Hypertension is a common risk factor for cardiovascular disease. Transcutaneous electrical acupoint stimulation (TEAS) may be effective for hypertension, but the evidence remains limited. The aim of this study is to evaluate the effectiveness and safety of the smart phone-based TEAS as adjunctive therapy for hypertension.This study is a 52-week cluster randomised controlled trial with 1600 hypertension patients in 32 community health service centres. Patients who meet the inclusion criteria will be randomised into usual care group or TEAS group in a 1:1 ratio. All patients will be provided with usual care as recommended by the guidelines. In addition to this, patients in the TEAS group will receive non-invasive acupoint electrical stimulation for 30 min at home, 4 times weekly for 12 weeks. The primary outcome will be the mean difference in the changes in office systolic blood pressure from baseline to 12 weeks between TEAS and usual care groups. Secondary outcomes will include the change of mean diastolic blood pressure, proportion of patients with controlled blood pressure (blood pressure <140/90 mm Hg), proportion of patients taking antihypertensive drugs, change in number of antihypertensive drugs and changes in 12-item Short-Form. Tertiary outcomes will include change in body mass index, change in waist circumference, physical activity and medication adherence. Safety outcomes will be any serious adverse events and clinical events.This study has been approved by ethics committee of Beijing University of Chinese Medicine (No. 2020BZHYLL0104). Written informed consent will be obtained from all patients before randomisation. Trial results will be disseminated in peer-reviewed publications.ChiCTR2000039400. In this randomised controlled trial, a large population of 1600 hypertension patients will be recruited from 32 community health service centres.This community-based cluster trial could lower the risk of contamination as much as possible and overcome the traditionally low detection of hypertension in hospital-based studies.The smart phone-based transcutaneous electrical acupoint stimulation (TEAS) can be received at home by the patients themselves to reduce the burden of logistics and lost wages.The background of TEAS software would recognise patients with poor compliance real timely and remind them of receiving TEAS to improve the adherence rate.Surrogate outcome, not clinical event, is used as primary outcome and blinding for patients was not feasible in this study.Cardiovascular disease is the most common cause of premature death and disability worldwide, and hypertension is the most common risk factor for cardiovascular disease.8Lifestyle modifications are recommended by all guidelines in different countries,Acupuncture, as a non-pharmaceutical therapy, was used for several cardiovascular diseases.This two-arm, open-label, cluster randomised controlled trial will be conducted at 32 community health service centres in China. The total trial period was 52 weeks, including 12 weeks of treatment and 40 weeks of follow-up. The study protocol  has been registered on Chinese clinical trial registry (No. ChiCTR2000039400). The protocol will be reported following the SPIRIT guideline.There are 16 districts and 346 community health service centres in Beijing, China. Of them, 32 community health service centres , 2 centr10.1136/bmjopen-2021-058172.supp1Supplementary dataOffice systolic blood pressure (SBP) from 140 to 159 mm Hg and/or diastolic blood pressure (DBP) from 90 to 99 mm Hg for patients who did not take antihypertensive drugs previously, or office SBP from 120 to 159 mm Hg and/or DBP from 80 to 99 mm Hg for patients who did not change antihypertensive drugs at least 1 month.Aged between 18 and 65 years .Answering and completing the questionnaires.Using smart phone.Written informed consent.Other diseases that can affect the blood pressure, including but not limited to diseases of renal parenchyma, renal artery stenosis, obstructive sleep apnoea syndrome, and primary hyperaldosteronism.Receiving medicines that affect blood pressure except antihypertensive drugs in last month, including but not limited to glucocorticoids and central nervous system inhibitors.Contraindications for the use of acupoint stimulators: wearing a pacemaker and other implanted medical devices; epilepsy; scars, bruises, scratches or inflammation on the skin of the acupoints; allergic to electrodes.Uncontrolled diabetes (HbA1c≥6.5%).Drug or alcohol abuse.Pregnant or breast feeding.Participated in other clinical trials in the past 3 months.The unit of randomisation will be the community health service centres. Thirty-two centres will be randomised to either TEAS or usual care group in a 1:1 ratio with a central randomisation system. All patients within the defined centre will receive the same allocated treatment. Each centre will not be randomised until total 50 patients are recruited to avoid selection bias. The randomisation sequence will be generated by an independent statistician with the Stata V.12.0 software and will be stratified by districts. The patients and the acupuncturists who teach patients how to locate acupoints and to receive TEAS at home will not be blinded. However, the family doctors who prescribe antihypertensive drugs, outcome assessors and statisticians will be blinded.All patients will be provided usual care at the respective community health service centre, in conjunction with any ongoing care that they are receiving from their family doctor. Patients at high or very high cardiovascular risk will receive antihypertensive drugs according to the recommendation of the guidelines,Hegu (LI4), Quchi (LI11), Zusanli (ST36) and Taichong (LR3) will be used in our trial. On the first day, the electrodes will be placed at the ipsilateral LI4 and LI11, and the appropriate stimulus intensity will last for 15 min. Then the opposite arm will be stimulated in the same way for another 15 min. On the third day, the ST36 and LR3 will be stimulated for 15 min per leg in the same way. Two pairs of acupoints (LI4-LI11 and ST36-LR3) will be stimulated alternatively every other day. Locations of acupoints are shown in In addition to the usual care, the patients in the TEAS group will receive 48 sessions of TEAS treatment (4 times weekly for 12 weeks). TEAS will be performed using a portable instrument  with a pair of rounded electrodes (diameter=38 mm) through smart phone. The adhesive electrodes will be applied to the skin as illustrated in The primary outcome will be the mean difference in the changes in office SBP from baseline to 12 weeks between TEAS and usual care groups. SBP will be measured as per the WHO STEPS protocol to ensure consistency of recordings, and an automated monitor  will be used at each visit. Patients will be asked to rest quietly for at least 5 min in the sitting position before measuring blood pressure. Blood pressure of both arms will be measured at baseline with the upper arm at heart level, and the arm with higher blood pressure will be the one measured throughout the entire study. At each time point, the blood pressure measurement will be repeated 3 times every 5 min, and the last two will be averaged.23 24Secondary outcomes will include differences in the changes in office DBP between the TEAS and usual care groups; the proportion of patients with well-controlled blood pressure (office blood pressure <140/90 mm Hg); the proportion of patients taking antihypertensive drugs; differences in the changes in number of antihypertensive drugs; and differences in the changes in 12-item Short-Form.Safety outcomes will be any serious adverse events and clinical events  at weeks 12, 26 and 52 in both groups. The schedule of enrolment, intervention and assessments is shown in The effective sample size (ESS) of 392 patients in each group is calculated for SBP on the basis of an alpha level of 0.05 (two sided), a beta level of 0.80, an expected between-group difference of 6 mm Hg,A full analysis set, a per-protocol set and a safety set will be used in this trial. The full analysis set will consist of all randomised patients according to the intention-to-treat principle. The full analysis set will be the primary analysis, and all analyses will be conducted for this population if not otherwise stated. The per-protocol set will include those who complete all follow-ups on time and without major violations. Major violations include but are not limited to not ineligibility according to the inclusion and exclusion criteria, receiving medicines that affect blood pressure except antihypertensive drugs, or not completing ≤38 sessions TEAS (80% of prespecified 48 sessions). The per-protocol set will be the secondary analysis set and will be used for the sensitivity analyses for the primary outcome. All those who receive at least one session of TEAS will be defined as the safety set, which is used for the safety analyses.Baseline characteristics will be summarised by groups. Continuous variables will be described using the mean (SD), or the median (IQR) if the normality assumption is violated. Categorical variables will be described using the frequency (percentage). The significance level of superiority test will be set at one-sided 0.025 for the primary outcome. The significance level will be set at two-sided 0.05 for secondary outcomes. All analyses will be carried out using SAS V.9.3.The change from baseline in office SBP at week 12 will be analysed by a mixed-effect model using baseline value as a covariate, treatment group as a fixed effect, and community and interaction between community and treatment as random effects. Multiple imputation will be used for missing data.https://yu.life.sjtu.edu.cn/redcap/) developed by Shanghai Jiao Tong University. All researchers will receive training about data input, inquiry and modification. Independent data managers will check the system to ensure the integrity, accuracy and timeliness of data. Any modifications of the data can be traced in the Research Electronic Data Capture system. Moreover, patient information will be anonymous, including name, ID number and telephone number, to protect privacy. After the trial is completed, this system will be locked by the data management team. Then the researchers can no longer modify the data. An independent data and safety monitor board will be established to review and interpret the trial data every 6 months.Data will be collected by using a web-based Research Electronic Data Capture system (The first author (JFT) and other coresearchers in community health service centres are patients with hypertension. They were involved in the design and conduct of the trial. During the design stage, choice of outcome measures, the number of study visits and methods of recruitment were determined by discussions with patients. Once the trial has been published, a brief summary of the findings will be presented to attendees in the community health service centres.This study conforms to the principles of the Declaration of Helsinki. The study protocol  was approved by the ethics committee of Beijing University of Chinese Medicine (No. 2020BZHYLL0104). Meanwhile, written informed consent will be obtained by the clinical research coordinator from all patients before randomisation. Results of the trial are expected to be published in a peer-reviewed journal.To our knowledge, this is the first cluster randomised trial to investigate the effectiveness and safety of the smart phone-based TEAS as adjunctive therapy for hypertension.This study is a community-based cluster randomised trial. There are several advantages for this design. First, contamination is one of the common biases, but it can be alleviated by the cluster design because only the communities randomly assigned to the TEAS group will have access to the instrument. Furthermore, communities were chosen with adequate geographical separation from each other. Second, patients will be recruited from their homes or communities. Unlike hospital-based studies, which only include those who seek medical help, our design will overcome the traditionally low detection of hypertension.The TEAS in this trial can be received through smart phone at home by the patients themselves. The majority of hypertension patients had to travel by taxi or use public transportation to attend physician visits and prescribe antihypertensive drugs. If the effectiveness of TEAS is verified, this non-pharmaceutical therapy will result in additional savings of cost and burden. The time, expense and lost wages are also identified as barriers for controlling blood pressure. The smart phone-based TEAS at home may contribute to improving treatment adherence. Furthermore, several patients sometimes forget to take medicine, especially when they are busy working or tripping. As we mentioned before, we could use the background of TEAS software to recognise patients with poor compliance real timely and remind them to complete treatment.The mechanism of acupuncture to reduce blood pressure is still unclear. It was found that TEAS could decrease sympathetic nervous system activity and increase parasympathetic nervous system activity,33 34Our study has several limitations. First, blinding for patients was not feasible; however, several steps will be implemented to minimise potential biases. Outcome assessors will be masked and an electronic data capture system with tablet has been developed to separate streams of data collection processes. Moreover, the blood pressure recordings were from automated devices to minimise biases for the key outcome. Second, surrogate outcomes are used in this study. There is a good evidence to support improved clinical outcomes with the reductions in blood pressure shown in other trials.This trial may provide high-quality evidence for the effectiveness of the smart phone-based TEAS as adjunctive therapy for hypertension. If the study hypothesis is confirmed, smart phone-based TEAS may help to attain the United Nations General Assembly Action Plan for a one-third reduction in premature mortality from cardiovascular disease.Recruitment was started on 18 November 2020 and is expected to close in June 2022.


