Total vasopressor demand in the first hour after reperfusion was lower after HOPE pretreatment, with reduced usage of norepinephrine  and significant reduction of epinephrine consumption . Serum potassium concentration dropped by a mean of 14.1% in transplantations after HOPE, compared to a slight decrease of 1% (p < 0.001) after SCS. The overall incidence of early allograft dysfunction (EAD) was reduced by 44% in the HOPE group (p = 0.04). (4) Conclusions: Pre-transplant graft preconditioning with HOPE results in higher hemodynamic stability during reperfusion and lower incidence of PRS and EAD. HOPE has the potential to mitigate ES by preventing hyperpotassemic complications that need to be addressed in LT with HOPE-pre-treated grafts.(1) Background: Post-reperfusion syndrome (PRS) and electrolyte shifts (ES) represent considerable challenges during liver transplantation (LT) being associated with significant morbidity. We aimed to investigate the impact of hypothermic oxygenated machine perfusion (HOPE) on PRS and ES in LT. (2) Methods: In this retrospective study, we compared intraoperative parameters of 100 LTs, with 50 HOPE preconditioned liver grafts and 50 grafts stored in static cold storage (SCS). During reperfusion phase, prospectively registered serum parameters and vasopressor administration were analyzed. (3) Results: Twelve percent of patients developed PRS in the HOPE cohort vs. 42% in the SCS group ( Liver transplantation (LT) is the only therapeutic option for patients with end-stage liver disease and certain liver malignancies in a curative setting. While its relevance in curing fatal diseases is undisputed, LT is also prone to several complications that might not only prolong convalescence but also jeopardize graft and, hence, recipient survival. Among these complications, one is particularly feared by LT physicians as it adversely affects further organ function immediately right at the beginning of the actual transplant process—post-reperfusion syndrome (PRS).PRS in liver transplantation was first described by Aggarwal et al. in 1987 and defined as a 30% decrease in mean arterial pressure (from baseline), lasting for at least 1 min and occurring within 5 min after vessel unclamping in graft reperfusion . Risk faIn addition to the hemodynamic effects during reperfusion, electrolyte imbalances can occur, with hyperpotassemia being the most feared. The rapid influx of potassium is thought to originate from the preservation fluid remaining in the graft at the time of reperfusion. The resulting systemic hyperpotassemia can occur in varying degrees of severity and can lead to cardiac arrhythmias and even cardiac arrest. PRS seems to be associated with the development of intraoperative hyperpotassemia . To counThe origin of most clinically relevant complications—that might also derive from or result in PRS—is the so-called ischemia-reperfusion injury (IRI) that occurs when oxygen-enriched blood hits ischemic cells. The consecutive formation of reactive oxygen species (ROS) amongst other cellular pathways mediates cell damage ,18. One In our center, HOPE treatment of liver grafts prior to transplantation was first introduced in 2019 and has been established as a standard of care prior to every liver transplantation since 2020. Over time, we have been able to confirm the positive effects as described in the literature with regard to excellent post-transplant outcomes. While previous studies focused mainly on mid- and long-term effects of machine perfusion, the present study was conducted to shed light on the immediate perioperative phase and to analyze differences in donor organ reperfusion after previous HOPE or SCS treatment in terms of hemodynamic parameters, vasopressor requirements, and electrolyte shifts—thus assessing the impact of HOPE on PRS.This study was designed as a retrospective analysis of perioperative variables in patients undergoing liver transplantation who were treated in a single reference center for hepatobiliary surgery and liver transplantation. The study was approved by the Institutional Review Board of the LMU University of Munich (protocol number EK-LMU 19-395).® device  was introduced in our transplant department and was established as a standard of care for liver graft preconditioning in 2020. Starting in November 2020, all liver grafts that underwent pre-transplant hypothermic machine perfusion were included in our analysis. All liver grafts were procured after declaration of brain death, preserved and transported in HTK solution on ice. Upon arrival, grafts were prepared for implantation and then connected to the LiverAssist device by cannulation of the portal vein. Organs were perfused with a University of Wisconsin machine perfusion solution (UW-MPS) at 8–12 °C and a portal vein pressure of 3–5 mmHg. Perfusion was continued while the recipient underwent hepatectomy. Grafts were subsequently flushed with HTK solution and implanted.In 2019, HOPE using the LiverAssistThe control group consisted of transplantations performed before implementation of HOPE as a standard of care. These grafts were stored on ice in HTK solution throughout back table preparation and during the recipient’s hepatectomy until the implant phase of the transplantation was reached.Induction of anesthesia, monitoring, and invasive line placement was carried out in standard fashion. Dissection and surgical technique for transplantation were not altered in or influenced by this study. During surgery, mean arterial blood pressure was monitored by invasive catheterization. Potassium levels were measured using sequential blood gas analyses. Administration of vasopressors was tracked at 60 min after skin incision—as a baseline value—and then 60 and 5 min prior to, as well as 30 s, 5 and 60 min after reperfusion. Infusion of fluids and transfusion of blood products was recorded prospectively.The primary outcome was the incidence of PRS during the reperfusion phase of a liver transplantation—defined according to literature as a 30% decrease in mean arterial pressure (from baseline), lasting for at least 1 min and occurring within 5 min after vessel unclamping in graft reperfusion .Donor-specific variables included the following parameters: Age, sex, Eurotransplant Donor Risk Index (DRI), cold ischemic time, as well as warm ischemic time. These variables were obtained from the Eurotransplant database.Recipient-specific variables included the following parameters: Age, sex, body mass index (BMI), match-MELD score, American Association of Anesthesiologists (ASA) Score, CHILD-Pugh Score, healthcare setting prior to transplant, number and type of comorbidities, as well as indication for transplant. These variables were retrieved from our liver surgery database and supplemented with data from electronic patient records.p-value (two-tailed) of <0.05 is regarded as statistically significant.Univariate comparisons were performed calculating Fisher’s exact test, Chi-Square test and Mann–Whitney U Test for non-parametrical comparisons. All predictors and variables were included as time-constant variables, using values from the assessment at the time of liver transplantation. For statistical analysis, SPSS statistical software package  and GraphPad Prism  were used. We included 100 patients in this study—50 of whom received HOPE-treated liver grafts in 2020 and 2021. They were compared to 50 patients who received an SCS-treated graft in 2018 and 2019 before our institution started regular HOPE utilization.Baseline donor characteristics are shown in p = 0.013), CHILD Score, number of relevant comorbidities and the need for high-level care in intensive or intermediate care units prior to transplantation, thus showing a slight tendency towards more morbid patients. Within the HOPE cohort, a mean perfusion time of 163.8 min [95% Confidence Interval (CI): 138.3–189.3] was registered.Baseline recipient characteristics are shown in n = 6 out of 50) in the HOPE group met the criteria for PRS, 42% (n = 21 out of 50) in the SCS group developed post-reperfusion syndrome. This difference was also highly significant (p = 0.0013). Respective graphic analysis is shown in In the cohorts studied, the incidence of post-reperfusion syndrome, as defined by Aggarwal et al., was distinctly lower in the perfused liver grafts. While only 12% of cases (p < 0.001). As shown in p = 0.122) reduction in the amount of norepinephrine administered and a −56% (p = 0.0184) significantly lower requirement for epinephrine compared to SCS. There were no relevant differences between the groups in vasopressin administration (p = 0.899).Perioperative hemodynamic variables are displayed in p < 0.001) in SCS grafts, requiring substitution in only 16% of patients (p = 0.0135) (p = 0.045). Apart from this, no significant differences in fluid or blood product substitution were observed between the two groups  . Thus, po groups .n = 14 out of 50) in the HOPE group met the criteria for EAD, 50% (n = 25 out of 50) in the SCS group developed EAD within the first seven days post-transplant (p = 0.04). In addition, no occurrence of PNF could be observed in the HOPE group compared with three cases in the SCS control cohort; no significant difference in 30-day survival was found in the studied groups  with targeted fluid bolus administration and adjustments in anesthetic levels may have a profound effect on MAP. One proposed mechanism for this MAP drop is myocardial stunning and transient loss of contractility due to an abrupt increase in serum potassium, decreased pH, and decreased temperature of the reperfusion blood that subsequently enters the systemic circulation . In addiFurthermore, inflammatory agents are thought to play a role in the pathophysiology of the reperfusion syndrome, with a correlation to increased complement cascade activation  and immuWhile this is considered beneficial in terms of hemodynamic stability, overshooting effects have been observed. The resulting hypopotassemia may itself pose dangers and has made potassium substitution necessary in a substantial number of cases. One possible explanation could be that hyperpotassemia after graft-reperfusion is expected by anesthesiologists . This isIn fact, there are some limitations to our study: the most obvious one is the retrospective nature of it. Nevertheless, we believe that, due to the significance and clear tendencies of our gained results, this study manages to provide relevant insights into one of the numerous beneficial effects of HOPE preconditioning prior to LT. Several studies have already assessed the effects of machine perfusion on perioperative results and postoperative outcomes; however, most of them have only demonstrated positive effects on PRS and EAD in cohorts with DCD grafts. In fact, the protective effects are even more pronounced in DCD-only cohorts and have been observed after both HOPE and NMP. While both techniques appear to shorten the length of hospital stay in recipients, HOPE is less prone to procedure-related complications . Then, ap = 0.013) and more patients required treatment in intensive or intermediate care wards  prior to transplantation, compared to SCS controls. Respecting these observations, the favorable effects of HOPE on the development of PRS described in this study might as well be interpreted as even more valuable than previously thought. Hence, one could conclude that, even in a sicker patient population, the hemodynamic benefits achieved by HOPE are still significantly beneficial. Clearly, further prospective evaluation is needed to support the findings of this study.The selection and composition of the two groups investigated is another limitation to our study. Since HOPE replaced SCS as the standard of care procedure for graft preconditioning prior to LT at our center, we were not able to select different LT cohorts transplanted at approximately the same time points. However, in order to minimize the risk of selection bias, performance bias and variation in standard practices in the performance of liver transplantation over time, we chose to include patients transplanted at closely spaced time points, directly prior and directly after implementing HOPE preconditioning at our institution. The retrospective study design and its observational approach imply a heterogenous group distribution and, although the sample size was not small, the present differences in cohort composition need to be addressed. Overall, LT recipients or waiting list candidates per se represent a rather heterogenous cohort of patients . While tPre-transplant graft perfusion through HOPE provides a number of benefits. In this study, we demonstrate an impact on both patient hemodynamics and post-reperfusion syndrome. HOPE results in greater hemodynamic stability during reperfusion with a reduced need for vasopressors and lower incidence of post-reperfusion syndrome as compared to SCS-treated grafts. Furthermore, we were able to demonstrate effects in electrolyte balance. In particular, a decrease in potassium levels after reperfusion was observed in the HOPE group, which in many cases even had to be compensated. The risk for hyperpotassemic cardiac arrhythmias—as described in previous years—can thus be significantly reduced. Whereas in the past a preventive potassium shift by glucose/insulin administration was often required, this should be omitted in HOPE-perfused livers to avoid hypopotassemia. Instead, possible potassium substitution should be anticipated.


