Knowledge of the circadian blood pressure (BP) variations in the acute hospital setting is very limited.This is a retrospective analysis of BP data for in-hospital patients stratified by age and sex. We used data collected with the help of a standardized electronic health record system between March 2014 and April 2018 on the adult general wards in 4 acute hospitals in Oxford, UK.A total of 41,455 unique patient admissions with 1.7 million sets of vital-sign measurements have been included in the study. The typical 24-hour systolic BP profile  was only seen in the younger age groups (up to 40–49 for men and 30–39 for women). For older age groups, there was a late nocturnal rise in systolic BP, the amplitude of which increased with age. The late nocturnal BP rise above the age of 50 was seen whether or not the patient was treated for or previously identified with hypertension.Hospitalized patients’ circadian patterns of BP largely mirror those found in the community. High-quality hospital data may allow for the identification of patients at significant cardiovascular risk through either opportunistic screening or systematic screening. Recent analysis5 of data from a registry-based, multicenter, national cohort that included 63,910 adults recruited over a decade showed that measurements made over 24 hours with ambulatory BP monitoring (ABPM) were a stronger predictor of all-cause and cardiovascular mortality than clinic BP measurements.It is well known that in the community blood pressure (BP) is characterized by fluctuations occurring over different time scales.7 These categories have been observed from studies using ABPM,9 home BP monitoring,11 and a small-sample study in elderly hospitalized patients.12 The riser or reverse dipping pattern has been found to be more common in older patients.13–15 A systematic review by Taylor et al.4 found nighttime dipping was associated with a lower risk of cardiovascular events while rising BP at night compared with daytime values was associated with increased risk.Nighttime BP profiles can be classified into 3 patterns: dippers , nondippers , and risers or reverse dippers (subjects in whom BP rises at night).16 Finally, being in hospital may present an opportunity to assess BP control while receiving prescribed medication.Measurements taken while in hospital have historically been recorded on paper charts. The advent of electronic vital-sign recording allows patterns of BP recorded in hospital to be analyzed at scale. The presence of multiple readings when patients are hospitalized may allow more reliable estimation of 24-hour BP profiles. Also, the stress associated with being in hospital may mimic laboratory studies suggesting that increased BP lability under stress itself predicts future cardiovascular events.In this article, we determine the 24-hour BP profiles in the hospitalized adult population stratified by age and sex using a large database of 1.7 million sets of observations. We assess whether those 24-hour BP profiles are affected by the presence of a diagnosis and treatment for hypertension or affected by observations taken when patients are physiologically unstable.Our study is a retrospective analysis of BP data for in-hospital patients stratified by age and sex. Linked prescription data were available from the electronic patient record.am) and at least one during the daytime (defined as from 10:00 am to 7:59 pm), with 2 observations at least 24 hours apart , with Confidential Advisory Group approval to process patient data without consent (reference: 16/CAG/0066). We included BP measured on all the adult wards (excluding the intensive care units) in 4 acute hospitals in the Oxford University Hospitals (OUH) NHS Foundation Trust. We included the first admission of each patient that had at least 3 observations, with at least one during the nighttime , which records vital-sign values, calculates an Early Warning Scorehttps://www.cerner.com/).Nurses and health care assistants within OUH NHS Trust measure patients’ vital signs and receive regular training updates. The patient position in which BP is taken is optional. OUH NHS Trust policy recommends that observations should be undertaken a minimum of 12 hourly, with the observation frequency increasing to 4 hourly and then hourly depending on the degree of abnormality as defined by the Early Warning Score. All vital-sign equipment used within the study was purchased and maintained  in accordance with the Oxford University Hospital Trust Medical Devices Management Policy. Other data  were obtained from the Patient Administration System (PAS) in the hospitals’ electronic patient record, Cerner Millennium  during the entire hospital stay. Subsequently, these were averaged (red line) and hourly values of averaged systolic BP constructed in a 24-hour plot  normotensive elderly group—patients above the age of 60 who did not have a prescription for any antihypertensive drug as listed in the British National Formulary19  and who 19 , (ii) hyt-test for difference of means.The differences in BP between 2 time points were assessed using 2-sample The overall dataset included 41,455 admissions of unique patients with a total of 1,701,812 BP sets of vital-sign measurements .Patients 50–89 years of age accounted for nearly three-quarters of all admissions (70.1%). The number of men and women included in the study was similar (49% men and 51% women) with a median age of 63 years for men and 64 for women.am and 3:59 am , with the greatest number of measurements taken between 5:00 am and 5:59 am  before nursing hand-over and again soon after the nightshift starts, between 8:00 pm and 8.59 pm . The ratio between the maximum and the minimum numbers of measurements per hour was 2.5:1.The frequency of BP measurements and the average value of systolic and diastolic BP, across the entire cohort, calculated for each 1-hour interval are shown in am and 5:59 am for both men ) and women ) with P < 0.001  is shown in  < 0.001 .am and 5:59 am) in mean systolic BP for both men and women  and normotensive  patients of 60 years and older are shown in nd women .The 24-hour systolic BP variation for different age groups  and 4 shThe effect of physiological instability on the 24-hour systolic BP variations for hospitalized patients  was asseLittle is known about BP characteristics and its circadian variation in the hospital setting. Using a large hospital database, comprised 1.7 million measurements collected between March 2014 and May 2018 in Oxford (UK), we have analyzed the 24-hour BP variation for men and women. The recording of BP in the hospital setting over a number of days and nights allowed us to compute 24-hour BP profiles. We excluded patients who stayed in hospital less than 24 hours, those with fewer than 3 measurements, and who did not have either daytime measurements or nighttime measurements.21—see also 22In-hospital variations of mean systolic and mean diastolic BP with age were similar to those observed in the outpatient populations11The nocturnal dipping pattern was not observed with in-hospital patients from late middle age onwards. Instead, it was replaced by a late nocturnal rise in BP above the age of 60, such that the peak nighttime systolic BP was greater than the peak daytime systolic BP, with the mean nighttime systolic BP also greater than the daytime systolic BP . The eff22 Our analysis may also be serendipitously synchronized with waking, as the most common time to measure BP in the hospitals was between 5:00 am and 5:59 am. The second most common time to measure BP was between 8:00 pm and 8:59 pm, suggesting nighttime rest may also be somewhat synchronized. These external hospital-imposed rhythms may contribute to the alignment of the circadian rhythms of patients, allowing the 24-hour BP curves for subpopulations stratified by age to show very clear patterns.ABPM studies are normally synchronized to waking.23 Taylor et al.,4 in their systematic review and meta-analysis of multiple ABPM studies, also reported that rising BP at night compared with the daytime is associated with increased risk of cardiovascular events. Cuspidi et al.24 in their recent review highlighted that although the literature on the clinical and prognostic implications of nocturnal rising, or reverse dipping, is very limited, it is a powerful marker of poor cardiovascular prognosis, after adjusting for traditional risk factors. The concept of chronotherapy, administering antihypertensive drugs to lower BP over 24 hours, while maintaining nocturnal dipping25 may help ameliorate these risks.The European Society of Hypertension Position Paper on ABPM states that patients with a nocturnal rising pattern have poor cardiovascular prognosis.9 Dipping or nondipping is assessed somewhat arbitrarily: if the mean nighttime BP is lower than the mean daytime BP by 10% or more, then the BP variation is said to follow a dipping pattern.7 The definition of the nighttime and daytime periods over which BP values are averaged to obtain the mean values varies extensively. For example, Taylor et al. report 13 different definitions of nighttime and daytime periods. We chose our ranges to be comparable to those used in most studies.7 The traditional assessment of dipping or nondipping tends to disguise the late nocturnal BP rise, which was the main characteristic of systolic BP data observed for in-hospital patients above the age of 60, as the lower BP found between midnight and 1:59 am balances the 4:00 am–5:59 am rise in the computation of mean nighttime BP.Comparison with studies investigating changes in BP is hampered by differences in definition. Nocturnal hypertension is normally characterized by a simple threshold (mean systolic BP during the night greater than 120 mm Hg).Our study has important limitations. First, it is a retrospective study using measurements made on the wards by nursing staff as part of their regular observations of in-hospital patients. Patients who have longer hospital stays will therefore contribute more data to a hospital database of vital-sign observations. We compensated for this by generating one 24-hour BP profile per patient, regardless of their length of hospital stay. Second, the question of selection bias also arises. The patients whose BP is of most concern to the nursing staff will have their BP taken most frequently, possibly more often at night. However, patients may also get observations at night as a result of their admission time and the hospital protocol. As a result, BP was frequently recorded across the 24-hour period.Several factors suggest that our findings may be robust to bias in sampling. In general, BP is measured more frequently in hospital to detect hypotension rather than the nocturnal hypertension described here for older patients. The late nocturnal BP rise for these patients is not accompanied by increased heart rates .A.M. is funded by an EPSRC grant (EP/N024966/1—Intelligent Wearable Sensors for Predictive Patient Monitoring) and undertakes consultancy work for Sensyne Health. P.W. works part-time for Sensyne Health and has share options in Sensyne Health. L.T. is a nonexecutive Director of Sensyne Health and holds share options in the company. R.J.M. has received BP monitors for research purposes from Omron and travel expenses and honoraria for speaking from the Japanese Society of Hypertension and the American Society of Nephrology.