To predict the risk factors for cardiovascular events within 5 years in patients with peritoneal dialysis-associated peritonitis and establish a nomogram for clinical prediction.A prediction model was established by conducting an observational study in 150 patients with peritoneal dialysis-associated peritonitis obtained from the Information Database of AnHui Medical University Affiliated Hospital. The nomogram was constructed using the multivariate COX regression model. The C-index and the calibration plot were used to assess the discrimination and calibration of the prediction model.p < 0.001).The elderly [HR = 2.453 (1.071–5.619)], history of cardiovascular events [HR = 2.296 (1.220–4.321)], alkaline phosphatase [HR = 1.004 (1.002–1.005)] and culture-positive [HR= 2.173 (1.009–4.682)] were identified as risk predictors of cardiovascular events, while serum albumin [HR = 0.396(0.170–0.924)] was identified as protective predictors of cardiovascular events. Combined with clinical studies, we constructed a nomogram based on the minimum value of the Akaike Information Criterion or Bayesian Information Criterion. The C index of the nomogram is 0.732, revealing great discrimination and appropriate calibration. Through the total score of the nomogram and the result of ROC, we classify patients into high-risk groups (cardiovascular events group) and low-risk groups (no cardiovascular events group). Cardiovascular events were significantly different for patients in the high-risk group compared to the low-risk group (HR = 3.862(2.202–6.772; The current novel nomogram can accurately predict cardiovascular events in patients with peritonitis associated with peritoneal dialysis. However, external validation is required before the model can be used in clinic settings. Peritoneal dialysis (PD) is a preferred modality of replacement therapy for end-stage renal disease, has little effect on hemodynamics, preserves residual renal function, and reduces cardiovascular risk. However, the primary complication of PD is peritonitis. Recent studies have found increased cardiovascular mortality in patients with PD-associated peritonitis .The risk factors for cardiovascular events are numerous. The Framingham risk score is one of the most widely used tools to estimate the individual risk of cardiovascular events and has been validated in racially diverse general populations . HoweverOnly limited data on predictive instruments for the risk of cardiovascular events in dialysis patients are available. An observational study to predict cardiovascular mortality in patients with PD included aging, history of cardiovascular disease, low hemoglobin and serum albumin, high-sensitivity C-reactive protein (CRP), and low 24 h urine output . However2.2.1.The current study enrolled consecutive incidents of initial peritonitis in adult patients reported from June 1, 2015 to May 31, 2021, at the AnHui Medical University Affiliated Hospital in China. All PD-related peritonitis met the 2016 ISPD diagnostic criteria . All pat2.2.Clinical and laboratory data were obtained using standardized forms. Following variables were considered: the demographic variables, including age, sex, and smoking status; physical examination variables, including systolic blood pressure (SBP) and diastolic blood pressure (DBP), which were measured twice with a mercury sphygmomanometer in quiet conditions after half an hour of rest after admission to the hospital during the first onset of peritonitis, and the average was taken, heart rate, body weight with dry abdomen and height, which were also collected at first admission during the first onset of peritonitis. The body mass index was calculated according to weight and height. A history of cardiovascular events (CVEs) ,12 was r2.3.The primary outcome was a cardiovascular event defined as a combination of hospitalizations for coronary heart disease, heart failure, stroke, peripheral arterial disease, and sudden death, death associated with a cardiovascular procedure, death due to aneurysm dissection or rupture, fatal pulmonary embolism . Heart f2.4.U test. Additionally, categorical variables were compared using Pearson’s χ2 or Fisher’s exact probability method test. Age, 24-h urine output, body mass index, and serum albumin were converted to categorical variables based on a routine cutoff point in clinical practice due to their skewed distribution. The rest of the variables were evaluated as linear predictors. All variables had less than 10% missing values, and all lost data were imputed using the miss Forest method, which is a nonparametric method for handling variables of different types simultaneously [P-value less than 0.05. The stepwise selection was used to screen variables for multivariable COX regression analysis, combined with clinical data, we chose the minimum value of the Akaike Information Criterion and Bayesian Information Criterion, build the final model and constructed a nomogram based on it. In a multivariate analysis, the models were adjusted for demographic variables , Framingham cardiovascular risk factors , factors associated with cardiovascular risk factors in patients with chronic kidney disease (CKD) , and confounding factors associated with cardiovascular risk factors . Calculate the variance inflation factor (vif) for each variable to evaluate the collinearity of the final multivariate model. If vif is more than 10, consider the existence of collinearity. The Somers’ D correlation was also calculated to assess the calibration of the model. We used time-dependent receiver operating characteristic (ROC) analysis and area under the curve (AUC) to predict nomograms’ accuracy measured at different cutoff times. The score for each predictor in the nomogram was also calculated. Segmentation was performed using the optimal cutoff value determined by nomogram total score and ROC curve outcome when the Youden index was maximum, and patients were classified as 'low’ or 'high’ risk group. Kaplan-Meier curves were plotted for the two risk groups and survival was compared using the log-rank test curve. The C index and the calibration curve were used to determine the accuracy of the prediction and the discriminative power of the nomogram. A sensitivity analysis and a bootstrap with 1000 resampling was also performed to further determine the robustness of the model. Statistical tests were performed using R software version 3.0.1. The statistical significance was set at 0.05.Continuous variables are expressed as mean ± standard deviation or median (interquartile range) and were compared using the T or Mann-Whitney aneously . We sele3.3.1.In total, 150 eligible patients were included in the analysis and the mean follow-up time was 28 months. During follow-up, a total of 56 patients demonstrated cardiovascular events; 6 patients developed new coronary heart disease, 20 patients developed new heart failure, 11 patients developed new stroke, 14 patients developed the new peripheral vascular disease, and 5 patients developed cardiovascular death . The mea3.2.p < 0.05), while serum calcium and serum albumin were negatively associated with cardiovascular events (p < 0.05).Univariate COX analysis showed that age, age (≥65year), systolic blood pressure, history of CVEs, alkaline phosphatase, culture-positive, and high mean transport were positively associated with cardiovascular events (p = 0.034), history of CVEs (p = 0.010), alkaline phosphatase (p < 0.001), and culture-positive (p = 0.047)were positive for cardiovascular events, while serum albumin (p = 0.032) was negative for cardiovascular events  (r events .3.3.p < 0.05), demonstrating a well-calibrated model between the observed and predicted probability of cardiovascular events in patients with PD-related peritonitis.In a multivariate COX regression analysis, we establish a series of consecutive models . Along w3.4.p < 0.001; The nomogram exhibited reliable performance in the prediction of cardiovascular events, with a time-dependent AUC of 0.728, 0.772 , and 0.781  at 1, 3, and 5 years, respectively . The sco3.5.To further verify the robustness of the prediction model, we added sensitivity analysis and internal Bootstrap validation. Due to the small sample size of early-onset peritonitis, the results were inaccurate and deleted. The results showed that the subgroups of late-onset peritonitis and patients with complete data were similar to the prediction model and showed good robustness. From the results of the bootstrap resampling, the model also has good robustness and sensitivity .4.The current study developed a novel prediction instrument for cardiovascular events risk in PD-associated peritonitis patients using five readily available baseline variables, including traditional cardiovascular risk factors and dialysis-specific factors. The nomogram demonstrated sufficient accuracy and discrimination.The current study has the following characteristics. First, patients with PD-associated peritonitis that was cured after their first infection was studied. Peritonitis is a common and serious complication in patients with PD, increasing the patients’ mortality and technical failure rates, and affecting patients’ peritoneal function even when cured . Antibiop < 0.001) [et al. found that undiagnosed hypocalcemia was a risk factor for cardiovascular events on hemodialysis [Interestingly, in univariate analysis, systolic blood pressure, hypocalcemia, and high transition peritoneal function were positively associated with cardiovascular events. First, In a blood pressure intervention trial, control of systolic blood pressure helped reduce cardiovascular events and revealed that patients with a systolic blood pressure ranging from 130 to 139 mmHg had significantly fewer cardiovascular events than those with a systolic blood pressure >140 mmHg (< 0.001) . Howeverdialysis . In thisRecent studies have found that early-onset peritonitis has a worse prognosis than late-onset peritonitis ,25. In t4.1.The prediction model was clinically instructive. How to use the nomogram: each variable in the figure was marked with a scale on the line segment, representing the value range, and the length of the line segment reflects the contribution to the resulting event. The points in the nomogram represent single scores corresponding to different values. The total points can be obtained by summing up the individual points . PatientThis study has some advantages. First, this study establishes a model for predicting cardiovascular events in patients with peritonitis for the first time. Second, the outcome events of the model in this study are relatively single, and there are no competing risk events.This model also has some limitations. First, the sample size of this study was small and no external verification was performed, so the significance of clinical guidance was reduced. Second, it is a retrospective study, there was inevitable recall bias and selection bias. Third, the observed indicators were limited, as brain natriuretic peptide, left ventricular function, coronary CT, and other cardiac function assessment indicators were excluded from the study. In addition, multiple comorbid conditions , nutritional status, malnutrition–inflammation complex syndrome (MICS), and some medication use are likely to enrich the estimate of the effects of cardiovascular events risk. It seems to be the potential area of bias and uncertainty in this study. Additionally, it may limit the generalizability of the findings. Fourth, age classification may reduce the usage of this model, especially in younger patients.In conclusion, this study developed a novel nomogram accurately to estimate the risk of cardiovascular events in PD patients with peritonitis within five years. However, the current nomogram model requires external data for validation prior to clinical application.Click here for additional data file.


