascular diseases, coronary heart diseases, stroke, and peripheral vascular diseases. Previous studies commonly used the same definition . MedicalParticipants responded to the following items based on the HBM . These items included: (1) one item measuring perceived susceptibility to COVID-19 (“You have a high risk of contracting COVID-19”); (2) one item measuring perceived severity of COVID-19 (“The consequences of contracting COVID-19 is severe”); (3) three items assessing perceived benefits of COVID-19 vaccination ; (4) two items measuring perceived barriers (“You worried about the safety of COVID-19 vaccination for DM patients” and “You concern about the side effects of COVID-19 vaccination”); and (5) three items assessing cues to action . These items were adapted from a published study targeting people with DM in China .n = 300) and the subgroup without any complications (n = 300) could detect the smallest between-group difference of 7.9% in COVID-19 vaccination uptake. Our target sample size was 600 DM inpatients. We assumed that 50% of the DM inpatients had at least one chronic DM complication. Given a statistical power of 0.8 and an alpha value of 0.05, the sample size of the subgroup of participants with chronic DM complications . Each AOR was obtained by fitting a single logistic regression model involving one of the independent variables of interest and all significant background characteristics. SPSS 26.0  was used for data analysis, and p < 0.05 was considered statistically significant.The differences in background characteristics, COVID-19 vaccination uptake levels, and perceptions related to COVID-19 vaccination between people with at least one chronic DM complication and those without any such complications were compared using linear regression (for continuous variables) or Chi-square tests . We compared the prevalence of specific types and any types of self-reported adverse events among vaccinated participants with and without chronic DM complications. Using uptake of at least one dose of COVID-19 vaccination as the dependent variable, this study investigated factors associated with the dependent variable in sub-samples of people with chronic DM complications and those without such complications. Associations between background characteristics and the dependent variable were first investigated using univariate logistic regression models, and crude odds ratios (ORs) were obtained. After adjusting for background characteristics with The majority of participants were Han Chinese (98.1%), married or cohabiting with a partner (88.2%), and without full-time work (72.2%). Over half of them were male (56%), aged 50–69 years (54.3%), and had not attended secondary schools (58.8%). Fewer than half of them had a monthly personal income of less than CNY 2000 (40.8%) or had urban workers’ medical insurance (46.0%). Regarding lifestyles and health status, 95% were type 2 DM, 61.6% and 64.7% were current smokers and current drinkers, respectively, 56.4% reported a family history of DM, and 31% received a first DM diagnosis more than 10 years previously. The prevalence of chronic DM complications was 36.9% for eye damage, 3.7% for foot damage, 7.4% for neuropathy, and 15.2% for nephropathy. Among all participants, 365 (56.6%) had at least one chronic DM complication. Among participants with chronic DM complications, 328 had only one complication and 37 had at least two complications. n = 365) and without complications (n = 280), significant differences were found in the following: educational level, relationship status, type of medical insurance, family history of DM, time since DM diagnosis, postprandial blood glucose level, and presence of chronic diseases that were not considered as chronic DM complications. (When comparing participants with chronic DM complications (cations. . p < 0.001) (p = 0.72), and no serious adverse events were reported during the study  . There whe study . Regarding perceptions related to COVID-19 vaccination, participants without any chronic DM complications had higher levels of perceived susceptibility, perceived severity, perceived benefits, and cues to action when compared to their counterparts with such complications. In contrast, participants without any chronic DM complications were less concerned about the safety of COVID-19 vaccination when compared to participants with such complications . In univariate analysis, being of older age, having urban residents’ medical insurance or participation in the New Rural Cooperative Medical Scheme, and a longer time since DM diagnosis were all associated with higher COVID-19 vaccination uptake. Being a current smoker or drinker, having a family history of DM, and the presence of chronic conditions that were not considered as chronic DM complications were all negatively associated with the dependent variable . After adjustment for these significant background characteristics, a perception of higher risk  and of severer consequences of COVID-19 infection , a belief that doctors would suggest that they receive COVID-19 vaccination , and a belief that relatives’ vaccination uptake would influence their own decision to receive a COVID-19 vaccination  were all associated with higher COVID-19 vaccination uptake. Concerns about the safety of COVID-19 vaccination  and the side effects of vaccination  for DM patients were negatively associated with the dependent variable . In univariate analysis, having a tertiary or above educational level and a monthly personal income of more than CNY 3500 were associated with higher COVID-19 vaccination uptake. Being female, being a current smoker or drinker, being of older age, participation in the New Rural Cooperative Medical Scheme, having a family history of DM, and the presence of chronic conditions that were not considered as chronic DM complications were all negatively associated with the dependent variable . After adjustment for these significant background characteristics, perceived severer consequences of COVID-19 infection , a belief that receiving COVID-19 vaccination could reduce the risk of infection , and a belief that relatives’ vaccination uptake would influence their decision to receive a COVID-19 vaccination  were associated with higher COVID-19 vaccination uptake. Concerns about the safety of COVID-19 vaccination  and the side effects of vaccination for DM patients  were negatively associated with the dependent variable. .To the best of our knowledge, this is one of the first studies comparing COVID-19 vaccination uptake and its associated factors between DM patients with and without chronic complications in China. This study showed that prevalence of COVID-19 vaccination uptake, levels of perceptions related to COVID-19 vaccination, and factors associated with COVID-19 vaccination uptake were different among participants with and with DM chronic complications. Such information provides a knowledge basis to develop tailored strategies to increase the vaccination coverage in these groups.Our study found that the prevalence of COVID-19 vaccination uptake in all people with DM 25.1%) was significantly lower than that reported among the general population (88%) in China during the same period . COVID-1.1% was sIn contrast to our hypothesis, people with chronic DM complications had lower perceived susceptibility and severity of COVID-19 than those without such complications. They might not have been aware of the association between the presence of chronic complications and the risk and severity of COVID-19, as COVID-19 vaccination promotion materials seldom mention such information. In line with our hypothesis, people with chronic DM complications had more concerns about the efficacy and safety of COVID-19 vaccination, as fewer of them perceived such vaccination was beneficial for them, and more of them had doubts about its safety. Such differences can partially be explained by the lack of evidence comparing the efficacy and side effects of COVID-19 vaccination between DM patients with and without chronic complications. In addition, we found that people with chronic DM complications are less influenced by their relatives than those without any complications. The behaviors of family members are unlikely to dispel concerns about vaccine efficacy and safety in this group. The findings provided some empirical implications for developing health promotion programs tailored to DM patients with and without chronic complications. For both groups, future programs should give more attention to people with DM who are current smokers and drinkers, who have a family history of DM, and who have other chronic conditions as these people