We aimed to clarify clinical implications of intrarenal hemodynamics assessed by intrarenal Doppler ultrasonography (IRD) and their prognostic impacts in heart failure (HF). We performed a prospective observational study, and examined IRD and measured interlobar renal artery velocity time integral (VTI) and intrarenal venous flow (IRVF) patterns (monophasic or non-monophasic pattern) to assess intrarenal hypoperfusion and congestion in HF patients (n = 341). Seven patients were excluded in VTI analysis due to unclear imaging. The patients were divided into groups based on (A) VTI: high VTI  or low VTI ; and (B) IRVF patterns: monophasic (n = 36) or non-monophasic (n = 305). We compared post-discharge cardiac event rate between the groups, and right-heart catheterization was performed in 166 patients. Cardiac index was lower in low VTI than in high VTI (P = 0.04), and right atrial pressure was higher in monophasic than in non-monophasic (P = 0.03). In the Kaplan–Meier analysis, cardiac event rate was higher in low VTI and monophasic groups . In the Cox proportional hazard analysis, the combination of low VTI and a monophasic IRVF pattern was a predictor of cardiac events (P < 0.01). IRD imaging might be associated with cardiac output and right atrial pressure, and prognosis. The abdominal compartment, which contains the kidney, liver, splanchnic vasculature, gut, etc., has recently been focused upon in HF patients9. Central venous pressure (CVP) measured with right-heart catheterization (RHC) is a commonly used surrogate to evaluate organ congestion11. On the other hand, Nohria-Stevenson profiles demonstrated the clinical importance of assessments of perfusion (“cold” vs. “warm”), as well as congestion (“wet” vs. “dry”)12. However, these profiles are relatively subjective.Heart failure (HF) is a widespread and serious problem that has been reported in many countries13. CRS is a disorder of the heart and kidneys whereby acute or chronic dysfunction in one organ may influence each other, and share common pathophysiology such as hemodynamics, neurohumoral, inflammatory, and oxidative injury14. Intrarenal congestion and hypoperfusion are critically involved in the pathophysiology of HF, and evaluation of renal function in HF patients is important16. Regarding renal congestion, it has recently been reported that intrarenal venous flow (IRVF) patterns  measured by intrarenal Doppler ultrasonography (IRD) are correlated with right atrial pressure (RAP), and a monophasic IRVF pattern was associated with higher RAP as well as worse outcome17. However, the usefulness of IRD to assess the clinical profiles, such as both hypoperfusion and congestion, has not been fully examined.Renal and cardiac functions have close and complementary interconnections; this is called the cardio-renal syndrome (CRS)In the current study, we aimed to: (1) examine the intrarenal hemodynamics assessed by IRD  in HF patients; and (2) clarify the clinical impacts of the IRD findings on prognosis in HF patients.N-acetyl-β-d-glucosaminidase (NAG). In contrast, hemoglobin and estimated glomerular filtration rate (eGFR) were lower. The low VTI group also had higher levels of left atrial volume index (LAVI), early trans-mitral flow velocity to mitral annular velocity ratio , right atrial (RA) area, tricuspid regurgitation pressure gradient (TRPG), pulmonary artery pressure, RA pressure (RAP) and pulmonary artery wedge pressure (PAWP) and lower levels of left ventricular ejection fraction (LVEF), left ventricular outflow tract-VTI (LVOT-VTI), right ventricular fractional area change (RV-FAC) and cardiac index. In addition, there were significant associations between interlobar renal VTI and age, heart rate, presence of New York Heart Association (NYHA) class III or IV, AF, hypertension, CKD, anemia, levels of hemoglobin, BNP, creatinine, eGFR, urinary albumin creatinine ratio, urinary NAG, LVEF, LAVI, LVOT-VTI, mitral valve E/e′, RA area, RV area, RV-FAC, TRPG, pulmonary artery pressure, RAP and cardiac index. These results suggest that decreased VTI indicates intrarenal hypoperfusion, underlying low cardiac output, and leads to urinary albumin transudation or tubular damage.Comparisons of the high and low VTI groups are summarized in Table Comparisons of the non-monophasic and monophasic groups are summarized in Table During the follow up period , 42 cardiac events including eight cardiac deaths and 34 worsening HF occurred. As shown in Fig. Intrarenal congestion and hypoperfusion determined by IRD  are associated with adverse prognosis in HF patients.To the best of our knowledge, the present study was the first to report that (1) the associations between parameters of not only intrarenal congestion (IRVF patterns), but also of intrarenal hypoperfusion  determined by IRD and both RHC and echocardiography, and that (2) prognostic impacts of intrarenal congestion and hypoperfusion in patients with HF. The combination of interlobar renal VTI and IRVF patterns might be a useful tool for evaluating intrarenal hemodynamic subsets such as the Nohria–Stevenson profiles, and may be therapeutic targets.21. High CVP, rather than low cardiac output, predetermines the risk of worsening renal function in decompensated HF10. Previous studies have shown that IRVF patterns were associated with increased RAP levels, and correlated with clinical outcomes22. The increased CVP causes the increase of renal interstitial pressure and intrarenal parenchymal compliance around the intrarenal vessels, fibrosis, and leads the resistance of IRVF24. It has been reported that 22.5% of HF patients showed monophasic IRVF pattern17, and that the IRVF patterns could be changed depending on the renal congestion, and their changes were associated with renal impairment and poor prognosis25. In the present study, prevalence of monophasic IRVF pattern was 10.6%, and was lower than 22.5% of previous study17. Although we could not fully explain the difference of their IRVF patterns, above changes in IRVF patterns25 depending on renal congestion might affect their differences. Increased renal interstitial pressure reduces hydrostatic and colloid osmotic pressure differences between glomerular capillaries and Bowman’s space26. In addition, systemic venous congestion raises neurohormonal activation (e.g. renin-angiotensin system) resulting in renal vasoconstriction28. Neurohormonal activation reduces the GFR30, decreases plasma natriuretic peptide31, leads to HF progression, may contribute to multiple organ failure32, and results in adverse prognosis33.Intrarenal congestion caused by increased CVP, namely increased right-sided pressure overload, has been one of the main pathophysiologic findings in CRS34. In pre-renal acute kidney injury, when renal hypoperfusion is sustained, eGFR is initially decreased without parenchymal damage35. The sustained inadequate oxygen and nutrient delivery to the nephrons and the adenosine triphosphate depletion activates epithelial cellular injury and death via necrosis or apoptosis, or both, which ultimately leads to endothelial injury, activation of inflammatory processes, and renal dysfunction35. Subsequently, afferent glomerular arterial vasoconstriction occurs and secretes renin, which further activates the renin–angiotensin system and results in efferent glomerular arterial vasoconstriction15.Regarding intrarenal hypoperfusion, the results of the current study suggest that low interlobar renal artery VTI was associated with low cardiac index, low systolic blood pressure, and low eGFR. Hypotension leads to intrarenal hypoperfusionThe current study reported the associations between impaired intrarenal perfusion and increased intrarenal congestion, as well as both cardiac function and prognosis. The combination of interlobar renal VTI and IRVF patterns might be a useful tool for evaluating renal hemodynamic subsets such as the Nohria–Stevenson profiles, and may be a therapeutic indicator for managing organ perfusion and congestion.Study limitations are as follows: first, the number of patients was relatively small and the follow-up period was comparatively short, because the study was carried out in a single center. We could not fully adjust confounding factors in the Cox proportional hazard analysis. Second, although HF patients with renal artery stenosis, dialysis or renal atrophy were excluded, we were unable to completely exclude the presence of subclinical renal diseases. Third, since we conducted the present study using variables measured only during hospitalization, changes in variables  after discharge were not examined. Fourth, since attending physician decided performing RHC, there might be potential selection bias. Therefore, the present results should be viewed as preliminary, and further studies with a larger population and longer follow up period are needed.3. Blood samples, abdominal ultrasonography and echocardiography were obtained at hospital discharge. Patients with poor quality of images from abdominal ultrasonography (n = 4), renal artery stenosis (n = 28), and/or end-stage renal disease receiving dialysis or renal atrophy (n = 7) were excluded. Of these 341 patients, RHC was partly performed in 166, among whom, in order to assess the interlobar renal artery VTI that could predict preserved cardiac index (≥ 2.2 L/min/m2), we measured the area under the curve of the receiver operating curve. A cut-off value with interlobar renal artery VTI of ≥ 14.0 cm predicted cardiac index (≥ 2.2 L/min/m2) with an area under the curve of 0.616 , with a sensitivity of 0.704 and specificity of 0.600. Of these 341 patients, 7 patients were excluded in VTI analysis due to unclear imaging. Finally, these patients were divided into groups based on A) interlobar renal artery VTI: high VTI group  or low VTI group  and B) IRVF pattern: monophasic group (n = 36) or non-monophasic group (n = 305).This was a prospective observational study of a total of 380 decompensated HF patients, who had undergone abdominal ultrasonography and were discharged from Fukushima Medical University Hospital between April 2018 and March 2019. The diagnosis of HF was defined by cardiologists based on the Framingham criteria, characterized by typical symptoms (e.g. breathlessness and fatigue) and accompanied signs . Cardiologists decided needs of hospitalization due to decompensated and/or worsening heart failure in all cases, when managements were necessary such as intravenous agents, respiratory care, dialysis, mechanical support, and etc37. The study protocol was approved by the Ethics Committee of Fukushima Medical University. All patients gave written informed consent. Informed consent from next of kin or legally authorized representatives is provided.First, we compared the clinical features and results from laboratory tests, echocardiography and RHC between the groups. In addition, we performed a correlation analysis of associations between levels of both of interlobar renal artery VTI or IRVF patterns, and parameters of laboratory tests, echocardiography, and RHC. Second, the patients were followed up until December 2019 for cardiac events as composites of cardiac death or unplanned re-hospitalization due to decompensated HF. For patients that experienced two or more events, only the first event was included in the analysis. Since these patients visited patient’s referring hospital monthly or bi-monthly, status and dates of death were obtained from the patient’s medical records. If these data were unavailable, status was ascertained by a telephone call to the patient’s referring hospital physician. This study complied with the Declaration of Helsinki and the STROBE  statement17. Pulsed Doppler waveforms of the interlobar arteries and veins were recorded simultaneously. As shown in Fig. 38. Doppler waveforms of IRVF were divided into three flow patterns: continuous, biphasic discontinuous, and monophasic discontinuous  IRVF patterns in the present study.Abdominal ultrasonography was performed by two experienced sonographers, who were blinded to all clinical data before discharge using an ultrasound system  equipped with a wideband convex i8CX1 multifrequency probe . Patients fasted for at least 12 h before the