Ankle-brachial index and arterial stiffness are associated with leg function in the elderly and in patients with peripheral arterial disease. Little is known about the meaning of these parameters in young and trained subjects and how they are related to physical performance. The main objective was to evaluate the mediating role of arterial stiffness and ankle-brachial index in physical performance. In a cross-sectional, case-control study, 240 male athletes were consecutively enrolled from the Laboratory of Cardiology and Sports Medicine, “G. d’Annunzio” University . All the subjects underwent the examination protocol for the annual medical evaluation for sport participation. Soccer  players compared to runners showed a lower level of ankle-brachial index, higher arterial stiffness, and lower systolic and diastolic blood pressure. In the treadmill stress test, soccer players compared to runners showed a greater maximal aerobic capacity. Differences in cardiovascular performance between soccer players and runners were mediated by better arterial stiffness and low level of ankle-brachial index; the estimated effect was 0.11 ± 0.05 and 0.24 ± 0.06, respectively. Vigorous strength training drops blood pressure and increases arterial stiffness. Taken together, our findings would seem to suggest that ABI and CAVI could be used as markers for athletes’ performance. There is scarce evidence on the physiological and/or performance differences that could help to identify top-level athletes, therefore, the determinants that predict and contribute to high-level performance in sports remain largely unknown . SeveralOur hypothesis considers arterial stiffness and blood pressure as potential cornerstones of the pathway that links the type of exercise training (aerobic vs. mixed aerobic-anaerobic) to physical fitness . TherefoFrom the Centre of Sports Medicine of the “G. d’Annunzio” University , 240 male top-level athletes (mean age 34.4 ± 14.2) were prospectively selected and recruited, who underwent the annually compulsory medical examination for sport participation and for planning a dietetic and physical training program. Among the study population enrolled, 111 (46.3%) were soccer players  and 37 (15.4%) were futsal players . Both groups, underwent a prevalently mixed aerobic–anaerobic training at least 4 times per week  and were, therefore, collapsed into a single group for further analysis. The remaining 92 subjects were runners, who had a specific aerobic training program, at least 4 times per week, and in the year before, participated in at least at two competitive marathons.The study was designed by the laboratory of Medicine and Sports Cardiology of the University Centre of Sports Medicine of the “G. d’Annunzio” University . According to Italian law, all the agonist athletes that are referred to the center for their annual medical visit undergo a clinical examination, a physical performance assessment, and an interview on dietary and lifestyle habits. The research protocol was not submitted to the local ethics review board, since this is the standard assessment in the routinely practice of the center, according to Italian law; nevertheless, written informed consent was obtained from all participants enrolled in the study.CAVI was measured using Vasera VS-1000 . Cuffs were applied to the 4 extremities, and electrocardiographic electrodes were attached to the upper arms. A microphone was placed on the sternal angle for phonocardiography. Two amorphous pulse wave sensors were placed symmetrically at the femoral and carotid artery. The subjects rested in the supine position for 5 min. To minimize cuff inflation-effects on blood flow dynamics, pulse waves were measured with cuffs inflated to lower than the diastolic blood pressure (50 mmHg). Then, the extremity blood pressure (BP) was measured by oscillometry. Systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP) were obtained by measuring the BP at the right brachial artery ,15. VaseBody weight and height were measured, to the nearest 0.1 kg and 0.1 cm, respectively, in a standardized position, using a stadiometer with a balance-beam scale ; subjects were dressed in light clothing and without shoes. Body mass index (BMI) was calculated as weight (kg)/height (m2). The body composition  was assessed by means of the electrical bioimpedance technique, using leg-to-leg 50 kHz frequency bioelectrical impedance scale . The test was executed in a standing position, without socks, after emptying the bladder, and after at least two hours of fasting. Participants also abstained from alcohol consumption within 24 h of the test.An exercise treadmill test was performed during the morning hours, preceded by a one-minute warm-up at a speed of 1.0 mph, with no slope, and adapted for a tilt treadmill with gradual and moderate increases of speed and slope. The patients were continuously monitored with a 12-lead ECG. The Treadmill exercise test was conducted according to a modified for athletes Bruce protocol, using standard criteria for stopping. The exercise capacity, resting, maximum, and recovery measures of heart rate (HR) were derived from the treadmill test results. Exercise duration was used as an estimate of physical fitness; HR and BP were recorded during each stage of exercise and for each minute of recovery. The rate-pressure product (RPP) was obtained by multiplying the maximum HR by the SBP at peak exertion.Continuous variables were reported as mean ± standard deviation, and differences between types of sports were analyzed with general linear models. Categorical variables were reported as frequencies and percentages, and the Chi-square test was applied to evaluate statistically significant differences between the groups considered; moreover, logistic regression was applied to produce estimates and to calculate odds ratio (O.R.) and 95% confidence interval (95%CI). Analyses were conducted using growth curve models (linear mixed models) to examine trajectories of BP, HR, and RPP, across time spent on the treadmill test. This analytical procedure address within-person and between-person variability simultaneously. In the p = 0.01 on the right and p = 0.009 on the left side), lower DBP measured at the ankle at the brachial, lower SBP at the ankle, and lastly a lower ABI, on both sides  and soccer players, all athletes were male. Soccer players compared to runners, showed statistically significant lower levels of CAVI (th sides .p =0.01).Between the two groups, no differences could be demonstrated in the body composition and in rest rate metabolism. Compared to runners, soccer players showed more frequently, in both legs, an ABI < 0.9  or an ABI ranging from <1 to >0.9 . In a sub-analysis considering only soccer players and clustering them according to classic soocer (11 players for every team) compared to Futsal (5 players for every team), the ABI was in the normality range (>1.0) in both legs only in 7/37 (18.9%) for Futsal players and in 48/111 (43.2%) for classic soccer , and RPP . Moreover, the trajectory of the SBP and the RPP showed a less pronounced increase in those athletes with an ABI < 0.9  even if they showed a statistically significant higher point when the maximal aerobic capacity was reached  and in the threshold at the maximal aerobic capacity ; but athletes with an ABI > 0.9, compared to all others, showed a more pronounced increase in heart rate  at every step (p = 0.09); but at every step for a lower level of CAVI, the increase in HR was less pronounced , and the threshold at the maximal aerobic capacity was higher .Heart rate did not show any significant differences between the two groups considered in the stress test .In In this study of a well trained and active young population, we found that lower ankle-brachial index, and lower level of Cardio-ankle-vascular index, could mediate differences in physical performance between soccer players and runners; moreover, in those subjects who play football, it could be demonstrated a more prevalent lower level of the ankle-brachial index compared to runners.In our theoretical model, ABI and CAVI were considered as mediators of physical performance, therefore rather than hypothesizing a direct causal relationship between the independent (type of exercise) and the dependent variable , the role of a third variable, the mediator, was analyzed to clarify the nature of this relationship. Endothelial function, measured by ABI and CAVI, together explains 35% of the difference in physical performance between “pure” aerobic training (runners) compared to concurrent training (soccer players). Numerous cross-sectional and longitudinal intervention studies have demonstrated the influence of regular aerobic training on vascular function in different populations ,20. ContAnkle-brachial index, particularly in the elderly, was largely recognized as a good predictor of physical function. In a case-control study, McDermott demonstrated that ABI has a direct and independent association with walking endurance and both usual and maximal walking velocity . In the A reason that can explain this inverse relationship could be related to the type of exercise that soccer players did, and the consequent modification on the type of metabolism, on body composition, and lastly on cardiovascular system adaptations. During exercise training, soccer players alternate high-speed runs, sprints, turns, jumps, and tackles, which provide a high impact on muscles and bones. From a metabolic point of view, this kind of exercise enhances fat oxidation during activity and results in a fat mass reduction  with a pIn our data, we could not find statistically significant differences between endurance and concurrent training in body composition and basal metabolism, therefore variation in rate and type of metabolism could not be demonstrated and consequently could not be considered as a keystroke in our model, even if the beneficial effect of soccer training was largely proved in young as in the elderly and in both sex .The exercise type done by soccer players could determine a reduction of BP, and in our data, particularly in the lower limb. Several mechanism could be considered in this process in response to physical training in soccer players: modulation in the autonomic nervous system, reductions in systemic vascular resistance, and plasma hormonal level ,30. In aSome limitations of this study must be acknowledged. A selection bias could be hypothesized; indeed, the