P-A) relationship, this study proposes a method to assess intersubject differences in local PWV independently from BP. The method was then used to analyze differences in local carotid PWV (cPWV) between hypertensive and healthy normotensive people before and after BP-normalization. Pressure (P) and diameter (D) waveforms were simultaneously acquired via tonometer at the left and ultrasound scanning at right common carotid artery (CCA), respectively, in 22 patients with Grade 1 or 2 hypertension and 22 age- and sex-matched controls. cPWV was determined using the D2P-loop method. Then, the exponential modeling of the P-area (A = πD2/4) relationships allowed defining a mathematical formulation to compute subject-specific changes in cPWV associated with BP changes, thus enabling the normalization of cPWV against intersubject differences in BP at the time of measurement. Carotid systolic BP (SBP) and diastolic BP (DBP) were, on average, 17.7 (p < 0.001) and 8.9 mmHg (p < 0.01) higher in hypertensives than controls, respectively. cPWV was 5.56 ± 0.86 m/s in controls and 6.24 ± 1.22 m/s in hypertensives. BP alone accounted for 68% of the cPWV difference between the two groups: 5.80 ± 0.84 vs. 6.03 ± 1.07 m/s after BP-normalization (p = 0.47). The mechanistic normalization of cPWV was in agreement with that estimated by analysis of covariance (ANCOVA). In conclusion, the proposed method, which could be easily implemented in the clinical setting, allows to assess the intersubject differences in PWV independently of BP. Our results suggested that mild hypertension in middle-aged subjects without target organ damage does not significantly alter the stiffness of the CCA wall independently of acute differences in BP. The results warrant further clinical investigations to establish the potential clinical utility of the method.Pulse wave velocity (PWV) is a powerful predictor of cardiovascular events. However, its intrinsic blood pressure (BP)-dependency complicates distinguishing between acute and chronic effects of increased BP on arterial stiffness. Based on the assumption that arteries exhibit a nearly exponential pressure-area ( The art for PWV . However for PWV , and (3) for PWV . While,  for PWV , mean BP for PWV , and pul for PWV  are ofte for PWV . As inte for PWV .P)-area (A)/diameter (D) relationship of arteries resembles an exponential function . Furthermore, CAVI and CAVI0 differ also in the normalizing pressure used to estimate β from haPWV, raising once more the question of which is the most appropriate pressure level for the normalization of PWV metrics , Pref is a reference pressure, Dref is the diameter at Pref, and γ0 is an index of arterial stiffness defining the exponential relationship between P and D2. Note that identical P-D2 relationships can be obtained with opportunely different combinations of Pref, Dref, and γ0 ], the pressure change used to normalize PWV(Pc) is determined as the difference between the two pressure levels: PT–Pc. Following from Eq. 3, PWV at PT can be determined as follows:Let us define a target pressure By combining Eq. 3 and 4, we obtain as follows:Pc to the desired target pressure PT. We noted that Pc is generally unknown and depends on the choice of the method used to estimate PWV. However, if γ0 is known, Pc for any PWV estimation method can be numerically estimated by solving Eq. 3.Eq. 5 allows us to convert PWV at pressure b) > 140 mmHg and/or DBP > 90 mmHg or based on active antihypertensive treatment. The final study population included n = 22 healthy normotensive controls and n = 22 patients with mild-to-moderate (or Grade 1–2) hypertension (n = 9) were treated (treatment duration < 1 year). The protocol of the study followed the principles of the Declaration of Helsinki and was approved by the institutional ethics committee “Comitato Etico di Area Vasta Nord Ovest” (reference number: 3146/2010). All subjects gave their informed consent to participate.The study sample came from individuals undergoing standard outpatient cardiovascular risk assessment at the Pisa University Hospital , omitting anyone with carotid atherosclerotic plaque, diabetes, and history of major cardiovascular events, atrial fibrillation, malignancy, or chronic inflammatory disease. Hypertension was defined as brachial SBP  after subjects had rested for at least 15 min in the supine position. Then, the pressure waveform of the left common carotid artery (CCA) and the diameter waveform of the right CCA were simultaneously acquired by tonometry  and ultrasound scanning , respectively. A similar coupling of waveforms acquired at the contralateral CCAs has been performed previously to achieve correspondence in heartbeats between the pressure and diameter signals, under the assumption that hemodynamic features are similar in the two CCAs due to their similar geometrical characteristics and downstream branching (b and DBP assuming a form factor of 0.43: MBP = DBP+0.43 (SBPb–DBP) (Both SBPranching . The ultranching . The curBPb–DBP) . Both acBPb–DBP) . FiguresD2P-loop method , as described previously . The BP-normalization of cPWV was performed using both mechanistic (Eq. 5) and statistical (ANCOVA) methods and considering four different pressure levels as normalizing pressure: (1) Pc, determined numerically by solving Eq. 3, (2) DBP, (3) MBP, and (4) SBP. The latter three pressure levels were chosen because often used as normalizing pressures in clinical studies. For each pressure level, PT in Eq. 5 was set to the average Pc, DBP, MBP, or SBP across groups. Data are generally presented as average ± standard deviation (SD). ANCOVA estimates are presented as average (95% CI). The p-value < 0.05 was considered statistically significant.Statistical analysis was performed using SPSS 23 . Comparison of variables between the two groups was first performed using Student’s p = 0.021). Carotid SBP was, on average 17.7 mmHg higher in hypertensives than controls (p < 0.001), while the difference in DBP was approximately half (p < 0.01). As a result, PP was also 8.7 mmHg higher in hypertensives than controls. Average CCA diameters at SBP and DBP were slightly higher in hypertensives than controls, but differences were not significant and were reduced further after appropriate SBP and DBP adjustments [7.62 (7.23–8.02) vs. 7.76 (7.37–8.16) mm and 7.15 (6.77–7.53) vs. 7.33 (6.95–7.71) mm]. Conversely, carotid IMT and IMT/Dd were higher in hypertensives than controls .Group characteristics are presented in p < 0.05) (p < 0.05). However, the pressure-normalized stiffness index γ0 did not differ significantly , suggesting that increased cPWV in hypertensives was likely mainly related to BP differences between groups. In fact, the average estimated P-A relationships of the two groups  , even afo groups  run almoPc, estimated from cPWV and γ0 by numerically solving Eq. 3, was 87.5 ± 10.3 in hypertensives and 78.4 ± 10.3 in controls, corresponding approximately to DBP + 0.085 (SBP–DBP) for both groups  (Pc as a confounder: 5.77 (5.33–6.20) vs. 6.03 (5.59–6.47) m/s (p = 0.41) .h groups . Notably  , right. Pc, SBP, MBP, and DBP as normalizing pressures. As expected, the corrections of cPWV were stronger when using higher values of normalizing pressure and, except when the normalizing pressure was set to DBP, showed good agreement between statistical and mechanistic methods. BP accounted for 90 (mechanistic) and 84%  with SBP as confounder, 75 and 69% with MBP, and 65 and 39% with DBP.via statistical methods  and the natural logarithm of the diameter distension (lnD) in early systole , Italy. The patients/participants provided their written informed consent to participate in this study.AG contributed to the conceptualization, data analysis, manuscript drafting, and editing. AG and AK developed the analytical method. AK, CP, JC, and MK contributed to the conceptualization, manuscript editing, and project supervision. CM contributed to the data acquisition and management. All authors contributed to the article and approved the submitted version.JC was a past president of the ARTERY  society. MK was responsible for clinical studies at Esaote SpA . The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


To evaluate the safety and efficacy of catheter-based radiofrequency renal sympathetic denervation (RSD) in a daily practice population of patients with uncontrolled resistant hypertension, on top of medical therapy.2. Patients were defined as responders if systolic BP decreased by at least 5 mmHg at ambulatory BP or by 10 mmHg at office BP at their last follow-up visit.Consecutive unselected patients with uncontrolled resistant hypertension undergoing RSD were enrolled. Office and ambulatory blood pressure (BP) measurements were collected at baseline and 3, 6 and 12 months after RSD. Efficacy was assessed even in patients with an estimated glomerular filtration rate (eGFR) below 45 mL/min/1.73 mForty patients with multiple comorbidities underwent RSD from 2012 to 2019. Baseline office and ambulatory BP was 159.0/84.9 ± 26.2/14.9 mmHg and 155.2/86.5 ± 20.9/14.0 mmHg, respectively. At 12-month follow up a significant reduction in office and ambulatory systolic BP, respectively by − 19.7 ± 27.1 mmHg and by − 13.9 ± 23.6 mmHg, was observed. BP reduction at 12-month follow-up among patients with eGFR < 45 mL/min was similar to that obtained in patients with higher eGFR. Twenty-nine patients (74.4%) were responders. Combined hypertension, higher ambulatory systolic BP and lower E/E’ at baseline emerged as predictors of successful RSD at univariate analysis. No major complications were observed and renal function (was stable up to 12 months), even in patients with the lowest eGFR values at baseline.RSD is safe and feasible in patients with uncontrolled resistant hypertension on top of medical therapy, even in a high-risk CKD population with multiple comorbidities, with a significant reduction in systolic BP and a trend towards a reduction in diastolic BP lasting up to 12 months.The online version contains supplementary material available at 10.1007/s40620-021-00966-7. Uncontrolled resistant hypertension is defined as systolic blood pressure of 140 mmHg or higher despite the adherence to at least three antihypertensive medications, including a diuretic, at maximally tolerated doses , 3, risiThis article reports the prospective clinical experience at our center and aims to evaluate the safety and the efficacy of RSD in unselected patients with uncontrolled resistant hypertension and multiple comorbidities, especially CKD, in a real-world clinical setting.All patients were referred to our Institution because of uncontrolled resistant hypertension. They were screened and eligibility for RSD was discussed among members of a multidisciplinary team composed of clinical and interventional cardiologists, nephrologists and hypertension specialists.Eligible patients had office systolic BP above 140 mmHg while on at least three antihypertensive medications from complementary classes, including a diuretic, all of which at the maximum tolerated doses.n = 3) therapy adherence was confirmed by urine samples. During follow-up medical adherence was assessed by direct questioning. In order to rule out a diagnosis of white coat hypertension, all patients were screened based on their home blood pressure diary, and in 24 patients based on basal 24-h ambulatory blood pressure monitoring (ABPM).Exclusion criteria were secondary forms of hypertension other than those related to CKD, significant valvular heart disease, recent acute cardiovascular events , and hemodynamically significant renal artery stenosis (diameter stenosis > 70%) with demonstration of a significant (> 20 mmHg) trans-lesional pressure gradient . FurtherThe enrollment protocol included clinical evaluation, imaging of the renal arteries, and blood sample collection. Office blood pressure (OBP) was measured as the mean of three recordings in the sitting position after a 5-min rest by mercury sphygmomanometer. 