Acute kidney injury is a common complication after pericardiectomy for constrictive pericarditis, which predisposes patients to worse outcomes and high medical costs. We aimed to investigate potential risk factors and consequences and establish a prediction model.We selected patients with constrictive pericarditis receiving isolated pericardiectomy from January 2013 to January 2021. Patients receiving concomittant surgery or repeat percardiectomy, as well as end-stage of renal disease were excluded. Acute kidney injury was diagnosed and classified according to the KDIGO criteria. Clinical features were compared between patients with and without postoperative acute kidney injury. A prediction model was established based on multivariable regression analysis.P < 0.001); had higher body mass index ; rates of smoking , hypertension , and renal dysfunction ; higher central venous pressure ; and lower cardiac index  than patients without acute kidney injury. Multivariable regression analysis showed that advanced age , high body mass index , preoperative atrial arrhythmia , renal dysfunction (OR 2.70 P = 0.043), high central venous pressure , and low cardiac index  were associated with a high risk of postoperative acute kidney injury. A nomogram was established based on the regression results. The model showed good model fitness (Hosmer-Lemeshow test P = 0.881), with an area under the curve value of 0.78 .Among two hundred and eleven patients, ninety-five (45.0%) developed postoperative acute kidney injury, with fourty-three (45.3%), twenty-eight (29.5%), and twenty-four (25.3%) in mild, moderate and severe stages, respectively. Twenty-nine (13.7%) patients received hemofiltration. Nine (4.3%) patients died perioperatively and were all in the acute kidney injury (9.5%) group. Eleven (5.2%) patients were considered to have chronic renal dysfunction states at the 6-month postoperative follow-up, and eight (72.7%) of them experienced moderate to severe stages of postoperative acute kidney injury. Univariable analysis showed that patients with acute kidney injury were older (difference 8 years, The prediction model may help with early recognition, management, and reduction of acute kidney injury after pericardiectomy. Pericardiectomy is the most common and only definitive treatment for constrictive pericarditis . PatientThis single-center observational study aimed to investigate the potential predictors of acute kidney injury after pericardiectomy in patients with constrictive pericarditis. Perioperative clinical features were compared between patients with and without acute kidney injury, and a prediction model was established based on the comparison results.This study was conducted in a tertiary hospital in Beijing, China. The hospital's institutional review board approved the study (No. S-K948), and patient informed consent was waived. The following inclusion criteria were used: patients who received isolated pericardiectomies for constrictive pericarditis. The following exclusion criteria were used: patients who received repeat pericardiectomy or concomitant cardiac procedures, such as coronary artery bypass grafting and valve surgeries, and patients already have end-stages of renal disease.The essential variables that were collected included preoperative comorbidities, etiologies, distinctive clinical manifestations, and hemodynamic parameters, and postoperative complications and outcomes.Preoperative comorbidities were collected by checking the past medical histories and preoperative examination results of the patients. The major comorbidities included hypertension, diabetes mellitus, coronary artery disease, myocardial infarction, cerebral infarction, and renal disease. Etiologies of the studied population included infection, postsurgery, postacute myocardial infarction (AMI), radiation and idiopathic causes. Infectious pericarditis was divided into tuberculosis (TB) and non-TB infection, based on pathological results, anti-TB treatment effects and a guideline-recommended diagnostic flowchart . Postsur−1), moderate to severe hyponatremia (serum sodium <130 mmol·L−1), hypoalbuminemia , coagulopathy and renal dysfunction , were determined from the blood test results. The test results of patients with prior uses of anticoagulation medication were excluded from the coagulopathy evaluation.The hemodynamic parameters collected included central venous pressure and cardiac index. Central venous pressure was measured via a central venous catheter, and the cardiac index was measured by using the thermodilution method with a pulse index continuous cardiac output device.The distinctive clinical manifestations that were evaluated included signs of fluid overload and major organ dysfunction, including cardiac, hepatic, and renal dysfunctions. Peripheral edema was determined by physical examination. Pleural effusion, ascites, pericardial calcification and hepatomegaly were determined from the ultrasound and computed topography imaging results. Atrial arrhythmia, including atrial flutter and fibrillation, was determined from the medical history and electrocardiogram. Biochemical disturbances including moderate to severe hypokalemia , as well as all of the accessible portion of the pericardium posterior to the left phrenic nerve. Liberation of the right atrium, along with the superior and inferior vena cavae and inferior part of the right ventricle adjacent to the diaphragm, was also performed to the greatest possible extent.−1 or urine output <0.5 ml·kg−1·h−1 for 6–12 h; (2) moderate stage: serum creatinine increased to 2.0–2.9 times baseline, or urine output <0.5 ml·kg−1·h−1 for ≥12 h; (3) severe stage: serum creatinine increased to 3.0 times baseline or ≥0.4 mg·dl−1; initiation of renal replacement therapy; in patients <18 years old, a derease in eGFR to <35 ml·min−1 per 1.73 m2, or <0.3 ml·kg−1·h−1 for ≥24 h or anuria for ≥12 h  criteria: (1) mild stage: serum creatinine increased to 1.5–1.9 times baseline or ≥0.3 mg·dlor ≥12 h , 12. Basor ≥12 h .Other postoperative complications that were recorded included low cardiac output, tachyarrhythmia, delirium, and the use of mechanical circulatory support devices. Low cardiac output was determined if patients required more than one inotrope to maintain enough organ perfusion. Tachyarrhythmia included new onset atrial fibrillation, atrial fibrillation with a rapid ventricular rate and supraventricular and ventricular tachycardia in the absence of electrolyte abnormalities. Delirium was evaluated by using the Confusion Assessment Method-Intensive Care Unit score every twelve hours and at times when delirium was suspected , 15. UseA dedicated data coordinating team performed all data management. Prespecified demographics and clinical and laboratory information were obtained from hospital charts that were reviewed by independent research personnel who were unaware of the objectives of the study, and accumulated data were then entered prospectively into the database.t test was performed to analyze the continuous variables with a normal distribution. The Mann-Whitney U tests were used for the analysis of continuous variables with a non-parametric distribution. The chi-square test was used to evaluate categorical data when the expected cell counts were >5; otherwise, Fisher's exact test was used.Statistical analyses were performed with SPSS 24.0.0.0 software (IBM Corp) and R 4.1.2 packages. Normality was tested with a Q-Q plot. Continuous variables with a normal distribution are expressed as the mean ± standard deviation; additionally, continuous variables with a non-normal distribution are expressed as medians (quartile), and categorical variables are expressed as case numbers and percentages. The independent P < 0.1 or considered to be clinically related to acute kidney injury, including age, BMI, hypertension, smoking, atrial arrhythmia, renal dysfunction, central venous pressure, and cardiac index, were selected for multivariable logistic regression using forward stepwise analysis and are shown in a coefficient plot. A nomogram was established based on the regression results. Model performance was evaluated using the same dataset as was used for model training due to the limited number of cases. Calibration was assessed with the Hosmer-Lemeshow goodness-of-fit statistic and calibration plot. Model discrimination was evaluated using the area under the receiver operating characteristic curve. All of the tests were two-tailed, and a P < 0.05 was considered to be statistically significant.Preoperative variables with a From January 2013 to January 2021, a total of 253 patients underwent pericardiectomy for constrictive pericarditis in the studied hospital. Nineteen combined operations were excluded from the study, including ten coronary artery bypass grafting surgeries, six valve surgeries, two tumor resections, and one ventricular aneurysm repair. Twenty-three patients with lost medical data were also excluded from the study. A total of 211 patients with constrictive pericarditis receiving pericardiectomy were included in the final analysis.4).Among the 211 patients, ninety-five (45.0%) of them developed postoperative acute kidney injury, with fourty-three (45.3%), twenty-eight (29.5%), and twenty-four (25.3%) patients in mild, moderate