The invasiveness of different surgical procedures is variable. The purpose of this study was to investigate the value of the postoperative neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as biomarkers in assessing the magnitude of surgery-related trauma in young and middle-aged patients with bicondylar tibial plateau fractures (TPFs).A total of 136 young and middle-aged patients with bicondylar TPFs who underwent surgical treatment between May 2016 and April 2020 were included. Details about demographic information, pre- and postoperative laboratory data, and surgical variables were obtained from the electronic database of our level I trauma center. According to the different surgery programs, all patients were divided into two groups: group 1, which represented minimally invasive reduction and internal fixation (MIRIF), and group 2, which represented open reduction and internal fixation (ORIF). Univariate and multivariate logistic regression and ROC curve analyses were used.P < 0.05). In the multivariate analysis, postoperative PLR ≥ 223.9, surgical incision > 19.0 cm and operative time > 130 min were closely related to severe surgery-related trauma. The ROC curve analysis indicated that postoperative PLR could predict severe surgery-related trauma with a specificity of 76.0 % and a sensitivity of 55.7 %.The operative time, intraoperative tourniquet use, intraoperative blood loss, length of incision, postoperative NLR, PLR, RBC and HCRP were significantly different between the two groups (Postoperative PLR appears to be a useful biomarker that is closely associated with magnitude of surgery-related trauma in young and middle-aged patients with bicondylar TPFs. Bicondylar tibial plateau fracture (TPF) management remains one of the most challenging orthopedic traumas, mainly occurring in young and middle-aged adults . BicondyThe peripheral blood neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been increasingly recognized as indicators of a systematic inflammatory response for many malignant tumors, cardiovascular disorders, fractures and polytrauma –12. A grTherefore, we performed a retrospective study to analyze the correlation between postoperative NLR and PLR levels and the magnitude of surgery-related trauma in young and middle-aged patients with bicondylar TPFs.n = 61) and group 2 . The flowchart of the patient screening process is shown in Fig. Data used in this study were extracted from an electronic database of our level I trauma center, in which a retrospective method was used to collect data on patients with bicondylar TPFs who underwent treatment with dual plating fixation  between May 2016 and April 2020. In this study, the inclusion criteria were defined as follows: (a) age ≥ 18 and ≤ 65 years; (b) diagnosis of closed bicondylar TPF; (c) surgical treatment with dual plating fixation; and (d) blood tests performed at hospital admission and on postoperative day 1. The exclusion criteria were as follows: (a) open wound, multiple trauma or compartment syndrome; (b) previous or pathologic fractures or old fractures (> 21 days); (c) active malignancy, systemic inflammatory or infectious diseases, systemic lupus erythematosus, HIV, severe neurovascular injury, or cardiovascular diseases; (d) treatment with external fixation or conservative methods; and (e) incomplete medical data. In this study, all patients with bicondylar TPFs were fixed by dual plating fixation. The patients were grouped according to the different surgical programs as follows: group 1  and adhered to the principles outlined in the Helsinki Declaration. Informed consent was obtained from all patients in the study.The indicators of interest were extracted mainly as follows: (1) Demographic data such as age, sex, body mass index (BMI), lifestyle risk factors , and chronic diseases ; (2) Characteristics of fractures, including injury mechanism (low- or high-energy) and fracture classification; (3) Surgery-related variables included preoperative stay, surgical program (MIRIF and ORIF), operative time, intraoperative blood loss, anesthetization, American Society of Anesthesiologists (ASA) grade, and hospital stay; (4) Pre- and postoperative laboratory tests included neutrophil (N) count, lymphocyte (L) count, platelet (PLT) count, hypersensitive C-reactive protein (HCRP), hemoglobin (HGB), white blood cell (WBC), red blood cell (RBC) and others.It is worth mentioning that the peripheral venous blood of patients was drawn by professionally trained phlebotomists. To control for circadian rhythms, all samples were routinely collected during the same time period (6:00 AM to 8:00 AM) on the1st day at admission and on the 1st postoperative day. The samples were transported to the biochemical laboratory for testing within an hour.. The surgical program of group 2 was as follows: two longitudinal incisions of approximately 10–15 cm were made on the medial and anterolateral tibial plateau, and two locking plates were inserted after prying reduction by Kirschner wires . The other steps were the same as in group 1. In addition, postoperative care of the two groups of patients was standardized and kept uniform.Surgical procedures for the patients with bicondylar TPFs were performed by orthopedic surgeons from the same research team, and all surgeons had more than 10 years of experience in orthopedic surgery. Our team performed two different surgical procedures (MIRIF and ORIF) for patients with closed bicondylar TPFs. Before surgery, patients received general anesthesia or intraspinal anesthesia and routine antibiotic prophylaxis. The surgical program of group 1 was as follows: a universal traction device was used for bone traction of the lower extremities. Specially designed jacking tools were used to reduce the collapsed articular fragments. Intraoperative fluoroscopy was used to examine the reduction status. Two locking plates were placed on the medial and anterolateral tibial plateau, and the minimally invasive percutaneous plate osteosynthesis (MIPPO) technique was applied through 4–5 small incisions of approximately 3 cm   with 95 % confidence intervals (CIs), sensitivity and specificity of the relevant variables were analyzed using the receiver operating characteristic (ROC) curve procedure. Data with skewed distributions were categorized by the cutoff and reference values. Variables with significant differences (P < 0.05) were entered into multiple logistic regression analysis to determine the predictive factors for the magnitude of surgery-related trauma. The strength of the associations was evaluated according to the odds ratios (ORs) with 95 % CIs. The fitting degree of the final model was assessed by the Hosmer-Lemeshow test, and P > 0.05 indicated an acceptable result. A P value of less than 0.05 was considered statistically significant.All statistical data in our study were analyzed with IBM SPSS version 23.0 . Continuous variables are presented as the mean ± standard deviation (SD) as appropriate, and categorical variables are presented as numbers and percentages (%). According to whether the variables conformed to a normal distribution, the independent samples Student’s During a 4-year study period, a total of 136 patients with isolated bicondylar TPFs were recruited . All patients were treated with dual plating fixation by one of two surgical procedures. The patients were divided into 2 subgroups by surgical procedure: group 1 included 61 patients (44.9 %) who underwent MIRIF, and group 2 consisted of 75 patients (55.1 %) who underwent ORIF.P < 0.001), intraoperative tourniquet use (P = 0.015), intraoperative blood loss (P < 0.001), length of incision (P < 0.001), postoperative 1st day NLR > 10.1 (P = 0.018), postoperative 1st day PLR > 223.9 (P < 0.001), postoperative 1st day RBC < lower limit (P = 0.021) and postoperative 1st day HCRP > 47.6 mg/L (P = 0.048) of patients in group 1 were significantly different from those in group 2. In addition, pre- and postoperative laboratory findings showed that postoperative RBC, HGB, and ALB were significantly lower than their preoperative values, and postoperative N count, PLT count, L count, NLR, PLR and HCRP were significantly higher than those before surgery (Table 3).In our study, the optimum cutoff values of related variables, such as the length of incision, operative time, intraoperative blood loss, pre- and postoperative NLR, PLR and HCRP, were determined by ROC curve analysis Table . In the P < 0.001), operative time > 130 min  and postoperative 1st day PLR > 223.9  had a significant association with severe surgery-related trauma (Table 3). The Hosmer-Lemeshow test showed the good fitness . We further constructed ROC curves and used the AUC, sensitivity, and specificity to evaluate the predictive ability of each biomarker or related index: length of incision , operative time  and postoperative 1st day PLR  .In the multivariate logistic regression analysis model, some related factors, such as age, sex, BMI, hypertension, diabetes, anesthetization and postoperative 1st day HGB, were included, which may influence the choice of surgical procedures and the body’s immune response. The final multivariate analysis results suggested that incision > 19.0 cm  was an independent predictor of severe surgery-related trauma in patients with isolated bicondylar TPFs.In recent years, many studies have found that the NLR and PLR are related to the prognosis of patients with severe trauma , 14, 17.In the past few years, minimally invasive treatment techniques such as MIPPO technology and double-reverse traction technology have been widely used in the treatment of bicondylar TPFs , 16. ComRecently, several ready-made parameters, derived from routine complete blood counts (CBCs), have been investigated as potential biomarkers. In response to major trauma, neutrophils can rapidly contribute to the inflammatory response; as part of a systemic inflammatory response, lymphocytes are involved in the adaptive immune response. It is characterized by an increase in neutrophil counts and a decrease in lymphocyte counts. Platelets are also activated after traumatic injuries as cellular effectors of inflammation , 21. PreIt is important to assess the severity of surgery-related trauma by identifying reliable biomarkers. Flohé et al.  reportedThe results of univariate analysis showed that there were significant differences between the two groups in incision size, operative time, intraoperative blood loss, postoperative RBC and HGB Table . This inOf note, the present study has some limitations. First, this study was a retrospective and single-center study. Second, this study failed to elaborate in detail on the pathogenesis of the elevated postoperative NLR and PLR levels caused by major surgery. Third, there is a lack of standardized management of postoperative hematology examinations in our center. Except for routine whole blood cell examination on the first day after surgery, there was no definite time for other blood examinations. Finally, the laboratory test results of certain clinical and inflammatory markers, such as interleukin (IL)-6, IL-10 and TNF-α, were not included in this study. Therefore, the results of this study should be verified in further prospective and multicenter studies.To our knowledge, this is the first study to clarify that postoperative NLR and PLR can be used to predict the magnitude of surgery-related trauma by restricting the fracture types and surgery programs. Postoperative 1st day PLR > 223.9, length of incision > 19.0 cm and operative time > 130 min were closely correlated with severe surgery-related trauma in young and middle-aged patients with bicondylar TPFs. The potential value of postoperative PLR in clinical practice needs to be established in additional studies.


