Blood pressure (BP) is a key modifiable risk factor for patients with chronic kidney disease (CKD), with current guidelines recommending strict control to reduce the risk of progression of both CKD and cardiovascular disease. Trials involving BP lowering require multiple visits to achieve target BP, which increases the costs of such trials, and in routine care, BP measured in the clinic may not accurately reflect the usual BP.We sought to assess whether a telemonitoring system for BP  was acceptable to patients with CKD and whether patients would provide sufficient BP readings to assess variability and guide treatment.A total of 25 participants with CKD were trained to use the telemonitoring equipment and asked to record BP daily for 30 days, attend a study visit, and then record BP on alternate days for the next 60 days. They were also offered a wrist-worn applanation tonometry device (BPro) which measures BP every 15 minutes over a 24-hour period. Participants were given questionnaires at the 1- and 3-month time points; the questionnaires were derived from the System Usability Scale and Technology Acceptance Model. All eligible participants completed the study.P=.05 , indicating that most variation in BP was short term.Mean participant age was 58 (SD 11) years, and mean estimated glomerular filtration rate was 36 (SD 13) mL/min/1.73m2. 13/25 (52%) participants provided >90% of the expected data and 18/25 (72%) provided >80% of the expected data. The usability of the telemonitoring system was rated highly, with mean scores of 84.9/100 (SE 2.8) after 30 days and 84.2/100 (SE 4.1) after 90 days. The coefficient of variation for the variability of systolic BP telemonitoring was 9.4% (95% CI 7.8-10.9) compared with 7.9% (95% CI 6.4-9.5) for the BPro device, Telemonitoring is acceptable for patients with CKD and provides sufficient data to inform titration of antihypertensive therapies in either a randomized trial setting (comparing BP among different targets) or routine clinical practice. Such methods could be employed in both scenarios and reduce costs currently associated with such activities.International Standard Randomized Controlled Trial Number ISRCTN13725286; http://www.isrctn.com/ISRCTN13725286 (Archived by WebCite at http://www.webcitation.org/74PAX51Ji). Chronic kidney disease (CKD) is estimated to affect between 5% and 14% of the adult population worldwide  and is sP value for interaction=.01); however, few patients with more advanced CKD  were included in these trials [The beneficial impact of BP lowering in the CKD population has not yet been fully established. First, it has been suggested that BP lowering reduces the risk of progression among patients with proteinuric CKD . Howevere trials ,9. Finale trials . StudiesNevertheless, BP control remains a key focus of those managing patients with CKD. BP measurements in the clinical setting are somewhat imprecise measures of long-term average BP , andHome BP monitoring, as an intervention, has previously been the subject of trials looking to improve BP control ,14. It hThe primary aim of the study was to assess the participants’ acceptability of BP telemonitoring over 3 months, determined by the proportion of patients providing at least 90% of expected data. Expected data were defined as daily readings for 30 days and alternate daily readings for a further 60 days.The 4 secondary aims were as follows: (1) to examine the usability and tolerability of the telemonitoring system as assessed using a questionnaire at the 1- and 3-month time points; 2) to determine the intraindividual variability in BP; (3) to quantify the proportion of patients reaching target BP by follow-up; and (4) to compare the telemonitoring measurements (and their variability) with those taken by an applanation tonometry device (“BPro”) ,19 that  to deterThe study consisted of 2 phases: intensive monitoring and titration. During the first month intensive monitoring phase, participants were asked to measure their BP daily after resting for 5 minutes, with 3 measurements on each occasion. Changes in BP medication were avoided during this period, unless required by a local clinical team. At the end of the intensive monitoring phase, participants were offered a BPro device to wear for 24 hours. Irrespective of the use of the BPro device, a titration phase followed lasting a further 2 months. During titration, participants were instructed to reduce the frequency of their BP measurements to alternate days, and additional antihypertensive agents were introduced, as necessary, by a study clinician, according to concomitant medications and comorbidities, with a target SBP of <140 mm Hg  or <130 mm Hg ; ie, according to current clinical guidelines . At the Participants were provided with an “off-the-shelf”, Bluetooth- enabled BP monitor  and a tablet computer with custom-developed software “app”; . Patient2. The most common primary causes of CKD were diabetes, glomerulonephritis, and hypertension.Between June 2016 and April 2017, 25 patients were recruited. Mean participant age was 58 (SD 11.0) years, with about half the cohort being >60 years old . Among tAmong the 25 participants, 18 (72%) provided >80% of the expected data and 13 (52%) provided >90% of the expected data throughout the whole study period . The resThe telemonitoring system was found to be a generally acceptable method to record home BP, with mean (SE) System Usability Scale