24-h ABPM was recorded using “GE-TONOPORT V” automated oscillometric devices; measurement intervals were 15 min during daytime and 30 min during night-time; a minimum of 70% of valid measurements was required. The protocol was approved by our Ethics Committee (CESC-2361) and by the Department of Health of our Region. All patients signed informed consent and were enrolled in the Global Symplicity Registry (GSR) .Each RSD procedure was performed by an expert interventional cardiologist. The procedure involves endovascular access via the femoral artery with advancement of a catheter-mounted device into the renal artery through a 6Fr guiding catheter and a floppy 0.014″ coronary wire. Local anesthesia and sedatives were administered to relieve patient discomfort. A renal angiogram was obtained to confirm suitability of the target vessel and was repeated at the end of the procedure. Until 2014, eligible patients underwent bilateral RSD using the unipolar catheter , while the tetrapolar catheter  was used thereafter. The automated algorithms in the generator box  continuously monitored temperature and impedance at the point of ablation to optimize the delivery of the radiofrequency energy.Follow-up visits consisting of clinical evaluation, accurate OBP measurements, assessment of medication intake by direct questioning, blood sample collection and ABPM were recommended 3, 6 and 12 months after the procedure. Renal artery imaging during follow-up was performed only if clinically indicated.Safety endpoints included; the absence of any device-related major complication, defined as any peri-procedural major vascular complication including renal artery perforation or dissection, any significant embolic event resulting in target organ damage, major bleeding as defined by the BARC (Bleeding Academic Research Consortium) classification , end-staEfficacy endpoint was determined by the interindividual change in OBP and ABPM from baseline to twelve months after the procedure, with interim analysis at three and six months. Variations from baseline of peripheral pulse pressure (p-PP), heart rate (HR), serum creatinine, and number of medications were also assessed.2 compared to the group with eGFR ≥ 45 mL/min/1.73 m2, since they had been excluded per-protocol from the Simplicity HTN-1, HTN-2 and HTN-3 trials.A secondary pre-specified analysis was conducted to evaluate the efficacy of RSD in patients with an eGFR below 45 mL/min/1.73 mA tertiary analysis included a comparison between “responders” and “non-responders” in terms of BP drop after the procedure. According to the literature, if ABPM had not been performed, patients were defined as responders if systolic BP decreased by at least 5 mmHg at ambulatory BP or by 10 mmHg at office BP at their last available follow-up visit , 23.t test. Comparisons between categorical variables were performed using Fisher’s exact test. Analysis of Covariance was employed to adjust for baseline blood pressure measurements. Binary logistic regression was applied to identify predictors of successful RSD, while multivariate analysis was not conducted due to the small sample size. A probability value of p ≤ 0.05 was considered statistically significant. All statistical analyses were performed using SPSS 26.0 .Statistical methods: continuous variables are presented as mean and standard deviation. Categorical data are reported as number and percentage. Comparisons between continuous variables were performed using the paired sample n = 30, 75%), including 19 patients in class III CKD, 7 in class IV and 4 on hemodialysis at study entry. Mean eGFR was 46.7 ± 27.36 mL/min/1.73 m2. Other comorbidities were diabetes mellitus (DM)  and peripheral artery disease (PAD) . Echocardiographic data were available for 29 patients. Mean left ventricle ejection fraction was 56% ± 9.2 and the mean thickness of the interventricular septum was markedly increased (14 ± 2.9 mm). Apart from the severity of CKD, baseline characteristics were similar between the two groups (eGFR < 45 mL/min and eGFR ≥ 45 mL/min).From 2013 to 2019, forty consecutive patients underwent RSD at our center and were included in the present analysis. Table p < 0.001) and the target ablation points in the Flex group were limited to the main artery alone, whereas treatment was delivered to the main artery and extended to the distal branches as well in the Spyral group. Furthermore, as a possible consequence of the operator’s learning curve, the amount of contrast medium administered was significantly lower in the Spyral group . No other significant differences were noted in terms of procedural duration or radioscopy time.Until 2014, six patients (15%) were treated with the unipolar catheter (Flex group), while between 2015 and 2019, thirty-four (85%) underwent RSD using the tetrapolar catheter . Bilateral RSD was performed in 38 (95%) patients since one patient had a chronic total occlusion of the left renal artery and one had a single kidney after surgical right nephrectomy . CompariNone of the 40 patients experienced any major complications as defined by the protocol. Three patients 13.4%) in the eGFR < 45 mL/min group and one patient (5.3%) in the other group had a transient increase in serum creatinine, defined by an absolute increase of about 0.3 mg/dL from basal values, that normalized after hydration therapy for 48 h. Two patients with uncontrolled BP (220/120 mmHg) values developed femoral pseudo-aneurysm despite all the precautions taken to avoid this complication and therefore required thrombin embolization. No significant interindividual differences in serum creatinine were observed at discharge or during follow-up, as shown in Fig. 3.4% in tPaired OBP measurements were available for 33 (83% of the eligible samples) patients at 3-month, 29 (81%) at 6-month, and 25 (76%) at 12-month follow-up, and paired data on ABPM were available for 19 (48%) patients at 3-month, 18 (50%) at 6-month, and 16 (48%) at 12-month follow-up. All patients underwent at least one follow-up visit. Two patients died from non-cardiac causes 10 and 11 months after the procedure, respectively. BP follow-up data collection was limited since several patients were referred and then followed-up at other institutions.p = 0.078) and office diastolic BP by − 1.5 ± 11.8 mmHg (p = 0.467). At 6-month follow-up, office systolic BP decreased by − 12.4 ± 26.7 mmHg (p = 0.019) and office diastolic BP by − 4.2 ± 15.4 mmHg (p = 0.152). At 12-month follow-up office systolic BP decreased by − 19.7 ± 27.1 mmHg (p = 0.001) and office diastolic BP decreased by − 3.8 ± 16.6 mmHg (p = 0.260). The proportion of patients that achieved target BP after RSD, defined as an office systolic BP < 140 mmHg, was 39%, 28% and 44% respectively at 3-month, 6-month and 12-month follow-up  compared to the Spyral catheter (n = 34) is reported in Table S.2. The mean individual change in ABPM from baseline is shown in Fig. p = 0.036) and 24-h diastolic BP by − 4.2 ± 10.3 mmHg (p = 0.091). At 6-month follow-up, 24-h systolic BP decreased by − 11.3 ± 22.8 mmHg (p = 0.050) and 24-h diastolic BP by − 2.6 ± 9.8 mmHg (p = 0.275). At 12-month follow-up, 24-h systolic BP decreased by − 13.9 ± 23.6 mmHg (p = 0.033) and 24-h diastolic BP decreased by − 6.1 ± 15.1 mmHg (p = 0.124). The proportion of patients that achieved target 24-h systolic BP at 12-month follow-up was 39%. The effect of RSD on p-PP is shown in Fig. p = 0.047), at 6-month follow-up  and at 12-month follow-up . The reduction in office p-PP was statistically significant at 12-month follow-up . During follow-up, non-significant changes were observed in terms of HR and number of medications.The mean change in OBP from baseline is shown in Fig. p = 0.998/p = 0.762). At 12-month follow-up no significant difference was noted in terms of reductions in 24-h BP between groups, adjusted for baseline measurements . No interindividual changes were noted in terms of HR, serum creatinine and number of medications during follow-up between groups.A secondary analysis compared the primary end point in the group with eGFR < 45 mL/min, as reported in Table p = 0.034). In the non-responder group prevalence of isolated systolic hypertension (ISH) was significantly higher  as was the E/E′ ratio  compared to responders. Non-significant differences were found in the procedural characteristics. No significant differences were observed in the average number of medications at baseline and during follow-up between responders and non-responders.In the responder-group, the number of medications at 12-month follow-up was significantly lower compared to the number of medications before RSD was performed .On the basis of the chosen definition, twenty-nine patients (74.4%) were “responders” at their last available follow-up, as reported in Table p = 0.028), combined with hypertension , and lower E/E′  were predictors of successful RSD. Multivariate analysis was not performed due the small sample size.Univariate analysis demonstrated that higher 24 h systolic BP , this is the largest series of RSD cases performed in Italy to date.Despite the relatively small number of patients , with a significant systolic and diastolic OBP reduction , with no significant effect on ABPM values. [(Relatively) few previous studies have quantified the safety and efficacy of RSD in CKD patients. This is unfortunate since the association between hypertension and CKD is strong. Hering and colleagues reported good results in a small cohort of 15 cases with uncontrolled resistant hypertension and moderate to severe CKD . This is in line with data from the world’s largest ongoing registry in this setting, the Global Simplicity Registry. Potential differences might be related to additional variables such as increased knowledge regarding renal nerve distribution, the better anatomic approach provided by a distal rather than a proximal application of radiofrequency, and the large number of ablations obtained with the new tetrapolar system. In our case, the possible effect of a procedural learning curve cannot be excluded since the monopolar catheter was used in the first six RSD cases.We acknowledge several limitations of our analysis. This is a single-center analysis, with a relatively small number of patients, and it was developed during the learning curve of the technique. Investigators were unblinded to the treatment, and there was no control group. Despite our best efforts, follow-up was not feasible in a number of patients in the cohort, mostly due to geographical reasons. Moreover, baseline non-adherence to medical therapy may represent a potential limitation as a possible cause of “pseudo-resistant” hypertension. During follow up, medical adherence was assessed by direct questioning. In conclusion, due to the relatively small sample of patients, potential predictors of the efficacy of RSD has to be read as hypothesis-generating and deserves further analysis in a larger population.In a “real-life population” of patients with uncontrolled-resistant hypertension and multiple comorbidities including CKD, RSD is a safe and feasible strategy when applied on top of medical therapy. In our experience RSD resulted in a significant reduction in systolic BP pressure for up to 12 months after the procedure and a trend towards a reduction in diastolic BP.Future prospective trials should explore the safety and efficacy of RSD in advanced CKD and ESRD.Supplementary file1 (DOCX 17 KB)Below is the link to the electronic supplementary material.