Dementia is the major predictor of death in old age. The aim of this paper was to determine whether 8-year mortality among 85-year olds with and without dementia, and if the contribution of dementia to mortality relative to other common diseases has changed. We used two population-based cohorts of 85-year-olds (N = 1065), born in 1901–02 and 1923–24, which were examined with identical methods in 1986–87 and 2008–2010 and followed for 8-year mortality according to data from the Swedish Tax Agency. Dementia was diagnosed according to DSM-III-R. Other diseases were diagnosed based on self-reports, close informant interviews, somatic examinations, and the Swedish National In-patient Register. Compared to cohort 1901–02, cohort 1923–24 had a lower 8-year mortality both among those with  and without dementia . Dementia was associated with increased mortality in both cohorts , and remained the major predictor of death, with a population attributable risk of 31.7% in 1986–87 and 27.7% in 2008–10. Dementia remained the most important predictor of death in both cohorts. The relative risk for mortality with dementia did not change between cohorts, despite a decreased mortality rate in the population.The online version contains supplementary material available at 10.1007/s10654-021-00745-5. The increased life expectancy worldwide will result in a substantial increase in the number of individuals living with dementia, from almost 50 million today to 132 million by 2050 . A numbeFew studies have investigated time-trends in mortality in relation to dementia, showing conflicting results –21. StudP = 0.011), and higher prevalence of depression , compared to participants [Two cohorts of 85-year-olds from the Gothenburg H70 Birth Cohort studies, Sweden, born 1901–02 and 1923–24, were examined in 1986–87  and 2008–10  , the Mini Mental State Examination (MMSE)  and the Semi-structured interviews with close informants were performed at baseline in 451 participants (91%) in 1986–87 and 443 (78%) in 2008–2010. The close informant interviews comprised questions about changes in behaviour and intellectual function , and background factors (e.g. history of stroke/TIA) .The diagnostic procedures were identical at both examinations, as described in detail previously . First, The details of the classification of different etiological subgroups are described previously . AlzheimInformation about other diseases  was obtained through semi-structured interviews, laboratory tests, information on medications, and the National Inpatient Register. Detailed information on diagnostics are found in online resource 1.Educational level was self-reported as compulsory education only or at least one more year.Information on date of death was available from the census records administrated by the Swedish Tax Agency, which records all deaths of Swedish citizens .P-values in the primary analyses were ≤ 0.2.Baseline characteristics were compared using Pearson’s Chi-square test for categorical variables, independent samples t-test for differences in means, and Mann–Whitney U Test for differences in medians. Median survival time and 95% confidence interval (CI) was derived from Kaplan–Meier survival analysis. Cox proportional hazards models were used to compare mortality between the cohorts in five models, presented as Hazard ratios (HR) and 95% confidence intervals (CI). As mean age was slightly higher in cohort 1923–24 [Analyses stratified by sex and dementia status were then performed using Models 1–5.In order to investigate potential effect modification by cohort, the interaction terms (sex*cohort), (dementia status*cohort), and (education*cohort) were used.Population attributable risk (PAR), which takes into consideration both the relative risk for mortality in individuals with the disease and the prevalence of the disease in the population, was calculated according to the formula:In this formula, p is the proportion of the population with the risk factor and r is the relative risk . The relAll models met the proportional hazards assumption based on Schoenfeld residuals. Analyses were performed using IBM SPSS STATISTICS 25 and R Statistical Software (version 3.5.3).Characteristics of the samples are given in Table The median survival time from baseline in cohort 1901–02 was 4.9 (95% CI 4.4–5.5) years, and in cohort 1923–24 5.7 (95% CI 5.2–6.2) years. Women had lower mortality than men both in cohort 1901–02  and cohort 1923–24 .When adjusting for sex and age (Model 1), mortality was lower in cohort 1923–24 compared to cohort 1901–02 , both in women  and in men . The cohort differences remained in the total group and in women in all models. Among men, the cohort difference was no longer significant when adding education (online resource 2). The interaction terms (sex*cohort), and (education*cohort) were not significant, indicating that cohort changes in mortality did not differ by sex or education.Mortality was higher in those with dementia compared to those without, both in cohort 1901–02 , and in cohort 1923–24 , when adjusting for age and sex. Compared to individuals without dementia, mortality was higher in AD , VAD , and in VAD or mixed dementia .When stratifying by dementia status, the median survival time from baseline among those without dementia in cohort 1901–02 was 6.0 (95% CI 5.5–6.5) years and in cohort 1923–24 6.5 (95% CI 6.0–7.0) years. Among those with dementia, the median survival time from baseline was 2.7 (95% CI 2.4–3.0) years in cohort 1901–02 and 3.0 (95% CI 2.5–3.5) years in cohort 1923–24. The mortality declined between cohorts among those without dementia , but the decline was not significant among those with dementia  (Model 1) . Adding dementia severity to the models, mortality was lower in cohort 1923–24 compared to cohort 1901–02 also among those with dementia . In Model 4 (online resource 2), the cohort difference remained in those without dementia, but not in those with. In the fully adjusted model , cerebrovascular disorders , and myocardial infarction . Congestive heart failure was an independent predictor only in cohort 1923–24 (PAR 9.8%).When adding dementia subgroups instead of total dementia to the model, sex, AD , VAD , mixed dementia , other dementia types , and myocardial infarction  were independent predictors for 8-year mortality both in cohort 1901–02 and 1923–24. In cohort 1923–24, cerebrovascular disorders (PAR 10.1%) and heart failure (PAR 9.8%) were also independent predictors for 8-year mortality. Results for subgroups stratified by sex can be seen in online resource 3.Among women, independent predictors for 8-year mortality in both cohorts were dementia , and cerebrovascular disorders . In cohort 1901–02, atrial fibrillation (PAR 7.7%) and myocardial infarction (PAR 12.6%) were also independent risk factors.Among men, independent predictors for 8-year mortality in both cohorts was dementia . In cohort 1901–02, chronic bronchitis (PAR 12.3%) was also an independent risk factor. In cohort 1923–24, heart failure (PAR 11.0%) and atrial fibrillation (PAR 13.4%) were also independent predictors.We aimed to examine whether 8-year mortality in relation to dementia, and whether the importance of dementia to predict mortality relative to other common diseases, changed between two representative samples of 85-year-olds from Gothenburg, Sweden, examined 22 years apart (1986–87 and 2008–10). We found that mortality decreased to a similar extent in those with and without dementia, and that dementia remained the major predictor of death with population attributable risks of 32% 1986–87 and 28% in 2008–10, despite a lower prevalence of dementia in the cohort born 1923–24.In relation to our first aim, the finding that mortality decreased to a similar extent in individuals with and without dementia is similar to findings from the Kungsholmen Study from central Stockholm, comparing populations aged 75 years and older examined in 1987–89 and 2001–2004 . The FreExplanations for the increased survival with dementia include a growing awareness that health-care interventions should be provided to patients with dementia , includiIn relation to our second aim, we found that dementia remained the major predictor of mortality over more than two decades. Thus, PAR for dementia was substantially higher than for any other diseases in both cohorts, and dementia predicted 32% of deaths among 85-year-olds in the 1980s and 28% of mortality in the 2010s. Similar to our findings for dementia, a MRC CFAS study reported that the relationship between frailty and mortality remained stable across cohorts , in contThe increased mortality in dementia is well-established , 38, 39,Our results showed that mortality has decreased in both men and women, and we found no interaction between sex and cohort in relation to mortality, indicating no sex difference in the decrease. This is in contrast to the view that decline in mortality has been steeper among men, resulting in a decreased gender gap in life expectancy , 44 HoweAmong the strengths of our study are identical methods and diagnoses in two population-based samples of 85-year-olds examined two decades apart. Further, dementia diagnoses were based on information from both neuropsychiatric examinations and close informant interviews, and all participants were examined for dementia without screening. In addition, we derived date of death from the Swedish Tax agency, which records all deaths of Swedish citizens . There aSupplementary file1 (DOCX 24 kb)Below is the link to the electronic supplementary material.