score of 84.9 (2.8) after the 1-month intensive monitoring phase . After tP=.05), and the DBP coefficient of variation for telemonitoring versus BPro was 9.7% (95% CI 7.2-11.5) versus 7.4%  were 13.8 and 7.4 mm Hg, respectively . Among tpost hoc analysis showed that the coefficient of variation for SBP measured using telemonitoring over 1 week was 8.3% (95% CI 5.6-10.9), similar to that for a longer period.A There was an improvement in the proportion of patients in target BP range over the course of the study from 3 to 9. The mean SBP at baseline, 152.5 (SD 16.2) mm Hg, reduced to 138.52 (SD 14.3) mm Hg at 3 months . A change in dose (5 participants) or choice (8 participants) of antihypertensive medication was made in 13 of 25 subjects.The Oxford Heart and Renal Protection Study-1 suggests that telemonitoring among patients with CKD is feasible and well tolerated. Telemonitoring has previously been used in the management of heart failure , type 2 Recording of regular BP readings is beneficial in both routine care and clinical trials. Home monitoring reduces the need for clinic visits, which can be time consuming and expensive for both the participant and clinical center, with suggestions that telehealth interventions such as telemonitoring have an overall favorable cost-effectiveness profile . FurtherOur quantitative data are supported by questionnaire data, which suggests that participants found the technology usable. Estimation of longer-term acceptance also scored high, with all analyzed constructs being evaluated with acceptable results. Patients who owned a smartphone, that is, who are likely to be more confident with similar technology, were more positive in almost every area, while patients without a smartphone increased their questionnaire score from the 1-month to the 3-month time point. This may suggest that additional education of patients without smartphones before using similar equipment could be beneficial.Telemonitoring equips patients with knowledge, skills, and technology to facilitate shared responsibility for their health care management. This must be balanced against the potential reduced patient-clinician contact and consequent missed opportunities to identify concerns. In order for a satisfactory quantity of data to be obtained so that home BP monitoring is feasible, participants must be able to understand and feel comfortable with the technology.Recording and analysis of large numbers of BP readings by the patients at home allows for assessment of BP variability and gives a more accurate indication of a patient’s true usual  BP status rather than isolated clinic readings . As expeThe BP variability seen in our cohort indicates that more intensive monitoring would be of use in both trial settings and routine clinical care. Furthermore, BP variability may be associated with cardiovascular and mortality outcomes over and above the effect of mean BP ,30, and The number of participants in our study was small, in keeping with a pilot study, which may limit generalizability of the results. Follow-up was only for 3 months; thus, we did not assess how durable the compliance with the study protocol would be in a long-term trial or routine clinical care. Telemonitoring in combination with clinical review of BP measurements and consequent modification of antihypertensive medication has previously been shown to have efficacy in improving BP control ,30. HoweWe found that the telemonitoring technology is a practical means of collecting large amounts of BP data with the additional benefit of enabling the recording of BP variability. BP telemonitoring, therefore, has potential in both future studies of CVD management and in improvement of routine clinical care in this at-risk group.


Non-cardiac surgery for hypertrophic obstructive cardiomyopathy (HOCM) is considered to require meticulous perioperative care. β-blockers are considered the first-line drugs for patients with HOCM, and they play a key role in preventing cardiovascular complications in perioperative care. The bisoprolol transdermal patch has recently become available in Japan, and it is useful for patients who are unable to take oral medication during perioperative care. The aim of this case series was to assess the hemodynamic features of patients with HOCM who used the bisoprolol transdermal patch during perioperative care for non-cardiac surgery.Between August 2016 and August 2018, we retrospectively analyzed 10 consecutive cases of HOCM with the patients using the bisoprolol transdermal patch during perioperative care. Hemodynamic and echocardiographic features were evaluated before and after patients were switched from oral bisoprolol to transdermal patch therapy or started transdermal patch therapy as a new β-blocker medication. In addition, cardiovascular complications  during the perioperative period were evaluated.There was no significant change in the patients’ heart rate, blood pressure, ejection fraction, and pressure gradient in the left ventricle after switching from oral bisoprolol to the transdermal patch therapy. On the other hand, patients who started using the bisoprolol transdermal patch as a new ß-blocker medication tended to have a decreased heart rate and pressure gradient thereafter, but there was no significant difference in blood pressure or ejection fraction. No cardiovascular complications occurred during the perioperative period.We described the utilization of