We aimed to compare the rate of stroke, transient ischemic attack, and cerebrovascular disease diagnoses across groups of patients based on their orthostatic blood pressure response in a transients ischemic attack clinic setting.2 test. The effect of confounders was adjusted using a multivariate logistic regression analysis.We retrospectively analysed prospectively collected data from 3201 patients referred to a transient ischemic attack (TIA)/minor stroke outpatients clinic. Trained nurses measured supine and standing blood pressure using an automated blood pressure device and the patients were categorized based on their orthostatic blood pressure change into four groups: no orthostatic blood pressure rise, systolic orthostatic hypertension, diastolic orthostatic hypertension, and combined orthostatic hypertension. Then, four stroke physicians, who were unaware of patients' orthostatic BP response, assessed the patients and made diagnoses based on clinical and imaging data. We compared the rate of stroke, TIA, and cerebrovascular disease (either stroke or TIA) diagnoses across the study groups using Pearson's χCerebrovascular disease was significantly less common in patients with combined systolic and diastolic orthostatic hypertension compared to the "no rise" group [OR = 0.56 (95% CI 0.35–0.89]. The odds were even lower among the subgroups of patients with obesity [OR = 0.31 (0.12–0.80)], without history of smoking [OR 0.34 (0.15–0.80)], and without hypertension [OR = 0.42 (95% CI 0.19–0.92)]. We found no significant relationship between orthostatic blood pressure rise with the diagnosis of stroke. However, the odds of TIA were significantly lower in patients with diastolic [OR 0.82 (0.68–0.98)] and combined types of orthostatic hypertension [OR = 0.54 (0.32–0.93)]; especially in patients younger than 65 years [OR = 0.17 (0.04–0.73)] without a history of hypertension [OR = 0.34 (0.13–0.91)], and patients who did not take antihypertensive therapy [OR = 0.35 (0.14–0.86)].Our data suggest that orthostatic hypertension may be a protective factor for TIA among younger and normotensive patients.The online version contains supplementary material available at 10.1186/s12872-022-02600-1. Globally, stroke is the second leading cause of adult mortality, morbidity and disability. The majority of these events occur in low to middle-income countries , 2. SincOHT is defined as an increase in BP upon assuming an upright position . It is cThe cut-offs and definitions of OHT and whether systolic and diastolic OHT may be different pathophysiological entities are currently unknown. Most of existing literature have not divided different types and patterns of OHT in their assessments for cerebrovascular correlations. In this study, we aimed to investigate the association between different patterns of orthostatic hypertension and the clinical diagnosis of stroke, transient ischaemic attack (TIA), or no cerebrovascular diagnosis in a large cohort of patients assessed in a TIA clinic in the East of England.We retrospectively assessed prospectively-collected data from 3201 patients who presented to a TIA clinic at a University Hospital in the East of England  between July 2002 and September 2009. The data were retrieved from a TIA database which is part of the Stroke & TIA Register that received Institutional approval from the local NHS Trust and ethical approval from Newcastle and North Tyneside Research Ethics Committee (ref: 17/NE/0277). Further information on the inclusion of patients is presented in Fig. : ≥ 20 mmHg systolic or ≥ 10 mmHg diastolic from lying to standing/sitting [The patients were classified into four categories based on their BP dynamics according to the most commonly used definition of Orthostatic Hypertension as an increase in BP of either/bothSystolic orthostatic hypertension (a rise in BP of ≥ 20 mmHg systolic from lying to standing/sitting regardless of DBP level).Diastolic orthostatic hypertension (a rise in BP of ≥ 10 mmHg diastolic from lying to standing/sitting regardless of SBP level).Combined orthostatic hypertension (a rise in BOTH ≥ 20 mmHg systolic and ≥ 10 mmHg diastolic from lying to standing/sitting).Patients without significant orthostatic rise in BP referred to as the "No orthostatic hypertension" group who consisted of patients without orthostatic blood pressure change and patients with orthostatic hypotension.The main study groups were:2), smoking status (yes/no), alcohol consumption (yes/no) and type of antihypertensive medications  were also collected. Stroke physicians would then visit the patients and make the diagnoses.At each clinic appointment, trained nurses measured supine and standing BP using a DINAMAP ®  automated BP device, with a cuff of the appropriate size,  prior to specialist stroke physician assessment . BP was recorded after 5 min of supine rest, and after standing for 3 min with feet on the floor. The sitting blood pressure reading was used for patients who were unable to stand. Age, gender, past medical history , diabetes, hyperlipidaemia and obesity defined as calculated BMI of ≥ 30 kg/mThe main outcome was diagnosis recorded as either TIA, stroke or other diagnoses (i.e. non-TIA/stroke). TIA was defined as one or more brief episodes of neurological dysfunction resulting from focal cerebral ischaemia not associated with permanent cerebral infarction, lasting shorter than 24 h . Stroke 2 test was used to compare proportions of outcomes in each of the orthostatic hypertension groups with the "no rise" group independently. We subsequently used a stepwise multivariate logistic regression approach to examine the association between blood pressure groups and diagnosis of cerebrovascular disease, transient ischemic attack, and stroke adjusting for confounding variables. Sensitivity analysis was used to assess for the effects of missing data.Data were analysed using Stata version 10.1 . Student’s t-test was used to compare mean values of continuous variables and Pearson's χAmong a total of 5311 patients in the cohort, we excluded 2110 participants due to missing data on BP measurements and age. Obesity and use of antihypertensive medications were significantly more common among patients in the included cohort compared to the excluded cohort  and non-smokers (OR 0.34 95% CI 0.15–0.80) compared to normal-weight people (OR 0.74 95% CI 0.42–1.28) and smokers (OR 0.73 95% CI 0.41–1.29) respectively. Also, the odds of a cerebrovascular disease diagnosis decreased more sharply in normotensive patients (OR 0.42 95% CI 0.19–0.92) with a rise in both systolic and diastolic blood pressure upon standing compared to patients with underlying hypertension (OR 0.64 95% CI 0.36–1.15) with the same orthostatic BP response  and combined (OR 0.51 95% CI 0.30–0.87) types of orthostatic hypertension compared to patients without postural rise in blood pressure. The latter correlation was the strongest among patients with combined orthostatic rise in systolic and diastolic blood pressure especially when adjusted for age and sex. Further analysis showed that the odds of TIA associated with orthostatic BP rise were lower among the subgroup of patients younger than 65 years compared to older patients (OR 0.17 vs. 0.86), those without a history of HTN compared with individuals with a past history of hypertension (OR 0.34 vs. 0.67) and patients who did not take medications for hypertension compared to those who took medications for hypertension (OR 0.35 vs. 0.73)  is a known risk factor for stroke and cerebrovascular diseases, the possible role of orthostatic hypertension has not been studied as well –26.The findings from the ARIC study showed a higher rate of lacunar stroke among patients with orthostatic rise or fall in blood pressure compared to patient without orthostatic changes in BP . Other sInterestingly, we found that OHT decreased the rate of TIA diagnoses but not stroke. This finding may be related to our study population at a TIA clinic which does not include major stroke patients who would refer to the emergency department. Moreover, incidence of TIA subtypes seems to vary in different regions of the world. One study evaluating TIA patients in Japan showed that the most common etiologic subtype was lacunar TIA accounting for 31% of total TIA cases and that these patients were at a higher risk of early recurrent stroke during admission . We knowAnother interesting area of research is the association between orthostatic changes in blood pressure and circadian BP patterns. Kario et al. proposed that orthostatic hypertension is associated with extreme nocturnal dipping of blood pressure . This paIn our study, the association between OHT and lower rate of TIA diagnosis was significantly stronger in patients younger than 65 years. Although OHT has been found more commonly among patients with hypertension, the association between OHT with lower rate of TIA diagnosis was stronger among non-hypertensive patients or individuals who weren't using antihypertensive medications in the current study , 39–41. The findings from a post-mortem study of stroke patients show that the mechanism underlying the association between cerebrovascular disease and OHT may be severe carotid baroreceptor damage associated with severe carotid atheromatosis in ischemic stroke patients . One stuA review of cases who had undergone carotid body resection shows that these patients have increased levels of BP variability associated with unopposed sympathetic activation . IncreasOur study should be interpreted considering the following limitations: We could not assess for the direction of the association due to the retrospective nature of data analysis and the observational design of our study. Although we adjusted for major known confounding variable in the analysis, observational studies are also limited by potential confounding from measured and unmeasured confounders. Moreover, a causal relationship cannot be inferred from the results. The control group included patients with orthostatic hypotension (OH) as well as patients with normal orthostatic BP dynamics; since OH may itself be associated with increased risk of cerebrovascular pathology, this may have introduced bias. Although, sensitivity analysis showed that excluding patients with postural hypotension did not affect the findings. Readers should also keep in mind that our study was carried out in a TIA clinic and the results cannot be generalized to the entire spectrum of patients with cerebrovascular disease; specifically, patients with severe and acute symptoms usually refer to emergency department and were not part of this study cohort. Thus, patients with major stroke who would refer to the emergency department were not assessed in our study and we cannot judge the effects of OHT on major stroke based on our findings.We recommend further research on this topic with a prospective design including a cohort of individuals with and without hypertension at various ages to compare the short-term and long-term effects of OHT on the incidence of cerebrovascular disease in relation to age and sitting BP.In conclusion, our study showed an association between combined and isolated diastolic orthostatic hypertension with a lower rate of TIA diagnosis and cerebrovascular disease but not stroke. These associations were stronger among patients younger than 65 years and without a history of diagnosed hypertension. It is possible that orthostatic hypertension is a protective factor for TIA among younger normotensive patients.Additional file 1. Comparison between the paticipants’ characteristics between the included and the excluded cohort.