soccer players were almost all pro or semi-pro, whereas among runners, almost all were amateurs, therefore, the former group could be less trained, or alternatively, be trained without a specific help of a qualified coach. Moreover, no standardized information was available about the intensity and regularity of the runners’ training. In any case, in this study, we enrolled only runners that belonged to a sportive association, and in the year before the enrolment in the study, had participated in at least two competitive marathons, ensuring regular and constant training.Another limitation that must be considered was the lack of a direct measurement of cardiac oxygen consumption. In all the analyses, we used the rate-pressure-product, that was largely used in the literature and reported to correlate quite well with maximal oxygen consumption in a wide variety of circumstances .In those subjects with an ABI level < 0.9, it was not possible to have a computed tomographic scan or magnetic resonance angiography because none of the athletes reported a paradigmatic symptom of peripheral-arterial-disease, nor was it possible to identify any significant reduction in blood flow at the Doppler and ultrasound images. Lastly, we did not consider in our analysis several well-known cardiovascular risk factors such as smoking habits, cholesterol, or vitamin D levels, as those data were not available for all the enrolled subjects. However, arterial stiffness is now regarded as an important biomarker of vascular function and a predictor of cardiovascular events more accurate than well-established traditional risk factor scores .Concurrent aerobic–anaerobic exercise compared to pure aerobic training appear to improve endothelial function; moreover, arterial stiffness (CAVI) and ankle-brachial index exert a positive effect on performance in the treadmill stress test. Lastly, CAVI and ABI could be suggested as determinants that could predict and contribute to high-level performance in sports.


MCA) was calculated by subtracting the hydrostatic pressure difference between heart and MCA levels from mean arterial pressure at the heart level. Non‐invasive cerebral perfusion pressure (nCPP) was estimated as the MAPMCA minus the non‐invasive ICP as determined from transcranial Doppler ultrasonography. Waveforms of arterial pressure in the finger and blood velocity in the MCA (MCAv) were obtained. Dynamic cerebral autoregulation was evaluated by transfer function analysis between these waveforms. The results showed that nCPP was significantly higher during neck flexion than during neck extension (p = 0.004). However, no significant differences were observed in mean MCAv (p = 0.752). Likewise, no significant differences were observed in any of the three indices of dynamic cerebral autoregulation in any frequency range. Although non‐invasively estimated cerebral perfusion pressure was significantly higher during neck flexion than during neck extension, no differences in steady‐state cerebral blood flow or dynamic cerebral autoregulation were evident between neck flexion and extension in seated healthy adults.Neck flexion and extension show differences in various physiological factors, such as sympathetic nerve activity and intracranial pressure (ICP). We hypothesized that differences would exist in steady‐state cerebral blood flow and dynamic cerebral autoregulation between neck flexion and extension in seated, healthy young adults. Fifteen healthy adults were studied in the sitting position. Data were collected during neck flexion and extension in random order for 6 min each on the same day. Arterial pressure at the heart level was measured using a cuff sphygmomanometer. Mean arterial pressure at the middle cerebral artery (MCA) level (MAP The present study evaluated steady‐state cerebral blood flow and dynamic cerebral autoregulation during neck flexion and extension in seated healthy adults. The present results suggest that there are no major differences in cerebral circulation between neck flexion and extension despite the significant difference in the index of cerebral perfusion pressure in seated healthy individuals. Confirming whether differences in cerebral circulation exist during neck flexion and extension may be beneficial to researchers. If cerebral circulation differs depending on head position with neck flexion and extension, researchers must pay attention to the head position of participants as a confounding factor when collecting data. In some cases, head position may be important for postlanding syndrome in astronauts , postural control, vestibular stimuli, neck muscle activity, and hydrostatic pressure. Neck flexion is well known to increase muscle sympathetic nerve activity  and was registered in the University Hospital Medical Information Network (UMIN) clinical trial registry (ID: UMIN000035059). All procedures adhered to the tenets of the Declaration of Helsinki. All participants provided written informed consent as well as a medical history regarding cardiovascular health and were screened based on a physical examination including electrocardiography and arterial pressure measurements. Exclusion criteria for health were as follows: failure to obtain blood velocity signals in the right middle cerebral artery (MCA) by transcranial Doppler ultrasonography (TCD); cardiovascular disease; autonomic disturbance; respiratory disease; current use of any medications; history of severe systemic disease; or allergy to the ultrasonic gel or polymer to be used in the study. Fifteen healthy adults  participated in the study. Mean (± standard deviation [SD]) age was 23 ± 2 years, mean height was 169 ± 4 cm, and mean weight was 64 ± 6 kg. All experiments were performed ≥2 h after a meal. Participants were asked to refrain from exercising heavily or consuming caffeinated or alcoholic beverages for at least 12 h before the experiments. All participants were familiarized with the measurement techniques and experimental conditions before the data collection experiments. We also confirmed that participants could smoothly flex and extend the neck 45° from the vertical plane and maintain that head position for 10 min without any complaints such as neck pain or difficulty breathing.2.22) by pulse oximetry were monitored . An infrared carbon dioxide sensor that can obtain a capnogram via both the mouth and nose was applied to detect respiratory rate and end‐tidal carbon dioxide pressure (EtCO2) . Arterial pressure waveforms were continually measured from the left middle finger using a volume clamping method with photoplethysmography as part of the feedback loop used to maintain clamping  and a height‐correction sensor was placed on the left arm at heart level (xiphoid process level). Arterial pressure at heart level was obtained by the oscillometric method with a cuff sphygmomanometer placed over the right brachial artery . Continuous waveforms of blood velocity in the MCA (MCAv) were obtained by TCD  at a depth of 50–60 mm using a 2‐MHz probe. The reproducibility of signals for MCAv from TCD is good when performed by an experienced sonographer and careful attention is paid to probe placement, as confirmed by the high intraclass correlation coefficient of approximately 0.9  and arterial oxygen saturation  was measured by the cuff sphygmomanometer during neck flexion or extension , hydrostatic pressure difference between the heart level and external acoustic meatus level was subtracted from the MAPHeart. Distances from the heart level to the external acoustic meatus level (DistanceHeart‐MCA) were measured for each head position. The external acoustic meatus level was applied as the MCA level in the present study. The hydrostatic pressure difference (mm Hg) was calculated as follows:Mean arterial pressure at the heart level  with reference to water at 37°C (density: 993 kg/m3) is 13.6, and the specific gravity of whole blood at 37°C with reference to water at 37°C is 1.06 , mean MCAv, SpO2.2.3Non‐invasive ICP (nICP) was calculated using the plugin “nICP Plugin” software (Klinkum Chemnitz GmbH) for ICM+ version 8.1 (Cambridge Enterprise) based on the mathematical model described by Schmidt et al. . This moMCA. Cerebrovascular resistance index (CVRi) was calculated as nCPP divided by the 6‐min average of MCAv  was also calculated by subtracting nICP from MAP2.2.4Beat‐to‐beat values of mean arterial pressure (MAP) and mean MCAv were obtained by integrating signals within each cardiac cycle from the waveforms of arterial pressure in the finger and MCAv using PC‐based commercial software (Notocord‐hem 3.3). Beat‐to‐beat data were then linearly interpolated and resampled at 4 Hz for spectral and transfer function analyses. Time series of data was first subtracted by the 6‐min average for variabilities. Fast Fourier transform and transfer function analyses were performed using a Hanning window on 512‐point segments with 50% overlap. This process resulted in five segments of data recordings over 6 min from which to assess the dynamic pressure‐flow relationship . The normality of data distributions was confirmed using the Kolmogorov–Smirnov test. A paired 3Heart during neck flexion tended to be higher than during neck extension, but this difference was not significant (p = 0.062). MAPMCA was significantly higher during neck flexion than during neck extension (p = 0.008). No significant difference in the 6‐min average of mean MCAv was evident between neck flexion and extension (p = 0.752) . Values for nCPP were significantly higher during neck flexion than during neck extension (p = 0.004)  . No significant differences in 6‐min averages of HR, respiratory rate, or SpO2 were noted between neck flexion and extension. The hydrostatic pressure difference between heart and MCA levels was significantly smaller during neck flexion than during neck extension (p < 0.001).Table ) Figure . No sign) Figure . CVRi te) Figure . The 6‐mTable 4Three major findings were obtained in the present study. First, nCPP during neck flexion was higher than that during neck extension in the upright sitting body position. Second, no significant differences in the 6‐min average of mean MCAv were apparent between neck flexion and extension in the upright sitting position. Third, no significant differences were identified in any indices of dynamic cerebral autoregulation between neck flexion and extension in the upright sitting position. Counter to our hypothesis, the present results suggest that steady‐state cerebral blood flow and dynamic cerebral autoregulation may not show any significant differences between neck flexion and extension in the upright body position, despite the higher non‐invasively estimated cerebral perfusion pressure during neck flexion than during neck extension.Heart – hydrostatic pressure difference – nICP”. In addition, MAPHeart tended to be higher during neck flexion than during neck extension in the present study. A previous study showed that muscle sympathetic nerve activity increased during neck flexion, but not during neck extension in a prone position  from the vertical plane for head positions during neck flexion and extension, resulting in a lower head