Increased or decreased blood pressure variability may affect the perfusion of tissues and organs, leading to acute kidney injury and death. This study was conducted to explore the relationship between mean arterial pressure variability and short- and long-term mortality in critically ill patients.We used patient data from the MIMIC-III database for cohort study. According to the recorded mean arterial pressure during the first 24 h in the intensive care unit, we calculated each patient’s two variability parameters –coefficient of variation and average real variability. The primary outcome was in-hospital mortality and the secondary outcomes were 28-day mortality and 1-year mortality. We conducted smooth spline models to examine the possible nonlinear associations between blood pressure variability and mortality. According to the smoothing curve, we further developed a two-piecewise linear regression model to find out the threshold effect. Multivariable logistic regression or Cox proportional hazards model was used to evaluate the relationship. Kaplan–Meier survival analysis for 28-day and 1-year mortality was performed. Subgroup analysis explored the factors modifying the relationship between them.A total of 12,867 patients were enrolled in the study, 1,320 in-hospital death, 1,399 28-day death, and 2,734 1-year death occurred. The smooth spline showed death risk was the lowest when average real variability was around 7.2 mmHg. After adjusting for covariates, logistic or Cox regression showed the highest MAP variability level was strongly associated with increased mortality in the hospital , at 28 days , and at 1 year  compared with the second level of average real variability group. The survival curve plot showed patients with higher average real variability had a higher risk of 28-day and 1-year mortality. This relationship remained remarkable in patients with low or high Sequential Organ Failure Assessment scores in the sensitivity analysis. The two-piecewise linear regression model showed that lower ARV was a risk factor for 28-day  and 1-year mortality  when ARV was less than 7.2 mmHg, higher ARV was a risk factor for 28-day mortality  and 1-year mortality  when ARV was greater than 7.2 mmHg.Blood pressure variability predicts mortality in critically ill patients. Individuals with higher or lower mean arterial pressure average real variability during the first day in ICU may have an increased risk of death. In clinical practice, blood pressure (BP) is routinely measured physiological variables. Under normal circumstances, blood pressure variability includes fluctuations between beats —— very short-term blood pressure variability (BPV), fluctuations over 24 h —— short-term BPV, daily fluctuations——medium-term BPV, and visits fluctuations——long-term BPV. Blood pressure variability may be a response to external stimuli and changes in daily life, aiming to maintain the so-called “steady state” of blood pressure .However, the continuous increase or decrease of BPV not only reflects the damage of the cardiovascular homeostasis regulation mechanism but also causes potential pathological damage by affecting organ perfusion. The role of BPV for cardiovascular disease or death has been studied widely in recent years. Studies have shown that the effect of BPV independent of mean blood pressure is related to target organ damage (TOD) in heart, blood vessel, brain, and kidney –3, and tHemodynamics in critically ill patients are often unstable, but there are few studies on the impact of blood pressure variability on prognosis in critically ill patients. Moreover, the current research on blood pressure variability lacks the corresponding safety threshold, which limits the clinical application of this index. This study intends to explore the relationship between mean arterial pressure (MAP) variability and prognosis in critically ill patients by analyzing the data in intensive care multiparameter intelligent monitoring database III (MIMIC-III). We present the following article in accordance with the STROBE reporting checklist.We collected the patients’ data from the MIMIC-III database and performed a retrospective cohort study. The database is maintained by Beth Israel Deaconess Medical Center  and the Massachusetts Institute of Technology  and contains the medical information of over 40,000 patients who were hospitalized in the intensive care unit (ICU) from 2001 to 2012 at Beth Israel Deaconess Medical Center, including demographic characteristics, vital signs, laboratory and radiology results, medications, comorbidities, nursing notes, physician discharge summaries, and survival outcomes . Any resAll patient information was obtained from the MIMIC-III databaseversion 1.4) . The inc.4 . The Since the records of all patients in the MIMIC-III database were anonymous, the institutional review committee of Beth Israel Deaconess Medical Center waived the requirement for individual consent of patients.The following patient data were extracted from the MIMIC-III database: age, gender, ethnicity, length of ICU stay, the first Sequential Organ Failure Assessment (SOFA) score, ventilation therapy (noninvasive and invasive), medication usage on day 1 of admission to the ICU, diseases , complete invasive mean arterial pressure(MAP) records, survival outcomes . Vasopressor medications included norepinephrine, phenylephrine, dopamine, isoproterenol, epinephrine, and vasopressin, and vasodepressor medications included nitroprusside, nicardipine, labetalol, esmolol, and diltiazem. Chronic lung disease includes obstructive chronic bronchitis and chronic obstructive asthma. Chronic liver disease includes a history of viral hepatitis, autoimmune hepatitis, non-alcohol fatty liver disease, cirrhosis, or liver failure as listed in the electronic health. All diseases in our study were classified using the International Classification of Diseases, Ninth Revision (ICD-9). Data were extracted using Navicat software.Blood pressure variability(BPV) was assessed with 2 different indexes: coefficient of variation (CV), average real variability (ARV). Standard deviation (SD) is the simplest statistical measure for describing variation but is highly dependent on the individual’s BP level. CV is derived from the SD by dividing it by the mean. Consequently, CV is less influenced by BP level and is therefore considered an applicable index in variability studies , 9. ARV N denotes the number of valid BP measurements in the data corresponding to a given subject, and k ranges from 1 to N-1. W means the interval time between two adjacent blood pressure records. In this study, we, therefore, used ARV as our main exposure variable because it can be relatively easily calculated in clinical practice, and a universal reference frame can be defined.where, We discarded BP readings with a mean arterial pressure <25 or >250 mm Hg to retain physiologically meaningful readings in the analysis and to ensure the reliability of variability indexes. Baseline blood pressure was the average of MAP on the first day of ICU admission.The primary outcome measure in our study was hospital mortality. The secondary outcome measures was 28-day and 1-year mortality. In addition, in-hospital and 28-day mortality were defined as short-term mortality, and 1-year mortality was defined as long-term mortality.2 or Fisher exact test, respectively.Data for continuous and categorical variables were presented as median with interquartile range and frequency with percentage, respectively. Continuous and categorical variables were compared using the Mann–Whitney test and the XTo assess the association of BPV  with the study outcomes, we used multivariate logistic regression models for in-hospital mortality and Cox proportional hazards models for 28-day and 1-year mortality. To assess confounding, we entered covariates into a Cox regression model in the basic model or eliminated the covariates in the complete model one by one and compared the regression coefficients. Those covariates altering initial regression coefficients by more than 10% were included such as age, sofa, average of MAP, coronary heart disease, chronic liver disease, sepsis. Considering that gender, hypertension, diabetes, use of vaso-drug and ventilation therapy in the first day are also important clinical covariates, they were also included in the final model. The odds ratios (ORs) were generated for logistic regression and hazard ratios (HRs) were generated for Cox proportional hazards, with their 95% CIs. We divided the population into 4 groups by quartiles of ARV. We estimated hazard ratios or odds ratios contrasting the risk for mortality in each level versus the average risk in the second level which the risk is lowest. Survival curves were constructed by the Kaplan–Meier method and compared by the log-rank test. We investigated the association between BPV and outcome in subgroups by SOFA score. We tested for interaction to determine whether the relative effect of BPV varied significantly among SOFA levels by introducing an interaction term in the models.P-values <0.05 were considered statistically significant.To explore the possibility of a non-linear relationship between BPV and outcomes, we fitted models with smooth spline and carried out nonlinear tests. We found that the risk of mortality was the lowest when MAP ARV is around 7∼8 mmHg. According to the smoothing curve, we further developed a two-piecewise linear regression model to find out the threshold effect, with adjustment for potential confounders. 1 Navicat software was used to extract population samples and variable information. Python was used to calculate the blood pressure variability index.All analyses were performed using R Statistical Software (The R Foundation).The SOFA score as a measure of organ dysfunction is associated with patient outcomes. We conducted subgroup analyses to determine whether the results persisted even when the severity of the clinical status changed. Based on the median first SOFA score, all patients were divided into the low (<5) and high (≥5) SOFA score groups where 5 was the median of SOFA. Logistic regression and Cox proportional hazards models were used to evaluate the BPV and outcomes in the subgroups.A total of 61532 ICU records were screened from the MIMIC-III database. We excluded 3746 records with multiple admission to the ICU, 8092 records with age <18, 7416 records with the length of stay in ICU <1 day, and 29213 records with blood pressure recording interval greater than 1 h and recording times less than 24 in the first 24 h after admission to the ICU. Finally, 12867 patients were included in the analysis . Among tP < 0.001), 28-day mortality , and 1-year mortality  . To veriWhen stratified by SOFA score (≥5 5898 patients versus <5 6969 patients), we found that our results almost persisted in the different subgroups after adjustment for all covariates. That is, the highest ARV group had a higher risk of mortality. In the group with low SOFA score, in-hospital, 28-day, 1-year mortality had ORs of 1.47 , HRs of 1.49  and 1.24 , respectively. In the group with high SOFA score, in-hospital, 28-day, 1-year mortality had ORs of 1.28 , HRs of 1.18  and 1.26 , respectively .In this study, we used ARV and CV to describe blood pressure variability. The results confirmed that there was a significant correlation between the variability of mean arterial pressure in the first 24 h after admission to ICU and in-hospital mortality, 28-day mortality, and 1-year mortality, independent of the confounding factors including BP levels. The relationships between BPV and outcomes were non-liner. In subgroup analysis, the results remained stable in populations with different sofa scores.In recent years, many studies have explored the relationship between blood pressure variability and adverse outcomes. The traditional view is that the blood pressure threshold is a risk factor for in-hospital mortality or poor long-term prognosis. With the development of technology and concept, people are not satisfied with using only static indicators to describe the state of patients but prefer to use dynamic indicators to measure the general situation of patients. In the context of cardiac surgery, many models and scoring systems used to predict postoperative adverse outcomes, such as STS, EuroSCORE, mainly consider static factors such as complications, drugs, and the nature of surgery. This limitation makes these models not perform well enough for high-risk and elderly patients . TherefoAs far as we know, our study is the first to study the relationship between blood pressure variability as a continuous variable and mortality by using the patient information of public database and to analyze the nonlinear relationship between them. The trend of the relationship between BPV and outcomes was similar to the outpatients with hypertension  and the Our research has some potential limitations. First of all, this study is a retrospective design. Although we have adjusted many covariates and conducted subgroup analyses, some information such as the frequency of blood pressure monitoring, height of most patients, and so on are lost. Second, MIMIC-III is just a single-center database. Selection bias is inevitable. As the database contains different kinds of ICUs, including internal medicine, surgery, and emergency ICU, their data may reflect the real situation encountered by ICU doctors. Third, the blood pressure records in the database are not routine measurements, and there may be different time intervals between every two blood pressure records. This study only discussed the relationship between the blood pressure variability ARV and CV derived from hourly blood pressure records and mortality. In the future, a well-designed multi-center prospective study should be conducted to evaluate the causal relationship between blood pressure variability and mortality in critically ill patients with more accurate time-resolution blood pressure records.In critically ill patients, we identified a statistically significant association between BPV and in-hospital, 28-day, and 1-year mortality. This relationship is not a simple linear relationship, but a U-shaped curve relationship. Future studies should evaluate the utility of indices of BPV to understand if there is a clinically intervenable target to improve outcomes in critically ill patients.https://physionet.org/content/mimiciii-demo/1.4/.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: The studies involving human participants were reviewed and approved by the Institutional Review Board of Beth Israel Deaconess Medical Center. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.CH: conceptualization, methodology, software, data curation, and writing- reviewing and editing. XW: software and data curation. YL: methodology, software, and validation. FH: conceptualization and supervision. All authors contributed to the article and approved the submitted version.XW was employed by Netbrain Technologies Inc. The remaining 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.