examination. IRD was recorded in the right kidney with the patient in the left lateral decubitus position. Color Doppler images were used to determine interlobar vessels. The velocity range of the color Doppler was set to approximately 12–16 cm/s in order to determine interlobar vessels, and the sample volume was set based on the color Doppler signals derived from interlobar vessels40. The echocardiographic parameters included LVEF, left atrial volume, LVOT-VTI, mitral valve E/e′, right atrium area, RV-FAC, inferior vena cava diameter, and TRPG. All measurements were performed using ultrasound systems 40.Patients underwent echocardiography performed by experienced echocardiographers using standard techniques as previously reported41.Of the 341 patients, RHC was partly performed based on remedial judgment of the attending physician in 166 patients. RHC was performed with in three days of abdominal ultrasonography, with the patients in a stable condition without changes in medications including doses, similar to setting of abdominal ultrasonography. All RHC was performed as previously reportedNormally distributed data are expressed as mean ± standard deviation. Non-normally distributed data are presented as median (interquartile range). The categorical variables are expressed as numbers (percentages), and the chi-square test was performed for its comparison. For the comparisons of parametric and non-parametric variables, Student’s t test and the Mann–Whitney U test were used, respectively. Associations between VTI and the parameters of laboratory data, echocardiography or RHC, were examined using Pearson’s correlation analysis for parametric variables, Spearman’s correlation analysis for non-parametric variables. Logistic regression analysis to determine the categorical variables associated with the interlobar renal artery VTI. Logistic regression analysis was also performed to determine the associations between monophasic IRVF pattern and other variables. Kaplan–Meier analysis was used with a log-rank test to assess cardiac event rates. These curves helped in identifying non-proportionality patterns in hazard function such as convergence (difference in risk between the groups decreases with time), divergence, or crossing of the curves. In addition, proportional hazard assumptions were confirmed by log–log analysis. We assessed IRVF patterns and interlobar renal artery VTI levels as predictors for post-discharge cardiac events using the univariate Cox proportional hazard analysis with only age and sex adjusted. Because of small number of events and sample size, as well as the presence of multicollinearity, we did not perform multivariate Cox proportional hazard analyses. In addition, we further classified patients into four subsets in accordance with Nohria–Stevenson clinical profiles: subset 1, high VTI and non-monophasic IRVF patterns (warm-dry); subset 2, high VTI and a monophasic IRVF pattern (warm–wet); subset 3, low VTI and non-monophasic patterns (cold–dry); and subset 4, low VTI and a monophasic IRVF pattern (cold–wet). The predictive value of classification was assessed using the Kaplan–Meier analysis and the Cox proportional hazard analysis. A value of P < 0.05 was considered statistically significant for all comparisons. These analyses were performed using SPSS ver. 26.0 .


To compare perioperative visual field (VF), balance functions (BF), and changes in the other ocular parameters in patients undergoing upper eyelid dermatochalasis (DC) surgery.  One hundred and fifty-eight eyes of 79 patients who underwent DC surgery were included in the study. The VF, BF, intraocular pressure (IOP), pachymetry (PM), macular, and optic nerve measurements were recorded. Measurements were repeated at postoperative month 1. The preoperative and postoperative ocular measurements and the balance data were compared. p < 0.05).  Nineteen of 79 (24.05%) patients were male and 60 of 79 (75.95%) were female, while the mean age of the patients was 58.65 ± 7.38 years. There were statistically significant differences in terms of VF and macular thickness between the preoperative and postoperative values. The improvements in mean defect, standard loss variance, and mean sensitivity values of global VF parameters in both eyes were statistically significant after surgery. Central macular thickness, mean macular thickness, and macular volume decreased significantly in all eyes after surgery ( Although a marked improvement was observed in VF and peripheral vision after surgery, no significant change was found in BF parameters including primarily falling risk. The significant change in the macular parameters was only remarkable, and we think that the decrease was due to subtle vasospasm. There is a need for further comprehensive studies including especially patients older than 65 with a view to understanding the effect of DC surgery on BF. Dermatochalasis (DC) is the most frequent cause of acquired pseudoptosis, which causes a decrease in superior visual field (VF) due to the loosening of the upper lid skin, which is folded by the atrophy of the elastic tissue with advanced age , 2. It lPosture control depends on the integration of information derived from proprioceptive, vestibular, and visual perceptive systems . Visual To the best of our knowledge, our study is the first to measure BF, macula, and optic nerve parameters as well in addition to perioperative VF, IOP, and PM measurements in patients with dermatochalasis. In particular, we think that BF evaluation will contribute to the literature as it can improve the quality of life in addition to its effect on visual quality after surgery., standard loss variance (sLV), and mean sensitivity (MS) values were assessed by perimetry . Central macular thickness (CMT), mean macular thickness (MMT), macular volume (MV), disc area, rim area, rim area/disc area ratio (RA/DA), ganglion cell layer (GCL), retinal nerve fiber layer (RNFL) thickness measurements, and also thickness measurements within four quadrants as superior, nasal, temporal, and inferior were assessed by optical coherence tomography . Intraocular pressure (IOP) and pachymetry (PM) values were measured with tonometry (Canon Noncontact TX-20).BF was measured by computer-based static posturography . Posturography is a diagnostic system which analyzes a subject's balance and the mechanisms employed to maintain balance. This method of posturography is based on the assessment of the vertical pressure fluctuations on four independent force plates, each placed beneath the two heels and toe parts of the subject while he/she stands in an upright position. The Tetrax plates  are equipped with a strain gauge, the output of which consists of fluctuations of voltage. This output is transformed by an A-D device into a digital signal, which is analyzed by Tetrax software. The weight of the examinee is automatically controlled by the software while height does not interfere with the Tetrax parameters, as shown by systemic examinations [STI is the numeric variable expression of a patient's postural defects and controls, which cannot be detected clinically. It evaluates changes in the center of gravity. The total amount of sway from the four footplates  is summed up and then divided by the subject's weight . That parameter was calculated as the square root of the sum of squared differences between adjacent pressure fluctuation signals, transmitted by the A-D device and sampled at a rate of 32 Hz for each of the four platforms. Limit values are considered as the standard deviations from 1.5 to 3. Higher values indicate higher imbalance , 15.The FHI is a regression analysis of postural sway intensity through the Fourier transform, which shows a different frequency for each lesion that causes instability. Transformations consisting of four independent wave signals are divided into eight different frequencies and recorded. The FHI evaluates the regression pattern of the eight Tetrax frequency bands. Tetrax program compares the Fourier power values of posturographic performance to a mathematically computed regression curve and evaluates the discrepancy between the graph obtained from the collected data and the theoretical “ideal” regression in the form of a coefficient. This spectral pattern is designated as Fourier Harmony and its coefficient as the Fourier Harmony Index. FHI is the assessment of normal posture performance. Values from 0.9 to 0.99 are the normal limits. If lower values are detected, they indicate problems in the visual, vestibular, and postural feedback mechanism .WDI shows discordant weight distribution in the foot platform and may be an indication of an orthopedic problem. WDI assesses the synchronization pressure patterns of feet and the pressure on the plates where the heel and the toe are placed, while the effectiveness of coordinated movements between the heel and the toes of each foot are also evaluated.Falling index is used to reevaluate the data. Its algorithm is based on the addition of standard deviation scores, which are obtained when calculating by how many standard deviations the performance of an examinee deviate from the mean of the normative database provided by IBS software. Adding the standard scores for stability, Fourier intensities of ∼0.3 and ∼1.00 Hz, and synchronizations, a fall index is graded as minimum falling risk (0–36), moderate level 37–58), high level (58–100), according to which precautions and supportive treatment can be planned , high le.t-test for paired samples. For the continuous variables that were not normally distributed, the Wilcoxon test was used to compare the preoperative and postoperative values. p values <0.05 were considered statistically significant.All data were analyzed with SPSS  software for Windows . Individual and aggregate data were summarized using descriptive statistics including mean, standard deviations, medians (min-max), frequency distributions, and percentages. Dependent variables with normal distribution were compared with Student's Out of 79 patients (158 eyes) who underwent upper DC surgery (blepharoplasty), 19 (24.05%) were male and 60 (75.95%) were female, while the mean age of the patients was 58.65 ± 7.38 years (Ranged: 36–84 years). In our study, no significant difference was found between the preoperative and postoperative visual acuity, IOP, and PM for both eyes .p < 0.05) (p < 0.05)  . Further < 0.05) .p < 0.05) decrease was observed in CMT, MMT, and MV values measured in all eyes (According to macular thickness and volume evaluation results; a statistically significant (all eyes . There wall eyes .While the balance functions in STI, FHI, and WDI dimensions were measured in various body, head, and eye positions , fallingThe VF test is applied for legitimizing the blepharoplasty. According to the international standard guidelines, upper margin-reflect distance should be more than 2.5 mm, and the VF has to improve by more than 30% after blepharoplasty . Kosmin Thirty percent of the population aged 65 and older die or become permanently disabled due to falling once a year or more . Every 1Retinal changes are observed mainly at early stages with the rise of retrobulbar hemorrhage after the blepharoplasty, followed by the application of local anesthetics containing epinephrine, vasospasm, inflammation, and systemic hypotension, respectively , 31. TheAtalay et al. assessed corneal hysteresis, corneal resistance factor, PM, and IOP and reported no significant difference in PM and IOP values after DC surgery . Bleyen In conclusion, BF, macula, and optic sinir parameters were evaluated for the first time in our study in addition to perioperative VF, IOP, and PM measurements in patients with dermatochalasis. Although a marked improvement was found in peripheral vision with VF, no significant change was observed in general in BF parameters including primarily fall risk. The significant change in the macular parameters was only remarkable, and we think that the decrease was due to subtle vasospasm. There is a need for further comprehensive studies including especially patients older than 65 with a view to better understanding the effect of blepharoplasty surgery on fall risk and balance functions.