Many previous studies indicate that heart failure (HF) increases the risk of cognitive dysfunction and stroke, showing the logic that several physiological factors associated with cardiac dysfunctions affect homeostasis in the cerebral circulation. In the chronic process of HF patients, it is suggested that reduced cerebral blood flow (CBF) and abnormal auto-regulation might result in impaired perfusion, metabolic insufficiency, and regional or global structural deteriorations in the brain. However, the mechanism underlying HF-induced brain disease remains unclear. Cardiac dysfunction in patients with HF or HF-induced several physiological abnormalities may cause brain dysfunction. Possible physiological factors should be considered for future studies to prevent brain disease as well as cardiovascular dysfunction in patients with HF. It has been reported that coronary heart disease almost triples the risk of a stroke, and cardiac failure is associated with a more than fivefold increased risk . In the HF, one of the leading causes of morbidity and mortality, is a systemic disease but affects the other organ system, especially the brain . For exaIn severe chronic HF patients, global CBF is reduced by 14–30% . Kim et On the other hand, Choi et al.  reportedPrevious studies demonstrated some compensatory mechanisms  against changes in arterial pressure and cardiac output to maintain adequate CBF . Thus, iCerebral autoregulation, which maintains steady-state cerebral blood flow in a relatively stable manner over a range of perfusion pressures from 60 to 150 mmHg ,33, is aArterial baroreflex function is the compensatory mechanism for acute changes in arterial pressure to maintain an adequate perfusion pressure. Ogoh et al.  demonstrIn addition to arterial baroreflex, the cardiopulmonary baroreflex is also essential for CBF regulation. An increase or decrease in central blood volume (CBV) possibly elevates or reduces cardiac output and consequently causes over- and under-cerebral perfusion . OrthostMoreover, the vascular bed of the external carotid artery is essential to regulate intracranial blood flow. For example, resistance-exercise-induced large arterial blood pressure increases common carotid artery blood flow but internal carotid artery blood flow that supplies blood to the cerebral cortical region is well maintained, while external carotid artery blood flow largely increased accordingly as a large increase in arterial blood pressure . This fiIt is known that sympathetic nerve activity and the renin–angiotensin-aldosterone system are enhanced in HF patients . The comAs well as the CBF compensatory mechanism, we may need to consider possible HF-induced physiological factors that decrease CBF rather than cardiac dysfunction in HF patients. One of them is, for example, greater arterial stiffness that is associated with left ventricular (LV) remodeling and reduced LV function ,56. HF pBased on the anatomy, cardiac function should directly affect CBF regulation because of the cerebral artery connected to the aortic arch. Indeed, changes in arterial blood pressure and cardiac output are directly associated with CBF regulation. However, cardiac dysfunction in patients with HF directly does not cause impairment in CBF regulation. The compensatory mechanism of CBF regulation; cerebral autoregulation, baroreflexes, and external carotid artery vascular bed, against cardiac dysfunction, are also modified in patients with HF. Thus, these alterations may affect CBF regulation. However, since sympathetic nerve activity and the renin–angiotensin–aldosterone system that play a role in blood volume regulation are enhanced in HF patients, the effect of these physiological factors on the compensatory mechanism of CBF regulation needs to be considered. Additionally, one of the possible important physiological factors of cerebral hypoperfusion in patients with HF is arterial stiffness. Our previous study demonstrated that arterial stiffening modified dynamic pulsatile hemodynamic transmission from the aorta to the brain. Cardiac dysfunction and cerebral unfavorable circulatory homeostasis may be linked by a common factor: central arterial stiffening rather than direct cardiac dysfunction.


The purpose of this study was to determine the association between different stages of chronic kidney disease (CKD) and sarcopenia and its components in the Chinese older population.The study comprised of 2,213 participants aged ≥ 60 years  recruited from Shanghai who were invited to participate in a comprehensive geriatric assessment. Sarcopenia was defined according to the AWGS 2019 consensus update on sarcopenia diagnosis criteria. The glomerular filtration rate (GFR) was estimated using the equation that originated from the CKD-EPI equation, the stages of CKD are classified according to the Kidney Disease—Improving Global Outcomes (KDIGO).p < 0.05). In logistic regression analysis model, compared with normal and CKD 1 patients, kidney failure was significantly associated with the increased risk of sarcopenia and low grip strength (p < 0.05); CKD 2, CKD 3–4 and kidney failure groups were significantly associated with an increased risk of low walking speed (p < 0.05), respectively; while the association between CKD and muscle mass was not shown.The overall prevalence of sarcopenia was 19.0%, which increased with the severity of CKD. The prevalence of sarcopenia in patients with CKD 3–4 and kidney failure was significantly higher than that in normal and CKD 1–2 (In our study, only decreased physical performance, as represented by walking speed, was significantly associated with increased CKD severity. This may improve the evidence for the prevention and intervention of sarcopenia in patients with CKD. Sarcopenia is an age-related loss of muscle mass, strength and physical performance that reduces mobility and quality of life, is significantly associated with a poor prognosis of disability and death, and can lead to fall-related injuries requiring costly hospitalization and long-term rehabilitation , 2. ManyChronic kidney disease (CKD) is a catabolic state known to be associated with protein depletion and multiple metabolic disorders, and muscle synthesis may also be reduced . EpidemiConsidering the increasing prevalence of CKD, the aim of this study was to determine the association between different stages of chronic kidney disease and sarcopenia in the Chinese older population. In addition, associations between the stages of CKD and sarcopenia and its components were compared.n = 1844) were from the community, and patients with kidney failure (n = 369) were from seven hemodialysis centers and had undergone stable hemodialysis for at least 3 months. The study was approved by the Ethics Committee of Shanghai University of Medicine and Health Sciences and the methods were carried out in accordance with the principles of the Declaration of Helsinki. All participants were informed and signed consent prior to enrollment in the study.This cross-sectional study recruited older adults ≥60 years of age living in Shanghai, China who had joined China's national free physical examination program between 2019 and 2021. This study included two population cohorts, the community-based elderly population of the Adult Physical Fitness and Health Cohort Study (APFHCS) (ChiCTR1900024880) and kidney failure population of seven hemodialysis units (ChiCTR1900027039). Participants with the following conditions were excluded from the study: (1) unable to communicate with interviewers or to grant informed consent, (2) no blood samples were collected, (3) major neurological disorders including dementia, malignancies, (4) serious physical illness  that hampered their completion of the functional fitness tests. Following these exclusions, the final analyzed population comprised 2,213 subjects . The older adults of normal and CKD1-4 groups  . Muscle strength was quantified using a handheld dynamometer . Grip strength is measured by the standard method of dominant hand in the elderly population, and it is measured by the side without fistula in patients with kidney failure. Participants were asked to exert their maximum effort twice and the strongest grip strength was recorded. To measure walking speed, two photocells connected to a recording chronometer were placed at the beginning and the end of a 4-meter course at the site clinic. Participants were instructed to stand with both feet touching the starting line and to begin walking at their usual pace after a verbal command was given. The time between activation of the first and the second photocell was measured and the average speed of two walks was recorded.A blood sample was obtained from the antecubital vein from patients who fasted overnight for at least 10 h. Blood sample analysis and blood pressure collection methods have been explained in our previous studies .The glomerular filtration rate (GFR) was estimated using the equation that originated from the CKD-EPI equation, which is more accurate than the equation from the MDRD Study group equation .2 were classified as normal and CKD 1, eGFR between 60 and 89 mL/min/1.73 m2 as CKD 2, eGFR between 15 and 59 mL/min/1.73 m2 as CKD 3–4, and eGFR <15 mL/min/1.73 m2 as CKD 5, kidney failure  classification, patients with eGFR ≥ 90 mL/min/1.73 m failure .P-values of < 0.05 were considered statistically significant.Characteristics of individuals at baseline were reported as medians (25–75th) percentiles for IPAQ; other continuous variables were presented as the means and standard deviation (SD), and categorical variables were expressed as percentages. We compared baseline patients' characteristics according to eGFR categories by Chi-Squared tests for categorical variables and one-way analysis of variance for continuous variables. Logistic regression analyses were used to assess the association between sarcopenia along with its individual components and CKD. Model 1 was adjusted for age and sex. Model 2 was adjusted for model 1 covariates plus BMI, widowed, farming, illiteracy, smoking, drinking, IPAQ, diabetes, hypertension, dyslipidemia, stroke