IntroductionHeart failure (HF) is a progressive clinical syndrome resulting from various cardiac disorders. Galectin-3 promotes adverse cardiac remodeling leading to chronic heart failure (CHF).AimTo estimate the levels of galectin-3 in chronic heart failure (CHF) patients and controls and to determine the association between galectin-3 levels with age, gender, and left ventricular ejection fraction (LVEF).Materials and methodsThe levels of plasma galectin-3 were estimated in CHF patients from January 2013 to October 2013 at Rajiv Gandhi Government General Hospital, Chennai, Tamil Nadu. The study was a case-control study. A total of 55 CHF patients were recruited as cases, and 55 controls were enrolled for the study. Participants' profiles were documented, and 5 mL of blood sample was collected. Galectin-3 levels in plasma were estimated by using an enzyme-linked immunosorbent assay (ELISA). Data were analyzed using SPSS 25.0 version. Mean, SD, and percentages were used to compare the characteristics of the two groups. The student's t-test was used to compare galectin-3 levels between CHF patients and the controls. ANOVA was employed to compare galectin-3 levels in the different age groups, gender, and LVEF. The receiver operating characteristic (ROC) curve was plotted for plasma galectin-3 in CHF.ResultsIn the present study, the mean age of CHF patients was 55.9±8.1 years and 54.1±9.4 years for controls. Males constituted 63.6% (n=35) and females were 36.4% (n=20) in the CHF group while 67.3% (n=37) were males and 32.7% (n=18) were females in the control group.The mean and SD for plasma galectin-3 was 9.95±2.8 ng/mL among CHF patients, while it was 4.08±1.3 ng/mL among controls (p<0.0001). As the age increased, levels of plasma galectin-3 increased in CHF patients and controls (p<0.00001). However, there was no statistical significance (p >0.05) for levels of galectin-3 among males and females in both groups. There was a highly significant difference in galectin-3 levels among cases and controls when classified into sub-groups based on their LVEF (p<0.0001). At the cut-off level of 8 ng/mL, plasma galectin-3 had a sensitivity of 92% and specificity of 71% in predicting CHF.ConclusionGalectin-3 helps in identifying CHF due to maladaptive remodeling of the heart. The present study concludes that estimating the plasma levels of galectin-3 is useful in diagnosing CHF. Heart failure (HF) is a progressive clinical syndrome resulting from various cardiac disorders. Multiple factors are responsible for the pathogenesis of HF. Some are cardiomyocyte damage, inflammation, and neuro-hormonal activation . The preGalectin-3, a member of the galectin family, is a vital factor in the pathophysiology of HF, chiefly due to its role in remodeling the cardiac ventricles. After a myocardial injury, inflammation is triggered, accumulating activated macrophages releasing galectin-3  . InitialGalectin-3 is thought to be a "disease mediator" instead of a "disease marker" . A multiLevels of galectin-3 were estimated in CHF patients between January and October 2013 at Rajiv Gandhi Government General Hospital, Chennai, Tamil Nadu, after obtaining Institutional Ethical Committee clearance (IEC Ref No. 36092012). It was a case-control study done with purposive sampling. For treatment, fifty-five CHF patients attending the cardiology out-patient department (OPD) were recruited as cases. In addition, 55 adults who attended the cardiology OPD for cardiac evaluation as a part of anesthetic fitness for non-cardiac surgeries were recruited as controls for the study. All the participants were included after informed consent for participation in the study.Inclusion criteriaCHF patients having LVEF less than 45% by echocardiogram were enrolled as cases. Patients in this group were on treatment for more than six months with standard therapy using diuretics, angiotensin-converting enzyme (ACE) inhibitors, β-blockers, and diuretics. The control group comprised adult patients without symptoms of HF and having an LVEF of more than 60% by echocardiogram.Exclusion criteriaPatients less than 18 years old, patients with acute CHF, renal failure (eGFR less than 90 mL/min), cirrhosis of the liver, malignancy, asthma/chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, multiple myeloma, stroke, chronic dermatological disease, auto-immune disorder, thyroid dysfunction, psychiatric illness, and septicemia were identified through the history and excluded in both the case and control groups.Participants’ profilesData regarding the age, gender, height (centimeters), weight (kilograms), history of smoking and alcohol intake, presence of diabetes mellitus or hypertension, and LVEF from echocardiography records were collected as participants' profiles.ProcedureVenous blood (5 mL) was sampled from participants consulting the OPD of cardiology. The blood was aliquoted into two pre-labeled tubes. Next, 3 mL of blood was transferred into an ethylenediamine tetraacetic acid (EDTA)-coated tube. In contrast, 2 mL of blood was transferred into a plain tube and transported in an ice-lined box to the laboratory. Blood samples were centrifuged immediately (within an hour) of collection. The supernatant plasma and serum were stored in a deep freezer (-70 C) until further processing.Serum creatinine was estimated for all the participants by Jaffe's method in an automated chemistry analyzer , using aStatistical analysis was done using IBM SPSS Statistics for Windows, Version 25.0. . The percentage was used to compare the characteristics of participants in both the study groups with respect to the following factors: gender, history of smoking and alcohol intake, presence of diabetes mellitus, or hypertension. Mean and SD were calculated for BMI, LVEF, eGFR, serum creatinine, and plasma galectin-3. The student's t-test was used to compare galectin-3 levels between CHF patients and the controls. ANOVA was employed to compare galectin-3 levels in the different sub-groups of age, gender, and LVEF. The ROC curve was plotted for plasma galectin-3.In the present study, the mean age of CHF patients was 55.9±8.1 years and 54.1±9.4 years for controls. Males constituted 63.6% (n=35) and females were 36.4% (n=20) in the CHF group, while 67.3% (n=37) were males and 32.7% (n=18) were females in the control group.Table Table Table Figure HF is the final manifestation of all cardiovascular disorders. Multiple factors are involved in its evolution. Galectin-3 may be involved in the pathogenesis of HF. It has an advantage over the presently used markers as it does not vary with sudden hemodynamic changes . The preIn the present study, plasma galectin-3 levels were markedly increased in HF than in the controls. Similar results were reported by Shi Y et al.  and JianThe ROC curve in the present study revealed that plasma galectin-3 was 92% sensitive and 71% specific for diagnosing CHF. Moreover, as LVEF increased, the concentration of galectin-3 decreased, considering the cut-off value of 8 ng/mL. Galectin-3 levels in HF patients increased as their heart functioning worsened.Jiang J et al. have reported that galectin-3 more than 15.9 ng/mL identified HF with preserved ejection fraction with 76% sensitivity and 72% specificity . DanielsThus, galectin-3 as a biomarker will help identify the sub-set of CHF patients in whom maladaptive remodeling is the predominant pathogenesis pathway. This, in turn, will aid in effectively reversing adverse cardiac remodeling by designing drugs antagonizing the effects of galectin-3.LimitationsThe present study was done for a period of 10 months only using a small number of participants. Different cardiologists performed echocardiography on different patients, so the subjective variation in LVEF determination could not be eliminated. Correlating galectin-3 levels with BNP levels (an established marker) was not considered in the present study.Galectin-3 has a distinct role in the pathogenesis of CHF. It is proven to be involved in the process of left ventricular remodeling. This study has also evidenced an increase in galectin-3 levels in the plasma of CHF patients when compared to the control group. Hence, higher concentrations of galectin-3 are predictive of CHF.Investigating galectin-3 levels during suspected CHF may have a role in early diagnosis, helping the physicians to achieve better therapeutic targets. Thus, it will improve the disease compliance of the patients and a future marker of research aiding disease-modifying therapy in CHF.