reported lower COVID-19 vaccination uptake. For people with chronic DM complications, additional efforts should target younger individuals, those with urban workers’ medical insurance and those with a shorter time since diagnosis. For people without such complications, future programs should focus on females, older individuals, those with lower socioeconomic status and those who are part of the New Rural Cooperative Medical Scheme. Different strategies for promoting COVID-19 vaccination should be applied to DM patients with and without chronic complications. First, the fear appeal approach, which has been widely used to promote recommended preventive behaviors ,31, may In addition, some similar strategies can be applied to both groups for promoting COVID-19 vaccination uptake. First, it is important to remove concerns about the safety and side effects of COVID-19 vaccination, as these concerns were associated with lower COVID-19 vaccination uptake in both groups. Health communication messages should emphasize that COVID-19 vaccination is safe for all people with DM and that most have only mild side effects after vaccination. Positive testimonials shared by vaccinated people with DM may alleviate their concerns about COVID-19 vaccination and enhance vaccination coverage. Second, family members or relatives’ COVID-19 vaccination uptake positively influenced COVID-19 vaccination uptake in both groups of DM patients. Future programs should involve family members of people with DM. They might serve as role models and convince people with DM to receive COVID-19 vaccination. This study had some limitations. First, we only targeted inpatients, so our findings could not be generalized to all people with DM. People with DM who do not stay in hospitals might have better control of their DM and fewer chronic complications, and they may have higher COVID-19 vaccination uptake than inpatients. Second, the sample was not representative of all people with DM in China because it was limited to one city. Third, selection bias might exist, as we could not obtain characteristics of refusals. These individuals might have had different characteristics as compared to participants. Moreover, we did not include perceived self-efficacy in the measurement, as self-efficacy is an important determinant of vaccination uptake. Last but not least, the causal relationship between predictors and outcome variables could not be determined because the study was a cross-sectional study.In conclusion, we found that people with DM reported a relatively low uptake of COVID-19 vaccination. Uptake rate was especially low among people with chronic DM complications. Different strategies might promote COVID-19 vaccination uptake in DM patients with and without chronic complications. Using the fear appeal approach and the recommendations of physicians are likely to succeed in people with chronic complications, while emphasizing the benefits of COVID-19 vaccination might work better among people without such complications. Some strategies, such as removing concerns about safety and side effects and using the influence of family members and relatives, are also useful to increase COVID-19 vaccination coverage in both groups.


Environmental exposure during fetal life may disrupt testicular development. In humans, a limited number of studies have investigated whether these adverse effects persist into adulthood. Using data from a prospective, population-based birth cohort study, The Copenhagen Mother-Child cohort, the objective was to assess if there is an association between fetal exposure to selected phenols and benzophenones and markers of testicular function in adult men.Pregnant women were recruited in 1997–2001. Their sons were examined clinically at 18-20 years of age, with focus on adult markers of reproductive function , semen quality and reproductive hormones). In total, 101 18–20-year-old men were included, whose mothers during pregnancy had a serum sample drawn and analyzed for bisphenol A (BPA) and seven other simple phenols, as well as six benzophenones. To investigate the association between chemical levels  in relation to markers of reproductive function, univariate and multiple linear regression analyses were performed.In fully adjusted analyses, increased levels of luteinizing hormone (LH) were observed with higher fetal exposure to BPA (percentage difference (95%CI))  and T3: 33% , compared to T1) and benzophenone-3 (BP-3) , T3: 18% ), while no clear association was seen to total testosterone (TT). Higher levels of BPA and BP-3 were associated with a lower TT/LH ratio, although only significant for BPA (p-trend=0.01). No associations were seen to AGD or markers of semen quality. In conclusion, high exposure to BPA and BP-3 was associated with a compensated reduced Leydig cell function but no other changes in markers of reproductive health. As maternal levels of BPA and BP-3 were not correlated, separate effects may be at play. Larger studies on long-term reproductive consequences of prenatal exposures are warranted to validate our findings. During recent decades there has been an increase in the incidence of several male reproductive disorders and an increased focus on environmental exposures that may explain some of these trends . It has Among the phenols is a group of industrial chemicals which primarily are used as precursors for various types of plastics. This includes bisphenol A (BPA), the most commonly used of the phenols, which is mainly used in polycarbonates and epoxy resins used in some food and drink packaging and also in various electronic equipment, and toys . Other pIn vitro and in vivo studies on different species have indicated that some UV filters, e.g. BP-3 can interfere with reproductive hormones by exerting estrogenic or antiandrogenic effects (in utero exposures (Because of the ultraviolet (UV) absorbing properties, benzophenones are used in a wide range of consumer products, including sunscreen formulations and skin lotions, but also as additives in e.g. plastic food packaging materials, paint, and textiles. In recent years, one of the most used UV absorbers, benzophenone-3 (BP-3) has been detected in most children and adults in US and Danish populations –23. Besi effects –27. In hxposures , 29.In general, human studies on prenatal exposure to environmental chemicals and male reproductive health in adulthood are scarce due to the inherent challenges in performing longitudinal studies with sufficient follow-up time while maintaining an adequate study participation rate. Thus, based on a unique mother-child cohort initiated in 1997 with repetitively, and long-term follow-up of the individuals, the aim in the present study was to investigate the association between maternal serum concentrations of phenols and benzophenones in pregnancy and reproductive function in the adult sons.This study is part of a prospective longitudinal birth cohort study of pregnant women and their sons born between 1997 and 2001 at three hospitals in the Copenhagen area, Denmark. Pregnant women belonging to the referral areas were enrolled during the first trimester of pregnancy and a blood sample was drawn at least once during pregnancy , althougThe study was performed following the Declaration of Helsinki II and approved by the Regional Committee on Health Research Ethics ((KF) 01-030/97 and H-17011468) and the Danish Data Protection Agency (1997-1200-074 and VD-2018-118/i-Suite 6358). All participants gave written informed consent prior to participation in the study.Information on maternal age at birth, smoking habits, parity and birth weight was obtained from hospital records. Pre-pregnancy weight was obtained from self-administered questionnaires during pregnancy.2). Furthermore, anogenital distance (AGD) was determined; Anoscrotal distance  and anopenile distance  were measured with a calliper with the men in lithotomy position. Body fat percentage was assessed by use of a whole-body dual x-ray absorptiometry (DXA) scan . Participants were compensated for their time (DKK 500 ≈ USD 78).All participating young men completed a detailed questionnaire, including information on lifestyle and general health, prior to the day of study participation, at which they delivered a semen sample, had a blood sample drawn for assessment of reproductive hormone levels, and had a physical examination . The exalow) and high (QChigh) concentration levels. The mean recovery was > 82% for all analytes except QClow for BP-7 (73%) and 4-PP (74%). The relative standard deviations (RSD) ranged from 7-15% in both spike levels for all analytes except QClow for BP-7 (19%), BPA (23%), TCC (26%) and 4-PP (18%) and QChigh for TCC (24%).In total, serum samples from 364 pregnant women, of which 100 samples belonged to a mother whose son(s) participated in the follow-up examination, were identified and analysed for chemicals at the Department of Growth and Reproduction, Rigshospitalet Figure 1All men had a fasting blood sample drawn in the morning. Samples were centrifuged and stored at -20°C until analysis. All serum hormone measurements were performed in the same laboratory at the Department of Growth and Reproduction in 2020. Testosterone, estradiol and sex hormone-binding globulin (SHBG) were measured by a chemiluminescent enzyme immunoassay , follicle stimulating hormone (FSH) and luteinizing hormone (LH) were measured using a two-sided fluoroimmunometric assay , inhibin B levels were measured by an enzyme-linked immunosorbent assay . Insulin-like factor 3 (INSL3) was determined using liquid chromatography-mass spectrometry (LC-MS/MS) with a limit of detection (LOD) of 0.03 μg/L . Finally® NC-3000™, Chemometec A/S, Alleroed, Denmark) and the total sperm count was calculated as the product of sample volume and sperm concentration. Sperm motility was assessed by placing 10 µl semen on a glass slide and using phase-contrast microscopy. Spermatozoa were classified as either progressive motile, non- progressive motile or immotile. Fixed and Papanicalaou stained morphology slides were prepared and evaluated according to ‘strict criteria’  guidelines . Brieflyriteria’ . All assMeasurements for each chemical were presented as percentiles and maximum values as well as number of samples above the analytical LOD Table 1.Basic characteristics and levels of reproductive hormones (n=101), semen parameters (n=99) and AGD (n=88) for the total study population are presented as medians and inter-quartile range.For chemicals where less than 30% of the samples had concentrations above LOD, analyses of associations with outcomes were not performed. For the remaining chemicals, the marginal correlation between each of the compounds were tested using Spearman’s rank-order correlation. Associations between chemical levels in relation to reproductive hormones, semen parameters and AGD were performed using univariate and multiple linear regression analysis. To accommodate potential nonlinear associations, chemical levels were analyzed in tertiles (T1-T3) and a trend test was performed by inserting the tertiles in the model as a continuous variable.a priori based on literature and included potential confounders for the association as well as covariates closely related to variation in the exposure or outcome measurements . Models were adjusted stepwise; an unadjusted model of the marginal association between exposure and outcome, Model I including adjustment for maternal factors , gestational age at blood sampling (continuous variable)), and Model II including additional adjustment for covariates related to the son , body fat percentage (continuous variable), weekly alcohol intake (continuous variable) and physical fitness (Good or very good/moderate/poor). All adjusted analyses with reproductive hormones were further adjusted for time of blood sampling (continuous variable), adjusted analyses with AGD measurements for height of the son, adjusted analyses with semen parameters for period of abstinence (continuous variable) and adjusted analyses with sperm motility for the time between delivery of semen sample and start of motility assessment (continuous variable). Estimates based on ln-transformed outcome variables were back-transformed using the formula: 100*(exp(β)-1), as described in . Testicular volume, sperm concentration and total sperm count were transformed by ln whereas the variables “% morphological normal sperm” and “% progressive motile sperm” remained untransformed. Covariates were selected ribed in . to reflIn subanalyses, further adjustment for maternal age (continuous variable) and parity  was performed in separate models. Also, one man with azoospermia was excluded from analyses with semen parameters as the outcome, and the findings were compared to the main findings. Finally, to account for multiple testing, all p-values from fully adjusted models were adjusted according to the Benjamini-Hochberg , 39 methP-values < 0.05 were considered statistically significant. Analyses were performed using SPSS v. 25 .Of the included chemicals, only BPA, TCS, 2-phenylphenol, BP-3, 4-hydroxy-benzophenone (4-HBP) and 4-methyl-benzophenone (4-MBP) could be detected in more than 30% of the samples Table 1.No difference in chemical concentrations was observed between mothers of men who did not participate in the follow-up examination and men who did except for TCS Figure 2The mothers’ median age at delivery was 31 years and their sons were 19 years old at follow-up Table 2.In fully adjusted analyses, higher prenatal levels of BPA  were significantly associated with higher LH levels in sons  and T3: 33%  compared to the reference category, T1, respectively) 3 but noNo clear associations were seen between any of the chemicals and the semen parameters and AGD with exception of 2-phenylphenol that tended to be positively associated to higher sperm concentration and total sperm count  .In this long-term prospective study, we observed that young men prenatally exposed to the highest levels of BPA and BP-3 had higher LH levels in adulthood and a lower TT/LH ratio indicating a compensated reduced Leydig cell function. However, no associations were seen to AGD as a marker of prenatal androgen action or to markers of semen quality. Testosterone production in men is characterized by a buffer capacity so that testosterone levels to some degree can be sustained by a compensatory increase in LH stimulation. Although our observational study cannot prove causality, our findings indicate a long-lasting effect of prenatal BPA and BP-3 exposure on Leydig cell function which has been described in experimental studies. A compensated Leydig cell function has been associated with an increased all-cause mortality in a long term follow-up study . Thus, win vitro studies have shown that BPA has both estrogenic and anti-androgenic properties due to its capability to bind and activate the estrogen receptor although with much lower affinity than estradiol  is the distance from anus to the genitals and has in rodents been shown to be determined by androgen action in early fetal life . Thus, rTo our knowledge, only one other longitudinal pregnancy cohort has investigated the association between prenatal BPA levels and reproductive hormones in adulthood. In contrast to our findings, results from that cohort indicated that maternal serum levels of BPA were positively associated with the sons’ sperm concentration and motility in adulthood, whereas no association was seen with levels of reproductive hormones, including LH . This diin vivo study in rodents showed that male offspring dermally exposed to BP-3 at up to 7 weeks of age and with dermally exposed mothers during pregnancy showed a substantial reduction in plasma testosterone levels  and the data should be replicated in larger studies. This project applied a single prenatal exposure measurement and a single adult reproductive health assessment despite the well-known intra-individual variation in both , which iIn conclusion, our findings indicate that young men prenatally exposed to BP-3 or BPA were characterized by a compensated reduced Leydig cell function in adulthood whereas no association was seen in relation to AGD or semen quality. Larger studies on long-term reproductive consequences of prenatal exposures are warranted to validate our findings.Katharina.Main@regionh.dk.The datasets presented in this article are not readily available because the data are not publicly available due to ethical restrictions. Requests to access the datasets should be directed to Katharina M. Main, The studies involving human participants were reviewed and approved by the Regional Committee on Health Research Ethics ((KF) 01-030/97 and H-17011468) and the Danish Data Protection Agency (1997-1200-074 and VD-2018-118/i-Suite 6358). The patients/participants provided their written informed consent to participate in this study.Conceptualization: SH, A-MA, AJ, JT, NS, KM. Data collection: LS, HF, KM. Data analysis and interpretation: SH, LS, A-MA, LP, NJ, NS, KM. All authors had full access to the data in the study and take responsibility for the integrity and the accuracy of the data analysis. All authors critically reviewed the manuscript and approved the submitted version. All authors contributed to the article and approved the submitted version.