and CHD. All statistical analyses were performed using SPSS v 26.0 , and p < 0.05). The age and muscle mass of CKD 3–4 group and kidney failure subjects were significantly larger than those of normal and CKD 1 group subjects, while the grip strength was the opposite. Current drinkers and farmers' occupation were significantly lower in kidney failure than in the other three groups, and the prevalence of hypertension, diabetes and stroke was significantly higher than in the other three groups (p< 0.05).Baseline characteristics of subjects were presented in p < 0.05).The prevalence of sarcopenia and its components classified by CKD stages was shown in The association between different CKD stages and sarcopenia and its components is shown in This study examined the association of CKD of varying severity with sarcopenia and its components in a larger population. We found that the prevalence of sarcopenia increased with the severity of CKD, especially in patients with kidney failure. However, after multivariate adjustment, the risk of decreased physical performance represented by walking speed increased gradually with the increase of the severity of CKD. The risk of sarcopenia and low grip strength increased significantly only in kidney failure, and low muscle mass was not significantly associated with different stages of CKD.2 , thus the specific effects of different stages are not reflected. Secondly, in our study, patients with kidney failure were treated with hemodialysis, and some studies have shown that hemodialysis is an independent risk factor of muscle weakness   . On the ctively) . The disctively) , 28. Walctively) . TherefoIt is worth noting that in our study, the prevalence of CKD in different genders has different trends. In CKD3-4 stage, women are much higher than men. However, in the stage of kidney failure, the prevalence of men is higher than women. These data are consistent with the trend of the results of the current study. The incidence rate of women in CKD is higher than that of men, and lower than that of men in renal replacement therapy . The effOur study has several strengths. We combined two independent population cohorts to supplement the samples of patients with different stages of CKD and comprehensively show the relationship between CKD and sarcopenia at each stage. Our results can supplement evidence on the relationship between physical performance and kidney function among older adults, which could contribute to providing appropriate treatment for the prevention of CKD. Although this study has its advantages, it still has some limitations. First, this is a cross-sectional study, so we cannot determine the causal relationship between CKD and sarcopenia. Secondly, our population are all participants with good functional status, who can participate in functional evaluation and have no obvious symptoms. Third, bioelectrical impedance method is used to evaluate muscle mass. Due to the large change of hydration state, this method may have errors in CKD patients. Future studies should expand the number of participants, add more relevant data and carry out more accurate and comprehensive assessments to further determine and enhance our understanding of the relationship between sarcopenia and CKD.In conclusion, we found that the prevalence of sarcopenia increased significantly with the development of CKD severity. With regard to its components, only the decrease in physical performance, represented by walking speed, was significantly associated with increased CKD severity, while the association with muscle mass is not shown. These findings inform clinical decision making and facilitate the development of therapies to prevent sarcopenia in older patients with CKD. Future studies should test the effectiveness of relevant interventions in older patients with CKD.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Shanghai University of Medicine and Health Sciences. The patients/participants provided their written informed consent to participate in this study.QG, SZ, and PS conceived the concept and design of the study. XC, HZ, XW, and YZ collected and assembled the data. YZ, JN, WD, and HZ analyzed and interpreted the data. YZ and PS drafted the article or revising it critically for important intellectual content. SZ and QG provided administrative support. XX and MG participated in data processing, statistical analysis, and revision of the manuscript. All authors approved the final version.This work was supported by the National Natural Science Foundation of China (No. 82172552).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.


Intracerebral hemorrhage (ICH) and acute ischemic stroke (AIS) have common vascular risk factors; however, ICH often occurs in adults aged < 70 years. Intracerebral hemorrhage and AIS in adults aged < 70 years should be preventable; however, it is unclear why different subtypes of ICH or AIS occur among adults aged < 70 years with vascular risk factors. This study aimed to identify independent variables for ICH or AIS onset in patients aged < 70 years.We included patients aged 40–69 years who experienced ICH or AIS between August 2016 and July 2019. Patients aged < 40 years were excluded because other diseases, rather than vascular risk factors, are often associated with stroke etiology in this age group. Data on age, systolic blood pressure (SBP), serum lipids, and serum fatty acid levels were compared between patients with ICH and those with AIS. In addition, we conducted multivariable logistic regression analyses to identify independent factors among the variables, such as blood pressure or biomarkers, with significant differences between the two groups.Of the 1252 acute stroke patients screened, 74 patients with ICH and 149 patients with AIS met the inclusion criteria. After excluding variables with multicollinearity, SBP, glycated hemoglobin (HbA1c), and eicosapentaenoic acid (EPA) proportion (%) of total fatty acids were identified as independent factors affecting ICH and AIS. The SBP and EPA% threshold values for ICH compared to AIS were ≥ 158 mmHg and ≤ 2.3%, respectively. The HbA1c threshold value for AIS compared to ICH was ≥ 6.1%.Systolic blood pressure, HbA1c, and EPA%, were independent factors between ICH and AIS. Patients aged 40–69 years with high SBP and low EPA% were at a higher risk of ICH than AIS, and those with a high HbA1c were at a higher risk of AIS than ICH.The online version contains supplementary material available at 10.1186/s12872-022-02625-6. Intracerebral hemorrhage (ICH) and acute ischemic stroke (AIS) have common vascular risk factors such as hypertension, dyslipidemia, diabetes mellitus, and obesity –3; howevThe etiology of stroke patients aged < 40 years frequently consists of vascular malformation, moyamoya disease, or autoimmune disease , 9. TherElevated blood pressure has been identified as the greatest risk factor for hemorrhagic or ischemic stroke . AdditioSerum FA levels at arrival performed under non-fasting conditions are associated with the dietary intake of TG immediately before stroke onset. Therefore, this retrospective cross-sectional study aimed to investigate the reason for onset of different stroke subtypes among adults aged 40–69 years with vascular risk factors and identify independent factors for ICH or AIS onset.2), because patients with these conditions suffer from possible malnutrition. Investigation of DGLA, EPA%, and DHA% were necessary to investigate the reason for the different onset of stroke subtypes, namely, early-onset ICH or AIS [We included patients admitted to our institution within 24 h of stroke onset between August 2016 and July 2019. We excluded the following patients: (1) aged < 40 years or ≥ 70 years, (2) those who did not undergo an examination of serum DGLA level, EPA%, and DHA% at arrival, (3) those with a severe disability or underweight status at admission, or (4) those with the etiology of vascular malformation, moyamoya disease, autoimmune disease, or cancer-related thrombosis. We defined a severe disability as a pre-hospital modified Rankin scale score ≥ 3 [H or AIS , 18.We collected patient data on anthropometric variables, blood pressure, National Institutes of Health Stroke Scale (NIHSS) score , historyrs) was used to measure the strength of the relationships between non-normally distributed variables with significant differences between the two groups. We truncated the rs below the second decimal point and defined: 0 ≤|rs|< 0.1 as no correlation, 0.1 ≤|rs|< 0.4 as a weak correlation, 0.4 ≤|rs|< 0.6 as a moderate correlation, and 0.6 ≤|rs| as a strong correlation. Variables with significant differences in the chi-square test or the Wilcoxon rank-sum test between the two groups were candidates for multivariable logistic regression analyses. We adopted the variable candidate with a smaller or the smallest probability (p) value or a larger or the largest absolute value of the Wilcoxon rank-sum test statistic (|z|) between or among variable candidates with mutually strong correlations (|rs|≥ 0.6). We defined multicollinearity as variance inflation factor ≥ 3, indicating that the multiple correlation coefficient is > 0.8. We conducted multivariable logistic regression analyses using variables without multicollinearity. We estimated the threshold values of independent ICH-onset variables using the receiver operating characteristic curves. Furthermore, we analyzed the data stratified according to age (40–54 vs. 55–69 years) as secondary analysis. We reported p-values up to four decimal places (< 0.0001). We presented p values using two-sided tests. Significance was set at p value < 0.05. JMP software  was used for all statistical analyses.The chi-square test was used to compare the categorical variables between the ICH and AIS groups. Non-normally distributed continuous variables were expressed as medians and interquartile ranges and the Wilcoxon rank-sum test was used to compare continuous variables between the ICH and AIS groups through normal approximation. A multivariable comparison