To analyze the correlation between balance function and gait parameters of patients with basal ganglia infarction. And to observe the influence of balance function on plantar pressure and hemiplegia gait based on the Berg Balance Scale (BBS) score.n = 140) and healthy people  were enrolled. The study group was evaluated with the BBS, the 10 m walking test (10MWT), and the timed up-and-go test (TUGT). The gait parameters and the peak plantar pressure were measured in both groups while walking, and the differences between the groups were compared. In addition, the characteristics of the plantar pressure curve of the hemiplegic and non-hemiplegic sides during walking and the correlation between the 10MWT, the TUGT, the plantar pressure peak, the gait parameters,and the BBS score were analyzed in the study group.One hundred and forty patients with cerebral infarction hemiplegia in the basal ganglia region . The BBS score negatively correlated with the 10MWT, the TUGT, the peak plantar pressure of the hemiplegic forefoot, midfoot, and the non-hemiplegic midfoot, the anterior to posterior position (ant/post position), hemiplegic stand phase, and the dual stand phase (P < 0.05). The BBS score positively correlated with the hemiplegic swing phase and stride length (P < 0.05).The peak plantar pressure of the forefoot and heel, stride length, lateral symmetry, stand phase, swing phase, and dual stand phase of both sides in the study group were significantly lower than those in the control group (A correlation was found between the forefoot plantar pressure and the stand phase of the hemiplegic limbs, the ant/post position, and the balance function after basal ganglion cerebral infarction. This association can be used in walking and balance assessment for stroke rehabilitation. Correcting forefoot pressure or the front and ant/post position can improve balance function. Motor dysfunction often occurs after a stroke . About 7Balance dysfunction is one of the main factors influencing walking in stroke-affected patients . Due to Abnormal gait in stroke-affected patients, including walking parameters, transfer ability, and plantar pressure, differs from healthy people and affects the recovery process . HoweverThe balance characteristics of infarcts in different brain regions are not identical, and failure to distinguish between stroke sites may affect the results of the study. Cerebral infarction in the basal ganglia area is common, and hemiplegia has a prominent gait . In the One hundred and forty patients with cerebral infarction treated in the Department of Rehabilitation Medicine of Beijing Tiantan Hospital between January 2021 and August 2022 were enrolled as a study group. Another one hundred and forty healthy people were collected as a control group. There were no significant differences in age, gender, height, or weight . This stThe inclusion criteria were: (1) age 40–70 years old, (2) primary basal ganglia area cerebral infarction diagnosed by magnetic resonance imaging or computed tomography, (3) the onset of the disease was >1 month ago, (4) no sensory impairments, (5) no serious cognitive dysfunction , (6) could walk 10 m or more independently, and (7) provided a signed informed consent form.The exclusion criteria were: (1) cerebrovascular disease progression and unstable vital signs; (2) other neurological or mental diseases, such as stroke, brain trauma, or Parkinson’s disease; (3) severe heart, lung, liver, or kidney dysfunction; (4) sensory aphasia, cognitive impairment, or unable to cooperate with the evaluation and examination; (5) fractures and arthritis affecting the walking function of patients; or (6) proprioception disorders.The suspension criteria were: (1) severe adverse reactions or inability to continue, (2) deterioration of the condition or serious complications, (3) failure to cooperate and to receive required treatment, or (4) patients and their families requesting withdrawal from the study.The 10-m walking test (10MWT) measures the walking ability of stroke-affected patients . PatientThe timed up-and-go test (TUGT) measures metastatic ability and postural control in stroke-affected patients . The patThe Berg Balance Scale (BBS) measures the balance ability of stroke-affected patients . It has 2) of the forefoot, midfoot, and heel, and the gait parameters. The gait parameters included the proportions of the stand, swing, and dual stand phases (%), and the step width (cm), stride length (cm), and the center of plantar (COP) included the anterior to posterior (ant/post) position (mm) and lateral symmetry (mm).The Zebris plantar pressure measurement system (Zebris FDM 1.12) was used to complete the evaluation. The participants had to take off their shoes, stand on the running platform, and hold their hands on the railings on both sides of the runway while a safety device was clamped on their chest. The runway was open, and the participant was instructed to follow it. The speed of the running platform gradually increased, and when it reached the speed at which the participant was comfortable, the participant was asked to release the railings, turn on the evaluation device, and then stop the device after walking for 30 s. The device mainly recorded the data of both lower limbs while walking, including the peak plantar pressure (N/cmt test (or Wilcoxon test) was used to compare this between the groups. The paired t test was used for intra-group comparisons, the unpaired t test was used for comparisons between the groups, and the chi-squared test was used for gender comparisons between the groups. The Pearson correlation coefficient was used to analyze the correlation between the BBS, the TUGT, and the 10MWT in stroke-affected patients and the correlation between the BBS score and the peak plantar pressure and gait parameters of the bilateral limbs. Any P values < 0.05 were considered statistically significant.Graph Pad Prism 9.0  was used for the statistical analysis and graphing. Standard deviations and means were used to describe measurement data that followed a normal distribution. Baseline data analysis of mean ± standard deviation or median and quartile were used for quantitative data. The spacing was described, and the P > 0.05). There were no significant differences in step width and ant/post position between the two groups (P > 0.05). In addition, the peak plantar pressure of the forefoot and heel, stride length, swing phase in the study group were significantly lower than those in the control group (P < 0.05), while the stand phase, dual stand phase and the lateral symmetry in the study group were higher than those in the control group (P < 0.05)  –3. The dP > 0.05). However, the peak plantar pressure of the forefoot and heel on the non-hemiplegic side and the non-hemiplegic swing and stand phase were significantly higher than in the hemiplegic side in the study group (P < 0.05) (There was no significant difference in the peak plantar pressure of the midfoot between the non-hemiplegic side and the hemiplegic side ( < 0.05) –3.r = −0.727, P < 0.001), as did the BBS and the TUGT . The BBS score was not correlated with step width, or lateral symmetry (P > 0.05), but it was negatively correlated with the ant/post position  and positively correlated with the stride length . The BBS score was not correlated with the peak plantar pressure of the non-hemiplegic forefoot, non-hemiplegic heel, or hemiplegic heel (P > 0.05), but it was negatively correlated with the peak plantar pressure of the hemiplegic forefoot , hemiplegic midfoot , and the non-hemiplegic midfoot . The BBS score was not correlated with the non-hemiplegic stand phase, non-hemiplegic swing phase (P > 0.05), but it was negatively correlated with the hemiplegic stand phase , hemiplegic swing phase  and the dual stand phase  (The BBS and the 10MWT had a negative correlation (< 0.001) –9.The gait patterns caused by cerebral infarction in different regions are dissimilar . This stStroke-affected patients have abnormal gait, weakened physical control, swaying trunk, asymmetrical weight-bearing of both lower limbs, and reduced ability to shift their center of gravity, resulting in unstable walking and an increased risk of falling .This study compared the plantar pressures in both groups. The plantar pressure of the forefoot and heel of the hemiplegic side of the study group was significantly lower than that of the non-hemiplegic side. The bilateral plantar pressure of the study group was significantly lower than that of the control group. The plantar pressure of the midfoot in both groups did not change significantly. These results indicate that the plantar pressure of patients with basal ganglia cerebral infarction was abnormal, and the non-hemiplegic side also showed abnormal plantar pressure distribution due to the influence of the hemiplegic side.This trial also compared the gait cycles of the two groups. In the study group, the hemiplegic side swing phase was higher than that of the non-hemiplegic side, while the hemiplegic side stand phase was lower than that on the non-hemiplegic side. In the study group, the swing phase was significantly lower while the stand and dual stance phases were significantly higher than those in the control group, indicating that the basal ganglia region stroke-affected patients had abnormal gait and poor walking stability. To avoid falls, the time taken for the forefoot to leave the ground to the heel to land is shortened, resulting in prolonged unilateral support. This study showed that the stride length of the patients in the study group was significantly reduced compared with that of the control group, and the lateral symmetry was significantly increased. This indicates that stroke-affected patients have a short stride length and a gait with poor left–right symmetry, and therefore suggests a high risk of falling, even if they could walk independently.In a meta-analysis, The results revealed no significant correlation between the BBS score and step width, but revealed positive correlation between the BBS score and stride length in stroke-affected patients. Koch et al. conducted a gait analysis of stroke-affected patients, finding these patients had balance disorders and unstable walking. Still, they did not analyze the correlation between the balance function and stride length and step width . This maAfter a stroke, the asymmetric gait during walking activates a compensation mode through muscle movement, posture, and gait training, which is conducive to the emergence of normal gait . Yang etThe present study suggested that the balance function of stroke-affected patients affects their gait symmetry. The balance function mainly affects the support line of the ant/post position. Better balance function of the patient may be associated with a stronger ability to support the front and back positions and better front–back symmetry, eventually resulting in a shorter length of the support line in the front and back positions. No significant correlation was found between equilibrium function and lateral symmetry, which needs to be explored further.The present study analyzed the correlation between the BBS score and dynamic peaked plantar pressure. The results showed there was no obvious correlation between the BBS score and non-paralytic forefoot and heel, and hemiplegic midfoot and heel, but a negative correlation with hemiplegic forefoot and midfoot and non-paralytic midfoot was found. Few reports exist about the changes in balance function and plantar pressure during walking. This study further explored the changes in plantar pressure in patients with stroke balance function during walking. It is believed that the balance function after stroke is closely related to the hemiplegic forefoot and midfoot and non-paralyzed midfoot. When stroke-affected patients walk, due to hemiplegic lateral foot inversion and toe flexion , the plaIn the present study, there was no obvious correlation between the BBS score and the stance phase, swing phase of the non-hemiplegic limbs, while the BBS score was negatively correlated with the stance and swing phases of the hemiplegic limbs and dual stance phase. The characteristics of gait under balance dysfunction caused by different reasons are dissimilar. The mature research is mostly about gait characteristics under proprioception impairment, and the effect of hemiplegic gait or balance function under abnormal postural control on gait is unclear . The plaExisting studies have shown that balance function affects walking in stroke-affected patients , and theThis study has certain limitations: (1) the small sample size may mean the changes in different variables may have been too small to be significant, impacting the final result and (2) there is a difference between the running platform and a normal walking mode, and the measurement of the plantar pressure may have caused errors and affected the test results. In future research, the sample size should be increased, the authority of the research should be enhanced, and the patient’s walking ability should be improved through the patient’s plantar pressure and front–back position symmetry to provide a new direction to treat stroke-affected patients.After cerebral infarction in the basal ganglia, there is typically asymmetry in the pressure of the forefoot and the ant/post position, which significantly affects the balance function. It is necessary to pay attention to the distribution of hemiplegic forefoot plantar pressure, the control of gait phase, and the processing of the ant/post position to better improve balance and posture control, reducing the risk of falling.The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The study was approved by the Ethics Committee of Beijing Tiantan Hospital Affiliated with Capital Medical University . The patients/participants provided their written informed consent to participate in this study.SL: methodology, validation, formal analysis, and writing—original draft preparation. HY: conceptualization, writing—review and editing, supervision, and project administration. ZW: software and data curation. PD: resources and visualization. All authors contributed to manuscript revision, read, and approved the submitted version.