To systematically evaluate the efficacy of Chinese herbal medicine Qiju Dihuang Decoction (QDD) for hypertension.  A comprehensive literature search of randomized controlled trials using QDD to treat hypertension was conducted in 7 electronic databases, including Chinese databases. Subjects and abstracts of the trials were read in NoteExpress for preliminary screening, and the full text was read for further screening. The data extraction table was made for the selected 19 trials, and risk of bias was assessed by using the Cochrane collaboration tool, followed by data analysis using Rev Man 5.3.  The antihypertensive efficacy of QDD is 1.45 times that of antihypertensive drugs and 1.56 times that of conventional therapies, which can also reduce the endothelin level. QPAD exhibits an antihypertensive effect, and its clinical efficacy is 1.34 times and 1.61 times that of antihypertensive drugs, which can not only significantly lower the diastolic blood pressure but also reduce the 24 h mean ambulate blood pressure. At the same time, it can decrease the TCM syndrome score, inhibit the inflammation, protect the renal function, reduce the insulin resistance, and improve the life quality of patients.  QDD can effectively reduce blood pressure and improve the life quality of patients with hypertension, which plays a certain role in preventing hypertension complications. However, due to the methodological deficiencies, more rigorous randomized controlled trials will be needed in the future to provide stronger evidence. Inner Canon of Yellow Emperor (Huang Di Nei Jing in Chinese). TCM believes that the onset of hypertension is mainly due to wind, phlegm, deficiency, blood stasis, and other diseases caused by the wind dizzy internal movement, phlegm and blood stasis, and Qi and blood block or Qing-qiao loss of nourishing, which results in the imbalance between Qi and blood and Yin and Yang. Therefore, the nature of hypertension is usually described as deficiency in origin and excess in superficiality.Hypertension is a common clinical cardiovascular disease with systemic arterial pressure increase as the main sign, which not only causes headache, dizziness, and other clinical symptoms but also damages important organs such as the heart, brain, kidney and eyes, and it further produces multiple system lesions or dysfunction . Its higMeasles Complete Book (Ma Zhen Quan Shu in Chinese), is one of the most commonly used TCM formulae for the syndrome of “liver and kidney Yin deficiency,” mainly used for vertigo, tinnitus, eyes acerbity photophobia, and vision dim [Lycium barbarum L.), Chrysanthemi Flos , Rehmanniae Radix Praeparata , Dioscoreae Rhizoma , Corni Fructus , Moutan Cortex , Poria , and Alismatis Rhizoma . Gouqizi and Shudihuang can benefit the kidney Yang and nourish essence, Juhua can clear the liver and improve the vision, Shanyao can tonify the spleen and nourish the kidney, Shanzhuyu can nourish the kidney and liver, Mudanpi can clear away the liver-fire, Fuling can induce diuresis with bland drug, and Zexie can infiltrate to remove dampness and turbidity. Pharmacological studies have found that QDD can improve the liver fat metabolism, reduce the capillary permeability, enhance the immunity, diminish the inflammation, delay the senility, and decrease the alloxan caused by high blood glucose. QDD contains many chemical components such as cycloene terpenes, flavones, cholines, and vitamin [Qiju Dihuang Decoction (QDD), recorded in the Qing Dynasty sion dim , 9. QDD  vitamin , 11. As  vitamin  but also vitamin , so as t vitamin , which p vitamin , regulat vitamin . AlthougThis study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) .gao xue ya” OR “xue ya” AND  that evaluated the effect of QDD for hypertension were searched in the following 7 electronic databases: the Chinese National Knowledge Infrastructure , Chinese Biomedical Literature Database , Wanfang Database (from 1998 to 2020), Weipu Database (from 1989 to 2020), PubMed (from 1959 to 2020), and Web of Science (from 1986 to 2020) and Springerlink (from 1996 to 2020). We used the following terms “blood pressure” OR “high blood pressure” OR “hypertension” OR “essential hypertension” OR “primary hypertension” OR “Trials were considered eligible for inclusion if the diagnosis of hypertension in the patients conformed to the diagnostic criteria established by the World Health Organization or International Hypertension Federation or the guidelines for the prevention and treatment of hypertension in China. And patients were not restricted by age, gender, or nationality. Studies were excluded if (a) the diagnostic criteria of the study object were unclear; (b) the patient had secondary hypertension; (c) the patient was accompanied by other adverse states ; (d) the patient was pregnant.The intervention measures in the treatment group should be QDD alone or in combination with other antihypertensive treatments. And, the control group should be other antihypertensive treatments or placebo, such as conventional therapy, conventional antihypertensive drugs, and lifestyle interventions (CADLI). However, trials involving qigong, TAI Chi, acupuncture, moxibustion, massage, and cupping as common interventions will be excluded.β2-microglobulin (β2-MG), N-acetyl-β-glucosidase (NAG), high sensitivity C-reactive protein (HsCRP), and adverse reactions.The primary outcome was defined as blood pressure, which included antihypertensive effects, systolic blood pressure (SBP), and diastolic blood pressure (DBP). The secondary outcomes included clinical effects, TCM syndrome score, life quality, 24 h ambulatory blood pressure, angiotensin II (Ang II), endothelin (ET), insulin sensitivity index (ISI), insulin (INS), mA1b, This study included a randomized controlled trial using QDD to treat hypertension in the experimental group. Studies were excluded if (a) they were not random; (b) no control group was used; (c) the experimental design was not rigorous and statistical methods are inappropriate; (d) it was on the indeterminacy of measurement index outcome criterion; (e) they failed to obtain effective analysis data; (f) they were animal experiments; (g) they were plagiarized.Two researchers independently screened the titles and abstracts of potential eligible studies, and then they retrieved and reviewed the full text of the possible studies based on the inclusion and exclusion criteria and extracted the data. If there was disagreement, they agreed through discussion or submitted it to a third party for evaluation. Data extraction table mainly included the basic information of the study , study characteristics , intervention and control measures , research methodology , and outcome measures.According to the Cochrane collaboration tool, two reviewers independently evaluated the methodological quality of each included study. It comprised the following seven aspects: random sequence generation, allocation concealment, blind method, incomplete result data, selective reporting, and other biases . The quaI2 test. I2 > 50% indicated that the heterogeneity of inter-study was significant, and the random effect model was adopted. And, the fixed effect model was adopted when I2 < 50% [Statistical analysis was performed using Rev Man 5.3 software. The results of a single study were firstly described. The binomial variables were described by using relative risk (RR) and 95% confidence interval (CI), and the continuous variables were described by mean difference (MD) and 95% CI to describe the effect value of the intergroup comparison. Heterogeneity was judged on the basis of the results of I2 < 50% . SubgrouBased on the retrieval strategy, 383 potential relevant literatures on the treatment of hypertension by QDD were preliminarily searched in 7 databases, and 244 literatures were retrieved after 139 copies were removed. After reviewing the titles and abstracts, 189 articles were excluded because they did not comply with the inclusion criteria and 55 articles initially met the intended criteria. After reading the full text, 19 eligible studies were included for meta-analysis –38. The β2-MG, and NAG were described in 1 trial [ 1 trial , and HsC 1 trial . All incn = 146; RR: 1.45; 95% CI: 1.03 to 2.05; p=0.03; n = 623; RR: 1.34; 95% CI: 1.14 to 1.58; p=0.0005; n = 230; RR: 1.56; 95% CI: 1.26 to 1.95; p < 0.0001; n = 193; RR: 1.09; 95% CI: 0.94 to 1.26; p=0.25).The antihypertensive effect was formulated in accordance with the criteria for the diagnosis and efficacy of TCM diseases . We usedn = 400; MD: −5.55; 95% CI: −7.19 to −3.19; p < 0.00001; n = 400; MD: −2.63; 95% CI: −8.06 to 2.81; p=0.34; n = 562; MD: −8.24; 95% CI: −10.04 to −6.45; p < 0.00001; n = 562; MD: −2.22; 95% CI: −19.37 to 14.94; p=0.80; n = 490; MD: −12.53; 95% CI: −15.79 to −9.28; p < 0.00001; Meta-analysis of 11 trials reported the changes in blood pressure levels before and after treatment , 37, 38.n = 172; RR: 1.61; 95% CI: 1.12 to 2.31; p=0.01; Clinical effect was determined by the TCM syndrome score. The clinical symptoms were significantly alleviated, and the TCM syndrome score was decreased by > 70% after treatment, indicating an obvious effect. At the same time, the TCM syndrome score was decreased by 50∼70% for improvement. No improvement or aggravation of symptoms and a reduction of TCM syndrome score below 50% is invalid. Obvious effect was used as an indicator of clinical efficacy. Two trials , 31 descn = 72; MD: −3.00; 95% CI: −3.61 to −2.39; p < 0.00001).The scoring method of TCM syndromes refers to the guiding principles for clinical research of new Chinese medicine . AccordiSF-36 was used to evaluate the life quality of patients. And, the higher the score, the higher the life quality.n = 172; MD: 9.12; 95% CI: 8.27 to 9.98; p < 0.00001; 2 trials reported changes in patients' life quality before and after treatment , 31. Comn = 80; MD: −13.30; 95% CI: −16.84 to −9.76; p < 0.00001) and diastolic blood pressure  as well as the standard deviation of systolic blood pressure . However, there is no obvious difference between QPAD and antihypertensive drugs in the standard deviation of diastolic blood pressure .24 h ambulatory blood pressure was only reported in one trial . Comparen = 100; MD: −76.00; 95% CI: −98.83 to −53.17; p < 0.00001). However, there was no remarkable difference between QDD and antihypertensive drugs .Ang II at baseline and after intervention was reported by 2 trials , 36. Comn = 72; MD: −9.12; 95% CI: −15.18 to −3.06; p=0.003).Only 1 trial described ET , and a sn = 60; MD: 1.13; 95% CI: 0.89 to 1.37; p < 0.00001).Only one trial reported ISI at baseline and after intervention , and then = 60; MD: −2.30; 95% CI: −3.23 to −1.37; p < 0.00001).INS level was also reported by the same trial as ISI, revealing that the reduction in INS was obviously greater for QPAD than that of antihypertensive drugs alone .Only 1 trial reported mA1b at baseline and after intervention . A remarβ2-MG level was reported in the same trial as mA1b. Compared with antihypertensive drugs, QPAD can lower the level of β2-MG better .The effect of QPAD on n = 90; MD: −4.97; 95% CI: −9.92 to −0.02; p=0.05).The same trial also reported the NAG level, in which QPAD was compared with antihypertensive drugs, and it was found to have a significant lowering effect in NAG .The HsCRP level at baseline and postintervention was reported by 1 trial that compared QPAD with antihypertensive drugs . The metNo adverse reactions were reported in all trials.Since fewer than 10 trials were included in each subgroup, publication bias could not be adequately analyzed.TCM has certain advantages and characteristics in the treatment of hypertension. In recent years, the classic TCM formulae for treating hypertension have attracted much attention –43. HoweThis systematic review and meta-analysis contained 19 trials and 2043 patients with hypertension, which evaluated the efficacy of QDD in the treatment of hypertension, including QDD vs. antihypertensive drugs, QDD vs. conventional therapy, QPAD vs. antihypertensive drugs, and QPCADLI vs. CADLI. In summary, this study has identified that QDD can significantly reduce the blood pressure, improve the antihypertensive efficiency, show an obvious lowering effect on TCM syndrome score, inhibit the inflammation, protect the kidney function, reduce the insulin resistance, and improve the life quality of patients. And, reduction of Ang II and ET levels is possibly one potential antihypertensive mechanism of QDD.Patients with long-term hypertension will lead to a variety of pathophysiological changes, which will not only cause headache, chest tightness, palpitations, and other symptoms but also may involve various organs and cause different complications. Therefore, hypertension is a major predisposing factor for many high-risk diseases. Many studies have also showed that the treatment of hypertension can play a preventive role in the occurrence of cardiovascular and cerebrovascular diseases . Effectiβ2-MG, and NAG, which proved that QDD could certainly prevent renal complications of hypertension.This study also discovered the potential mechanism of QDD for the reduction of blood pressure and the prevention of complications. Ang II vascular remodeling is one of the important pathological changes in the pathogenesis of hypertension, such as vascular smooth muscle proliferation, apoptosis, and other lesions, which will damage vascular walls, decrease vascular compliance, and lead to the imbalance of vascular active substances and disorder hemodynamic, all of which will lead to increase blood pressure. And, it was also reported to regulate the constriction of arterioles throughout the body and increase blood pressure . In addi2+, so it can significantly lower the blood pressure [QDD contains 8 single TCMs, including Lycii Fructus (Gouqizi), Chrysanthemi Flos (Juhua), Rehmanniae Radix Praeparata (Shudihuang), Dioscoreae Rhizoma (Shanyao), Corni Fructus (Shanzhuyu), Moutan Cortex (Mudanpi), Poria (Fuling), and Alismatis Rhizoma (Zexie). Anthocyanins from Gouqi  can not pressure . Alisol pressure . In addipressure , and elepressure .Hypertension belongs to vertigo or headache in TCM, and it often follows other symptoms according to its complex etiology. So, its treatment should consider the alleviation of some relative symptoms. Our research results showed that QPAD could significantly decrease the TCM syndrome score of patients and improve the life quality of patients. So, it has an obvious effect on reducing the clinical symptoms.With the accelerating pace of our life, the incidence of hypertensive patients increases year by year and shows a trend of becoming younger . TherefoAlthough the effects of QDD on hypertension were evaluated using a meta-analysis, there were some limitations. Firstly, though all of 19 included trials reported randomization, only 6 trials had the random number table. In 19 trials, one used a medical order and the rest of the test randomness was not clear. However, all trials had some deficiencies such as random allocation concealment, blinding of participants, personnel and outcome assessors, or selective outcome reporting. Secondly, no publication bias had been evaluated, because the number of trials included in each subgroup was too small (no more than 10). And, regarding the efficacy of QPAD for SBP, there was a greater heterogeneity among the 7 included trials. Thirdly, there are still 9 trials using modified QDD that does not exactly reflect the effect of QDD. Fourthly, QDD is widely used in the treatment of ophthalmic diseases in the clinic , but no β2-MG, NAG, and HsCRP level. At the same time, QDD can improve the effect of insulin resistance and patients' life quality. However, due to some less standard design of the included randomized controlled trials, more long-term, randomized and double-blind clinical trials will be needed in the future to provide stronger evidence for the treatment of hypertension with QDD.In summary, this study identified that QDD can significantly reduce the blood pressure of hypertension patients and improve the antihypertensive effects; furthermore, it shows a significant ET-lowering effect. Combining with antihypertensive drugs, it can also exhibit an obvious reduction on TCM syndrome score and average blood pressure of 24 h, Ang ?, INI, mA1b,


Chronic kidney disease (CKD) is an emerging disease worldwide. We investigated the relationship between blood pressure (BP) control and parafoveal retinal microvascular changes in patients with CKD. This case–control study enrolled 256 patients with CKD (stage 3–5) and 70 age‐matched healthy controls. Optical coherence tomography angiography showed lower superficial vascular plexus (SVP) vessel density, lower deep vascular plexus (DVP) vessel density, and larger SVP flow void area in the CKD group. The BP parameters at enrollment and during the year before enrollment were collected in patients with CKD. Partial correlation was used to determine the relationship between BP parameters and microvascular parameters after controlling for age, sex, diabetes mellitus, axial length, and intraocular pressure. The maximum systolic blood pressure (SBP) (p = 0.003) and within-patient standard deviation (SD) of SBP (p = 0.006) in 1 year were negatively correlated with SVP vessel density. The average SBP (p = 0.040), maximum SBP (p = 0.001), within-patient SD of SBP (p < 0.001) and proportion of high BP measurement (p = 0.011) in 1 year were positively correlated with the SVP flow void area. We concluded that long-term SBP was correlated with SVP microvascular injury in patients with CKD. Superficial retinal microvascular changes may be a potential biomarker for prior long-term BP control in these patients. Approximately 10–15% of the world’s population have CKD2, and the prevalence could be as high as 40% among diabetic patients3. CKD is associated with many systemic vascular complications such as atherosclerosis, cerebrovascular disease, and cardiovascular disease1. End-stage kidney disease may increase the risk of cardiovascular mortality by 10–30 folds1.Chronic kidney disease (CKD) is an emerging disease worldwide that is highly prevalent in elderly individuals and in patients with hypertension or diabetes mellitus (DM)6. Fundus photography provided a convenient tool for correlating the risk of systemic vascular diseases and retinal vasculature [e.g. the central retinal arteriolar equivalent (CRAE) and the central retinal venular equivalent (CRVE)]5. However, recent publications showed that systemic diseases may cause retinal capillary alterations preceding any visible pathology in fundus9. Optical coherence tomography angiography (OCTA) technology provides a rapid non-invasive method to quantify microvasculature at the capillary level in the different retinal layers. It could detect early subtle retinal microvascular changes from systemic diseases11.Retinal vasculature, which can be directly visualized using non-invasive tools, has been considered a potential window for systemic vascular complications12. eGFR was an independent factor associated with SVP vessel density13. However, the pathogenesis of these microvascular rarefactions in patients with CKD is yet to be determined12. Hypertension commonly comorbid with CKD; more than 80% of patients with CKD may have hypertension14. Nevertheless, the effects of hypertension on different layers of the retinal microvasculature are controversial17. We hypothesized that poor blood pressure (BP) control in patients with CKD may result in various microvascular changes among different retinal layers. This study aimed to evaluate the relationship between different BP parameters and microvascular changes in different retinal layers in patients with CKD. This information could help guide the management of patients with CKD and preventing retinal microvascular injury in them.Using OCTA, we had demonstrated decreased parafoveal microvascular vessel densities in both superficial vascular plexus (SVP) and deep vascular plexus (DVP) in patients with CKD18.In total, 256 patients with CKD and 70 healthy controls were enrolled in this study. The demographic data and clinical characteristics of the participants in both groups are summarized in Table 2. In total, 111 (43%) patients had DM whereas 221 (86%) patients had a history of hypertension. Recent (within 3 months) glycosylated hemoglobin (HbA1c) level was available in 93 of the 111 CKD patients with DM. The mean HbA1c was 7.2 ± 1.8%. The mean duration of hypertension was 7.6 ± 5.2 years.The mean duration of CKD was 7.8 ± 6.0 years. The CKD group consisted of 114 patients (44.5%) with stage 3, 47 (18.4%) patients with stage 4, and 95 (37.1%) patients with stage 5 disease. In total, 40 (42%) and 38 (40%) patients with stage 5 CKD were undergoing hemodialysis and peritoneal dialysis, respectively. The mean serum creatinine (Cr) of the patients in the CKD group was 4.7 ± 4.4 mg/dL, mean blood urea nitrogen was 44.2 ± 27.8 mg/dL, and mean estimated glomerular filtration rate (eGFR) was 27.8 ± 20.3 mL/min/1.73 mIn this study, the BP of most patients with CKD was well controlled during enrollment. There were no statistical differences in systolic blood pressure (SBP) and diastolic blood pressure (DBP) at enrollment between the CKD and control groups Table . DetailsTable Figure 20. The effect of blood pressure on different layers of retinal microvasculature is controversial, and diverse results have been found in patients with hypertension17. Chua et al. measured capillary density within a circular region of 1 mm diameter centered on the fovea in a group of patients with uncomplicated hypertension10. They found that compared with patients with well-controlled BP, patients with poorly controlled BP showed a lower foveal capillary density at DVP. In another study, Ciloglu et