Pregnancy-induced changes in cardiovascular status make women more susceptible to pulmonary edema. During cesarean section, to counterbalance the effect of hypotension caused by spinal anesthesia, anesthesiologists must choose between two fundamental approaches to maintain the hemodynamic state—intravenous fluids or vasopressors—and this choice will depend upon their particular opinions and experience. We aim to assess for any correlations between thoracic ultrasound A- and B-line artifacts, brain natriuretic peptide (BNP) levels, and the amount of intraoperative fluids administered.p = 0.035) between the patients presenting B-lines in at least one basal area of their thoracic ultrasound and patients with no evident B-lines . Dividing the population on whether their BNP levels were higher or less than 20 pg/mL, no statistically significant difference was revealed with regard to fluids administered in the first 24 h (p = 0.537).From December 2016 to August 2018, at the University-Hospital of Udine, we enrolled 80 consecutive pregnant women undergoing cesarean section. We observed a statistically significant difference in the volume of fluids administered in the first 24 h (Thoracic ultrasound is a non-invasive and easy-to-use tool for detecting fluid intolerance in pregnant women undergoing cesarean section. BNP levels were slow to rise following the cesarean section and did not show any clear correlation with fluid volumes administered. In the obstetric population, thoracic ultrasound (TUS) assessment and monitoring is a feasible and helpful diagnostic tool . ImportaThis observational, single-center, retrospective study was carried out at the University-Hospital of Udine —a level-3 maternity center performing approximately 300 cesarean sections per year. Ethical approval was provided by the Regional Ethics Committee of Friuli-Venezia-Giulia on 5th February 2019, ID #2637, for principal investigators Dr. V.L. and Dr. T.D.Before performing the statistical analysis, the trial was registered at clinicaltrials.gov with NCT number 03851679 on 20th February 2019. Given the retrospective design of the present study, patient consent was waived, but the European Privacy Regulation 2016/679 on General Data Protection Regulation (GDPR) was respected. Only pregnant women aged 18 years or over undergoing elective cesarean section in the absence of hypertensive disorders at gestational age no less than 37 weeks were included in the study; all women presented a physical status of 2 according to the American Society of Anesthesiologists classification system. Exclusion criteria were: emergent cesarean section, a history of pre-existing respiratory or cardiac disease, twin pregnancy; refusal to participate in the study.In the operating theater, non-invasive standard monitoring with heart rate, non-invasive arterial pressure, and peripheral oxygen saturation were used . For subarachnoid anesthesia, the patient was placed on their left side and a 25 G Sprotte needle  inserted by the resident physician or the consultant anesthesiologist following a failed first attempt. Following cephalorachidian fluid spread, 2 mL hyperbaric bupivacaine 0.5%   plus 0.1 mg morphine , as long-term analgesia, were injected. Immediately afterward, the patient was returned to the supine position, and the uterus pushed to the left. Arterial hypotension was controlled using a 3 mL/kg fluid challenge of crystalloids  or an ephedrine bolus . A bladder catheter was placed in the ward before coming into the theater. The surgeon then performed a Pfannenstiel skin incision with the layered opening of the abdomen and celiotomy. The bladder–uterine fold was opened and the bladder detached at the bottom. A transverse incision was made on the lower uterine segment and the uterine breach opened by digital divulsion followed by fetal extraction .T0). Postoperative BNP was measured at 6 (T1) and 24 h (T2) after surgery. Blood was collected in EDTA and lithium heparin vacutainer tubes, and sent immediately for analysis to the laboratory  where BNP concentrations were assayed using a Bayer ADVIA Centaur-TM. Test values were not known in real-time, and the physician and patients were blind to their results.Patient venous access was obtained before entering the operating theater, and a blood sample taken for the first BNP dosage , at T1 (6 h after cesarean section), and T2 (24 h after surgery).Thoracic ultrasound was performed in a semi-recumbent position using a SonoSite machine  with a convex or linear probe and the “eight-region technique” as defined by the “International Consensus Conference on Lung Ultrasound” . The proThe perioperative data collected also included details regarding the duration of surgery; the spinal thermal level at discharge from the operating room, blood loss (mL); intraoperative diuresis (mL); and administered crystalloids (mL). Follow-up was planned until discharge.T0, T1, and T2) and applied ANOVA to assess for any statistically significant differences between the three groups. We used Hommel’s method to correct for multiplicity /BNP1) at the different time points (iplicity .http://www.R-project.org).All statistical analyses were carried out using SPSS Statistical Package version 22  and R-Cran ver. 3.4.2 language and environment for statistical computing , 80 patients would allow us to obtain an estimate of this prevalence with an accuracy of 10%, which for this study was considered acceptable from the clinical point of view.p = 0.035)  and 6 (T1) and 24 h (T2). As regards the relative increase between the three analysis times , we found a statistically significant difference between the last two time comparisons . The BNP comparisons are shown in Fig. T2) greater than 20 pg/mL, we did not observe a statistically significant difference with regards to fluid balance in the first 24 h . A statistically significant correlation was observed between the median BNP value at the time of delivery and 24 h ; while no correlations were observed between BNP and TUS, or between BNP and the volume of fluid administered  correlate in the first hours with the volume of fluids given during the perioperative period of cesarean section, whereas BNP levels were slow to increase and did not shown any clear correlation with administered fluid volumes. Thoracic ultrasound is a non-invasive and easy-to-use tool that holds great promise for the detection of fluid intolerance in pregnant women. A multi-center study is now warranted to confirm our results.


Metabolic acidosis is associated with the high mortality seen in hemodialysis patients. The panorama of metabolic acidosis in hemodialysis in Brazil is unclear since 1996 when the analysis of bicarbonate levels was no longer a compulsory exam. We aimed to establish the prevalence of metabolic acidosis in a hemodialysis population and analyze the factors associated with low bicarbonate levels.A cross-sectional study was carried out to assess the prevalence of metabolic acidosis in adults undergoing regular hemodialysis from January to April 2017, in four dialysis centers from Niteroi, Rio de Janeiro, Brazil, and surroundings. For blood gas analysis, samples of 2 mL were collected in heparinized syringes before a midweek dialysis session.2 in the midweek session was 22.7 ± 3.0 mEq/L. The prevalence rate of serum bicarbonate below DOQI recommendation (22 mEq/L or higher) was 40.3%, and 6.5% had serum bicarbonate < 18 mEq/L. The dialyzer use count and the use of low-flux dialyzers were negatively associated whereas age and the standard Kt/V values were positively associated with the serum bicarbonate levels.384 patients with a mean age of 58.1 ± 15.8 years  were included. Approximately 30% had diabetes and 48%, hypertension. Nearly 88% used primary arteriovenous fistula as vascular access. The pre-dialysis mean serum tCOThe findings were in agreement with global data reported in previous studies. However, because the sample was relatively small and non-representative of the Brazilian population, a more comprehensive study, addressing national data is necessary to substantiate our findings. Data were collected from January to April 2017. The convenience sample consisted of patients from four centers who agreed to participate. Patients less than 18 years old, with less than 3 months in hemodialysis, or positive serology for hepatitis and HIV were excluded. The Ethics Committee of the Medical School of Universidade Federal Fluminense approved the study under the number CAAE 57822316900005243 and all patients provided signed informed consent. The study conformed to the principles of the Declaration of Helsinki.®, Gambro, Bad Homburg, Germany); and center 4, low-flux dialyzers . In every center, dialyzers were reprocessed with peracetic acid as the sterilant solution by an automated system for a maximal of 20 times following Brazilian renal replacement therapy regulations. Fresenius Medical Care  manufactured all the dialysis concentrates used. Characteristics of the dialysis treatment of each center are listed in Dialysis centers were numbered from 1 to 4. In centers 1, 2, and 3 dialysis sessions were performed using 4008S hemodialysis machines . In center 4, hemodialysis machines consisted of Diamax or Surdial . Centers 1 and 2 used high-flux polysulfone dialyzers ; center 3, high-flux polyamix dialyzers  before a midweek dialysis session. Species were collected from the indwelling needle used to puncture the arterial limb of the arteriovenous fistula or directly from the central intravenous catheter after discarding the volume corresponding to the priming capacity of the device. After collection, the syringe was stored on ice and collectively transported to the laboratory within one hour.http://www.hdcn.com/calcf/ley.htm), and requires the urea reduction ratio value for computation.We collected all clinical data and routine laboratory tests from patients’ charts. Blood pressure values were taken as the mean of pre-dialysis measurements of the last three dialysis sessions before enrollment. Routine laboratory tests were extracted from the patient’s chart and calculated as the mean of the last three available values for each patient. Serum albumin was measured by the green bromocresol method. The formula used for calculating standard Kt/V is available online .Continuous variables are reported as mean ± S.D. or median and inter-quartile range, as appropriate. Categorical variables are reported as frequencies. The samples were tested for normality with the Kolmogorov-Smirnov test. Differences between centers were tested by the chi-square test and one-way ANOVA or its nonparametric equivalent  complemented by the Tukey’s test. Associations were tested in a logistic regression model using the “Enter” method in which the predictive variables were selected on clinical grounds. 