We aimed to evaluate and compare the association between globulin to albumin ratio (GAR) and globulin to prealbumin ratio (GPR) and 3-month functional prognosis of acute ischemic stroke (AIS) patients receiving intravenous thrombolysis therapy. t-test, Mann–Whitney U test, Chi-square test, logistics' regression analysis, and receiver operating characteristic (ROC) analysis were performed. 234 AIS patients undergoing intravenous thrombolysis were retrospectively enrolled with acute ischemic stroke from February 2016 to October 2019. Blood sample was collected within 24 h after admission. Poor outcome was defined as the modified Rankin Scale (mRS) ≥ 3 and a favorable outcome as mRS < 3. Severe stroke was defined as the National Institutes of Health Stroke Scale (NIHSS) score > 10 on admission. Student's p = 0.001, p < 0.001, respectively). Severe stroke was also associated with these two increasing variables. After adjustment for confounding factors, multivariate logistic regression analysis indicated that GPR was an independent indicator predictor of AIS.  Patients with poor functional outcome had higher GAR and GPR levels compared with favorable functional group  intravenous thrombosis. Stroke has become the most major cause of death and adult disability in China and the second leading cause of death in the world –3. RecomGlobulin to albumin ratio (GAR) is a common indicator of inflammation and nutritional status . Serum aThis retrospectively study was conducted among 408 patients with AIS from February 2016 to October 2019. All patients had accepted treatment at the Third Affiliated Hospital of Wenzhou Medical University. The demographic and baseline data of AIS patients about age, sex, hypertension, diabetes, history of stroke, hyperlipidemia, and atrial fibrillation were obtained from medical records. Blood chemistry analyses were performed within 24 h on admission. GAR was calculated as globulin/albumin and GPR as globulin/prealbumin.National Institutes of Health Stroke Scale (NIHSS) scores at admission were used to evaluate the severity of ischemic stroke by stroke neurologists. Severe stroke was defined as NIHSS > 10 . Two expt-test was used to compare the continuous variables of normal distribution. Mann–Whitney U test was used to compare nonnormally distributed variables. Pearson chi-square test or Fisher exact test was used to compare categorical variables. The cut-off values for GAR and GPR were determined by receiver operating characteristic (ROC) curve. The optimal cut-off values were evaluated using Youden index (Youden index = maximum [sensitivity − (1 − specifity)]). To show the predictive ability of indicators, the area under the curve (AUC) of poor outcomes was also calculated. The variables with p < 0.05 in univariate analysis were included in further multivariate logistic regression. A p value <0.05 was considered to be statistically significant.Statistical analyses were performed by using SPSS 25.0 software . The continuous variables of normal distribution were expressed as mean ± standard deviation (SD), while variables of nonnormal distribution were expressed as median (interquartile range [IQR]). Frequency and percentage expressed the classified variables. All subjects were divided into two groups according to the 3-month mRS score. Independent sample n = 65) were on average older and had more often a risk profile about hypertension, atrial fibrillation, and history of stroke. Meanwhile, they had higher baseline NIHSS score, which revealed that their neurological functions were worse damaged. By comparing the 24 h laboratory indexes, prealbumin levels increased in the favorable outcome group, but they had lower levels of WBC, GPR, and GAR. As Baseline characteristic and 24 h laboratory indexes were described in p < 0.001) and a sensitivity of 58.5% and a specificity of 69.8% , respectively. By using the cut-off value to categorize patients, To further investigate the relationship between GPR or GAR and 3-month outcomes, ROC curves were calculated . The optp value (p < 0.05) in univariate analysis comprising age, hypertension, history of stroke, atrial fibrillation, WBC, BUN (blood urea nitrogen), and baseline NIHSS score were incorporated into multivariate logistic regression models. For further study, multivariate logistic regression analysis was performed  in the model 2. After adjustment for all significant indicators mentioned above in the model 3, GPR was independently associated with poor outcomes . The significant correlation between GAR and short-term poor outcome disappeared in the adjusted models.Univariate logistic regression was performed to investigate the correlation between GAR and GPR and 3-month poor outcome . We founerformed . Model 1As far as we know, our study is the first one to investigate the correlation between GPR and the outcomes of AIS patients receiving r-tPA intravenous thrombolysis therapy. The main findings of this retrospective study are as follows: (1) we found that the evaluated 24 h GPR and GAR were associated with 3-month poor outcomes. (2) Patients in the high GPR group tended to have higher mRS scores. (3) After being adjusted for confounding factors, GPR was an independence predictor of AIS prognosis, but the significance of GAR was no longer outstanding.α (TNF-α), interleukin 6 (IL-6), and interleukin 1 (IL-1), which have immunomodulatory function [α, and other cytokines can be applied to the liver and induce the liver to synthesize positive acute phase reactants through acute phase protein gene, many of which are globulins, such as C-reactive protein, α2-macroglobulin, prothrombin, fibrinogen, and serum amyloid A [α can strongly upregulate matrix metalloproteinase 9 (MMP-9) [Inflammatory response and immune mediation are involved in the process of lipid deposition in atherosclerotic arteries . Atherosfunction . These pmyloid A . Previoumyloid A  Meanwhil (MMP-9) –20. Stud (MMP-9) . Another (MMP-9) .Evidence showed that malnutrition was an independence risk factor for mobility and mortality in AIS patients , 23, 24.The high mortality rate and disability rate of stroke cause great social burden and clinical burden.  PredictiHowever, there are some limitations in our study. First, patients in a single study center were enrolled in this study, which might cause bias in the results. Secondly, it is a retrospective study with small sample size. The small sample size maybe the reason why GAP did not show significance in the multivariate analysis. More detailed multicenter prospective study needs to be conducted to further clarify the issue. What is more, we lack the data of fraction volume, but there is a high correlation between baseline NIHSS score and infarct volume. To some extent, NIHSS score can be used as a substitute for infarct volume . FourthlThe 24 h GPR level can predict the 3-month poor functional outcome in AIS patients accepted r-tPA intravenous thrombosis.


The aim of this study was to analyze prognostic indicators of in-hospital mortality among patients listed for urgent liver transplantation (LT) for non-acetaminophen (APAP)-induced acute liver failure (ALF).ALF patients listed for LT according to the King’s College Criteria were retrospectively reviewed. Variables were recorded from medical records and electronic databases (HCMED and RedCap).The study included 100 patients, of which 69 were subject to LT and 31 died while waiting for LT. Patients were 35.5 ± 14.73 years old, and 78% were females. The main etiologies were virus (17%), drug-induced (32%), autoimmune (15%), and indeterminate hepatitis (31%). The prioritization-to-LT time interval was 1.5 days (0–9). The non-LT patients showed higher lactate (8.71 ± 5.36 vs. 4.48 ± 3.33 mmol/L), creatinine (229 ± 207 vs. 137 ± 136 µm/L), MELD (44 ± 8 vs. 38 ± 8), and BiLE scores (15.8 ± 5.5 vs. 10.3 ± 4.1) compared to LT patients (p < 0.05). Multiple logistic regression analysis identified creatinine and lactate as independent prognostic factors, and a creatinine-lactate (CL) score was developed. ROC analysis showed that creatinine, lactate, MELD, BiLE, and CL scores had considerable specificity (71–88%), but only BiLE, lactate, and CL presented high sensitivities . AUCs were 0.696 for creatinine, 0.763 for lactate, 0.697 for MELD, 0.814 for BiLE, and 0.835 for CL.CL and BiLE scores predict mortality with more accuracy than MELD in patients with ALF during prioritization time. Creatinine and lactate are independent prognostic factors for mortality. The mortality of non-acetaminophen (APAP)-induced ALF patients listed for liver transplantation is an important concern. Acute liver failure (ALF) is a life-threatening multisystem syndrome that is defined by the development of encephalopathy during the course of jaundice in patients without previous liver disease . The devIn the last decades, the introduction of routine liver transplantation (LT) as a treatment option for ALF patients with poor prognosis has been a turning point, and the survival rate has increased dramatically . Since tA great number of ALF patients still fail to receive transplants and die while waiting for a graft . FurtherIn a multicenter study including 267 patients with ALF, Escorsell et al.  observedSome authors show that poor outcome after LT is correlated with renal function, acidosis, and severity illness indexes such as Apache III . NeverthWe retrospectively analyzed 100 patients with ALF who were referred for urgent LT and were admitted to the Liver and Gastrointestinal Transplant Division of Hospital das Clinicas, University of Sao Paulo School of Medicine. The study was approved by the Ethics Committee of the Hospital das Clinicas (CAPPesq-HCFMUSP number 4245/2012). ALF was defined according to Trey and Davidson’s criteria [(2 g t.i.d.) and fluconazole (400 mg q.d.). Patients presenting hepatic encephalopathy grade 3 or 4 according to the West-Haven criteria [During the preoperative period, patients were subjected to a standard care protocol of preemptive cefotaxime criteria , 15 wereClinical and laboratory data were recorded from medical records and our electronic databases HCMED and RedCap. All variables were recorded from day 1 of the patient listing for LT. The following parameters were recorded: (1) clinical parameters: age, sex, etiology of hepatitis, jaundice-to-encephalopathy time interval, grade of hepatic encephalopathy (1–4), time interval from patient listing to transplantation (if applicable), date of liver transplantation, date of death (if applicable); (2) laboratory data: INR, total serum bilirubin, serum creatinine, arterial blood lactate, serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), MELD score , and thet test or the Mann–Whitney U test according to the normal distribution of variables. Simple and multiple logistic regressions were performed to determine the prognostic value. ROC curves were calculated to complete the evaluation of the most important variables. Statistical analyses were performed with R Statistical Software for Windows, version 2.12.The primary end point of this study was death due to any cause during pre-transplant hospital stay. Results were expressed as the means with standard deviations, medians with ranges, and percentages in some cases. Categorical variables were evaluated with the Fisher exact test. Continuous variables were evaluated with a Among the 100 patients referred for liver transplantation for ALF, the mean age was 35.5 ± 14.7 years, and 78% were women. The etiologies were viruses in 17% of cases, drug-induced liver injury (DILI) in 32%, autoimmune in 15%, indeterminate in 31%, and other causes in 5%. The prioritization-to-LT time interval was 1.5 (0–9) days, and the grade of encephalopathy at prioritization was 3 (1–4). The median interval between the development of jaundice and the onset of encephalopathy was 15 (1–60) days in the whole group, with 15 (1–60) days in the group of transplanted patients and 14 (1–60) days among patients who died before transplantation. Multiple organ failure associated with ALF was the main cause of death in non-transplanted patients.A comparison of clinical and biochemical features at baseline between both groups is summarized in Table Figure The highest patient survival without undergoing transplantation was 7 days. Based on that, five variables  were included in a multiple logistic regression model. The analysis identified creatinine and lactate as independent prognostic factors Table . A new CAccording to Table ALF is an acute syndrome with high morbidity, and even cases subjected to urgent LT have inferior survival rates compared to those transplanted electively for chronic liver disease. Several authors have studied prognostic factors for selecting earlier patients who will inevitably have indication for LT , 17, 18.To date, no criteria have been defined to stratify these patients according to disease severity during the wait for transplantation. Nevertheless, Figorilli