al. demonstrated that compared with healthy controls or pregnant women without pre-eclampsia, those with pre-eclampsia had lower parafoveal DVP vessel density17. By contrast, Lee et al. found decreased parafoveal SVP vessel density in patients with chronic hypertension (≥ 10 years) or relieved hypertensive retinopathy15. Similarly, Hua et al. showed that compared with healthy controls, patients with a history of hypertension for 5–10 years or more than 10 years showed decreased parafoveal SVP vessel density16. Our study also suggested that BP control is significantly correlated with the microvascular injury in SVP. These discrepancies might be attributed to the different severity and chronicity of hypertension in different studies.Microvascular rarefaction in both SVP and DVP has been found in patients with CKD, but the role of hypertension is yet to be determined. excluded patients with end-organ complications , and the mean eGFRs exceeded 90 mL/min/1.73 m2 in both groups in their study10. The “poorly” and “well” controlled BP groups were classified by a 24-h ambulatory BP measurement in their study. Similarly, pre-eclampsia in pregnant women is a temporary disorder in which their BP is usually carefully controlled and monitored by gynecologists after diagnosis. The intergroup difference in DVP vessel density in the above conditions might represent short-term vascular changes in response to BP elevation through autoregulation. Autoregulation is an important mechanism for maintaining a constant blood flow to the retina22. Retinal vasoconstriction can be readily observed in acute blood pressure elevation21. Improvement in retinal capillary rarefaction has also been reported after commencement of antihypertensive treatments in patients with hypertension11.Chua et al. and Hua et al. had either a long-term history of hypertension, or end-organ damage (e.g. hypertensive retinopathy)16. Our study also enrolled patients with specific end-organ disease, i.e. CKD. The decreased SVP vessel density in these patients may represent an accumulated or persistent damage of retinal microvasculature owing to the hypertension. A rodent model demonstrated the failure of autoregulation and morphological changes in retinal vessels after long-term hypertension21. Combining all these evidences and our results, we speculate that, in patients with CKD, retinal microcirculation in SVP might be more susceptible to injuries caused by chronic hypertension than retinal microcirculation in DVP is. Further longitudinal studies are required to confirm this speculation. Some patients in this study had severe microvascular rarefaction in SVP but relative good vessel density in DVP . However, it is intriguing that average SBP and proportion of high SBP measurement correlated only with SVP flow void area, but not with SVP vessel density. This might imply that increased parafoveal focal flow void area, which represents focal vascular defects, in the SVP may be an early sign of microvascular injury in patients with CKD. It might be a more sensitive parameter than SVP vessel density, which represents more diffuse microvascular changes in the retina.The maximum SBP and within-patient SD of SBP were 34. Controlling SBP may lower the risk of above complications37. However, DBP has recently attracted attention on its ability to predict cardiovascular outcome, especially in younger subjects39; its effects in retinal microvasculature should be further examined.SBP seems more important than DBP is in causing SVP microvascular injuries in this study. This observation is consistent with the prior theory that SBP was associated with systemic vascular complications such as cardiovascular disease, cerebrovascular disease, progression of CKD, and mortality43. Possible etiology may involve endothelial dysfunction, arterial stiffness and arterial remodeling46. Our study demonstrated BP variability’s potential influence on retinal microvasculature. Since retinal microvascular changes could be readily observed in vivo, they could be useful in future studies on the mechanism of vascular injury from BP variability.The BP parameters in the past 1 year, but not SBP/DBP at enrollment, correlated with microvascular parameters. This indicated that long-term BP control is more important than temporary BP elevation in causing microvascular changes in SVP. Furthermore, our study also showed that BP variability correlates better with SVP microvascular changes than with average BP. Visit-to-visit variability of BP is associated with the risk of cardiovascular diseases, cerebrovascular disease, progression of CKD and mortality48. Prior studies showed that 5–6 BP readings could be adequate to identify the relationship between visit-to-visit BP variation and end-organ injury49. Most patients follow up regularly in 1–3 month intervals in our study. The average number of BP measurements for each patient is 8.7 in the past 1 year. This could provide enough data for evaluating the BP variability in this study.There are various methods to measure visit-to-visit BP variation50. However, due to the associated cost and discomfort, ambulatory monitoring is usually only performed during the initial diagnosis of hypertension or when out-of-office hypertension is suspected (e.g. non-dipping hypertension or masked hypertension)50. Although we did not have ambulatory BP data in this study, most of our patients visit the same clinic regularly and BPs were measured at similar time points during their visits. This may minimize the influence of circadian rhythm.Because human BP exhibits a circadian rhythm, ambulatory 24 h BP monitoring is considered a better assessor of BP variability and a better predictor of cardiovascular events than traditional office BP is51. Because of high patient flow in our hospital, our patients’ BP was measured once in each routine follow up visit, instead of 3 times. It has been shown that after appropriate resting, the first AOBP measurement could highly correlate with the mean of 3 AOBP measurements (r = 0.92)47. A recent study also showed that one BP measurement appears adequate for patients with normal initial BP values52. Because patients with initial BP higher than normal could benefit from multiple BP measurements52, our hospital does perform multiple BP measurements for patients with higher than normal BP upon the physician’s request. Our patients were also encouraged to perform home BP monitoring (HBPM) and submit the data during follow-up visits. HBPM is as accurate as ambulatory BP53, and may facilitate physician’s adjustment of antihypertensive medications.Our hospital generally used unattended automated office BP (AOBP)—which could be similar to daytime ambulatory BP and is more accurate than traditional office BP measurement8, which could affect OCTA parameters in CKD patients12. Among CKD patients with DM, the HbA1c level was correlated with SVP vessel density. We repeated the statistical analysis in this subgroup by replacing DM with HbA1c as a covariate in the partial correlation models. The results were similar to those from the entire CKD group except that the correlation between average SBP and SVP flow void area had become insignificant (p = 0.253). The maximum SBP and within-patient SD of SBP were correlated with SVP vessel density (p = 0.008 and 0.006) and SVP flow void area (p = 0.003 and < 0.001). This may support that BP variability and blood sugar control are independent factors for microvascular injuries in this subgroup of patients.DM was a covariate in our partial correlation models because it may cause retinal microvascular changesThis study has several limitations, one of which is its small sample size. Subgroup analysis (such as different stages or different etiologies of CKD) was difficult in this study owing to the small number of patients. Moreover, the duration of CKD and of hypertension had no significant correlation with OCTA parameters. However, the duration may be inaccurate because these diseases are typically diagnosed with an unspecified delay after onset. The effect of different classes of antihypertensive medications was not evaluated in this study. The variation in the classes and the dosage of medications used make statistical analyses difficult for the small sample size of this study. Finally, ambulatory 24 h BP monitoring data from the CKD group and long-term BP data from the control group were not available.In summary, our study demonstrated that the long-term BP parameters correlated with parafoveal SVP vessel density and parafoveal SVP flow void area on OCTA in CKD patients. The SBP variability may play an important role in the SVP microvascular injury. Further longitudinal studies are warranted to confirm whether retinal microvascular parameters on OCTA can be potential biomarkers to help monitor long-term BP control in CKD patients. Animal models would also help illustrate the possible mechanisms of these retinal vascular injuries.We conducted a prospective case–control study between August 2017 and July 2019 in the Department of Nephrology and the Department of Ophthalmology in our hospital. This study was approved by the Chang Gung Memorial Hospital Institutional Review Board (IRB No.: 201602022B0 and 201702074A3) and followed the tenets of the Declaration of Helsinki.2 for more than 3 months54. Using the Chronic Kidney Disease Epidemiology Collaboration equation, eGFR was calculated from serum Cr55. Patients with CKD who were regularly followed up in the Nephrology Department for ≥ 1 year were invited to participate in this study. CKD was classified according to the eGFR values into stage 3 (30–59 mL/min/1.73 m2), stage 4 (15–29 mL/min/1.73 m2), and stage 5 (< 15 mL/min/1.73 m2). The inclusion criteria for the CKD group were patients (1) with CKD stages 3–5 ; (2) aged ≥ 21 years; and (3) with no visual symptoms. Controls were age-matched healthy subjects without retinal disease in a 4:1 ratio. Patients with (1) significant ocular media opacity; (2) inadequate quality of spectral-domain optical coherence tomography (SD-OCT) or OCTA image ; (3) pregnancy; (4) axial length ≥ 26 mm; (5) blood pressure measurements undertaken < 3 times in the past 1 year in the CKD group; or (6) presence of any diabetic retinopathy were excluded. Written informed consent was provided by each participant. If both eyes were illegible, the eye with better OCTA image quality was chosen for statistical analysis.CKD was defined as (1) abnormalities of kidney structure or function that present for more than 3 months and (2) eGFR < 60 mL/min/1.73 mAll patients underwent BP measurement at each visit in the Nephrology Department, as well as on the date of enrollment. An unattended automated office BP (AOBP) was measured in a BP Suite of our hospital. Patients sat with their backs supported for at least 15 min. SBP and DBP were then measured using an automatic blood pressure monitor . The data would then be automatically