Nature gives immense resources that are beneficial to humankind. The natural compounds present in plants provide primary nutritional values to our diet. Apart from food, plants also provide chemical compounds with therapeutic values. The importance of these plant secondary metabolites is increasing due to more studies revealing their beneficial properties in treating and managing various diseases and their symptoms. Among them, flavonoids are crucial secondary metabolite compounds present in most plants. Of the reported 8000 flavonoid compounds, luteolin is an essential dietary compound. This review discusses the source of the essential flavonoid luteolin in various plants and its biosynthesis. Furthermore, the potential health benefits of luteolins such as anti-cancer, anti-microbial, anti-inflammatory, antioxidant, and anti-diabetic effects and their mechanisms are discussed in detail. The activity of luteolin and its derivatives are diverse, as they help to prevent and control many diseases and their life-threatening effects. This review will enhance the knowledge and recent findings regarding luteolin and its therapeutic effects, which are certainly useful in potentially utilizing this natural metabolite. Plants have a vast majority of chemical compounds which are used daily. Due to knowledge of plant-based therapeutic benefits, bioactive compounds have been explored in past decades to treat various human diseases in addition to being utilized in their prevention . The useThe flavonoid compounds structural activities depend on their hydroxyl groups. Among the flavonoids, luteolin  is an important dietary compound present in different plant species . Most ofCeltis and Ulmus species, respectively  revealed anti-inflammatory and antioxidative properties in lipopolysaccharide (LPS)-stimulated murine macrophages, as the mRNA expression of inflammatory mediators including cyclooxygenase-2 (COX-2), interleukin-6, and IL-1B was inhibited by luteolin-7-O-glucuronide treatment . The co-Matrix metalloproteinase 9 (MMP-9) plays a critical role in the inflammatory response. One study established that LUT decreases MMP-9 expression to treat ischemic stroke, colon cancer, and diabetes. CASP3 is the main terminal-cleaving enzyme, and the activation of CASP3 causes apoptosis and inflammation, but LUT can increase CASP3 expression to induce apoptosis in the HaCat cells and cancer cells . LuteoliLuteolin also reversed TNF-α-induced senescence and suppressed TNF-α, causing inflammatory injury. In addition, luteolin-3′-O-phosphate (LTP) shows better anti-inflammatory activity by inhibiting the mitogen-activated protein kinase and NF-κB more effectively than luteolin. Also, at the concentration of 10 µM, LTP showed higher anti-inflammatory activity in comparison to luteolin . In a prAlzheimer’s disease is a prime cause of memory loss among the world’s population. The main characteristic of the disease is the accumulation of β amyloid peptides in the brain’s extracellular matrix . A treatFurther, it significantly reduced the expression of Bax and caspase-3 and induced the expression of Bcl2. A high amount of LUT may have potential toxicity, inhibiting Aβ25-35 and inducing cell apoptosis. It also activates the ER/ERK/MAPK signaling pathway to protect Bcl2 cells against Aβ25-35 and induce apoptosis via specifically acting on ERβ . LuteoliLuteolin produced during counteraction in the in vitro effect on oxidation is associated with the abnormal enhancement of endogenous free radical suppression of the mitochondrial viability of mitochondria membrane potential and a decrease in the glutathione content. The catalyzing activity indicates that the multilayer modulatory pathway plays a role in luteolin neuroprotection activity. The protection is a result of possible balancing in the pro-oxidation or antioxidation ratio. Further, the neuroprotective mechanism helps to restore the depressed endogenous enzymatic and non-enzymatic antioxidative defense system known as ROS scavenging activity . Luteoli2O2-induced cell apoptosis through the Bcl2 pathway, thus improving neuronal synaptic plasticity. Furthermore, it increases the Bcl2/Bax ratio by reducing caspase-3, and also prevents the depletion of TH+ve neurons in the substantia nigra (SN) and neuro fibers in the striatum, thus improving mice behavior in the pole trait and traction test and implicating its potential in applied PD therapy . The celThe superoxide dismutase activity is enhanced due to LUT, which helps to decompose OH-mediated lipid peroxidation. Luteolin suppresses the higher expression of Cyclin-dependent kinase-5 (Cdk5) and p35 due to oxidation stress. Thus it proves its effectiveness in influencing the extracellular signal-regulated kinase 1/2 (Erk1/2)- and dynamin-related protein 1 (Drp 1)-dependent survival pathways  Figure .The luteolin compound in various plant sources has many beneficial properties in favor of a healthy and disease-preventive lifestyle for humans. It possesses the property of managing heart ailments such as myocardial infarction. Cardiovascular diseases (CVDs) can result from various factors such as unhealthy lifestyle, unbalanced diet, and sedentary lifestyle. They can be prevented by eating healthy food and having an active lifestyle. The luteolin molecule helps to reduce the risk of myocardial infarction, as its inclusion in food may help in reducing CVD. In a study involving myocardial ischemia/reperfusion (I/R) (MIRM) rats, the luteolin compound treatment reduced the damage to the heart valves by reducing the Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) regulation and upregulating the STAT3 pathway, resulting in decreased inflammatory response . 2+-ATPase (SERCA) protein level by SUMOylation, and the expression of the SERCA was modulated by the Sp1 transcription factor, which has positive regulation over the SERCA gene. This process helped recover the heart tissue injury caused by myocardial infarction compared to the control [The reduced damage to heart muscles is due to the luteolin treatment, as it reduces the cytokine level in the serum of the treated animal models. In addition, luteolin helps in balancing the Siti1/NLRP3/NF-κB pathway, as it was affected in the MIRM rats . The adm control ,103. 2+ transport, which reduce in the failing cardiomyocytes and are prevented by upregulating the SERCA2a gene [The anti-apoptosis property is important in preventing heart tissue damage. In one study, administering luteolin reduced apoptosis in the simulated ischemia/reperfusion (sI/R) model by upregulating the AKT signaling . CardiacA2a gene . The impA2a gene . The carAnother lifestyle disorder is obesity, which is the high accumulation of fats. It leads to many non-communicable disorders such as cardiac arrest and diabetes, musculoskeletal disorders such osteoarthritis, and cancers such as colon, ovarian, breast, liver, prostate, kidney, and gallbladder . LuteoliLXR-α), scavenger receptor class B member 1 (SRB1), and ATP-binding cassette transporter G1 (ABCG1). It showed that luteolin reduces cholesterol by regulating the various genes involved in the cholesterol efflux pathway [The obesity studies involving C57BL/6N mice showed that artichoke leaves (AR), having luteolin, helped in reducing the obesity-related complications in mice when given along with a high-fat diet . The obe pathway . Thus, tThe phytocompounds used in managing or treating a particular disease or its related symptoms must be in a precise dose, so that other cellular functions are not affected by the compound administration. Thus, toxicity studies help provide crucial information for the compounds used in the study. The LUT compound toxicity was studied by treating human retinal microvascular endothelial cells (HRMECs) against the anti-angiogenic effect. The treatment with 10 μM of LUT had no toxic effect but increasing the concentration up to 100 μM affected the cells ,115. In Verbena