and severe stages, respectively. All clinical data were summarized and compared between patients with (AKI group) and without (non-AKI group) postoperative acute kidney injury –4.P < 0.001) and had a higher BMI  than the non-AKI group. The AKI group had higher rates of smoking  and hypertension  than the non-AKI group. No differences in other comorbidities were observed between the AKI and non-AKI group , higher central venous pressure  and lower cardiac index  than the non-AKI group  patients had renal dysfunction before pericardiectomy, and twenty-two (71.0%) of them developed postoperative acute kidney injury. The overall mean central venous pressure was 17 ± 5 cmHKI group .P < 0.001), tachyarrhythmia , delirium ; and use of hemofiltration , ECMO , and IABP  than the non-AKI group. A total of twenty-nine (13.7%) patients received hemofiltration, with twenty-eight (29.5%) patients in the AKI group, and one patient in the non-AKI group. One patient in the non-AKI group started preventive hemofiltration early after pericardiectomy, because the clinicians considered him at high risk of developing low cardiac output due to a dramatic fluid shift back into the intravascular space. The AKI group had longer ventilator hours  and lengths of ICU  and hospital stays  than the non-AKI group  than non-AKI group. All deaths  occurred in the AKI group. Seven patients died in the hospital due to multiple organ dysfunction. Two patients were self-discharged due to financial reasons, with one patient dying of multiple organ dysfunction within hours and the other patient dying of an unknown cause within days.Regarding mortality, the AKI group had higher mortality . The two patients in the non-AKI group already had chronic renal dysfunction before pericardiectomy due to a previous history of renal disease. All the clinical features were compared between patients with (CRD group) and without (non-CRD group) postoperative chronic renal dysfunction. Parameters with statistically significant between-group differences are listed in At the 6-month postoperative follow up, eleven (5.2%) patients were considered in chronic renal dysfunction states, with nine from the AKI group and two from the non-AKI group , kidney disease history , atrial arrhythmia , and renal dysfunction  than the non-CRD group. The cardiac index was lower in the CRD group than in the non-CRD group . Postoperatively, the CRD group had higher rates of low cardiac ouput , acute kidney injury , tachyarrhythmia , and use of hemofilatration  than the non-CRD group. The ventilator duration was longer  in the CRD group than in the non-CRD group. The other clinical data were similar between the CRD and non-CRD groups. These results should be carefully interpreted due to the limited case numbers in the CRD group.Preoperatively, the CRD group had higher rates of smoking , high body mass index , preoperative atrial arrhythmia , renal dysfunction , high central venous pressure , and low cardiac index  were independent predictors of acute kidney injury (P = 0.881) results showed good model fitness. The receiver operating curve depicted an area under the curve value of 0.78  (A multivariable logistic regression test was performed based on the comparison results between the AKI and non-AKI group to identify predictors for actue kidney injury after pericardiectomy . The resy injury . A nomogy injury . Both thy injury  and Hosm< 0.001) . No regrThis study showed that acute kidney injury is a common complication after pericardiectomy for patients with constrictive pericarditis, with an overall incidence of 45.0%, and the rates of hemofiltration and chronic renal dysfunction were 13.7 and 5.2%, respectively. The established prediction model showed that advanced age, high body mass index, renal dysfunction, atrial arrhythmia, high central venous pressure, and low cardiac index were independent predictors of acute kidney injury after pericardiectomy.Multiple studies have reported the negative impact of renal dysfunction on patient outcomes and medical costs in pericardiectomy , 16, 17,Our study demonstrated that patients with constrictive pericarditis were at high risk of developing prerenal insufficiency, and the nomogram provided a precise risk evaluation score for each predictor. One major mechanism for prerenal insufficiency is compromised renal perfusion due to a high central venous pressure and a low cardiac index. Renal perfusion, defined as the mean arterial pressure minus renal venous pressure, is associated with the progression of acute kidney injury in critically ill patients , 21. A lCardiac and renal function always closely interact with each other , 28. In This study had some limitations. First, this is a single-center observational study and suffers from all of the shortcomings of this type of study. Second, the study results only applied to patients with constrictive pericarditis receiving isolated pericardiectomy. Patients receiving combined surgeries may have completely different clinical pictures, and their management requires further investigation. Third, the prediction model lacks external validation, and further studies in other medical centers are required to test the model's performance.Acute kidney injury is a common complication after pericardiectomy for constrictive pericarditis; if not treated promptly, it may lead to worse outcomes and high medical costs. Patients with advanced age, high body mass index, preoperative renal dysfunction, arrhythmia, high central venous pressure, and low cardiac index were associated with a high risk of postoperative acute kidney injury; therefore, clinicians should make an effort to optimize these factors. A prediction model was established to help clinicians in the early evaluation and management of this complication.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Peking Union Medical College Hospital. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.JW and CY designed the study. JW collected the data and drafted the manuscript. JW and YZ analyzed the data. YH revised the manuscript. All authors contributed to the article and approved the submitted version.This research was funded by the Beien fundings from the Bethune foundation (Grant number: bnmr-2021-009).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


In medicine, a legacy effect is defined as the sustained beneficial effect of a given treatment on disease outcomes, even after cessation of the intervention. Initially described in optimized control of diabetes, it was also observed in clinical trials exploring intensification strategies for other cardiovascular risk factors, such as hypertension or hypercholesterolemia. Mechanisms of legacy were particularly deciphered in diabetes, leading to the concept of metabolic memory. In a more discreet manner, other memory phenomena were also described in preclinical studies that demonstrated long-lasting deleterious effects of lipids or angiotensin II on vascular wall components. Interestingly, epigenetic changes and reactive oxygen species (ROS) appear to be common features of “memory” of the vascular wall. Cardiovascular diseases (CVDs) are the leading cause of death worldwide, with a major impact not only in developed nations but also in low- and middle-income countries, where they account for nearly 30 percent of all deaths . Risk faIn this paper, we reviewed clinical trials that revealed a legacy effect and established this concept in cardiovascular medicine. We searched in PubMed MEDLINE database for English written studies using specific terms: “legacy effect”, “metabolic memory”, “diabetes”, “hypertension”, and “hypercholesterolemia”. A vast majority of included trials were randomized control trials, with an open label follow-up period . In paraHistorically, the concept of the legacy effect emerged at the beginning of 21th century from two clinical studies conducted in diabetic patients . The DCCConcordant results were observed later in UKPDS, a study conducted in 3867 newly diagnosed type 2 diabetic patients. In the intervention period, after a three-month diet, patients were randomized either to intensive glucose-lowering treatment  or to conventional dietary management and followed up for 10 years. Intensive glucose lowering was associated with a significant decrease in any diabetes-related endpoint (of 12%), any diabetes-related death (of 10%), and microvascular endpoints of 25%). At this point, there was no significant reduction in macrovascular endpoints [%. At thiSubsequently, several other studies failed to reproduce the same legacy effect: the Veterans Affairs Diabetes Trial (VADT) performed in long-standing type 2 diabetic patients ,12,13, tOn the other hand, additional real-life studies reinforced the legacy effect theory in diabetes control, such as the Fremantle Diabetes Study , the AngTaken together, the above-mentioned data suggest that to obtain a legacy effect, interventions on glycemic control need to be implemented early in the disease, certainly before any cardiovascular event, perhaps even within the first year. The accrued evidence then led to a new concept in diabetes clinical care: the sooner, the better.Conversely, the failure to obtain a favorable effect from intensive treatment in long-lasting, under-controlled diabetic