the bisoprolol transdermal patch during perioperative care for non-cardiac surgery in patients with HOCM. We determined that the hemodynamic features of these patients did not change significantly after switching to patch therapy. Further, initiation of the bisoprolol transdermal patch as a new ß-blocker medication sufficiently tended to decrease the pressure gradient. This unique approach can be an alternate treatment option for HOCM.UMIN000036703). The date of registration was 10/5/2019 and it was “Retrospectively registered”.The registry was registered in the University Hospital Medical Information Network Clinical Trials Registry ( Hypertrophic cardiomyopathy (HCM) is a complex and relatively common genetic cardiomyopathy characterized by remarkable thickness of the left ventricular (LV) wall, which is not solely explained by hypertensive heart disease or heart valve disease –3.Resting- or exercise-provoked LV outflow tract (LVOT) obstruction, which primarily develop various symptoms, is present in most patients with HCM . A thirdβ-blockers, which inhibit increases of LV contraction, heart rate, and the LV pressure gradient during stress, are used as first-line drugs for patients with HOCM . MoreoveThe aim of this case series was to evaluate the hemodynamic features of patients with HOCM who used the bisoprolol transdermal patch during perioperative care for non-cardiac surgery.Ten consecutive patients with HOCM were enrolled from the Department of Cardiovascular Medicine of our institute from August 2016 and August 2018. Before non-cardiac surgery, we reviewed and optimized the medications prescribed to the patients. When non-cardiac surgery could be postponed for a few months, percutaneous transluminal septal myocardial ablation (PTSMA) or surgical septal myectomy was considered for patients if their symptoms were lifestyle-limiting after optimization of their medication and if resting or a provoked pressure gradient > 50 mmHg was confirmed by at least one method. We excluded patients who exhibited only sigmoid septum but without significant hypertrophy. We treated patients with HCM with mid-ventricular obstruction similar to those with LVOT obstruction using the bisoprolol transdermal patch.Patients in the current study were retrospectively registered. The registry was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000036703). Written informed consent was obtained from all patients, and ethical approval was obtained from the review committee of Nippon Medical School , and the study design conformed to the ethical principles of the Declaration of Helsinki.We diagnosed HCM based on the presence of maximal LV wall thickness ≥ 15 mm by transthoracic echocardiography (TTE) and cardiac magnetic resonance imaging (MRI) according to the guidelines of the American College of Cardiology Foundation/American Heart Association . FurtherThe patches were applied once a day to the chest, upper back, or upper arm. The antihypertensive and heart rate-lowering effects of the 8-mg bisoprolol transdermal patch are similar to those of a 5-mg oral tablet of bisoprolol fumarate, and these effects are dose-dependent in the 2–8-mg range of the bisoprolol transdermal patch  . We switThe patches were applied once a day to the chest, upper back, or upper arm too. Patients with HOCM received the bisoprolol transdermal patch for the first time when they were reaching their maximum dose.We routinely conducted examinations of their symptoms, heart rate, and blood pressure, and TTE was performed before and after switching therapy from oral bisoprolol to the bisoprolol transdermal patch. In the TTE study, the resting pressure gradient by Doppler echocardiography, which is used to evaluate hemodynamic changes, was assessed as well as LV end-diastolic diameter, LV end-systolic diameter, left atrial diameter, interventricular septal thickness, posterior wall thickness, and ejection fraction (EF).Cardiovascular complications during the perioperative period included all-cause death, cardiac death, heart failure, ventricular tachycardia, and ventricular fibrillation. We evaluated the anesthetic record during non-cardiac surgery, and all patients in the present study were assessed by continuous electrocardiographic monitoring during the perioperative period. We also assessed appropriate and inappropriate discharges of defibrillators by the device’s memory in patients with an implanted defibrillator. Cardiac death and heart failure were defined as per the report by the American College of Cardiology/American Heart Association task force on clinical data standards .p-value < 0.05 was considered statistically significant.Continuous variables are presented as medians with interquartile ranges, and categorical variables are expressed as prevalence rates (%). Continuous variables were compared using Mann-Whitney’s U-test for analysis of unpaired comparisons. Paired changes in continuous variables were analyzed using Wilcoxon’s signed-rank test. All statistical analyses were performed using SPSS Statistics 23.0 , and a two-sided Ten patients with HOCM underwent non-cardiac surgery during the study period. All surgeries were performed under total anesthesia. Eight patients had LV outflow obstruction, and 2 patients had mid-ventricular obstruction. Four patients who had already undergone PTSMA were included. Their median age was 75 (interquartile range [IQR]: 58–80) years, and 7 (70%) were women. Six