recorded into the patients’ electronic medical records. Patients with BP above normal may receive repeat BP measurements at the physician’s discretion.The average SBP/DBP in 1 year were calculated by averaging all available blood pressure measurements in the past 1 year. The maximum SBP/DBP indicated the highest recorded SBP/DBP in the past 1 year. The within-patient SD of SBP/DBP, defined as the SD of all BP measurements of individual patients within the past 1 year, was used to evaluate the within-patient blood pressure fluctuation. The proportion of high SBP measurement in each CKD patient was defined as the number of measurements with SBP > 140 mmHg/total number of BP measurements.A complete ocular exam was performed for each patient on the date of enrollment. BCVA was measured using a Snellen chart and converted to the logarithm of the minimum angle of resolution (logMAR) for statistical analysis. Intraocular pressure and axial length were measured using a non-contact tonometer  and an IOLMaster , respectively. SD-OCT and OCTA images were acquired using AngioVue . Retinal microvascular parameters including parafoveal SVP vessel density, parafoveal DVP vessel density, foveal avascular zone, and parafoveal SVP flow void area were determined from OCTA images.12. In brief, the OCTA image of each eye was acquired through a 304 × 304 A-scan covering an area of 3 × 3 mm2 centered on the fovea in the macular region. The AngioVue software (version: A201710151) automatically segmented the vascular area into four layers, i.e., superficial, deep, outer retina, and choroidal. The SVP included the vasculature between the internal limiting membrane and 10 μm above the inner plexiform layer; the DVP included the vasculature between 10 μm above the inner plexiform layer and 10 μm below the outer plexiform layer12. Vessel density was defined as the percentage area occupied by all the large and small vessels within the region of interest. The foveal region is a circle measuring 1 mm in diameter, and the parafoveal region is a 1-mm wide circular annulus. Foveal avascular zone size, parafoveal SVP vessel density, and parafoveal DVP vessel density were automatically calculated by the AngioVue software.The acquisition and analysis of OCTA images were similar to our prior report57. We conducted an in-house validation of the OCTA vessel density measurements by using the data from 20 eyes without retinopathy. The mean intra-visit coefficients of variation (CV) was 1.7% (SD 1.9%) for SVP and 1.5% (SD 1.6%) for DVP; while the inter-visit CV was 3.3% (SD 3.8%) and 3.1% (SD 3.0%), respectively.These OCTA parameters had good reliability and reproducibilityThe parafoveal SVP flow void area in each eye was determined from a superficial OCTA image. It was analyzed automatically by Python codes using three developed systems, including (1) image quantification, which applies three histogram equalizers to optimize the skeleton method, (2) generation of the Gaussian density map system, and (3) ischemic area detection Fig. .Figure 458 are applied to separate the obvious large vessel and the obscure small vessel. Given a grayscale image x, after applying the equalizer the pixel intensity x is converted to h), wherecdf(v) is the cumulative distribution function , and MN is the size of the image.In the process of OCTA image quantification, OpenCV color histogram equalizers61, to calculate the perfusion area, we apply Zhang’s skeletonized method36 to quantify the density vessel. Second, the Gaussian Blur filter in OpenCV with a block size of 35 is used to define the perfused area rather than using the color-coded based method60, because the Gaussian Blur filter facilitates representation of the perfused area of OCTA images. The Gaussian Blur filter G is given asL is the block size, i, j = 0, 1, …, L − 1, and α is the scale factor to make According to the statistics of the vessel color distribution, a pixel value around 185 is chosen as the threshold for binarization. After performing the color histogram and binarization three times, the vessels with a variety of sizes can be well extracted. Further, according to previous studies37 is adopted to calculate the areas of non-vessel regions and determine the sizes of the foveal avascular zone over the parafoveal area.Third, after generating a clear perfusion map, the ischemic areas are identified. The non-perfused vessel detection algorithm is applied to identify low-pixel-value regions, which are the regions with less blood vessels, from the vasculature Perfusion Map. Finally, the famous contour detection methodt-test for continuous variables. The difference between the start and the end of the study was evaluated by comparing the first and last BP measurement by paired sample t-test. Partial correlation was used to determine whether BP parameters, duration of CKD, and duration of hypertension correlated with parafoveal retinal microvascular parameters among patients with CKD after controlling for age, sex, DM, axial length, and intraocular pressure. Among patients with CKD and DM, partial correlation was used to determine the relationship between recent HbA1c level and parafoveal retinal microvascular parameters after controlling for age, sex, axial length, and intraocular pressure. A two-tailed P value < 0.05 was considered statistically significant. All data were analyzed using SPSS version 17.0 .The demographic data and clinical characteristics between the CKD and control groups were compared using Pearson's chi-squared test for categorical variables and the independent sample


Residents in a large area of North-Eastern Italy were exposed to perfluoroalkyl substances (PFAS) via drinking water. Studies on the association between PFAS and blood pressure levels are limited, and results are inconsistent. Using cross-sectional data from the Regional health surveillance program, we aimed to quantify the associations between PFAS serum concentrations and blood pressure and hypertension prevalence.n = 327), or individuals with missing information on the selected covariates (n = 111) were excluded, leaving 15,786 subjects for the analyses. Hypertension was defined as any self-reported diagnosis, use of antihypertensive drugs, or elevated systolic blood pressure (SBP ≥ 140 mmHg)/diastolic blood pressure (DBP ≥ 90 mmHg). Generalized additive models were used to investigate the relation between perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA)) natural log (ln) transformed and by decile, and SBP, DBP, hypertension, adjusted for potential confounders.The study comprised 16,224 individuals aged 20–39 years. Pregnant women (Both SBP and DBP increased significantly with an increase in the ln-transformed serum PFAS concentrations in a monotonic way. The predicted increase in SBP and DBP were 1.54 mmHg (95%CI 0.61–2.47), 1.60 mmHg (95%CI 0.92–2.27) from lowest to highest decile of PFOA. The associations were stronger for SBP in men and for DBP in women. One unit increase in each In-transformed PFAS was positively associated with an increased odd of hypertension in men: PFOA OR = 1.06 (1.01–1.11), PFOS OR = 1.13 (1.03–1.23), PFHxS OR = 1.08 (1.02–1.15), PFNA OR = 1.20 (1.02–1.40).. Although the magnitude of the observed effect was relatively small, if confirmed it would be of public health relevance since even small increases in blood pressure levels at the population level may be associated to a raised risk of adverse outcomes such as cardiovascular disease and target organ damage.Our findings suggest that serum PFAS concentrations were associated with increased systolic and diastolic blood pressure in a large highly exposed young adult population Perfluoroalkyl substances (PFAS) are ubiquitous and highly persistent man-made chemicals widely used for a variety of commercial and industrial applications due to their grease-, stain, and water-repelling properties . ConsequPFAS exposure has been associated with a number of risk factors of cardiovascular disease (CVD) including dyslipidemia, metabolic syndrome and thyroid disease . High blGroundwater of a vast area of the Veneto Region  was found to be contaminated by PFAS from a manufacturing plant active since the late 1960s. Residents were exposed to high concentrations of PFAS, particularly perfluorooctanoic acid (PFOA) through drinking water, until autumn 2013 [The study consisted of 16,224 individuals aged 20–39 years recruited in the health surveillance program offered to the community of Veneto Region who was exposed for several decades to PFAS via drinking water distributed by contaminated public waterworks. The health surveillance program has been described in more detail elsewhere [n = 327), and individuals with missing information on the selected covariates (n = 111) were excluded, leaving in the analyses 15,786 subjects. No missing data on exposure and outcome variables were present : perfluorooctanesulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorohexanesulfonic acid (PFHxS), perfluorononanoic acid (PFNA), perfluoroheptanoic acid (PFHpA), perfluorobutanesulfonic acid (PFBS), perfluorohexanoic acid (PFHxA), perfluorobutanoic acid (PFBA), perfluoropentanoic acid (PFPeA), perfluorodecanoic acid (PFDeA), perfluoroundecanoic acid (PFUnA), and perfluorododecanoic acid (PFDoA). Details of the analytical method have been described elsewhere .n = 6), PFOS > 50 mg/L (n = 9), PFHxS> 100 mg/L (n = 3), PFNA > 10 mg/L (n = 1)).Method performances allow analytes to be detected as low as 0.1 ng/mL (LOD) and to be quantified above 0.5 ng/mL (LOQ). Only four PFAS quantifiable in at least 40% of samples were considered for the analyses: PFOA (detected in 99.86% of people), PFOS (detected in 99.70% of people), PFHxS (detected in 96.72% of people), PFNA (detected in 49.86% of people). Samples below the LOQ were assigned a value equal to LOQ/√2. The most extreme outliers of PFAS serum levels were removed as followings: (PFOA> 700 mg/L (n = 1078). Otherwise, the mean of the two measurements was considered when both measurements were above the cut-offs (n = 636).Blood pressure (BP) was measured by trained nurses with participants first sitting at rest for at least five minutes, according to the European Society of Hypertension recommendations . A validMedical history data were collected directly from participants by trained nurses via structured software-based questionnaire using in-person interviews at the study enrolment. The questionnaire included items on personal health history (“Which diseases do you suffer from?”) and medications .Hypertension was defined considering any self-reported diagnosis of hypertension, reported use of antihypertensive medications, or raised SBP (≥140 mmHg) or DBP (≥90 mmHg).2), normal weight (18.5–24.9 kg/m2), overweight (25–29.9 kg/m2), obese (≥30 kg/m2). Alcohol consumption was categorized in 0, 1–2, 3–6, 7+ alcohol units per week. Smoking status was subdivided into current smokers, previous