This study aimed to explore the association between cerebral hemodynamic parameters focused on the critical closing pressure (CCP) and enlarged perivascular spaces (EPVS).Cerebral blood velocity in the middle cerebral artery (MCAv) and non-invasive continuous blood pressure (NIBP) were measured using a transcranial Doppler (TCD) and Finometer, followed by the calculation of cerebral hemodynamic parameters including CCP, resistance area product (RAP), pulsatility index (PI), and pulse pressure (PP). EPVS were graded separately in the basal ganglia (BG) and centrum semiovale (CSO), using a visual semiquantitative ordinal scale. Patients with EPVS >10 were classified into the severe BG-EPVS group and severe CSO-EPVS group, and the remainder into the mild BG-EPVS group and the mild CSO-EPVS group. Spearman’s correlation and binary logistic regression analysis were performed to analyze the relationship between hemodynamic parameters and BG-EPVS and CSO-EPVS, respectively.p < 0.05). There was no statistical difference in hemodynamic parameters between the severe CSO-EPVS group and the mild CSO-EPVS group. Spearman’s correlation analysis showed that CCP was positively associated with BG-EPVS  and CSO-EPVS . The binary logistic regression analysis showed that CCP was independently associated with severe BG-EPVS (p < 0.05) and not with CSO-EPVS (p > 0.05) after adjusting for confounders.Overall, 107 patients were enrolled. The severe BG-EPVS group had higher CCP, mean arterial blood pressure (MABP), systolic blood pressure (SBP), and diastolic blood pressure (DBP) than that in the mild BG-EPVS group (CCP representing cerebrovascular tension was independently associated with BG-EPVS. EnlargeNumerous recent studies have underlined the importance of cerebral vascular hemodynamics in the pathophysiological mechanisms of EPVS, specifically pulsatility index (PI) , cerebroCritical closing pressure (CCP) is an index of cerebral vascular tone, defined as the lowest arterial blood pressure at which vessels collapse and flow ceases, reflecting the degree of contraction and diastole of vascular smooth muscle , 16. CCPTherefore, this study was conducted to explore the relationship between cerebral hemodynamic parameters focused on CCP, PI, and EPVS.2.2.1.Between February 2022 and December 2022, this study collected data on 125 consecutive CSVD patients without acute cerebrovascular events who were admitted to the Neurology Department of the Second Affiliated Hospital of Guangzhou Medical University.The inclusion criteria were as follows: 1. aged ≥45, 2. patients with CSVD evaluated by MRI in accordance with the guidelines for reporting vascular abnormalities on neuroimaging (STRIVE) . The exc2.2.Ethical approval for this study was granted by the Clinical Research and Application Ethics Committee of the Second Hospital of Guangzhou Medical University according to the ethical standards outlined in the Declaration of Helsinki. Written informed consent was acquired from all participants or their authorized representatives before enrollment.2.3.On admission, experienced neurologists conducted face-to-face consultations to collect information. General demographic information (including age and gender), vascular risk factors , laboratory tests  were acquired. Smoking was the history of ever smoking (yes/no). Drinking status was divided into drinking and never drinking. Hypertension was defined as a history of hypertension, taking antihypertensive treatment, or documented elevated blood pressure (systolic ≥140 or diastolic ≥90 mmHg). Diabetes mellitus was defined by self-report or history of treatment for diabetes with diet, insulin, or oral hypoglycemic agents , 24. Cer2.4.MR imaging of the brain for all subjects was performed on a 1.5 T MRI Achieva scanner  equipped with an 8-channel phased array head coil. Sequences included axial diffusion-weighted imaging (DWI), T1-weighted, T2-weighted, and fluid-attenuated inversion recovery (FLAIR). The following parameters were applied to DWI , T2-weighted , FLAIR , and T1-weighted sequences : field of view (FOV), 250 × 250 mm; matrix size, 256 × 256; slice thickness, 5 mm; interslice gap, 1 mm.Structural image analysis of CSVD features, including WMH, lacunes, and EPVS, was performed according to the STRIVE criteria . All MRI2.5.EPVS were defined as ≤2 mm round or linear cerebrospinal fluid-isointense lesions (T2 hyperintense and T1/FLAIR-hypointense with respect to the brain) along the course of penetrating arteries . EPVS dePatients with BG-EPVS >10 were classified into the severe BG-EPVS group  and the 2.6.Patients completed hemodynamic monitoring in a constant temperature- and noise-controlled clinical investigation room. The participants were instructed to abstain from coffee, alcohol, and physical exercise for a minimum of 12 h and to abstain from chocolate and larger meals for a minimum of 4 h before the measurement. Cerebral hemodynamic monitoring was performed with blinding clinical information by a physician specializing in neurovascular ultrasound. In order to make sure that cerebral hemodynamic parameters were accurate, participants rested for 15 min while the equipment was put on.p values to the level of heart, and continuous cerebral blood velocity was recorded with transcranial Doppler ultrasound  from the middle cerebral arteries (MCAs) using 2 MHz probes secured in place with a head-frame to maintain the optimal position and angle. The blood velocity of the middle cerebral artery (MCAv) signal was identified using established standards. The middle cerebral artery blood velocity signal was recognized by established criteria based on wave characteristics, signal depth, and the velocity constant throughout the testing session (Non-invasive continuous beat-to-beat blood pressure (NIBP) was recorded using a servo-controlled plethysmograph  attached to the middle finger of the left hand, with a brachial cuff to correct B session , 29. In A self-developed software processed the digital signals offline. We selected waveforms of NIBP and MCAv in 6 continuous cardiac cycles (that at least covered one respiratory cycle). The cross-correlation function was used to align pressure and flow velocity curves to remove possible time lags. Pulse pressure (PP) was computed as systolic blood pressure (SBP) minus diastolic blood pressure. The pulsatility index was calculated by PI = (Vs–Vd)/Vm. CCP and resistance area product (RAP) were calculated using the equation proposed by PANERAI .The peak systolic velocity (Vs) was calculated as the mean of all peaks in the flow velocity curve corresponding to complete cardiac cycles. The diastolic velocity (Vd) was defined as the average of all troughs in the flow velocity curve corresponding to complete cardiac cycles. For each cycle, the mean blood velocity through the MCA (Vm) and mean arterial blood pressure (MABP) were determined. Vm was defined as the mean blood flow velocity over all complete cardiac cycles in the flow curve. The bilateral parameters were calculated independently, with data reported for the side with the higher CCP.2.7.The Shapiro–Wilk test was performed to determine the normality of data distribution. Categorical variables were reported as the rate (percentage). Continuous variables with a normal distribution were characterized as mean ± standard deviation (SD), while those that were non-normally distributed were presented as the median (interquartile range). The independent sample t-test, Mann–Whitney U test, or chi-square test were used to compare the differences between the severe BG-EPVS group vs. the mild BG-EPVS group and the severe CSO-EPVS group vs. the mild CSO-EPVS group.Spearman correlation analysis was performed to observe the correlation between hemodynamic parameters and EPVS. Grouping was considered as the dependent variable, and binary logistic regression analysis was performed to explore which hemodynamic parameter  was independently related to EPVS after adjusting for confounding factors.p-values <0.05 were considered as significant.Statistical analyses of the data were performed using SPSS software version 25.0 . Two-tailed 3.3.1.A total of 125 participants without an acute cerebral event were enrolled; 107 participants completed the cerebral hemodynamics monitoring with complete and fully analyzable data. In this study, 11 participants were excluded because their imaging quality was insufficient (due to movement artifacts) to identify CSVD markers, and 7 people were excluded because they had poor Doppler envelopes.p = 0.002), a history of diabetes , and higher blood HbA1c levels  compared with the mild group. There were no differences observed for the remaining clinical features. In terms of imaging characteristics, the group with severe BG-EPVS showed more severe WMHs [Fazekas score: 3 . This trend indicated that they are common imaging features of cerebral small vessel disease.p = 0.003) and the proportion of current smoking in the severe CSO-EPVS group were higher than in the mild CSO-EPVS group . There were no differences in the proportion of men, diabetes, and the levels of laboratory tests. However, imaging characteristics between the severe CSO-EPVS group and the mild CSO-EPVS group still showed the same trend with statistically significant differences [Fazekas score: 3  vs. 2  vs. 2 , 3, p = 3.2.Vs, Vd, and Vm between the severe BG-EPVS group and the mild BG-EPVS. group.p < 0.001), SBP , DBP (mean 67.64 vs. 62.93 mmHg), and MABP (mean: 88.39 vs. 83.38 mmHg). When BG-EPVS was used as a continuous variable, Spearman’s rank correlation coefficient with CCP was 0.331 (p < 0.001), 0.217 (p = 0.025) with PI, 0.239 (p = 0.013) with SBP, 0.213 (p = 0.028) with DBP, and was 0.223 (p = 0.021) with MABP, while no correlation was found with RAP or PP. When performing binary logistic regression analysis, SBP, DBP, and MABP were excluded to avoid subsequent collinear problems. The results of the binary logistic regression analysis showed that CCP was independently related to BG-EPVS after adjusting for sex, age, diabetes, HbA1c, WMHs, and lacunes. The detailed analysis results are shown in The severe BG-EPVS group had higher CCP  and 0.215 (p = 0.026) with PI, while no correlation was found with RAP or PP. The results of the binary logistic regression analysis did not show any hemodynamic parameters independently associated with CSO-EPVS after adjusting for sex, age, smoking, WMHs, and lacunes. The detailed analysis results are shown in There was no statistical difference in hemodynamic parameters between the severe CSO-EPVS group and the mild CSO-EPVS group. When CSO-EPVS was used as a continuous variable, Spearman’s rank correlation coefficient with CCP was 0.193  and CSO-EPVS . Another5.This study identified an independent association between CCP and BG-EPVS and provides a new perspective for studies on the pathogenesis of EPVS.6.There are several limitations in this study. Firstly, the causal relationship between CCP and EPVS in basal ganglia could not be determined according to this observational study. It is needed for longitudinal research to further understand the correlations identified in our study. Secondly, the sample size of the severe CSO-EPVS group was relatively small (n = 28), which may have affected the statistical validity of the multivariate analyses. Thirdly, CCP cannot be evaluated directly because, in most clinical conditions, arterial blood pressure does not fall to the extremes that produce circulatory arrest. Prior studies relied on estimations derived from linear assumptions rather than real CCP . Future The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving humans were approved by the Clinical Research and Application Ethics Committee of the Second Hospital of Guangzhou Medical University. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.JZ and WL designed the study protocol and drafted the manuscript. JC was involved in data quality control and statistical analysis. JZ and JC were involved in patient collection. QG revised the manuscript, conceptualization, methodology, project management, and funding acquisition. All authors contributed to the article and approved the submitted version.