2 and 24.6 ± 5.0 kg/m2 for men and women, respectively. Thirty percent had diabetes and 48%, hypertension. Nearly 88% used a native arteriovenous fistula as the vascular hemodialysis access. The mean pre-dialysis systolic blood pressure was 147 ± 20 mmHg and the diastolic, 78 ± 13 mmHg. The mean dialysis vintage was 58 ± 55 months; twenty-eight percent were smokers. The laboratory data of the participants are shown in 2 (tCO2) was 22.7 ± 3.0 mEq/L, and 40.3% of patients had levels < 22 mEq/L. The prevalence rates of the assigned ranges of tCO2 in the whole sample and each dialysis center are shown in The general characteristics of the enrolled patients are shown in 2 values < 22 mEq/L is presented in 2 values < 22 mEq/L; the dialyzer utilization number in the day of the blood gas analysis and the use of low-flux membrane dialyzers were associated with an increased risk of low tCO2.A logistic regression model in which the dependent variable was tCO,,,,Patients on hemodialysis have a high mortality rateFifty percent of the participants of the present study were receiving treatment form the Public Health System, which is markedly lower than the national population under publicly funded treatment (82%).2 in a midweek session of our sample (22.7 mEq/L) was very similar to global data reported in 2 studies, 21.9 mEq/LThe present study included 384 patients, with a demographic profile comparable to the ones reported in the last Brazilian Dialysis Census.,2 in center 1, and the lowest one in center 4. Discrepancies in the dialysis prescription may again have accounted for these differences: for instance, the center with the lower mean tCO2 values was the only one in which all patients underwent three dialysis sessions per week.As a whole, 40.3% of patients had serum bicarbonate levels below DOQI recommendation (22 mEq/L).2 below 22 mEq/L, which included the following variables: age in decades, gender, diabetes, body mass index, hemoglobin, blood flow, dialyzer use count, use of low-flux membrane dialyzers, hours of dialysis per week, and standard Kt/V. Four variables in the model showed a statistically significant association with a blood tCO2 below 22 mEq/L: older age and higher standard Kt/V were protective factors whereas higher dialyzer use count and the use of low-flux membrane dialyzers were associated with increased risk.A logistic regression model was designed to test associations with tCO,,The negative impact of dialyzer reuse and the use of low flux membrane dialyzer on serum bicarbonate, even after extensive adjustment, did come as a surprise and should await further confirmation. The dialyzer reuse does not seem to affect the effectiveness of dialysis and is a widely used practice in countries with restricted resources.,,The association of age and higher levels of bicarbonate had already been reportedThe study presents some limitations, the main one being a relatively small sample not representative of the Brazilian population. These limitations restrict the generalizability of the findings; however, the information generated regarding this important and unexplored subject in Brazil, the metabolic acidosis in maintenance hemodialysis, is of great value.2 in a midweek session of the studied sample was 22.7 mEq/L. The prevalence rate of serum bicarbonate below DOQI recommendation (22mEq/L or higher) was 40.3%, and 6.5% had serum bicarbonate below 18 mEq/L. The dialyzer use count and the use of low-flux membrane dialyzers were negatively associated with serum bicarbonate levels. Older age and higher standard Kt/V values were positively associated with serum bicarbonate levels.The mean pre-dialysis serum tCOOur findings conform to global data reported in previous studies but a more comprehensive study addressing national data is necessary to substantiate our findings.


Obesity in pediatric surgical patients is a challenge for the anesthesiologist. Despite potentially beneficial properties, propofol might also induce hypotension. This study examined whether a dose adjustment in overweight children could avoid hypotension and if there would be differences regarding hormonal regulation in children under anesthesia. Fifty-nine children undergoing surgery under general anesthesia were enrolled in this prospective observational trial. Participants were allocated into two groups according to their BMI. The induction of anesthesia was conducted using propofol . The maintenance of anesthesia was conducted as total intravenous anesthesia. Hormone levels of renin, angiotensin II, aldosterone, copeptin, norepinephrine and epinephrine were assessed at different timepoints. Blood pressure dropped after the administration of propofol in both groups, with a nadir 2 min after administration—but without a significant difference in the strength of reduction between the two groups. As a reaction, an increase in the plasma levels of renin, angiotensin and aldosterone was observed, while levels of epinephrine, norepinephrine and copeptin dropped. By adjusting the propofol dosage in overweight children, the rate of preincision hypotension could be reduced to the level of normal-weight patients with a non-modified propofol dose. The hormonal counter regulation was comparable in both groups. The release of catecholamines and copeptin as an indicator of arginine vasopressin seemed to be inhibited by propofol. Total intravenous anesthesia (TIVA) is one of the standard regimens for general anesthesia in the pediatric and adolescent population ,2. PropoThere is still no consensus regarding the optimal dose of propofol for induction in pediatric anesthesia due to the fact that several dose-finding studies have examined different primary endpoints ,10,11. IThe renin–angiotensin–aldosterone system (RAAS) has a broad impact on blood pressure regulation and hypertension in the pediatric population . It was Besides the RAAS, a crucial role for the sympathetic nervous system in the regulation of blood pressure in obese patients has been postulated as well, a higher body mass index (BMI) was shown to be associated with increased levels of norepinephrine , potentiHowever, the exact regulatory mechanisms of these hormonal imbalances in children are still unknown, especially in the context of general anesthesia. The current study therefore aimed at evaluating the effect of a propofol-based general anesthesia on hormonal homeostasis in children. Additionally, it should be examined whether a dose adjustment of propofol might lead to a reduction in the incidence of hypotensive events in overweight or obese children undergoing general anesthesia.After approval by the local ethics committee at the University of Leipzig (Protocol-No. 078-12-05032012) and with respect to the World Medical Association Declaration of Helsinki, a total of 59 children between 6 and 16 years old (American Society of Anesthesiologists (ASA) classifications I or II), undergoing a surgical or orthopedic procedure under general anesthesia with endotracheal intubation, were enrolled into this prospective observational trial. The consent for enrollment was provided by the child’s parents or legal guardian. The following patients were considered not to be eligible for this study: patients who might have been pregnant or where no consent could be obtained, patients with malignant diseases or under long-term medication with corticosteroids, opioids or any other sedative agent. The study was registered in the German Clinical Trials Register .Due to the observational nature of the study, there was no randomization. However, participants were allocated into two different observational groups according to their age- and gender-specific BMI: Children would be classified as “overweight”, if their BMI was higher than  the 90th percentile, all other children were considered to be of “regular weight”, i.e., below the 90th percentile. The distribution of the groups is shown in In accordance with the current guidelines of the European Society of Anesthesiology, all patients were allowed to drink clear liquids up to two hours before the induction of anesthesia . An oralBlood pressure and heart rate were recorded twice before the induction of anesthesia , then every two minutes for the first 10 min after propofol administration, and after that every 5 min until 45 min after propofol administration. The size of the blood pressure cuff was adjusted according to the manufacturer’s specifications in each case to the circumference of the upper arm to avoid systematic incorrect measurements.Plasma levels of renin, angiotensin II, aldosterone and copeptin, as well as norepinephrine and epinephrine were assessed after arrival in the pre-operative holding area (T0), 15 min (T1) and 45 min after the induction of anesthesia (T2). The amount of blood taken was 5 mL up to a maximum of 10 mL at each measurement point. Blood samples for renin were stored at room temperature, samples for the evaluation of plasma levels of all other hormones were immediately cooled and centrifuged at 4 °C and 3000 rpm for 15 min  and then stored at −80 °C until further analysis. The assessment of angiotensin II levels was performed using a radioimmunoassay after sample extraction . We handled three different test kits with individual reference probes for the recovery of the analyte after extraction. The comparability of the individual extraction procedures was ensured by the adjustment of all samples to 100% recovery. Plasma levels of epinephrine and norepinephrine were examined via liquid chromatography and electrochemical detection, as previously described ,22.All other relevant information, like blood pressure and heart rate to the defined time points and the consumption of infusions, propofol, fentanyl and cis-atracurium, as well as the duration of anesthesia and the operation, were recorded in a separate study protocol.2 or the Fisher’s exact test, where appropriate. Due to the relatively small sample size, no normal distribution of the values was assumed. Non-parametric data are reported as median (interquartile range (IQR)) and were compared using a Mann–Whitney U test. Blood pressure and hormone levels over time were examined using the Friedman test. A p-value of <0.05 was considered to be statistically significant. The statistical analysis and the creation of the figures were performed using SPSS  and Microsoft Excel .Categorical data are reported as the number of patients, together with the corresponding percentage of the total (“regular weight” versus “overweight”). Differences between the proportions of qualitative data, such as the patients’ gender, ASA status or type of surgery were assessed with the χA total of 59 patients were included in the study and underwent further analysis. p < 0.001) and corresponding BMI (25.8 (23.0–29.4) for “overweight” vs. 18.2 (15.7–20.8) for “regular weight”, p < 0.001) than patients in the “regular weight” group. Additionally, percentiles for height were higher in the “overweight” group (87 (40–96) vs. 55 (28–78), p = 0.008). There was no significant difference between the groups in terms of the distribution of the ASA status (p = 0.368) and the type of surgery (p = 0.478).Patients in the “overweight” group had a significantly higher body weight (median 71 kg (IQR 53.8–80.6) for “overweight” vs. 48.5 kg (33.5–54.5) for “regular weight”, p < 0.001) as well as of propofol  for “overweight” vs. 11.6 mg/kgBW (10.9–12.2) for “regular weight”, p = 0.005) compared to patients in the “overweight” group  for “overweight” vs. 7.4 mL/kgBW (5.4–8.9) for “regular weight”, t” group .p < 0.001, A Spearman’s correlation analysis examining the relationship between the preoperative systolic blood pressure and the patients’ BMI revealed a moderate correlation between these two factors , as well as of norepinephrine . All other hormone levels did not show any significant relationships, except for a correlation between plasma renin levels with the patients’ BMI . Focusing on the hormone levels at the three different time points (preoperative (T0), 15 min and 45 min after the induction of anesthesia (T1 and T2)), there were significant changes in all measured parameters. The hormones of RAAS  showed an increase in plasma levels over the course of time, while epinephrine and norepinephrine levels dropped. In the comparison of the groups (regular weight vs. overweight), there was only a difference in epinephrine at timepoint T2, whereby the level in the overweight patients decreased to be significantly less in absolute terms compared to the initial value (n = 59 with α = 0.05 and ρ = 0.452), which corresponds to a high statistical power.A limitation of the current study could be the monocentric design with a relatively small number of patients. The number of patients is partly due to the rather complex laboratory measurements but is comparable to other similar studies. Furthermore, due to the study design and the research question, it was not possible to randomize the patients or to blind the investigators. Due to the lack of comparable data at the time of the study design, no power analysis/sample size calculation was performed in advance. However, an exemplary post hoc power analysis for the correlation of BMI with blood pressure see  resultedp < 0.001). This result is in accordance with previous investigations, which in the meantime have been able to prove a corresponding connection [We found a moderate positive correlation between patients’ BMI and preoperative systolic blood pressure  ,12,24. BLooking at the amount of crystalloids applied in the period under investigation, there is also a significant difference between the two groups. In relation to body weight, the patients in the “overweight” group received significantly less fluid per kg of bodyweight. However, the absolute amount in mL did not differ significantly between the groups and was a median of 350 mL in both. It can only be assumed that the clinical routine of the anesthesiologists was more important than a weight-adapted procedure.Regarding hormonal regulation, three essential aspects stand out: After the induction of anesthesia, there was a continuous increase in the components of the RAAS . However, no significant increase in the release of copeptin, as a surrogate parameter of arginine vasopressin (AVP), with a decrease 15 min after anesthesia induction and a return to approximately baseline levels after 45 min, was observed . The catp = 0.005). The basic course of hormone levels did not differ between the two groups. Copeptin levels also showed no significant increase, although their release would have to be induced by a relative lack of volume. A possible explanation might be that the release of copeptin (and thus the effect of AVP) could be inhibited by propofol as well [The lack of counter regulation of the catecholamines epinephrine and norepinephrine can most likely be explained by a propofol-induced blockade of the sympathetic nervous system ,30,31. T as well . This efThe RAAS therefore appears to make the essential contribution to maintaining and restoring adequate blood pressure levels in both groups. All components rise equally during the course of anesthesia, whereby the initial values did not differ significantly between the two groups and, at the later measuring points, no significant difference could be detected for one of the hormones. This therefore indicates that this form of hormonal regulation is independent of BMI.The impact of fentanyl on hormonal regulation is not yet fully understood. It seems logical that untreated intraoperative pain causes an increase in various stress hormones . Therefore, as in any anesthesia, sufficient pain therapy was given a high priority. During the study, there was no significant difference in the consumption of fentanyl between the two groups based on body weight. It was concluded in older studies, with high doses of opioids, that the suppression of hemodynamic or hormonal stress responses is not related to opioid dose . Apart fTaking various influencing factors into account, the current study shows that the increased rate of preincision hypotension in overweight children can be reduced by adjusting the propofol dosage to the level of normal weight patients with a non-modified propofol dose. Nevertheless, in both groups, relevant drops in blood pressure occur after the induction of anesthesia with propofol. The hormonal counter regulation seems to take place in both groups in a comparable way, primarily through the activation of the components of the RAAS. The release of catecholamines and copeptin, as an indicator of AVP, seems to be inhibited by propofol as well. Further investigations in larger study populations appear necessary to prove our findings and to clarify the influence of other hormones on the blood pressure regulation of normal and overweight children under general anesthesia.


Patient journeys for hypertensive individuals after detection at screening have not been well examined in a general population. Thus, we aimed to assess the medical treatment status and subsequent longitudinal changes in blood pressure in a middle-aged Japanese population.We conducted a cohort study using a nationwide Japanese health screening cohort, from April 2014 to March 2019. Among health screening participants aged 40–74 years who had not previously received treatment for hypertension, hypertensive patients were newly identified based on screening results, and their medical treatment status for hypertension during the year following their initial screening was assessed. The main outcomes were longitudinal changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP) over 4 years after initial screening.Of the 153,523 screening participants (mean age = 49.7 years), 16,720 (10.9%) and 4150 (2.7%) were newly detected as having hypertension, with baseline SBP of 140–159 mmHg (grade 1) and ≥ 160 mmHg (grade 2–3), respectively. Among them, 15.9% of the grade 1 hypertensive participants and 36.3% of the grade 2–3 hypertensive participants started receiving medical treatment during the year following initial screening. A linear generalised estimating equation with propensity score matching showed that receiving medical treatment was associated with 5.77 mmHg lower SBP (95% CI − 6.64 to − 4.90) and 3.82 mmHg lower DBP (95% CI − 4.47 to − 3.16) in the grade 1 hypertensive group, and 14.69 mmHg lower SBP (95% CI − 16.35 to − 13.04) and 8.42 mmHg lower DBP (95% CI − 9.49 to − 7.34) in the grade 2–3 hypertensive group.Health screenings detected hypertension in a substantial percentage of the middle-aged population in this study. However, detection was often followed by insufficient medical treatment and inappropriate blood pressure management. These findings indicate an inadequate link between health screenings and medical treatments in patients with hypertension. Using nationwide large-scale data combining health screening results and medical claims longitudinally, we assessed patient journeys for hypertensive participants after detection at screenings. Among middle-aged screening participants, 10.9 and 2.7% were detected to have grade 1 (SBP 140–159 mmHg) or grade 2–3 (SBP ≥160 mmHg) hypertension, respectively. Only 15.9% of grade 1 hypertensive and 36.3% of grade 2–3 hypertensive participants had started medical treatment after 1 year from initial screening.Medical treatment after screening was associated with better blood pressure management for the subsequent 4 years, compared with non-treatment.A substantial percentage of hypertensive participants could be newly detected at health screenings. However, the detection of hypertension was often followed by insufficient medical treatment and inappropriate blood pressure management. To maximise the effectiveness of a screening programme and improve population health outcomes for hypertensive patients, screening programmes need to be redesigned to ensure continuity of care from screening to medical intervention.The number of patients with hypertension, representing a major public health issue, is increasing globally. The global prevalence of hypertension is reported to be as high as 25% , 2. CaseVarious efforts are being made globally concerning screening, diagnosis, and disease management of hypertension. In Japan, a screening programme for metabolic syndromes—including hypertension—has operated nationally since 2008 . AccordiThis study analysed medical claims and health screening data of middle-aged adults from a nationwide health screening database in Japan, estimated the prevalence of hypertension newly detected at health screenings, and described patients’ medical treatment status after screenings. Furthermore, we analysed the associations between treatment status and blood pressure in patients identified during screenings as having hypertension.2CE), one of the largest employment-based health insurance associations in Japan. HIA2CE provides health insurance to approximately 400,000 insured individuals in approximately 1800 construction-related companies throughout Japan, from large general contractors to small regional construction companies.Health screening and medical claims data were extracted from the Health Insurance Association for Architecture and Civil Engineering companies , haemoglobin A1c (HbA1c), systolic blood pressure (SBP), diastolic blood pressure (DBP), low-density lipoprotein (LDL) cholesterol, current smoking status, exercise habits, and alcohol consumption.In Japan, all residents are insured by one of the public health insurance plans, which cover virtually all care including medical care, dental care, long-term care, and some preventive care like health screening. The public health insurance plans are basically either an employment basis or a community basis, depending on the individual employment status. Much of the health care costs 70–90%) are covered by public funds, and the rest is either paid out of pocket or covered by private supplementary health insurance [0–90% are2CE after 1 year, we excluded him/her from the analysis.We conducted a cohort study in which health screening data and medical claims data were integrated longitudinally. The study participants had received health screenings and were aged between 40 and 74 years. There were 199,534 individuals in this age group who received initial health screenings; however, 46,011 were excluded due to a treatment history for hypertension. If previous medical claims reflected a medical treatment history with hypertension-related disease codes , the patient