patients could be ascribed to a “metabolic memory” underlying an adverse legacy effect, as explained below.The phenomenon of “metabolic memory” had already been described in animal models before the concept of the legacy effect emerged from clinical studies. In 1987, in a dog model of diabetic retinopathy, Engerman et al. observed that animals with late onset optimization of glycemic control had a higher incidence of progression of this microvascular complication of diabetes . A few yThese models allowed the proposal of some putative mechanisms as follows: hyperglycemia induces an overproduction of mitochondrial superoxide. The ensuing oxidative stress leads to the activation of five major pathways: increased formation of AGEs (advanced glycation end products), expression of its receptor (RAGE), activation of protein kinase C isoforms, overactivity of the hexosamine pathway and polyol pathway that, in turn, activate inflammatory reactions. The same mediators also produce long-lasting epigenetic changes driving sustained expression of proinflammatory genes, despite restoration of glycemic control, leading to the observed hyperglycemic memory ,28,29,30Moreover, upon epigenome profiling of white blood cells of patients from the DCCT trial, an enrichment of histone acetylation marks as promoters of inflammatory genes and other genes related to diabetic complications was observed in selected patients with progressive retinopathy and nephropathy compared to controls. This epigenetic mark also significantly correlated with the mean HbA1C during the trial .As for diabetic patients and optimized glycemic control, lipid-lowering therapies also showed long-term benefit on cardiovascular outcomes . In the In the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA), 10,000 hypercholesterolemic and hypertensive patients with at least three other cardiovascular risk factors were randomized to receive either atorvastatin or placebo in primary prevention. The trial was stopped prematurely (median of 3.3 years of intervention) because of a 36% relative risk reduction in the primary outcome  in favor of atorvastatin and a non-significant reduction in CV deaths (of 16%) and all-cause mortality (of 13%) . In the The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) included a subgroup in which hypertensive patients with a least another cardiovascular risk factor received pravastatin compared to usual care. No effect of the intervention was observed in all-cause mortality or coronary heart disease. This may be due to the modest differential in lipid profile between the intervention group and usual care group (16.7% lower LDL-C compared to control). Moreover, the study was not blinded, at a period of publication of a series of guidelines stimulating optimization of the lipid profile and statin use contributed to treatment crossovers. Indeed, the trial follow-up showed a decrease in total cholesterol and LDL-C over time in both groups . ConsistBeside the beneficial legacy effect of optimized control on lipid profile, long-term detrimental effects of a transient exposure to hypercholesterolemia have also been demonstrated. In a study in young adults born prematurely, endothelial function assessed by measurements of pulse wave velocity was compared between those who received intravenous lipids at early stage of life as part of parenteral nutrition and matched controls with equivalent perinatal characteristics who did not receive such supplements. Perinatal hyperlipemia secondary to intravenous lipids administration was associated with a significantly altered endothelial function compared to controls in adult life .As for metabolic memory, several in vitro studies evaluated the effects of transient exposure to lipoproteins on the vascular wall or its components, leading to the concept of trained immunity  resultinTNFα, IL-6, IL-18, and MCP-1 genes. Pretreatment of monocytes with the histone methyltransferase inhibitor MTA completely prevented the oxLDL-induced proinflammatory phenotype [Upon pre-incubation with oxLDL in vitro and further stimulation by a toll-like receptor (TLR) agonist, such as lipopolysaccharide (LPS) or lipopeptide PAM3cys4, endothelial cells expressed ICAM-1, VCAM-1, and E-selectin, which are adhesion molecules controlling rolling, adhesion, and transendothelial migration of leukocytes. In parallel, oxLDL priming also induced the enrichment of activating histone marks (H3K27ac and H3K4me3) on the ICAM-1 promoter . In humahenotype . Anotherhenotype ,54. In phenotype . More reSimilar legacy findings were observed with blood pressure control . A meta-The above-mentioned ASCOT study also included one arm of blood pressure control, in which patients were assigned either to an amlodipine-based regimen (with perindopril if required) or to atenolol (with bendroflumethiazide if required). Although mean blood pressure reduction was similar in both groups, cardiovascular events and all-cause mortality was significantly lower in the amlodipine (plus perindopril) group, suggesting that hypotensive medications are not equal in the prevention of CVD . Long-teOther randomized studies, however, failed to detect any legacy effect in blood pressure lowering. In the previously cited study ALLHAT, more than 30,000 patients were randomized to receive either chlorthalidone, amlodipine, or lisinopril for at least 4 years (active phase) with an observational period of 8 to 13 years afterward. No differential effect between these interventions was observed during the trial phase, explaining the absence of legacy effect . As citeNevertheless, one class of blood pressure-lowering therapy emerged from clinical studies with a potential beneficial effect on cardiovascular outcomes beyond blood pressure lowering. In patients with heart failure resulting from myocardial infarction, a RAAS inhibitor led to prognosis improvement with only minimal (if any) effect on blood pressure . MoreoveAngiotensin II, as the main product and effector of the RAAS stimulation, is a physiological regulator of blood pressure ,73. InfuThis review of clinical trials testing optimized control of cardiovascular risk factors in at-risk patients provided convincing evidence in favor of a legacy effect, despite heterogeneity in study populations, duration of in-trial and follow-up periods, and clinical outcomes. A legacy effect was firmly established in diabetic patients, but also discernible in hypercholesterolemic and hypertensive patients. One common feature is that, to be effective and produce legacy, interventions on risk factors have to be implemented at early stages. The expression “the sooner the better” should therefore be extended from diabetes to the control of hypertension and hyperlipidemia.The mechanisms underlying such legacy effects were thoroughly examined in diabetic conditions with preclinical models showing metabolic changes that led to sustained oxidative stress and epigenetic modifications; these, in turn, induced a feed-forward phenomenon (or “vicious circle”) that perpetuated oxidative stress, inflammation, and damage to the vascular wall . The mecEven if pathophysiological mechanisms are not completely understood, the idea of an organ memory rather than memory specific to each risk factor is an attractive theory, which needs to be substantiated by further investigation, either through clinical trials or in vitro/in vivo studies. Arterial beds, for example, can be considered as a unique organ, consisting of highly sensitive and interacting cell types, directly in contact with blood flow where the inner endothelial cell lining could perpetuate oxidative stress induced by an initial aggressor; among these, oxLDL is known to produce endothelial dysfunction and to prime monocytes, thereby promoting pro-inflammatory susceptibility ,52; in rNotably, epigenetic mechanisms appeared at the center of all the above-mentioned memory effects. In metabolic memory, several epigenetic changes  were involved in the sustained oxidative stress in endothelial cells ,30. In tSome of the epigenetic changes at the basis of a legacy effect of precited cardiovascular risk factors were also implicated more broadly in the development of cardiometabolic diseases.In another model of hypertension in vivo, spontaneously hypertensive rats (SHR) exhibited a significantly higher expression of angiotensin 1α receptor (AT1aR), encoded by Atgr1α, compared to Wistar-Kyoto control rats (WKY), which was associated with an hypomethylation of the Atgr1α promoter . In otheAs epigenetic modifications are reversible, they could be interesting targets for innovative therapies. Histone deacetylase (HDAC) inhibitors were tested in experimental diabetes with some favorable effect: vorinostat, a nonspecific HDAC inhibitor, showed beneficial effects on diabetic nephropathy in mice . An agonIn conclusion, clinical trials on the optimization of cardiovascular risk factors demonstrated the legacy effect of interventions on glycemic, lipid profile, or blood pressure control. While the mechanisms underlying this organ legacy are not yet fully understood, future investigations are expected to identify epigenetic signatures of “memory” that facilitate early detection of patients at risk and, possibly, lead to new therapeutic strategies by erasing them.