The valve’s maximum pressure gradient echocardiographic parameter was present in most models assessed . Overall, our study provides insights with a wider perspective to explore and consider CAVD as a neurocardiovascular pathology. This pathology involves autonomic-driven compensatory mechanisms that seem generated by the aortic valve deterioration.The aim of this work was to obtain insights of the participation of the autonomic nervous system in different stages of calcific aortic valve disease (CAVD) by heart rate variability (HRV) analysis. Studying subjects with no valve impairments and CAVD patients, we also sought to quantify the independent contribution or explanatory capacity of the aortic valve echocardiographic parameters involved in the HRV changes caused by active standing using hierarchical partitioning models to consider other variables or potential confounders. We detected smaller adjustments of the cardiac autonomic response at active standing caused specifically by the aortic valve deterioration. The highest association  was found between the aortic valve area and the active standing changes in the short-term HRV scaling exponent α Calcific aortic valve disease (CAVD) is manifested as aortic valve sclerosis (AVSc) at an early stage, or as aortic valve stenosis (AVSt) that may require surgical treatment . CAVD prAVSt occurs at the end of an inflammatory process caused by endothelial damage owing to mechanical stress and lipid penetration of leaflets that lead to fibrosis, thickening, and finally calcification ,5,6. CalWhereas AVSc is not always diagnosed, most patients with AVSt are usually identified when a cardiac auscultation reveals a systolic murmur or owing to the presence of indicative symptoms . SymptomThe analysis and interpretation of heart rate variability (HRV), the beat-to-beat variation in either the instantaneous heart rate or the R-R interval, has become a recurrent clinical and investigational tool, in particular for cardiovascular diseases. These temporal fluctuations are widely believed to reflect changes in the cardiac autonomic regulation . Even thOnly a few studies have searched for an association between the echocardiographic valve function parameters and the HRV indices in CAVD. Arslan et al.  calculatGiven the above reported differences in the autonomic response to active standing in patients with different stages of CAVD, we hypothesized that the echocardiographic parameters of the aortic valve function are independently associated with changes provoked by active standing in the HRV indices once several other variables that can also modify such indices are considered. The aim of this work was then to quantify among subjects not having impairments in the aortic valve and CAVD patients the independent contribution or explanatory capacity of such echocardiographic parameters in the HRV changes provoked by active standing.A cross-sectional study was carried out at the National Institute of Cardiology “Ignacio Chávez” at Mexico City including participants having normal aortic valve (NAV), AVSc and AVSt. These 3 groups were chosen to include different stages of CAVD.Exclusion criteria were: coronary ischemic disease, renal function alterations, liver disease, recent infections (last month), influenza vaccination within the last six months, autoimmune diseases , or moderate or significant injury in the mitral or tricuspid valves. For the NAV and AVSc groups, volunteers who were considered healthy were recruited after an invitation alongside staff and patient’s relatives of the Institute. They had no known comorbidities and were not taking any medication. Afterwards, an echocardiogram was performed on each volunteer, and they were classified within the NAV or AVSc group. The AVSt group comprised patients previously diagnosed with calcific aortic valve stenosis, being candidates for the elective valve replacement program, who were recruited during a follow-up visit to the outpatient’s clinic of the Institute. Patients with bicuspid aortic valve or AVSt rheumatic etiology were excluded.We obtained a group of 22 NAV subjects, 73 AVSc and 32 AVSt patients. Any previous history of hypertension, diabetes, dyslipidemia, alcoholism, and smoking was obtained from a questionnaire of each participant and corroborated by the clinical records in AVSt patients.Anthropometric measures, oscillometric blood pressure, and resting 12-lead standard electrocardiogram (ECG) were obtained. A second continuous ECG recording (using a sample rate of 250 Hz) was performed with a chest band   while pa2, AVA), aortic valve area indexed to body surface area , left ventricular ejection fraction , left ventricular mass , left ventricular mass indexed to body surface area , and relative wall thickness (RWT). The patients were classified within a study group  according to current guidelines [One specialist measured the echocardiographic parameters by two-dimensional Doppler, employing a commercial machine . Using a pulsed-wave Doppler recording, the following echocardiographic parameters were obtained: maximum aortic valve transvalvular velocity  and mean and maximum mean pressure gradient , aortic valve area (cmidelines .About 5 min of the chest-band ECG recordings in each position (supine position and active standing) were selected to obtain 300 heart-period intervals or HRV time series. The ECG QRS complexes were identified by a second derivative algorithm , followe1 was calculated for each original HRV time series by applying detrended fluctuation analysis within the short-range of scales  [1, algorithms obtained from Physionet [The following HRV time-domain indices were calculated for each time series: mean NN , SDNN , pNN20 , and RMSSD  . For esttervals) . This intervals)  was alsotervals) . For Samhysionet  were useMean breathing frequency (MBF) was obtained using the respiratory movements data (sample rate of 25 Hz) from the same chest band from which the ECG was registered. From these time series, the frequency spectrum was calculated using the Fourier Transform, and the frequency that had the maximum power value was chosen as the MBF.We collected 10 mL blood samples from each participant. The samples were centrifuged at 3000 rpm for 15 min, at 4 °C, and stored in aliquots, at −76 °C. Serum concentrations of matrix metalloproteinase-1 (MMP1), matrix metalloproteinase-2 (MMP2), matrix metalloproteinase-3 (MMP3), matrix metallopeptidase-9 (MMP9), tissue inhibitor of metalloproteinase-1 (TIMP1), interleukin 4 (IL-4), interleukin 6 (IL-6), interleukin 10 (IL-10), interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), tumor growth factor beta (TGF-β), leukotriene B4 (LTB4), lipoxin A4 (LXA4), endothelin 1 (ET-1), prostaglandin E2 (PGE-2), and resolving D1 (RvD1) were measured by enzyme-linked immunosorbent assays with commercial kits (R&D Systems) following the manufacturer’s instructions. The serum levels of C-reactive protein (CRP) were determined by nephelometry (Beckman Coulter).Markers of the inflammatory process were divided into groups depending on their function: anti-inflammatory mediators , lipidic resolving mediators (LXA4 and RvD1), lipidic inflammatory mediators (LTB4 and PGE-2) and inflammatory mediators . Two other groups of variables were created, the matrix metalloproteinases (MMPs) and TIMP1, and the ratio between the MMPs and TIMP1 .The biochemical parameters concentration of serum glucose, hemoglobin, cholesterol, and triglycerides were also measured.For continuous numeric variables, an Anderson–Darling test ,27 was aA post hoc bivariate analysis was considered  by using a Mann–Whitney test, Student’s t test or a chi-square test, depending on whether or not the variables showed a normal distribution or were categorical. The significance level was adjusted using a Bonferroni correction for multiple comparisons .hier.part” function in the “hier.part” package was used  [Hierarchical partitioning analysis was used to estimate the independent explanatory capacity of each independent variable  on the dependent variables  while also taking into consideration all the other covariables or confounding measurements shown in the diagram of n 3.6.0) .hier.part” program was run 10 times by changing the order in which the predictor variables were entered for the case of the dependent variable Δα1, which involved more than 9 predicting or independent variables. The independent contributions were then estimated by averaging the results of all those repetitions.The “For the echocardiographic parameters regarding the valve function , the resThe echocardiographic parameters regarding the ventricular function of the AVSt group were also different from the other two groups . LVMi in1, the values from the AVSt group were smaller and different from the other two groups. Additionally, for ΔLF/HF and ΔLFn, the AVSc groups show differences with the NAV group. For ΔLF, the groups AVSt and AVSc were different from the NAV group. In general, for the HRV indices that show differences between the groups, their magnitude values changes (Δ) diminish with the disease progress, from NAV to AVSt.Before applying the hierarchical partitioning, multiple linear stepwise regression models were considered to select the variables in each category of independent variables and covariables. In summary, for ΔpNN20, the independent variable selected was PGmean, and the covariables were age, albumin, CRP, medication intake and ΔmeanNN. For ΔmeanNN, considered as a dependent variable, the independent variable selected was PGmean, and LVMi, glucose, triglycerides, ET1, age, medication intake and MBF were the covariables. Although ΔRMSSD did not have a valve function parameter selected as independent variable, age, medication intake and ΔmeanNN were the covariables. ΔSDNN also did not have an independent valve function parameter variable, but it had CRP, IFN-γ, BMI, and medication intake as the covariables selected in the multiple linear stepwise regression model.1, the independent valve function parameter variable was AVA, and the covariables were RWT, LVEF, triglycerides, ET1, IL-4, SBP, age, medication intake MBF and meanNN.For ΔSampEn, the independent variable was PGmean, and the covariables were MMP2/TIMP1, SBP and ΔmeanNN.The most present covariables that were selected in the multiple linear stepwise regression models were ΔmeanNN (in 8 out of 10 models), medication intake (in 6 out of 11 models), SBP (in 6 out of 11 models), MBF (in 5 out of 11 models), and age (in 4 out of 11 models).1 (4.591%); Δα1 was also the dependent variable with the highest number of covariables included in its stepwise regression model.The main findings of this work are the associations between the echocardiographic parameters of the aortic valve and the differences in the cardiac autonomic response to active standing as suggested by most of the changes (Δ) of the HRV indices studied. These associations remained significant even when considering other covariables and their differences among studied groups such as age, the changes in meanNN, medication intake, and several others.We also observed a smaller autonomic response or adjustment with the severity of the valve deterioration because the changes (Δ) to active standing in the HRV indices were significantly smaller in the case of either smaller AVA as well as AVAi or higher Vmax, PGmean and PGmax.Using the hierarchical partitioning analysis, we were also able to estimate the percentage of independent exploratory capacity for the echocardiographic parameters of the aortic valve. This percentage indicates the changes in the autonomic-related dependent variables to active standing that can be specifically attributed to the valve deterioration.1 with a 4.591%, but the echocardiographic valve parameter that was present in more models assessed by hierarchical