officinalis, a traditional medicinal herb containing luteolin 3′-methyl ether 7-glucuronosyl-(1-2)-glucuronide, resulted in prenatal toxicity when administered in high doses during the gestation period in female Sprague Dawley rats [In a study involving ley rats . In anotley rats . The toxClinical studies for the compound LUT have been carried out with various objectives. According to the clinical trials website, 18 entries were found to be involved in using the LUT compound. Among them, three studies are in starting phase, seven studies have been completed, and two were terminated. A clinical study to treat the olfactory dysfunction of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)-affected persons showed that the administration of palmitoylethanolamide (PEA) and luteolin helped in the recovery of olfactory functions . In anot® contains LUT as one of the components used to treat cardiovascular and liver function in metabolic syndrome. The results of one study showed that intake of Altilix® supplementation helps to improve liver and cardiovascular functions [Another clinical study involved LUT treatment of delirium, a condition of cognition and awareness disorder. Post-operative delirium conditions were prevented when subjects were administrated with 700 mg of co-ultra-micronized palmitoylethanolamide (PEA) + 70 mg luteolin . The prounctions . In anotunctions . The effunctions . The cliThe plant-derived phytocompound LUT is present in most plants on earth. Plants containing the LUT compound have been used in various traditional medicines. The advent of modern analytical techniques highlighted the occurrence of LUT in plants as an important secondary metabolite in different cellular responses. Meanwhile, LUT is currently being explored for its beneficial activity in treating various human ailments. It has been made clear that the plant-obtained compound is a potential candidate in the treatment of various diseases, as it possesses the properties of anti-cancer, anti-inflammatory, anti-diabetic, and antioxidative effects. These beneficial activities of LUT have been proven and validated in multiple studies.From a future perspective, the synergistic application of LUT with other natural or synthetic drugs in chemopreventive studies could be carried out, as this approach will be more effective in controlling and managing diseases. In addition, the bioavailability of LUT can be enhanced by nanoformulation using nanotechnology, which will increase its efficacy in administration to humans and also caters to specific and efficient disease management. To make this possible, comprehensive studies should be carried out to unravel the role of LUT in treating several other diseases at a molecular level and explore the exact mechanism behind its beneficial activity. This paves the way for different strategies to employ in studies aimed at improving the well-being of humankind.


CI = −3.93 to −0.19) and depressive symptoms  were significantly correlated with lower scores. In this study, older adults with MCI showed low psychological resilience during the COVID-19 pandemic, and people with low psychological resilience indicated poor sleep quality and depressive symptoms. Our findings suggest directions for devising interventions to maintain mental health and psychological resilience among the vulnerable population of older adults with MCI living under the socially isolated conditions of COVID-19 pandemic restrictions. Our recommendation includes continuous assessment of this population and appropriate care for poor sleep quality and depressive symptoms.Psychological resilience refers to the ability to cope with adversities, and deficits in resilience might lead to mental illness. The COVID-19 pandemic has had impact on psychological resilience for older adults, but there are as yet no data on its impacts on the mental health of older adults who were living with mild cognitive impairment (MCI). Therefore, the aim of this study was to investigate the impact of the COVID-19 pandemic on psychological resilience in older adults with MCI and to explore associated physical and psychosocial factors. In this cross-sectional study of 268 older adults aged 65–85, we defined MCI as age- and education-adjusted cognitive decline with a standard deviation of 1.0 or more from the reference threshold. During December 2020 to April 2021, we carried out to all participants the 10-item version of the Connor-Davidson Resilience Scale (CD-RISC-10) to measure psychological resilience. We also conducted a comprehensive geriatric assessment including sleep quality and depressive symptoms . To identify factors associated with CD-RISC-10 scores (mean: 23.3 ± 0.4), multiple regression analysis revealed that older age  was significantly correlated with higher scores, whereas poor sleep quality (coefficient = −2.06, 95%  The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began spreading in Japan in January 2020. Prevention measures such as social distancing effectively reduced new infections . AlthougResearchers found that isolation caused by infection prevention measures was linked to depression, anxiety, and cognitive decline as well as lower self-worth, which are factors involved in the concept of resilience .Resilience is the ability to adapt positively in the face of adversity and maintain mental health , and it We conducted this cross-sectional study as part of the World-Wide FINGERS SARS-CoV-2 survey  in WorldWe recruited all participants from the Japan-multimodal intervention trial for prevention of dementia (J-MINT) conducted by the National Center for Geriatrics and Gerontology (NCGG) in Aichi Prefecture . The incWe collected participants' demographic information  by questionnaire. The response options for household income were in increments of JPY 2,000,000, and for self-reported medical history, we asked about the following diseases: diabetes, hypertension, dyslipidemia, atrial fibrillation, congestive heart failure, chronic kidney disease, liver disease, cerebrovascular disease, malignant tumor, thyroid disease, coronary artery disease, neurodegenerative disease, depression and insomnia. For our analyses, the self-reported medical history was divided no medical condition or one or more.We used the CD-RISC-10 score to evaluate respondents' psychological resilience. Respondents rate each item on a scale from 0  to 4 , so that the total score ranges from 0 to 40. Higher scores reflect greater psychological resilience.To explore factors related to the older adults' psychological resilience in this study, we conducted a CGA, a inclusive method of assessing psychological and functional capability of older adults . For allP < 0.05 as statistically significant.All participants' demographic information is expressed as mean ± SD, median and interquartile range (IQR) or number of people and percentage. We used simple regression to analyze the associations between the CD-RISC-10 and each CGA variable, and we used multiple regression to analyze the CD-RISC-10-variable relationships that were statistically significant in the simple regressions, with the CD-RISC-10 score as the response variable and the statistically significant variables as explanatory variables. Moreover, we entered sex and education, which were related to psychological resilience in a previous study , as confOf 298 original participants, 279 responded to the questionnaire of the CD-RISC-10 between December 2020 and April 2021 (response rate: 93.6%). From those 279, we excluded six respondents who self-reported depression and five whose CD-RISC-10 responses were incomplete, which left the data on 268 participants for the analysis. CI = 0.06–0.39) was related to higher CD-RISC-10 score, and depressive symptoms  and poor sleep quality  were associated with lower score  from the NCGG. The funders had no role in the preparation of this manuscript.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.