test was used to compare all possible pairs of variables with significant differences between the two groups. Spearman’s rank correlation coefficient  and 149 with AIS (66.8%) met our inclusion criteria . In the subgroup analysis for age, only two (5.4%) of 37 patients aged 40–54 years and 30 (26.8%) of 112 patients aged 55–69 years with AIS took DL drugs pre-AIS (p = 0.0023). , and blood pressure, high SBP or DBP, was the only factor for ICH. In the subgroup analysis patients aged 55–69 years, the ratio of ICH decreased to 0.3 (48/160), high SBP and DBP were factors for ICH, and high HbA1c and low HDL levels were significant factors for AIS. As the age advanced, the ratio of ICH decreased, and diabetes or dyslipidemia became significant for AIS onset. In the subgroup analysis for age, only six (23.1%) of 26 patients aged 40–54 years and 13 (27.1%) of 48 patients aged 55–69 years with ICH took antihypertensive drugs pre-ICH (ns). Additionally, only four (10.8%) of 37 patients aged 40–54 years and 48 (42.9%) of 112 patients aged 55–69 years with AIS took antihypertensive drugs pre-AIS  took antihypertensive drugs before experiencing ICH, suggesting a lack of appropriate blood pressure control. The threshold value of EPA% for ICH compared to AIS was ≤ 2.3%, and the threshold value of HbA1c for AIS compared to ICH was ≥ 6.1%.Low compliance of antihypertensive drugs may be associated with ICH onset for patients aged 40–54 years and 55–69 years. In patients aged 40–54 years, blood pressure was the only significant factor for ICH, and the ratio of ICH was higher than that in patients aged 55–69 years, suggesting the importance of blood pressure control to prevent ICH in patients aged 40–54 years. On the other hand, HbA1c, antihypertensive drug use, or DL drug use increased in patients with AIS with advancing age. The ratio of AIS was higher in patients aged 55–69 years than patients aged 40–54 years, suggesting the importance of blood pressure control, HbA1c management, or dyslipidemia treatment to prevent AIS. Diabetes is an independent risk of ischemic stroke , and serThe occurrence of hypertension is proportional to salt intake . In addiA reduction in sodium intake lowers blood pressure . CompareIn this study, no difference was found in the DGLA level between ICH and AIS patients; however, a high DGLA level is significantly associated with ICH onset at a younger age . TherefoFor prevention of ICH, blood pressure should be controlled in adults aged 40–69 years, particularly those aged 40–54 years, and dietary EPA% should be increased for adults aged 40–69 years to prevent ICH. In addition, for prevention of AIS, blood pressure should be controlled, HbA1c should be managed, or dyslipidemia should be treated in adults aged 40–69, particularly those aged 55–69 years.This study has several limitations. First, a small number of patients were included, and the study was retrospective and cross-sectional. A cross-sectional study has reverse causality. Second, our study did not investigate dietary intake of sodium, FA, or carbohydrates. Third, because most of the patients were Japanese, generalization of the study outcomes to non-Japanese populations may not be possible. There might be racial differences in the association of ICH-related factors with the threshold values of factors for ICH. Fourth, data on basic demographic information , lifestyles , and family history of acute stroke were not collected, which may have led to a bias in the results. Fifth, our patients did not undergo analysis for the genome associated with early-onset high blood pressure or high HbA1c. A prospective randomized control study using a food frequency questionnaire, blood pressure measurement, and serum FA levels is needed to determine the effects of sodium and fish on ICH or AIS and prevention of stroke in patients aged 40–69 years.Systolic blood pressure, HbA1c, and EPA% were independent factors with significant differences between ICH and AIS in patients aged 40–69 years. Patients with high SBP and low EPA% were at a higher risk of ICH, and patients with high HbA1c were at a higher risk of AIS. Further studies are warranted to investigate the influence of race, ethnicity, or genome and the effects of changing lifestyle on the prevention of ICH and AIS in patients aged 40–69 years.Additional file 1. Flow chart of patient selection for the analysisAdditional file 2. The etiology of acute strokeAdditional file 3. Spearman’s rank correlation coefficients between individual variables with significant differences between the study groupsAdditional file 4. Variance inflation factors of three variables for multivariate analysisAdditional file 5. Characteristics of patient aged 40-54 yearsAdditional file 6. Characteristics of patient aged 55-69 years


The nutrition support team (NST) comprises doctors, nutritionists, pharmacists, and nurses who provide intensive nutritional treatment designed for each patient by evaluating their nutritional status of hospitalized patients. This study aimed to identify the clinical characteristics of patients referred to the NST among those admitted to a tertiary hospital and to understand the factors affecting their clinical course and changes in pressure sore grades.This study included 1,171 adult patients aged 18 years or older referred to the NST at a tertiary hospital in a metropolitan city between 1 January 2019 and 31 December 2020. Patients were divided into five age groups, neuro department and non-neuro department, those treated in the intensive care unit (ICU), and those not treated in the ICU. Patients were also compared based on the presence of pressure sores at the time of NST referral and changes in pressure sore grades at the first time of NST referral and discharge . In addition, this study examined the factors affecting changes in pressure sore grades.p < 0.001), and the neuro department showed a significantly lower proportion of low albumin levels and pressure sores (p < 0.001). The proportion of patients with pressure sores was higher (64.9%), and this patient group showed significantly higher rates of low albumin levels (p < 0.001) and treatment in the ICU (p < 0.001). The group with aggravated pressure sore grades had a significantly higher proportion of patients in the surgery department (p = 0.009) and those treated in the ICU (p < 0.001). Admission to the surgery department was a factor that aggravated the grade of pressure sores . When patients were not treated in the ICU, the grade of the pressure sores was less likely to worsen .As age increased, the proportion of both low albumin levels and pressure sores significantly increased (Pressure sores and low albumin levels are closely related, and the risk of developing and aggravating pressure sores is particularly high in patients in the surgery department and those receiving ICU treatment. Therefore, it is necessary to actively implement NST referral to ensure that overall nutrition, including albumin, is well supplied, especially for patients in the surgery department and treated in the ICU, as they are at high risk of pressure sore development and aggravation. Moreover, since low albumin levels frequently occur in elderly patients, it is necessary to consider including the elderly in the indications for referral to the NST. Malnutrition is a common problem among hospitalized patients. Previous studies have reported that 40% of all hospitalized patients had risk factors associated with malnutrition, and 75% became more malnourished during hospitalization . MalnutrThe nutrition support team (NST) aims to implement intensive nutritional treatment for each patient by pre–assessing the malnutrition status and the possibility of malnutrition by evaluating the nutritional status of hospitalized patients. It is an expert group comprising doctors, nutritionists, pharmacists, and nurses. Developed countries, such as the United States, began organizing the NST in the late 1960s to provide appropriate nutritional support for patients needing parenteral and enteral nutrition (PN and EN). South Korea started the NST with the voluntary participation of experts active in nutrition support in the late 1990s. As the “intensive nutrition treatment fee” became an item of health insurance in August 2014, the importance of nutritional treatment was further highlighted. Since then, more hospitals have installed and operated NST, and awareness regarding the importance of nutrition management for inpatients has been increasing. However, studies on the characteristics and treatment effects of patients referred to the NST are insufficient.Therefore, this study aimed to investigate the direction and focus of NST activities by identifying the clinical characteristics of patients referred to the NST among those hospitalized in tertiary hospitals and to understand the factors influencing their clinical course and changes in the grade of pressure sores.The participants were 1,490 adult patients (18 years or older) referred to the NST at least twice, with an interval of 1 week at tertiary hospitals in the metropolitan city between 1 January 2019 and 31 December 2020. After excluding 309 patients who received more than 75% of the required caloric supply at the time of referral and 10 patients with insufficient data for nutritional assessment, the data of 1,171 patients were used. Information on the referred patients was retrospectively analyzed using electronic medical records and NST patient management sheets. This study was approved by the hospital’s Institutional Review Board (2022-09-001). The requirement for consent was waived due to the study’s retrospective nature (2022-09-001).This study included 1,171 patients referred to the NST of a tertiary hospital at least twice with an interval of 1 week. The targets of NST referral were those who satisfied at least one of the following criteria: (1) serum albumin ≤ 3.0 g/dl, (2) receiving EN; (3) receiving PN; (4) receiving treatment in an intensive care unit (ICU); and (5) when it was determined that intensive nutritional treatment was necessary based