position during neck flexion than during neck extension. The differences in height of the MCA between neck flexion and extension may be the primary reason for differences in nCPP as calculated by “MAPThe present results showed that the 6‐min average of mean MCAv did not differ between neck flexion and extension in the sitting position. This result suggests a lack of difference in steady‐state cerebral blood flow between neck flexion and extension in the upright body position, consistent with a previous study conducted in the horizontal body position  but significantly higher during neck extension than during neck flexion, consistent with findings from a previous study  and higher EtCO2 during neck extension in the present study. Although increases in PaCO2 have been shown to increase steady‐state cerebral blood flow and to weaken dynamic cerebral autoregulation  between neck flexion and extension in the present study was unlikely to have any obvious effects on steady‐state MCAv or indices of dynamic cerebral autoregulation.The present study showed that EtCO4.1Some limitations in the present study must be considered when attempting to interpret the findings. First, the evaluation of cerebral blood flow by TCD may have been affected by changes in MCA diameter, the angle of isolation, the position of the isolation window, and/or the position of the MCA in the brain during the neck flection and extension. However, the frequency response of phase, which may be minimally affected by changes in these factors, was almost identical between neck flexion and extension in the present study. Second, heterogeneity in vasomotor control along the arterial tree may disrupt the concept of transfer function analysis using velocity in the MCA as a conduit artery to indicate the capability of arterioles in some situations . Third, the present study evaluated only the right MCA under TCD. Previous studies have shown hemispheric differences in the response of cerebral blood flow during mental tasks or dominant arm movements ”, and by JSPS KAKENHI grant number JP20K06844 for additional data analysis and editing of the manuscript.The authors declare that no conflicts of interest exist.The study protocol was approved by the Institutional Review Board of Nihon University School of Medicine . Written informed consent and medical histories were obtained from all participants before the study began.


Antihypertensive therapy in the acute phase of intracerebral hemorrhage (ICH) can reduce hematoma expansion. Numerous studies have demonstrated that blood pressure variability secondary to antihypertensive therapy has adverse effects on neurological outcomes, but the conclusions are diverse, and the mechanism of this occurrence is unknown. The aim of this research was to analyze the impact of blood pressure variability after antihypertensive treatment on the prognosis of patients with acute ICH, along with the possible mechanism.A total of 120 patients within 20 h of onset of ICH were divided into a good prognosis group (mRS ≤ 2 points) and a poor prognosis group (mRS ≥ 3 points) according to their 90-day mRS scores. The basic patient information, NIHSS score, GCS score, mRS score at 90 days after admission, head CT examination at admission and 24 h and CTP examination at 24 h were collected from some patients. The blood pressure values of patients were collected within 24 h, and multiple blood pressure variation (BPV) parameters within 1 and 24 h were calculated.P = 0.045] and coefficient of continuous variation (SV) within 24 h [OR: 2.912 CI (1.818–71.728) P = 0.009] were still independent factors affecting the 90-day mRS in ICH patients. (2) There was a negative correlation between SBP SV and CBF in terms of the difference between the contralateral side and the perihematomal region at 24 h .(1) After excluding confounding factors such as age, whether the hematoma ruptured into the ventricle, confounding signs, amount of bleeding, edema around the hematoma, NIHSS on admission, operation or non-operation, and 24-h hematoma increment, the fourth quartile systolic blood pressure (SBP) maximum and minimum difference within 1 h [OR: 5.069, CI (1.036–24.813) Blood pressure variability after antihypertensive therapy in acute ICH is one of the influencing factors for 90-day mRS in patients. A 1-h dramatic drop in SBP and 24-h SBP SV may affect the long-term prognosis of patients by reducing whole cerebral perfusion. Elevated blood pressure in the acute phase of cerebral hemorrhage (ICH) patients is not only the cause of bleeding but also an important clinical manifestation . High blThus, we investigated the clinical data of hospitalized patients experiencing ICH within the past 2 years to observe whether the BPV caused by acute antihypertensive treatment affects the 90 mRS of patients and to explore the possible mechanism.This was a prospective study. Written approval was obtained from the Medical Ethics Committee of our hospital. In addition to the diagnostic criteria set by the 2019 Chinese Guidelines for the Diagnosis and Treatment of Intracerebral Hemorrhage as the inclusion criteria, patients also met the following conditions: age > 18 years old, onset < 24 h, SBP > 140 mmHg, neurological deficit symptoms, and imaging examination suggesting intracerebral hemorrhage. Exclusion criteria were intracerebral hemorrhage patients with onset > 24 h or admission SBP < 140 mmHg, subarachnoid hemorrhage, arteriovenous malformation, cerebrovascular amyloidosis, anticoagulant drugs, and secondary intracerebral hemorrhage due to vasculitis. Patients with severe illness and short-term death were also excluded.Patients with cerebral hemorrhage were given intravenous antihypertensive therapy with urapidil and maintained for 24 h after admission. The goal was to reduce the 1-h systolic blood pressure as much as possible to 120–140 mmHg or 20% lower than that at admission. Blood pressure measurements were recorded during the first 24 h and every 5 min from admission until 30 min after admission, every 10 min from 30 min to 1 h after admission, and every hour from 1 to 24 h after admission, for a total of 34 times. The blood pressure variability index (BPV) was calculated. Basic clinical data were collected, and mRS scores were followed up for 3 months. It was defined good prognosis group (mRS ≤ 2 points) and a poor prognosis group (mRS ≥ 3 points).A GE Light VCT 64-slice spiral CT scanner and an AW4.5 independent workstation were used as imaging equipment. Head CT at admission and 24 h after admission was completed, and simultaneous CT perfusion (CTP) examination was performed in some patients. Hematoma volume was measured using the formula of Taguda and calculated in ml. The final result was calculated as the mean of the measured values of two attending physicians. The increase in hematoma at 24 h  was calculated as the volume of hematoma at the 24-h reexamination (ml) − the volume of hematoma at admission (ml).The selection of regions of interest for head CTP included 3–4 regions of interest (ROIs) selected 1 cm along the edge of the hematoma and the contralateral mirror region. The perfusion parameters cerebral blood flow (CBF) and cerebral blood volume (CBV) were obtained.Microsoft Office Professional Plus 2013 was used to access all the data of the input after completion for BPV parameters, including the average (Mean), difference (Max − Min), standard deviation (SD), coefficient of variation (CV), and continuous variation (SV).t-test was used to compare the continuous variables with normal distribution between groups. The non-parametric Mann–Whitney U test was used for comparisons between groups if the distribution was not normal. Categorical variables were compared between groups using the chi-square test. Variables that were significantly different in univariate analysis were further included in multivariate binary logistic regression analysis to assess the association between the 90-day mRS score and BPV. In the comparison of continuous variables between the cerebral perfusion value and BPV, Pearson correlation analysis was used for those with a normal distribution. If the data did not conform to a normal distribution, Spearman correlation analysis was used. Statistical differences were observed at P < 0.05.Statistical Product and Service Solutions (SPSS) 24.0 statistical packages were used for data analysis. In univariate analysis, an independent sample A total of 120 patients were enrolled in this study, including 71 patients in the good prognosis group and 49 patients in the poor prognosis group. The results showed  that ageP < 0.05). The 1-h SBP SV (P < 0.1) was included in the multivariate analysis.The effect of BPV at different time periods (within 1 and 24 h) on clinical outcomes was evaluated. The results showed  that theP > 0.05, data not listed).There was no significant difference in diastolic blood pressure variation parameters between the two groups (P = 0.008) 24 h SBP Max-Min , 1 h SBP SD , 24 h SBP SV , suggesting that the above variables were correlated with prognosis  was negatively correlated with 24 h SBP SV, while there was no statistically significant difference in the correlation analysis of CBF and CBV around the hematoma or CBF and CBV in the mirror area .A 43-year-old male presented with 3 h of numbness and immobility in the right limb. Head CT  showed cIn the past 10 years, a number of large-scale international clinical studies have confirmed that early intensive antihypertensive therapy can effectively control hematoma expansion and bring more obvious blood pressure fluctuations , which may have adverse effects on patients with ICH.P = 0.04). There was no significant difference in mortality or severe disability rate between the two groups . This suggests that early and rapid lowering of blood pressure may be harmful. P = 0.016; OR = 1.57, P = 0.012). It is suggested that smooth and sustained control of blood pressure is needed in the ultra early stage. P = 0.001), CV , SV , and the effect of SBP variability on the risk of poor functional outcomes in ICH patients was affected by country, study design, mean age, stroke type, outcome definition, and study quality.The aim of our study was to observe the 90-day prognosis of patients with ICH after antihypertensive treatment. The results showed that after excluding other factors that clearly affect the prognosis of ICH, the top quartile of SBP 1-h max-min and 24-h SBP SV was still an independent risk factor for ICH patients with a poor prognosis at 90 days. We hypothesized that BPV affects clinical outcomes through the following mechanisms: 1. Destroy perihematomal perfusion. 