Autonomic regulation of blood pressure and cardiac rhythm progressively declines with increasing age. Impaired cardiovascular control promotes a variety of age-related cardio-vascular conditions. This study aims to provide a database of high-resolution biological signals to describe the effect of healthy aging on cardiovascular regulation. Electrocardiogram and continuous non-invasive blood pressure signals were recorded simultaneously at rest in 1,121 healthy volunteers. With this database, we provide raw signals as well as basic demographic information such as gender and body mass index. To demonstrate validity of the acquired data, we present the well-known decline of heart rate variability with increasing age in this database.  In addition, impairment of autonomic regulation of the cardiovascular system seems to accelerate the decline of cognitive performance and promotes the risk to develop age-related diseases3.As the elderly population has a high prevalence of cardiovascular diseases, representing the globally leading cause of death, it is essential to detect bodily changes that adumbrate cardiovascular impairments4. Recent scientific studies have suggested that an elevation of blood pressure and signs of thrombosis in midlife increase the risk to develop Alzheimer’s disease or other dementias in later life6.It is well established that arterial and ventricular stiffening, reduction of myocardial contractility, or degeneration of organ innervation impair cardiovascular function in an aged population and promote sustained hypertension, thrombosis, and atherosclerosis9. The feedback loop decelerating heart rate due to increasing blood pressure, i.e. baroreflex function, is progressively diminished with increasing age. Structural changes such as the loss of sinoatrial pacemaker cells and left ventricular hypertrophy as well as functional changes of receptors initiating autonomic reflexes (e.g. baroreceptors) contribute to an altered cardiovascular regulation related to aging11.A decreased sensitivity of vagal reflexes such as respiratory sinus arrhythmia leads to elevated heart rates and diminished heart rate variability in elderly participants12. Hillebrand et al. reported that healthy participants with diminished resting heart rate variability (HRV) have a 32–45% increased risk to suffer from a first cardiovascular event13. Resting heart rate and HRV were demonstrated to predict cardiovascular disease as well as cardiac and overall mortality14.Lower levels of vagally modulated HRV have been associated with increased cardiovascular morbidity and mortality in the elderlyIn this study, we enrolled healthy volunteers between 2010 to 2020. Participants were recruited from the local community as well as employees of the University Hospital. We recorded electrocardiograms and continuous noninvasive blood pressure at carefully controlled resting state conditions in our laboratory with a constant well-defined room temperature and humidity, a defined illumination level and without any environmental noise. Available data might be used to describe the influence of aging on cardiovascular autonomic regulation to better understand mechanisms of healthy aging in contrast to pathological changes.Resting state physiological recordings of 1,121 healthy volunteers were obtained. Exclusion criteria were any medical conditions, illegal drugs or medication potentially influencing cardiovascular function. Thorough physical examination, resting electrocardiography (ECG) and routine laboratory parameters  had to be without any pathological finding (results are not part of the database). Demographic information is depicted in Table The study was approved by the ethics committee of the Friedrich-Schiller-Universität Jena. All research was performed in accordance with relevant guidelines and regulations. Informed written consent and consent for anonymous data sharing were obtained from all participants.All measurements were recorded at the Department of Psychosomatic Medicine and Psychotherapy at Jena University Hospital.An ECG (lead II) was recorded at 1000 Hz either by an MP150  or Task Force Monitor system . Pre-gelled Ag/AgCl electrodes  were attached according to an Einthoven triangle . The Task Force Monitor is equipped with a module for continuous blood pressure measurement. The MP150 system digitizes the signal acquired by a separate monitor CNAP 500 . The sampling frequency was 100 Hz for both systems.Continuous blood pressure was recorded non-invasively using the vascular unloading techniqueNaN. When demographic data was missing, respective cells were filled with NaN.During some recordings, the system measured brachial blood pressure again for re-calibration. This led to loss of continuous NIBP signal over a short time span. Missing data points have been set to 16. For pre-processing of heart beat interval time series, we used an adaptive filter algorithm that is also available online17. Outliers in age bins were excluded when exceeding three times the median absolute deviation18.To demonstrate plausibility of collected data, we investigated a number of fundamental heart rate variability indices and their dependence on age. Therefore, heart beats were extracted and analyzed using the freely available PhysioNet Cardiovascular Signal Toolbox implemented in MATLAB . As exemplification, standard deviation of heart beat intervals (SDNN), root mean squared difference of successive heart beat intervals (RMSSD), and deceleration capacity (DC) was assessed using the PhysioNet Cardiovascular Signal ToolboxMeasurements were performed in our autonomic laboratory that was temperature controlled at 22 °C. During recordings, the environment was quiet and fully shaded. The illumination level was kept constant via an indirect light source. The recording session started with an interview of the participant. Then, the purpose and design of the study was explained. All study volunteers gave his or her written consent to participate. Weight was measured using a person scale  and height using a stadiometer .After participants lied down comfortably on the examination tilt table, electrodes and pressure cuffs were placed. For the resting state recording, participants were instructed to avoid movement, yawning or coughing.The instructor waited a few minutes for the participant to calm down and checked the quality of the acquired signals. In case of insufficient signal quality, electrodes and cuffs were re-arranged. Otherwise, the recording was started. The length of the recording was 8 to 35 minutes and was supervised by the instructor.20. Each recording is stored as a data file with signals of ECG and blood pressure. Blood pressure values were spline-interpolated and resampled to 1000 Hz. Additional information can be found in subject-info.csv that is included in the repository.Data are available at PhysioNet21. To assure that none of our participants can be identified based on demographic information, we generalized individual age to age groups. The applied a k = 2 anonymity condition and an average re-identification risk of 5%23. Files were pseudonymized to numbers 0001–1121 after random ordering.Data was anonymized using the free open-source Data Anonymization Tool ARX0023.hae: ‘0023 2 1000 1226975’). Each of the following lines include information regarding one signal, namely, file name, defined bit resolution, bit gain, baseline in brackets followed by a slash, units, bit resolution followed by a zero, first bit, checksum followed by a zero and signal name /mV 16 0 −13073 17059 0 ECG’). There is a script to convert wfdb files to mat format (and reverse) in the Waveform Database Software Package for MATLAB (wfdb2mat.m) available at PhysioNet24.Recorded data of each participant are stored in a data file (.dat) with raw signals of ECG and blood pressure. Amplitudes are included as a sequence of unsigned 16-bit integers for each signal. An associated header file is an ASCII text file storing meta information on this recording. The first line gives file name, number of signals, sampling frequency and number of samples separated by spaces (e.g., first line in subjects.tsv gives basic demographic information i.e., age bin, gender and body mass index as well as length of recording in minutes and recording device.The table To explore validity of recorded data, the sample was divided into age bins of ten years see Fig. . We esti


In patients with diabetes and hypertension, proteinuria is independently associated with all-cause death. However, in the general population, urinary albumin to creatinine ratio (UACR) is less used to predict all-cause mortality. When the urinary albumin to creatinine ratio is within the normal range (UACR< 30 mg/g), the clinical relevance of an increased urinary albumin excretion rate is still debated. We studied the relationship between UACR and all-cause mortality in community populations, and compared UACR groups within the normal range.The participants were the inhabitants from the Wanshoulu community in Beijing, China. The average age is 71.48 years, and the proportion of women is 60.1%. A total of 2148 people completed random urine samples to determine the urinary albumin to creatinine ratio (UACR). The subjects were divided into three groups according to UACR: Group 1 (UACR< 10 mg/g), Group 2 (10 mg/g < UACR< 30 mg/g), Group 3 (UACR> 30 mg/g). We used Kaplan-Meier survival analysis and Cox regression model to verify the relationship between UACR and all-cause mortality.At an average follow-up of 9.87 years , the total mortality rate were 183.4/1000. In the Cox proportional hazards model, after adjusting for possible confounders, those with normal high-value UACR (group 2) showed a higher all-cause mortality than those with normal low-value UACR (group 1) . Those with proteinuria (group 3) showed a higher all-cause mortality than those with normal low-value UACR (group 1) .Urinary albumin to creatinine ratio is an important risk factor for all-cause death in community population. Even if it is within the normal range (UACR< 30 mg/g), it occurs in people with high normal value (10 mg/g < UACR< 30 mg/g), the risk of all-cause death will also increase. With the acceleration of aging, when the age structure of the population becomes less young, tools for predicting the risk of all-cause mortality in the middle-aged and elderly have become more and more important in research, policy, and clinical practice –4. ChronSampling and research methods were reported elsewhere , 26. TheMen and women filled out detailed baseline health and lifestyle questionnaires, and 2162 people participated in a health check conducted by trained nurses using standard procedures. At the time of consultation, a random urine sample was randomly selected to determine the urinary albumin to creatinine ratio (UACR). Information about drinking and smoking status, diabetes, hypertension, coronary heart disease history, NIHSS stroke scale, MMSE simple intelligence scale, ADL daily activity scale and other information were obtained from baseline health data and lifestyle questionnaires. The body mass index (BMI) is calculated by dividing the weight (Kg) by the square of the height (m), measuring the height with a stand-alone distance meter, and calculating the weight with an electronic scale. After the participant sat and rested for 5 min, the blood pressure was measured using a sphygmomanometer. The systolic and diastolic blood pressure were measured twice, and the average of the two was used for analysis. Hypertension is defined as high blood pressure or systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg as diagnosed by a doctor. Routine blood tests for fasting blood glucose, 2 h postprandial blood glucose, glycosylated hemoglobin, total serum cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglycerides were measured on an automatic biochemical analyzer. All on-site urine samples were taken to determine the concentration of urinary albumin (mg/l) and the concentration of urinary creatinine (g/l), and calculate the UACR (mg/g). All biochemical analyses were performed in the Department of Biochemistry of the Chinese People’s Liberation Army General Hospital. Among the subjects, 1854 agreed to participate in the telephone follow-up or signed a written informed consent for community on-site follow-up, which constituted our study population. Regarding age and gender, there is no difference between responders and non-responders. This study was ethically approved by the Ethics Committee of the Chinese People’s Liberation Army General Hospital.Our observations add to more and more evidence, and they challenge the idea that UACR< 30 mg/g means albumin excretion is “normal” . Our resEndpoint death cases were defined as indicator events that occurred between baseline and follow-up until December 31, 2020. During the follow-up period, the main concern was all-cause death. In these analyses, all-cause death is defined as death from any cause, and the cause of death comes from the results of telephone calls or on-site follow-ups provided by family members. For some members of the group whose telephone numbers were lost to follow-up or whose home address was changed, our staff sought help from Wanshoulu community staff and police officers from the population management archives office of Wanshoulu police station.P < 0.05. All statistical tests are two-sided, and the significance level is α = 0.05. Use SPSS software (version 26.0) for statistical analysis.All continuous data are expressed as mean ± standard deviation, while categorical data are expressed as absolute numbers and percentages (%). The Kolmogorov-Smirnoff test is used to check whether the data has a normal distribution. One-factor analysis of variance (ANOVA) test is used to analyze the baseline characteristics of the study populations. Post hoc multiple comparisons, the LSD test is used to assume that the variances are equal, and the Tamhane’s T2 test is used to assume that the variances are unequal. The chi-square test was used to compare the all-cause mortality of different groups after 10 years. The Kaplan-Meier method and log-rank test were used to compare cumulative probabilities. In the analysis of the Cox proportional hazards model, hazard ratio (HR) and 95% confidence interval (CI) were calculated after adjusting for age, gender, height, weight, BMI, waist circumference, systolic blood pressure, diastolic blood pressure, triglycerides, blood creatinine, blood uric acid, history of coronary heart disease, history of diabetes, history of drinking. A multivariate logistic regression model was established to show the relationship between UACR and all-cause mortality. In the cox regression analysis, the Omnibus test is used to test the model coefficients, and the results are analyzed by one-minus survival analysis function, hazard function, and LML function. In all hypothesis tests, the risk of the first type of error is set a priori as Among the 1854 study populations, there were 229 people with a UACR greater than 30 mg/g, and the prevalence of proteinuria was 12.3%; 1149 people with a UACR less than 10 mg/g, accounting for 62.0% of the total; 476 people with a UACR of 10 mg /g to 30 mg/g, accounting for 25.7% of the total number of people. Women accounted for 59.2% of the population. One-factor analysis of variance (ANOVA) test is used to analyze the baseline characteristics of the study populations. Post hoc multiple comparisons, the LSD test is used to assume that the variances are equal, and the Tamhane’s T2 test is used to assume that the variances are unequal. Table During the average follow-up period of 9.87 years , 1854 subjects were followed up with 340 deaths (185 men and 155 women). The total population mortality, the rough all-cause mortality rates for males and females were 183.4/1000, 99.8/1000 and 83.6/1000, respectively. The mortality rate of men is slightly higher than that of women, which is consistent with the results of other studies in the region. Table p < 0.001, tested by Log-Rank). It can also be seen from the Risk function graph that the greater the UACR, the greater the cumulative survival risk of the group.As shown in Table In order to study the effect of urine albumin-creatinine ratio on all-cause mortality, we performed Cox proportional hazards model fitting on the data. In addition to UACR, the following variables that can be used to explain all-cause deaths and differences in the group in the baseline analysis are included in the regression analysis: age, gender, height, weight, BMI, waist circumference, systolic blood pressure, diastolic blood pressure, triglycerides, blood creatinine, blood uric acid, history of coronary heart disease, history of diabetes, history of drinking. After adjusting for the above variables that may affect survival, compared with Group 1 (UACR< 10 mg/g), Group 2 (10 mg/g < UACR< 30 mg/g) and Group 3 (UACR> 30 mg/g) have significant all-cause mortality increase. The Cox proportional hazard model was used to analyze multiple variables, which allows us to compare the effects of different variables on deaths from all causes. The results are summarized by the hazard ratio, by plotting the adjusted risk ratio as a function of UACR, and by plotting the causal specific cumulative correlation function of specific covariate values.P < 0.001), and the greater the UACR, the greater the risk of death in the group. In the Cox proportional hazard model, taking group 1 (UACR< 10 mg/g) as a reference, the hazard ratio  of group 2 is 1.289 times that of group 1 (P = 0.048). The hazard ratio  of group 3 is 1.394 times that of group 1 (P = 0.037). From Table As shown in Fig. P = 0.048). The hazard ratio  of group 3 was 1.394 times that of group 1 (P = 0.037). The normal urine albumin-creatinine ratio recognized in our country is < 30 mg/g. Group 2 (10 mg/g < UACR< 30 mg/g) is a community population with a higher urine albumin-creatinine ratio within the normal range. Our results show that even if the urinary albumin and creatinine ratio is normal, if the UACR value is higher, it will still have a certain impact on all-cause death. This is the innovation of our research. Before our research, there have been reports at home and abroad that microalbuminuria (30 mg/g < UACR< 300 mg/g) can predict the risk of cardiovascular and all-cause death [In this present study, after adjusting age, gender, height, weight, BMI, waist circumference, systolic blood pressure, diastolic blood pressure, triglycerides, blood creatinine, blood uric acid, history of coronary heart disease, history of diabetes, history of drinking, taking group 1 as a reference, the hazard ratio of group 2 was 1.289 times that of group 1  within the normal range (less than 30 mg/g) would also increase the risk of cardiovascular disease. The optimal cut-off value of UACR for diagnosing diabetic left ventricular hypertrophy is 10 mg/g . In our In predicting the occurrence of cardiovascular disease, a 2005 study in the United States presented evidence that challenged the concept that UACR< 30 mg/g means normal . This isOur study is the first time that groups within the range of normal urine albumin to creatinine ratio are used to predict all-cause mortality in community populations with 10-year follow-up. In terms of the pathological mechanism of the relationship between urine albumin-creatinine ratio and all-cause death, proteinuria may be an early sign of vascular endothelial dysfunction, which easily leads to the development of individual atherosclerosis . AtherosCompared with other studies, our study has a 10-year follow-up, a novel grouping standard, and enough community populations to prove the relationship between urine albumin-creatinine ratio and all-cause deaths in Chinese community populations. However, our study also has some shortcomings. First, most of our follow-ups are conducted through telephone consultation, and the degree of cooperation and response accuracy of the interviewed population may be biased. Secondly, in our study, 294 (13.7%) lost follow-up in 10 years. This tendency to attrition may have weakened our results. In the end, we had 1854 people included in the study, and the reduced sample size also reduced the robustness of our conclusions.Previously, only in patients with hypertension and diabetes, doctors would pay attention to the patient’s urinary albumin to creatinine ratio, because many studies have shown that proteinuria is independently related to all-cause death. However, in the non-diabetic hypertensive population and the general community population, people pay insufficient attention to the ratio of urinary albumin to creatinine ratio. Through our research evidence, in clinical practice, doctors will pay more attention to the UACR indicator and have more choices in predicting the indicators and standards of death from all causes.