on the medical opinion of the physician in charge.This study analyzed the patients’ clinical characteristics and course according to sex, age, presence of pressure sores, changes in the grade of pressure sores at the first time of NST referral and discharge, treatment in the ICU, and clinical department. Clinical characteristics included sex, age, height, weight, body mass index (BMI), clinical department, whether the physician in charge was a member of an NST , whether EN or PN was supplied, whether the patient could eat independently, fasting or not, the presence of pressure sores, the grade of pressure sores at the first time of NST referral, laboratory findings at the time of NST referral , low albumin levels , and difficulty chewing and swallowing. The clinical course included the number of weeks until reaching the target calorie when 75% or more of the required calorie was supplied, based on body weight, whether the grade of pressure sores aggravated at discharge, and whether to be treated in the ICU. If a patient was treated in the ICU, the Acute Physiology and Chronic Health Evaluation II (APACHE II) score was used.Age was divided into five groups: 18–50, 50–59, 60–69, 70–79, and ≥ 80 years. Pressure sores were determined by referring to the pressure sore evaluation sheet in the medical record. The pressure sores were classified into five grades (0–4). The grades at the first NST referral and that at discharge were compared, and classified into three groups: aggravation, improvement, and no change, the differences between the three groups were compared. The departments were compared by classifying them into a neuro department (neurology and neurosurgery) and a non-neuro department . They were also classified into internal medicine departments  and surgery departments .t-test or One-way ANOVA was used for continuous variables. Pearson’s chi-square test was performed, and when the expected frequency of each cell was less than 5, more than 20% of the cells were interpreted as Fisher’s exact test values. In addition, multinomial logistic regression analysis was used to examine the factors that improved or aggravated the sore stage changes. Statistical significance was set at P < 0.05 (two-tailed). All statistical analyses were performed using SPSS .First, the demographics, nutritional status, general conditions, and laboratory findings were compared between females and males, neuro and non-neuro departments, those with and without pressure sore, and those with and without ICU treatment. Second, age was divided into five categories, and demographics, nutritional status, general condition, and laboratory findings were compared according to age groups. Third, changes in pressure sore grade during admission were divided into three categories, and demographics, nutritional status, general conditions, and laboratory findings were compared according to these categories. Pearson’s chi-square or Fisher’s exact test was used for categorical variables, and the p < 0.001). In the younger age groups, more NST referrals were made by the surgery department than by the internal medicine department. In the older age groups, more NST referrals were made by the internal medicine department than by the surgery department. The rate of low albumin levels and the presence of pressure sores significantly increased with age (p < 0.001). The APACHE II score at the time of ICU admission also significantly increased (p = 0.007) with increasing age. In laboratory tests, serum albumin and total cholesterol levels decreased significantly (p < 0.001) with age.This study divided 1,171 patients referred to the NST into five age groups  and analyzed them to understand the differences according to age . The resp < 0.001). Fewer physicians in the neuro department received NST training (17.2 vs. 36.6%). Plasma hemoglobin (Hb), serum sodium (Na), albumin, and total cholesterol levels of patients in the non-neuro department were significantly lower than those of patients in the neuro department group (p < 0.001).This study divided patients into the neuro and non-neuro departments and compared them to examine the differences according to department . The neup < 0.001). The neuro department had a lower proportion of patients with pressure sores than the non-neuro department . Patients with pressure sores had higher rates of low albumin levels (43.8 vs. 28.0%) and EN (39.2 vs. 31.1%) and a lower rate of spontaneous feeding (12.0 vs. 19.2%). Additionally, the rates of accompanying edema (6.2 vs. 2.2%), difficulty chewing (37.0 vs. 28.7%), and swallowing (29.1 vs. 23.4%) were higher in patients with pressure sores. In contrast, the rate of poor appetite was lower in patients with pressure sores (9.5 vs. 15.6%). Patients with pressure sores (89.7%) had a higher rate of no change in the grade of pressure sores at the first NST referral and at the time of discharge. In contrast, patients without pressure sores were more likely to have aggravated pressure sores at discharge . A higher proportion of patients with pressure sores were treated in the ICU (31.3 vs. 21.4%) for a longer (27.24 ± 23.96 vs. 16.00 ± 14.42). The group with pressure sores had lower plasma Hb (10.48 ± 2.12 vs. 10.81 ± 2.24), serum albumin (3.13 ± 0.52 vs. 3.32 ± 0.57), and total cholesterol levels (133.33 ± 46.55 vs. 145.07 ± 41.54) than that without pressure sores.This study divided the patients into a group with pressure sores and a group without pressure sores and compared both groups to examine the differences according to the presence of pressure sores . Among tp = 0.003 and 0.002, respectively), and the proportion of patients in the surgery department was also higher (p = 0.009). In addition, the presence of ascites was significantly higher in the group with aggravated pressure sore grades than in the other groups (p = 0.002), and the rate of treatment in the ICU was significantly higher in this group than in the other groups (p < 0.001). Multinomial logistic regression analysis was performed using significant variables (p < 0.05) in the crossover analysis and one-way analysis of variance to examine the factors affecting the change in the pressure sore grades .The target patients were divided into those who were treated in the ICU (ICU group) and those who were not treated in the ICU (no ICU group), and both groups were analyzed to evaluate the differences according to ICU treatment . The resThis study describes that low albumin levels frequently occur in elderly patients and that pressure sores and low albumin levels are closely related. We found that the risk of aggravating pressure sores was particularly high in patients in the surgery department and those receiving ICU treatment.This study found that the proportion of patients with low albumin levels increases with age. As previous studies have shown that healthy older people have normal albumin levels, age in itself is not a pathophysiological mechanism for hypoalbuminemia . In contAmong patients admitted to the neuro departments of a tertiary hospital, the proportion of acute diseases such as cerebral infarction, cerebral hemorrhage, and encephalitis is higher than that of chronic and intractable neurological disorders . For thiThe Waterlow tool is used to assess the risk of pressure sores. This tool consists of 11 elements: BMI, visual risk area/skin condition, sex, age, nutritional status, urine and feces control, mobility, and unique risk factors, including tissue malnutrition, neurological deficit, major surgery or trauma, and drugs . In thisTreatment in the ICU also worsened the patient’s pressure sore grade. Patients who did not receive ICU treatment were less likely to have worsening pressure sore grades. This could be because patients who did not receive ICU treatment had low-severity symptoms, and many of them could easily change their body positions, which impacted the pressure sore grade. Since ICU treatment is one of the current indications for NST treatment , it is nThe strength of this study is that it was conducted on a relatively large number of patients. However, this study had several limitations. First, it was difficult to generalize the characteristics of the patients because only those who visited a tertiary hospital were included. However, the results of this study are believed to be reliable because it targeted patients who met the NST treatment indications, and these indications were the same in other hospitals. Second, this study could not analyze clinical data such as the patient’s underlying disease or the disease being diagnosed and treated. Therefore, the results should be interpreted with caution because other potential factors may have influenced the results of this study. Finally, this study may have selection bias because the data were collected and analyzed retrospectively.Since there is a close relationship between pressure sores and low albumin levels, it is necessary to actively provide overall nutrition, including albumin, by actively implementing NST referrals, especially for patients in the surgery department and those treated in the ICU, as they are at a high risk of pressure sore development and aggravation. Furthermore, since low albumin levels occur more frequently in elderly patients, additional studies are needed to examine whether elderly patients should be included in the NST treatment indications.The original contributions presented in this study are included in the article/This study was approved by the hospital’s Institutional Review Board (2022-09-001). The requirement for consent was waived due to the study’s retrospective nature (2022-09-001). The patients/participants provided their written informed consent to participate in this study.JB and HK: conceptualization and writing—review and editing. JB, S-YK, HR, and HK: methodology. HR and JC: software. JC, B-SS, and HK: validation. S-YK: investigation and visualization. JB and HR: resources. B-SS and HK: writing—original draft preparation. HK: supervision and funding acquisition. All authors read and agreed to the published version of the manuscript.