Mechanical ventilation is essential for supporting patients’ respiratory function when they are under general anesthesia. For cats with limited lung capacity, the different effects of volume-controlled ventilation (VCV) and pressure-controlled ventilation (PCV) on respiratory function remain elusive. The objective of the present study was to compare the efficacy of VCV and PCV in cats under general anesthesia using a cuffed endotracheal tube (ETT).2 were recorded from 60 trials for airway control during the use of VCV or PCV. Data were compared using Fisher’s exact test with a significance level of p<0.05.Twelve healthy cats were randomly allocated to either a VCV or PCV group. Five tidal volumes  were randomly applied to assess the efficacy of VCV, and respiratory rates were adjusted to achieve a minute ventilation of 100 mL/kg/min. Peak inspiratory pressures  were randomly applied to assess the efficacy of PCV, and respiratory rates were adjusted to achieve a minute ventilation of 100 mL/kg/min. Blood pressure, gas leakages, and end-tidal CO2O mL) compared with PCV .Leakages did not differ between VCV (1/60 events) and PCV . Hypercapnia was identified when using VCV (6/60 events) less frequently than when using PCV , but did not reach statistical significance. Hypotension  occurred less frequently with VCV (0/60 events) than with PCV . Moreover, VCV provided a significantly lower work of breathing (151.10±65.40 cmHVCV in cats using a cuffed ETT causes less hypotension than PCV. It should be noted that VCV provides a more stable tidal volume compared with PCV, resulting in a more stable minute volume. Nonetheless, VCV should not be used in patients with an airway obstruction because higher peak airway pressure may occur and lead to lung injury. We also compared the work of breathing and its components between VCV and PCV. Other parameters  and by the Ethical Review Board of the Office of National Research Council of Thailand (NRCT license U1-07457-2561). Written consent was obtained from all cat owners, and the experiment complied with the Kasetsart University Institutional Animal Care and Use Standards.The study was conducted from June 2018 to June 2019. The study was conducted on 12 cats visiting the Kasetsart University Veterinary Teaching Hospital, Bangkok, Thailand.® Jelly 2% . The ETT size was selected according to the hospital’s guidelines .Twelve client-owned cats  enrolled in the present study were undergoing professional dental examinations . Each ca2O using a pressure gage. The ETT was secured with gauze. Using capnography, the airway connector was placed between the airway device and the Y-piece of the anesthesia machine . Anesthesia was maintained with a sevoflurane vaporizer  and an oxygen/air mixture (FiO2 targeted at 90%) at a flow of 2 L/min, using an infant circle rebreathing system. The end-tidal concentration of sevoflurane in each cat was set at 2.5% .All cats underwent the same anesthetic protocol applied by the same veterinarian (NN). Before undergoing anesthesia, the results of a physical examination and the cat’s body temperature, heart rate, and electrocardiogram (EKG) results were recorded. An intravenous (IV) catheter was placed in a cephalic vein, and normal saline (0.9%)  solution was administered at a rate of 5 mL/kg/h. The cats were pre-oxygenated for 5 min before induction. Anesthesia was induced with a slow IV infusion of propofol, and the amount of propofol  needed for induction in each cat was recorded. The depth of anesthesia was assessed before intubation based on the following five criteria : Palpebr2), heart rate, EKG, body temperature, and non-invasive blood pressure were recorded every minute by the monitoring machine . The ETCO2, respiratory rate, VTi, expiratory tidal volume (VTe), PIP, sevoflurane concentration, and gas leakage were monitored every minute by the anesthesia machine . Hypotension was defined as a mean arterial blood pressure <60 mmHg. To detect leakage, the difference between VTi and VTe was monitored. Hypercapnia was defined as ETCO2 >45 mmHg. Hypothermia was monitored and prevented with a water-circulating blanket  placed under the cat’s body and a Bair Hugger warming blanket .Baseline values for pulmonary and cardiovascular measurements were recorded during spontaneous ventilation after intubation. When breathing and the depth of anesthesia were stable, mechanical ventilation was initiated by the anesthesia machine , a beta value of 0.8, and an effect size of 5 mmHg. All data were tested for normality using a Shapiro–Wilk test. All parametric data, including dosage of propofol and static respiratory measurements of the cats in the VCV and PCV groups, were analyzed using a paired t-test. A non-parametric Wilcoxon signed-rank test was used to compare the difference in the respiratory work between PCV and VCV. The association of leakage and hypercapnia was determined using Fisher’s exact test. The significance level was set at p<0.05.STATA 12  was used to estimate the required sample size using a For each tidal volume and inspiratory pressure, respiratory rates were adjusted in each cat to allow a minute ventilation of 100 mL/kg/min, and there was no significant difference in respiratory minute volume between the VCV and PCV groups p>0.05; . Airway 2 > 45 mmHg) was compared between the VCV and PCV groups. Hypercapnia was identified when using VCV (6/60 events) less frequently than when using PCV (7/60 events). No significant difference in the number of hypercapnia occurrences between the VCV and PCV groups was detected (p=0.76) (The occurrence of hypercapnia (ETCO(p=0.76) .Hypotension  was compared between the VCV and PCV groups. There was no significant difference in hypotension between the different tidal volume settings of the VCV group and the different PIP settings of the PCV group. However, of the 60 total trials, there was significantly more hypotension in the PCV group (9/60 events) than in the VCV group  .Measuring the work of breathing is necessary to evaluate the status of patients during the use of mechanical controlled ventilation . The worThe efficacy of ETT in cats under general anesthesia with VCV or PCV was evaluated in the present study. Our results revealed no difference in leakages when comparing VCV and PCV. Hypercapnia was less frequently identified when using VCV compared with PCV, but the frequency did not reach statistical significance. Hypotension occurred at a significantly lower frequency in the VCV group than in the PCV group. Moreover, VCV provided significantly lower work of breathing compared with PCV. Our results suggested that VCV not only provided a more stable tidal volume compared with PCV but also was associated with fewer complications.2O to minimize damage to tracheal mucosa, the increased risk of aspiration pneumonia, and interference with mechanical ventilation [Leakage during ventilation was evaluated in the present study. Our results indicated that there was no significant difference in respiratory leakage between VCV and PCV. Peak pressure below the cuff pressure and high-volume/low-pressure cuffs was used; therefore, there was no leakage in the present study. In a previous study, airway leakages were found less in the ETT group than in the supraglottic airway device group because the ETT provides a better air seal than supraglottic airway devices . The cuftilation ,7.2 was monitored, and the dead space volume of the ETT and the minute ventilation in both groups were controlled. There was no significant difference in the presence of hypercapnia when comparing VCV and PCV. Nonetheless, a higher occurrence of hypotension in cats with PVC was identified compared with VCV. Positive pressure ventilation has both positive and negative hemodynamic effects [The volume of dead space is also influenced by the alteration of tidal volume and the frequency of ventilation . In the  effects . The pos effects . When th effects ,7,9,22.2<60 mmHg), severe hypoventilation (PCO2>60 mmHg), severe circulatory shock, and excessive work of breathing [The indications of mechanical ventilation for VCV and PCV are severe hypoxemia despite oxygen therapy (PaOreathing . The worOne limitation of the present study is the small sample size. Because the study was designed using a paired sample, the use of a small sample size was feasible. Another limitation is the use of only healthy cats; the results of this study cannot be applied to cats with respiratory diseases. Mechanical ventilation is fraught with numerous adverse outcomes, such as airway complications, pneumothorax, interstitial emphysema, barotrauma, infection, and hypotension, in patients with pre-existing hypovolemia because positive end-expiratory pressure increases the intrathoracic pressure and reduces systemic venous return and cardiac output . In addiOur results indicate that VCV causes less hypotension than PCV. VCV also provides a more stable tidal volume compared with PCV, resulting in a more stable minute volume. Nonetheless, VCV should not be used in patients with an airway obstruction because a higher peak airway pressure may occur and lead to lung injury.NN: Designed the study, conducted literature review, performed the study, interpreted data, and drafted manuscript. NT: Designed the study, interpreted data, and reviewed the manuscript. All authors read and approved the final manuscript.