partitioning was the PGmean .The highest association  was found between AVA and Δα1 was in fact the HRV index with more covariables chosen other than ΔmeanNN  that exert influence on its changes to active standing. This could explain why it is useful and extensively used to differentiate and explore different pathologies [In addition to the echocardiographic valve parameter AVA, Δαhologies .The hierarchical partitioning analysis also allowed us to identify other relevant covariables to explain the changes in the HRV indices to active standing. The covariable that showed the highest percentage of independent explanatory capacity was in fact ΔmeanNN . As expected by previous publications ,33, it wIn the CAVD patients, the smaller changes in HRV found  can be attributed to a modified response to the ANS modulation because we used a controlled stimulus (active standing) for which the expected response has been well studied. Active standing usually causes between 500 and 800 milliliters of blood volume to shift from the upper to the lower parts of the body, and this redistribution causes a drop in both venous return and right atrium pressure, reducing the stroke volume and eventually the blood pressure . It is gAs just described, the active standing test provokes a vagal withdrawal and an increase in the sympathetic cardiac response that leads to a higher heart rate and smaller meanNN. This decrease in the meanNN was limited in our patients with CAVD because we found smaller changes or Δ for cases with a higher valve deterioration. As indicated before, the valve function parameter  associated with the ΔmeanNN was PGmean . This association could therefore suggest that the baroreceptors of the aortic arch  detect these changes in the pressure gradient and, as a result, respond to them by limiting the cardiac sympathetic response when there is a change in position, which would limit the increase in heart rate and, therefore, the increase in blood pressure.These smaller adjustments to active standing have also been observed in patients with hypertension ,40, whicAnother compensatory mechanism that could be involved is the one in which the patients with CAVD have a sympathetic hyperactivity that has been identified through muscle sympathetic nerve activity (MSNA)  and the The two mechanisms considered  could be the cause of the smaller changes in meanNN observed here. Given this, the relevant participation that the ΔmeanNN had as a covariable for the other HRV dependent indices  must be mentioned and considered. Previous studies have disclosed that there exists an unequivocal relationship between the meanNN and other HRV indices ,49, whicThe association between autonomic cardiac modulation and CAVD at different stages suggests potential clinical implications to be explored in future investigations. Sympathetic predominance could have a role in the early stages of CAVD (AVSc and mild AVSt) due to a less efficient vagal modulation of a low-grade inflammation ,50. EarlGiven our study design, we are not able to infer the causality between the independent variables and covariables and the HRV indices. Our study subjects had comorbidities , different ages (CAVD is considered an age dependent disease) and medication intake (due to the comorbidities), which can clearly influence the HRV indices. However, the approach followed here, based on hierarchical partitioning, allowed us to take into consideration and quantify the particular effect of those different variables among groups while still identifying the independent explanatory capacity of the echocardiographic parameters of the aortic valve on the HRV indices. This is the reason why such variables were included in several of our final models (as indicated in Other strategies such as larger heterogeneous samples with stratified analysis may be useful in further studies to increase the generalization of the present findings. Our study sample had missing data in certain covariables. The sample size was thus explicitly described.Although hierarchical partitioning models are very useful in finding an exact value of association between variables, the way that association is calculated depends on the R² obtained from those models, so changing the number of variables added into the models may change the percentage assessed for the independent explanatory capacity. Additionally, the models used here were based on a linear regression approach, so another type of model could be used as well to consider the potential non-linear relationship between variables.We did not explore here the possibility of transforming variables to warrant homoscedasticity or normal distribution, which could favor linear correlations. It is then also required to study the effect that heteroscedasticity could have in the hierarchical partitioning analysis and specifically to the analysis involving HRV indices.The hierarchical partitioning analysis allowed us to find the independent explanatory capacity of the valve parameters in relation to the adjustments of the HRV indices during active standing. This framework led us to detect a smaller adjustment of the cardiac autonomic response during active standing, caused specifically by the valve deterioration present in CAVD, mainly in AVSt.1; nonetheless, PGmean was the valve echocardiographic parameter most recurrent in the hierarchical partitioning models. The hierarchical partitioning analysis also enabled us to identify and quantify the effect, and their differences among groups, of other important covariables such as the ΔmeanNN, SBP and MBF. With these results, we were able to suggest additional pathophysiological mechanisms potentially involved in the CAVD progress. These mechanisms were the existence of a higher basal sympathetic activity with limited adjustment range, and the restriction of the cardiac response to the sympathetic activity owing to a higher-pressure gradient in the aortic valve by means of the baroreceptors.The highest percentage of independent explanatory capacity for the echocardiographic parameters was found between AVA and ΔαOverall, our study distinctly revealed insights with a wider perspective to explore and consider calcific aortic valve disease as a neurocardiovascular pathology. This pathology involves autonomic-driven compensatory mechanisms that seem generated by the aortic valve deterioration in itself.


Sham group had surgical preparation only. Blood gases, invasive venous and arterial blood pressure, intestinal microcirculation and superior mesenteric blood flow were measured. The PDNO group had significantly increased intestinal microcirculation compared with Controls during IAH . The mean arterial pressure and abdominal perfusion pressures (APP) were decreased, and the cardiac index were increased in the PDNO group. Also, systemic and pulmonary vascular resistances were lower in the PDNO group compared with Controls. These experimental findings indicate that NO should be further explored with potential application to improve intestinal microcirculation in IAH patients.Intraabdominal hypertension (IAH) is negative for outcome after intensive care. Little research has focused on medical intervention to improve visceral circulation during IAH. A nitric oxide (NO)-donor was compared with placebo in 25 pigs; each pig was randomized into three groups: PDNO (NO-donor), Control (placebo), or Sham. IAH was induced by COThe online version contains supplementary material available at 10.1007/s12265-022-10299-w. Intraabdominal hypertension (IAH) and the subsequent condition, abdominal compartment syndrome (ACS) as defined by organ dysfunction, were identified in the 1980s and are often seen after ruptured abdominal aortic aneurysms . Recent As a cardiovascular signalling molecule, nitric oxide (NO) has been shown to positively affect both lung and kidney function after aortic cross clamping by having a mitigating effect on the systemic inflammatory response , 8. OrgaLittle has been explored about the effects of using a vasodilator, e.g., an NO-donor, on organ perfusion and the development of organ dysfunction during elevated abdominal pressure. It may seem paradoxical to use a vasodilator in IAH with the risk of a further reduction in abdominal perfusion pressure. However, it has been shown that nitroglycerin and NO synthase inhibition have beneficial and harmful effects, respectively, on renal perfusion and function in IAH , 14.The aim of the present study was to explore the circulatory and metabolic effects, focusing on the intestines, of a vasodilator in a porcine IAH model. Comparisons were made with the NO-donor PDNO and placebo conditions.A randomized experimental study, with an animal model, was performed at the research laboratory in the University Hospital. A total of 25 locally farmed Hampshire and Yorkshire crossbreeds’ domestic pigs were included with the only inclusion criteria: age 3–4 months old and weight 25–36 kg. A block randomization without blinding was used. The report is following the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines. The study was approved by a regional animal ethics committee , controlled by a veterinarian, with all experiments to be performed by a certified animal research team in accordance with the guidelines of the European Union Directive 2010/63/EU for the protection of animals used for scientific purposes .−1 h−1, Diprivan®, AstraZeneca, Södertälje, Sweden), together with intravenous bolus injections of pethidin , following intubation and volume-controlled ventilation with End tidal CO2 monitored. The tidal volumes were set to 10–15 ml kg−1 and respiratory frequency to 20–22 min−1 at baseline to achieve normoventilation and the tidal volumes were adjusted throughout the experiments to partially compensate for the CO2 accumulation in the IAH groups. Airway pressures and tidal volumes were measured with the spirometer unit of the intensive care unit monitor. Muscle relaxants were not given, and control of anesthetic depth was performed throughout the experiments. Ringer’s acetate and 5% glucose solution were infused at 15 ml kg−1 h−1 and 1.5 ml kg−1 h−1, respectively, and 750 mg cefuroxime  was given as a prophylactic antibiotic. At the end of the experiment, the animals were euthanized with a bolus of propofol and pethidine together with the rapid injection of potassium chloride (40 mmol), after which asystolia was confirmed by ECG.The protocol for the anesthesia has been published previously . In brie2 insufflation and visual control of the intraabdominal measurements. The midline incision was closed with an airtight running suture.The surgical preparation has been described elsewhere . In brie−1 h−1  served as the placebo drug.The NO-donor PDNO was prepared as has been previously reported  and infu2 pneumoperitoneum with intraabdominal pressure of 30 mmHg to induce IAH was established in the PDNO and Control groups. After 2 h of IAH, infusion of PDNO (in a dose of 30 nmol kg−1 min−1) and the placebo drug was initiated and continued for 4 h until the experiment was ended. The PDNO dose was determined in pilot experiments. The Sham group was prepared identically to the intervention groups, but the animals were not exposed to IAH or drugs. After a stabilization hour (baseline) and at the end of each hour hemodynamic, respiratory and renal variables and intestinal laser Doppler flux were recorded, and blood samples were taken.Surgical preparation was followed by a stabilization period of 1 h. The animals were then randomly assigned to 3 groups: (1) the PDNO group , (2) the Control group treated with placebo , and (3) the Sham group that only had surgical preparation . Thereafter, a CO2) = 0.0734 × weight (kg) 0.656, abdominal perfusion pressure (APP) = systemic mean arterial pressure – intraabdominal pressure, the cardiac index (L min−1 