patients were switched from oral bisoprolol to the bisoprolol transdermal patch in preparation for non-cardiac surgery, while 4 patients started treatment with the bisoprolol transdermal patch as a new β-blocker medication. The baseline characteristics, type of surgery performed, surgical risk estimate, symptoms, and echocardiographic parameters are shown in Table The medication was switched from 5-mg oral bisoprolol to the 8-mg bisoprolol transdermal patch in 5 patients Fig. . In 1 pap = 0.72); systolic blood pressure/diastolic blood pressure, from 109 (IQR: 102–114)/68 (IQR: 57–71) to 103 (IQR: 85–112)/57 (IQR: 51–67) mmHg (p = 0.12/p = 0.25); left ventricular ejection fraction (LVEF), from 68 (IQR: 62–78) to 67 (IQR: 62–75)% (p = 0.59); and pressure gradient, from 9 (IQR: 6–68) to 9 (IQR: 9–69) mmHg (p = 0.52)  to 63 (IQR: 59–68) beats/min [bpm]  and pressure gradient  before and after the change in medication. However, there was no significant difference in the systolic blood pressure/diastolic blood pressure (from 128 [IQR: 123–132]/69 [IQR: 65–77]) to 116 [IQR: 110–133]/69 [IQR: 57–87] mmHg, p = 0.27/p = 0.58) or LVEF  , and the pressure gradient by echocardiography at rest was controlled below 30 mmHg in some patients. However, even if the pressure gradient seemed to be relatively low at rest, many patients with HOCM presented with a substantial pressure gradient during exercise . Hence, The present study had several limitations. First, because of the single-center study design, the number of cases was limited, and a comparison of transdermal patch therapy and standard oral bisoprolol therapy was not performed in our study. Second, all data analyses were performed retrospectively. Third, we might have underestimated the efficacy of β-blockers because we included some patients who were not very symptomatic (New York Heart Association classes I and IIs) or patients who experienced improvement in their severe symptoms after the previous intervention. Forth, the groups in our study showed heterogeneity. This may make it difficult to assess the drug effect as an individual entity. A prospective study comparing oral bisoprolol and bisoprolol transdermal patch should be performed.We described the utilization of the bisoprolol transdermal patch during perioperative care for non-cardiac surgery in patients with HOCM. We determined that the hemodynamic features of these patients did not change significantly after switching to patch therapy. Further, initiation of the bisoprolol transdermal patch as a new ß-blocker medication tended to decrease the pressure gradient. This unique approach could be an alternate management strategy for HOCM. However, a prospective comparison study is needed to confirm our results.Additional file 1. : Detailed baseline characteristics of each patient.


Uncertainty persists over the optimal management of blood pressure (BP) in the early phase of acute ischemic stroke (AIS). This study aims to determine the safety and effects of intensive BP lowering on cerebral blood flow (CBF) and functional in AIS patients treated with intravenous thrombolysis.In a randomized controlled trial, 54 thrombolysed AIS patients with a systolic BP of 160 to 180 mm Hg will be randomized to early intensive BP lowering (systolic target range 140–160 mm Hg) or guideline-based BP management (systolic range 160–180 mm Hg) during first 72-hours using primarily intravenous labetalol. We hypothesize that early intensive BP lowering will not reduce CBF by 20% and/or increase the volume of hypoperfused tissue by >20% on computed tomographic perfusion. Clinical outcome will be assessed using a dichotomized modified Rankin scale (scores 0–1 as excellent outcome vs scores 2–6 as dead or dependent) at 90 days. Other outcome would be symptomatic intracerebral hemorrhage. The trial is registered at ClinicalTrials.gov, NCT03443596.This randomized study will provide important information about the physiological effects of BP reduction on cerebral perfusion after intravenous thrombolysis in AIS. Whether treatment of this acute hypertensive response improves clinical outcome is unknown.,8 Arguments in favor of treatment include the strong positive relationship between degree of elevation in BP and death or dependency, cerebral edema, early and late stroke recurrence,,12 and extrapolation of potential benefits in acute intracerebral hemorrhage (ICH).–15 Arguments against treatment center on the natural tendency for BP to normalize within a few days of presentation,,5,6 and potential harms associated with altered cerebral perfusion related to dysfunction of autoregulation.,16,17 Some studies suggest that adverse outcomes are associate with early antihypertensive therapy.,19Elevated systolic blood pressure (BP), defined as >140 mm Hg, is commonly observed in patients with acute ischemic stroke (AIS).The primary aim of the study is to determine the effect of early intensive BP lowering (systolic BP target 140–160 mm Hg) initiated within 6 hours of symptom onset and maintained for 72 hours in AIS patients treated with intravenous tissue plasminogen activator (IV-tPA) on cerebral blood flow (CBF), measured with computed tomographic (CT) perfusion imaging. We hypothesize that this treatment approach is safe and that such magnitude of BP lowering does not reduce CBF by 20% and/or increase the volume of hypoperfused tissue by >20% on CT perfusion or adversely affect functional