Predictors chosen for our model were older age, male sex, subjective fever, dyspnea, altered consciousness, temperature ≥ 37.5 °C, heart rate ≥ 100 bpm, systolic blood pressure ≥ 160 mmHg, diabetes mellitus, heart disease, chronic kidney disease, cancer, dementia, anemia, leukocytosis, lymphocytopenia, and thrombocytopenia. In the external validation, when age, sex, symptoms, and underlying disease were used as predictors, the AUC used as an evaluation metric for our model’s performance was 0.850 in predicting whether a patient will require at least oxygen therapy and 0.833 in predicting whether a patient will need critical care or die from COVID-19. The AUCs improved to 0.871 and 0.864, respectively, when additional information on vital signs and blood test results were also used. In contrast, the protocols currently recommended in Korea showed AUCs less than 0.75. An application for calculating the prognostic score in COVID-19 patients based on the results of this study is presented on our website ( Since effective vaccines were recently developed, more than 5 billion doses have been administered worldwide. Still, however, more than 5 million people are being diagnosed with COVID-19 every week1. The treatment of COVID-19 mainly relies on symptomatic relief and supportive care, oxygen therapy, and critical care, depending on the disease severity. Thus, it is crucial to triage COVID-19 patients rapidly and efficiently so that limited medical resources, including quarantine facilities, hospital beds, and critical care equipment, can be allocated appropriately.Since the World Health Organization (WHO) declared the coronavirus disease 2019 (COVID-19) a pandemic in March 2020, it has been raging on, taking the lives of many people 5. Furthermore, since sudden disease progression in initially mild or asymptomatic COVID-19 patients is not rare with reported incidences of 6–12%9, we should base the triage and referral of COVID-19 patients on the worst severity expected during the disease course, rather than the severity at the time of diagnosis.The current protocols recommended for triage and referral of COVID-19 patients in many countries or by WHO are based on known risk factors and expert opinion but have not been validated on the actual patient data20. There may be limitations, however, to applying these models for COVID-19 patient triage under some real-world circumstances. Most of these models require patients’ information obtained from a blood test or imaging study. However, we often need to triage and refer COVID-19 patients immediately after the diagnosis with limited information depending on the situation.Data about the pandemic has now accumulated sufficiently to enable development of a data-driven prediction model for patient triage decision-making. Several prediction models for disease severity in COVID-19 patients have been proposedTherefore, we aimed to develop and validate an easy-to-use tool for COVID-19 patient triage based on a predicted prognosis, with the flexibility to adapt to variable availability. We categorized variables into four groups—demographics and symptoms, underlying diseases, vital signs, and laboratory findings—and develop separate algorithms for different combinations of the variable groups. We compared the performance of our models with the currently used triage protocols. Lastly, we validated the final model in an independent external cohort.Of the total 5,596 COVID-19 patients in the model development cohort, approximately half of the patients (52.1%) were 50 years or older, while people aged younger than 20 years accounted for only 4.9% Table .Table 1PIn the external validation cohort of 445 patients, the mean age was 59 years  with the ratio of males to females of 4.7:5.3. Of these, 8.8% (39/445) required intensive treatment or died of COVID-19. The detailed characteristics are summarized in Supplementary Table The full results of predictor selection are in Supplementary Table The predictors selected from Tier 1 variables for Model 1 were age, sex, and symptoms of subjective fever, rhinorrhea, dyspnea, and altered consciousness. As opposed to other selected predictors, rhinorrhea was associated with a better prognosis.The predictors chosen for Model2A were age, sex, subjective fever, dyspnea, and altered consciousness from Tier 1 (rhinorrhea excluded), and underlying diseases of hypertension, diabetes mellitus (DM), heart disease, chronic kidney disease (CKD), cancer, and dementia from Tier 2 variables.The predictors were age, sex, subjective fever, rhinorrhea, dyspnea, and altered consciousness from Tier 1, and high body temperature and tachycardia from Tier 3 variables.The predictors were age, sex, subjective fever, dyspnea, and altered consciousness from Tier 1 (rhinorrhea not included), severe hypertension (systolic blood pressure ≥ 160 mmHg), DM, heart disease, CKD, cancer, and dementia from Tier 2, and high body temperature and tachycardia from Tier 3.The predictors were age, sex, subjective fever, dyspnea, and altered consciousness from Tier 1, severe hypertension, DM, heart disease, CKD, cancer, and dementia from Tier 2, and high body temperature from Tier 3 (tachycardia excluded), and anemia, leukocytosis, lymphocytopenia, and thrombocytopenia from Tier 4 variables.Older age, altered consciousness, dyspnea, lymphocytopenia, leukocytosis, CKD, temperature of ≥ 38.5 °C, dementia, thrombocytopenia, cancer, subjective fever, male sex, anemia, DM were associated independently with prognosis, in decreasing order of odds ratio (OR) from the multivariable ordinal logistic regression (OLR) in the entire cohort Fig. .Figure 1In predicting whether a patient will require more than supportive care, the Korea Medical Association (KMA) model showed an area under the curve (AUC) of 0.723  with a sensitivity of 54.9 (48.3–61.4)% and a specificity of 7.6 (6.3–9.1)%, and the AUC, sensitivity, and specificity of the Modified Early Warning Score (MEWS) were 0.598 (0.563–0.633), 56.8 (50.1–63.4)%, and 23.5 (21.2–25.9)%, respectively, in the internal validation cohort  at different cutoff probabilities for the OLR models are presented in Supplementary Table https://nhimc.shinyapps.io/ih-psc/), where the results of validation ongoing in our institution are periodically updated; the results on the website will be different from those in this study after updates.In the external validation, the AUCs of Models 1, 2A, 2B, 3, and 4 were 0.829 , 0.850 (0.809–0.895), 0.838 (0.796–0.879), 0.861 (0.822–0.902), and 0.871 (0.834–0.910) in predicting whether a patient will require at least oxygen therapy, and 0.827 (0.754–0.901), 0.833 (0.759–0.907), 0.833 (0.759–0.907), 0.851 (0.786–0.912), and 0.864 (0.802–0.916) in predicting whether a patient will need critical care or die, respectively  because it showed comparable performances to the other algorithms in the final evaluation. Furthermore, a linear model like the OLR is more interpretable and easier to use even without a computer device, as nomograms can be used instead. We also observed the linear model’s superiority in predicting COVID-19 prognosis in our previous study in which we developed a model to predict the risk of COVID-19 mortality based on demographics and medical claim data20. However, those models were designed to be used for hospitalized patients, requiring information that is usually obtained after hospitalization such as laboratory test results or imaging studies. In contrast, our model is intended to be used in various situations, not only for hospitalized patients but also for early triage immediately after the diagnosis. Therefore, our model uses different algorithms depending on the available variable subsets. Health workers sometimes need to triage newly diagnosed COVID-19 patients even by a phone call alone, and patients commonly do not know their underlying disease exactly. Therefore, we expect that our model’s flexibility may make our model distinct from previous models and lead to a more widespread use. Lastly, we divided disease severity into three categories. This is more helpful than the binary categorization , because not all medical facilities capable of oxygen therapy can also provide critical care, such as mechanical ventilation or ECMO.Our current model has a few differences compared to other proposed models. Above all, our main purpose was to develop an easy-to-use prediction model that can be used widely in various real-world fields. This was another reason that we preferred a linear prediction model to other complex machine learning algorithms; simply by knowing the coefficients of the linear model, anyone can calculate the predicted risk using various methods: the nomogram or web-based application we developed, or even paper-and-pencil calculation. Several published prognostic models have also used linear logistic regression and proposed nomograms possibly for the same reason21. However, it was unexpected that chronic obstructive pulmonary disease (COPD), a known strong risk factor, was not selected as a predictor. We assume that this is because there were only 40 patients with COPD in the entire cohort, of whom 65% had dyspnea, and the disease severity of COPD might have varied widely. Thus, it is likely that the number of COPD cases was too small  to play a significant role independently from the other strong predictors.The predictors chosen in this study are not much different from the known risk factors of developing into critical conditions from COVID-19There are limitations to our current model. First, since we trained and validated our model on Koreans’ data, it is unsure whether it can be generalizable to patient cohorts in other countries or races. We hope to be able to develop a triage model that can be used globally through collaboration. Second, we converted continuous variables such as blood test results into categorical variables, which may have resulted in some loss of information. Our intention was, however, to prevent small differences in continuous variables  from overfitting models. Furthermore, all the variables categorized in this study have well-established cutoff values classifying them into categories . Third, our data lacked some important variables, such as smoking, respiratory rate, and oxygen saturation, and had missing values in some of the Tiers-2/3/4 variables, which may have affected the training and performance of the algorithms using those variables. We did not perform imputation for missing values because we did not want the uncertainty and potential bias from imputation, and imputation for missing values did not make significant differences in our preliminary analysis. Lastly, we did not experiment more machine learning algorithms such as extreme gradient boost. Thus, we cannot conclude that OLR is superior to all other machine learning algorithms.In conclusion, we developed and validated a set of models that can be used for disease severity prediction and triage or referral of COVID-19 patients. Our prediction model showed a good performance with age, sex, symptoms, and the information on underlying disease used as predictors. The model performance was enhanced when further information on vital signs and blood test results were also used.The Institutional Review Board of National Health Insurance Service Ilsan Hospital (NHIMC 2020-08-018 and 2021-02-023) approved this retrospective Health Insurance Portability and Accountability Act-compliant cohort study and waived the informed consent from the participants. We performed all methods in accordance with relevant guidelines and regulations.This study used two datasets. For model development and internal validation, we used a dataset containing the epidemiologic and clinical information of patients diagnosed with COVID-19 in South Korea, which the Korea Disease Control and Prevention Agency collected, anonymized, and provided to researchers for the public interest. The data included 5,628 patients who either were cured or died from COVID-19 infection by April 30, 