was defined as being previously treated for hypertension. Supplement eTable n = 16,720) or grade 2–3 hypertensive (n = 4150) at the screening were included.Initial health screening data  were used to define hypertension at health screenings. To ensure accuracy, the measurement procedures of blood pressure at health screenings are standardised according to the government’s guidelines , 8. As aFor patients diagnosed with hypertension at the initial screening, their medical treatment status after the initial screening was determined using medical claims data for 1 year following the initial screening. If the patient received medical treatment for any hypertension-related disease code during that year, that patient was defined as receiving medical treatment for hypertension after the screening. According to the definition, medical treatment includes both behavioural interventions and pharmaceutical therapies.Our main outcomes were based on SBP and DBP (mmHg), which were obtained from the second to fourth annual health screenings (repeated measures of blood pressure levels).Using the initial health screening data, we estimated the prevalence of hypertension detection at the screenings. Participants’ characteristics based on SBP levels at screenings were considered. We described the cumulative probability of being treated for hypertension by baseline SBP levels, using the Kaplan-Meier method.Following propensity score matching, we assessed the associations between treatment and blood pressure control . We calcWe conducted complete case analysis in our main analysis. To assess the effect of missing data of covariates, we performed an analysis in which the covariates with 3% or greater missing values were excluded from the model, to estimate propensity scores. In another sensitivity analysis to assess the differences at the final follow-up results (year 4), we assessed associations between treatment statuses and blood pressure levels for years later using generalised linear models with propensity score matching. In another sensitivity analysis, to assess the robustness to the classification of hypertension, we conducted an analysis using the other classification based both on SBP and DBP . Finally, to discuss generalisability of the study participants, the prevalence of hypertension and antihypertensive drug use in the health screening cohort were compared with those in the Japanese general population.To evaluate the status of blood pressure during follow-up, we also described proportions of patients with controlled blood pressure level (SBP < 140 mmHg and DBP < 90 mmHg) over 4 years by treatment status eTable .p < 0.05 was used.All analyses were performed using Stata version 15.1 . All tests were 2-tailed; a significance level of Figure Among hypertensive participants with 209,751 person-month follow-ups, 3460 individuals started treatment for hypertension, and the incidence rate of starting treatment was 16.5 per 1000 person-years . Higher SBP at baseline was associated with higher incidence of starting treatment , we found longitudinal declines in SBP and DBP (year 1 to year 4) in both untreated and treated participants Fig. . DiffereUsing a 1:1 nearest neighbour propensity score matching within the calliper distance of 0.10, we obtained 1539 and 811 matched pairs in the grade 1 and grade 2–3 hypertensive group, respectively. As a result, we included 3078 (1539 pairs) and 1622 (811 pairs) participants in propensity score matching analysis in the grade 1 and grade 2–3 hypertensive group, respectively.n = 3078) revealed that the treatment group had lower SBP  and lower DBP , compared with the non-treatment group. Among grade 2–3 hypertensive participants (n = 1622), the treatment group had lower SBP  and lower DBP , compared with the non-treatment group , we found consistent associations between treatment status and blood pressure . We found consistent differences in blood pressure levels between groups at the final follow-up results (year 4) . Our findings were qualitatively unaffected by the use of the different classification of hypertension  or grade 2–3 (160 mmHg or greater) hypertension, respectively. At 1 year after detection at screening, only 15.9 and 36.3% had started receiving treatment for hypertension among grade 1 or grade 2–3 hypertensive participants, respectively. Treatment after screening was associated with subsequent better blood pressure (SBP and DBP) management for 4 years. The results of this study pose important questions concerning the lack of sufficient medical management for hypertension after detections at health screenings.This study analysed patients over time from screening and detection to medical treatment using real-world data. To our knowledge, this is the first large-scale longitudinal analysis of patients’ journeys after detections of hypertension at health screenings in a general population. Since medical claims and health screening data were longitudinally merged on an individual basis, we could define medical treatment status before and after screening, as well as follow-up health screening results, in clear chronological order. In this study, universal health screenings of middle-aged individuals demonstrated that many potentially hypertensive patients could be detected early , 18. HowOur results of low percentage of medical treatment are consistent with previous studies –21. The Our results indicated the clinical importance of medical treatment after detection of hypertension, as medical treatment was associated with substantial decreases in blood pressure over 4 years. Those population-level differences in blood pressure have a substantial impact on clinical outcomes for cardiovascular disease, cerebrovascular disease, and kidney disease , 22. MedThis study has several limitations. First, while this observational study examined the associations between treatment status and subsequent blood pressure, it did not make random assignments for treatment status. Therefore, differences in participant characteristics between the non-treatment and treatment groups might exist, which could confound the associations. However, our propensity score analysis improved the balance parameters after matching. We also found that the balance plot of propensity scores improved after matching. Second, the database used in this study included more men than women. We only analysed participants who received the health screening, and the information about non-participants was unavailable. Screened participants may be healthier than non-participants. Given that our study focused on screened participants in Japanese employment-based health insurance (many of them are working-age men), our findings may not be generalisable to non-employees or to populations of other countries. Third, this study used annual health screening data to identify participants and define their blood pressure results. Participants’ blood pressure measured during screening may have fluctuations between measurements and might be affected by measurement conditions. Fourth, we were not able to assess details of medical treatments, as we extracted diagnosis codes, but not procedure codes or medication codes, from medical claims. Therefore, we could not discuss variations in medical treatments, such as type, dose, and number of anti-hypertensive drugs. Further, information on compliance to the drugs were not available from medical claims data. Given that some patients might not take the prescribed drugs, the estimated effect of treatments could be under-estimated. Fifth, participants with higher cardiovascular risk may be more likely to visit physicians seeking antihypertensive medications, compared with those with lower cardiovascular risk. The residual confounding due to unmeasured variable of cardiovascular risk may lead to an overestimation of the treatment effect, even though we used propensity score matching. There may be some unmeasured confounding variables, such as geographical and socioeconomic variables. Future research to assess such variations may be needed. Finally, we were not able to assess other interventions outside health insurance, which may affect change in blood pressure. Some patients might receive traditional medicines and join health promotion activities. Those treatments and activities were not recorded in the medical claims database.Many middle-aged individuals with hypertension can be detected by health screenings; however, these screenings are often followed by insufficient medical treatment and poor blood pressure management. These findings indicated the lack of a bridge between health screenings and medical treatments in patients with hypertension. To maximise the effectiveness of screening programmes and improve population health for hypertensive patients, screening programmes need to be redesigned to ensure continuity of care from screening to medical intervention.Additional file 1: eTable 1. ICD-10 Codes that defined diseases in the medical claims data. eTable 2. Participant characteristics according to treatment status in hypertensive participants before propensity matching . eFigure 1. Balance plots of propensity scores before and after matching. The density plots on the left (Raw: before matching) indicate balance of propensity scores between treatment and non-treatment in total participants, and the density plots on the right (Matched: after matching) indicate balance of propensity scores between treatment status in propensity scores for matched participants. eFigure 2. Sensitivity analysis excluding covariates with 3% or greater missing values . We estimated differences in systolic blood pressure (SBP) and diastolic blood pressure (DBP) for 4 years between treated and untreated groups among hypertensive participants, using linear generalized estimating equations with propensity score matching. For propensity score matched participants, we included 3860 (1930 treated and 1930 untreated) and 2046 (1023 treated and 1023 untreated) individuals from the subgroup with baseline SBP 140–159 mmHg and subgroup with baseline SBP ≥160 mmHg, respectively. eFigure 3. Sensitivity analysis to assess the differences at the final follow-up results (year 4). We estimated differences in systolic blood pressure (SBP) and diastolic blood pressure (DBP) 4 years later between treated and untreated groups among hypertensive participants, using generalized linear models with propensity score matching. eTable 3. Sensitivity analysis using the other classification based both on systolic blood pressure (SBP) and diastolic blood pressure (DBP) . We estimated differences in systolic blood pressure (SBP) and diastolic blood pressure (DBP) between treated and untreated groups among hypertensive participants, using generalized linear models with propensity score matching. eTable 4. To assess generalizability of the study participants, the prevalence of hypertension and antihypertensive drug use in the health screening cohort were compared with those in the Japanese general population. eTable 5. Proportion of patients with blood pressure level < 140/90 mmHg during follow-up.