outcomes at 90 days. Secondary aims are to obtain preliminary estimates of the clinical impact of early intensive BP lowering on functional outcomes and symptomatic intracerebral hemorrhage (sICH).22.1Patient inclusion/exclusion criteria are provided in Table 2.2We reiterate that all patients included in this clinical trial would have received IV-tPA as standard of care before assessing their eligibility. All patients undergo a baseline clinical evaluation that includes an assessment of severity of neurological impairment according to the National Institutes of Health Stroke Scale (NIHSS), and estimate of their premorbid functional status . All of them would have undergone a noncontrast brain CT-scan (or magnetic resonance imaging) with or without angiography as per the institutional practice. Information for demographics, risk factors  and use of antihypertensive medications is also collected.2.3All study subjects undergo CT perfusion to obtain the baseline cerebral hemodynamic parameters. Participating patients are randomly assigned to early intensive BP lowering (140–160 mm Hg) or the guideline-based management (160–180 mm Hg) in a 1:1 ratio using a central computer generated sequence with minimization according to age (<60 vs ≥60 years), severity (NIHSS score <10 vs >10), and baseline systolic B (<150 vs >150 mm Hg). The treating physician is unblinded to the treatment assignment as he/she is required to titrate BP control with IV labetalol. However, all 90-day outcome assessments are conducted by physicians who are kept blind to the treatment allocation.2.4Patients allocated to early intensive BP lowering are to receive IV labetalol according to a predefined protocol Table , whereas2.5All patients will be managed in a high-dependency stroke unit with repeated neurological examination using the NIHSS, noninvasive BP, and heart rate monitoring . All BP measurements are obtained from the nonparetic arm. Rescue endovascular intervention (before inclusion into the study and randomization) is allowed according to local institutional practice. Figure 2.6All patients undergo repeat CT-perfusion scans at 24 and 72 hours postrandomization, to obtain the estimates of the effects of BP on various cerebral perfusion parameters. NIHSS scores are assessed daily until day 7   criteria as large local or remote parenchymal ICH (type 2) combined with a neurological deterioration (≥4 points on the NIHSS) from baseline or death within 36 hours.2.8An independent data safety monitoring board is in place to monitor the safety of intensive BP lowering as well as repeated CT perfusion studies. The board reviews clinical and imaging data in batches of 10 patients each. Unexplained clinical deterioration in intensive BP control arm is reviewed in a multidisciplinary meeting . Treating stroke neurologist is allowed to discontinue intensive BP lowering treatment , if this is considered to be the sole/leading cause of neurological deterioration. Radiation safety officer will be using the real patient data as well as a phantom to monitor radiation exposure to brain, eyes, and thyroid gland. For reassurance, we used a phantom and evaluated the radiation dose exposure for one non-contrast CT (NCCT) + CT angiogram + CT perfusion (CTP), which was quite low as 6.13 mSv.2.9With dynamic, quantitative CT perfusion, an additional contrast bolus of 35 to 45 mL is administered via an injector (at a rate of 7 mL/s), with a saline “chaser” of 20 to 40 mL at the same injection rate. The contrast used (omnipaque) has high concentration, typically 350 to 370 g/dL for optimal signal-to-noise ratio for perfusion maps calculation. Imaging begins a few seconds after injection, and selective axial sections to image selected areas of the brain using “toggle mode” expands the anatomic coverage by toggling the table between 2 locations during dynamic scanning of 4 cm cuts of the brain. A Philips 64 slice scanner with standard resolution is used with collimation 32 × 1.25, thickness 5 mm, 3.8 seconds cycle time, 80 kV at 150 mA, matrix 512, and window-center/width of 40/80. Scans take 55 to 60 seconds to complete 15 jog cycles.2.10 The total perfusion deficit volume will defined using a threshold DT >6 seconds (DT). The pretreatment (baseline) ischemic core will be defined as tissue with a CBF of <30% inside the perfusion deficit. The penumbra will be defined as tissue within the DT deficit which was not the ischemic core . Hypoperfused tissue, penumbral, and core volumes will be measured at all 3 time points.Perfusion images will be analyzed centrally by investigators blinded to BP treatment and clinical data. Raw CTP source images will be transferred to a computer workstation and postprocessed using the MIStar software package, version 3.2 . An arterial input function will be selected automatically in the contralateral middle cerebral artery. An arrival time insensitive singular value decomposition, deconvolution algorithm will be used to calculate voxel-wise maps of CBF, cerebral blood volume (CBV), mean transit time (MTT), and delay time to peak of the residual function (DT).Final infarct regions of interest will be drawn on the 24 hour NCCT and coregistered to CBF, CBV, MTT, and DT maps obtained at all 3 time points. The mean absolute perfusion value within each region will then be measured. Mean perfusion values will also be measured in homologous regions of the contralateral hemisphere. rCBF, relative