Aim of the Study. The aim of the study was to evaluate presence of subclinical cardiovascular damage in patients with limited and diffuse SSc in comparison with a cohort of healthy individuals.  Vascular damage is recognized as a diagnostic landmark in systemic sclerosis (SSc), both in its limited and diffuse subtypes. Early detection at a subclinical stage with transthoracic echocardiography (TTE) and carotid femoral pulse wave velocity (cfPWV) may be helpful in therapeutic planning and management.  Consecutive patients with limited and diffuse SSc underwent complete TTE and cfPWV and a complete review of clinical data. As controls, 23 healthy subjects with similar hemodynamic profiles were selected. p=0.24) and augmentation index . Patients with limited SSc were 10 years older than patients with diffuse SSc. In the multiple regression analysis, only age (p=0.0154) and disease duration (p=0.0467) resulted as the significant determinant of cfPWV. When compared to healthy controls, no significant difference emerged in TTE or hemodynamic indexes.  41 patients , 21 with diffuse and 20 with limited SSc, were recruited. Past medical history, cardiovascular risk factors, gender distribution, and disease duration were similar in the two groups as well as TTE parameters and hemodynamic indexes—cfPWV . Systemic sclerosis (SSc) is a chronic and progressive connective tissue disease arising as a consequence of altered immunologic processes, with vascular injury, inflammation, and fibrosis of the skin and different internal organs . A “limiCarotid-femoral pulse wave velocity (cfPWV), the gold standard for noninvasive evaluation of arterial stiffness , has demcfPWV has been shown to be higher in SSc patients than in healthy, age-matched controls in some –9 but noThe aim of the study was to evaluate the presence of subclinical cardiac organ damage and arterial stiffness, as a landmark of macrovascular damage, with the current gold standard represented by transthoracic echocardiography and cfPWV in patients with SSc, focusing in particular on differences between limited and diffuse SSc.Consecutive patients referred to the Rheumatology Department of “Città della Salute e della Scienza,” University Hospital in Turin , were recruited. All patients met the ACR–Euler criteria for SSc diagnosis and classification . Past mePatients with either limited or diffuse systemic sclerosis were compared to a well-matched control population consisting of healthy, normotensive volunteer subjects , free of cardiovascular diseases , evaluated at the Hypertension Unit of the same institution. The study was approved by the local ethical committee, and all patients gave their informed consent to participate.All subjects involved in the study underwent a complete evaluation of cardiovascular target organ damage with a complete transthoracic echocardiogram (TTE) and with central pressure appraisal and cfPWV measurement.∗ILW)/LVIDd. Patterns of left ventricular geometry were defined according to the ESH/ESC recommendations. LV hypertrophy was defined as LV mass indexed to BSA >95 g/m2 in women or >115 g/m2 in men. Body surface area (BSA) was calculated using the DuBois and DuBois formula. LV volumes were assessed through Simpson's biplane technique from apical 4- and 2-chamber views and indexed to body surface area and then used to evaluate LV systolic function . Offline analysis and measurements were performed in agreement with the last International Guidelines [A two-dimensional (2D) TTE was performed in all patients at rest in the left lateral decubitus position, with a commercially available ultrasound system equipped with a S5 probe for 2-dimensional and tissue Doppler imaging acquisition . In brief, left ventricular (LV) mass was calculated from the end-diastolic LV internal diameter (LVIDd), interventricular septum (IVS), and inferolateral wall thickness (ILW) and normalized to body surface area (BSA). Relative wall thickness (RWT) was calculated as . The mean value from these three measurements was used for further analysis.t, in seconds), is measured by subtracting the time between ECG-R wave and proximal (carotid) waveform foot from the time between ECG-R wave and distal  waveform foot. In consideration of the strong heart rate dependence, PWV values which were obtained with heart rate difference >10% between carotid and femoral sites were discarded. The distance covered by the pulse wave  is supposed to be the surface distance between the carotid and femoral recording sites. Therefore, it is calculated by multiplying the surface distance measured between the two points by a correction factor of 0.8, as previously described in detail and validated [cfPWV was measured along the descending thoracoabdominal aorta by the foot-to-foot velocity method, with a dedicated instrument  as previously published and validated . With thalidated , 14.t. A cfPWV value > 10 m/sec was considered pathologic [cfPWV is obtained as D/thologic .The assessment of the augmentation index and central pressures was allowed by the estimation of aortic pressure waveforms, which were obtained through the measurement of radial artery waveforms, by using a high-fidelity micromanometer . Radial artery tonometry was performed, and a validated transfer function  was applied in order to calculate aortic pressure waveforms. The calibration of central artery pressure was obtained by using noninvasively recorded brachial blood pressure as surrogate of radial arterial pressure. This method is based on the fact that mean blood pressure remains constant and diastolic blood pressure does not significantly change along the artery tree . Augmentst and 3rd quartiles), where appropriate. The difference between groups was evaluated with the T-test or a three-way ANOVA for normally distributed variables. The Mann–Whitney-Wilcoxon test was used for nonnormally distributed variables, and the χ2 test or Fisher's exact test was used when appropriate. Correlations among different variables were performed using Person or Spearman's test where appropriate. An alpha-error <0.05 was considered significant in all analysis.The statistical analysis was performed using R, a free software environment for statistical computing and graphics  . The parA total of 41 patients , 21 with diffuse SSc and 20 with limited SSc were recruited. p=0.009). Clinical features were as expected different, with patients with diffuse SSc showing higher prevalence of pulmonary fibrosis, a trend to poorer—although nonstatistically significant—performance on the 6-minute walking test, worse pulmonary function as evaluated by FVC, and an higher MRSS.Comparing patients with the two different subtypes of SSc, it clearly showed a similar background: past medical history, familiarity, cardiovascular risk factors, gender distribution, and disease duration were all similar. However, patients with limited SSc were averagely 10 years older than patients with diffuse SSc . Tissue Doppler parameters evaluating diastolic function were within normal limit for the majority of the population and showed no significant difference between limited and diffuse SSc. The few patients (n=5) that showed abnormal Tissue Doppler parameters were all significantly older than patients showing no abnormalities. Indexed left atrial volume was increased in only 5 patients, again significantly older than the ones showing normal atrial volume, and again with no significant difference between the two subgroups. None of the patients had increased pulmonary pressure values on TTE evaluation.Echocardiographic parameters  describip=0.24) and Ai . A total of 4 patients showed increased (>10 m/sec) cfPWV, with no significant difference in distribution among limited or diffuse form of the disease. These patients were averagely older (73.5 vs. 55.5 years p=0.01) but had similar disease duration than the patients with normal cfPWV (p=0.27). Dividing patients on the basis of the presence or absence of classical cardiovascular risk factors did not lead to significant difference in the recorded cfPWV, nor cfPWV showed significant difference when the subanalysis was made on the basis of presence of clinical manifestation such as acral ulcers, esophageal hypotonia, pulmonary fibrosis, or positive finding on capillaroscopy (data not shown).Patients with limited and systemic SSc also showed similar arterial stiffness, both in terms of cfPWV  and a fair correlation with disease duration . As expected, cfPWV was significantly correlated with both peripheral  and central blood pressure values , while Ai did not show significant correlations with any of those variables.In the regression analysis, cfPWV showed a good correlation with age , while only height was significantly and inversely correlated with Ai (p=0.001)  .p=0.458), and no difference in cardiac organ damage, as evaluated with echocardiography, was detected. In a multiple regression analysis mirroring the one performed in SSc patients only, only age maintained significant correlation with cfPWV (p=0.008) after correction for disease status (patient vs. controls) and central and peripheral hemodynamic parameters.Compared to healthy subjects with well-matched hemodynamic profiles  does not automatically imply similarity, especially within a small population like the one we present here. Indeed, it might be related to the small sample size, and the study itself might be underpowered to thoroughly assess the lack of any significant differences between SSc patients and controls in terms of cfPWV and cardiovascular organ damage. However, the correlation analysis did not show a significant impact of SSc nor its subtype on cfPWV values, highlighting at the same time the importance of age in the determination of arterial stiffness.Second, in the analyzed population, cfPWV values are mostly within normal limits, with very few patients showing pathologically increased cfPWV  . HoweverThird, we underline the limitations related to the techniques used in this study to calculate central hemodynamic parameters, since the method to calibrate central pressures may introduce some errors, even if previously validated.Echocardiography is one of the tools used for annual screening in systemic sclerosis patients, in order to detect patients at high risk for pulmonary arterial hypertension (PAH) at early stage. For the diagnosis of PAH, the gold standard remains right heart catheterization. The main aim of our paper was to analyze subclinical cardiovascular organ damage in SSc patients and to study in depth the potential role of TTE and cfPWV in cardiovascular risk stratification.Compared to control, patients affected by SSc did not present significantly increased subclinical cardiac damage nor arterial stiffness as evaluated, respectively, with standard echocardiogram and cfPWV, irrespective of their specific clinical subtypes. The two forms of SSc—limited and diffuse—showed hemodynamic and cardiac features that were similar to those of a well-matched healthy population.Considering the increasingly growing importance of cost-effectiveness in patient management, our data suggest that cfPWV analysis and echocardiogram may be used in the subsets of SSc patients with additional classical cardiovascular risk factor, better than routinely applied for risk stratification of the general SSc population. Efforts in identifying SSc patients at increased cardiovascular risk should probably be redirected toward use of different technologies.