Non‐dippers had higher nighttime BP (p < .05), but not office and daytime BP, compared to dippers. MSNA burst incidence  was higher and brachial artery FMD  was lower in non‐dippers compared to dippers. MSNA and FMD each predicted nighttime systolic  and diastolic BP  in multivariate‐adjusted analyses. Our novel findings demonstrate that unfavorable nocturnal BP profiles are associated with elevated SNS activity and endothelial dysfunction in CKD. Specifically, CKD patients with higher nighttime BP and the non‐dipping pattern have higher MSNA and lower FMD. These support our hypothesis that SNS overactivation and endothelial dysfunction are linked to the dysregulation of nighttime BP as well as the magnitude of BP lowering at nighttime in CKD.Elevated nocturnal blood pressure (BP) and nocturnal non‐dipping are frequently observed in patients with chronic kidney disease (CKD) and are stronger predictors of cardiovascular complications and CKD progression than standard office BP. The sympathetic nervous system (SNS) is thought to modulate diurnal hemodynamic changes and the vascular endothelium plays a fundamental role in BP regulation. We hypothesized that SNS overactivity and endothelial dysfunction in CKD are linked to elevated nocturnal BP and non‐dipping. In 32 CKD patients with hypertension (56 ± 7 years), office BP, 24‐hr ambulatory BP, muscle sympathetic nerve activity (MSNA) and endothelial function via flow‐mediated dilation (FMD) were measured. Participants were subsequently divided into dippers  and nocturnal non‐dipping are frequently observed in patients with chronic kidney disease (CKD) and are stronger predictors of cardiovascular complications and CKD progression than standard office BP. Our novel findings demonstrate that unfavorable nocturnal BP profiles are associated with elevated SNS activity and endothelial dysfunction, supporting our hypothesis that SNS overactivation and endothelial dysfunction are linked to dysregulation of nighttime BP as well as the magnitude of BP lowering at nighttime in CKD. Prior eCKD is also associated with reduced endothelial nitric oxide (NO) synthesis  CKD ; diabetes; HIV infection; clinical evidence of chronic heart failure or ejection fraction below 35%; any history of past coronary artery, cerebrovascular, aortic, or peripheral vascular disease; symptomatic heart disease determined by electrocardiogram, stress test, and/or history; hepatic enzyme concentrations greater than two times the upper limit of normal; severe anemia with hemoglobin level < 10 g/dl; history of nephrolithiasis; any serious systemic disease that might influence survival; current treatment with clonidine, levodopa, or methotrexate; clinic BP greater than 160/90 mmHg; office BP less than 110/60; change in medications or surgery within the past 3 months; drug or alcohol abuse.Thirty‐two participants with CKD and age‐matched hypertensive controls without CKD were recruited and enrolled from outpatient clinics at the Atlanta Veterans Affairs (VA) Healthcare System. All CKD participants had a confirmed diagnosis of either Stage 2 [estimated glomerular filtration rate (eGFR) of 60–89 ml·min2.2After written informed consent was obtained, office BP, 24‐hr ABPM, basic metabolic panel, and urinary microalbumin and creatinine levels were obtained during a screening visit. During two separate study visits, brachial artery flow mediated‐dilation (FMD) and muscle sympathetic nervous activity (MSNA) by microneurography were obtained. All measurements were obtained in a quiet, temperate (21°C) environment between 8 and 10 a.m., after abstaining from food, caffeine, smoking, and alcohol for at least 12 hr, and exercise for at least 24 hr. All participants reported having taken prescribed medications as normally directed. This study was approved by the Emory University Institutional Review Board and the Atlanta VA Healthcare System Research and Development Committee.2.32.3.1Office BP was measured after 5 min of rest in a seated position with the arm supported at heart level using an appropriately sized cuff per American College of Cardiology/American Heart Association (ACC/AHA) guidelines  which is the most commonly used device for ABPM monitoring meeting the validation criteria of the British Hypertension Society  and non‐dippers (n = 24) for group comparison analyses.SBP and DBP were measured every 20 min during the daytime and every 30 min during the nighttime over a consecutive 24‐hr period. Wake and sleep periods, defined by self‐report, were used to compute mean daytime BP and mean nighttime BP values, respectively. Artifactual ABPM readings were identified by the Spacelabs software. Participants were asked to attend to their usual activities and avoid strenuous physical activity. Participants were instructed to keep motionless at the time of each measurement. Participants had no access to ABPM values. The average BP reading success rate was 91.2 ± 7.6%. ABPM data had recordings of good technical quality , in line with the minimum requirements recommended by the European Society of Hypertension  was used longitudinally 2–10 cm above the antecubital fossa to record brachial artery measurements. Baseline values were obtained by averaging diameter and blood velocity over three cardiac cycles measured via ECG gating to capture end‐diastolic arterial diameters. The forearm cuff was inflated to suprasystolic levels (50 mmHg above SBP) using a rapid cuff inflator (D.E. Hokanson) for 5 min. Peak hyperemic blood velocity was measured by Doppler ultrasound during the first 10 s following cuff release. Diameter measurements were obtained 60 and 90 s following cuff release. FMD calculations were made using 60‐s and 90‐s measurements to determine peak diameter. Arterial diameters were measured and analyzed by a single investigator blinded to the clinical status of the participant from digitized images utilizing customized software . FMD is given as the percent change in artery diameter from baseline: (peak hyperemic diameter – baseline diameter)/baseline diameter. Shear rate at baseline and peak hyperemia was calculated as 4 × peak blood velocity/arterial diameter. FMD values were then normalized for peak hyperemic shear rate. This calculation of the shear rate is consistent with our previous reports  as well as a significant linear association between MSNA and the difference of day to night SBP . Based on these estimates, enrolling 32 participants had > 80% power with an α of 0.05 to detect group differences and linear associations if they truly exist.A power analysis was conducted using estimates from a relevant study  for analysis. R‐waves were detected and marked from the continuous ECG recording. MSNA bursts were automatically detected by the program using the following criteria: 3:1 burst‐to‐noise ratio within a 0.5‐s search window, with an average latency in burst occurrence of 1.2–1.4 s from the previous R‐wave. After automatic detection, the ECG and MSNA neurograms were visually inspected for accuracy of detection by a single investigator (J. Park). MSNA was expressed as burst incidence (bursts/100 heartbeats) and burst frequency (bursts/min).2.4.3SD) unless otherwise noted. Differences in participant characteristics between dippers and non‐dippers were determined using independent t‐tests for continuous variables or chi‐square tests for categorical variables. The group difference in primary outcomes  was tested by independent t‐tests. In a secondary analysis, one way‐ANOVA analysis was performed to examine the 3‐group comparison in primary outcomes with controls, CKD‐dippers and CKD‐nondippers followed by LSD‐post hoc tests. Pearson correlation test was performed to examine the linear relationship between BP variables and MSNA and FMD. Multivariable linear regression tests were used to describe the predictability of MSNA and FMD on nighttime BP variables after controlling for age and body mass index (BMI) and smoking status as covariates . To determine the relative association of office, daytime, and nighttime BP with MSNA and FMD, linear regression models predicting MSNA or FMD were run with the different BP initially entered as predictors . The only predictor variable(s) retained in the regression models after the step‐wise variable selection method  indicates a higher degree of relevance with the dependent variable.Values are presented as mean ± standard deviation , an unknown cause combined with HTN (n = 5), polycystic kidney disease (n = 2), glomerulonephritis (n = 1) and unknown (n = 10). All participants in both groups had HTN. There were no significant differences in demographics, anthropometric characteristics, proportion of smokers, obstructive sleep apnea (OSA) or antihypertensive medication use, or HMG CoA reductase inhibitors (statins) between dippers and non‐dippers with CKD.Thirty‐two participants with CKD who met the eligibility criteria were enrolled in the study. Table 3.2There was no difference in office and daytime BP variables between dippers and non‐dippers in patients with CKD Table . However3.3p = .019) and burst frequency  were higher in non‐dippers compared to dippers with CKD  and FMD corrected for shear stress  was significantly lower in non‐dippers compared to dippers  for a 3‐group comparison, there was a significant group effect in MSNA burst incidence =10.2, p < .001), burst frequency =8.8, p = .001), FMD =12.1, p < .001) and FMD/shear =6.5, p = .004). Post hoc tests showed that MSNA burst incidence (51.2 ± 22.0 bursts/100 HR) and burst frequency (30 ± 16 bursts/min) in controls were lower compared to CKD‐dippers  and CKD‐nondippers (p < .001 for both), while FMD (7.8 ± 6.6%), FMD/shear (3.4 ± 2.2%/s‐1x103) in controls was similar to CKD‐dippers (p > .05 for both) but higher than CKD non‐dippers .In a secondary analysis that included data from six sex‐, age‐, and race‐matched hypertensive controls without kidney disease . In contrast, there was no significant association between office BP and MSNA burst incidence or burst frequency (p > .05 for both).Daytime, nighttime, and nighttime‐minimum BP variables and the magnitude of BP dipping were significantly associated with MSNA burst incidence and burst frequency in patients with CKD . No significant association was found between any of the outcome variables (MSNA and nighttime BP) and any of the covariates .Multivariable linear regression analysis demonstrated that MSNA burst incidence significantly predicts nighttime SBP, DBP, and MAP after adjusting for age, BMI, and smoking status  as potential predictors of MSNA burst incidence. As opposed to daytime SBP and office SBP, only nighttime SBP remained as a significant predictor of MSNA burst incidence in the multivariable linear regression model with a stepwise variable selection method  .Daytime, nighttime, and nighttime‐minimum BP variables, the magnitude of dipping and office BP were associated with FMD  Figure 3a~h.Model 4 ~ 6, Table p < .05 for all).Multivariable linear regression analysis demonstrated that the variability of nighttime BP is in part explained by FMD after adjusting for age, BMI, and smoking status  for FMD  and FMD/shear rate . Regression‐based mediation analysis showed that approximately 31% of the variation in nighttime SBP was accounted by the combination of two predictors, FMD and MSNA burst incidence  or FMD and MSNA burst frequency , after adjustment for age and BMI. FMD was no longer a significant predictor for nighttime SBP  after controlling for MSNA burst incidence as a mediator and age and BMI as covariates, while FMD remained marginally significant after controlling for MSNA burst frequency, age, and BMI as mediators . The indirect effect of MSNA burst incidence and burst frequency explained 46.9% and 13.3% of the relationship between FMD and nighttime SBP  and , respectively) after adjusting for age and BMI (Table MSNA burst incidence and burst frequency were significantly associated with FMD (p = .097), but not with MSNA burst frequency . The indirect effect of FMD explained 28.2% and 71.7% of the relationship between nighttime SBP and MSNA burse incidence and burst frequency, respectively  and , respectively) after adjusting for age and BMI.Moreover, when FMD was considered as a mediator, MSNA burst incidence was still a marginally significant predictor for nighttime SBP  that showed that MSNA was, indeed, numerically higher in reverse dippers compared to non‐dippers without reverse dipping (n = 17)  and dippers . These results were independent of OSA which is highly prevalent in patients with CKD and is also associated with SNS overactivation and nocturnal hypertension .J.J. and J.P. conceived and designed research; D.D., A.A.Q. and J.P. performed experiments; J.J., I.T.F., and J.P. analyzed the data; J.J., I.T.F., A.A.Q., and J.P. interpreted the results of experiments; J.J. and J.P. prepared figures; J.J. and J.P. drafted the manuscript; J.J., I.T.F., A.A.Q., D.D., and J.P. edited and revised the manuscript; J.J., I.T.F., A.A.Q., D.D., and J.P. approved the final version of the manuscript.