CBV, and relative MTT will be calculated as the ratio of the absolute mean value in the infarct core and homologous contralateral region. Relative DT will be defined as the difference between the absolute mean in infarct region and that in the contralateral homologous region.2.11Allowing for within-subject and between-subjects variation, a sample size of 27 patients per group was estimated to allow detection of a difference of 20% [15% standard deviation (SD)] in relative change in CBF and/or the volume of hypoperfused tissue between the early intensive BP lowering and control groups, with 90% power and significance set at 5% . The sample size was increased to 30 patients per group to allow for treatment dropouts, crossovers, and potential loss to follow-up.2.12t test and Mann-Whitney U test as indicated. Comparisons of BP and NIHSS scores between the 2 groups at different time-points will be analyzed using repeated-measures analysis of variance for the overall effect. Finally, the relative changes in BP, CBF, and NIHSS scores at 1, 24, and 72 hours after the initiation of treatment, and 90-day outcomes, will be compared using analysis of covariance. Baseline BP and use of antihypertensive medications before admission will be used as covariates in analyses of BP differences. Baseline NIHSS will be used as a covariate in analyses of stroke severity. Statistical significance is set at the 5% level. There would be no interim analysis  and nominal variables tabulated as absolute and/or relative frequencies. Comparisons between binary outcomes will be performed using Fisher exact test. Continuous variables will be compared using the unpaired is Table .2.13This study is funded by the National Medical Research Council, Singapore as a research grant as part of a Clinician Scientist Award to Dr Vijay K. Sharma. The study has been approved by the institutional ethics committee. The trial is registered at ClinicalTrials.gov, NCT03443596.3,10,12 both high and low systolic BP are considered harmful. Interestingly, the nadir for optimal outcome appears to be a systolic BP of 140 to 160 mm Hg. Thus, we hypothesize this systolic BP as being the best target for functional outcome and reduced risk of sICH.As a U-shaped relationship of systolic BP and outcomes after IV-tPA is suggested in various studies,,22 There is good experience of the use of labetalol in patients with AIS and it has a predictable and uniform dose-response relationship.Labetalol was chosen for BP lowering because of ready availability, minimal adverse effects on heart rate, and cardiac output due to being a mixed α and β antagonist effects, rapid onset of action (5 minutes) and reasonable duration of action (3–6 hours). Studies indicate stable effects of labetalol on CBF, cerebral oxygen consumption, and cerebral circulation.With serial BP measurements (including comparison of different intensities of BP lowering), NIHSS and repeated CT perfusions, this study will provide mechanistic data to elucidate the relationship between BP, cerebral perfusion, and functional outcomes in thrombolysed AIS cases. Our findings may assist the ongoing studies (such as ENCHANTED BP intensity arm results due in early 2019) and improve the design of future clinical trials of BP management in AIS (in thrombolysed and endovascularly treated) patients.Finally, we wish to clarify that study is not aimed at evaluating the relationship between early intensive BP reduction and arterial recanalization or persisting occlusion. Study participants are recruited after the arterial recanalization treatment strategies (IV thrombolysis and/or EVT) have already been implemented. While the first CT perfusion serves as the baseline for a particular patient, subsequent perfusion scans provide information about the longitudinal changes in cerebral hemodynamic parameters in response to the changes in BP levels.Vijay K. Sharma, Benjamin Y.Q. Tan, and Sim M. Ying were responsible for concept of the study, writing the draft, and editing of the manuscript. Amit Kulkarni, Philip A. Seowa, Chiew S. Hong, Zhengdao Du, Lily Y.H. Wong, Jintao Chen, Elaine Y.H. Chee, and Bridget S.M. Ng were responsible for data gathering. Low Yingliang and Nicholas J.H. Ngiam were responsible for data analysis. Hock L. Teoh, Prakash R. Paliwal, Rahul Rathakrishnan, Arvind K. Sinha, and Bernard P.L. Chan were responsible for editing the manuscript. Kenneth Butcher and Craig S. Anderson provided critical appraisal and editing of the manuscript.Conceptualization: Vijay K. Sharma, Benjamin Y.Q. Tan, Hock L. Teoh.Data curation: Vijay K. Sharma, Amit Kulkarni, Chiew S. Hong, Zhengdao Du, Elaine Y.H. Chee, Bridget S.M. Ng, Low Yingliang, Nicholas J.H. Ngiam, Rahul Rathakrishnan, Arvind K. Sinha.Formal analysis: Amit Kulkarni, Bridget S.M. Ng, Low Yingliang, Nicholas J.H. Ngiam, Arvind K. Sinha.Funding acquisition: Vijay K. Sharma.Investigation: Vijay K. Sharma, Low Yingliang, Prakash R. Paliwal, Rahul Rathakrishnan, Bernard P.L. Chan.Methodology: Vijay K. Sharma.Project administration: Vijay K. Sharma, Philip A. Seow, Zhengdao Du, Lily Y.H. Wong, Jintao Chen, Prakash R. Paliwal.Resources: Philip A. Seow, Jintao Chen.Software: Kenneth Butcher.Supervision: Leonard L.L. Yeo, Hock L. Teoh, Prakash R. Paliwal, Bernard P.L. Chan, Craig S. Anderson.Writing – original draft: Benjamin Y.Q. Tan, Sim M. Ying.Writing – review and editing: Leonard L.L. Yeo, Kenneth Butcher, Craig S. Anderson.