2020. After excluding 32 patients who lacked the information on disease severity or the presence or absence of symptoms, a total of 5,596 patients comprised the model development cohort. The dataset was randomly divided into training and internal validation cohorts with a ratio of 7:3 while preserving the disease severity distribution. We trained and optimized models using the training cohort and validation them on the internal validation cohort.For external validation, we used a cohort of COVID-19 patients treated in National Health Insurance Service, Korea, between December 19, 2020 and March 16, 2021. After excluding 59 patients who were referred with severe conditions requiring oxygen therapy or mechanical ventilation at the time of admission, a total of 445 patients comprised this external validation cohort  none or supportive treatment, (2) oxygen therapy, (3) critical care such as mechanical ventilation or ECMO, or death from COVID-19 infection.We intended to develop a model that can be used flexibly in real-world circumstances where some of the variables may not be available. Therefore, we categorized variables into four tiers based on their accessibility Table .Tier 1 variables can be obtained by simply asking a patient questions: age, sex, body mass index, pregnancy, and symptoms. The symptoms included were subjective fever, cough, sputum, dyspnea, altered consciousness, headache, rhinorrhea, myalgia, sore throat, fatigue, nausea or vomiting, and diarrhea. We separated this group of variables from others because there could be times when we need to triage a patient quickly without physical contact.Tier 2 variables are underlying medical conditions: hypertension, DM, heart disease, asthma, COPD, CKD, chronic liver disease, cancer, autoimmune disease, and dementia. We categorized these variables into a separate group because sometimes patients may not know exactly their underlying medical conditions. In this case, further actions may be required, including reviewing medical records or other examinations.Tier 3 variables are blood pressure, body temperature, and heart rate. Our data lacked information on breathing rate. We separated these variables from the first two tiers because these can be obtained only when a patient visits a medical facility or can measure their vital signs on their own. Blood pressure and heart rate were transformed into binary categorical variables by merging categories that were not significantly associated with disease severity based on the preliminary results in the training cohort: severe hypertension (systolic blood pressure ≥ 160 mmHg) and tachycardia (heart rate ≥ 100 bpm). We assumed that many patients had their body temperature measured while taking antipyretics, although our data did not contain the information on such patients’ proportion.3/µL), lymphocytopenia , and thrombocytopenia .Tier 4 variables are hemoglobin, hematocrit, white blood cell (WBC) count, lymphocyte count, and platelet count, which are available only after a blood test. As with Tier 3, these variables were also transformed into binary categorical variables: anemia (hematocrit < 40%), leukocytosis  100 times with shuffling and choose variables that were selected more than 900 times out of 1,000 trials (> 90%) based on two algorithms: Least Absolute Selection and Shrinkage Operator (LASSO) and RF. A variable was selected if its coefficient was non-zero on LASSO, and its variable importance on RF was positiveWe used four machine learning algorithms: OLR, multivariate RF, L-SVM, and R-SVM. For each algorithm, five models were created using one of the following five predictor sets: predictors chosen from the Tier 1 variables (Model 1), Tiers 1/2 variables (Model 2A), Tiers 1/3 variables (Model 2B), Tiers 1/2/3 variables (Model 3), and Tiers 1/2/3/4 variables (Model 4). We optimized the hyperparameters for RF and SVM through a tenfold CV with a grid search in the training cohort, using AUC as an evaluation metric.Y here, is classified into one of three categories: supportive treatment (y1), oxygen therapy (y2), and critical care or death (y3), the dependency of Y on X  can be expressed as:Y ≥ yj) is the cumulative probability of the outcome; αj is a respective intercept; and βi is a coefficient corresponding to the xi variable. Readers interested in more detailed explanation are referred to the paper by Singh et al.24.OLR is a general term for logistic regression with  ordinal outcomes. Among different OLR models, we used proportional odds model which assumes that the effects of input variables are proportional across the different outcomes, as interpretation under this model deemed logical and meaningful in our case. In case of the current study, as the outcome of each patient, denoted as 25.In this study, the number of outcomes were more than two (not binary), which is considered multiclass or multinomial classification in machine learning. OLR and RF can perform multiclass classification inherently. With SVM, we performed multiclass classification using the one-vs.-rest schemeWe validated the optimized models in the internal validation cohort after fitting them onto the entire training dataset. Based on the probabilities for each outcome category, we assessed the diagnostic performance of each model for whether or not a patient will require treatment (Outcome 1 vs. 2/3), and whether or not a patient will require critical care or die (Outcome 1/2 vs. 3). Sensitivity, specificity, accuracy, precision, and NPV according to different probability cutoffs were calculated, in addition to AUC. We also drew calibration curves to compare the predicted and observed probabilities visually.26. These are two of the protocols that the Korean government currently recommends using with some modifications depending on the situation5. Since we did not have information on smoking status, oxygen saturation, and respiratory rate, these variables were considered normal when applying the protocols. These protocols are described in detail in Supplementary Tables As a baseline for comparison, we also tested two protocols used to triage a newly diagnosed COVID-19 patient: a protocol proposed by the KMA and MEWShttps://nhimc.shinyapps.io/ih-psc/).We tested the final model in the external validation cohort in the same manner as the internal validation. We also developed a web-based application for calculating the probability of requiring oxygen therapy or critical care based on the results of this study, where users also can view the ongoing validation results in our institution (Supplementary Information.


Gastro-intestinal (GI) intolerance is a frequently reported outcome in patients with kidney failure receiving maintenance dialysis and those who have received kidney transplants. Symptoms of GI intolerance  are associated with significant reduction in quality of life, morbidity, and increased used of healthcare resources. Having chronic kidney disease (CKD), together with related changes in diet and medication, may alter the gut microbiota and the microbial-derived uraemic metabolites that accumulate in kidney failure, and contribute to various complications including chronic diarrhoea, opportunistic infections, and drug-related colitis. Despite the high disease burden among patients with kidney replacement therapies, GI symptoms are often under-recognised and, consequently limited resources and strategies are devoted to the management of gastrointestinal complications in patients with CKD.The CKD Bowel Health Study is a multi-centre mixed-methods observational longitudinal study to better understand the bowel health and GI symptom management in patients with CKD. The program comprises of a longitudinal study that will assess the burden and risk factors of GI intolerance in patients treated with maintenance dialysis; a semi-structured interview study that will describe experiences of GI intolerance  in transplant candidates and recipients; and a discrete choice experience to elicit patient preferences regarding their experiences and perspectives of various intervention strategies for the management of GI symptoms after kidney transplantation.This proposed program of work aims to define the burden the GI intolerance in patients with kidney failure and generate evidence on the patients’ experiences of GI intolerance and their perspectives on their clinical and own management strategies of these symptoms, ensuring a patient-centred approach to guide clinical decision making and to inform the best study design for intervention trials.ACTRN12621000548831. This study has been approved by the Western Sydney Local Health District Human Research Ethics Committee of New South Wales Health (HREC ETH03007). This study is supported by a National Health and Medical Research Council (NHMRC) Australia Investigator Grant (APP1195414), and an NHMRC Australia Postgraduate Scholarship (APP2005244).This study is registered on the Australian New Zealand Clinical Trials Registry (ANZCTR):  Gastro-intestinal (GI) intolerance is a frequently reported outcome in patients with kidney failure receiving maintenance dialysis and those who have received kidney transplants. Symptoms of GI intolerance  are associated with significant reduction in quality of life (in particular anxiety and life participation), substantial morbidity burden, increased used of health care resources, and increased risk of allograft complications (including acute rejection as a result of a reduction in immunosuppression). Prior observational studies reported up to 50% of kidney transplant recipients experience adverse GI side effects from immunosuppression, such as mycophenolate mofetil and tacrolimus. Many patients require dose-reduction of immunosuppressive agents that could predispose to a higher risk of acute rejection –6. AlterRuminococcus, Dorea, Coprococcus, and Bacteroides) may be associated with post-transplant non-infectious diarrhoea [There are many reasons for the observed GI changes and symptoms in kidney disease, but retention of uremic molecules produced by microbial metabolism within the gastrointestinal tract may have played a key role in the clinical syndrome of uraemia and its complications . These miarrhoea . Prior wiarrhoea , 12. Faciarrhoea . Prior wThe intestinal microbiota, therefore, represents a new therapeutic target to improve outcomes of CKD including reducing uraemic symptoms and metabolic abnormalities in patients with CKD and kidney failure, delay the progression of CKD, and possibly reduce the development of cancer . NutritiTo better understand the prevalence, severity and management strategies of GI intolerance in kidney transplant candidates and recipients.To determine the prevalence and risk factors of GI intolerance and symptoms in patients: with kidney failure ; before transplant (candidate listed on the transplant waiting list or have a pre-emptive donor); and after kidney transplantation.To describe the experiences, symptoms and management strategies of GI intolerance in kidney transplant candidates and transplant recipients.To elicit patients’ preferences regarding experiences and perspectives on the management strategies for GI symptoms and intolerance after transplantation.An observational longitudinal study of the burden and risk factors of GI intolerance in patients treated with kidney replacement therapyA semi-structured interview study in kidney transplant candidates and kidney transplant recipients.A discrete choice experiment of patient preferences regarding the perspectives of the different treatment and intervention strategies for the management of GI symptoms in patients with kidney transplants.An outline of the three study designs and study procedures is displayed in Fig. STROBE  for the observational study and discrete choice experience ;COREQ  for the qualitative interviews .This protocol is developed to address the reporting checklists for:This study is registered on the Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12621000548831. This study has been