m−2) = cardiac output · body surface area − 1), the mesenteric flow index (L min−1 m−2) = mesenteric arterial flow · body surface area − 1), mesenteric oxygen uptake (ml O2 m−2 min−1) =  · the mesenteric flow index, systemic vascular resistance =  · the cardiac index − 1), and finally pulmonary vascular resistance =  · the cardiac index − 1).The following variables were calculated: body surface area .Data are presented as means and standard errors of the mean (SEM). A linear mixed model for repeated measurements was used for data analysis using an autoregressive correlation structure. Specific measurements were used as outcome variables, and group, time, and their interaction as independent variables. Data showing skewed distributions when evaluated by the Shapiro–Wilks test were log-transformed (laser Doppler flux) before statistical analysis. At baseline all animals displayed normal values, and there were no statistically significant differences between the groups.Intraabdominal pressure measured in the urinary bladder showed the same value as the gas pressure insufflated via the trocars throughout the experiment and served as a control for the model. Urinary output decreased significantly when IAH was induced and stayed at a decreased level throughout the experiment without any difference between the intervention groups Fig. .Fig. 1InIntraabdominal hypertension induced increased heart rate, and there was no difference in heart rate between the intervention groups. IAH decreased cardiac index significantly during the whole experiment in the Control group while PDNO increased cardiac index significantly Fig. . Mean arAbdominal perfusion pressure was initially almost halved by IAH compared with the Sham group. APP slowly recovered during the experiment in the Control group while it remained unchanged in PDNO group. There was no significant difference between Control and PDNO during the experiment Fig. .Systemic vascular resistance was increased by IAH, and the duration of IAH worsened vascular resistance. However, systemic vascular resistance was normalized by PDNO infusion Fig. . Mean puGut mucosa perfusion was decreased by IAH to approximately 60% of baseline value but was unchanged in the Sham group. PDNO increased the laser Doppler flux to almost 120% during the last 3 h of the experiment, compared with baseline, whereas it was unchanged in the Control group  dropped drastically when IAH was initiated, and PDNO prohibited the restitution seen in Controls compared with sham. However, APP did not differ significantly between Control and PDNO during the experiment. In spite of the significant drop in APP induced by PDNO, no negative metabolic changes were seen, although this experiment was short. Perfusion pressure is indeed important but has to be evaluated together with peripheral vascular resistance and flow in order to obtain the overall picture of the end organ physiology during IAH.Microcirculation in the intestine and perfusion of the intestinal mucosa were investigated in the present experiment by means of laser Doppler. Laser Doppler has previously been used to determine gut microcirculation and has been shown to be in good agreement with other methods of measuring intestinal perfusion, such as microdialysis . In the One of the main limitations of this study lies in the short time span of the intervention, which may have affected our ability to explore the metabolic consequences of the NO-donor. Also, the fact that the model directly induced IAH with 30 mmHg means that most cardiovascular changes became extreme, which does not reflect a clinical scenario where it might be relevant to administer a NO-donor. A histopathological analysis of the intestinal wall could have strengthened the microcirculatory finding. Moreover, only the initial phase of the physiological changes after induction of IAH was explored in this experiment and in future research it is of interest to investigate the responses to reperfusion after normalization of abdominal pressure.In conclusion, we found that the NO-donor PDNO decreased systemic and pulmonary vascular resistances, elevated the cardiac index score and, most importantly, counteracted decreased microcirculatory blood flow in the intestinal mucosa during IAH in a porcine model. These findings warrant further research to explore a potential application to improve intestinal microcirculatory perfusion in intensive care patients with intraabdominal hypertension.As the presence of intraabdominal hypertension is negatively linked to the survival of ICU patients and there has been little efforts to find noninvasive therapies to reverse the course of the disease early, this exploratory experimental work has clinical relevance. Based on the results of this study, it is not possible to justify clinical use of NO treatment during IAH. However, the results show the possibility that NO can facilitate intestinal perfusion during IAH and open up for further research on this treatment option.Supplementary Table(DOCX 33.4 KB)


Hypertension and dementia are common disorders in the elderly. The objective of this study is to investigate the association of blood pressure in midlife and late life with the risk of vascular dementia (VaD) using United Kingdom (UK) primary care data.We conducted a retrospective population-based cohort study using The Health Improvement Network (THIN). Two independent study cohorts were created: 1) midlife: individuals aged 60 to 65 with at least 1 blood pressure measurement between the age of 60 to 65; 2) late-life: individuals aged 70 to 75 with at least 1 blood pressure measurements between the age of 70 to 75. The baseline blood pressure for midlife and late-life cohort were categorized into four levels: normal, prehypertension, stage 1, and stage 2 hypertension. Cases of VaD and other risk factors, such as stroke, diabetes, were identified using the Read codes listed in the Quality and Outcome Framework- National Health Science (QOF-NHS). Descriptive statistics were used to compare the demographics and clinical conditions for patients in different blood pressure levels. we used the proportional subdistribution hazard model was used to estimate the association between blood pressure levels with risk of VaD while treating death as a competing risk. Multiple imputation method was used to impute the missing values for the variables of smoking status and Body mass index (BMI) categories.In total, there were 265 897 patients (65.1% with stage 1 and 2 hypertension) in the midlife and 211 909 patients (76.3% with stage 1 and 2 hypertension) in the late life cohort, respectively. For midlife cohort, the risk of VaD increased with higher BP levels after adjusting the potential risk confounding factors with a hazard ratio (HR) of 1.15 for prehypertension, 1.32 for stage 1 hypertension, 1.33 for stage 2 hypertension; for late-life cohort, after adjusting all the confounding factors, there was no statistically significant association between the risk of VaD and BP levels  for stage 1 hypertension, and 1.11 for stage 2 hypertension). Our study show high blood pressure in midlife is a significant risk for vascular dementia in the late-life. Given the strength and consistency of this evidence, greater effort should be placed for early diagnosis of hypertension and tight control of blood pressure for hypertensive patients in the prevention of vascular dementia.


Compliance was good for all CFTR modulators, azithromycin, aztreonam, and tobramycin in solution for inhalation. The patients with the best compliance were older; they had exacerbations and the greatest deterioration in lung function during this period. The three variables with the highest importance for the compliance of the generated Random Forest (RF) models were age, FEV1%, and use of Ivacaftor/Tezacaftor. This is one of the few studies to assess adherence to CFTR modulators and symptomatic treatment longitudinally. CF patient therapy is expensive, and the assessment of variables with the highest importance for a high MPR, helped by new Machine learning tools, can contribute to defining new efficient TA strategies with higher benefits.Cystic fibrosis (CF) is a genetic and multisystemic disease that requires a high therapeutic demand for its control. The aim of this study was to assess therapeutic adherence (TA) to different treatments to study possible clinical consequences and clinical factors influencing adherence. This is an ambispective observational study of 57 patients aged over 18 years with a diagnosis of CF. The assessment of TA was calculated using the Medication Possession Ratio (MPR) index. These data were related to exacerbations and the rate of decline in FEV Cystic fibrosis (CF) is a genetic and multisystemic disease that requires significant therapeutic demands for its control, both in terms of nutritional recommendations and physical activity, as well as compliance with multiple treatments, with an estimated daily average of up to seven . The plaUntil a few years ago, the existing therapies were only aimed at alleviating the symptoms caused by the disease: physical exercise, physiotherapy, bronchodilators, hypertonic or mucolytic substances to improve mucociliary clearance, immunomodulators, and antibiotics to control inflammation and bronchial infection, dietary recommendations, pancreatic enzymes, and vitamin supplements to maintain a good nutritional status . In receIn CF, therapeutic adherence (TA) is essential for controlling the disease, preventing exacerbations, and slowing progression . TA is tAdherence questionnaires are generally unreliable in CF compared to other methods because they overestimate adherence ,15. The Due to the high availability of medical and health information provided by portable networked devices, the use of health data for research purposes is becoming increasingly common . In mediThe study’s hypothesis is that CF is a multisystem disease requiring complex, time-consuming treatments for patients, so a low TA is assumed. Poor TA will have consequences on the clinical course. The aim of this study was to evaluate longitudinally, in a population of adult patients with CF, how adherence to the different treatments has been over the last 2.5 years, to study, in relation to the degree of TA the clinical consequences in terms of lung function and the number of respiratory exacerbations, and to assess the possible predictors of adherence.n = 30; 49.2%), moderate or MPR50–80%  and low or MPR < 50%  , resulting in a total of 57 patients to evaluate. Patients evaluated in this study were analyzed according to the mean compliance for all treatments followed throughout the study, classified into patients with high or MPR > 80%  .1%) and the mean percentage of Forced Vital Capacity (FVC%), was 71.0 ± 20.3 and 82.7 ± 15.6, respectively. Chronic bronchial infection by Pseudomonas aeruginosa was presented in 22 patients (38.6%), and 16 (28.1%) and 10 (17.5%) for methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA), respectively , mainly for the age range 20–30 years (p = 0.017). Gender, Body Mass Index (BMI), and genotype type were similar in the three groups, being the most compliant group (MPR > 80%), the group with the highest proportion for females (63.3%), and F508del homozygotes (46.7%). In addition, the most compliant group had a higher proportion of patients with pancreatic insufficiency , allergic bronchopulmonary aspergillosis , and massive hemoptysis , although this difference was non-statistically significant. Lung function showed a trend of improvement for all three groups during the study, although a non-statistically significant differences were observed between them. The group with the highest compliance had the lowest FEV1% and FVC values each year and overall. For chronic bronchial infection, a non-statistically