In minor hand surgery, tourniquet is typically inflated to 250 mmHg. The pressure may be too high and cause unnecessary adverse effects. Limb occlusion pressure plus safety margin or recommended tourniquet pressure (RTP), has been reported as optimal pressure to provide bloodless field in limb surgeries. This study aimed to compare the RTP with the standard tourniquet pressure of 250 mmHg in minor hand surgery.A double-blinded randomized control trial was conducted from July to December 2019 and June 2020 to May 2021. Patients were randomly assigned into two groups: RTP and 250 mmHg with 3:1 ratio allocation. The outcomes were measurement of cuff pressure reduction, time to develop of tourniquet pain and discomfort, pain score, discomfort score, motionless and bloodless of operative field determined by the surgeon’s satisfaction.P < 0.001). Even though, time to develop pain was not significantly different, the RTP group reported significantly less pain and discomfort, according to the pain score (P = 0.02) and discomfort score (P = 0.017). The RTP group provided better motionless field, while both groups equally created a bloodless field.A total of 112 patients were included, 84 were in RTP and 28 were in 250 mmHg group. Mean of tourniquet pressure was significantly lower in the RTP group (228.3 ± 17.2 mmHg) .I. For limb surgeries, tourniquets are used to create a bloodless surgical field. Although the standard tourniquet pressure is commonly used, it may apply an amount of pressure that is higher than necessary and may cause some adverse effects . The mosTourniquet pain is a common complaint for patients in minor hand surgery, many anesthesia techniques, tourniquet position and even if necessity of tourniquet used have been proposed for alleviate this problem.The Wide-awake Local Anesthesia No Tourniquet (WALANT) technique has become increasingly popular in hand surgery. The benefit of this technique is the ability to assess the active movement during the operation such as flexor tendon repair or fracture fixation . AlthougAnother useful tourniquet technique is intravenous regional anesthesia or Bier block regional technique which could be performed for most upper extremity surgery, there switching of the tourniquet from the distal cuff to the proximal cuff that eliminates tourniquet pain after 20 min. The advantage of this technique is the procedure time can proceed for up to 90 min, thus there is more suitable for major operation. However, there is a challenging technique and require waiting time for pain subside compared with the minor surgery and some complication was reported of anesthetic toxicity after tourniquet released .Limb occlusion pressure (LOP) is the minimum pressure that can stop blood flow between the proximal and distal parts of the limb, which varies for each person. The LOP plus a safety margin, adding to prevent blood pressure fluctuation, can be used as the optimal tourniquet pressure or recommended tourniquet pressure (RTP) , 5, 6.Currently, a Doppler stethoscope is the gold standard to obtain the LOP , 7. LOP From previous studies, RTP can sufficiently maintain the quality of bloodless field during operations with lower pressure than standard tourniquet pressure , 5, 6. HA double-blinded randomized control trial was conducted at Ramathibodi Hospital from July to December 2019 and June 2020 to May 2021. Patients older than 20 years of age, with an RTP less than 250 mmHg, and who were diagnosed with de Quervain’s disease, trigger finger, carpal tunnel syndrome or carpal ganglion cyst  were included. Patients with bleeding diathesis and contraindications for tourniquets  [The demographic parameters of the patients, including sex, age, body weight, height, arm circumference (mid-point between shoulder and elbow joint), systolic blood pressure, LOP and RTP, were collected. Underlying diseases such as hypertension, diabetes and dyslipidemia were also recorded. The type of minor hand operation was also classified.Sample size determination was based on mean differences of visual analog scale (VAS) compared between LOP and standard tourniquet. Adding 20 percent of loss to follow up resulting in 116 patients to be included . The patThe LOP was measured for all the patients using automatic LOP measurement equipment  Fig. . The RTPTourniquet application guidelines were made to control the confounding factors that produced incapable results. The size of the tourniquet was determined by width of the cuff is more than half of arm diameter. Skin under the cuff was protected by 2 layers of 4-inch webril bandage. The cuff was applied on the upper arm which is widest part of the limb to allow as much tissue as possible to lie between the cuff and any nerves or vascular structures susceptible to damage. LOP pulse sensor was attached to the patient’s finger on the limb that the tourniquet has been applied. The corresponding LOP button on the equipment was started for LOP determination. The equipment calculated and displayed the LOP and RTP on the monitor screen approximately within 30 s then pulse sensor was detached from the patient’s finger.After the operative field was prepared with a sterile technique, 1% lidocaine without adrenaline was infiltrated over the incision site before tourniquet inflation, 2 ml for trigger finger and de Quervain’s release and 5 ml for carpal tunnel release and dorsal carpal ganglion excision. Limb was elevated and 3-inch elastic bandage was exsanguinated from fingers to proximal forearm. Tourniquet pressure was applied to the patient by assigned staff who opened the envelope. RTP was applied to the patients in the RTP group, and 250 mmHg was applied to the patients in the control group. The surgeons, well-trained Orthopaedic resident, was not informed about the amount of pressure applied to the patient.During the perioperative period, the total tourniquet time was noted. The patient was instructed to inform staff when pain or discomfort (tightness or tense) occurred at the tourniquet site. Time of pain or discomfort began (time to developed pain) were documented. Pain and discomfort were assessed using VAS separately .Tourniquet was deflated after wound closure and bandage. The surgeon was asked to complete a questionnaire to evaluate the quality and their satisfaction with the surgical field during the operation. The quality of the bloodless and motionless fields was scored as 1 = poor, 2 = fair, 3 = satisfied, and 4 = very satisfied. A poor field was defined as blood or motion occurring and making the operation impossible; a fair field was defined as blood or motion occurring but not significantly disturbing the operation; a satisfactory field was defined as blood or motion occurring with no disturbance to the operation; and a very satisfactory field had no blood or motion occurring. All adverse effects at the tourniquet site after the operation such as coldness, numbness and skin redness were also noted in the questionnaire. One week after the operation, pain, discomfort and adverse events were also monitored.P value < 0.05 was considered significant.All statistical analyses were analyses based on intention to treat analysis using STATA version 16.1 . Baseline characteristics and outcomes of interest were described based on the mean, median, standard deviation (SD) and percentage. Continuous variables between the two groups were compared, and the differences were analyzed with either unpaired t-test or Fisher’s exact test. For non-normally distributed variables, Mann–Whitney U test was used. One hundred and twelve patients were included in this study: 84 patients in the RTP group and 28 patients in the control group Fig. .Fig. 2COP < 0.001).For the outcomes of interest shown in Table The time to develop pain and discomfort was 8 min in the RTP group and 10 min in the standard 250 mmHg group. Although pain and discomfort occurred slightly quicker in the RTP group, the difference was not significant. Patients developed pain only 43% in the RTP group, while 61% of controls reported pain  (Table The RTP group reported significantly less pain and discomfort than the standard 250 mmHg group. The mean levels of pain and discomfort (VAS score) in the RTP group were 17.08 and 17.29, respectively, while those in the standard 250 mmHg group were 32.50 and 33.57, respectively (P = 0.049). However, there was no significant difference in the bloodless field between the two groups (P = 0.92). This study showed no conversion of the patients that had to move from RTP to the standard 250 mmHg group due to bleeding problem during surgery.Based on the surgeon’s satisfaction evaluation, the motionless field score in the RTP group was higher than that in the standard 250 mmHg group  with equal of the median between the two groups which was marginal significant difference (P = 0.8).Adverse effects at the tourniquet site were reported as coldness, numbness and skin redness immediately after the operation and at the one-week follow-up. However, there was no significant difference between the two groups  and also predict RTP from LOP. The formula was based on the recommended RTP prediction (Predicted RTP = Predicted LOP + Safety Margin). For predicted LOP = 63.41 + (0.31*age) + (0.65*BMI) + (0.42*SBP). Safety Margin was determined by plus 50 mmHg for LOP 90–130 mmHg, plus 75 mmHg for LOP 131–190 mmHg and plus 100 mmHg for LOP above 190 mmHg. This correlation is considered as the optional method to determine RTP when there is no LOP measurement equipment available.Tourniquet position for upper limb surgery have been debated between using arm and forearm tourniquet. The previous studies showed no significant difference in patient pain, physiological response, tourniquet time, bloodless field or length of operation. However, the arm tourniquet was less obstruction  while thThe strengths of this study were that it was a double-blinded randomized controlled trial, with balanced prognostic factors, well-controlled confounders and adequate sample size. However, there are couple limitations including subjectivity of the surgical field evaluation outcome and many surgeons responsible for the operation. Moreover, to measure the LOP the automatic equipment is required.In minor hand surgery, using LOP with safety margin to determine RTP as the tourniquet pressure can significantly reduce pain and discomfort, while providing enough pressure to create a high-quality surgical field. With limitation of requiring automatic equipment, the RTP still be a useful option to provide the optimal tourniquet pressure for minor hand surgeries.