et al.  evaluateIn our results, the similarity in encephalopathy, bilirubin, and INR levels may have occurred in part because all patients selected for urgent transplantation fulfilled KCC. The overall mortality on the waiting list without transplantation was 31%, without any case of spontaneous recovery. The majority of reports have shown cases of spontaneous recovery in groups that have not fulfilled criteria for LT indication  observedIn our case series, the more frequent causes of ALF included DILI as the main cause (32%). Although idiosyncratic drugs constitute the dominant cause of hepatitis, in this study, no case of APAP-induced hepatitis was reported. However, APAP is responsible for 13 to 60% of ALF cases in the USA, UK, Nordic countries, and Australia , 21. On In 2007, we reported 28 cases of DILI, including methyldopa in 25% of the cases, antituberculosis in 14.3%, flutamide in 10.7%, anorexigens in 10.7%, antithyroid agents in 10.7%, and other agents in 28.6% . PatientIn this study, we suggested possible poorer outcomes of ALF patients who are referred for transplantation with increased creatinine and lactate blood levels, MELD scores, BiLE scores, or the new CL score. This indicates that patients with a rapid increase of these parameters should undergo transplant earlier or should be diagnosed as too sick to treat in order to obtain better results. Further studies are necessary to assess the impact of CL score to evaluate long-term outcome of LT for patients with non-APAP ALF.e creatinine is an independent predictor of the survival of cirrhotic patients undergoing a transjugular intrahepatic portosystemic shunt. In ALF, evaluation of blood creatinine is an important issue since creatinine levels may be underestimated due to liver metabolic failure [The negative impact of renal failure on survival of cirrhotic patients is well known. In 2000, Malinchoc et al.  showed t failure . Acute k failure , 29.The multiple logistic regression analysis of our data reveled creatinine and lactate blood levels at prioritization day were independent prognostic factors of mortality on the waiting list for LT. Other authors have demonstrated the prognostic implications of high lactate blood levels in decreasing survival of ALF patients, particularly in APAP-induced hepatitis , 31. In The combined CL score was developed to determine the prognosis of patients with non-APAP ALF on the waiting list. This score presented the highest AUC-ROC of 0.835. The cutoff value of 179.51 showed high sensitivity to predict the wait-list mortality with slightly lower sensitivity than the MELD score. In 2002, the system for liver allocation in the US was based on the MELD score . Since tIn 2004, Kremers et al.  evaluateIn 2008, the BiLE score, including bilirubin levels, lactate levels, and etiology, was proposed to determine the prognosis of patients with ALF exclusively. Evaluation of AUC-ROC suggested that even the BiLE score (0.814) presented greater accuracy than MELD (0.697). Additionally, the sensitivity was higher than that of the MELD score and even KCC, which showed comparable specificity to the BiLE score . On the In 2012, Hadem et al.  reinforcFinally, several reports have addressed the implication of prognostic markers to improve the indication for LT in patients with ALF , 19, 44.In 2021, Patidar et al.  developeIn conclusion, our study has shown that creatinine and lactate are independent prognostic factors for the mortality of patients with non-APAP ALF who fulfill KCC. In these patients, CL and BiLE scores can predict mortality with more accuracy than MELD during the prioritization period. Additionally, development of new scores could allow better selection of patients according to the severity of the disease. This would allow for either earlier transplantation of cases at risk of death without LT or the precise identification of cases at high risk of death after transplantation.


This study aimed to assess the role of leukocyte telomere length (LTL) in the development of atrial fibrillation (AF) among Chinese patients.This is a cross-sectional study. A total of 350 patients from June 2016 to December 2017 were retrospectively analyzed. These included 219 AF patients and 131 with sinus rhythm in the control group. Quantitative real-time PCR was used to measure relative LTL.P < .001) with age. The AF-group had significantly shorter LTLs  and were older  than controls. LTLs among patients with persistent AF (PsAF), paroxysmal AF (PAF), and controls were significantly different (P < .001), with LTLs of PsAF patients being the shortest and controls being the longest. After adjusting for possible confounding factors, the PsAF group still showed significantly shorter LTLs than the PAF and control groups . After an 18-month follow-up, 20 out of 119 PAF patients had progressed into PsAF and a relative LTL of ≤0.73 was an independent predictor for progression of PAF into PsAF.The relative LTLs of all subjects (n = 350) ranged from 0.4 to 2.41 (0.98 ± 0.29), showing a significant negative correlation (LTL was found to be shorter in patients with AF than in age-matched individuals with sinus rhythm and positively correlated with severity of AF. LTL shortening could be an independent risk factor for progression from paroxysmal AF to persistent AF in the short term. Aging is one of the strongest risk factors for atrial fibrillation (AF), with the prevalence of AF in subjects aged <55 years being <0.1% and increasing to approximately 10% in 80-year-old population.,4Atrial fibrillation is the most prevalent form of arrhythmia worldwide, contributing to an extensive economic and public health burden.,6 These chromosomal caps prevent DNA degradation during replication, which could otherwise cause deleterious chromosomal fusions. Humans have telomere lengths of up to 15 to 20 kb, which shortens withaging because of somatic cell division. For example, telomere length of human peripheral white blood cells has been consistently reported to shorten with aging.,10 However, the rate of telomere shortening, termed as telomere attrition, could be accelerated by several genetic and environmental factors. Premature or excessive telomere attrition may trigger DNA damage response, which leads to p53 up-regulation and cell apoptosis. In addition, emerging evidence indicates a correlation between short leukocyte telomere length (LTL) and atherosclerosis, heart failure, and left ventricular hypertrophy, which have long been recognized as age-related cardiovascular diseases. Despite the critical importance of aging in AF, its relationship with LTL is controversial.–17 In the present study, we aimed to determine whether there is an association between LTL and AF  using a cross-sectional analysis approach.Telomeres are the distal ends of eukaryotic chromosomes and comprise tandem repeats of specific DNA sequences .22.1This is an observational case-control study. The institutional review board of Beijing Chaoyang Hospital approved this study and all participants have signed informed consent. The study protocol conforms to the ethical guidelines of the 1957 Declaration of Helsinki, as reflected in a priori approval by the Institution's Human Research Committee. All telomere analyses were carried out by a technician who was blind to clinical patient information.A total of 568 subjects were enrolled in our hospital from June 2016 to December 2017. The inclusion criteria were as follows: aged 18 and older; clinical confirmed diagnosis of atrial fibrillation; have no medical history of valvular heart disease, cardiomyopathy, or acute myocardial infarction; have signed consent form and agreed with the use of blood sample. Paroxysmal AF (PAF) was determined as AF episodes that were self-terminating or converted within 7 days. Persistent AF (PsAF) was classified as AF that lasted longer than 7 days, including episodes terminated by cardioversion after 7 days or more. Concurrently, 131 individuals were recruited as non-AF subjects after multiple telephone follow-up conversations and electrocardiogram (ECG)-examinations for 1 year to rule out undetected AF to the greatest extent possible.2.2Treatments of AF included beta-blockers, amiodarone, and catheter ablation AF patients were treated with catheter ablation or antiarrhythmic agents according to their clinical conditions.Forty two (35.3%) PAF patients and 39 (39%) PsAF patients underwent catheter ablation. All patients had successful isolation of pulmonary veins (PVs), and the superior vena cava was isolated in 58 (71.6%) patients. In addition to pulmonary vein isolation (PVI) and superior vena cava isolation, LA ablations (including complex fractionated electrograms) were performed on 63 (77.8%) patients. The sets of ablation lesions around the contra lateral PVs intersected at the roof or the posterior wall in 57 (70.4%) patients.2.3All participants’ data were collected from electronic medical records which included demographic features; clinical features; blood routine indexes; echocardiography information. Left ventricular dysfunction was determined as ejection fraction <50% on echocardiography. Renal insufficiency was defined as glomerular filtration rate lower than 30 mL/min. Blood samples were drawn into EDTA-containing tubes at administration and were centrifuged within 2 hours. All samples were processed within 4 hours and stored at –80 °C until use.2.4QIAamp DNA Blood Midi Kits  were used to manually extract DNA from blood cells after centrifugation of whole blood samples. Red blood cells were lysed and removed by a series of wash steps. The remaining white blood cells were lysed and solubilized protein was removed by precipitation and centrifugation. DNA quality was determined by ultraviolet absorption at 260 nm/280 nm (Nanodrop 2000 Thermo Scientific).2.5 The telomere repeats  of a single gene  in each sample were measured using quantitative real-time PCR. The relative telomere length was calculated as the ratio of telomere DNA repeats to single-copy gene (SCG) copies (t/s ratio), with HBG being designated as the single-copy gene. All rtPCR experiments were conducted in triplicate for each sample.The genomic DNA of peripheral blood leukocytes was isolated to measure LTL by quantitative polymerase chain reaction, which was modified from the method reported by Cawthon.2.6From Jun 2016 to Dec 2017, all PAF patients and sinus rhythm controls were routinely followed-up with at 3, 6, 12, and 18 months through outpatient clinic attendance, telephone contact, or review of medical notes. Additionally, unplanned visits were recorded. AF was discovered using ECG records, Holter telemetry, or ECG monitoring devices. 12-lead ECGs or Holter telemetry were arranged at each visit. ECG and Holter results were reported by patients if they were not able to return to our outpatient department. Follow-up patients admitted in our department were monitored through an in-hospital long-term ECG monitoring device or examination of patient history in combination with ECG confirmation during regular or unplanned visits. New AF cases in the sinus rhythm group or progression of PAF into PsAF were used as endpoints. Occurrences of new onset AF or progressions of PAF into PsAF were documented. New onset AF was defined as recorded AF on an ECG in sinus rhythm patients. Progression of paroxysmal AF into persistent was defined as: reported AF symptoms and confirmation by ECG or Holter telemetry which lasted >7 days at visits or visited with an AF state (likewise confirmed by ECG or Holter telemetry) but did not convert within 7 days after the onset of symptoms.2.7t test or one-way analysis of variance (ANOVA) for normally distributed continuous variables, while Wilcoxon rank-sum test for non-normally distributed variables. Variables in univariate analysis with P value <.1 were further included in multivariate analysis. Logistic regression was used to compare LTL among groups after adjusting for potential confounders including body mass index (BMI), heart rate, sex, history of hypertension and diabetes, left ventricular dysfunction, high sensitive C-reactive protein (hsCRP), LA diameter, and the use of statins and renin angiotensin aldosterone system (RAAS) inhibitors. The value of t/s ratio was negatively transformed.Continuous variables were expressed as mean or median ± standard deviation for normally distributed and non-normally distributed ones, separately. Numerical differences between 2 groups were assessed by chi-square test for categorical variables, and t/s were defined as the point with the largest value of specificity + sensitivity and were used for follow-up analysis. Predictors for AF incidence or progression were calculated from a Cox proportional hazards model with confidence intervals of 95% and covariate adjustment. AF progression events (new onset AF developed from sinus rhythm or PsAF developed from PAF) for LTL with predefined values were