significant difference was observed except for Haemophilus influenzae (p = 0.004), which was higher for patients with low compliance (4 patients: 50.0%) (Patients with low compliance (MPR < 50%) had a statistically significantly lower mean age (: 50.0%) .The mean number of exacerbations and number of days with exacerbations were assessed for both oral and intravenous cycles of antibiotic treatment. During the study period (2.5 years), for oral cycles, there was a mean total number of exacerbations of 1.5 ± 1.1, and for intravenous cycles, it was 0.2 ± 0.3 . The meap > 0.05).Regarding the statistical evaluation of the resulting change, only mean values for full years  were considered. Therefore, months in the year 2021 were excluded to avoid potential biases. The decreasing trend was only statistically significant for the reduction in the number of days assessed per intravenous cycle between 2019 and 2020 (Mean compliance was assessed for each type of treatment . All treThe mean compliance for each treatment type was assessed each year . All treχ2(1) = 3.133, p =0.077). This trend continued throughout all years of the study , the lung function of MPR <50% group showed a positive percentage change between the first and last year of the study for FEV1% and FVC% . The MPR 50–80% group had an increase in percentage change . However, the group MPR > 80% decreased its percentage change for FEV1% (−0.25%) and improved for FVC% (+6.0%). The three groups’ percentage change was not statistically significantly different for FEV1 (p = 0.625) but for FVC% (p = 0.029).When we analyzed which group, based on their MPR% , had better lung function , we founIn order to assess which variables have the most predictive power to the response variable and due to the RF method can handle a large number of predictor variables with a small size of observations , the preValidation was estimated internally during the algorithm’s execution using the out-of-bag (OOB) method, which measures the prediction error of random forests using Bootstrap aggregation . The assThe RF analysis provides the Mean Decrease Accuracy (MDA) and Mean Decrease Gini (MDG) indices of the predictors evaluated in each of the models . We main1% (MDG: 3.3), use of Ivacaftor/Tezacaftor treatment (3.0), age (MDG: 3.0), total days of oral exacerbations (3.0), presence of methicillin-sensitive Staphylococcus aureus (MSSA) (2.5). Similarly, for the model using non-compliance (MPR < 50%) as a response variable, the main predictors were mean FEV1% (MDG: 1.4), mean FVC% (1.4), BMI (1.4), presence of Haemophilus influenzae (1.4), BMI (1.5), age (1.3).For the model that uses high compliance (MPR > 80%) as a response variable, the top five relevant predictors were mean FEVy-axis) for a data point of the characteristics of the individual variables. The marks on the x-axis reflect the distribution of the assessed feature, showing how relevant a region is for interpretation (few or no points mean that we should not over-interpret this region).Besides analyzing which characteristics were most important for explaining the response variables in each generated model , we are interested in how the characteristics of these variables influence the predicted outcome. Partial dependence plots (PDP) were constructed for the factor variables with the highest relevance to characterize the relationship between the characteristics of the factors with the highest importance and the %MPR . Each PD1%) or the mean number of days with oral exacerbations and MPR > 80% (Staphylococcus aureus (MSSA).Our results showed that most quantitative variable factors assessed in both models were not linearly associated . For exaPR > 80% A–D. FurtHaemophilus influenzae, was also positively related to low compliance (For low compliance (MPR < 50%), there was a positive non-linear effect for lung function A,B and ampliance A,E.This is one of the first studies to longitudinally assess TA in CF, including CFTR modulator therapy among the different treatments evaluated. In addition, this study is also novel in terms of the application of new Machine Learning tools, specifically the creation of RF models, to assess which variables are most important in terms of compliance.Overall, compliance was good for all CFTR modulators , azithromycin, as well as aztreonam and tobramycin in inhalation solution. Compliance was moderate for the remaining treatments, and close to low compliance was observed with rhDNAsa. Among the inhaled antibiotics, colistin for inhalation and dry powder had the poorest MPR.In our study, we observed a decrease in respiratory exacerbations, both oral and intravenous, during the study period, favored by isolation and prevention measures, hand washing and widespread use of masks during the pandemic ,23.1% mean, use of Ivacaftor/Tezacaftor, Age, mean number of days with oral exacerbations, and presence of methicillin-sensitive Staphylococcus aureus. On the other hand, for low compliance, the top predictors in the model were FEV1% mean, FVC% mean, presence of Haemophilus influenzae, BMI, and age.We identified relevant predictors of high (MPR > 80%) and low compliance (MPR < 50%) from the generated RF model. Overall, we found that the top 5 variables contributing to high compliance were FEVA recent study on compliance over one year with the CFTR modulators Ivacaftor, Lumacaftor-Ivacaftor, and Tezacaftor-Ivacaftor analyzed a total of 2548 patients, 1289 (50.6%) patients with Lumacaftor/Ivacaftor, 784 (30.8%) with Ivacaftor and 475 (18.6%) with Tezacaftor/Ivacaftor. The mean MPR value for all CFTR modulators was higher than 80; they concluded the importance of monitoring TA due to the high cost of these treatments .Haemophilus influenzae chronic infections were associated with TA, and in CF, this pathogen is often associated with milder disease, perhaps not surprisingly associated with lower MPR  . Data we1% in each year of the study and the number of respiratory exacerbations per year, an exacerbation is considered the need to prescribe additional antibiotic treatment in the presence of clinical changes, with the number of courses of oral antibiotics in the case of mild or moderate exacerbations or intravenous antibiotics in the case of severe exacerbations being collected.The following clinical variables were collected: age and BMI at baseline, sex, CFTR gene mutation, exocrine pancreatic insufficiency, CF-related diabetes , chronic bronchial infection (defined by the presence of the same microorganism in 50% of sputum samples collected in 1 year), history of allergic bronchopulmonary aspergillosis and massive hemoptysis (more than 240 mL in 24 h or 100 mL in 1 h), the best FEV1% decline rate, and a number of exacerbations, whether treated with oral or intravenous antibiotics.Low, moderate, or high MPR was related to age, sex, chronic bronchial infection, lung function, 2.5-year FEVt-test) was performed. When one of these two assumptions was not met, a non-parametric test  was performed. In the case of qualitative variables, the comparison of proportions was tested using the chi-square test or Fisher’s exact test whenever necessary.First, a descriptive analysis of the characteristics of the total patients and their total compliance during the study was performed, calculating the mean and standard deviation of the quantitative variables. The Shapiro-W Kolmogorov-Smirnov test was performed to check the normality of continuous variables. Homoscedasticity was tested using Levene’s test. When the distributions were normal and homoscedastic, a parametric test  and non-compliant (MPR < 50) patient profiles. The importance of the variables was assessed through the Mean Decline in Accuracy (MDA) and Mean Decline in Gini (MDG) indicators, although to assess the importance of the variables, we focused mainly on the use of the MDG parameter since the classifications produced by this index provide more robust results . The hig


After exclusion due to image quality, outlier values or missing data, DWI was analyzed for ten subjects; BOLD for eight subjects. The diffusion coefficient ADCD decreased in the CsA-treated group over time, whereas it increased in the EVE group . The change in ADCD from months 4.5 to 12 significantly differed between groups in the cortex (p = 0.033) and medulla (p = 0.019). In BOLD, cortico-medullary transverse relaxation rate R2* increased (decreased tissue oxygen) in the CsA-treated and decreased in EVE-treated groups over time. Similarly, R2* values at month 12 were higher in the CsA-treated group compared to the EVE-treated group. There was no significant difference for the perfusion fraction FP. In conclusion, this prospective sub-study of the ZEUS trial suggests an impact of immunosuppressive regimen on fMRI parameters of the kidney graft.The ZEUS study was a multi-center randomized controlled trial investigating the effect of early conversion from a ciclosporin-based to an everolimus-based regimen on graft function twelve months post-transplantation. In this investigator-initiated sub-study, functional magnetic resonance imaging (fMRI) of kidney grafts was prospectively performed to non-invasively assess differences in graft oxygenation, diffusion and perfusion between groups and time-points using diffusion-weighted imaging (DWI) and blood oxygen level-dependent (BOLD)-MRI. Sixteen patients underwent DWI and BOLD-MRI at months 4.5 and 12 post-transplantation on a 3 Tesla and 1.5 Tesla ( Kidney transplantation is the treatment of choice for patients with end-stage kidney disease, prolonging survival . Thanks The ZEUS study was a multi-center, open-label randomized controlled trial designed to investigate the effect of an early conversion from a calcineurin inhibitor-based immunosuppression with ciclosporin (CsA) to a mammalian-target-of-rapamycin inhibitor-based regimen with everolimus (EVE) on graft function twelve months post-transplantation . An imprFunctional magnetic resonance imaging (fMRI) techniques represent an attractive diagnostic tool for renal investigations allowing the non-invasive simultaneous assessment of several aspects of kidney function, such as tissue structure, perfusion and oxygenation, in addition to morphological imaging, without the need for contrast media ,9.Diffusion-weighted imaging (DWI) evaluates organ diffusivity and microperfusion, while blood oxygen level-dependent (BOLD)-MRI assesses tissue oxygenation. Whereas DWI has been investigated as a non-invasive marker of kidney function, BOLD has proven particularly useful to study the acute and chronic effects of various interventions ,10,11,12The purpose of this investigator-initiated local sub-study of the ZEUS trial was the evaluation of additional aspects of kidney graft function according to the immunosuppressive regimen using fMRI methods. With the exception of one study performing BOLD after acute intake of ciclosporin, this question has not been addressed so far to the best of our knowledge . Due to The protocol of the present investigator-initiated, prospective, single-center sub-study of the ZEUS trial was approved by the local ethics committee  and conducted in accordance with the Declarations of Helsinki and Istanbul ,16.All kidney transplant recipients included in the ZEUS trial from our study center were eligible for the current study . SpecifiThe ZEUS study was a 12-month multi-center randomized controlled parallel-group trial, the protocol of which has been published previously . Patient®; Siemens Healthcare, Erlangen, Germany) for all subjects except three who underwent MRI on a 1.5 T MR scanner . During each of the two MRI sessions, anatomical MRI, DWI and BOLD-MRI were performed.MRI data were acquired on a 3.0 T whole body MR Scanner , field of view (FOV) = 400 × 400 mm2, matrix = 128 × 128, six averages, bandwidth = 2300 Hz/pixel and partial