Accurately measuring blood pressure (BP) is essential for maintaining physiological health, which is commonly achieved using cuff-based sphygmomanometers. Several attempts have been made to develop cuffless sphygmomanometers. To increase their accuracy and long-term variability, machine learning methods can be applied for analyzing photoplethysmogram (PPG) signals. Here, we propose a method to estimate the BP during exercise using a cuffless device. The BP estimation process involved preprocessing signals, feature extraction, and machine learning techniques. To ensure the reliability of the signals extracted from the PPG, we employed the skewness signal quality index and the RReliefF algorithm for signal selection. Thereafter, the BP was estimated using the long short-term memory (LSTM)-based neural network. Seventeen young adult males participated in the experiments, undergoing a structured protocol composed of rest, exercise, and recovery for 20 min. Compared to the BP measured using a non-invasive voltage clamp-type continuous sphygmomanometer, that estimated by the proposed method exhibited a mean error of 0.32 ± 7.76 mmHg, which is equivalent to the accuracy of a cuff-based sphygmomanometer per regulatory standards. By enhancing patient comfort and improving healthcare outcomes, the proposed approach can revolutionize BP monitoring in various settings, including clinical, home, and sports environments. Hypertension diagnosis is a common procedure in clinical practice, and its associated morbidity has doubled over the past decade . Thus, eTo mitigate the risks of high BP, physicians recommend behavioral and lifestyle changes with dietary control, appropriate nutrition, and quality sleep. Moreover, exercise aids in lowering BP, managing weight, and relieving mental stress. Although BP may be temporarily elevated after exercise, extreme fluctuations may indicate hypertension. Physiologically, systolic blood pressure (SBP) increases during exercise, whereas diastolic blood pressure (DBP) remains relatively stable. Therefore, controlling and monitoring BP during exercise is essential, especially during therapy.Cuff-based measurement paradigms have dominated ambulatory BP measurement for decades. However, the accurate measurement of BP during exercise is challenging owing to the complexity of modeling the physiological dynamics. Currently, cuffless sphygmomanometers are gaining prominence as they provide adequate accuracy and validity for measuring BP at rested conditions ,5,6. NonVarious biological applications of machine learning have been studied, such as individualized blood pressure control methods  and predAlthough a significant increase in systolic BP is a risk factor  and needTo date, various methods have been developed to estimate BP using cuffless sphygmomanometers, including the photoplethysmogram (PPG)-based cuffless sphygmomanometer that utilizes the PPG signal singularly or coupled with other biosignals, such as the electrocardiogram, phonocardiogram, impedance signal, and ballistocardiogram . An alteT1–3, which represents the variations in arterial PP. Conventionally, BP is estimated by analyzing the pulse peaks and parameters integrated within the PDA model [The pressure waveform obtained by applying the PDA and its second derivatives reveals the typical trend of PPG signals and the characteristics of their second derivatives in DA model ,17,18,19Lumped parameter models of the cardiovascular system are commonly employed in PDA to simulate the arterial BP waveform and wave propagation, wherein the SBP and DBP are fitted using the resistor impedance and capacitance. Thus, BP can be measured not only by a pressure sensor but also by r by analyzing the PPG waveforms as a reference. Herein, the second derivative of the PPG (SDPPG) signal was analyzed based on the amplitudes of waves a–e, which were produced during the systolic phase of the heart cycle  Figure . MoreoveHowever, as suggested in previous studies, physiological dynamics during physical exercise differ from that prevailing in the rest state ,22,23. FIn this study, the proposed BP estimation method involved signal preprocessing, feature extraction, and BP estimation; the processing procedure is illustrated as a flowchart in Data were collected from 20 young males . The age range of the participants was narrow because of the relatively high safety involved with young participants during long-term exercise. For reference, the SBP, DBP, and PPG were measured sequentially using a voltage clamp-type continuous BP monitor . CNAP is based on the vascular unloading technique. It is the basic principle for detecting blood volume changes in the finger and transforming plethysmographic signals into continuous blood pressure information. Blood pressure can then be calculated beat-to-beat, after calibration with the built-in standard oscillometric measurement (NBP) of the monitor. From these protocols, the gap between intermittent NBP and continuous invasive blood pressure is bridged. Before and after the experiments, a cuff-based sphygmomanometer  was used to measure the SBP and DBP for further reference.The experiment consisted of three parts. After sitting on an ergometer , the subjects initially rested for 20 min, followed by exercise with the ergometer for another 20 min at 80 W and 50 rpm; after this, the subjects were allowed to recover for 20 min. Due to the challenges related to measurement, peri-exercise has received less investigation as an effective method for inducing significant variations in blood pressure. To the best of our knowledge, this is one of the few studies dedicated to cuffless BP estimation during exercise ,25. The s report .During the preprocessing, a skewness signal quality index (SSQI) was applied to each PPG signal. As motion artifacts can affect the PPG signals during exercise, the signal quality must be appropriately annotated. The increased skewness of the PPG signals revealed a detailed morphology of the pulse waveform . Therefoσ denote the empirical estimate of the mean and standard deviation of ix, respectively, and N indicates the number of samples in the PPG signal. The SSQIs were calculated for each PPG signal.Skewness is a measure of the symmetry (or lack thereof) of a probability distribution, defined as follows:The distribution of each SQI within a given subset exhibited significant variability, making a simple fixed threshold inadequate for optimal classification. A linear support vector machine (SVM) was utilized as the classifier, and each annotator annotated the PPG signals based on the most dominant PPG signal. Our primary focus was to determine the optimal SQI for which a simple classifier with a fixed threshold would be satisfactory. However, there were variations in the distribution of each SQI, making a simple fixed threshold unsuitable as an optimal classifier. Consequently, the robust SQIs were determined for each phase. Z-score techniques and obtaining the amplitude-limited data.M and SD, respectively, denote the mean and standard deviation of the feature value iy, and n indicates the number of samples. To extract information from the signal, all signals were normalized using the The 17 features presented in After feature extraction, the feature matrix was trained using machine learning algorithms. The analysis was performed in three phases: rest, exercise, and recovery. The LSTM layer, designed for sequence learning, proves effective in estimating BP . In thisMAE), root mean square error (RMSE), and standard deviation (STD) were evaluated from the experiments.To measure the error from the models used in the experiments, mean absolute error .R):Correlation coefficient . In particular, a higher rejection rate for high-error signals and a lower MAE were achieved. As such, daily BP monitoring requires considerable care when attaching a PPG sensor. Motion artifacts during exercise affected the PPG measurement. The E can be expressed as follows:r0 denotes the end-diastolic radius, h0 indicates wall thickness, Δp represents pulse pressure, and Δh denotes the variation in thickness per cardiac cycle [The heightened cardiac pulse during exercise expands the arterial wall which then decreases the thickness of the arterial wall depending on arterial stiffness. We assumed that the arterial wall is incompressible, isotropic, and exhibits no strain in the axial direction. Accordingly, the elasticity ac cycle ,32.The second peak corresponded to the lower elasticity, which altered the pulse pressure and wall thickness. During exercise, the first peak corresponds to a large pulse pressure and thinner wall thickness, which bears a lower elasticity. As the second peak corresponds to the reflected wave, the second peak is typically lower owing to the lower elasticity . A typicThe Bland–Altman plot of SBP error indicated a systemic error. Although the range of the systolic BP was extremely narrow, the error between the reference and estimated BPs was linear. The time course of BP at three distinct epochs is depicted in Automated sphygmomanometers, which are currently widely used, are compliant with resting state  and blood pressure variation .According to the above standards, the resting accuracy of automated sphygmomanometers is defined as within ±5 ± 8 mmHg (±mean ± standard deviation), and the blood pressure estimation accuracy required for cuffless sphygmomanometers is also considered to meet this standard.The device used as a reference in this study  calibrates the blood pressure curve using NBP approved by ISO81060-2 (NBP), and the accuracy of continuous blood pressure has been confirmed.The errors of the proposed method for systolic blood pressure are 0.50 ± +/− 7.19 mmHg, 0.32 ± 7.76 mmHg, and −0.48 ± 7.55 mmHg (±mean ± standard deviation) for resting, exercise, and recovery periods, respectively; for diastolic blood pressure, 0.39 ± 5.48 mmHg, −0.91 ± 7.15 mmHg, and −1.77 ± 6.94 mmHg (±mean ± standard deviation) at rest, during exercise, and during recovery, respectively. The accuracy was confirmed to follow the accuracy set by ISO standards.Although the accuracy of the proposed method meets the accuracy of a cuff-type automated sphygmomanometer, there are still issues to be addressed regarding the clinical application of the proposed method. The small number of subjects is one of them. Since the waveform shape used in this study varies with gender and age, it is necessary to verify the method in a wide subject population in the future. In particular, when applied to detect blood pressure fluctuations in diseased groups, it is possible that a change trend different from that of the young adults targeted in this study may occur.In summary, we proposed a novel waveform-based LSTM model for continuous blood pressure estimation using PPG waveforms. The proposed model extracted the essential features and captured the temporal variations, yielding BP measurement accuracies that satisfy the existing regulatory standards. The present study addresses the need for noninvasive and accurate blood pressure monitoring during exercise, providing a potential solution for improving patient comfort and healthcare outcomes.The research demonstrates the feasibility of utilizing machine learning algorithms to analyze PPG signals for blood pressure estimation, demonstrating the effectiveness of the proposed model. The proposed method will aid in the development of cuffless blood pressure monitoring devices, offering a noninvasive and accurate alternative to traditional cuff-based sphygmomanometers.Note that the limitations of this research include the small sample size and the need for validation in larger cohorts to ensure generalizability and reliability of the proposed model. Thus, in the future, research should focus on refining the model and exploring its performance in diverse populations as well as investigating its integration into wearable devices for real-time blood pressure monitoring.