Chronic kidney disease is a worldwide public health issue, with increasing prevalence resulting in high morbidity and mortality. As a result, recognizing and treating it early can lead to improved outcomes. We hypothesized that some providers might be more comfortable making this diagnosis than others.Retrospective study of 380 patients with chronic kidney disease seen between 2012 and 2016 in an outpatient setting.p = 0.001; had lower GFR, 37  vs 57  ml/min/1.73 m2, p < 0.0001 and were more likely to be seen by a physician compared to an advanced practice provider: 272/316 (86%) vs 46/64 (71.8%), p = 0.008. In multivariate analyses, care by a physician, OR = 2.27 (1.13–4.58), p = 0.02 was associated with increased recognition of chronic kidney disease. On the other hand, higher GFR was associated with decreased diagnosis of chronic kidney disease, OR = 0.95 (0.93–0.96), p < 0.0001.Three hundred and sixteen patients were treated by physicians and sixty-four by advanced practice providers. Chronic kidney disease was identified by the primary care providers in 318 patients (83.6%). Patients recognized with chronic kidney disease were older, 76 ± 8.8 vs 72 ± 7.45 years, The odds of chronic kidney disease recognition were higher amongst physicians in comparison to non-physician providers. These patients tend to suffer from poorly controlled hypertension (HTN) and diabetes (DM) with low rates of statins, angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARB) use despite their high cardiovascular risk. [Recent assessments of patients in the United States with estimated glomerular filtration rates (GFR) <60 mL/min/1.73 mHigher GFR, younger age, female sex, use of serum creatinine without adjusting for GFR and absence of hypertension or diabetes were previously identified as risk factors for missing the diagnosis of CKD in the outpatient setting. With the introduction of GFR, the recognition of CKD, proteinuria testing, prescription of ACEIs/ARBs and avoidance of nephrotoxins has modestly improved. This has led to an increase in Nephrology referrals, especially at earlier stages of CKD. Although there are plenty of studies describing the patient characteristics associated with under-recognition of renal disease, there is paucity of data studying the association of primary care provider characteristics with recognition of CKD. Identifying these factors when present can further increase the quality of care for these patients.We hypothesized that recognition of CKD can be influenced by factors independent of patient characteristics and that some primary care providers might be more comfortable making the diagnosis of CKD than others.This research was approved by the Institutional Review Board at Rice Memorial Hospital in Willmar Minnesota, protocol 10222014. The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Three hundred and eighty patients with CKD seen between 2012 and 2016 in the outpatient setting were included.2 or proteinuria was obtained. The diagnosis of CKD was confirmed by manual revision of the charts.Initially, a computer-generated list of patients with GFR less than 60 mL/min/1.73 m2. Proteinuria was defined as urine protein to creatinine ratio ≥200 mg/g per day or urinary albumin excretion ≥300 mg/24 h.Chronic kidney disease was defined as evidence of structural or functional kidney abnormalities that persisted for at least 3 months, with or without a GFR of less than 60 mL/min/1.73 mTwo types of primary care providers were identified: physicians  and advanced practice providers (nurse practitioners or physician assistants). Each group of providers was solely responsible for delivering primary care to their patients. Each provider’s visit note over a period of 4 years in the medical chart was reviewed, looking for a documented diagnosis of chronic kidney disease or a corresponding ICD-9 or ICD-10 code.The ICD-9 or ICD-10 codes for proteinuria, chronic kidney disease, chronic renal insufficiency, chronic kidney insufficiency, kidney disease, renal disease, renal insufficiency, kidney stone, renal calculus, renal atrophy, renal sclerosis, kidney failure, renal failure, cystic kidney disease, kidney cyst, polycystic kidney, multicystic kidney, glomerulonephritis, nephritis, nephropathy, and hypertensive chronic kidney disease were used.Patients on renal replacement therapy or with a renal transplant; patients younger than 18 years of age or pregnant.t-test. For highly skewed data, the Wilcoxon–Mann–Whitney test was used.For parametric data, differences in the mean were compared by the Student’s Differences in proportions were assessed by the Chi- square or Fisher’s exact test.For multivariate analyses, logistic regression models were used for variables with P values < 0.1 in univariate analyses.P values ≤ 0.05 were considered statistically significant. All the analyses were performed using JMP statistical software version 14 .Three hundred and sixteen patients were cared by physicians and sixty-four by advanced practice providers. The baseline patient characteristics are described in Chronic kidney disease was identified in 318 patients (83.6%) and urinary protein excretion was measured in 321 patients (84.5%).2, seven (25.9%) were not recognized as having CKD. In those with GFR above 60 mL/min/1.73 m2, five patients (20%) were not diagnosed with CKD.In patients with proteinuria and GFR below 60 mL/min/1.73 mp = 0.40.One hundred and forty-three patients (45.1%) with recognized CKD were treated with ACEIs vs 33 patients (51.6%) with unrecognized CKD, p = 0.15.Angiotensin receptor blockers were prescribed in 63 patients (19.8%) with CKD diagnosed vs seven patients (11.2%) with undiagnosed CKD, p = 0.006.Non-steroidal anti-inflammatory drugs (NSAIDS) were prescribed in 19 patients (30.5%) not diagnosed with CKD vs 49 patients (15.4%) with CKD diagnosis, In univariate analyses, the characteristics associated with increased recognition of CKD included older age, lower GFR and care by a physician .In multivariate analyses, lower GFR and care by a physician were independently associated with increased CKD recognition .Chronic kidney disease is a worldwide public health issue, with increasing prevalence and high morbidity and mortality rates. As a result, recognizing CKD and treating it early can lead to improved outcomes.In the present study, the rate of CKD recognition was high, probably due to the fact that our population was older with a lower baseline GFR, with significant comorbidities and with the GFR automatically included in the electronic medical records. Proteinuria, as recommended in the current guidelines was measured in most patients, likely due to the high prevalence of HTN and DM.These findings are in line with prior studies which demonstrated that assessing renal function with GFR  translates into increased CKD diagnosis. , 122), HTN, proteinuria and DM were prevalent in this population, with increased risks of end- stage renal disease and cardiovascular events. Despite this, 15%–30% of the patients were not recognized as having CKD. Furthermore, 20%–25% of patients with proteinuria were not diagnosed with CKD.Stage 3 CKD . Similarly, the importance of following GFR trends and the recognition of proteinuria as a marker of adverse renal and cardiovascular outcomes needs to be disseminated among primary care providers.The above actions could lead to increased testing and diagnosis of CKD, better blood pressure control, timely referral to Nephrology and better renal outcomes. To the best of our knowledge this is the first study assessing the primary care provider characteristics associated with CKD recognition. Limitations of this study include being a retrospective, single center study in a rural setting with a relatively small number of patients. Other shortcomings include the lack of histology and ultrasonography assessment, along with reliance on ICD-9 or ICD-10 codes for diagnosis of some cases of CKD. At the same time, we did not compare treatment decisions or outcomes of care among different providers or specialties.In conclusion, we have found that in this high-risk population, the odds of CKD being recognized were higher with physicians in comparison to non-physician providers


Positive end-expiratory pressure (PEEP) is a respiratory/ventilation procedure that is used to maintain or improve breathing in clinical and experimental cases that exhibit impaired lung function. Body fluid shift movement is not monitored during PEEP application in intensive care units (ICU), which would be interesting specifically in hypotensive patients. Brain injured and hypotensive patients are known to have compromised cerebral blood flow (CBF) autoregulation (AR) but currently, there is no non-invasive way to assess the risk of implementing a hypotensive resuscitation strategy and PEEP use in these patients.The advantage of electrical bioimpedance measurement is that it is noninvasive, continuous, and convenient. Since it has good time resolution, it is ideal for monitoring in intensive care units (ICU). The basis of its future use is to establish physiological correlates. In this study, we demonstrate the use of electrical bioimpedance measurement during bleeding and the use of PEEP in pig measurement.2 inhalation. The total measurement time was 4.12 hours.In an anesthetized pig, we performed multimodal recording on the torso and head involving electrical bioimpedance spectroscopy (EIS), fixed frequency impedance plethysmography (IPG), and bipolar  measurements and processed data offline. Challenges (n=16) were PEEP, bleeding, change of SAP, and COSystemic circulatory results: Bleeding caused a continuous decrease of SAP, cardiac output (CO), and increase of heart rate, temperature, shock index (SI), vegetative - Kerdo index (KI). Pulse pressure (PP) decreased only after second bleeding which coincided with loss of CBF AR. Pulmonary arterial pressure (PAP) increased during PEEP challenges as a function of time and bleeding.EIS/IPG results: Body fluid shift change was characterized by EIS-related variables. Electrical Impedance Spectroscopy was used to quantify the intravascular, interstitial, and intracellular