smokers and non-smokers. Degree of physical activity  was defined based on an algorithm that combined information reported by the subject on intensity, duration, and frequency of all types of physical activity practiced during the week [We obtained information on age, gender, country of birth, education level, smoking habits, body mass index (BMI), physical activity, history of certain diseases, medication, alcohol consumption, and food intakes including salt habit. Standard data checks and cleaning procedures (e.g. range and consistency checks) were used to minimize errors and missing values and to maximize data quality. Data on food consumption were transformed from number of serving per day/week/month to number of serving per week for all the food categories to create harmonized diet pattern classification. After checking the accuracy of data on BMI regarding height and weight, BMI was recalculated and classified as underweight (< 18.5 kg/mwww.dagitty.net) implemented in R .Covariates to be included as potentially confounders of the BP/PFAS association were selected from the available variables, based on related literature, through the construction of a directed acyclic graph (DAG) representing the identification of a minimally sufficient set of variables to control confounding. The minimally sufficient adjustment set was identified using DAGitty v1.0  and percentiles. Since data on PFAS were markedly skewed to the right, concentrations were natural log (ln) transformed in order to improve normality of the data distribution. Spearman’s correlation (ρ) was used to describe pair-wise relations between the PFAS.n = 406) were excluded, leaving 15,380 subjects in analysis  to analyze the relation between each (ln) PFAS and BP outcomes, adjusted for the potential set of confounders. In order to explore the shape of possible associations between PFAS and BP levels the models used thin plate spline smooth terms  for the For the analyses on PFAS associations with hypertension prevalence, a binomial link function was used in the models and Odds Ratios (ORs) were calculated, together with their 95% confidence intervals (95%CI).All analyses were fully adjusted for the established set of covariates: age, BMI, time-lag between the enrolment and the beginning of the study  and categorical covariates including gender, physical activity, smoking habits, food consumption , salt habit, country of birth, alcohol consumption, education level and center in charge of the BP measurement .All the above analyses have been also stratified according to gender and an interaction term between gender and ln-PFAS was also added to the main models.Since PFAS are predominantly excreted by the kidney through glomerular filtration and impaired kidney function is associated with raised BP , to asseFinally, we analysed SBP and DBP associations with PFAS excluding subjects with raised BP (SBP ≥ 140 mmHg or DBP ≥90 mmHg).The procedures of the health surveillance program changed over time: until 31 December 2017, blood sampling, and interview and BP measurement were carried out in the same session for each participant, whilst thereafter they were performed in two different sessions roughly 1 month apart in order to be able to provide blood test results on the day the participant came for the interview and the BP measurement. To explore whether this organizational change may have affected the PFAS/BP associations, analyses were also restricted to the subgroup of 10,656 individuals recruited after 31 December 2017.http://www.R-project.org/) was used for statistical analyses.The level of statistical significance was set at 0.05. The statistical software STATA/SE version 13.0  and R , followed by PFOS (median 3.7 ng/mL), PFHxS (median 3.6 ng/mL), and PFNA (median 0.35 ng/mL). The highest serum levels of all PFAS were found in males compared to females. Moderate to strong correlations were observed among the measured PFAS. The most highly correlated compounds were PFHxS with PFOA (ρ = 0.91); while the least correlated were PFNA with PFOA and PFHxS (both ρ = 0.40). The Spearman correlation coefficients of PFOS with PFOA and PFHxS were 0.63 and 0.68, respectively.Hypertension was detected in 1971 (12.5%) of the recruited subjects . Significant differences in demographic and lifestyle characteristics according to hypertensive status were observed among participants . Adjusting for eGFR did not change the results of the observed associations between PFAS and SBP or DBP .Table In the present cross-sectional study consisting of more than 15,000 young adults from a highly exposed community, serum PFAS concentrations displayed a positive association with blood pressure levels and were also associated with a raised prevalence of hypertension in men. The magnitude of the association with blood pressure was relatively small and for/regarding systolic blood pressure, was significantly modified by gender, with associations seen almost only for men.n = 7543) reported no significant association with blood pressure, but blood pressure was not the primary outcome of this study [n = 1655) found no evidence of an association between serum PFAS and blood pressure or hypertension [n = 2251) found a positive significant association between PFOS and DBP among males [n = 48–187) reported positive [n = 1612) investigated the association between blood pressure and several PFAS congeners, including linear and branched isomers [To the best of our knowledge, this is the first study that formally investigated the shape of the association between serum PFAS and blood pressure in a large population of highly exposed community residents  consisting of a homogeneous age group of young adults from 20 to 39 years old. Literature on the association between PFAS exposure and blood pressure and/or hypertension (defined as self-reported diagnosis or treatment or elevated measured blood pressure) is relatively limited, with contradictory findings. Some large cross-sectional studies were conducted on representative samples of the US general population with background exposure using data from the NHANES survey , 18, 19.is study . The othis study , 18, yieng males . Other cpositive , 13, nulpositive  or negatTo our knowledge, only two studies assessed the association between PFAS exposure and blood pressure or hypertension with a longitudinal design , 22. In As outlined above, the available literature shows several inconsistencies: the direction, statistical significance, and magnitude of associations, as well as the gender effect modification, were different among studies. This may be attributable to the heterogeneous characteristics of the investigated populations, in terms of age, social context, and levels of exposure. Moreover, reported effect sizes are poorly comparable with each other. The two studies more comparable with the present one in terms of design and population size were conducted on the general US population with exposure levels quite different from ours , 12. MinAlthough the magnitude of the observed effect was relatively small, if confirmed it would be of public health relevance since the greatest magnitude of effect was observed at lower serum PFAS concentrations corresponding to background exposure and it is widely recognized that even small increases in blood pressure levels imply a raised risk of adverse outcomes such as CVD and target organ damage . It has The biological mechanisms underlying the association between PFAS exposure and elevated blood pressure have still to be fully elucidated. Potential biological pathways may include oxidative stress leading to impaired vasodilation –37. OxidThe observed gender differences were inconsistent between studies , 11 and Strengths of this study include the large population and the availability of an accurate measure of the internal dose of PFAS and of information on several anthropometric, lifestyle, and clinical variables, that allowed adjustment for many possible confounders. The high dispersion of serum PFOA concentrations in our population allowed to model concentration-response curves over a wide range of internal doses, covering both background and high exposure levels. Moreover, we systematically evaluated gender-specific associations. The main limitation is the cross-sectional design that precludes evaluation of the temporal relationship between exposure and outcome. A limitation in looking at individual PFAS is that they are highly correlated. Especially for the compounds with lower serum levels, such as PFNA in our study, the association may reflect associations driven by the correlated PFAS at higher concentration. The high correlation also prevents multipollutant models to assess their mutual adjustment. Also, we were unable to investigate the role of different PFAS isomers since only total PFAS serum concentrations were available. Another important limitation is that in most subjects we relied on a single blood pressure measurement. Blood pressure is subject to high intra-individual variation, therefore a single measurement may be poorly representative of an individual's mean blood pressure . MoreoveIn conclusion, our findings suggest that serum PFAS concentrations are associated with raised blood pressure levels with the greatest increases seen at the lower internal dose range. These are cross-sectional associations and should be interpreted with caution and the average change in blood pressure is quite modest. However, PFAS exposure is widespread and so if the association is causal, it would imply a significant population health impact. Such findings should be confirmed by further studies with a longitudinal design and more refined methods to measure blood pressure levels. Moreover, longitudinal studies are warranted to assess whether PFAS exposure is a risk factor for the development of cardiovascular events.Additional file 1: Figure1. Flowchart of the study population.Additional file 2: Table1. Descriptive statistics of diet and center where Blood Pressure has been measured.Additional file 3: Table2. Descriptive statistics in subjects with or without hypertension, stratified by gender.Additional file 4: Figure 2. Exposure–response curves for PFAS exposure and Systolic and Diastolic Blood pressure from GAM models using thin plane splines, with 95% confidence intervals, stratified by gender. The predicted levels are based on average characteristics used as covariates in the models.Additional file 5: Figure 3. Predicted values of Systolic and Diastolic Blood Pressure by deciles of PFAS distribution.Additional file 6: Table3. GAM model with using PFAS thin plate spline smooth terms: EDF and p-values.Additional file 7: Table 4. GAM models adjusted by eGFR (cut-off 90 ml/min).Additional file 8: Table 5. GAM models on a restricted population recruited after December 2017 .Additional file 9: Table 6. GAM models on a restricted population, excluding subclinical hypertensive .