Blood pressure management is a critical aspect of patient care, particularly in surgical and critical care settings. Closed-loop systems, which utilize real-time data and feedback to adjust treatment interventions, have gained attention for their potential to enhance blood pressure control. This review explores the application of closed-loop systems in blood pressure management. We discuss various closed-loop approaches, including their mechanisms, benefits, and limitations. By harnessing real-time patient data and feedback, closed-loop systems can tailor interventions dynamically, thus enhancing blood pressure regulation. Additionally, we examine the integration of advanced monitoring technologies and artificial intelligence algorithms in closed-loop systems. The review highlights recent studies and their findings, emphasizing the evolving landscape of closed-loop blood pressure management across different clinical scenarios. From the perioperative period to critical care settings, closed-loop systems hold the potential to optimize patient outcomes by precisely adjusting vasopressor administration in response to continuous blood pressure fluctuations. By providing insights into the current state of closed-loop systems for blood pressure control, this review offers a comprehensive overview of their potential contributions to improved patient outcomes and future directions for research and implementation. With the advent of autonomous systems, a lot of research has been dedicated to the development of closed-loop self-driving systems for drugs to maintain blood pressure (BP).Normal human physiology tends to self-regulate blood pressure by reflexes mediated by hemodynamic centers in the brain stem. This mechanism is disrupted in pathological states such as traumatic brain injury, critical illness, or states of controlled physiology such as under general anesthesia.Organ and tissue perfusion depends on the flow of blood and the pressure gradient between the afferent ) and efferent vessels (tissue venous pressure). For any given state, therefore, tissue perfusion is proportionate to MAP. Exceptions to this rule exist, for example, coronary artery perfusion which depends on aortic diastolic pressure. Reduced MAP leads to tissue ischemia and increased MAP can cause bleeding. To prevent these, rapid in vivo control of blood pressure is mediated by the autonomic nervous system Figure , so nameHaving a closed-loop autonomic system to maintain blood pressure allows for a far better beat-to-beat control of BP. These machines are better at observing and analyzing biodata and are robust at interventions as per their programming. Additionally, they are non-fatigable. Physicians looking after patients are also free to focus on other aspects of care.Design of a biological system to maintain blood pressureMean arterial pressure (MAP) is a product of blood flow (cardiac output (CO)) and systemic vascular resistance (SVR).MAP = CO * SVRTo maintain MAP in an optimum range, either CO or SVR must be altered. In general, CO is dependent on contractility and end-diastolic volume i.e., inotropy and pre-load. Pre-load depends on a person’s circulating volume. Systemic vascular resistance depends on vascular tone which is activated by endogenous catecholamines. In disease, the body’s ability to maintain these are affected. Physicians in the emergency department, perioperative care, and critical care departments play an important role in regulating acute changes in a patient’s blood pressure.Vasoactive pharmacologic agents act on the peripheral vessels to increase vascular tone (vasopressor) or reduce it (vasodilator). If CO remains the same, MAP is directly proportional to SVR. A basic control system to control SVR would thus be as shown in Figure In a closed loop, a controller observes specific system variables and provides corresponding interventions to regulate the system, following a predefined algorithm. Furthermore, the system Figure  should rThe necessity of closed-loop blood pressure managementThe Clinical SettingBlood pressure allows adequate driving force for organ perfusion. Normotension is necessary to maintain an adequate homeostatic environment for cellular processes to function. Low blood pressure reduces perfusion thereby disrupting the supply and clearance of vital substrates and oxygen to cells causing apoptosis. On a tissue level, ischemia results causing organ dysfunction, which if left unchecked can cause gangrene. Normal homeostatic processes maintain blood pressure in an awake, non-diseased individual. The same individual has limited capability to control their BP under disease state or under anesthesia including general and neuraxial. Timely BP management thus plays a vital role in the perioperative period to improve surgical outcomes as well as during critical illness in the ICU. Disturbed physiology causing impaired regulation of BP also occurs in accidents and trauma victims arriving in the emergency. Hypotension has been associated with organ dysfunction and adverse myocardial, cerebral, and renal outcomes ,4.The ProviderEmergency physicians, anesthesiologists, and critical care physicians look after patients who may develop hypotension or hypertension and associated organ dysfunction during their hospital stay. These providers in addition need to assess, administer, treat, and monitor a wide variety of parameters such as oxygen saturation, fluid balance, electrolyte disturbances, pain control, sedation, and interpersonal communication. Automation of tasks can enable physicians to prioritize other tasks and improve patient outcomes. Additionally, autonomous systems are better at observing, calculating, and dosing and are less prone to human error. Additionally, they are non-fatigable.In this review, we will focus on the use of closed-loop blood pressure management systems in the perioperative period and critical illness period.Basic requirements of closed-loop control of BP managementEffective beat-to-beat control of a patient’s BP requires 1) a monitor capable of beat-to-beat measurement and display of blood pressure ; 2) A pathological state causing BP changes secondary to changes in vasomotor tone with minimal influences from circulating volume and inotropy; 3) Either boluses or continuous Infusion of rapidly titratable vasopressor or vasodilator medications (Fast onset and short duration).Early studies using closed-loop systems for BPR.V. Jackson and colleagues described in 1977 how a controlled infusion of sodium nitroprusside was used to treat otherwise refractory malignant hypertension . They usR = K1 + K2eR: Rate of infusionK1: Infusion rate corresponding to desired mean blood pressure when stable control has been achievedK2: Constant of proportionality or gain. e: Error term which represents the difference between the desired blood pressure and the actual blood pressure (mmHg)As per the terms described above, the desired target of the algorithm was that K2e should approach zero thus allowing R to equal K1. The microprocessor was an 8-bit device. Its instructions were altered by way of a visual display unit (VDU) or teletype. The teletype allowed the generation or loading of paper tape programs. Programming was in machine code. The digitized mean BP was loaded into a memory register every two seconds via a microprocessor input/output port. Comparison of actual BP with desired BP allowed “e” to be calculated.Initially, an approximate value of K1 was entered into the control algorithm. K1 was incremented or decremented after each BP sample, depending on whether the BP exceeded or not attained the desired value.In this case, the blood pressure was maintained around the target range. Brief interruptions of sodium nitroprusside (SNP) infusion were done to evaluate if a patient would respond to oral anti-hypertensive therapy. Thiocyanate concentrations were measured as an index of toxicity. After six days, blood pressure control was maintained with oral therapy alone.The above-described successful management of malignant hypertension with SNP and successful transition to oral therapy was performed with a microprocessor system whose minimal requirements were a pressure transducer and amplifier, a microprocessor, a teletype, and a visual display unit Figure .With the improvement of microprocessor technology, more robust systems were developed in the coming years focused on BP control.Yasuhiro Fukui and colleagues conducted two experiments - one using a hybrid computer model and the second using six dogs, using increasing or decreasing halothane concentration to control MAP using a discrete digital control system . The delIn the modern age, systems have advanced to the point of incorporation of artificial intelligence (AI) and machine learning to be far more robust and capable of analyzing multiple patient parameters so as to even predict hypotension before it occurs ,8.Use of closed-loop vasopressor systems in the perioperative periodIntraoperative hypotension is commonly observed during surgical procedures and is likely to exert a negative influence on postoperative outcomes -11. SeveNotably, a multicentre randomized controlled trial by Futier et al. demonstrated a promising approach to mitigate these risks . Their sAchieving an ideal balance of flow and pressure involves ongoing assessment of these factors and adhering to established protocols for administering vasopressors and fluids. This approach, known as "individualized hemodynamic management," has demonstrated a clear advantage over standard care by reducing postoperative complications . Additionally, hypotension emerges as a delayed clinical signal of underlying hemodynamic instability after exhaustion of compensatory mechanisms. To tackle these challenges, the integration of artificial intelligence has emerged as a solution to facilitate the early identification of hypotension and, in certain scenarios, even predict its occurrence to support prompt interventions. Machine learning, a discipline of computer science dedicated to analyzing extensive datasets and developing predictive models, exhibits clear relevance within the realm of healthcare. Employing artificial intelligence to forecast hypotension based on hemodynamic data represents an innovative and captivating strategy. TM Hypotension Prediction Index (HPI) software, developed by Edwards Lifesciences in Irvine, CA, USA, employs artificial intelligence, specifically machine learning techniques, to predict hypotension based on distinctive features found within blood pressure waveforms [The Acumenaveforms ,8. The Haveforms . Computeaveforms ,20,21. IA study, conducted by Ribeiro Marques and colleagues, described a new approach to managing blood pressure . They usClosed-loop vasopressor system and its role in obstetricsTwo earlier trials provided data comparing the use of automated closed-loop systems for administering vasopressors (phenylephrine or ephedrine) with manual control in patients scheduled for elective cesarean sections under spinal anesthesia ,25. In tNgan Kee et al. compared the performance of two different closed-loop techniques (boluses versus continuous infusion) for the administration of phenylephrine . 