Early neurologic improvement (ENI) after intravenous thrombolysis is associated with favorable outcome, but associated serum biomarkers were not fully determined. We aimed to investigate the issue based on a prospective cohort.In INTRECIS study, five centers were designed to consecutively collect blood sample from enrolled patients. The patients with ENI and without ENI were matched by propensity score matching with a ratio of 1:1. Preset 49 biomarkers were measured through microarray analysis. Enrichment of gene ontology and pathway, and protein-protein interaction network were analyzed in the identified biomarkers.Of 358 patients, 19 patients with ENI were assigned to ENI group, while 19 matched patients without ENI were assigned to Non ENI group. A total of nine biomarkers were found different between two groups, in which serum levels of chemokine (C-C motif) ligand (CCL)-23, chemokine (C-X-C motif) ligand (CXCL)-12, insulin-like growth factor binding protein (IGFBP)-6, interleukin (IL)-5, lymphatic vessel endothelial hyaluronan receptor (LYVE)-1, plasminogen activator inhibitor (PAI)-1, platelet-derived growth factor (PDGF)-AA, suppression of tumorigenicity (ST)-2, and tumor necrosis factor (TNF)-α were higher in the ENI group, compared with those in the Non ENI group.We found that serum levels of CCL-23, CXCL-12, IGFBP-6, IL-5, LYVE-1, PAI-1, PDGF-AA, ST-2, and TNF-α at admission were associated with post-thrombolytic ENI in stroke. The role of biomarkers warrants further investigation.Clinical Trial Registration: https://www.clinicaltrials.gov; identifier: NCT02854592. Stroke is the second leading cause of disability and mortality worldwide, which prevalence increased annually in China . IntraveIn the previous studies, female sex, blood glucose < 8 mmol/L, absence of cortical involvement on brain computerized tomography at 24 hours after thrombolysis, leptomeningeal collaterals status, hyperdense artery sign and fall in systolic blood pressure at 24 hours after thrombolysis were found to be associated with ENI in ischemic stroke –9. GivenIn INTRECIS (INtravenous Thrombolysis REgistry for Chinese Ischemic Stroke within 4.5 hours of onset) study , five ceFrom August 2018 to July 2019, patients receiving intravenous thrombolysis within 4.5 hours were consecutively screened to collect blood samples before thrombolysis from five selected hospitals participating in the INTRECIS study. The registry study is nationwide, multicenter, and prospective, which enrolled consecutive adult patients who were eligible for intravenous thrombolysis within 4.5 hours. Details of the trial design and primary outcomes analyses have been previously reported . BrieflyThe baseline data of patients were obtained from electronic database: age, gender, smoking, alcohol consumption, medical history, previous use of antiplatelet, blood pressure and glucose at admission, symptom onset-to-thrombolytic time, NIHSS scores, and TOAST classification. Authors had no access to information that could identify individual participants during data collection. ENI was defined as a decrease of ≥4 on the NIHSS scores within 24 hours after thrombolysis from baseline in the present study [Before intravenous thrombolysis, four milliliters of peripheral venous blood samples were collected from each patient at admission. The blood samples were centrifuged with the condition of 1000 ⊆ g for 10 minutes at 4°C, and then transferred into 1.8 milliliter cryotube and stored at -80°C until detection.According to the manufacturer’s instructions, pre-customized protein microarray analysis (Raybiotech Inc) was used to simultaneously detect and quantify serum levels of biomarkers, which were pre-designed based on published data. Identified biomarkers were defined as those variations with p value < 0.05, and fold change > 1.20 or < 0.83. We conducted functional enrichment analysis and protein-protein interactions network to explore mechanism in identified biomarkers2 tests were used to analyze the categorical variables.Descriptive statistics was performed to compare variables between groups. Continuous variables with normal distribution were described as means and standard deviation, which included age, blood pressure and glucose at admission, symptom onset to thrombolysis time, NIHSS score, and detected serum concentration of biomarkers. The t tests were used to analyze the normally distributed continuous variables. Categorical variables were described as number and proportions, which included gender, smoking, alcohol consumption, medical history, previous use of antiplatelet, and TOAST classification. The Pearson χThe empirical Bayes based linear model method was used to analyze the differential expression of biomarkers between different stages or disease with R package limma. The normalized biomarker values were transformed into log values with base 2, and then input into the analysis. The differential expression was evaluated by adjusted p value (BH method) based on moderated t statistics. In all analysis, differences were considered statistically significant with P value < 0.05. The free statistical language R (version 3.10.3) was used for the outcomes and graph in microarray analysis.Overall, 358 thrombolytic patients were consecutively screened in the current study and 234 patients were excluded due to the following reasons: 135 patients with urokinase and 25 patients with non-standard dose of alteplase, 10 patients with endovascular treatment, 3 patients with incomplete baseline data, and 61 patients without blood samples collection. Finally, 124 patients were included into the study, including 19 patients with ENI, and 105 patients without ENI. With the matching ratio of 1:1, 19 patients without ENI were matched to Non ENI group for analysis . BaselinP < 0.05, Compared with the Non ENI group, a total of 9 biomarkers with significant difference in ENI group were observed (The comprehensive gene ontology (GO) enrichment analysis, which consisted of biological process, molecular function, and cellular component analysis, was conducted to gain a deeper insight into the main functions of the identified biomarkers. The biological process analysis showed that CCL-23, CXCL-12, TNF-α, and PAI-1 were mostly related to the mononuclear cell migration . The molAccording to the information of Search Tool for the Retrieval of Interacting Genes (STRING) database, we build the protein-protein interaction network among identified biomarkers . The resTo our best knowledge, this is the first study to comprehensively investigate serum biomarkers associated with post-thrombolytic ENI by microarray analysis. A total of nine biomarkers were found higher in ENI group than Non ENI group, including CCL-23, CXCL-12, IGFBP-6, IL-5, LYVE-1, PAI-1, PDGF-AA, ST-2, and TNF-α.Up to date, only a few biomarkers, such as ADAMTS13 activity, Aquaporin-4, leukocyte count, and neutrophil to lymphocyte ratio, were found to be associated with post-thrombolytic ENI in stroke –13. The Based on functional enrichment analysis, mononuclear cell migration, receptor ligand activity, platelet alpha granule lumen, and cytokine-cytokine receptor interaction were significantly enriched items. After brain injury, CCL-23 and CXCL-12 modulate immune response through promoting migration of monocytes to the local sites of injury ,20. As tThe main strength of this study is the first report of nine biomarkers associated with post-thrombolytic ENI through comprehensively screening preset biomarkers in a prospective cohort. The findings may contribute to further understanding of potential mechanisms underlying early post-thrombolytic outcome improvement in ischemic stroke. However, we recognize several limitations of our study. First, smaller sample size in the present study weaken the power of conclusion. Second, the sensitivity of identified biomarkers for predicting ENI need to be validated in other cohorts with more patients. Third, we could not rule out the effect of an acute phase reaction or comorbidity on these biomarkers. Fourth, in the present study, we only collected the blood sample before thrombolysis and excluded the patients who received mechanical thrombectomy. Therefore, we did not investigate dynamic changes of these biomarkers over the course of follow-up, as well as the effect of reperfusion treatment such as thrombolysis and mechanical thrombectomy on these biomarkers. Last, complex roles of identified biomarkers need further be investigated.For the first time, we found that higher serum levels of CCL-23, CXCL-12, IGFBP-6, IL-5, LYVE-1, PAI-1, PDGF-AA, ST-2, and TNF-α at admission were associated with post-thrombolytic ENI in ischemic stroke. The value of these newly identified biomarkers warrants further investigation.