examined with an unadjusted Kaplan–Meier curve; a log-rank test was used to compared the AF progression events of patients with t/s values below and above cut-off values. The threshold for significance was P = .05. All statistical analyses were conducted using SPSS, Version 23.0 .Receiver operating characteristic (ROC) curves were conducted to evaluate diagnostic effects of telomere length for subtypes of AF. Cut-off values of 33.1A total of 568 AF patients and 131 controls were included in this study. Three hundred fifty were eventually finished follow-up and enrolled for further analysis, including 219 AF patients (119 PAF cases and 100 PsAF cases) and 131 controls. Patient flow diagram of all participants was illustrated in Fig. P value <.001, Besides, there were statistical differences in age (P = .007), sex (P = .043), heart rate (P < .001), presence of hypertension (P = .005), and diabetes (P = .005), history of left ventricular dysfunction (P = .013), RAAS inhibitors (P = .001), and statins (P = .023) intaken between the 2 groups. No other significant difference was found.The mean age was 60.92 years (ranges from 42 to 85) and there were 207 men 59.1%) and 143 women (40.9%). Demographic characteristics were displayed in Table % and 1433.2P < .001) with age. After adjusting for potential confounders, Table P = .009). Additionally, male patients , heart rate , and diabetes  were independent risk factors (Table P = .011) acted as a protective factor against AF.Results from linear regression Fig. A showed 3.3P = .013), sex (P = .033), heart rate (P < .001), presence of hypertension (P = .015), and diabetes (P = .015), history of left ventricular dysfunction (P < .001), RAAS inhibitors (P = .004), and statins (P = .027) intaken, LA diameter (P < .001), and HsCRP (P = .004) among the 3 groups. No other significant difference was found, specifically, PsAF group had the shortest LTLs (mean t/s 0.88), followed by PAF group (mean t/s 0.97) and control group (mean t/s 1.07) and they were significant different from each other with P value <.001 . However, the significant difference of LTLs between paroxysmal AF with non-AF individuals disappeared after adjustment .To further substantiate the association of telomere length and AF subtypes, we performed logistic regression after adjusting for potential confounders. As described in Table 3.5t/s ratios is superior for predicting AF or progression of AF when P < .05. As shown in Fig. P < .001. The AUC values were 0.61 and 0.67 for PsAF versus PAF and PsAF versus sinus rhythm control, respectively, with asymptotic significance below 0.05. AUC for PAF versus control was 0.58 with P value .037. Cutoff values of LTLs were 0.96 for AF versus sinus rhythm and 0.73 for PsAF versus PAF. These results indicate a potential predictive role of LTL in discriminating PsAF from either PAF or sinus rhythm. Cut-off values were used for the follow-up study.From the observation of the significant shorter LTLs in AF patients, especially the PsAF group, we investigated whether shortened LTLs could predict AF onset (defined by development of PsAF or PAF from sinus rhythm) or AF progression (defined by development of PsAF from PAF or sinus rhythm) based on ROC analysis. The results from area under the curve (AUC) analysis indicate that diagnostic value of shorter LTLs represented by 3.6t/s value of 0.73 revealed significant difference in heart rate (P = .020). Patients from both groups showed no significant difference in use of β-blocker (P = 1), amiodarone (P = 0.136), and catheter ablation (P = 1). HATCH score was not statistical significant between groups (P = 0.501). In a multivariate Cox proportional hazards model, LTL ≤0.73 remained independently significantly related with progression from PAF into PsAF . Heart rate did not remain significant in multivariate analysis . Kaplan–Meier analysis at 18-month follow-up . For patients who progressed into persistent AF, the median time was 11 months.At the end of the follow-up, 20 out of 119 patients primarily diagnosed with paroxysmal AF eventually progressed into persistent AF, while no patient in the control group were newly diagnosed as AF. LTL ≤0.73  was used as the only classified factor for paroxysmal AF patients. Fifteen 14.4%) of 119 paroxysmal AF patients presented with LTL ≤0.73, among which 7 (46.7%) developed persistent AF. As shown in Table .4% of 114Increasing evidence has indicated that atrial fibrillation is closely linked to aging. It is justifiable, therefore, to examine biological indicators of aging to provide a better understanding of the etiology of atrial fibrillation. We chose age-dependent telomere attrition rate in peripheral blood leucocytes as an indicator in the present study. The principal findings were as follows: LTLs were independently associated with history of AF; LTLs were significantly shorter from sinus rhythm to paroxysmal AF to persistent AF in an ordinal way; shorter LTL was an independent risk factor for persistent AF, but not for paroxysmal AF; shorter LTLs could be a promising biomarker in predicting the progression of AF. utilized a cross-sectional analysis strategy and observed a significant association between AF and LTL after adjusting for age and cardiovascular risk factors. After examining the AF subtypes, paroxysmal AF, but not persistent AF, was associated with LTL. Our former research incorporated 277 patients received catheter ablation and found that shorter LTL is an independent risk factor for AF recurrence at 14.20 ± 5.04 months of follow-up . However, the difference in LTL was not compared between paroxysmal and persistent AF. The current study utilized cross-sectional analysis similar to the Carlquist et al study, and the results agree in part with this study in that we observed a significant association of AF and LTL. As for the AF subtypes, however, we found that shorter telomere length correlated with more severe the type of AF. The disparity between the 2 studies could be Carlquist et al challenged a long-recognized notion that there was a progression from paroxysmal to persistent AF. One possible explanation could be the different selection of the study population. The participants of the former study came from a population that underwent angiography and most of whom had coronary heart disease, thus they had a significant higher rate of coronary artery disease than persistent or permanent AF patients  which could lead to potential selection bias. Mean LTL could reflect systemic influences on telomere attrition rate, especially the senescent of circulating immune cells, a major pro-inflammatory process. While inflammation has been extensively attributed to the cause of pathogenesis of atrial fibrillation in vivo and in vitro,,22 telomere attrition in immune cells (namely leukocyte telomere length shortening in the present study) should be a relevant factor in the etiology of atrial fibrillation. Additionally, atrial fibrillation, especially persistent AF, could induce inflammation and subsequent cardiac remodeling (described as “AF begets AF”), in which telomere attrition causes further attrition. This vicious circle would be likely to cause a shorter LTL in persistent AF patients than in paroxysmal AF patients, as seen in the present study.Persistent AF is thought to be a more severe type than paroxysmal AF as its longer course of arrhythmia condition and less sensitivity of cardioversion. In 2014, Carlquist et al Siland et al, and Staerk et al conducted longitudinal study designs rather than cross-sectional study focusing on the relationship between incidence of AF and LTLs. These 3 prospective studies came to similar conclusions, finding that aging and short LTL were independent risk factor for AF. Although study designs were similar in these 3 studies, their study population varied. In studies by Roberts et al and Siland et al, after inclusion and LTL determination, both groups independently used a considerable sample size of subjects without prevalent AF  for >10 years. Although the incidence of AF was found to be much higher by Roberts et al than Siland et al (28.1% vs 4.7%), it likely owed to the older age of the participants, and they found no association between LTL and incidence of AF after a mean follow-up time of 11.6 and 11.4 years when age and other known AF risk factors were accounted for. In the Framingham Heart Study from Staerk et al, the mean follow-up time was 15.1 ± 4.2 years, but only 184 of 1143 (16.1%) participants developed AF and no association between LTL and AF was found. One significant point was the study population in these studies might have been either too young or too old to observe development of AF. The hazard ratio of age in AF underwent a dramatic ascending trend in AF patients aged from 50 to 70. Therefore, it is reasonable to conclude that studies incorporating younger or older subjects will underestimate the influence of telomeres because most individuals would not have developed AF in younger individuals  and there is evidence that telomeres exert a milder or inverse influence on cardiovascular diseases in young men; the impact of telomeres would be mitigated in much older subjects because of increasingly effects of other AF risk factors. In agreement with these studies, our study did not find significant difference in LTL between PAF and sinus rhythm patients after incorporating multiple factors which are different between the 2 groups. In addition, no newly onset cases of AF were observed in the sinus rhythm group after 18 months of follow-up. However, we did find a significant association between persistency of AF and LTLs. We then found out a cut-off LTL value (t/s = 0.73) that best distinguished PsAF from PAF based on ROC curve analysis. Using this cut-off value as a grouping factor, we found that the LTLs have a significant role in predicting future persistency from paroxysmal AF within a median follow-up period of 11 months . These findings indicate that LTL might correlated to AF progression from paroxysmal to persistence. But did not predict new onset of AF in those with normal rhythm. The progression of AF from paroxysmal to persistent increased would significantly enhance the risk for AF-related comorbidities and resistance to AF therapies, such as stroke and AF recurrence after catheter ablation. Therefore, the results of our study potentially provide a new biomarker which could help guide therapeutic decisions and shed light on prognostic evaluation.Roberts et al,5 despite being of a similar sample size, thus further studies and/or meta-analysis are still needed to increase statistical power. Second, the follow-up time was relatively short and the cross-sectional design, we could not conclude any causal relationship or role of possible residual confounding factors. However, we did carry out multiple regression analyses in an attempt to adjust for the known AF risk factors and clinical conditions which differed among the different groups, after which the different LTLs remained significant. In addition, the follow up data lent strength to the role of LTL in predicting progression of AF from paroxysmal to persistent. Third, we determined relative LTL based on a real-time PCR analysis instead of the gold standard Southern blotting, but our method has long been a recognized measure in determining LTL/disease association studies as well. It may be necessary to utilize the absolute length of LTLs as measured by Southern blotting in clinical settings, but this did not undermine the conclusions of the present study. Fourth, despite LA volume is the best measurement for atrial enlargement, its measurement is not a routine procedure, so we could not obtain this data in the present study. Because LA diameter is often utilized for evaluation of atrial enlargement, it could be used as a substitute for LA volume in daily clinical practice. Finally, the follow-up method did suffer from possible omissions, 24-hour Holter monitor was arranged for all 350 patients during followed-up at 3, 6, 12, and 18 months. However, we were unable to discover patients with asymptomatic PAF if they presented with normal ECG and Holter moniter results during follow-up, so the progression and new onset of AF might have be underestimated.The present study suffers from several limitations. First, the results differed in part from the previous study,6In conclusion, we observed a significant shorter LTL in patients with AF, and the significance remained in patients with persistent AF, but not paroxysmal AF, after adjustment for other known AF risk factors. In addition, shorter LTLs could be a potential biomarker in predicting persistent AF from paroxysmal AF.Data curation: Yuanfeng Gao.Funding acquisition: Xinchun Yang.Investigation: Siyu Wang, Lei Zhao, Roumu Hu, Ye Liu.Supervision: Yuanfeng Gao, Lei Zhao, Xinchun Yang.Writing – original draft: Ye Liu.Writing – review & editing: Siyu Wang, Roumu Hu, Xinchun Yang.