214 heaHence, data from these trials suggest that arterial blood pressure is controlled better with a closed-loop system. Typically, these systems utilize non-invasive blood pressure measurements to calculate phenylephrine infusion rates during the perioperative period, but they are limited by the influence of movement and shivering artifacts on blood pressure readings. In the future, research should explore innovative methods to predict patients susceptible to spinal hypotension, enabling the customization of vasopressor treatments based on individual risk profiles.Closed-loop vasopressor system in moderate to high-risk surgeriesIn a first-in-man study, Joosten et al. developed a closed-loop vasopressor (CLV) controller Figure  to invesJoosten et al. also investigated the role of the CLV system, guided by continuous non-invasive blood pressure, in high-risk patients undergoing renal transplant surgery . In thisFurthermore, Joosten and his colleagues conducted a randomized controlled trial comparing automated closed-loop to manually controlled norepinephrine infusion . This stIndividualized hemodynamic management, formerly known as "goal-directed hemodynamic therapy," has displayed enhanced patient outcomes compared to standard care during major surgeries, as recently validated by two meta-analyses ,32. , JoRinehart et al. introduced a CLV controller to improve hypotension correction in postcardiac surgery patients . They hyWhile closed-loop vasopressor therapy has shown its effectiveness when targeting baseline mean arterial pressure (MAP), limited information exists regarding its performance when systolic arterial pressure (SAP) is the controlled variable. Therefore, Rinehart et al. conducted a prospective cohort feasibility study with 12 patients undergoing intermediate- to high-risk abdominal surgery . A compuClosed-loop vasoactive system in the critical care unitAs previously mentioned, vasopressor therapy plays a pivotal role in maintaining hemodynamic stability in critically ill patients. Vasopressors, such as norepinephrine and vasopressin, are frequently administered to maintain adequate perfusion and prevent organ failure. However, the manual titration of vasopressors is often limited by variations in clinical assessments and time-consuming adjustments, potentially leading to under- or overtreatment. Ideally, adjustments in vasopressor infusion rates should promptly correspond to fluctuations in blood pressure readings. Nevertheless, accomplishing such a finely tuned feedback loop poses challenges.Rinehart J. and his colleagues analyzed MAP data from 3623 patients (2530 from the ORs and 1093 from the ICU) who were on vasopressors. The coefficient of variations {=  *100} of MAP were 13.7 ± 5.4% and 18.4 ± 9.8% in the OR and ICU, respectively . PatientHigh-fidelity mathematical models are being developed to replicate the cardiovascular (CV) responses of a critically ill patient with vasoplegic shock-induced hypotension to vasopressor therapy. They can be incorporated into closed-loop control algorithms for autonomous vasopressor administration once it is extensively validated . Several studies have investigated the impact of closed-loop vasopressor administration on patient outcomes. Evidence suggests that closed-loop systems can lead to more stable hemodynamics, reduced variability in blood pressure, and decreased incidence of hypotensive and hypertensive episodes compared to manual titration. These systems have also been associated with shorter durations of vasopressor use and reduced healthcare resource utilization . In a prospective cohort study conducted by Rinehart J. et al., a comparison was made between the performance of a group of anesthesia providers and a closed-loop management system known as the Learning Intravenous Resuscitator (LIR). This study utilized a simulated hemorrhage scenario with cardiac output monitoring. The results demonstrated that the closed-loop system maintained more consistent hemodynamics compared to the practitioners. This was attributed to the closed-loop system administering fluids earlier in the protocol and optimizing cardiac output before the onset of hemorrhage. In contrast, the practitioners tended to initiate resuscitation only after substantial hemodynamic shifts indicated the necessity for intervention . A single-center, two-arm, parallel-group, randomized controlled superiority study concluded that closed-loop control of norepinephrine infusion significantly decreases postoperative hypotension compared to manual control in patients admitted to the ICU after cardiac surgery . Utilizing a fuzzy logic algorithm for closed-loop control, which restricts the amount of norepinephrine exposure, could potentially maintain the efficacy and reservoir of α1-receptors. As a result, this approach might contribute to reducing patient resistance toward norepinephrine infusion. Thus, a closed-loop system based on fuzzy logic algorithm results in the use of much lower norepinephrine doses during weaning in patients with septic shock and leads to a decrease in the duration of weaning duration . The MonMultiple internal fuzzy controllers can be structured in one system, each responsible for calculating the appropriate dosage of a medication. A system proposed by N. Sprunk et al. underwent testing within a simulation environment that mimics a canine cardiovascular system and its reactions to various medications . The vasAn automated closed-loop control system proposed by Wassar T. et al has demonstrated that it is able to keep MAP near target and its performance is superior to that of manual control of infusion . SimilarMaintaining hemodynamic stability in brain death (BD) donors is essential for preserving the quality of donated organs for transplantation. Manual stabilization is challenging due to the absence of vasomotor function in BD donors. Closed-loop stabilization offers a way to enhance the availability of suitable donor organs, indicating feasibility in less demanding patient populations. A dynamic model representing the pharmacology of nitroglycerine was identified using an experiment involving an anesthetized pig, employing a gradient-based output error approach for controller design. This model was then utilized to create a robust PID  controller aimed at preventing hypertension. The controller's effectiveness was assessed in a subsequent experiment involving another brain-dead pig. Simultaneously, hypotension was prevented through closed-loop control of noradrenaline infusion, utilizing a controller previously published in the literature. The study demonstrated the feasibility of the investigated modeling and control synthesis approach in maintaining normotension in a porcine BD model . A summaChallenges Despite promising results, closed-loop vasopressor administration faces several challenges. The study of cardiac function has not received as much attention when it comes to closed-loop pharmacologic interventions. This can be attributed to the unique nature of the physiological effects caused by cardiac medications, such as altering heart rate or boosting heart muscle contraction strength. Many of these effects are complex and don't follow a linear pattern, and they often reach a maximum limit even when the medication is administered at low rates. There have been only a few studies conducted with inotropes, and it's clear that more clinical research is required in this area. While blood pressure is crucial for end-organ oxygen delivery, it is important to consider that an adequate cardiac output (CO) is also an essential component. Overly constricting blood vessels can raise systemic vascular resistance and reduce end-organ blood flow. To prevent this "dry vasoconstriction," optimizing CO with fluids should be pursued in parallel to vasopressor therapy. Furthermore, a comprehensive arterial pressure management system would possess the capability to adjust all these factors using medications or similar methods. Considering the complex nature of these systems with multiple inputs and outputs, along with safety and regulatory considerations, it may take some time before such a system becomes widespread. Moreover, integration of various monitoring devices and compatibility with existing ICU infrastructure can be complex and costly. Algorithms need continuous refinement to accommodate patient heterogeneity and adapt to dynamic physiological changes. Furthermore, ethical considerations surrounding the delegation of clinical decisions to automated systems and potential algorithm errors require careful attention. A significant challenge in terms of control and application lies in the complexity and transparency of the algorithm. A straightforward physiological logic would make it easier for clinicians to comprehend how the system functions and its limitations. This enhanced understanding improves safety, ultimately aiding the process of regulatory approval .Closed-loop hemodynamic systems should serve as supportive tools for clinicians, never as substitutes. The human touch and qualities that we provide to patients and their families should not be replaced by machines. While clinicians can acquire the expertise to rely on artificial intelligence models, there is uncertainty about the extent to which patients will trust algorithms and how they prefer to receive algorithm-generated results. Consequently, qualitative research is essential to explore the ethical, cultural, and societal impacts of integrating AI into clinical practices.Even though none of the experimental closed-loop systems are currently accessible to clinicians, various systems have been extensively researched and exhibit considerable potential. In order to drive forward closed-loop innovations, active collaboration with regulatory bodies, control experts, and software engineers will be crucial in the future.Future prospectsThe field of closed-loop vasopressor administration holds great potential for further advancements. Improved algorithmic models, leveraging artificial intelligence and machine learning, could enhance the accuracy of dose calculations and responsiveness to patient needs. Additionally, the integration of closed-loop systems with electronic health records and interoperability among different medical devices could streamline data exchange and enhance clinical decision-making. There is a growing interest in merging basic automated systems with the increasingly popular field of artificial intelligence and machine learning. Allowing adaptive artificial intelligence systems to control the co-administration of fluids and vasopressors would create safer, more tailored systems for unique patient scenarios, although it will demand substantial engineering and clinical collaboration. In the end, it's crucial to understand that the primary aim of these closed-loop systems is to improve the management of each patient and their clinical outcomes.The future of closed-loop systems likely involves interconnected systems that can interpret, integrate, and optimize the key determinants that influence cardiac output and organ perfusion. Another significant development to enhance the automation of closed-loop systems will involve shifting from a responsive system to a predictive one. Closed-loop systems should incorporate safety mechanisms, including cut-off points, in case of input loss  or treatment application issues . Nevertheless, advanced closed-loop hemodynamic systems are rapidly evolving, enhancing adherence to goal-directed strategies and potentially boosting outcomes compared to manual control. These systems should be viewed as tools supporting clinicians, with authors and developers working to enhance perioperative safety and consistency for patients.Closed-loop vasopressor administration offers potential benefits in optimizing hemodynamic stability for surgical and critically ill patients. These systems use real-time patient data and advanced algorithms for precise and individualized blood pressure control. Adoption is increasing due to the promise of maintaining consistent optimal blood pressure levels during surgery and critical care. Throughout this review, we explore a range of closed-loop approaches, from algorithms based on simple physiological principles to those incorporating advanced monitoring technologies and artificial intelligence. Each approach has demonstrated the ability to effectively titrate vasopressor infusions, resulting in improved hemodynamic stability and, consequently, better patient outcomes. Potential advantages include reducing healthcare provider workload and preventing hypotensive episodes. Moreover, the potential reduction in the workload of healthcare providers and the prevention of hypotensive episodes further underscore the clinical significance of closed-loop systems. While challenges such as technological integration and algorithm refinement persist, the potential benefits in terms of improved patient outcomes and resource utilization are substantial. The authors agree that there exists a significant potential in closed-loop systems to revolutionize certain aspects of patient care positively. Nonetheless, it's essential to consistently assess and address risks to ensure patient safety. Continued research, development, and clinical validation are essential to fully harness the capabilities of closed-loop systems and shape the future of vasopressor therapy in perioperative as well as in the critical care settings. Large-scale randomized controlled trials are still needed to establish the superiority of closed-loop systems over conventional methods in terms of mortality and morbidity outcomes.