Fourier 6/8. Ten diffusion gradient b-values were applied (in s/mm2): b = 0, 10, 20, 50, 100, 180, 300, 420, 550 and 700. The gradients were applied in three orthogonal directions and subsequently averaged, minimizing effects of diffusion anisotropy. Parallel imaging  with a reduction factor of 2 was applied. A TE of 64 ms was used. Acquisition time for DWI was 8:06 min.Intravoxel incoherent motion (IVIM)-DWI yielded the perfusion-cleared apparent diffusion coefficient ADC* , which correlates to tissue oxygen content provided that confounding factors such as blood volume or hydration state are excluded [2 and a matrix size of 256 × 256, on average. Other parameters were: TR of 65 ms, TE of 6–52 ms, inter-echo spacing time of 4.2 ms, flip angle of 30° and bandwidth of 330 Hz/pixel. Twelve T2*-weighted images, corresponding to 12 different echoes, were acquired for each slice within a single breath-hold of 17 s.BOLD-MRI takes advantage of deoxygenated hemoglobin as an endogenous contrast agent, which influences the relaxation time T2*, yielding the transverse relaxation rate R2excluded ,9. For B® and MATLAB®. The obtained values were read into MS Excel® for further statistical processing. GraphPad Prism 9® and MS Powerpoint® were used for figure preparation.A maximum of three regions of interest (ROIs) traced in medulla and cortex were analyzed in every slice  for each medulla and cortex. ROIs were manually defined by the same blinded investigator on images handed over in a random fashion. ROIs were traced in the medulla and cortex. Data were analyzed using in-house custom-scripts written in IDL® machine. Recorded parameters were resistive indices (RI) measured at intralobar arteries .Duplex ultrasound scan (DUS) was performed at both study visits by the same experienced nephrologist on a Siemens Acuson Sequoia 512® device . Recorded variables were the overall mean arterial systolic, diastolic and mean pressures and dipping effect (in mmHg).Ambulatory blood pressure measurement was performed at both study visits using a Profilomat IILaboratory analyses were performed according to the ZEUS study protocol as specified in Histopathological analysis of renal tissue obtained from protocol graft biopsies was performed according to clinical routine in the department of pathology of the University of Bern. Pathologists were not blinded to patient treatment. Biopsy reports were retrospectively assessed for the presence of IFTA, arteriolar hyalinosis and rejection in a semi-quantitative manner. There was no study-specific histological re-analysis.D, FP, R2* and medulla/cortex ratios (MCR) MCR ADCD, MCR FP and MCR R2* at month 12; as well as in the changes in ADCD, FP, R2* and the MCR from month 4.5 to month 12. Secondary outcomes were the changes in ADCD, FP, R2* and cortico-medullary ratios from month 4.5 to month 12 in each medication group; the differences in mean RI and overall mean systolic, diastolic and mean blood pressure and dipping values between time-points for medication groups and the difference in changes from baseline to month 12 between groups; and the correlations of fMRI parameters and their changes over time across and within medication groups for eGFR, RI, overall mean systolic, diastolic and mean blood pressure and dipping values.Primary outcomes were the differences between the CsA-treated and EVE-treated patient groups in ADC® and MS Office 2007®.Continuous variables are expressed as means with standard deviation (SD) or medians and range . Wilcoxon-signed-rank-test was used for cortico-medullary differences and longitudinal changes in fMRI, RI and ABPM parameters within groups. Mann–Whitney U-test was performed for comparisons across groups of absolute fMRI, RI and ABPM values and of longitudinal changes in these parameters. Correlations between fMRI absolute values and changes over time and differences across groups in eGFR, medication levels, RI and ABPM were determined by Kendall’s Tau correlation coefficient analysis. Data were analyzed using IBM SPSS Statistics 24From September 2005 until December 2006, 70 patients received a kidney transplant in our center and were screened at the outpatient University Clinic for Nephrology and Hypertension in Bern for participation in the ZEUS trial and the MRI substudy. A total of 37 subjects were enrolled in the ZEUS trial, 16 of which were included in the current study and underwent MR measurements. One patient was subsequently excluded because of lack of randomization, one patient resigned from participation .Clinical characteristics of the subjects are shown in The MRI protocol, including morphological sequences, DWI and BOLD, could be performed in all of the patients at baseline and in 12 patients on study day 2. Subjects without a second measurement were not included in the analysis . Data ofD as a marker of pure diffusion are shown in D was noted . In the CsA-treated group, medullary and cortical ADCD values decreased in all but one subject from month 4.5 to month 12 (p = 0.14 and p = 0.14), whereas in the EVE-treated group, medullary and cortical ADCD values increased from month 4.5 to month 12, reaching statistical significance for the medulla . At baseline, there was a tendency for higher ADCD values in the group randomized to CsA as compared to the group randomized to EVE. In contrast, at month 12, ADCD values were higher by trend in the EVE-treated group vs. the CsA-treated group  or medication groups.Mean overall medullary and cortical values for the apparent diffusion coefficient ADCed group . This waed group . There wP are shown in D, no significant cortico-medullary differences were found for FP at either time-point . There was no difference in FP or MCRFP between medication groups at baseline nor at twelve months , in the cortex  or in the MCRFP .Mean medullary and cortical values for the fraction of perfusion Fe months  Furthermp = 0.012) with lower cortical R2* values, compatible with the known relative medullary hypoxia. Inverse trends were noted according to medication assignment, including increasing medullary R2* values  in all of the CsA-treated patients and decreasing medullary and cortical R2* values in five and four of six EVE-treated patients, respectively .Mean resistive indices measured by duplex ultrasound scanning are shown in Mean ABPM-derived blood pressure values are shown in Mean serum creatinine values and estimated glomerular filtration rates are shown in The number of available biopsies was six and five at baseline and five and five at month 12 in the groups randomized to CsA and EVE, respectively. No difference in the degree of IFTA (reaching from none to mild) or arteriolar hyalinosis (reaching from none to severe) was revealed between nor within medication groups .To investigate medication-induced changes in fMRI parameters and correlations of fMRI parameters with selected clinical, biological and histological parameters, exploratory correlation testing was performed.D over time were not correlated with changes in eGFR or histological parameters. Cortical ADCD at twelve months correlated negatively with the resistive indices measured by DUS .Changes in ADCP correlated positively with eGFR at twelve months . A negative correlation was found between FP and the diastolic and mean blood pressure by ABPM .The perfusion fraction FNo correlation of R2* with blood pressure, RI or graft function was noted.In this investigator-initiated study, we tested the hypothesis that diffusivity, perfusion and tissue oxygenation as measured by fMRI techniques differ between kidney transplant recipients included in the ZEUS trial randomized to continuing ciclosporin or to being switched to everolimus. The results show an improvement in graft diffusivity after switch to everolimus as compared to patients maintained on ciclosporin.D significantly differed between the medication groups showing increase in EVE-treated patients while decreasing in CsA-treated patients. (2) Medullary ADCD significantly increased after switching to everolimus. (3) Medullary and cortical R2* values showed inverse trends in medication groups with increasing values  in the CsA-treated group and decreasing values in the EVE-treated group.The main findings are the following: (1) The mean changes in medullary and cortical ADCD as a marker of perfusion-free diffusion, decreased in patients maintained on CsA, whereas it increased in patients converted to everolimus. The ADCD has previously been shown to be reduced in various states of acute and chronic kidney diseases and to correlate to biological kidney function markers and interstitial fibrosis [P was not affected in this study, possibly due to lack of statistical power; moreover, in addition to capillary perfusion, this parameter is believed to reflect tubular processes. Lastly, an influence of the higher proportion of recipients of living donor kidneys in the EVE-treated group together with a higher number of transplantations from extended criteria donors in the CsA-treated group cannot be excluded.First, ADCfibrosis ,22,23,24Second, R2*, as a marker of tissue oxygenation—if confounding factors are excluded—increased (lower tissue oxygenation) in CsA-maintained patients, whereas it decreased (higher tissue oxygenation) in EVE-treated patients. This may suggest ameliorated graft tissue oxygenation under everolimus as compared to ciclosporin, possibly due to the expected vasoconstrictor effect of calcineurin inhibitors . HoweverP showed no significant changes over time nor between medication groups. Studies in kidney grafts have suggested lower FP values in cases of decreased graft function and acute rejection and a correlation with chronic tubulo-interstitial damage [P correlated positively with eGFR at month 12, which corresponds to previous reports [The DWI-derived fraction of perfusion Fl damage ,23,26. I reports .D and FP. This is in accordance with previous studies from our center showing a loss of cortico-medullary differentiation over time in transplanted kidneys from living donors [In this study, no cortico-medullary differences were found for ADCg donors ,21,22.D values at month 12. Similarly and expectedly, mean blood pressure values as measured by ABPM increased by trend in the CsA-treated group over time but remained stable in the EVE-treated group.Other relevant findings include significantly higher resistive indices as measured by DUS in the CsA-treated group as compared to the EVE-treated group at month 12, possibly in the context of calcineurin vasculopathy. Baseline RI values 4.5 months after transplantation corresponded to reference values in kidney grafts . HoweverD are nominally independent from field strength, whereas for FP the sequence can be adapted so that values are comparable even at different field strengths; in contrast, BOLD-derived parameters are not comparable across different field strengths. Consequently, these data were excluded for BOLD-MRI. Lastly, post hoc correction for multiple comparisons was not carried out in this exploratory analysis of clinical correlations.There are important limitations to our study: First, the number of subjects available for final analysis was limited, precluding formal statistical analysis of the BOLD data and multivariate analysis of clinical correlations. Second, for technical reasons, three patients underwent MRI at 1.5 T , as opposed to 3 T for the other patients. For DWI, the results for ADCIn conclusion, this prospective small cohort from the ZEUS trial suggests early MRI modifications following CsA to EVE switch. Whether these modifications are linked to the absence of vasoconstrictive effects of calcineurin inhibitors or reflect an early signal of allograft protection needs to be clarified by further studies involving a larger number of patients with systematical and standardized histological analysis.