We termed “a” as PWVslope and “b” as PWVbaseline. All available demographic parameters and clinical data were correlated with eaPWV, PWVslope and PWVbaseline. 108 subjects had repeated 24 h recordings. Mean age was 60.7 years and 48.7% were female. 92.5% had hypertension, 22.9% were smoker, 20.5% had diabetes mellitus and 29.6% eGFR < 60 ml/min/1,73 m2. Direct correlation was observed between age, SBP and eaPWV, while diastolic BP (DBP) and eGFR correlated inversely with eaPWV. PWVbaseline correlated directly with age and inversely with DBP, while PWVslope didn’t correlate with any inputted parameter. Using simple mathematical approach by plotting eaPWV and cSBP values obtained during ABPM, it is possible to visualize unique course of individual PWV related to BP. Using PWVslope and PWVbaseline as novel parameters could be a feasible way to approach BP-independent PWV, though their clinical relevance should be tested in future studies. Our data underline the importance of BP-independent expression of PWV, when we use it as a clinical surrogate parameter for the vascular damage.The utility of pulse wave velocity (PWV) as a surrogate parameter of arterial vessel damage (AVD) beyond the traditional brachial blood pressure (BP) measurement may be questioned as changes in BP are often accompanied by the corresponding changes in PWV. We sought to establish a new way for BP-independent estimation of AVD with PWV. We retrospectively analyzed data from 507 subjects with at least one available 24 h ambulatory BP- and pulse wave analysis, performed with Mobil-O-Graph . Individual relationship between eaPWV and central systolic BP (cSBP) was analyzed for every 24 h recording. The analysis revealed linear relation between eaPWV and cSBP in all subjects, which is described by equation eaPWV = a Aortic stiffness (AS) is considered to be associated with increased cardiovascular risk. Thus, European Society of Hypertension recommends screening for elevated AS in hypertension . Pulse wEmerging non-invasive oscillometric devices use mathematical approaches and are able to deliver an estimated aortic PWV (eaPWV) based on pulse wave analysis and wave separation analysis, whereby major clinical determinants are age, central systolic BP (cSBP) of the patient and aortic characteristic impedance . ValidatAll included subjects received long-term (24 h) ambulatory BP and pulse wave monitoring as a part of clinical routine in our Department of Nephrology at Campus Benjamin Franklin, Charité University Berlin. Charité University Berlin review board approved the study (EA4/112/18). No informed consent was required for the study purpose. We screened all available recordings from our database, which comprised time period from August 2012 to February 2018, and included all subjects with at least one representative 24 h recording of peripheral BP, central BP and PWV. All available demographic and clinical data were collected. Smoker status was missing in 50%, exact protein-creatinine ratio in 64% and albumin-creatinine ratio in 65% of study subjects. Other demographic and clinical parameters were completely present in all subjects. We could analyze 648 long-term BP and pulse wave analysis recordings from 507 patients with 43,567 single measurements. Available demographic and clinical data were summarized and analyzed. For the purpose of the study “hypertension” was defined, when the diagnosis “hypertension” has been mentioned in the medical record, subject had antihypertensive medication or the BP level was higher than 130/80 mmHg in the ambulatory BP monitoring. Due to retrospective study design the diagnosis “hyperliproteinemia” and smoking status were based on data from the medical record. All implemented procedures were in accordance with institutional guidelines.All recordings were performed with Mobil-O-Graph  and data analysis was performed with HMS Client Software, Version 5.1. The Mobil-O-Graph is a non-invasive oscillometric device, which combines ambulatory blood pressure monitoring with long-term pulse wave analysis . The cuf∗cSBP + b. We termed factor “a” as “PWVslope” and factor “b” as “PWVbaseline.” In order to assess the course of eaPWV depending on change in BP, we used scatter plots to visualize a possible correlation. All single measurements of cSBP and corresponding eaPWV from each of the 648 24-h readings were included in separate scatter plots. The relationship between cSBP and eaPWV was linear and could be described with following equation: eaPWV = aWe tested the impact of each available demographic and clinical parameter on eaPWV, PWVslope, and PWVbaseline using single regression analysis. Those with significant result in single regression analysis were included in multiple regression analysis.For a part of the study collective repeated measurements were recorded. One hundred and eight patients had two recordings. Twenty five patients had three recordings. Five subjects had four recordings and one patient had five recordings. Data from at least one follow up recording were compared to the initial measurement, respectively. The change of eaPWV, PWVslope, and PWVbaseline between recordings was assessed and possible factors impacting this change were evaluated.T-Test was used in case of proven normal distribution and Wilcoxon paired test in case of non-normal distribution. A multiple regression approach was used to determine relationship between available parameters. Two-sided p-values lower than 0.05 were considered as statistically significant. Statistic analysis was performed with SPSS Statistics 23.0 .This study is retrospective. For each continuous variable mean and standard deviation were calculated. For each dichotomous variable number of affected subjects and the ratio related to the whole study collective in per cent were determined. Normal distribution of parameters was proofed with Kolmogorov-Smirnov-Test. In order to compare parameters from repeated measurements paired 2. 92.5% of patients had established diagnosis of hypertension, 33.7% of hyperlipoproteinemia and 22.9% were smoker. Approximately a fifth had DM (20.5%) and 29.6% have had chronic kidney disease with an estimated glomerular flow rate (eGFR) below 60 ml/min/1,73 m2 according to creatinine-based CKD-EPI equation with the mean protein/creatinine-ratio of 363 ± 1,025 mg/g and the mean albumin/creatinine-ratio of 248 ± 792 mg/g. The mean brachial SBP was 133 mmHg and DBP 80 mmHg with the mean heart rate of 69.5 beats/min. The mean cSBP was 121.6 ± 13.4 mmHg and the mean eaPWV was 9.2 ± 2.2 m/s. The mean PWVslope was 0.035 with the range from 0.026 to 0.050 m/s∗mmHg and the mean PWVbaseline was 4.9 with the range from −0.21 to 11.2 m/s. Further details regarding demographic and clinical parameters as well as details about medication can be found in Five hundred and seven patients were included in the analysis. Approximately half of the study collective was female (48.7%). The mean age was 60.7 [18–92] years and the mean body-mass index was 27.4 kg/mp = 0.001; and 5.2 ± 2.2 vs. 4.6 ± 2.1 m/s; p < 0.001). No differences in PWVslope were observed between female and male subjects.eaPWV and PWVbaseline increased with rising BP and age , 3. PWVsIn the single regression analysis we observed statistically significant correlation between eaPWV and age, SBP, DBP, mean BP, PP, heart rate, sex, DM, hyperlipoproteinemia, eGFR, history of hypertension, coronary artery disease, myocardial infarction, stroke, peripheral arterial disease, medication with ACE-Inhibitor/Angiotensin receptor blocker, calcium channel blocker, thiacids, beta blockers and central alpha-agonists. Multiple regression analysis revealed independent significant influence of age, SBP, DBP, eGFR and history of myocardial infarction on the eaPWV. Increased age and SBP were associated with increasing in eaPWV, while decreased DBP and eGFR were associated with the rise in eaPWV. Study patients with history of myocardial infarction had higher eaPWV than patients without previous myocardial infarction. Using the same demographic and clinical parameters inputted in single and multiple regression analyses we showed independent influence of DBP and age on PWVbaseline . In cont2. 42% were female. The mean eGFR was 72.1 ml/min/1.73 m2 according to creatinine-based CKD-EPI equation with ca. 29% of the patients having chronic kidney disease with an eGFR < 60 ml/min/1.73 m2. The mean brachial BP was 134.9/80.1 mmHg with the mean heart rate of 67.3 beats/min. The mean eaPWV was 9.2 m/s with the mean PWVslope of 0.035 and PWVbaseline of 4.9 m/s. One hundred and eight patients have had repeated recordings. The mean between-recording time was 4.5 ± 5.8 months. The mean age of these patients was 60 years and the BMI was 27.8 kg/m120, while SBP, DBP, PP and heart rate didn’t change significantly between recordings (120 (delta-eaPWV120) across the range of change in SBP, DBP, heart rate and PP as well as change in eaPWV120 related to absolute level of initial SBP, DBP, heart rate and eaPWV120. Increase in DBP between the measurements was statistically significant associated with decrease in eaPWV120 . Higher absolute value of initial PP was statistically significant associated with increase in follow-up eaPWV120 . We did not observe any statistically significant correlation between the change in SBP, heart rate and PP, absolute level of initial SBP, DBP, heart rate, eaPWV120 and change in eaPWV120 between the measurements  were established. The authors observed a linear relationship between BP and PWV and quadratic relationship between PWV and age . The strIn our study, we used a device, which is able to estimate aortic PWV using oscillometric approach. Currently required parameters for the eaPWV calculation are age, measured brachial BP and data from pulse wave analysis . ApproacTo our knowledge, this is the first time serial BP and corresponding PWV changes have been reported. The relation between cSBP and eaPWV can readily be translated to the relation between obtained brachial SBP and eaPWV, as we observed well known strong correlation between SBP and cSBP in our data (Pearson correlation coefficient 0.96). We choose cSBP as an independent variable based on the original publication of the method, where authors described cSBP as one of the major determinants needed for the calculation of the eaPWV .We observed well-known association between eaPWV with age and SBP. As in the study published 2010 by Arterial Stiffness’ Collaboration  the corrRecent data pointed out that changes in heart rate could also contribute to significant changes in PWV  and adjuMany studies demonstrated severe differences in PWV between female and male subjects . We obseMany studies demonstrated significant influence of smoking on AS . We did Comparison of repeated ABPM readings, which were performed on average 4.5 months apart, revealed statistically significant change in eaPWV120. However, the mean difference of 0.1 m/s is not relevant from the clinical point of view. We observed no clinically relevant impact of any hemodynamic parameter on eaPWV120, no matter whether the amount of difference between initial and follow up recording or absolute value of the initial recording were considered , 3, althAssuming that remodeling of vessel wall is a very slow