2. Change the microcirculation of the whole brain.Whether early lowering of blood pressure results in lower early cerebral perfusion remains controversial. On the basis of INTERACT1 and ATACH experiments, studies such as ICH ADAPT suggest that there is no significant correlation between the magnitude of blood pressure reduction and the relative cerebral blood flow around the hematoma . Moreovep = 0.032).In addition, the above studies were limited to the hyperacute phase. Regarding sustained blood pressure reduction, a recent study by To further explore the relationship between BPV and cerebral perfusion, we performed correlation analysis on the related variation parameters affecting the poor prognosis of patients and ultimately showed that there was a negative correlation between 24-h SBP SV and the CBF difference between the healthy side and the affected side in patients with ICH; that is, the larger the 24-h SBP SV was, the smaller the CBF difference value. It is speculated that the reason for this phenomenon is that the cerebral perfusion around the hematoma loses its autoregulation ability early due to compression by the hematoma and edema and is less affected by blood pressure fluctuations.Previous studies  have demThere was no significant difference in cerebral perfusion parameters between healthy brain areas and surrounding hematoma, which may be related to the small sample size or the fact that the difference did not reach statistical significance. Unfortunately, although 1-h SBP max-min is a poor prognostic factor in ICH patients, its role in cerebral perfusion is not clear due to the short time from admission to hospitalization.The 1-h quartile difference in SBP and 24-h SBP SV are independent risk factors for poor prognosis in patients with intracerebral hemorrhage. Excessive hypotension and secondary continuous blood pressure fluctuations cause secondary brain injury through whole-brain perfusion and then aggravate the neurological impairment of patients with cerebral hemorrhage.The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by the Ethics Committee of Affiliated Hospital of North Sichuan Medical College 2020ER194-1. The patients/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.XS: project design, declaration, experiment coordinating and organization, translation, and revision. XJ: data collection, analysis, and draft. QM, QY, and TC: clinical cases. GJ: project administration. All authors contributed to the article and approved the submitted version.


Aims: To evaluate the efficacy of different pharmacologic treatment for severe hypertension during pregnancy.Methods: Two reviewers searched Ovid MEDLINE, Ovid EMbase, and the Cochrane Library for randomized clinical trials from the establishment of the database to 15 July 2021 that were eligible for inclusion and analyzed the pharmaceuticals used for severe hypertension in pregnancy.Results: 29 relevant trials with 2,521 participants were involved. Compared with diazoxide in rate of achieving target blood pressure, other pharmaceuticals, including epoprostenol , hydralazine\dihydralazine , ketanserin , labetalol , nifedipine , and urapidil , were statistically significant in the rate of achieving target blood pressure. According to the SUCRA, diazoxide showed the best therapeutic effect, followed by nicardipine, nifedipine, labetalol, and nitroglycerine. The three pharmaceuticals with the worst therapeutic effect were ketanserin, hydralazine, and urapidil. It is worth noting that the high ranking of the top two pharmaceuticals, including diazoxide and nicardipine, comes from extremely low sample sizes. Other outcomes were reported in the main text.Conclusion: This comprehensive network meta-analysis demonstrated that the nifedipine should be recommended as a strategy for blood pressure management in pregnant women with severe hypertension. Moreover, the conventional pharmaceuticals, including labetalol and hydralazine, showed limited efficacy. However, it was important to note that the instability of hydralazine reducing blood pressure and the high benefit of labetalol with high dosages intakes should also be of concern to clinicians. Hypertension is a common systemic disease that affects multiple organs and increases the risk of other diseases . Severe The most commonly used antihypertensive pharmaceuticals in international practice guidelines are methyldopa, labetalol, and nifedipine. There are three pharmaceuticals and methods commonly used in the treatment of severe hypertension during pregnancy: intravenous administration of labetalol, oral administration of nifedipine, intravenous administration of (di)hydralazine . LabetalTo date, although many antihypertensive pharmaceuticals are used in women with hypertension during pregnancy, their efficacy and safety are not guaranteed. This study conducted a systematic evaluation of current pharmaceuticals for the treatment of hypertension and compared their antihypertensive effects.Supplementary Method 1). There were no language restrictions for publications. Some of the available references included in the studies were retrieved as data support.This network meta-analysis was developed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . As of 1The inclusion criteria were as follows: 1) All study participants were women with severe hypertension during pregnancy, wherein the criteria for severe hypertension , i.e., SDuplicate studies and those that compared different dosages and durations of the same pharmaceuticals were excluded.Three authors , in consensus with each other, screened the literature independently and extracted data strictly according to inclusion criteria. Any disagreement among the authors was settled by discussions with a fourth author (Chao Zhang). Basic information of the literature including year, study design, and outcomes were extracted from each study.Two researchers  independently assessed risk of bias using the Revised Cochrane Risk of Bias tool for randomized trials (RoB-2) . Risk ofp < .05, respectively  with 95% confidence interval (CI) and mean difference (MD) with 95%CI, at a significance level of ectively . Heterogtatistic . I2 valuwas used .ith trial (i = 1 to dth design (d = 1 to D) for the basic parameters. i of design d. If design d compares treatments J and K, then model implies Network meta-analyses can provide reliable evidence for direct and indirect multiple-intervention comparisons . The netodifiers . The “loodifiers . All stan = 40), discrepancy of intervention (n = 26), discrepancy or lack of available outcome data according to inclusion criteria (n = 19), review (n = 15), study protocol (n = 3) and other (n = 16) were excluded, and 29 studies  was statistically significant in Compared with diazoxide in the results of network meta-analysis, other pharmaceuticals, including epoprostenol , hydralazine\dihydralazine , ketanserin , labetalol , nifedipine , and urapidil , were statistically significant in Eleven RCTs  with 959versus hydralazine , epoprostenol versus ketanserin , hydralazine versus ketanserin , ketanserin versus labetalol , ketanserin versus nicardipine , and ketanserin versus nifedipine , were statistically different in versus hydralazine , hydralazine versus ketanserin , and hydralazine versus labetalol , were significant differences in In the network meta-analysis, the results, including epoprostenol Seven studies  includinversus labetalol  and labetalol versus nifedipine , were statistical difference in In the network meta-analysis, the results of network meta-analysis, including hydralazine Eight studies  includinversus nitroglycerine , while other comparisons showed no statistical difference in None of the network comparison results showed statistically significant differences. Direct comparison showed statistical differences between nifedipine Eight studies  includinversus prostaglandin A1  and nifedipine versus nitroglycerine , were statistical difference, while others were not , labetalol (49.3%) and hydralazine (40.5%). A larger area indicates a better effect of medical treatment on this outcome, the higher the effective rate of blood pressure reduction after medication. The analysis results of several previous studies were consistent with our results, for example, two previous studies  showed tThis study evaluated the outcome of the time required to reach the target blood pressure after medication. These three pharmaceuticals for this outcome were ranked according to the area of the SUCRA plot labetalol (41.6%), nifedipine (33.8%), and hydralazine (7.1%). The larger the area, the shorter the time required for the pharmaceutical to treat severe hypertension in pregnancy. We found that labetalol took less time than nifedipine and hydralazine to obtain the maximum effect. However, another study  showed tIn addition, it was found that hydralazine required only fewer dosages to lower blood pressure compared to nifedipine and labetalol. These three pharmaceuticals for this outcome were ranked according to the area of the SUCRA plot hydralazine (75.0%), nifedipine (63.4%) and labetalol (5.7%). A larger area indicates that only a smaller therapeutic dose is required for pharmaceutical treatment of severe hypertension in pregnancy. There were studies  conducteEvaluation of the hypotensive effect of each pharmaceutical after the patient took the pharmaceutical revealed that hydralazine could reduce more values of blood pressure, and the blood pressure of patients using nifedipine and labetalol was significantly higher than that of patients using hydralazine. These three pharmaceuticals for this outcome were ranked according to the area of the SUCRA plot. Nifedipine (55.2%), hydralazine (39.1%) and labetalol (33.4%) for Systolic Pressure. These three pharmaceuticals for this outcome were ranked according to the area of the SUCRA plot nifedipine (28.5%), hydralazine (65.9%) and labetalol (57.5%) for Diastolic Pressure. The larger the area, the greater the value of lowering blood pressure by pharmaceutical treatment of severe hypertension in pregnancy. One other study  also arrMethyldopa can lower blood pressure by binding to α2-adrenergic receptor as an agonist , and it This network meta-analysis has more significant advantages than head-to-head meta-analysis, as the effects of different interventions to treat the disease can be quantified and ranked, according to the efficacy of different outcome measures to help select the best treatment plan. Compared with a previous study , our stuThere are several limitations in this study. Firstly, insufficient information, and no further analysis and discussion of the efficacy of medications for history, urine volume, first or second pregnancy, preeclampsia or eclampsia, may have affected the validity of the results. Moreover, differences in dosages use can lead to heterogeneity when comparing antihypertensive pharmaceuticals. Secondly, the limited sample size of the included studies means that there is a potential difference between the estimated value and the actual effect; this may affect the statistical power of our study. Thirdly, part of the trials in this network meta-analysis had unclear risks of bias, the results may be slightly biased.This comprehensive network meta-analysis demonstrated that the nifedipine should be recommended as a strategy for blood pressure management in pregnant women with severe hypertension. Moreover, the conventional pharmaceuticals, including labetalol and hydralazine, showed limited efficacy. However, it was important to note that instability of hydralazine reducing blood pressure and high benefit of labetalol with high dosages intakes should also be of concern to clinicians.