The joint statement is a synergistic action between HyperChildNET and the European Academy of Pediatrics about the diagnosis and management of hypertension in youth, based on the European Society of Hypertension Guidelines published in 2016 with the aim to improve its implementation. The first and most important requirement for the diagnosis and management of hypertension is an accurate measurement of office blood pressure that is currently recommended for screening, diagnosis, and management of high blood pressure in children and adolescents. Blood pressure levels should be screened in all children starting from the age of 3 years. In those children with risk factors for high blood pressure, it should be measured at each medical visit and may start before the age of 3 years. Twenty-four-hour ambulatory blood pressure monitoring is increasingly recognized as an important source of information as it can detect alterations in circadian and short-term blood pressure variations and identify specific phenotypes such as nocturnal hypertension or non-dipping pattern, morning blood pressure surge, white coat and masked hypertension with prognostic significance. At present, home BP measurements are generally regarded as useful and complementary to office and 24-h ambulatory blood pressure for the evaluation of the effectiveness and safety of antihypertensive treatment and furthermore remains more accessible in primary care than 24-h ambulatory blood pressure. A grading system of the clinical evidence is included. A.Recommendations are based on randomized trials  with high levels of internal validity and statistical precision, provided that the trial results can be directly applied to the patients because of similar clinical characteristics and outcomes have clinical relevance.B.Recommendations are based on randomized trials, systematic reviews, or prespecified subgroup analyses that have lower levels of precision, or need to extrapolate from studies in different populations or using validated intermediate/surrogate outcomes.C.Recommendations are based on trials that have lower levels of internal validity and/or precision, trials for which non validated surrogate outcomes were used, or results from observational studies.D.Recommendations are based on expert opinion alone.The first and most important requirement for the diagnosis and management of hypertension (HTN) is an accurate measurement of office blood pressure (BP), because in adults, studies on HTN as a cardiovascular risk factor and randomized trials on the beneficial effects of antihypertensive treatment have both been obtained via office BP measurements  ABPM is increasingly recognized as an important source of information and is regarded as an established tool for the diagnosis of HTN in children and adolescents in several guidelines –12, 26. -h ABPM i•Lack of reference values for the non-European White Caucasian population. The most widely used data were published by Wühl and co-workers  and masked hypertension (MH). The clinical relevance of WCH and MH in children and adolescents is a matter of debate because: (a) in young people studies on the relationship of these conditions with clinical outcomes are unfeasible (b) whether WCH and MH are associated with more frequent or severe HTN-mediated organ damage (HMOD) has been addressed in only few studies . If the difference  is ±5 mmHg or more, the cuff placement should be adjusted, and the procedure repeated. If the difference persists the ABPM device should be checked for calibration.REMOVING THE MONITOR•Remove the monitor after 24-h.•Determine day and night-time periods according to patient´s report or set daytime from 8:00 AM to 8:00 PM and night-time from midnight to 6:00 AM.ABPM patient diary can be found in the supplementary material.Home BP (HBP) allows multiple BP measurements away from the office setting, with the advantage of providing measurements on multiple days at rest and away from a potentially stressful environment. Like ABPM home BP values are more reproducible than the office BP values , 37. Bas•Lack of reference values. The most widely used data originate from the relatively small Arsakeion School study which provides percentiles tables according to sex and a height of 120 cm and above .•Assess home BP ideally for 7 days but for at least 3 days with at least 12 readings.•Take duplicate morning and evening measurements (before drug intake if treated) with a 1-minute interval.INTERPRETATION•Preference of automated report and averaging of readings stored in the device memory (or smartphone). Alternatively, review readings reported in a logbook.•Discard the first day and calculate the average of all the other readings.•Average home BP ≥95th percentile for sex and height, as long as the values are inferior to the adult criteria ≥135/85mmHg, indicate home HTN.•Home BP measurement alone not to be used for treatment decisions in children.www.hyperchildnet.eu) under the link https://hyperchildnet.eu/paediatric-home-bp-calculator/.Home blood pressure monitoring diary can be found in the supplementary material. A calculator for home blood pressure classification is provided by HyperChildNET (The first and most important requirement for the diagnosis and management of hypertension is an accurate measurement of office blood pressure. Out-of-office blood pressure measurements in youth is now widely and increasingly recognized as an important source of information. Twenty-four-hour ambulatory blood pressure is regarded as an established tool for the diagnosis of hypertension in children and adolescents with well-known recommendations. Gaps in knowledge lead to ambiguity regarding interpretation and management decisions with relevant research questions on the practical application. Action is required to be addressed in future studies.