process, the period of 4.5 months is likely to be too short to reveal a real change in the architecture of the vessel wall explaining why the individual BP-adjusted eaPWV did not change in our study. Thus far, published studies compared initial and follow up PWV-values without individual BP-adjustment. For instance, 2011 published study by Ignace et al. compared cfPWV before and after kidney transplantation . Though In conclusion, using simple mathematical approach by plotting eaPWV and cSBP values obtained during ABPM, it is possible to visualize unique course of individual PWV related to BP. Using PWVslope and PWVbaseline as novel parameters could be a feasible way to approach BP-independent PWV, though clinical relevance should be tested in future studies. Our data underline the importance of BP-independent expression of PWV, when we use it as a clinical surrogate parameter for the vascular damage.We acknowledge several limitations of our study: Attributable to the oscillometric method, which we used, obtained PWV-values were not measured but estimated based on pulse wave analysis and utilization of age and central BP. BP-adjustment of eaPWV using obtained individual PWVslope could thus represent the extent of arterial damage. However, the clinical potential of the obtained novel parameters PWVbaseline and PWVslope is not yet established and the next necessary step would be to correlate these parameters to relevant clinical endpoints.Worth mentioning is the fact that pulse wave analysis is done in the brachial artery, which is a muscular artery, used as a surrogate for PWV in the aorta, which is an elastic vessel. As the anatomy of elastic and muscular arteries is different, they could stiffer in distinct manner .Retrospective design of the study precludes inferences about causal relationships. All available demographic and clinical parameters were included, however, unidentified confounders cannot be ruled out. For instance, no information about the cuff position was available, which is known to be potential influence factor on the PWV. The study population was limited to a specific group of non-severe ill subjects, with a majority having hypertension, mild kidney disease and obesity. Thus, further studies are needed in other populations to confirm and generalize our findings. Low prevalence of diabetes mellitus and advanced kidney disease might have diminished the known effect of these influence factors on PWV. Small part of the subjects with repeated measurements and short follow up period could be a reason for clinically non-relevant change in eaPWV120, obtained in the study.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethic Review Board Charité University Berlin. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.AR and MG: conceptualization. AR: methodology, formal analysis, writing—original draft preparation. K-UE and MG: writing—review and editing. MG: project administration. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Factors related to bad asthma control were inadequate prescription (OR: 3.65), non-adherence to treatment (OR: 1.8), and inhaler misuse (OR: 3.03). A higher number of risk factors were associated with a higher probability of having badly controlled asthma.Several modifiable factors leading to poor asthma control have been described. We aimed to determine the proportion of patients with inadequate treatment, adherence to it, or critical mistakes with inhaler technique, and their impact on asthma control. We conducted a cross-sectional multicenter observational study including asthma patients referred from primary to specialist care for the first time. Data collected were adequate prescription according to guidelines, treatment adherence, and disease control. Of the 1682 patients , 35.9% showed inadequate prescription, 76.8% low adherence, and 17% critical mistakes with inhaler technique, with significantly less critical mistakes among Easyhaler users versus other dry powder inhaler users (10.3 versus 18.4%;  Its prevalence is increasing worldwide: nearly 1000 people die from asthma every day according to a study published in 20152. Latest data about asthma global prevalence estimate that it affects 334 million people globally3. However, its prevalence varies greatly between countries with the highest prevalence seen in developed ones1. High direct  and indirect  costs are especially linked to exacerbations3.Asthma is a common disease and it accounts for considerable healthcare costs and loss of work productivity4 visits emphasizing the poor control of asthma in affected patients. Many factors can trigger an exacerbation5: exposure to external factors, poor adherence to treatment, inadequate therapy, and poor inhaler technique are among the most important modifiable causes in the case of uncontrollable asthma6. Several studies have demonstrated poor treatment adherence in asthmatic patients: <50% in children and 30–70% in adults, depending on the country, age, sex, and ethnicity8. The reasons for this variation were limited comprehension or recognition (among patients and/or physicians), beliefs or side effect concerns, inhaler characteristics, and instructions for their use. Frequently, the key aspect of poor asthma control is that many patients, especially with mild to moderate asthma, are undertreated6.Currently, asthma exacerbations are one of the most frequent causes of Emergency Department9. Better control would improve not only cost effectiveness but also quality of life, reduce school absenteeism, and increase work productivity as well3.Thus asthma control as a therapeutic goal, is far from being achieved11.The same situation is reflected in primary care management of asthma. Several studies about asthma in primary care seem to suggest that asthma control in clinical practice is suboptimal despite available therapies. During the past years, little apparent improvement in symptom control has been documented by European publicationsThe primary objectives of this study are to (1) determine the appropriateness of prescribed treatment as well as the presence of poor adherence and critical mistakes in the inhalation technique in patients referred from primary care to a specialist for the first time; and (2) to study the relationship between these factors and poor asthma control. This real-life study may allow us to explore whether asthma management in primary care has improved in terms of quality of prescription, inhaler technique, and patients’ adherence to treatment, 30 years after the implementation of asthma guidelines in Spain.The number of patients enrolled in the study was 1682, of whom 64.6% were men. The mean age was 45 ± 17 years. The characteristics of the cohort are shown in Table p < 0.0001; Table According to Global Initiative for Asthma (GINA) recommendations, 35.9% of patients had an insufficient or inadequate prescription Table . In ordep < 0.0001; Table Regarding adherence to treatment, 76.8% of patient had a low adherence measured by the Test of Adherence to Inhalers (TAI) questionnaire and 68.5% by the Morisky–Green (MG) questionnaire Table . Moreovep < 0.0001; Table p < 0.05): 10.3% of patients showed critical errors with EH, 19.5% with Accuhaler, 16.0% with Nexthaler, and 17.5% with Turbuhaler (p < 0.01). As a consequence  in inhaler technique Table ; among pce Table , a signiRegarding asthma control, 71.7% of patients had a poorly controlled asthma according to the GINA criteria and 65.7% according to ACT test. Several factors were shown to be related with poor asthma control according to the GINA criteria and the ACT test Table : inadequp < 0.0001; Table Each one of these risk factors  has a statistically significant impact on poor asthma control . The corresponding tables for the GINA asthma control that are quite similar to the ACT control are shown in Supplementary Tables The control of asthma according to the GINA score compared to the ACT questionnaire score showed a moderate concordance  ranging from 23.4 to 75.6% in 638 asthmatic patients, depending on the patients’ medical consultation. On average, almost half of the patients showed poor control. The authors of another study20 have estimated that 45% of asthmatic patients who received any type of treatment in Spain had no controlled asthma (ACT ≤ 19). Asthma control in other European countries is also not encouraging: a recent Swedish study in primary care calculated that 53.6% of patients had no controlled asthma (≥600 doses of short-acting beta agonists and/or ≥1 exacerbations/year)21. In the European LIAISON study22, asthma control was assessed according to the Asthma Control Questionnaire: the percentage of patients with partly or not controlled asthma was 56.5 across 12 countries that participated in the study. In USA, the situation is similar: 50% of patients who attended primary care for a non-respiratory consultation had non-controlled asthma (ACT < 19)23. Most of studies show slightly lower percentage of poorly controlled patients compared with our study, which probably could be related with selection bias as the patients referred to specialized care are not expected to be asymptomatic.In our study, 71.7 and 65.7% of patients  showed a poor control of symptoms. Several studies have been conducted in primary care during the past years, with different measurable variables and design9.More than one-third of our patients, at the time of referral from primary care, had an inadequate treatment, which was associated with a less adequate asthma control. Both providers and patients are prone to underestimate asthma severity, which can be the reason why many patients might be undertreated24, although it is well known that a bad diagnosis and treatment suppose a detriment to the patients’ health25, which in turn increase care demand and health costs. In this sense, the ACT was created as a tool to detect poorly controlled asthma and, as a consequence, to identify those patients who require the most adequate treatment. It has been shown that it allows a better treatment adjustment when the physician uses it routinely26.The lack of time and economical resources are some of the causes of not a fully satisfactory management of asthma in the primary care setting27 that could be the gold standard28 (they are an objective method to assess patients’ adherence), but they are expensive and difficult to use for many patients. Thus self-reports seem to be the most cost-effective measure to assess it7, although patients are hesitant to report poor adherence in some occasions29. In this study, two adherence questionnaires were used, and the TAI questionnaire seems to have more sensitivity than the MG one . Also it is shown that the TAI has a better correlation with patient real adherence30. Moreover, when asthma control is compared according to the ACT punctuation and the GINA criteria, a statistically significant relationship with poor adherence  is found. Similarly, in the REcognise Asthma and LInk to Symptoms and Experience (REALISE) study11, almost 50% of patients showed a poor adherence to treatment, and in the LIAISON study a higher rate of low adherence (according to the MG) was present in patients with poorly controlled asthma, compared to the ones with controlled asthma22. To stress the importance of a