approved by the Western Sydney Local Health District Human Research Ethics Committee of New South Wales Health (HREC ETH03007).This multi-centre study will be based at two hospitals in Australia: The Western Renal Service , New South Wales, Australia (primary location); and the Renal Medicine and Transplantation Department , Sir Charles Gairdner Hospital, Western Australia, Australia (secondary location).We will obtain informed consent from each adult participant, caregiver, or legal guardian. There will be no implied consent. To ensure COVID-19-safe practices, we will allow for video or phone verbal consent. Participants can withdraw their consent for the study at any time without affecting their specialist care or disease management in any way.2 and albuminuria > 300 mg/g) [To be eligible for this program of work, participants must be: adults aged 18 years and older, with kidney failure (CKD Stage 4 to 5D: estimated glomerular filtration rate = 0 to 29 mL/min/1.73m00 mg/g) , on dialPrior bowel resection, chronic pancreatic insufficiency, or recent infection-related diarrhoea in the last 3 months. Pre-dialysis patients. Transplant recipients we will exclude recent rejection episodes, and unable to give informed consent.All eligible patients will be identified using the renal databases and through communication with the medical and nursing staff of the unit. This will be either via phone recruitment or consecutive patients attending the outpatient clinics. Participant consent forms, clearly and succinctly outline the screening procedure and the associated harms will be given to all eligible patients to read through at the face-to-face recruitment by the research staff. Informed consent was written where possible and to ensure COVID-19-safe practices, we will allow for video or phone verbal consent as approved by the ethics committee. For patients with non-English speaking background, a qualified health care interpreter will translate information sheets into the patient’s native language. Participation in the study is entirely voluntary. Patients are in no way obliged to participate and if they do, they can withdraw anytime from the study, with their care unaffected in any way.General patient contact information, demographic characteristics, medical history, and CKD health status via the Observational Questionnaire (Baseline).The baseline assessments, pre-transplant of observational data via the Observational Questionnaire (Baseline) which will collect transplant status, current medications and supplements, general health via the EQ-5D Questionnaire , faecal To repeat the instruments, the Observational Questionnaire (Follow-Up) will be administered at 4-, 12-, and 28-weeks post-transplant . This questionnaire contains the same instruments without the patient contact information and demographic sections.Recruitment of participants will occur anytime pre-transplant and the following will be collected Table :General The primary outcomes are: (1) prevalence of GI intolerance (any severity) in patients with kidney failure and kidney transplants; and (2) change in GI symptom burden before and after transplantation. Secondary outcomes are: (1) risk factors of GI intolerance; (2) stool characteristics; (3) general health status, and (4) quality of life.Instruments: the observational questionnaires (baseline and follow-up) will collect a broad range of both clinically important and patient-reported outcomes  using a Statistical analysis: we will undertake a descriptive analysis of the prevalence and management strategies of GI intolerance in patients with kidney failure and have a kidney transplant. Baseline characteristics and dietary patterns will be compared between recipients with and without GI intolerance using chi-square , analysis of variance  and Kruskal-Wallis tests . Longitudinal mixed models with random intercepts will be conducted to assess the relationship between dietary patterns and GI intolerance, accounting for confounders including age, sex, medication use, and CKD stage.Sample size calculation: If the true prevalence of GI intolerance and symptoms is 7–10% in patients with kidney failure, a sample size of 100 will ensure 95% certainty that the prevalence measure in this sample between 5 to 15%, where n = minimum sample, p = estimated prevalence, q = 100-p, E = 5 (margin of sampling error) q/E1.962 .Participants who were identified as eligible for the observational longitudinal study at recruitment (anytime pre-transplant), and who reported the presence of GI symptoms, burden and intolerance, will be invited to participate in the qualitative semi-structured interviews. This will be a longitudinal qualitative study and purposive sampling will be used to ensure a broad range of demographics are included in this study. We plan to enrol a minimum of 30 CKD patients from this study population until saturation. Participants will be interviewed twice: once at baseline (anytime pre-transplant) Visit 1, Table , Table 1A semi-structured interview will be conducted with each participant in their choice of setting either in a clinic room or via video conference. The interviews will be administered by the study research coordinators who are research academics with training in qualitative research. Some participants may be known to the interviewer but only from the recruitment process. The interviewers will not have clinically treated the participants.The interview guide will include the following sections: (1) demographics; (2) Interview 1: general perspectives and experience of gut health in CKD; perceived causes, impact and management of GI symptoms in CKD ; expectations of transplantation; reasons for participating in the study; (3) Interview 2: experience of being in the study; experience of the transplant; experience of GI symptoms post-transplant.The guide was developed following a review of the literature and discussion among the research team consisting of multidisciplinary clinicians and researchers and a consumer advisor –32.Thematic analysis: interviews will be recorded with the participant consent and transcribed verbatim. Transcripts and field notes will be thematically analysed to independently code all transcripts and notes line by line by two study personnel to identify concepts.All participants identified as eligible for the observational longitudinal study, as well as post-transplant patients presenting at the renal clinics, will be invited to participate in the discrete choice experiment. We plan to enrol 70 participants and the survey will be administered at either Visit 3 or Visit 4 Table , or anytFigure Statistical Analyses: we will use NLOGIT, version 5.0  to analyIn regard to written information from questionnaires and electronic survey, all personal information and demographics data will be entered onto a secure web platform. The online database will allow for survey and questionnaire results to be de-identified, using only a study code, to anyone other than the study personnel. The face-to-face qualitative interviews will be identifiable but still linked to each pre-assigned study code. No identifiable information will be shared outside the interview room or video call. For publications and conference presentations, only de-identified outcomes and information will be published in peer-reviewed journals. No identifiable information will be shared during presentations or scientific meetings.All data will be de-identifiable with multiple password-protected entry points and backed-up on secure hospital networks and only approved study personnel will have access to the respective programmes as outlined in the above study methods.Data will be stored for a minimum of 5 years post-publication of the results.This research project has been designed to make sure the researchers interpret the results in a fair and appropriate way and avoids study doctors or participants jumping to conclusions. We do not believe there are any other potential biases that could arise during the conduct of this study.GI symptoms and intolerance are important and debilitating outcomes for patients with kidney failure and transplants. Understanding the risk factors can inform patients, clinicians and other health professionals about the potential treatment strategies, stratification of an individual’s risk of the adverse outcomes in the development of care, policy planning and to provide the necessary evidence that underpins future intervention trials. Interventions such as probiotics or synbiotics could possibly reduce the harmful effects of bacterial imbalance, strengthen the immune system, protect the gut barrier, and reduce the detrimental effects of uremic toxins in patients with CKD.


Improving sleep quality in patients with obstructive sleep apnea (OSA) by positive airway pressure therapy is associated with a decrease of blood pressure (BP). It remains elusive, whether treatment of sleep disturbances due to restless legs syndrome with symptomatic periodic limb movements in sleep (PLMS) affects BP as well. The present study provides first data on this issue. Retrospective study on patients undergoing polysomnography in a German University Hospital. Inclusion criteria were first diagnosis of restless legs syndrome with PLMS  with subsequent initiation of levodopa/benserazide or dopamine agonists. Exclusion criterion was an initiation or change of preexisting positive airway pressure therapy between baseline and follow-up. BP and Epworth sleepiness scale were assessed at two consecutive polysomnographies. After screening of 953 PLMS data sets, 114 patients (mean age 62.1 ± 12.1 years) were included. 100 patients (87.7%) were started on levodopa/benserazide, 14 patients (12.2%) on dopamine agonists. Treatment was associated with significant reductions of PLM index  and ESS . Systolic BP decreased from 132.9 ± 17.1 to 128.0 ± 15.8 mmHg (p = 0.006), whereas there was no significant change of diastolic BP  and heart rate . The number of antihypertensive drugs remained unchanged with a median of 2 . Dopaminergic treatment of PLMS is associated with an improvement of sleep quality and a decrease of systolic BP comparable to treatment OSA. Treatment of obstructive sleep apnea by continuous positive airway pressure (CPAP) is associated with a decrease in blood pressure. Metaanalyses show a mean reduction of 3 mmHg in systolic and 2 mmHg in diastolic blood pressure (BP)4. This effect occurs even in resistant hypertension and increases with baseline blood pressure, young age, and the severity of oxygen desaturations6. The effects of CPAP exceed the blood pressure lowering effects of nocturnal oxygen supplementation7. Whereas the effects of treatment of obstructive sleep apnea on BP are thus well defined, the effects of treatment of restless legs syndrome with PLMS remain elusive.Obstructive sleep apnea and periodic limb movements in sleep (PLMS) are associated with increased cardiovascular risk including hypertension8. This assumption is supported by the finding that limb movements in sleep are associated with sudden increases of heart rate and BP even in otherwise healthy subjects1. First data on the vasoregulatory effects of dopaminergic treatment are controversial. Whereas pramipexole did not affect autonomic balance during wakefulness in a small study of 20 patients with periodic leg movements, rotigotine at optimal doses (1–3 mg/24 h) showed some effect on nocturnal systolic BP10. With regard to these conflicting data, it remains unclear, whether the proposed rotigotine effect is substance-specific and whether dopaminergic treatment is able to affect daytime BP as well.There is evidence linking PLMS to hypertension, but the underlying mechanisms are unclear. Since the nocturnal BP of patients with PLMS is higher than those with insomnia, it may be suggested that PLMS affects autonomic regulation beyond a mere disturbance of sleepThe present retrospective analysis for the first time examines the effect of dopaminergic treatment of PLMS on office BP.12. Results