To determine the Homocysteine levels in type 2 diabetics and correlate homocysteine with HbA1c levels, BMI, blood pressure and duration of diabetes.This cross-sectional study was conducted in Endocrinology Unit of Hayatabad Medical Complex (HMC) Peshawar and Rehman Medical Institute (RMI) Peshawar over a period of six months from July 2015 to December 2015. Data was recorded and analyzed in SPSS v 20. P value of less than 0.05 was taken as significant. Bivariate Pearson’s correlation test was used to see the relationship between homocysteine and BMI, systolic BP and duration of diabetes.2 was 28.71±4.76, mean systolic blood pressure was 130±20.98 mmHg, mean diastolic blood pressure was 83.36±11.28 mmHg and mean duration of diabetes was 7.018± 6.18 years. Significant correlation was found between systolic blood pressure  and duration of diabetes with homocysteine . The correlation of homocysteine with HbA1c and BMI was not significant.One hundred twenty five patients were included in our study in which female were 68% and 32% were male with mean age of 51.45 ±8.37 years. Mean BMI expressed in kg/mSystolic blood pressure and duration of diabetes showed a significant positive correlation with homocysteine. The correlation of homocysteine with HbA1c was not certain from researcher’s point of view and further studies of larger sample size and longer duration must be conducted to ascertain the association between the two variables. The same survey has estimated that in the year 2025, Pakistan will be on the 4th position with 14.5 million people having diabetes.6Diabetes is a metabolic disease characterized by hyperglycemia due to defective secretion of insulin, its action, or both.Homocysteine (Hcy), formed after methionine demethylation, is a sulfur containing amino acid. Methionine being an essential amino acid is obtained from recycling it or from diet.12et al. showed that increasing plasma Hcy levels 5 μmol/L above normal increases the cardiovascular risk to 1.6-1.8 times.15A number of studies have shown a positive association of coronary artery disease, stroke and venous thrombosis with increased plasma Hcy levels.Literature from this part of the world appears scarce. No comprehensive study has been conducted in the recent past. Thus, the aim of this study was to determine the Hcy levels in type 2 diabetics and correlate Hcy with HbA1c levels, BMI, blood pressure and duration of diabetes. The results of this study will provide us with local statistics of the homocysteine as a risk factor in cardiovascular disease in type II diabetes and this will open window for further research.This cross sectional study was conducted in Endocrinology Unit of Hayatabad Medical Complex (HMC) Peshawar and Rehman Medical Institute (RMI), Peshawar over a period of six months from July 2015 to December 2015. The study includes diagnosed cases of Type 2 diabetes, both male and female, aged 40-60 years old without any complications. All patients who had type 1 diabetes mellitus and Patients with anemia or taking vitamin B supplements, pregnant or breastfeeding women were excluded. One hundred twenty five patients were recruited in our study by taking 37%Beckman Allegra TM 6R centrifuge at 3000 revolutions per minutes for 10 minutes to obtain plasma. The plasma was separated in eppendorff tubes and froze at -80°C for analysis of tHcy. Hcy was measured through Chemiluminescentmicroparticle Immunoassay (CMIA)Data about demography medical history and general physical examination was recorded. Body mass index was calculated by taking height and weight. The auscultatory method of Blood Pressure (B.P) measurement was used and B.P taken in rested sitting position by mercury sphygmomanometer and Littman stethoscope. Both systolic and diastolic B.P was recorded. A 3ml fasting blood sample was taken from the patients under aseptic conditions using disposable syringe. The whole blood was used to measure HbA1c through immunoassay method and then centrifuged in Data was recorded and analyzed in SPSS v 20. Mean + SD was calculated for numerical variables like age, BMI, serum Hcy level, HbA1C levels systolic blood pressure and duration of diabetes. Frequencies & percentages was calculated for categorical variables like gender’s p value of less than 0.05 was taken as significant. Bivariate Pearson’s correlation test was used to see the relationship between Hcy and |BMI, systolic BP and duration of diabetes.2 was 28.71±4.76 20(16%) had normal BMI, 60(48%) were overweight and 45(36%) were obese. Out of 20 patients having normal BMI 12(60%) were females and 8(40%) were males, among 60 overweight patients 35(58.33%) were females and 25(41.66%) were males and altogether in 45 obese 38 were females and seven were males. Good glycemic control is indicated by HbA1c0 ≤7% and poor glycemic control is indicated by HbA1c0 > 7%. five male patients (4%) have good glycemic control while 35 male patients (28%) have poor glycemic control. The data in the given table also indicates that 11 females (8.8%) have good glycemic control and 74 (59.2%) have poor glycemic control. These two groups were not significantly different from each other (p= 0.945).One hundred twenty five patients were included in our study in which female were 85(68%) and 40(32%) were male with mean age of 51.45 ± 8.37 years. Mean BMI expressed in kg/m2 was 28.71±4.76, mean systolic blood pressure was 130±20.98 mmHg, mean diastolic blood pressure was 83.36±11.28 mmHg and mean duration of diabetes