good adherence, it should be mentioned that its absence is linked to a higher risk of asthma exacerbations, increased use of oral corticosteroids, need of Emergency Department attendance and/or hospitalization, deterioration of forced expiratory volume in 1 s values31, and finally higher costs and poor quality of life7. Strategies to improve adherence have been explored, such as to review frequently the inhaler usage technique as well as patient adherence in every visit. Also electronic reminders should be used as they can be very effective33. In primary care, it has been established that an educational program could be effective in terms of improving adherence, controlling, and reducing costs. The program should involve medical practitioners as well as nursing services, after an adequate training is given34.The best strategy to evaluate adherence are electronic devices12. In some studies, the percentage of critical errors is higher than the one in our study (ranging from 50 to 90%)35; however, without a doubt this step remains crucial in order to achieve asthma control. It has been established that a poor inhaler technique is associated with more symptoms36, more need for hospitalization12, and definitely a less effective asthma control. In a Dutch study, between 47.7 and 64.9% of patients referred to primary care presented inhaler misuse; a pragmatic intervention showed a significant improvement of this factor37.Regarding the third important factor responsible for poorly controlled asthma, inadequate inhaler technique, this study showed that 17% of the patients referred from primary care make critical mistakes, and it is directly related to bad asthma control . Serious mistakes with inhaler technique can be defined as errors potentially limiting the drug uptake and its distribution to the lungs39. In addition, several studies suggest that an explanation regarding the inhaler use and a practical demonstration of patient skills with the apparatus, as well as by taking into consideration patients’ preferences, could improve satisfaction with the inhaler and usage technique that consequently may result to a better asthma control41. For instance, some publications advocate for providing an explanation of inhaler technique at the Emergency Department, before patient discharge42.The percentage of serious errors differs significantly among inhaler devices. In our study, patients showed a better performance with the DPI devices versus the MDIs, as expected. Among the DPIs, EH was associated with a lower number of critical errors compared to other devices . This finding is supported by previous studies that demonstrated better acceptance and satisfaction with the EH device24, and this control becomes worse as more risk factors are present, ranging from 58.4% of poor control (ACT ≤ 20) when one condition is implicated to 93.5% when all conditions are present (or 54–100% with the GINA criteria). Our study seems to confirm such a concordance between the ACT and the GINA criteria regarding asthma control, although the GINA could identify a higher number of undercontrolled patients than the ACT.Inadequate prescriptions, adherence to treatment, and inhaler technique overall contribute to the fact that 73.3% of patients have poorly controlled asthma (according to the GINA criteria) or 65.7% according to the ACT questionnaire. As mentioned above, these 3 parameters are essential for asthma control11 half of the patients did not take correctly their maintenance medications, and among patients with poor control 50% did not take maintenance medication as prescribed because they thought it was not necessary. In another study10, almost 50% of patients believed that their asthma was well controlled, even when they had severe and persistent symptoms. Educational interventions could improve patients’ knowledge and consequently their adherence to treatment.Results regarding asthma knowledge and understanding are not encouraging, and they are remarkable factors of asthma poor control: most patients believe that bronchodilators are the main treatment in managing asthma and that the anti-inflammatory treatment can be stopped during remission periods. When asthma understanding is analyzed as predictive factor of asthma poor control through a binary logistic regression, it seems to be an independent predictor of asthma control. These concerns probably influence patients’ adherence: in the REALISE study28, we tried to use modern tools to verify whether recent advances in asthma management provided any changes in the preventable factors associated with asthma control. The result is not especially encouraging: although nowadays good recommendations for asthma control are provided, in real life this aim is far from been achieved, and an underestimation of risk appears critical between primary care physicians and their patients. Maybe educational programs with the aim to improve recognition of the importance of adherence to a proper, early, and sustained therapy and good inhaler technique for improving asthma control, as well as knowledge of asthma as chronic illness, should be taken into consideration. The mean problem about improving asthmatic patients’ education by physicians and nurses is probably the lack of time addressed to this aim, especially in some Health Care Systems. This is a common problem in chronic diseases. Probably, the first step could be the obligatory establishment of a time addressed only to education to the knowledge of asthma disease and the correct use of the devices for its treatment. These kinds of interventions could improve outcomes and cost-effectiveness as it was demonstrated by the Finnish program34.This study aims to determine the proportion of patients with inadequate treatment and offer an updated insight into modifiable factors involved in asthma control at primary care level. Because results are different in clinical trials and real life, as it has been widely shown43. Finally, study population is heterogeneous regarding comorbidity, previous diagnostic and treatment, and habits. Although this heterogeneity lies closer to real life, it is s not easy to extrapolate these results to a concrete population. Anyway, the aim of the current study is not to criticize primary care management of asthmatic patients but to get a picture of referred asthmatic patients’ condition.There are several limitations in this study. No reason for patients’ referral from primary care to pneumologist or allergologist was recorded, which could create a bias during patients’ selection. Furthermore, in primary care all tools of GINA treatment steps are not available, so patients with severe asthma hardly would be well controlled at primary care. Patients were enrolled during a relatively short period of time (from September to December): patients with seasonal respiratory symptoms, due to a specific allergy profile, were not enrolled in the study. In this study, the ACT cut-off point was established at 21, while it was fixed at 19–20 in other studies. An overestimation of asthma poor control could be present in this study. Regarding critical mistakes, assessing inhaler technique may be challenging because some aspects of the technique are subjective, such as “synchronization between actuation and inhalation” when evaluating pMDI devices or “inhale deeply” when evaluating DPI devices. However, the investigators who assessed inhaler technique were well trained and had lots of experience educating patients; therefore, we think that the reliability of inhaler technique evaluation is good. In addition, the use of pMDI with spacer devices was not evaluated. However, the use of a spacer is generally recommended for children and older people, and its use is not common in adultsOur results suggest that poor asthma management, adherence to treatment, inhaler technique, and poor asthma knowledge constitute, at primary care level, critical factors resulting in reduced asthma control. Many patients do not receive adequate treatment and adherence to therapy is poor when referred to a Specialist. In addition, patients showing critical mistakes in the inhaler technique is a frequent finding.This study demonstrates that there is yet room for improvement by acting on these modifiable factors that appear as key opportunities for the improvement of asthma management at primary care level by optimizing therapy, retraining on inhaler technique and asthma knowledge, and developing new tools to improve adherence to treatment.A cross-sectional multicenter observational study was conducted in patients aged ≥18 years who made use of any type of inhaler device and were referred from primary care to a pneumologist or allergologist for the first time for every kind of reason. Data were collected from September to December 2016. Exclusion criteria were the lack of a signed informed consent and incapacitating illness or mental disease, making the participation to the study, according to the research criteria, difficult. All patients were undergone to a spirometry and a bronchodilator test in order to confirm/exclude asthma diagnose.44 , treatment adherence according to the MG questionnaire , adherence to inhalers 46, and critical errors with patient inhaler technique46 identified through item 12 of the TAI questionnaire. Only the main inhaler for maintenance therapy was evaluated. This item consists of a practical demonstration of patients’ inhaler technique, in addition to discover critical errors by the physician. This item shows 2 categories of patients: with ≥1 or without critical errors. Additional patient knowledge about asthma was evaluated through a questionnaire from the GEMA educational material47 , and asthma control according to both GINA and ACT criteria48. According to GINA, these items were taken into account: patients’ day/nighttime symptoms (<2 times/week daytime symptom and no nighttime symptoms), treatment to relieve symptoms (<2 times/week), and no activity limitations in the past 4 weeks. Thus patients were classified into 2 categories: well controlled , partially/not controlled (with 1–4 of previous items). According to the ACT, patients were classified into the same 2 categories, but in this case established through 5 items of the ACT validated Spanish version . Patients having a body mass index >30 were diagnosed as obese.The following clinical data were collected: asthma severity according to the 2015 GINA criteriaAll data were collected in a single visit, through an online patient notebook, proportioned to the needs of the study. Ethics Committee permission  was obtained, and the study was performed according to the Helsinki Declaration (1964). Informed consent was obtained from all participants.χ2) for categorical data and with analysis of variance test for continuous data. A binary logistic regression was used in order to establish the independence of detected factors (OR). Relationship and concordance between ACT/GINA about asthma control were expressed through Cohen’s k coefficient, Spearman’s correlation coefficient, and R square (R2). All data were analyzed with SPSS 20.0 version.Statistical inference was analyzed with the Pearson’s chi-squared test (Further information on research design is available in the Supplementary InformationReporting Summary