Decreased baroreflex sensitivity (BRS) has been shown to be a marker of cardiovascular (CV) risk. In the present study, the difference in CV risk biomarkers in type 2 diabetes (T2D) patients receiving oral antidiabetic drugs (OAD) with and without hypertension has been assessed.Ninety-two T2D patients on OAD without hypertension (control group) and eighty-eight diabetic patients with hypertension on OAD and antihypertensive drugs (test group) matched for age, gender, body mass index, serum glucose, glycated haemoglobin, and duration of the disease were recruited for the study. Their blood pressure (BP) variability including BRS, heart rate variability (HRV), insulin, lipid profile, osteoprotegerin (OPG), and tumor necrosis factor-α (TNF-α) were estimated. The association of various factors with BRS was assessed by Spearman correlation and multiple regression analysis.BRS was decreased (13.90 ± 5.27 vs 6.76 ± 4.58), HRV sympathetic indices , HOMA-IR, atherogenic index of plasma (AIP), OPG (223.08 ± 103.86 vs 287.60 ± 121.36) and TNF-α were increased, and parasympathetic indices  were decreased in the test group compared to control group. In control group, parasympathetic indices, AIP, OPG, and TNF-α had a significant correlation and OPG had an independent association  with BRS. In test group, BP, LF-HF ratio, parasympathetic indices, AIP, OPG, and TNF-α had significant correlation, and TNF-α alone  had an independent contribution to decreased BRS.Despite antidiabetic and antihypertensive treatments, T2D patients with hypertension had more cardiometabolic risks in comparison to normotensive T2D patients. Inflammation could be the inciting factor for rise in BP and decrease in BRS (CV risk) in hypertensive T2D patients. Hypertension in diabetes could attenuate the link of OPG to the reduction in BRS. Reduction in BRS could be a physiological marker of CV risk in T2D patients treated with OAD. Hypertension is present in more than 50% of diabetes mellitus (DM) patients contributing significantly to microvascular and macrovascular complications , 2. IndeFor long, the first line of drugs of choice for the management of type 2 diabetes mellitus (T2D) is sulfonylurea and biguanides, either as monotherapy or in combination . At the Baroreflex sensitivity (BRS) and heart rate variability (HRV) have recently been reported as sensitive markers of CV risks in various clinical disorders –19. We hAlthough alteration in HRV and BRS has been reported in DM , the magThis was a cross-sectional analytical study conducted in Biochemistry, Physiology, and Medicine departments at Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India. This study was first reviewed and approved by an institutional review board (JSAC), followed by Institutional Ethics Committee (Human studies: JIP/IEC/2018/305) before the study was conducted. Written informed consent was obtained from all participants at the time of recruitment.n = 92) consisting of T2D patients on treatment with oral antidiabetic drugs (OAD), and the test group consisting of T2D patients (n = 88) on treatment with antidiabetic and antihypertensive drugs . We screened around 2200 diabetic patients between November 2018 and January 2020 and recruited 201 T2D patients following exclusion and inclusion criteria. Twenty-one patients with uncontrolled diabetes/hypertension were excluded from the study. Thus, the final sample size for the present study was 180. Among them, 92 patients had no hypertension and 88 patients had hypertension. Accordingly, they were divided into two groups: the control group  between two independent means of BRS (17.23 vs 9.07) based on the previous report  and a siThe study protocol was explained to the patients in their local language before obtaining written informed consent. All the participants were asked to avoid intake of coffee, nicotine, and alcohol 24 hours before the recordings. They were instructed to report next morning to the autonomic function test (AFT) lab between 8:30 am and 9:30 am in overnight fasting state. Fasting blood samples were collected the next day morning, and basal recordings were obtained 2 h after a light breakfast meal.Basal demographic and anthropometric data were collected using a wall-mounted stadiometer to measure height, and a digital weight balance was used to measure the weight of individuals with light clothing. Body mass index was (BMI) derived using Quetelet’s formula. Basal demographic and anthropometric parameters of all the participants were recorded, and the personal history was noted using a structured data sheet.t 8.30 am. Their age, body weight, height, and BMI were recorded. Omron (SEM 1 Model), the automatic BP monitor apparatus , was used to measure their BP. The cuff size of the equipment used was 121 mm (width) × 446 mm (length), and the cuff tube length was 600 mm. The patients sat upright with backs straight on a wooden armed chair. After placing one forearm comfortably on the table, the middle of the arm of the subjects was coincided with the heart level. The BP cuff was tied on the arm roughly 2 cm above the cubital fossa, which was neither too tight nor loose. For each participant, heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were recorded at an interval of 5 minutes in each arm twice, and the mean of the four recordings was considered for each parameter.Patients reported in the autonomic function laboratory of Physiology Department at abouThe CV parameters and BRS were measured using the continuous BPV method . Finapres is a non-invasive continuous hemodynamic CV monitor that uses the principle of finger plethysmography as described in detail in our earlier reports , 21. TheFor the recording of short-term HRV, the HRV measurement and analysis procedures described earlier were followed , 23. ECGFollowing overnight fasting, five ml of venous blood was collected under aseptic precautions in clot activator tubes. Blood samples were centrifuged for 15 min after coagulation at 2500 RPM. Serum separated was processed for fasting glucose and lipid profile. Fasting serum glucose (FSG) was estimated by the Hexokinase method and lipid profile was measured by an automated AU5800 chemistry analyzer using commercial kits . LDL-C was analyzed by direct estimation. Total cholesterol, HDL-C, and triglyceride were analyzed by cholesterol oxidase, direct immunosuppression method, and Lipase/Glycerol phosphate oxidase method, respectively.TNF-α , insulin , and OPG  were estimated by an enzyme-linked immunosorbent assay (ELISA). In the method of ELISA for OPG, the polyclonal goat anti-human OPG antibody binds to human endogenous OPG. Thus, the monomeric and dimeric OPG form a complex with the antibody. The washing step removes the nonspecific bound materials, while a second antibody complexed with streptavidin-HRP detects this complex, which follows the principle of sandwich ELISA. The concentration of OPG is directly determined by the standard dose-response curve. HOMA-IR was calculated using formula. HOMA-IR = Glucose X Insulin / 405 . The intP value < 0.05 was considered significant.All the clinical characteristics and variables were expressed in frequencies and percentages for categorical variables. Continuous variables were expressed as Mean ± SD. The normality of data was checked by the Shapiro-Wilk test. Chi-square test was used for comparison between two groups for all the nominal data. For comparison between continuous parameters, Student’s unpaired t-test and Mann–Whitney-U test was used for normally distributed variables and non-normally distributed variables, respectively. The relationship between the variables in each group was evaluated by Spearman’s rank correlation analysis. For assessing the independent contribution of variables to BRS, multiple regression analysis was used. This was followed by stepwise regression analysis to elucidate the most important variable contributing to alteration in BRS. All statistical tests were performed using SPSS version 20.0. A total of 180 diabetes mellitus patients were recruited from October 2018 to January 2020. The distribution of age, gender, and other histories are shown in Table A significant increase was observed in the HR, SBP, DBP, MAP, and RPP in T2D patients with hypertension Table .Among the BPV parameters, SV, LVET, CO, and TPR were significantly increased, while BRS was decreased in the test group Table .Among the HRV indices TP, SDNN, RMSSD, NN50, and pNN50 were significantly less in T2D patients with hypertension Table . LFnu waThe serum concentration of glycemic parameters, lipid profile, and atherogenic indices among study participants are presented in Table p = 0.009) and RPP  in the test group  and LF/HF  and TNF-α  in test group (Table p = 0.000) and for T2D patients without hypertension (Table p = 0.004) in the test group.Decreased BRS was significantly associated with rise in HR  compared to the control group  Table . BRS wasr = − 0.595, P = 0.000) compared to the control group   and we found that OPG  had more significant association with decrease in BRS compared to TNF-α   in the entire study population (7) Table . This inDiabetes and hypertension share several pathophysiologic mechanisms such as inappropriate activation of the renin-angiotensin-aldosterone system (RAAS), oxidative stress, impaired insulin-mediated vascular function, inflammation, increased sympathetic activation, dysfunctional immune responses, and abnormal renal handling of sodium , 51. PerThe glycemic status (levels of serum glucose and glycated hemoglobin) is known to influence HRV . TherefoThough the major limitation of the present study is that we did not take a pure nondiabetic control group to compare cardiometabolic risks of diabetic patients with nondiabetic subjects, based on our previous data of control subjects , 21 we cDespite antidiabetic and antihypertensive treatment, patients with hypertension and diabetes had more cardiometabolic risks compared to normotensive patients with diabetes. Inflammation could be the inciting factor for rise in BP and decreased BRS in hypertensive diabetics. Decreased BRS could be the marker of CV risk in T2D patients.