volume changes during the application of PEEP and simulated hemorrhage. The intravascular fluid compartment was the primary source of blood during hemorrhage. PEEP produced a large fluid shift out of the intravascular compartment during the first bleeding period and continued to lose more blood following the second and third bleeding. Fixed frequency IPG was used to quantify the circulatory responses of the calf during PEEP and simulated hemorrhage. PEEP reduced the arterial blood flow into the calf and venous outflow from the calf.Head results: CBF AR was evaluated as a function of SAP change. Before bleeding, and after moderate bleeding, intracranial pressure (ICP), REG, and carotid flow pulse amplitudes (CFa) increased. This change reflected vasodilatation and active CBF AR. After additional hemorrhaging during PEEP, SAP, ICP, REG, CFa signal amplitudes decreased, indicating passive CBF AR. 1) The indicators of active AR status by modalities was the following: REG , CFa , and ICP ; 2) CBF reactivity was better for REG than ICP; 3) REG and ICP correlation coefficient were high (R2 = 0.81) during CBF AR active status; 4) PRx and REGx reflected active CBF AR status. CBF AR monitoring with REG offers safety for patients by preventing decreased CBF and secondary brain injury.We used different types of bioimpedance instrumentation to identify physiologic responses in the different parts of the body (that have not been discussed before) and how the peripheral responses ultimately lead to decreased cardiac output and changes in the head. These bioimpedance methods can improve ICU monitoring, increase the adequacy of therapy, and decrease mortality and morbidity. PEEP is a respiratory/ventilation procedure that is used to maintain or improve breathing in clinical and experimental cases that exhibit impaired lung function. PEEP has been applied to such cases, including, acute respiratory distress syndrome (ARDS) , stroke The application of PEEP first affects the lungs and pulmonary system. PEEP increases lung volume, alveolar recruitment, and lung compliance thereby reducing the work of breathing . The incAs stated by : “The efDetailed descriptions of the effects of PEEP on individual physiologic systems are given in the Deranged Physiology series  of cliniShekerdermian and Bohn  have proHemorrhage is a leading cause of death in both civilian and military trauma , 16, 17.Continuous monitoring of hemodynamic, autonomic, and/or metabolic responses may provide earlier recognition of hemorrhage than standard vital signs and allow interventions before the onset of hypovolemic shock . The ShoHemorrhage and PEEP is not only a CBF manipulation but also triggers a change in body water compartments (intra-and extra-cellular and vascular fluid shift) which can be measured by BIS non-invasively. The EIS  used in this study, combines a fixed frequency Impedance Plethysmograph [IPG] and a multi-frequency electrical impedance spectrograph (EIS) into one unit. The IPG mode was used to quantify the total segmental conductive volume and associated circulatory parameters . The EISEarly bioimpedance research began with thoracic [cardiac] measurements, which were soon followed by measurements of brain circulation. The term “rheoencephalography” was first used by Jenkner to refer to this technique and more recently the Food and Drug Administration definition has been stated that “A rheoencephalograph is a device used to estimate a patient’s cerebral circulation by electrical impedance methods with direct electrical connections to the scalp or neck area” . The ori2 inhalation, Trendelenburg position, carotid occlusion, and hemorrhage. The REG pulse amplitude relationship to cerebral blood volume was previously documented in humans with the radio-iodinated human serum albumin method during CO2 inhalation  CPP=SAP-ICP . PEEP wiPEEP is applied during the end of expiration to maintain the alveolar pressure above atmospheric pressure. PEEP is different from continuous positive airway pressure (CPAP) because this one refers to a positive pressure maintained during the inspiration and expiration phase of spontaneous ventilation. The benefit of PEEP has been demonstrated in terms of preventing cyclic opening and collapsing alveoli in acute respiratory distress syndrome patients (ARDS). Moreover, protective ventilation, even in noninjury lungs, should be considered such as during the perioperative period aiming to prevent collapsing of alveoli. However, applying PEEP may affect cardiac function and vital organ perfusion by complex mechanisms. To minimize the adverse effects of PEEP in the intensive care unit and in the operating room, better knowledge and understanding of the interaction between heart, lung, and brain during applying PEEP are required . In the 2), temperature, respiration, carbon dioxide (CO2) methods. Bedside monitors show these traces and calculate numerical values. A ventilator is a separate device in which several respiratory variables are needed to set up, such as PEEP pressure, volume, frequency, etc. Additionally, in neurocritical care, invasive monitoring is ICP, laser Doppler flow (LDF), brain O2/temperature, quantitative CBF; noninvasive monitoring is near-infrared spectroscopy (NIRS), electroencephalogram (EEG), transcranial Doppler (TCD). For details see . About 20–25% of patients with brain injury developed ARDS, which was associated with high mortality. Guideline for mechanical ventilation in ARDS recommended low tidal volume and moderate to high levels of PEEP. Nevertheless, the use of PEEP in brain injury led to an increase in intrathoracic pressure, impeded venous return, and reduced cerebral venous drainage from superior vena cava. Finally, these effects induced high ICP and CPP. However, in clinical studies, these effects occurred only when applying PEEP more than 15 cm Hpatients . Higher patients . NB: thepatients , 75. A rpatients . It can 2 inhalation; REG correlated well (AUC= 0.84 with p<0.0001) to laser Doppler flow during CO2 inhalation [It was demonstrated that BOLD MRI can reflect an early impairment of cerebrovascular reserve after aneurysmal subarachnoid hemorrhage . Since Rhalation .The clinical importance of these findings is that REG can be measured more conveniently and continuously in humans than Doppler ultrasound. Therefore, the measurement of CBF AR by REG has the potential for use as a life sign monitoring modality in neurocritical care units as well as in the military environment.Additionally, to civilian cases, military medicine offers practical use for bioimpedance, since the dominant cause of death is hemorrhage and TBI , 81, 82.In civilian clinical practice, invasive SAP and ICP monitoring are typically used to detect the status of CBF AR. However, in military medical practice, these invasive modalities cannot be used during the transport of injured, deployed military personnel. Moreover, in military medical practice, resuscitation techniques used to treat injured service members on the battlefield can result in the unintended consequence of secondary brain injury. After brain/blast injury cerebral vascular reactivity (CVR) can be lost, which is a bad prognosis. In the absence of the ability to maintain cerebral perfusion, a state of hypotension results in significant ischemia and secondary brain injury. Currently, however, there is no way of assessing the risk of implementing a hypotensive resuscitation strategy in a patient suspected of having traumatic brain injury , 87, 89.Traumatic brain injury is a frequent component of the combat casualty's injury profile in addition to hypovolemic hypotension. Furthermore, disruption of CBF AR has been recently associated with poorer outcomes, however, currently; there are no non-invasive approaches to evaluate the status of cerebral autoregulation. A major diagnostic limitation for the blast-induced head-injured patient is the inability to image the cranium using MRI due to the possibility of embedded metal fragments from improvised explosive devices. Additionally, CT angiography sometimes fails to detect vasospasm due to the associated metal artifact. Based on previous results, REG seems to be a practical noninvasive and continuous monitoring modality of traumatic brain and blast injuries, since REG signal seems to be insensitive to the presence of metal fragments . REG monWe used multiple invasive and noninvasive procedures to present an integrated sequence as to how PEEP affects the different regions/organs of the body – at three levels of PEEP after bleedingIllustrated how different bioimpedance measurements can provide a fuller characterization of physiologic responses to clinical and environmental stress - bipolar to monitor cerebral circulation, the fixed frequency at 50KHz to measure total segment volume and hemodynamic state, impedance spectroscopy to quantify fluid compartment volumes, and fluid transfer between compartments. Lastly, (perhaps) calculation of phase angle and/or cell membrane capacitance to investigate cell hydration.Identified those methods/parameters that can best be used during bedside monitoring and for research.We demonstrated that the use of PEEP in brain-injured and hypotensive patients is safe only if CBF AR is monitored.REG indicated the point at which CBF AR is lostThe use of the Shock and Kerdo indices can quantify cardiovascular and autonomic stress responses before vital signs are abnormal.Guide for Care and Use of Laboratory Animals, NRC Publication, 2011 edition. This work was supported by the U.S. Army Medical Research and Materiel Command (D43_0025_2005_WRAIR) and SBIR Grants (1 R43 HL074524-01 and 2 R44 HL074524-02A2).Material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the author and are not to be construed as official, or as reflecting trueviews of the Department of the Army or the Department of Defense. The research was conducted under an approved animal use protocol in an AAALAC International-accredited facility in compliance with the Animal Welfare Act and all other federal statutes and regulations relating to animals and experiments involving animals and adheres to principles stated in the