Non-pharmaceutical interventions have been implemented around the world to control Covid-19 transmission. Their general effect on reducing virus transmission is proven, but they can also be negative to mental health and economies, and transmission behaviours can also change voluntarily, without mandated interventions. Their relative impact on Covid-19 attributed mortality, enabling policy selection for maximal benefit with minimal disruption, is not well established due to a lack of definitive methods.We examined variations in timing and strictness of nine non-pharmaceutical interventions implemented in 130 countries and recorded by the Oxford COVID-19 Government Response Tracker (OxCGRT): 1) School closing; 2) Workplace closing; 3) Cancelled public events; 4) Restrictions on gatherings; 5) Closing public transport; 6) Stay at home requirements (‘Lockdown’); 7) Restrictions on internal movement; 8) International travel controls; 9) Public information campaigns. We used two time periods in the first wave of Covid-19, chosen to limit reverse causality, and fixed country policies to those implemented: i) prior to first Covid-19 death (when policymakers could not possibly be reacting to deaths in their own country); and, ii) 14-days-post first Covid-19 death . We then examined associations with daily deaths per million in each subsequent 24-day period, which could only be affected by the intervention period, using linear and non-linear multivariable regression models. This method, therefore, exploited the known biological lag between virus transmission (which is what the policies can affect) and mortality for statistical inference.After adjusting, earlier and stricter school  and workplace closures  were associated with lower Covid-19 mortality rates. Other interventions were not significantly associated with differences in mortality rates across countries. Findings were robust across multiple statistical approaches.Focusing on ‘compulsory’, particularly school closing, not ‘voluntary’ reduction of social interactions with mandated interventions appears to have been the most effective strategy to mitigate early, wave one, Covid-19 mortality. Within ‘compulsory’ settings, such as schools and workplaces, less damaging interventions than closing might also be considered in future waves/epidemics.The online version contains supplementary material available at 10.1186/s12889-022-13546-6. Non-pharmaceutical interventions were considered one of the few options for reducing the transmission of Covid-19 prior to vaccines, and so have played a critical role in the policy response . CountriPublic attention on effectiveness of Covid-19 measures has largely focused on different countries’ strategies, with certain countries singled out as exemplars based on unadjusted descriptive analysis . HoweverHowever, evidence is still needed empirically on the effectiveness of non-pharmaceutical interventions on Covid-19 mortality, particularly comparing specific intervention effects. A number of studies have examined effects of interventions observed in previous epidemics , 14, notFinally, there are studies, like ours, which attempt to examine relative intervention effects using multiple cross-country counterfactuals. For example, Kontis et al. examined all-cause mortality in 21 industrialised countries using Bayesian models to group countries in terms of overall death toll . Liu et A key limiting factor to all of the analyses above (and this one too) is that there are no current best practice methods in health policy research for analysing multiple interventions introduced simultaneously, as has been the case in response to Covid-19. This lack of definitive methods makes it essential to examine the question using a variety of different methodological approaches to expand the evidence base and to complement inherent weaknesses in any single method.We aimed to add to this literature base by examining the relative association between strictness and timing of individual non-pharmaceutical interventions and Covid-19 mortality in wave one, adjusting for concurrent interventions. Results complement the current literature and together inform the understanding of the drivers of differences in mortality across countries and policy choice for future waves and epidemics.We analysed observational data from 130 countries and exploited cross-country variation in policy implementation. We used a novel approach in the current literature, exploiting the known time lag between intervention implementation and mortality –26 to mihttps://www.ecdc.europa.eu/en/covid-19/data-collection) on 1st June 2020. The ECDC compiles data from multiple sources, mostly sourced from individual country Ministries of Health or National Public Health Institutes. This does indicate that the precise definition of Covid-19 death varies somewhat across country , and it does not distinguish between deaths directly from- or deaths with-Covid-19. Covid-19 mortality was measured as country daily deaths per 1 million population, with World Bank country population estimates from 2018 used as the denominator. Days in each country were indexed in time by first reported Covid-19 death to proxy for virus transmission rate and to make rates comparable over time.Our outcome of interest was Covid-19 attributed mortality rate. We obtained daily Covid-19 deaths for 130 countries from the European Centre for Disease Prevention and Control (ECDC) website  on 1st June 2020 . Data arWe also collated country-level co-variates , which might affect the outcome and the uptake of non-pharmaceutical interventions  and mortality. This approach was employed to address concerns of bias due to potential reverse causality caused by policymakers introducing non-pharmaceutical interventions in response to a rising mortality rate, which would downwards bias the effect of introducing the interventions. It also allowed us to examine effects of multiple policies concurrently, drawing on inter-country intervention variation. Evidence suggests a mean lag between virus transmission and symptom onset of 6 days , 25, andWe considered two distinct time periods of 24 days to account for the changing magnitude of effects of an exponentially transmitted virus: i) 0-24 days and ii) 14-38 after the first Covid-19 indexed death. The analysis at 0-24 days is very unlikely to suffer from bias caused by reverse causality since policymakers cannot possibly be reacting to deaths within their own country. The 14-38 days analysis, on the other hand, has a small risk of this bias if policymakers react quickly to deaths within the first 14 days. However, the mean number of cumulative deaths in the analysis sample at 14 days was 31 (SD 68) suggesting the mortality rate was still relatively low in most countries. Indexing all countries to these relative mortality dates also had the benefit of comparing country interventions at comparable stages of the pandemic.For each of the two 24-day periods we calculated, and fixed for each country, the strictness and timing of each of the nine non-pharmaceutical interventions prior to the start of the period, i.e. strictness/timing of interventions implemented before the day of the first reported Covid-19 death were analysed for the 0-24 day period analysis; and strictness/timing of interventions up to 14 days after the first reported Covid-19 death were analysed for the 14-38 day period analysis.For our primary analysis we generated an aggregated measure of both strictness and timeliness to account for the changes in interventions over time, equivalent to an interaction of strictness and timing. Mean intervention strictness was calculated for each of the 24-day time periods: i) from 30 days before (to ensure comparable time periods over which the average was taken) the first Covid-19 death; and ii) from 30 days before until 14 days after the first Covid-19 death. Countries with earlier and stricter non-pharmaceutical interventions, therefore, had higher mean strictness values.Due to the dynamic nature of policy implementation, it is inadequate to observe only intervention strictness or timing alone, which is why we prefer our primary analysis measure. However, additionally separating analysis by strictness or timing alone assisted in interpretation of the analysis of the combined mean score. For secondary analysis we took the maximum strictness value  prior to first Covid-19 death; ii) 14-days-post first Covid-19 death) nine concurrent non-pharmaceutical intervention statuses on daily Covid-19 deaths per million population over the subsequent 24-day period. This means we did