Yet there is still no explicit evidence strongly supporting that PM2.5 with per unit increment can increase the risk of hemorrhagic stroke (HS). Literatures were searched from PubMed, Cochrane, and Embase. After the systemic review of relevant studies, random effects model was used to perform meta-analysis and to evaluate the association between PM2.5 and risk of HS. Seven cohort studies were finally included, involving more than 6 million people and 37,667 endpoint events . Total scores of quality assessment were 50. Pooled hazard ratio (HR) for crude HRs was 1.13 (95%CI: 1.09–1.17) . Pooled HR of subgroup analysis for current smoking with exposure to growing PM2.5 was 1.14 (95%CI: 0.92–2.15) and for never and former smoking was 1.04 (95%CI: 0.74–1.46). Ambient PM2.5 level is significantly associated with the risk of HS, which might be a potential risk factor of HS. Smoking does not further increase the risk of HS under exposure of PM2.5.Ambient fine particulate matter of 2.5 μm or less in diameter (PM According to the data from the World Health Organization, 58% of premature deaths were related to outdoor air pollution. Especially, the fatal effects of air pollution were presented as ischemic heart diseases and strokes resulted from exposure to fine particulate matter of 2.5 μm or less in diameter (PM2.5). Moreover, hemorrhagic stroke (HS) accounted for one-third of strokes. Therefore, PM2.5 might be closely related to risk of HS. Recently, Sheng Yuan .This systemic review was performed according to the protocol published on the database of International Platform of Registered Systematic Review and Meta-analysis Protocols  for article management. All literatures were independently reviewed and analyzed by two authors (Kai Zhao and Yu Guo). If there is inconsistency between them, another author (Mingfei Yang) would be consulted or the literature search strategy would be modified to reach a consensus.The full strategy of searching literature in PubMed and Cochrane was as follows: (((((((((Stroke[MeSH Terms]) OR Strokes[Title/Abstract]) OR “Cerebrovascular Accident*”[Title/Abstract]) OR CVA*[Title/Abstract]) OR Apoplexy[Title/Abstract]) OR “Vascular Accident*, Brain”[Title/Abstract]) OR “Brain Vascular Accident*”[Title/Abstract]) OR stroke[Title/Abstract])) AND (((((((((((“Air Pollution”[MeSH Terms]) OR “Pollution, Air”[Title/Abstract]) OR “Air Quality”[Title/Abstract]) OR “Particulate Matter”[MeSH Terms]) OR “Airborne Particulate Matter”[Title/Abstract]) OR “Particulate Matter, Airborne”[Title/Abstract]) OR “Air Pollutant*, Particulate”[Title/Abstract]) OR “Particulate Air Pollutant*”[Title/Abstract]) OR “Pollutant*, Particulate Air”[Title/Abstract]) OR “Ambient Particulate Matter”[Title/Abstract]) OR “Particulate Matter, Ambient”[Title/Abstract]).The full strategy of searching literature in Embase was as follows:  and .2.5” and “hemorrhagic stroke.” Final exclusion criterion: absence of hazards ratio (HR) or “increase of PM2.5.” Screening of articles was conducted by one author (Kai Zhao) and examined and verified by another author (Jing Li). The third author (Mingfei Yang) would settle disagreement.Articles from three electronic databases were pooled to complete the preparation of screening. After deleting the duplications, we established two initial criteria for inclusion and exclusion, respectively. Inclusion criteria included cohort studies, “stroke” and “particulate matter” found in title or abstract. Exclusion criteria: studies without cohort design, animals, or special people enrolled as subjective of studies, and no MeSH term in abstract. After completion of initial screening, final criterion was used to select studies for meta-analysis. Final inclusion criterion for full texts of article: “PM2.5, and HR with 95% confidence interval (CI) were extracted. When there were different results of HR with 95%CI for different models adjusted for various covariates, data and relative information of all models were extracted.The data of first author’s name, publication year, study region, exposure, period, total numbers of participants, gender ratio , definition of endpoints, increase extent of PM2.5, and other factors that could influence the outcome, objectivity, and accuracy of determination of endpoint.All enrolled studies were independently assessed by two authors (Kai Zhao and Yu Guo) according to Newcastle-Ottawa Quality Assessment Scale Cohort Studies (NOS). All eligible studies were assessed from three main aspects: representativeness of participants included, levels of ambient PMThere were various factors that were adjusted to different proportional hazard models. If the coefficient of each factor was supplied in full text, crude data would be restored by conversion formula. The data adjusted by the least factors would not be selected to perform data processing, unless there was no way to acquire crude data. Likewise, data adjusted by different factors would be processed in the same way.2) was used to test the heterogeneity. Funnel plot asymmetry and Egger’s regression were used for detecting publication bias. Sensitivity analysis was used to attenuate heterogeneity, in which each study was omitted one by one and the pooled HR of the rest studies was retrieved or the random effects model was switched to fixed effects model. Meta-analysis was completed through corresponding modules in Software for Statistics and Data Science . All p values were two-sided with a significant level at 0.05.The pooled HR and 95%CI was calculated by random effects model. I-square . After removing duplicates, 1975 articles were initially included. After excluding reviews, researches of animals, and titles and abstracts that were not conformed to the theme of “PMAll the studies were assessed by NOS. Six studies were scored 7 points and one study was scored 8 points. All studies were scored in representativeness of the exposed cohort, ascertainment of exposure, comparability of cohorts on the basis of the design or analysis, assessment of outcome, and a long follow-up duration. Only one study , gender (5 studies), education (4 studies), body mass index (4 studies), and smoking status (5 studies). Besides, 2 studies exhibited crude HR . Nevertheless, different editions and ranges of items in detail might result in bias of the meta-analysis. Three studies , which indicated a positive association between exposure to growing PM2.5 and incidence or mortality of HS. Yet the heterogeneity of these studies was significant . There was no publication bias according to Funnel plot and Egger’s regression  until the study . Publication bias was not evident according to Funnel plot and Egger’s regression . Subgroup analysis and its sensitivity analysis carried out through switching the random effects model to fixed effects model is shown in Fig. According to the definite fact that smoking could damage the vascular endothelium, smoking might aggravate the effect of PM2.5 is a kind of the inhaled particulates that could enter the circulatory system via permeating alveolar epithelium and vascular endothelium. Therefore, PM2.5 might be transmitted to the arteries in the brain and deposited on the surface of vascular endothelium, further leading to HS. Thus, effect of deposition or particulates trundle might result in inflammation and injury of vascular endothelium. Finally, the suffered arteries might have corrosion damaging the vessel wall.PM2.5. Many articles reported relationship between long-term exposure to PM2.5 and increased risks of incident stroke  and the subgroup analysis outcomes of smoking status were 1.08  for never smoking, 1.11  for former smoking, and 1.08  for current smoking. This meta-analysis included less literatures than previous studies and had un-unified PM2.5 increment levels. Besides, due to limited data of included studies, the subgroups in this meta-analysis were divided into the current smoking subgroup and the subgroup of never smoking and former smoking.Chronic diseases  at the beginning period of a study. Exposure measurement is related to the sensitivity and accuracy of the outcome; therefore, the third scientific institutions and proper mathematical models would be used. As to adjustment for covariates, according to this meta-analysis, educated levels, classification of body mass index, and different age grade might be new researchable variables, which can be arranged to appropriate scales for subgroup analysis in the future. Definition of endpoints would be standardized and detailed according to professional items in the world; especially, adequacy of follow-up of cohorts will be manifested in articles.In perspective of recommendations for further research about relationship between PM2.5 was not unified, which ranged from 1.4 μg/m3 to 10 μg/m3. Numerous covariates were concealed in data synthesis, which might result in bias or heterogeneity of the meta-analysis and subgroup analysis.As previously mentioned, there were several limitations of this systemic review. Only 7 articles from 3 open electronic databases during 2017 to 2019 were included in meta-analysis. Therefore, those not published in open platform were lost. Moreover, increment of PM2.5 level was significantly associated with the risk of HS, which might be a potential risk factor of HS. Additionally, under exposure of PM2.5, smoking does not further increase the risk of HS.Ambient PM