The current research is aimed at analyzing the relationship between kidney stone (KS) and abdominal aortic calcification (AAC) and the relationship between KS components and AAC.t test, the chi-squared test and binary logistics regression were performed.This is a retrospective, case–control study. Kidney stone formers (KSFs) were treated at the Department of Urology, West China Hospital, Sichuan University for urological calculus disease from January 2014 to January 2020. Matched non-stone formers (non-SFs) were drawn from the same hospital for routine health examination from January 2018 to February 2019. Research-related information was collected and reviewed retrospectively from the hospital’s computerized records. AAC were evaluated using available results of computed tomography imaging and abdominal vascular ultrasound. The relationships of AAC between KSFs and non-SFs were compared. The composition of renal calculi was analyzed by Fourier-transform infrared spectrophotometer. KSFs were divided into AAC groups and non-AAC based on AAC. The relationship of the composition of renal calculi between AAC and non-AAC were compared. The independent-sample p < 0.001). The result of KSFs showed that calcium oxalate calculi (CaOx) was significantly associated with AAC in multivariable model 3  .Altogether, 4516 people were included, with 1027 KSFs and 3489 non-SFs. There were no significant differences in the laboratory parameters between KSFs and non-SFs. The association between the presence of AAC and KS was significant in multivariable model 2  (OR 5.756, 95% CI 4.616–7.177, The current study pioneered the revelation of the relationship between CaOx and AAC. Through an elimination of the confounding factors, the study demonstrated that KS and AAC were connected. Nephrolithiasis, with a high recurrence rate of more than 50% within 10 years . The diaAt the same time, abdominal CT is an ideal tool to evaluate abdominal aortic calcification (AAC). In recent years, epidemiologic study have provided evidence for an association between nephrolithiasis and cardiovascular disease . When usBoth KS and AAC are easy to evaluate. In the case of kidney stone evaluation, performing abdominal CT imaging is an efficient technique. Nonetheless, no studies have been done on the correlation between AAC and KS. The study was based on a hypothesis that there is a relationship between KS and AAC. In specific, AAC leads to a higher probability of KS occurrence, and the two may have common pathogenesis.We retrospectively collected the conditional information of abdominal aorta in patients with KSFs and non-SFs, and the composition information of stones in patients with renal calculi. The purpose of the present research is to analyze the relationship between nephrolithiasis and AAC and the relationship between KS components and AAC, followed by a discussion on whether AAC can predict the occurrence of stones.This is a retrospective, case–control study. KSFs were treated at the Department of Urology, West China Hospital, Sichuan University for urological calculus disease from January 2014 to January 2020. Matched non-SFs were drawn from the same hospital for routine health examination from January 2018 to February 2019. Kidney stones were diagnosed by professional physician with (non-contrast or contrast) abdominal CT, kidney–ureter–bladder X-ray photography (KUB), or urinary ultrasound.Demographic and clinical variables of both KSFs and non-SFs include general items , laboratory examination , abdominal CT, abdominal aortal ultrasonography, kidney–ureter–bladder X-ray photography (KUB), or urinary ultrasound, etc. KSFs undergone stone composition analysis were included. Non-SFs were unable to evaluate aortic calcification were excluded, and were diagnosed with urinary calculi or underwent urolithiasis-related operations were also excluded. Patients with hyperparathyroidism, renal tubular acidosis, and hereditary urinary lithiasis were excluded. The screening process of patients with KSFs and non-SFs is presented in Figs. KSFs were divided into AAC group and non-AAC group based on AAC, shown in Fig. Research-related information was collected and reviewed retrospectively from the hospital’s computerized records. Specifically, the following parameters were collected: age, gender, body mass index (BMI), diabetes mellitus, hypertension, smoking history, drinking history, stone size, stone location, and laboratory data: FBG, UA, TG, TC, Ca, and pH.n = 6) and drug-induced calculi (n = 1) were categorized as “other”.The composition of renal calculi was analyzed by Fourier-transform infrared spectrophotometer , which were categorized according to EAU guidelines . EvaluatAAC were evaluated using available results of abdominal CT imaging and abdominal vascular ultrasound. Ultrasonographic examination of the abdominal aorta is just a supplement. To increase the accuracy of diagnosis of vascular calcification, abdominal vascular ultrasound and abdominal CT were used for mutual verification of AAC. The measurement range of the abdominal aorta starts at 1 cm from the starting point of the abdominal aorta and ends at 1 cm under iliac bifurcation. AAC exists if the aortic wall area is larger than 1 mm^2, and the density is over 130 Hounsfield unit (HU) using available CT imaging . In an ut test was performed. Otherwise, the rank sum test is used. For categorical variables, when T ≥ 5 and sample size n ≥ 40, the chi-square test was selected for data analysis. If 1 ≤ T < 5 and n ≥ 40, the continuity corrected chi-square test was carried out.In this study, continuous variables were calculated by means ± standard deviations (SD), whereas categorical variables were measured by counts (percentages). If the continuous variable conforms to the normal distribution, an independent-sample Binary logistics regression was utilized to assess the correlation between KS and AAC. Beyond that, multivariable model 1 was set up to adjust age and gender, and multivariable model 2 was designed to adjust age, gender, BMI, diabetes mellitus, hypertension, smoking history, drinking history, FBG, UA, TG, Ca, and urine pH, which studies have confirmed that these factors may be closely related to the occurrence and development of KS .KS were divided into two groups based on AAC, to evaluate the relationship between AAC and the stone composition. Here, binary logistics regression was performed and multivariable model 3 was framed to adjust age, diabetes mellitus, hypertension, smoking history, drinking history, and TG, which these factors have been shown to be closely related to vascular calcification .p value was less than 0.05, the analysis was considered statistically significant. All statistical analyses were performed with SPSS software . The study protocol was approved by the Biomedical Ethics Committee at West China Hospital, Sichuan University (No. 2015-202).This was a two-tailed test and when p < 0.001). Table p < 0.001), which was not found among non-SFs with the unadjusted model 1. In multivariable model 1 that was designed to adjust age and gender, it was observed that KSFs had higher AAC . In a similar vein, the relationship was also significant in multivariable model 2 which also adjusted hypertension, diabetes mellitus, drinking history, smoking history, FBG, UA, TG, Ca, and urine pH variables .In total, 4516 samples were included, including 1027 patients diagnosed with nephrolithiasis, and 3489 non-SFs  as controls. Variables of interest were categorized by the presence or absence of KS, as shown in Table p = 0.006; OR 0.667, 95% CI 0.487–0.912, p = 0.011; OR 0.341, 95% CI 0.148–0.785, p = 0.011, respectively), except for UA and others . However, only CaOx had a significant association with AAC , after adjustment for age, hypertension, diabetes mellitus, drinking history, smoking history, and TG.The stone composition of 1027 KSFs was investigated, which include 705 CaOx, 222 CaP, 55UA, 37 struvite, and 8 others . The baseline characteristics of KSFs based on a composition analysis are presented in Table p < 0.001) [p = 0.004) [Several interesting findings were disclosed in our research. First, multivariate analysis 2 confirmed that kidney stone disease is independently associated with AAC through a comparison of KSFs and non-SFs, despite the fact that potential confounders were noticed. Shavit L. et al. reported that KSFs with relapsing nephrolithiasis had a more severe AAC score than non-SFs (< 0.001) . Patient= 0.004) . The mul= 0.004) .In what follows, our study is the first of its type to reveal the relationship between calcium oxalate stone and AAC after adjusting the vascular calcifications related confounding factors. Then, after controlling the KS-related confounding factors, our study still found a positive correlation between KS and AAC.p < 0.001). Karen L. Stern et al. claimed that AAC was more widespread among the KSFs [A further exploration also showed that the prevalence of KS in patients with AAC was significantly higher than non-SFs , whereas patients with AAC were less likely to have CaP- and struvite-composed stones than those without AAC . Multivariate analyses model 3 confirmed that AAC is independently associated with CaOx . Pietro Manuel Ferraro et al. have detected an association between AAC and CaP [p = 0.016), however, they did not probe the correlation between the two parameters [We discovered a higher prevalence of obesity, hypertension, diabetes mellitus, drinking history, smoking history, hyperlipidemia and hypercholesterolemia in patients with AAC, if compared with those without AAC. In the unadjusted model 2, we analyzed the relationship between the components of KS and AAC, and found that patients with AAC was 1.48 times more likely to have CaOx-composed stones than those without AAC (OR = 1.476,  and CaP . In this and CaP –20. PateTaguchi et al. disclosed that the production of M1 macrophages was induced by an oxalate-inducing diet . Liu et Furthermore, a new mechanism for the formation of kidney—mineral nanoparticles has been found in calcified blood vessels and kidney , 37. WonSome limitations must be taken into account when interpreting the findings of the study. The composition of stones cannot be quantified, so the study could only reveal the main components of stones. Beyond that, since this is a retrospective study, data collection might have been influenced by some unknown confounding factors. For instance, a participant diagnosed with KS may have changed the previous unhealthy lifestyle and exercised more, which is likely to change the profile of confounders that influence the occurrence and development of AAC. It is also true that the accurate time of AAC and KS formation could not be evaluated, as this is a cross-sectional study. Hence, it is necessary to carry out longitudinal studies to understand this relationship in a more comprehensive manner. Moreover, patients with chronic diseases like hypertension and diabetes usually take drugs for a long time, which might also affect the formation kidney stones and AAC.In conclusion, this study blazed the trail to investigate the correlation between calcium oxalate stone and AAC after an adjustment of confounding factors. The analyses show that KS and AAC are closely associated. Patients with AAC are more likely to have kidney stones. However, whether aortic calcification can predict KS needs further exploration. In a similar vein, the specific pathophysiological mechanisms of KS and aortic calcification need to be further clarified.