not overly-rely on the accuracy of the 24-day period informed by the literature, able to capture daily deaths at any point from 0 to 38 days over the combined analyses. We also included a range of covariates (see Table n = 130) with no missing intervention indicators, outcome, or covariates at each time point.We excluded countries with less than a population of 100,000 and we analysed data for countries  to check the consistency of the direction and significance of intervention effect across non-linear models.Figure In unadjusted analysis  , whilst Other cross-country comparisons of non-pharmaceutical interventions have identified that travel restrictions were associated with slower geographical spread and initial case numbers, but failed to quantify the specific effect . One stuOur results are most consistent with those using statistical methods to examine relative effects on the effective reproduction number of Covid-19. Haug et al. likewise found that small gathering cancellations (which included mandatory home working in their case) and closure of education facilities were the most effective interventions. Although they found that stay at home interventions could also reduce transmission, they concluded that “less disruptive and costly NPIs [interventions] can be as effective as more intrusive, drastic, ones ” . Liu et The finding that selected non-pharmaceutical interventions are associated with lower Covid-19 mortality is not surprising given the known reductions in social contacts and transmission from these interventions, and their historical use to control epidemics. However, it may be unexpected that workplace and, particularly, school closures were associated with relatively lower Covid-19 mortality across countries whilst interventions such as stay-at-home measures were not. One plausible interpretation is that schools and workplaces involve ‘compulsory’ interactions with others, as individuals feel obliged to attend in person and may be concerned for loss of earning or educational opportunities. This compares to interventions targeting other sources of human interaction which are more ‘voluntary’ and may reduce irrespective of whether mandated policies are introduced .prior  to stay-at-home implementation in US states which introduced measures [without stay-at-home measures compared to those with (61%) [This mechanism is supported by multiple studies examining the effects of non-pharmaceutical interventions on mobility. One US study found mobility reductions in all US states, even those not adopting formal stay-at-home measures, due to individuals’ voluntary behaviour changes . Notablymeasures , and mobth (61%) . Likewisth (61%) . Unfortuth (61%) , 40. Thith (61%) . We do nSchool closing having the largest effect is also interesting, in that children are known to be relatively less personally affected by the negative effects of Covid-19 than older adults . This reOverall, policymakers should note that efforts to reduce social interactions through restricting compulsory activities, such as school and work, may be more effective in reducing mortality than targeting actions where individuals have more freedom in choice or where activities are likely diminished due to other actions. However, our results only apply directly to the early stages, wave one, of the Covid-19 pandemic. For identifying responses to subsequent waves, or other novel pathogens, understanding the complex behaviour changes from specific interventions is necessary for appropriate mitigation. There is no guarantee that the behaviour changes outlined above would be replicated if population complacency or a primary focus on other immediate pressures, such as financial hardship, prevailed.Future research should examine long-term effects of interventions, such as whether countries suppressing stricter/earlier are more vulnerable to future outbreaks. Understanding the inter-connected nature of different interventions and their impacts on population behaviours, including how these behaviours change over time, is key. The important role of different countries’ health systems, supply chains and/or cultures, and ‘pre-existing conditions’  should also be understood as important mediators in preventing Covid-19 mortality. Understanding how the targeting of specific interventions to certain populations and protecting high-risk groups (e.g. elderly) and institutions  will hopefully reveal more nuanced policy responses for future outbreaks. Integrating policy options into wider behavioural science, for example through nudging or encouraging select behaviours , might oEarly workplace and, particularly, school closures were associated with the lowest Covid-19 wave one mortality rates across 130 countries. Focusing on protecting individuals from social interactions by targeting more ‘compulsory’ places (including schools and workplaces) as opposed to more ‘voluntary’ interactions and changing behaviours of those with lower individual-risk appear to have been most effective strategies mitigating early Covid-19 mortality.Additional file 1.


Patients intra-operatively treated with CytoSorb® were compared to a control group. The primary outcome was the change in the vasoactive-inotropic score (VIS) from pre-operatively to post-operatively. (3) Results: A total of 52 patients were included in the analysis, where 23 were treated with CytoSorb® (CS) and 29 without (controls). The mean VIS increase from pre-operative to post-operative values was significantly lower in the CS group compared to the control group . In-hospital mortality in the control group was 20.7% (6 patients) and 9.1% (2 patients) in the CS group (p = 0.26). Lactate level changes were comparable, and the median intensive care unit and hospital lengths of stay were similar between groups. (4) Conclusions: Despite notable imbalances between the groups, the signals revealed point toward better hemodynamic stability with CytoSorb® hemoadsorption in complex cardiac surgery and a trend of lower mortality.(1) Background: Cardiac surgery may evoke a generalized inflammatory response, typically magnified in complex, combined, redo, and emergency procedures with long aortic cross-clamp times. Various treatment options have been introduced to help regain control over post-cardiac surgery hyper-inflammation, including hemoadsorptive immunomodulation with CytoSorb Cardiac surgery may evoke a generalized inflammatory response in patients, with sometimes serious clinical consequences, despite advances in pharmacology, perfusion technology, cardiovascular monitoring, and anesthetic and surgical techniques . As a reEven with significant technical improvements in recent years, cardio-pulmonary bypass (CPB) itself remains a frequent trigger for the development of a dysregulated hyper-inflammatory host response, similar to sepsis. This is accompanied by elevated levels of inflammatory mediators and may result in a compromised microcirculation, increase in lactate levels, vasoplegia and subsequent organ dysfunction . PersistVarious techniques, technological advancements, and treatment options have been introduced during recent decades with the aim of helping to regain control over this post-cardiac surgery hyper-inflammation . The hemoadsorption of inflammatory mediators has recently emerged as a promising strategy with the goal to attenuate the deleterious effects of the dysregulated inflammatory response while preserving the ability of the patient’s immune system to mount an appropriate defense against these challenges during the peri-operative period .