An oral squamous cell carcinoma (OSCC) is a tumor of the oral cavity that has a five-year survival rate of only around 50%. As this rate has not increased in recent decades, despite improvements in diagnosis and therapy, novel, easily accessible biomarkers for prognosis assessment are still needed. In our study, we measured the growth factor protein progranulin/GP88 in the serum of OSCC patients and demonstrated that an increased serum GP88 level is associated with a better prognosis for the OSCC patients in our study group. Furthermore, serum GP88 levels were not significantly associated with age, sex, or the tumor’s histological features, indicating that serum GP88 levels may be an independent predictor of an individual OSCC patient’s prognosis. These findings may help to improve therapy management of an OSCC in personalized medicine. p = 0.0005, log-rank-test) as well as in uni- and multivariate Cox regression analyses . This effect was predominant in OSCC patients older than 60.5 years (p = 0.027), while in younger patients no significant association between serum GP88 levels and prognosis could be observed. Altogether, lower serum GP88 levels are significantly associated with a worsened outcome for an OSCC and may be an interesting candidate for risk stratification during OSCC therapy.Progranulin (PGRN)/GP88 is a growth factor that is expressed in a wide range of tumor tissues. The secreted form is involved in various biological processes including proliferation and inflammation. In several tumor types, the serum GP88 level is associated with a patient’s prognosis; however, data for oral squamous cell carcinomas (OSCCs) have not yet been reported. We measured the serum GP88 levels in 96 OSCC patients by an enzyme immunosorbent assay (EIA) and correlated these data with clinicopathological parameters and patient outcomes. The GP88 levels in the serum of OSCC patients and healthy volunteers were comparable. In OSCC patients, the levels did not correlate with age, sex, or TNM status. In a Kaplan–Meier survival analysis, a serum GP88 level < 68 ng/mL was significantly associated with worsened survival ( An oral squamous cell carcinoma (OSCC), which mainly comprises cancer of the oral cavity and adjacent histological structures, is the fifteenth most-diagnosed cancer worldwide . The staLiquid biopsies offer the advantage of low-invasive detection of a wide variety of metabolic products or molecular factors generated by the tumor. Given the applicability of glycoprotein 88 (GP88) to serum measurements in a wide variety of body fluids ,10,11, nProgranulin/GP88 is a member of the unique growth-factor family, expressed as a soluble 88 kDa glycoprotein and identified with others in the teratoma PC cell line . It contThe aim of this study was to measure GP88 levels in the serum of 96 OSCC patients and correlate these data with the demographic, clinicopathological and prognostic data of the patients to determine whether serum GP88 levels are associated with OSCC occurrence and progression.Ninety-six patients suffering from an oral squamous cell carcinoma (OSCC) were included after a positive evaluation of the study by the local ethics committee of the Medical Faculty of the Martin Luther University Halle–Wittenberg . The patients gave written informed consent. The median age of the patients was 60.5 years range: 42–87), with 69 (71.9%) men and 27 (28.1%) women enrolled. Blood sampling was performed in all cases in this study on the day of the surgical excision of the tumor with no prior treatment. Twenty-six patients (27.1%) received radiotherapy subsequent to excision, 11 patients (11.5%) received chemotherapy with cisplatin, and one patient received taxol (1.0%). The patient group is part of the previously described cohort ,42. Demo–87, withg, and serum was then transferred to separate reaction tubes and subsequently stored at −80 °C. A serum aliquot was thawed directly before enzyme immunosorbent assay (EIA) measurement.Ten milliliters of venous blood was drawn on the day of surgical excision of a patient’s tumor. Blood was immediately centrifuged at 400× Serum GP88 levels were measured by a quantitative GP88 sandwich EIA developed and manufactured by A&G Pharmaceutical Inc.  according to the manufacturer’s protocol . ROC curves were performed for the comparison of serum GP88 levels of healthy volunteers against OSCC patients and for the assessment of an optimized cut-off value through Youden index calculation. The distribution of serum GP88 levels in different groups  were compared by a ChiSquare test and non-parametric tests . Survival analyses were calculated by Kaplan–Meier analyses and uni-/multivariate Cox regression analyses. Overall survival (OS) was assessed from the date of serum collection to the last follow-up date or death of the patient.p = 0.10; unpaired Student’s t-test). Median serum GP88 levels did not significantly differ in healthy blood donors in comparison to age-matched OSCC patients ; however, this difference was not significant  exhibiting a lower serum GP88 level and 31 patients (32.3%) having a higher serum GP88 level. In the Kaplan–Meier survival analyses, a serum GP88 level below 68 ng/mL was significantly associated with shortened mean survival (75.8 months (95% CI: 60.2–91.4 months) vs. 84.8 months (95% CI: 74.6–95.1 months); test see a.p = 0.004; see p = 0.008; see Furthermore, in an univariate Cox regression analysis, a lower serum GP88 level in the OSCC patients was associated with a 4.6-fold increased risk of death  and older (≥60.5 years) individuals. Age-adjusted cut-off values for both groups were calculated by Youden index optimization, which gave an unchanged cut-off value for the younger patients (68.0 ng/mL) while the cut-off for older patients was lower (65.0 ng/mL). Uni- and multivariate Cox regression analyses revealed that in the older patient group, the relative risk of death was significantly increased for those with lower serum GP88 levels  and assessed its impact on their demographic, clinicopathological characteristics and prognosis. In our study, serum GP88 levels were not significantly different in patients with an OSCC (52.1 ng/mL) compared to those of healthy volunteers (57.6 ng/mL). Although limited information is available on GP88 serum levels for patients with an OSCC, compared those of healthy volunteers, this result is in contrast to the available literature on other tumors. Breast cancer patients showed increased GP88 serum levels having mean levels of 40.7 to 45.3 ng/mL compared to 28.7 ng/mL for age-matched healthy volunteers, with no significantly different expression due to age or ethnicity . In non-We were able to demonstrate a significant association between a lower (< 68 ng/mL) serum GP88 level and worsened survival in OSCC patients. On the other hand, an elevated serum GP88 level at three months after surgery and chemotherapy was associated with worsened survival for ovarian cancer . TherefoAdditionally, we showed that a lower serum GP88 level is an indicator of a poor prognosis, especially in elderly (≥60.5 years) OSCC patients, but in younger patients the effect was less pronounced. Previously, we were able to demonstrate that lower serum GP88 levels were more frequently found in younger prostate cancer patients, while elevated levels were found in older patients . HoweverWe assessed for the first time the serum levels of GP88 in patients with an oral squamous cell carcinoma. These patients did not exhibit significantly higher serum GP88 levels than found in healthy volunteers. While serum GP88 expression was not correlated to age, sex, or clinical T or N stage of the tumor, a decreased serum GP88 level was significantly associated with worsened OSCC patient survival. GP88 is a pleiotropic factor that has effects on tumorigenesis and metastasis and has an anti-inflammatory effect. Since the OSCC cases investigated here were either local or regional, it is possible that in this study the effect of GP88 was mainly the result of its inflammatory action. To sum up, we identified GP88 is an independent prognostic factor in an OSCC and as a promising biomarker in combination with both the TNM system and other prognostic markers. Measurement of serum GP88 levels, therefore, might be an interesting option for OSCC risk stratification and therapy management.