were interpreted by physicians with long-lasting experience in sleep medicine. Hypertension was defined as either systolic office blood pressure > 140 mmHg, diastolic blood pressure of > 90 mmHg, or use of antihypertensive medication. The study was approved by the ethical committee of Ruhr-University Bochum (Reference number 18-6725-BR).We performed a retrospective study of polysomnographic recordings and clinical data of patients undergoing in-laboratory polysomnography in a German University Hospital. We made use of an electronic data extraction approach to identify subjects suffering from a restless legs syndrome with PLMS that had been admitted to our institution from 2010 to 2020. Inclusion criteria were clinical features of restless legs syndrome with first diagnosis of PLMS  and subsequent initiation of therapy with dopamine agonists or levodopa/benserazide. Exclusion criterion was an initiation or change of preexisting positive airway pressure therapy between baseline and follow-up polysomnography. Clinical data were taken at baseline polysomnography prior to initiation of therapy for PLMS. Follow-up polysomnography was conducted after a median of 8 months after initiation of therapy. The daytime sleepiness was assessed using the Epworth Sleepiness Scale (ESS) questionnaire. BP and ESS were assessed at baseline and follow-up. Polysomnographic monitoring comprised simultaneous noninvasive recordings of electroencephalogram, electrooculogram, submental and bilateral leg electromyogram, nasal or oral airflow, oxygen saturation (pulse oximetry), snoring microphone, chest and abdominal respiratory movement, body position and electrocardiogram. Polysomnography results were scored according to standard criteria according to American Academy of Sleep Medicine guidelines by an experienced observer13. According to the official World Association of Sleep Medicine (WASM) standards for recording and scoring periodic leg movements in sleep PLM is associated with respiratory events and should not be scored when an overlap respiratory event and PLM occurred or the interval between PLM and the respiratory event is less than 0.5 s, regardless which event is first15. The PLM frequency was quantified by a periodic movement index, calculated as the number of movements per hour of total sleep time, with ≥ 5 movements per hour considered abnormal14. The movement-related arousal index was calculated as the number of PLMS related arousals per hour of total sleep time. According to our center’s standard we start treatment with levodopa/benserazide (start dosis 100/25 mg) in patients > 60 years and dopamine agonists in you younger patients (0.18 mg pramipexole or 1 mg ropinirole per day). Thereafter, patients were uptitrated to their optimal dose by their general practitioner or neurologist.PLMS was assessed and defined according to the American Sleep Disorders Association criteria (10) as bursts of muscle activity on the anterior tibialis electromyogram of 0.5–10 s duration, > 25% of the amplitude of a voluntary movement, and as a part of a series of ≥ 4 movements separated by 5–90 sOffice blood pressure was assessed auscultatorily according to Riva-Rocci at admission by trained observers in a seated position in a quiet room of the laboratory after a resting time of ≥ 5 min. Measurements were performed at daytime during a physical examination prior to the polysomnography. The cuff size was chosen in dependence of the upper arm circumference using a standard bladder cuff 13 × 24 cm for a circumference of 24–32 cm, 15 × 30 cm for a circumference of 33–41 cm, and 12 × 22 cm for a circumference of < 22 cm. The cuff was deflated by a maximum of 3 mmHg per second. Two measurements were obtained and the mean of these measurements was used for further analysis.t test, a study size of 90 is necessary to achieve a power of 80% and a two-sided level of significance of 5%, for detecting this difference in blood pressure. We aimed to exceed this number by > 20% for drop-outs due to incomplete study data.With regard to studies on the effect of CPAP on blood pressure in subjects with obstructive sleep apnea, we anticipated an effect of 3 mmHg on systolic blood pressure with a standard deviation of 10 mmHg for the sample size calculation. Based on a paired two-tailed t test. Age, ESS score, and number of antihypertensive drugs are presented as median and interquartile range (IQR). Baseline and follow-up ordinal data were analyzed by the Wilcoxon signed rank test. Dichotomous parameters were compared by Chi-squared test. Association of baseline systolic BP, PLMI, ESS score and change of systolic BP from baseline to follow-up was analyzed by univariate linear regression analysis. P < 0.05 was regarded statistically significant. All statistical analysis was done using SPSS Statistics 25 .Data were checked for normality of distribution by the Shapiro–Wilk Test. Since both data on blood pressure and periodic limb movements turned out to be normally distributed, measures at baseline were compared to follow-up by a paired two-tailed This study was conducted in accordance with the declaration of Helsinki and was approved by the ethics committee of Ruhr-University Bochum (Reference number 18-6725-BR). The need for patient approval and informed consent was waived by ethics committee of Ruhr-University Bochum due to the retrospective nature of the study.After screening of 953 data sets, 114 fulfilled all in- and exclusion criteria and were included in the analysis. The study population had a median age of 63 (IQR 52–72.5). 47 patients (41.2%) of the study population were female. 90 patients (78.9%) had hypertension. The median number of antihypertensive drugs in the overall study population was 2 (IQR 1–3) at baseline and follow-up. The most prevalent further cardiovascular comorbidities were diabetes , coronary heart disease  and hyperlipidemia . Epidemiological and clinical baseline parameters are presented in Table 40 (35.1%) of the study population underwent their first polysomnographic examination. The diagnosis of obstructive sleep apnea was preestablished in 74 (64.9%) and 24 (21.1%) were found to have obstructive sleep apnea at baseline investigation. 74 (64.9%) underwent polysomnography with established CPAP therapy. Baseline median ESS index was 6 (IQR 3–10.5). All the patients were diagnosed to have PLMS and treatment was initiated. At follow-up, 100 patients (87.7%) were administered levodopa/benserazide and 14 patients (12.2%) dopamine agonists (pramipexole or ropinirole). Mean levodopa/benserazide dosage was 159.0 ± 67.8 mg ranging from 62.5 to 375 mg. In 12 (10.5%) patients, pramipexole was initiated in a dosage of 0.08 to 0.52 mg (mean 0.3 ± 0.1 mg). Ropinirole was used in two (1.7%) patients in a dosage of 1 to 4 mg (mean 2.5 ± 1.5 mg).Table AHI did not significantly differ from baseline to follow-up . On the contrary, PLMI decreased significantly from 81.2 ± 65.0/h to 39.8 ± 51.2/h, p < 0.001. ESS was significantly reduced from 6 (IQR 3–10.5) to 5 (IQR 3–10) p = 0.013. Systolic office BP was significantly diminished from 132.9 ± 17.1 mmHg to 128.0 ± 15.8 mmHg, p = 0.006. The change of systolic BP from baseline to follow-up significantly depended on baseline systolic BP  but well managed by pharmacological treatment prior to administration of dopaminergic therapy. Therefore, the present BP lowering effects of treatment of PLMS are indeed comparable or even exceed the effects of positive airway pressure therapy in sleep apnea.Treatment of obstructive sleep apnea by continuous positive airway pressure (CPAP) contributes to BP control in hypertensive patients. The present study shows for the first time that treatment of restless legs with PLMS is associated with a significant decrease of systolic BP as well. The mean reduction of systolic BP was 5 mmHg, which numerically exceeds the average BP lowering effects of positive airway pressure therapy in sleep apnea of about 3 mmHg19.In contrast to systolic BP, treatment of PLMS did not reveal a significant effect on diastolic BP. Whereas somewhat surprising at first sight, this finding fits to general experiences with antihypertensive interventions as well. Thus, the antihypertensive effects on diastolic BP are inferior to systolic BP in other pharmacological and non-pharmacological interventions as well including positive airway therapy in sleep apnea21. The reasons for this diverging finding remain elusive. On the one hand, the study size may have been too small to detect a significant finding. Noteworthy, there is indeed a non-significant trend to higher effects on BP in subjects with higher PLMI. On the other hand, the BP reduction may partially be mediated by BP-lowering side effects on levodopa/benserazide and dopamine agonists independent of an improvement of sleep quality.The reduction of BP did not significantly depend on baseline PLMI and ESS. This finding contrasts data on application of positive airway pressure in obstructive sleep apnea. Here, the effects on BP are more pronounced in subjects with higher AHI and sleepiness86% of the patients in this study had coincident obstructive sleep apnea. As requested by the exclusion criteria, however, none of these subjects had an initiation, nor a change of preexisting positive airway pressure therapy from baseline to follow-up. Thus, it can be ruled out that CPAP therapy was responsible for the observed changes of BP from baseline to follow-up. Accordingly, AHI did not significantly differ between baseline and follow-up. Moreover, the number of antihypertensive drugs did not differ between baseline and follow-up.22. Specifically, a change in heart rate variability and cortical activation was shown to reflect sympathetic activity22. Thus, a reduction of sympathetic activity might contribute to the decrease of BP. Whether the reduction in the number of leg movements or CPAP therapy contributed to the reduction in blood pressure cannot be conclusively assessed in this study.PLMS is associated with increased sympathetic activity. A previous study showed increased sympathetic activity in PLMS19. In the Syst-Eur trial, placebo and treatment group differed in systolic BP by 10 mmHg and the incidence of stroke was reduced by 42%23. Thus, a 5 mmHg reduction may be associated with a relative risk reduction of approximately 20%.Treatment of PLMS reduced systolic BP by a mean of 5 mmHg in the present population. This reduction has to be regarded as clinically relevant. Even a 1 to 2 mmHg reduction in BP is associated with a reduction in major cardiovascular events, stroke, and especially heart failure24. Noteworthy, however, office BP is closely correlated to ABPM and constitutes the diagnostic standard in polysomnography laboratories25.The study is limited by its BP measurement technique, its study size and its retrospective design. We made use of office BP as primary endpoint. Ambulatory blood pressure monitoring (ABPM) would have ruled out a white coat effect, would have had a higher prognostic value and would have provided insight into nighttime BPThe small study results from a very strict definition of inclusion and exclusion criteria. These strict criteria were a crucial prerequisite to exclude effects of changes in pharmacological antihypertensive therapy or treatment of sleep apnea on BP. Regarding the study design, a prospective randomized study design would have necessitated to withhold therapy of PLMS in 50% of the symptomatic study population, which would be ethically disputable. For the same reason, it was not able to provide a control group in this retrospective analysis.In conclusion, the present study shows for the first time that dopaminergic treatment of restless legs with PLMS is associated with a clinically relevant decrease of systolic BP. The reduction of 5 mmHg is comparable or even exceeds the effects of treatment of sleep apnea and is larger in subjects with higher baseline BP. Future studies should investigate the effects of PLMS treatment on 24 h ambulatory BP.