The BRS estimation with the delayed sequences also increased the number of data points and sequences and decreased the estimation error compared to the original time series. The modified sequence method with delayed signals may be useful for the measurement of baroreflex sensitivity in ESRD patients with a shorter recording time and maintaining an estimation error below 0.01 in both the supine and active standing positions. With this framework, it was corroborated that baroreflex sensitivity in ESRD is decreased when compared with healthy subjects.Impaired baroreflex sensitivity (BRS) is partially responsible for erratic blood pressure fluctuations in End-Stage Renal Disease (ESRD) patients on chronic hemodialysis (HD), which is related to autonomic nervous dysfunction. The sequence method with delayed signals allows for the measurement of BRS in a non-invasive fashion and the investigation of alterations in this physiological feedback system that maintains BP within healthy limits. Our objective was to evaluate the modified delayed signals in the sequence method for BRS assessment in ESRD patients without pharmacological antihypertensive treatment and compare them with those of healthy subjects. We recruited 22 healthy volunteers and 18 patients with ESRD. We recorded continuous BP to obtain a 15-min time series of systolic blood pressure and interbeat intervals during the supine position (SP) and active standing (AS) position. The time series with delays from 0 to 5 heartbeats were used to calculate the BRS, number of data points, number of sequences, and estimation error. The BRS from the ESRD patients was smaller than in healthy subjects ( The leading cause of mortality in end-stage renal disease (ESRD) is cardiovascular disease ,2. The pChanges in the baroreflex function, including the baroreflex sensitivity (BRS), may reflect alterations in the autonomic control of the cardiovascular system ,9,10. CoAfter recognizing that baroreceptors are stimulated not only by abrupt pressure changes but by small, continuous fluctuations during daily life, low-cost methods that can be used in a noninvasive fashion to analyze the spontaneous beat-to-beat variability have been pursued and proposed. The BRS index can be estimated by extracting it from the power spectral analysis ,11,16 orWe propose to use the delayed sequence method where the studied time series allows for the estimation of BRS with an optimal recording time shift, employing shorter time series than the 15 min traditionally required for the sequence methods in healthy subjects . HoweverThe study included one group of 22 healthy volunteers and consecutively recruited 18 ESRD patients treated with hemodialysis thrice per week, for at least 3 months. The description of the population is shown in We followed the study protocol described previously ,26. BlooFrom the digitized blood pressure recordings, the last 15 min of recording in each position (supine position and active standing) were copied and stored into separate files for further processing. The blood pressure recordings were filtered using the second derivative method , and theUsing the SBP and IBI signals, the BRS index was calculated using the sequence method . The regTo calculate the optimal recording time, the standard error of the slope (ξ) for each sequence was calculated using Equation (1):The reference error  and standard deviation (SDIBI) of IBI values .p < 0.05 [https://la.mathworks.com/products/matlab.html, accessed 1 November 2020) and SPSS version 26 .Results are shown as median (percentile 25–percentile 75). Our data has abnormal distributions according to the Kolmogorov-Smirnov test. Categorical values were compared using Fisher’s exact test. Quantitative variables were compared between groups, and within positions by Wilcoxon rank sum and signed rank (for paired observations) tests. Statistical significance was considered p < 0.05 . StatistThe number of sequences  was largFew differences are observed between the healthy and ESRD groups regarding the determination coefficient . Some diBRS measurement using the sequence method for spontaneous SBP and IBI fluctuations is widely known ,16,28. T2) was similar between groups under most conditions.The modified method showed that the BRS of ESRD patients, which is already reduced during resting conditions (supine position), does not decrease significantly when facing the active orthostatic challenge when positive sequences are used, in contrast with the clear reduction of BRS in the healthy group during active standing . The ortRegardless of the differences between the groups in the estimation error, the modified delayed sequences method allowed for the expected estimation of BRS with a time series shorter than 15 min, with a similar optimum recording time between groups and conditions .The reduction of the optimal recording time, with an estimation error in delayed signals below the original data error, may shorten the time needed for BRS calculation during the active standing test, which is often uncomfortable in patients with more deteriorated health, and minimize the stress of actively standing for a long time.BRS is an important mechanism of hemodynamic stability in patients undergoing chronic hemodialysis. It is known that peripheral vascular resistance is higher in patients prone to develop intradialytic hypotension, which also has an impaired BRS response . A myriaAs mentioned above, the pathophysiological pathways for the disruption of BRS are diverse. Additionally, with aging, cardiac and total body noradrenaline spillover and skeletal muscle sympathetic outflow increase. That is, the delivery of noradrenaline to its receptors increases ,34. ThisBaroreflex sensitivity is markedly reduced in middle-aged and juvenile patients with ESRD due to the combined effects of aging, arterial stiffening, and autonomic neuropathy ,38. In pThe heterogeneity of the results when using different protocols to evaluate the integrity or deterioration of the ANS in ESRD patients leads to a search for other protocols or processing methods. Regarding the BRS and the hemodynamic control, it has been proposed that, in the closed-loop spontaneous resting conditions, the sympathetic hemodynamic control could be mainly feedforward (non-baroreflex), while the feedback, baroreflex-mediated responses occur in response to active perturbations ,42. HoweThe upright posture strengthens the coupling between IBI and SAP consistently, with major participation of the arterial baroreflex, while paradoxically decreasing BRS . These aThe limited sample size of the studied population does not permit the generalization to other sets of patients, where the use of antihypertensives and diet restrictions may modify BRS. We found a significant difference in BMI between ESRD patients and healthy subjects, and three patients had diabetes mellitus (a common cause of dysautonomia), hence, a portion of the biological effect of the active standing test may be influenced by these conditions, and further research is needed to address these issues. It is plausible that some clinical variables, such as peripheral resistance and vascular calcification, influence the measurement of BRS with the presented algorithm. This potential relation remains to be explored in future studies, as well as its clinical application in the susceptibility of intradialytic hypotension, cardiovascular risk, or the response after HD. Future studies should also consider 24-h ambulatory blood pressure measurements.We applied low-pass filtering to the SBP and IBI time series to attenuate the effect of respiration and to enhance the low-frequency fluctuations that are associated with the baroreflex modulation . The infESRD patients with hypertension controlled only with HD show a diminished BRS in the supine position and active standing position compared with healthy subjects. These patients also have a marked BRS response during active standing, as is observed in healthy subjects. These measurements can be obtained using the modified sequence method with delayed signals and maintaining an estimation error below 0.01 while requiring shorter recordings (<15 min).