This study aimed to explore the spatial distribution of brain metastases (BMs) from small cell lung cancer (SCLC) a homogenous sample, and to identify the metastatic risk levels in brain regions.T1-enhanced magnetic resonance imaging (MRI) from SCLC patients were retrospectively reviewed from three medical institutions in China. All images were registered to the standard brain template provided by the Montreal Neurological Institute (MNI) 152 database, followed by transformation of the location of all BMs to the space of standard brain. The MNI structural atlas and Anatomical Automatic Labeling (AAL) atlas were then used to identify the anatomical brain regions, and the observed and expected rates of BMs were compared using 2-tailed proportional hypothesis testing. The locations and sizes of brain lesions were analyzed after image standardization.P = 9.80 ×10−15, 9.04 ×10−6), whereas temporal lobe were low-risk regions (P = 1.65 ×10−4). More detailed AAL atlas revealed that the low-risk regions for BMs was inferior frontal gyrus (P = 6.971 ×10−4), while the high-risk regions for BMs was cerebellar hemispheres (P = 1.177 ×10−9).A total of 215 eligible patients with 1033 lesions were screened by MRI, including 157 (73%) males and 58 (27%) females. The incidence of crucial structures were as follows: hippocampus 0.68%, parahippocampal 0.97%, brainstem 2.05%, cauate 0.68%, putamen 0.68%, pallidum 0.2%, thalamus 1.36%. No BMs were found in the amygdala, pituitary gland, or pineal gland. The cumulative frequency of the important structures was 6.62%. Based on the results of MNI structural atlas, the cerebellum, deep white matter and brainstem was identified as a higher risk region than expected for BMs (Many crucial structures including the hippocampus, parahippocampus, pituitary gland and thalamus etc. have low frequency of brain metastases in a population of SCLC patients. This study provides the help to investigate the clinical feasibility of HA-WBRT and non-uniform dose of PCI in a population of SCLC patients.The online version contains supplementary material available at 10.1186/s40644-021-00410-w. Small cell lung cancer (SCLC) is one of the most common malignancies worldwide, with a prevalence of 13 to 15% among all types of lung cancer. Over 25% of SCLC patient were initially diagnosed with brain metastases (BMs), with an average survival of 9 months after maximal treatment . ProphylImage analysis with CT or MRI has become the typical approach for the relationship between the spatial distribution of BMs and primary lung cancer types. The development of image registration and 3D structure deformation algorithms allow the detection of the slightest differences in spatial distribution by registering individual brain images onto an averaged standard brain image. Accumulating evidences have suggested that the spatial distribution of BMs from different types of cancer are different , 12. QuaIn this study, we analyzed the spatial distribution of BMs from SCLC in a large database from three medical institutions in China. Two different atlases were also applied to identify the location of BMs in different brain regions, as well as the risk level of metastasis in the brain.This study was approved by each institutional review board, and each ethics committee waiver informed consent due to the character of this research. A total of 215 SCLC patients with BMs from January 2014 to December 2018 were enrolled in this research from three medical institutions in China. Inclusion criteria were as follows: (1) patients firstly diagnosed with BMs from SCLC and had no identification of BMs in the previous MRI; (2) no contradictions to MRI; (3) To reduce the divergence in the identification of the BMs for different clinicians, the patients with obvious metastases which had the number of metastases ≤20, and metastasis diameter ≥ 2 mm were included. Exclusion criteria were: (1) patients with history of brain surgery or any form of brain radiation therapy; (2) patients with meningeal metastasis; (3) the presence of other types of malignant tumors.Coil: 8-channel cross cranial coil. Position: supine position. T1WI, T2WI, and T2WI-FLAIR of the head were followed by enhanced scanning. Scanning parameters: T1WI TR: 250 ms, TE: 2.3 ms, layer thickness: 6 mm, number of excitation: 1; T2WI TR: 2105 ms, TE: 80 ms, layer thickness: 6 mm, number of excitation: 1. Contrast-enhanced scanning: Gd-DTPA was injected intravenous mass and measured at 0.1 mmol /kg. Transaxial, sagittal and coronal T1WI scanning was performed, respectively.http://www.mitk.org/). Image registration was performed to transform the coordinate space of MRI image data to the standard Montreal Neurological Institute (MNI) space. The high-resolution T1 weighted standard brain template with 1.0 mm isotropic provided by the MNI152 database was adopted as the reference image [https://fsl.fmrib.ox.ac.uk/fsl) on Ubuntu 16.04 [The volume of interest (VOI) of each BM on MRI was manually delineated slice-by-slice using Medical Imaging Toolkit (MITK) software  and recorded as the location of BM.Both MNI structural atlas  and an mTo visualize the spatial distribution of BMs, a frequency map was constructed as binary spheres with a diameter of 20 mm at the locations of BMs and some spheres may be overlaid. A heat-map for the overlap frequency of all spheres was counted at each voxel .In each anatomical brain region, the observed rate of BMs was calculated as the number of BMs in the region divided by the number of BMs in all regions. By assuming an equal risk of metastasis from SCLC for each voxel, the expected rate of BMs in each brain region was calculated as the proportion of region’s volume in the total volume of all regions. To identify the risk of metastasis in each brain region, the observed and expected rate of BMs were compared using 2-tailed proportional hypothesis testing  as follop is the observed rate of BMs, p0 is the expected rate of BMs, n is the number of BMs, and Z is the z-score.Where, P value of the z-score was calculated as the cumulative probability of normal distribution, and the Bonferroni correction was used for the correction of multiple testing across all anatomic ROIs. Therefore, the corrected significance level of P value was calculated as the significance level 0.05 divided by 53 which was the number of ROIs, and the P value needed to reach statistical significance was P ≤ 9.434 × 10–4. In the brain regions with statistically significant P values, the brain regions with positive or negative z-score were the regions which had observed rate of BMs significantly higher or lower than the expected rate of BMs.The corresponding From the database of newly diagnosed patients with BMs from three medical institutions in China, a total of 215 eligible patients with 1033 lesions were screened, including 157 (73%) males and 58 (27%) females. The age was ranged between 36 and 83 years old, with a median age of 61 years. With regard to the location of the primary lung cancer, we observed 50.2% (108/215) of cases from the left lung as compared with a 49.8% (107/215) from the right lung. The time from the first diagnosis of SCLC to the onset of BMs was ranged from 0 to 45.5 months, with the median of 7.1 months. The median number of metastatic brain tumors was 5 per patient. Detailed patient characteristics and demographic information were shown in Table A heat map of the spatial distribution of BMs was obtained by superimposing the normalized tumor centroid Fig. . VisualiP = 9.80 ×10−15, 9.04 ×10−6), whereas temporal lobe, frontal lobe and occipital lobe were regions with lower risk than expected (P < 0.05). The temporal lobe remained significant after the correction of multiple testing (P = 1.65 ×10−4). Analysis based on a more detailed ALL atlas shows that BMs incidence was lower than expected in many deep brain structures, including inferior frontal gyrus (2.24% VS 4.42%), superior temporal gyrus (0.97% VS 2.28%), supramarginal gyrus (0.49% VS 1.36%), rectus gyrus (0.1% VS 0.67%), occipital superior-middle-inferior gyrus (3% VS 4.23%), middle temporal gyrus (2.82% VS 3.93%), temporal pole (1.17% VS 1.92%), inferior temporal gyrus (2.05% VS 2.83%), cuneus gyrus (0.78% VS 1.24%), angular gyrus (0.78% VS 1.23%), hippocampus (0.68% VS 0.79%) etc. From Table P < 0.05), including cerebellar hemisphere, inferior frontal gyrus, cerebellar peduncle, precentral gyrus, superior temporal gyrus, supramarginal gyrus, rectus gyrus. The BMs lower risk than expected areas were inferior frontal gyrus, superior temporal gyrus, supramarginal gyrus, rectus gyrus. In contrast, the remaining regions have higher risk than expected. The cerebellar hemispheres and inferior frontal gyrus remained significant after the correction of multiple testing .Based on the MNI atlas, the comparison of the observed and expected rates of BMs showed that the cerebellum, deep white matter and brainstem were area with higher risk than expected  and ALL atlas (38 regions) to determine the anatomical brain regions in standard brain template, then compared observed rates of BMs to the expected rates of BMs under the assumption that all voxels were at equal risk. The frequency heat map of BMs from SCLC showed that the BMs from SCLC were mainly located at the frontal lobe (27%) and cerebellum (20.9%), while both insula and putamen regions (1.2%) had the lowest frequency of BMs. More detailed quantitative analysis data are presented in tables for future inquiry by other researchers.In our study, it was found that only 0.68% of the metastases were located in the hippocampus and 0.97% in the parahippocampus. Such results were similar to those reported by Wu et al. . by 0.5%In addition to protecting the hippocampus and neural stem cells, it is debatable whether other important functional structures such as the limbic system, amygdala, hypothalamus, pineal gland, pituitary gland, and areas near the inner ear need to be protected as well . The limP = 9.80 ×10−15), while the observation frequency of temporal lobe, frontal lobe and occipital lobe was significantly lower than the expected frequency, and the difference of temporal lobe was more significant (P = 1.65 ×10−4), which was similar to the results of previous studies on heterogenous primary pathological type of brain metastases [P = 6.97 ×10−4) and cerebellar hemispheres (P = 1.17 ×10−9). Our new findings fully validate the non-random spatial distribution of BMs in SCLC.To further verify the non-random spatial distribution of BMs in SCLC, we assumed that each voxel had the same risk of SCLC metastasis. The expected rate of BMS in each brain area was calculated as a proportion of brain area volume to total brain volume. Through comparison, we found that the observation frequency of cerebellum was significantly higher than the expected frequency  and volumetric modulated arc therapy (VMAT), allowing the delivery of high dose radiation to the high-risk brain regions, and low dose radiation to the low-risk regions . This moLimitations of our study should also be noted. First, no brain metastases were found in several brain regions, which may be due to the low brain volume in these regions, or the small sample size, which needs further study to confirm. Second, since our study only focused on BMs from SCLC, the differences in spatial distribution between SCLC and other pathological BMs need to be further compared, which is precisely what we lack. Both of these limitations may be solved by further analysis with a larger cohort to reach definite conclusions.We confirmed that the cerebellum was identified as a higher risk region than expected for BMs from SCLC, whereas temporal lobe was a lower risk region than expected. More detailed atlas revealed that the cumulative BMs incidence of many important structures was low in a population of SCLC patients, including the hippocampus, parahippocampus, pituitary gland, basal ganglia, thalamus, and so on. This study provides the help to investigate the clinical feasibility of HA-WBRT and non-uniform dose of PCI in a population of SCLC patients.Additional file 1: Supplementary Table 1. Distribution of brain metastases based on AAL atlas.