®. The aim of our study is to evaluate CytoSorb® therapy in the setting of complex cardiac surgery.One of the most widely investigated immunomodulating hemoadsorptive treatments is CytoSorb® (CS group) were compared to a control group without intra-operative CytoSorb® use (Control group). Inclusion criteria were: (1) patients with a CPB time longer than 120 min and (2) the procedure was labeled as “complex” by the operating team, or was a redo procedure. The observational period was between December 2018 and October 2021. Informed consent was waived due to the retrospective nature of this study.The present study considers a single-center, retrospective observational study of patients undergoing complex cardiac surgery. Patients with intra-operative use of the hemoadsorption device CytoSorb® therapy  is a blood purification technique based on the adsorption of hydrophobic molecules of up to approximately 60 kDa of molecular weight. It is installed in an extracorporeal circuit of various platforms and used for the removal of excess levels of cytokines, together with some metabolites such as bilirubin and myoglobin, and also antithrombotic medications, such as ticagrelor and/or rivaroxaban  vs. 64 years [60–68] in the CS group (p = 0.01). The patients were predominantly male in both groups (61% in the CS group and 66% in the control group). For almost half of the control group (45%), this was a redo procedure, while only 22% of the CS group included re-operations (p = 0.08). The median cross-clamp time was 121.5 min [100–156] in the CS group but was significantly longer in the control group, 154 min  (p = 0.04). Another significant difference was in the pre-operative usage of an intra-aortic balloon pump (IABP) which was present in almost 22% of patients in the CS group while no patients among the controls needed this treatment before the operation . The baseline characteristics of all patients are given in A total of 52 patients who underwent open-heart surgery on CPB were included in the analysis. Almost all patients required combined procedures comprising multiple valve surgery, coronary artery bypass grafting (CABG), and various procedures involving the aorta. Twenty-three patients were treated with CytoSorbThe vasoactive-inotropic score increased post-operatively in both groups .p = 0.05 (The mean VIS increase  from prep = 0.05 .p = 0.26), as did not the difference in the post-operative VIS - 5.7 with CytoSorb® vs. 6.6 without hemoadsorption (p = 0.53). The median ICU and hospital lengths of stay were similar between groups. Lactate levels for both groups increased after 6 h post-operatively, however, they decreased comparably over the following 24 hrs. Both groups were similar in terms of the mechanical ventilation time and CRRT requirement  and 9.1% (2 patients) in the CS group, however, this difference did not reach statistical significance  manifesting as severe hypotension, with normal or elevated cardiac index (CI). Some patients develop vasoplegic shock, involving deleterious vasodilation and hypotension, even with normal CI and adequate fluid resuscitation, leading to reduced tissue perfusion and metabolic acidosis. First-line treatment includes high-dose vasopressors, particularly catecholamines, to maintain adequate mean arterial pressure. Vasoplegic shock that is refractory to these agents is detrimental . Rescue ® therapy might significantly reduce hyper-inflammation and improve hemodynamic stability in patients undergoing complex cardiac surgery.Considering the substantial proportion of frail patients with multiple comorbidities in cardiac surgery today, the ever-present CPB-induced systemic hyper-inflammation, together with the high rate of complex and redo procedures, we hypothesized that intra-operative CytoSorb® therapy is not supposed to suppress the physiological inflammatory response, but rather aid the immune system to regain control and modulate its dysregulated response. Furthermore, while removing overshooting levels of cytokines, the concurrent removal of trigger molecules, such as PAMPs (pathogen-associated molecular patterns) and DAMPs (damage-associated molecular patterns), which reside in the above-described adsorption range, have been observed [® therapy aims at helping the patient’s body mitigate the cytokine hyper-release cytotoxic effects and attenuate the dysregulated inflammatory response, intending to prevent the progression of organ dysfunction.CytoSorbobserved . In this® is the reduction in vasopressor demand [®-mediated attenuation of hyper-inflammation associated vasoplegia in our patients, we expected the VIS change from pre-op to post-op to be improved in the CytoSorb® group compared to controls. The results of our study show that the post-operative VIS increase was, in fact, significantly lower in the CytoSorb® group, indirectly confirming that hemoadsorption of excessive levels of cytokines prevented an overwhelming development of vasoplegia, potentially also influencing mortality. Survival was numerically better in the CS group than in the control group , but this difference was not statistically significant within this small cohort. The present study was designed as a pilot study at our center when we started with this innovative adjunctive therapy in 2018.One of the most prominently reported outcomes in clinical investigations with CytoSorbr demand ,22,23,24r demand ,26 with r demand . Conside® was used intra-operatively demonstrated significantly better hemodynamic stability and shorter lengths of ICU and hospital stays [® treatment, but hemoadsorption was delivered post-operatively, utilizing either continuous renal replacement therapy (CRRT) or extracorporeal membrane oxygenation (ECMO) as the delivery platform. In both studies, VIS significantly decreased after CytoSorb® therapy was administered in patients who developed septic shock post cardiac surgery [In two very recent single-center controlled studies involving high-risk infective endocarditis (IE) patients, the authors could show that intra-operative hemoadsorption lowered the incidence of sepsis, sepsis-related death , and oveal stays , as wellal stays . It has al stays . To our  surgery  or in ot surgery . Our stu® patients were significantly older. Nevertheless, the results of this study represent real-world data, being a report on a single-center experience, the first of this kind in India, that, in our opinion, can serve as a valuable guideline for designing future large prospective trials investigating the role of hemoadsorption in complex cardiothoracic surgery.None of the aforementioned secondary outcomes were different between the two groups in our study. The plausible reasons for this most probably lie in the fact that the two groups were not well balanced. Mortality, for example, was substantially higher in controls, but it has to be taken into account that the aortic cross-clamp time was significantly longer and re-sternotomies were twice as frequent in this group. On the other hand, the need for IABP was exclusively present in the CS group reflecting the high acuity of such patients. Moreover, the EuroSCORE II was notably higher in the treatment group, the pre-operative VIS was twice as high as in control patients, and the CytoSorb12 inhibitors, such as ticagrelor (after PCI), intra-operative hemoadsorption holds promise to prevent bleeding complications [Another important indication which was not covered in this analysis is the increasing use of antithrombotic medications, especially in high-risk and elderly patients. A noteworthy proportion of such patients suffer from non-valvular atrial fibrillation and might undergo a simultaneous maze procedure or occlusion of the left atrial appendage. As these patients are commonly treated with DOACs  or P2Yications ,32.There were several significant baseline differences between the groups causing a notable imbalance which represents a serious limitation of our study. The lack of sequential VIS values beyond the first post-operative day may be considered as another shortcoming, however, we believe that the potential effects of intra-operative hemoadsorption would have a rather short term effect that would be seen immediately after the surgery and that the further course in the ICU may be influenced by many other factors which would introduce even more confounders. Therefore, the post-operative VIS calculation was limited to the first 24 h only. Moreover, the retrospective nature and small sample size, together with possible patient selection bias all call for caution when interpreting the results of this study.Notwithstanding the above, this is the largest case-control study evaluating complex cardiac surgery patients treated with intra-operative hemoadsorption in India so far and the signals revealed with the performed analysis may guide future investigations in this clinical setting.® to improve clinical outcomes and is a guide for the design of future studies. In the present study, signals point toward better hemodynamic stability with the use of CytoSorb® in complex cardiac surgery, and a trend towards lower mortality. However, the role of hemoadsorption and the potential routine implementation of this approach requires further evaluation in prospective studies.To our knowledge, this is the largest case-control study in the setting of complex cardiac surgery involving various, mostly combined procedures, that has evaluated the effects of cytokine hemoadsorption in a high-risk patient population in India. As such, it represents real-world data, albeit with several important limitations . However, it also provides excellent insight into the potential of CytoSorb