Autosomal dominant polycystic kidney disease (ADPKD) is the most commonly inherited kidney disease. In the absence of targeted therapies, it invariably progresses to advanced chronic kidney disease. To date, the only approved treatment is tolvaptan, a vasopressin V2 receptor antagonist that has been demonstrated to reduce cyst growth and attenuate the decline in kidney function. However, it has various side effects, the most frequent of which is aquaresis, leading to a significant discontinuation rate. The strategies proposed to combat aquaresis include the use of thiazides or metformin and a reduction in the dietary osmotic load. Beyond the prescription of tolvaptan, which is limited to those with a rapid and progressive decline in kidney function, dietary interventions have been suggested to protect against disease progression. Moderate sodium restriction, moderate protein intake (up to 0.8 g/kg/day), avoidance of being overweight, and increased water consumption are recommended in ADPKD guidelines, though all with low-grade evidence. The aim of the present review is to critically summarize the evidence on the effect of dietary modification on ADPKD and to offer some strategies to mitigate the adverse aquaretic effects of tolvaptan. Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease and the fourth most frequent renal disease leading to kidney replacement therapy in the United States . IndividA common approach to the management of these patients is to make them understand that the disease is inherited, but their lifestyle is in their hands and will have a notable impact on its outcome. Therefore, the goal is to try to minimize the effects of the disease and to avoid simply waiting for the genetic fate to take its course. Here, one should differentiate between healthy diets for chronic kidney disease (CKD) and those for certain specific aspects of ADPKD, in particular, and acknowledge the advertisement of unpublished diets that promise much more than they have been able to demonstrate. There are no relevant dietary intervention trials in patients with ADPKD, suggesting that patients with ADPKD should be treated differently than other patients with CKD. Miracle diets not only do not have a positive effect but can even be harmful, and worse, can even lead patients to despair. It is the task of the nephrologist to help the patient discern between dietary interventions that are medically meaningful and scientifically proven and promising diets that lack a scientific basis.Until now, only one treatment, tolvaptan, has been approved to slow ADPKD progression. Tolvaptan is an orally active nonpeptide arginine vasopressin V2 receptor antagonist that has been demonstrated to inhibit cyst growth and, consequently, produce a modest reduction in the glomerular filtration rate slope . HoweverIn this manuscript, we aim to review the evidence for published dietary interventions in ADPKD and the quality of life impact of tolvaptan, offering some mitigation strategies for aquaretic effects, as many of them are linked to nutritional counseling.Hypertension is the most common manifestation of ADPKD , and it The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) showed an association between urine sodium excretion, a surrogate marker for dietary sodium, and the rate of increase in total kidney volume at relatively early stages of the disease .In the HALT-PKD trial, all participants were instructed to follow a sodium-restricted diet (≤2.4 g/day) ,15. A poIn the absence of trials assessing salt intake for patients with ADPKD, probably the most sensible advice to follow would be to use the previous guidelines for CKD patients ,17 and tIn summary, dietary sodium restriction allows other medications that are commonly used in ADPKD to be more effective with blood pressure reduction. Additionally, there is evidence of a detrimental effect of dietary sodium on the rate of progression of ADPKD so a sodium-restricted diet should be suggested in the management of ADPKD. As rigorous blood pressure control has been associated with better kidney outcomes , a multi2 and avoiding intake >1.3 g/kg/day in adults with CKD at risk of progression [2 [In ADPKD, a high protein intake can not only induce hyperfiltration but also increases vasopressin level, which might lead to cyst growth and kidney function decline . Experimgression . Studiesssion [2 . On the ssion [2 . The samssion [2 .The 2015 KDIGO Controversies Conference on ADPKD did not recommend any specific protein-restricted diet for ADPKD and referred to the 2012 KDIGO guideline on CKD . The updEven in the absence of clear evidence of a positive effect of a protein-restricted diet on ADPKD, it seems wise to advise a healthy moderate protein intake of around 0.8 g/kg/day . Thus, fFood restriction has been shown to decrease oxidative stress and age-related renal dysfunction and to delay the progression to later stages of CKD in the rat remnant kidney model ,29,30. AIn addition, the benefit of fasting has been established in a reproduced non-orthologous PKD rat model (Han: SPRD), not only through time-restricted feeding (compared with ad libitum) but also with a ketogenic diet given ad libitum . The effUnfortunately, long-term caloric restriction is unlikely to be well-tolerated by most patients. It may also have harmful effects, such as anemia, muscle wasting, weakness, light-headedness, irritability, fatigue, and depression. A recently completed clinical trial (NCT03342742) investigated the feasibility and tolerability of a caloric deficit of 34% in 30 overweight adults with ADPKD. Time-restricted eating and intermittent fasting are being studied as alternatives to caloric restriction in patients with ADPKD . More studies in humans are needed to determine the timing and degree of caloric restriction that may provide beneficial effects in ADPKD.Overweightness has been found to be associated with a faster rate of kidney enlargement and functional decline in early stage ADPKD . AlthougThe reasoning behind using a ketogenic diet for ADPKD is based on the fact that cyst cells have been shown to be dependent on glucose , which cThe advice that ADPKD patients should increase water intake is based on the upregulated cAMP in ADPKD cells. Increased fluid intake prevents the action of vasopressin, and therefore, a decrease in cAMP is expected. However, the level of water intake achieved by taking tolvaptan seems unachievable by means of a high water intake diet in the absence of increased thirst. In addition to a potential effect on ADPKD progression, high water intake can help prevent nephrolithiasis, a well-known complication of the disease .Small trials trying to assess the effect of increased water intake on ADPKD failed to achieve significant results ,40. HoweEven in the absence of evidence of a positive effect of high water intake, it is wise to follow KDIGO advice and increase water intake to suppress endogenous vasopressin, especially in patients not receiving tolvaptan. Although the minimum water intake has not been established, in ongoing trials, the fluid prescription is titrated in order to achieve a urine osmolality of ≤270 mOsmol/kg ,42. HoweCaffeine may increase the renal concentrations of cAMP in the ADPKD cell, which is apparently an important driver of renal cyst growth. However, in small observational studies of patients with ADPKD, there was no correlation between caffeine intake and kidney outcomes ,45. Due There is a lack of specific information regarding other nutritional counseling in ADPKD. Fruit and vegetables have been shown to be beneficial in patients with CKD, including early stages, and, indeed, KDOQI guidelines recommend their consumption in CKD to reduce net acid production ,46. In aMore controversial is the impact of dietary fiber on kidney outcomes. However, via inflammation regulation and improving microbiota, new evidence is emerging on its protective effect . LikewisPivotal clinical trials testing the attenuation of kidney function progression, namely REPRISE and TEMPO 3:4 and 4:4, demonstrated that the tolvaptan mechanism of action-derived effects was frequent and led to important rates of treatment discontinuation ,49. SpecIn general, ADPKD is associated with poorer quality of life. Age, progression biomarkers, kidney and liver volume, and disease-specific symptoms (such as ascites or pain) have been linked to worse physical well-being ,52,53. HThree small prospective studies aimed to determine the impact of aquaresis on quality of life. First, using the Kidney Disease Quality of Life Short Form (KDQOL-SF) 1.2 scale, Anderegg et al. evaluated the effect of tolvaptan on the quality of life in 98 patients with ADPKD (68 with no indication for tolvaptan and 30 with prescribed tolvaptan at stable doses) . During The definitive results of the ACQUIRE prospective study, which aims to explore patient-reported outcomes and health-related quality of life among patients with rapidly progressive ADPKD (NCT02848521) , are curBeyond the time-dependent attenuation of the aquaretic effects, some strategies have been proposed to reduce these effects, but the evidence of their efficacy is scarce. A recent open-label clinical trial was performed on ten patients with ADPKD who randomly received antihypertensive therapy with or without trichlormethiazide, a thiazide diuretic, for 12 weeks. A modest but significant reduction in urine volume was demonstrated with the use of trichlormethiazide, without any short-term impact on renal function  . KramersSome dietary interventions could affect polyuria in patients with ADPKD treated with tolvaptan. In addition to blood pressure reduction, low salt intake in patients receiving tolvaptan leads to a reduction in natriuresis and consequently in diuresis volume . Beyond Caffeine is a well-known stimulus for AMP accumulation. Until now, its effect on kidney disease progression in ADPKD has not been demonstrated. Published guidelines recommend that while excessive consumption should be avoided, consumption should be sufficient not to forego the beneficial cardiovascular effects . The resThere are no magic diets with a great impact on the evolution of ADPKD. Despite this, nephrologists should advise a healthy diet, low in salt and without excessive protein, as well as healthy lifestyle habits, as suggested in the KDIGO guidelines for patients with CKD. While ADPKD is inherited, it is in the hands of the patient to stay in good shape and have a healthy lifestyle that will improve morbidity and quality of life.Tolvaptan is the only approved drug for ADPKD, with evidence that it reduces disease progression. However, its aquaretic effects influence patient quality of life, leading to a significant discontinuation rate. Some strategies may be implemented to attenuate aquaresis , especially during the first 18 months, when aquaretic effects are more pronounced.