BK virus infection after kidney transplantation can negatively impact the prognosis of patients. However, current risk factor analyses primarily focus on BK virus nephropathy, while BK viruria and BK viruria progressing to BK viremia receive less attention. This study aims to analyze the risk factors associated with BK viruria and BK viruria progressing to BK viremia in recipients of donation after cardiac death (DCD), with the goal of facilitating early intervention.Donor characteristics and clinical data of recipients before and after transplantation were evaluated, and logistic univariate and multivariate analyses were performed to determine the risk factors associated with BK viruria and the progression of BK viruria to BK viremia. Additionally, machine learning techniques were employed to identify the top five features associated with BK viruria evolving into BK viremia.p = 0.047] and donor procalcitonin (PCT) levels  were identified as independent risk factors for BK viruria. High BK viruria , recipient age , and immunoinduction regimen  were independent risk factors for BK viruria progressing to BK viremia. Machine learning analysis confirmed the importance of high BK viruria, recipient age, and immunoinduction regimen (ATG) in predicting the progression of BK viruria to BK viremia.During a median follow-up time of 1,072 days , 69 transplant recipients (15.6% incidence rate) developed BK viruria after transplantation, with 49.3% of cases occurring within 6 months post-transplantation. Moreover, 19 patients progressed to BK viremia. Donor age [OR: 1.022 , The development and progression of BK virus in DCD kidney transplant recipients is influenced by multiple factors. Early intervention and treatment could potentially extend the lifespan of the transplanted organ. The BK virus is a common resident in healthy individuals and typically reactivates when the immune system is weakened , 2. AfteThe screening of risk factors for BK virus infection mainly focuses on BKVN and BK viremia. A meta-analysis has summarized the risk factors for BK viremia and BKVN . It has Traditional logistic regression has long been the primary method for investigating risk factors associated with BK virus infection , 14. HowThis study enrolled 353 kidney transplant recipients who received kidneys from deceased donors in the Organ Transplantation Department of Renmin Hospital of Wuhan University from November 2018 to September 2021. Inclusion criteria required single kidney transplantation from organ donation after cardiac death (DCD), and all DCD donors were Maastricht III. Exclusion criteria included allocation of donor kidneys from other hospitals, combined heart-kidney or liver-kidney transplantation, death within 1 month after surgery and living kidney transplantation. The flow chart of case screening is shown in In order to track BK virus (BKV) DNA levels in urine and blood, we employed quantitative polymerase chain reaction (qPCR) at regular intervals. Specifically, we conducted monthly monitoring in the first year post-transplant, every 3 months in the second year, and annually thereafter until the fifth year.3 copies/ml. BK viruria was defined as the detection of BKV DNA load in urine ≥103 copies /ml, and high BK viruria was defined as the detection of BKV DNA load in urine ≥107 copies/ml (3 copies/ml (The diagnostic criteria for acute kidney injury (AKI) followed the guidelines recommended by the Kidney Disease: Improving Global Outcomes (KDIGO), which included an increase in serum creatinine (sCr) level ≥ 26.5 µmol/l (0.3 mg/dl) within 48 h or a known or presumed increase in sCr to 1.5 times or more of the baseline value within the past 7 days . Delayedopies/ml . BK vireopies/ml .The collection of clinical data involves both donor pre-donation data and recipient clinical data. Donor data include: (1) Clinical data such as gender, age, BMI and blood group; (2) Comorbidities and primary disease; (3) Relevant laboratory test indicators such as terminal albumin, terminal urea, terminal serum creatinine, terminal eGFR, terminal hemoglobin, terminal urine protein, terminal procalcitonin (PCT), and terminal hematuria sputum culture. Recipient data included: (1) Clinical data such as gender, age, BMI, and blood group; (2) Type matching data including PRA, HLA mismatch number; (3) Dialysis data including preoperative dialysis mode and duration; (4) Comorbidities and primary disease; (5) Postoperative laboratory examination indicators such as BKV DNA load in urine, BK viruria time, BKV DNA load in blood, and BK viremia time; (6) Hospitalization information including length of hospitalization (LOH) and DGF; (7) Immunosuppressant use such as Immunosuppressive and induction regimen.p < 0.1 were included in a multivariate logistic proportional risk regression model. In addition, a single-factor logistic proportional risk regression model for BK viremia was fitted for the population with BK viruria, and variables with p < 0.1 were included in a multivariate logistic proportional risk regression model. All statistical tests and confidence intervals were two-sided, and p < 0.05 were considered to be statistically significant. To validate the results obtained through logistic regression, a machine learning approach was used to assess the importance of potential risk factors for the progression of BK viruria to BK viremia. Categorical variables were treated in the dataset of 69 BK viruria cases by creating dummy variables, and the number of variables was reduced by lasso regression and 10-fold cross-validation, with the final number of variables determined by the lambda with the minimum mean square error. We used the random forest model for model fitting, with the dependent variable set to whether the patient progressed to BK viremia and the independent variables set to features other than the dependent variable, ranked in importance using Gini importance for the independent variables.The statistical analysis was performed utilizing the Statistical Package for Social Sciences (SPSS), version 25.0 , and R4.2.1. The continuous variables were determined using either an independent t-test or Mann–Whitney U test and presented as means ± SD or medians with interquartile ranges, respectively. Categorical variables were evaluated using the Chi-squared or Fisher’s exact tests and expressed as numbers (percentages). Initially, a univariate logistic proportional risk regression model was fitted for BK viruria in the entire renal transplant population. Subsequently, variables with p = 0.01) and a greater proportion of donor pre-donor PCT at 0.5-10 ng/ml . No statistical differences were observed in other comparisons. Please refer to This study analyzed a total of 353 kidney transplant recipients, of which 284 were free of BK virus infection, and 69 had BK viruria after the transplant surgery. All donors provided DCD kidneys, and the transplantation was carried out using a single kidney from a donor with the same blood group as that of the recipient. The immunosuppressive maintenance regimen used by 97.7% of the recipients was Tacrolimus + Mycophenolate mofetil + Glucocorticoid (TAC + MMF + GC), and 37.1% of the recipients received Antihuman thymocyte globulin (ATG) for immune induction. When compared to the control group, the BK viruria group had a higher donor age , and donor PCT (0.5–10 ng/ml). After including these variables in the multivariate analysis, it was found that donor age  and donor PCT  were independent predictors of BK viruria. The association between BK viruria and various variables was analyzed using a univariate logistic proportional risk regression model. Variables with a value of p less than 0.1 were included in the multivariate logistic proportional risk regression model. The univariate analysis identified certain variables with p = 0.012), a higher proportion of high BK viruria , and a lower proportion of ATG use , as compared to the control group. However, no significant differences were observed in the remaining donor-recipient profiles, and detailed donor-recipient profiles can be found in After stratifying the 69 patients with BK viruria into control and BK viremia groups based on whether they developed BK viremia or not, we observed that the BK viremia group had a higher recipient age , high BK viruria, recipient age, and immunoinduction regimen (ATG). Following inclusion of these variables in a multivariate analysis, it was determined that high BK viruria , recipient age , and immunoinduction regimen  were independent predictors of BK viremia. A univariate analysis of BK viremia was performed, revealing variables with The study revealed that BK viruria had an incidence of 15.6%, with a median follow-up period of 1,072 days . We further used machine learning approaches to analyze the importance of potential risk factors for the evolution of BK viruria to BK viremia. We used a lasso regression approach for data dimensionality reduction, and when the minimum mean square error of λ was 0.065, the variables were reduced to eight, namely: recipient transplantation etiology (polycystic kidney disease), recipient blood group (O), recipient DGF, recipient age, high BK viruria, recipient immunoinduction regimen, donor diabetes and donor age. The variables were screened as shown in BK virus is commonly present in the kidneys of most adults. However, in kidney transplant patients who receive immunosuppressive therapy for an extended period of time, the virus can become reactivated. The process starts with lysis of renal tubule cells, leading to urinary excretion of the BK virus. The virus then replicates in interstitial cells and penetrates the peritubular endothelial barrier to enter the bloodstream, resulting in BK viremia. Once the virus reaches the allograft, it attacks renal tubular epithelial cells, causing interstitial fibrosis and leading to the development of BKVN. This condition can ultimately result in renal graft degeneration and transplant failure. A study has shown that approximately 33% of patients with BK viruria progress to BK viremia and subsequently to BKVN without any intervention .In this study conducted at a single center, 69 kidney transplant recipients developed BK viruria, of whom 19 also developed BK viremia. The rate of progression to BK viremia was 27.5%, which was slightly lower than the 33% reported in other studies. No BKVN was identified as no kidney biopsy was performed. Similar to findings from other centers, the incidence of BK viruria at our center was highest within the first 6 months post-transplantation, followed by a declining trend. However, there was a subsequent increase in incidence observed at the 2-year post-transplantation mark . The stup = 0.047]. Deceased donors are typically older, and in this study, the average donor age was 54.00  years. The percentage of ECD is as high as 42.8%. Notably, the age of donors in the control group was significantly lower than that in the BK viruria group . Advanced donor age is often indicative of poor kidney quality, and it may be a contributing factor to BK virus infection. The biomarker PCT, which is linked to bacterial infection and inflammation, has been found to be a useful predictor of AKI in critically ill patients  stays, bacterial infections may still occur despite efforts to avoid sepsis. The PCT range of 0.5 to 10 ng/ml may reflect this phenomenon. Bacterial infections may activate the immune system, which could inhibit BK virus replication. Moreover, DCD donors often receive multiple antibiotics, and it is worth exploring whether the antiviral properties of these antibiotics inhibit the growth of microorganisms that promote BK virus transmission.Prior research has identified several potential risk factors associated with postoperative BK virus infection in kidney transplant patients, including recipient age, deceased donor, tacrolimus regimen and male recipient , 9, 24. patients , 26. Ourp = 0.018], high BK viruria , and the immunoinduction regimen . Consistent with prior literature, recipient age and high BK viruria were found to be independent risk factors for the development of BK viremia , 2, p = 0. viremia . For exa < 0.001 ]. Anothe < 0.001 . In cont < 0.001 . However < 0.001 . To reduIn addition, we used a machine learning approach to assess important variables associated with the progression of BK viruria to BK viremia. The results showed that recipient age, high BK viruria and immunoinduction regimen (ATG) appeared in the top five variables of the random forest model. Thus when patients present with BK viruria, close attention to such patients and timely intervention may be helpful in the progression of BK virus.This study aims to identify risk factors associated with BK virus infection and the progression of BK viruria to BK viremia, using a machine learning approach to evaluate the significance of potential variables in predicting such progression. These factors are critical in our study population and can aid clinicians in making informed decisions. However, certain limitations must be considered. Firstly, in order to obtain complete clinical data, we excluded donor kidneys from other hospitals, which may slightly underestimate the actual incidence of BK virus infection. Secondly, the results of our study may not be generalizable to other centers, as all participants were recipients of DCD donor kidneys, close to half of which belonged to ECD, and the majority of recipients were receiving a tacrolimus-dominant triple immunosuppressant postoperatively. Therefore, the difference in the study population may affect the results. Thirdly, we acknowledge that there is a sample size problem in single-center studies, and therefore, further expansion of the sample size is needed to validate our findings.BK virus infection in kidney transplant recipients is influenced by multiple factors related to both the donor and the recipient, particularly in the context of DCD. Identifying and screening high-risk groups for BK virus infection and implementing early intervention and treatment can help prolong the lifespan of the transplanted organ.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 Ethics Committee of Renmin Hospital of Wuhan University. The patients/participants provided their written informed consent to participate in this study.JZ and TQ designed the study. YL and CK carried out data collection and analyzed the data. TW, YZ, and HH made the figures. YL, HH, and CK drafted and revised the paper. All authors contributed to the article and approved the submitted version.This study was supported by the National Natural Science Foundation of China (Reference numbers: 81870067 and 81400753).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.


IntroductionAutosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic disorder that affects the kidney, which affects all ethnical groups worldwide, with varied clinical presentations and severity. The studies done in various parts of the world on the association between angiotensin II type 1 receptor (AT1R) A1166C gene polymorphism and ADPKD patients have revealed inconsistent results. This study was done to assess the role of AT1R A1166C gene polymorphism in ADPKD in the South Indian population, which is the first of its kind.MethodologyThis is a case-control study, conducted at a tertiary care center in South India. This study was concerned with the frequency of exposure (genotype) in ADPKD patients. Peripheral blood samples from 85 unrelated ADPKD patients and 94 controls without diabetes, hypertension, or any kidney-related disease were collected. The AT1R A1166C polymorphism was compared between (i) the cases and controls, (ii) early and late stages of chronic kidney disease (CKD) (ADPKD) subjects, and (iii) ADPKD subjects with and without hypertension.Results. AC  and allelic model A vs. C  between the early and late CKD stages of ADPKD were also not significant. No significant association of gene polymorphism was found between the non-hypertensive and hypertensive groups of ADPKD.Among the ADPKD patients, 45 (52.9%) subjects showed early stage (CKD stages 1-3), and 40 (47%) subjects showed late stage CKD (CKD stages 4 and 5). The genotype distribution of the studied 85 ADPKD patients was almost similar. No significant association was found between the genotype distribution of AT1R A1166C polymorphism in AA vs. AC  and A vs. C  between cases and controls. The genotype distributions in genetic model AA vsConclusionThe results of our study suggest there is no significant association between AT1R A1166C polymorphisms and ADPKD in the South Indian population. Further, the gene polymorphism is not related to the progression of ADPKD or the presence of hypertension in ADPKD cases in South India. Autosomal dominant polycystic kidney disease (ADPKD) is a multi-system disorder and the most common monogenic disorder that affects the kidney. It affects all ethnical groups worldwide, with an estimated frequency of 1:500 to 1000 . Extra-rThe severity of the disease, age at onset of ESRD, and the extra-renal manifestations vary widely even between the affected individuals of the same family , indicatThe role of renin-angiotensin in hypertension and the progression of chronic kidney disease (CKD) is well known. Hypertension is present in around 60% of ADPKD patients even before the glomerular filtration rate starts declining, denoting that it is a crucial risk factor in the progression of kidney failure . The angThe most well-studied polymorphism, AT1R A1166C rs5186), has shown a faster decline in glomerular filtration rate in ADPKD in Argentinians  and an a6, has shThis is a case-control study. Patients with ADPKD in various stages, visiting our center, a tertiary care teaching hospital located in Chennai, for treatment, were the case samples. All participants were more than 18 years of age, with established ADPKD diagnosis, with or without type 2 diabetes. Patients with other causes of CKD or type 1 diabetes mellitus were excluded. Subjects without diabetes, hypertension, or any kidney-related disease were included as controls.The sample size was calculated using the Power and Sample Size Calculation program (version 2.1.31). Based on a power analysis, 85 unrelated ADPKD patients and 94 control subjects were chosen. Procedures for the protection of human subjects in this study were approved by the Institutional Ethical Review Committee of Sri Ramachandra University, Chennai (IEC-NI/09/MAR/08/09). Written informed consent was collected from the study participants before collecting the blood samples.The study participants were examined and blood pressure was measured with a sphygmomanometer. The average of the three blood pressure values was taken. Blood samples were collected for hemoglobin, blood urea nitrogen, creatinine, sodium, potassium, bicarbonate, and calcium. The estimated glomerular filtration rate (eGFR) was calculated with the Modification of Diet in Renal Disease (MDRD) formula and CKD was staged on the basis of Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines. The ADPKD patients were split into two groups: early (stages 1-3 of CKD) and late (stages 4 and 5 of CKD). Further classification of cases, based on the presence or absence of hypertension, was also made.http://faculty.vassar.edu/lowry/VassarStats.html). Hardy-Weinberg exact test was applied to assess the consistency of the observed and expected genotype frequency distribution, based on the Hardy-Weinberg equilibrium hypothesis. At any stage, if the observed or expected number in each cell was below five, Fisher’s exact test was applied. The Hardy-Weinberg equilibrium test and the comparison of allele and genotype distribution were done by chi-square test with one degree of freedom and Monte Carlo simulation test applying the HWSIM program. A p-value less than 0.05 was considered significant for all statistical tests. Clinical characteristics were compared with Student’s unpaired t-test and the χ2 test.From the collected intravenous blood samples of study participants, DNA was extracted by a modification of the salting out method of Miller et al., precipitated in ethanol, and re-suspended in 500 µL of Tris-ethylenediaminetetraacetic acid (EDTA) (TE) buffer . The visThe case group had 85 subjects  with ADPKD and 94  healthy subjects not related to the case group were assigned to the control group. The mean age of the case group was 46.9 ± 10.4 years and the control group was 53.3 ± 12.4 years, and the difference was statistically significant (p < 0.001) .In the case group, 40 (47%) subjects showed late CKD stage (eGFR < 30 mL/min/1.73 m2) with a mean age of 50.5 ± 10.0 years, and 45 (52.9%) subjects showed early stage (eGFR > 15 mL/min/1.73 m2) with a mean age of 44.1 ± 10.0 years and the difference was found to be statistically significant (p < 0.008) , AC = 7 8.24%), and CC = 0 (0%) and that of 94 control subjects was AA = 87 (92.5%), AC = 7 (7.45%), and CC = 0 (0%)  genotypes expressed as odds ratio, 95% confidence interval, and association chi-square test were calculated and documented in Table AT1R A1166C polymorphisms and CKD stagesOf the 85 case participants, 40 (47%) were in the late CKD stage group with a mean age of 50.5 ± 10.0 years, and 45 52.9%) subjects showed early stage with 44.1 ± 10.0 years of mean age, which was statistically significant (p < 0.008). Of the 40 late-stage CKD patients, the genotype distribution was AA = 35 (87.5%), AC = 5 (12.5%), and CC = 0 (0%), and among the 45 early stages of CKD patients, the distribution was AA = 43 (95.5%), AC = 2 (4.4%), and CC = 0 (0%) , with a mean age of 48 ± 14.0 years, and hypertensives (n = 70), with a mean age of 46.6 ± 9.57 years. However, there was no statistically significant difference between the non-hypertensive and hypertensive groups p = 0.734) of ADPKD patients. Of the 15 patients in the non-hypertensive group, the genotype distribution was AA = 14 (93.3%), AC = 1 (6.6%), and CC = 0 (0%), and among the 70 patients in the hypertensive group, the genotypes were AA = 64 (91.4%), AC = 6 (8.57%), and CC = 0 (0%)  and hypertensive/non-hypertensive groups also, there was no statistically significant association. Our study revealed that the AT1R A1166C gene polymorphism does not have any impact on ADPKD, CKD progression, or hypertension in ADPKD patients.Angiotensin II is the major biologically active product of the renin-angiotensin-aldosterone system (RAAS), formed from its original precursor angiotensinogen, by two successive enzymatic cleavages. Angiotensin II acts as a potent vasoconstrictor and exerts its effects through two structurally different receptor subtypes: angiotensin II type 1 receptor and type 2 receptor . In humaThe AT1R 1166-C allele has demonstrated an increased risk for coronary artery disease, ischemic stroke, heart failure, ESRD, and hypertension. It has been associated with glomerular filtration rate decline in ESRD caused by ADPKD in Argentinians . Polish Evidence suggestive of the linkage of hypertension to the genetic area containing the AT1R gene has been confirmed with a logarithm of the odds score of 2.9 in a study from Finland by Kainulainen et al. . AlthougIn the Ohasama study, ambulatory blood pressure (ABP) monitoring in a general Japanese population of 802 Japanese subjects, aged 40 and above, found that the A/C1166 gene polymorphism of the AT1R gene was not associated with any clinical parameters associated with hypertension or atherosclerosis . A prospStudies thus far have not shown consistent evidence for the association between AT1R gene polymorphisms and hypertension among different races. In accordance with previous studies, our study also observed that there was no association between the AT1R A1166C polymorphisms and non-hypertensive/hypertensive groups in ADPKD patients.However, this study has few limitations. First, we have not measured serum levels of AT1R to correlate it with gene polymorphisms. Second, the sample size was too small to conclude the results. Further studies are warranted with a large sample size covering multi-center/population with gold standard (sequencing) protocols to confirm our results. In lieu of applying next-generation sequencing technologies to study complex diseases, it is also possible to apply the same to unravel the complexity of CKD progression in ADPKD and hypertension-induced ADPKD.There was no significant association between AT1R A1166C gene polymorphism in ADPKD cases and control subjects in the South Indian population. There was no significant association found between the early and late CKD stages or between the non-hypertensive and hypertensive groups of ADPKD cases. However, the family history of type 2 diabetes mellitus and age of more than 60 years were found to be significantly associated with the CKD stages.