was 7.018± 6.18 years.Mean BMI expressed in kg/mThere was significant correlation of systolic blood pressure and duration of diabetes with Hcy. However, the correlation of Hcy with HbA1c and BMI was not significant.Ssignificant positive correlation of duration of diabetes and Hcy  is shown in The present study revealed no correlation of Hcy and HbA1c. These findings endorse the report of other studies including a study conducted in Iran in which healthy controls were compared with type 2 diabetics having either good or poor glycemic control. They observed that although Hcy levels were higher in diabetics but not significantly different among various groups. They concluded that glycemic control does not influence Hcy levels and no correlation exists between the two variables.21No correlation of Hcy with BMI was found in the present study. Similar findings were reported by a study conducted on Kenyan type 2 diabetics, which showed no correlation of BMI with Hcy levels in patients without cardiovascular disease.Systolic B.P showed a significant positive correlation with Hcy in the present study, which is in agreement with the finding of Passaro et al.21The present study showed a significant positive correlation of duration of diabetes and Hcy levels. Similar findings were observed in a study by Sonkar et al in which plasma Hcy levels were correlated with duration and complications of type 2diabetes.It can be inferred that systolic blood pressure and duration of diabetes showed a significant positive correlation with Hcy. The correlation of Hcy with HbA1c was not certain from researcher’s point of view and further studies of larger sample size and longer duration must be conducted to ascertain the association between the two variables.Z, AK: Conceived, designed and did statistical analysis & editing of manuscript.SR, TG, AK, Z: Did data collection and manuscript writing.AK: Did review and final approval of manuscript.


The present study is undertaken to investigate the fibrinogen levels in type 2 diabetes mellitus (T2DM) and its relation to peripheral artery disease (PAD) based on a more accurate and applied noninvasive measurements of duplex ultrasonography.  We performed a cross-sectional study including 1096 T2DM patients . The odds ratios (ORs) and 95% confidence intervals (CIs) were presented to show the association between PAD and fibrinogen in the subjects divided by fibrinogen levels quarterly. Furthermore, the univariate and multiple logistic analyses were performed to explore the correlation between PAD and fibrinogen levels, individual components in the cross-sectional study. P < 0.001). Multiple logistic analyses revealed that higher fibrinogen quartiles were positively related with the development of PAD in the adjusted model. After adjusting for known confounding parameters, the ORs for PAD were 1.993 , 2.469 , and 2.942  for Q2, Q3, and Q4, respectively .  Finally, 887 (80.9%) T2DM patients meet the diagnostic criteria of PAD and these patients had considerably higher serum fibrinogen concentration than non-PAD group ( Our results suggest that serum fibrinogen concentration can be considered as an independent risk factor for PAD in T2DM patients. Type 2 diabetes mellitus (T2DM) enhances the risk of lower extremity peripheral artery disease (PAD) and hemostatic and inflammatory disturbances with serious consequences on morbidity and mortality . PAD is Fibrinogen, as one of hemostatic and inflammatory markers, is present in diabetic patients and has generated considerable attention. Previous reports declared that circulating fibrinogen is increased in T2DM –11. MoreBased on the relationship of the fibrinogen and PAD which is controversial and the insufficiency of the ABI, more indicators to evaluate whether PAD exists in diabetes are essential. High-resolution duplex ultrasonography provides both anatomic location and functional information about the lower-extremity arterial system and has good sensitivity and specificity as compared with invasive angiography –21. The Between June 2008 and July to August 2013, Chinese patients with type 2 diabetes aged 18 years or above who got treatment in the endocrinology department and in line with inclusion criteria at the First Affiliated Hospital of Wenzhou Medical University were selected. Subjects were doctor-diagnosed as T2DM according to 1999 World Health Organization criteria . We perfOf all subjects, the clinical research coordinators collected physical assessment data, including age, sex, height, weight, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), waist circumference, and hip circumference. At every visit, height, weight, waist circumference, and hip circumference were measured by a team of trained nurses in the morning twice during the health examination. While weight was measured without heavy clothing and recorded to the nearest 100 g, height was measured without shoes and recorded to the nearest mm with a stadiometer. Waist circumference and hip circumference were measured to the nearest 1 mm using a stadiometer and a metal anthropometric tape, respectively. BMI was calculated as dividing the weight by the height squared. The waist/hip ratio was calculated as waist circumference divided by hip circumference. Blood pressure was measured at the brachial artery of the person in a seated position after they had had an at least fifteen-minute rest with an automatic instrument .Blood samples were collected and analyzed from antecubital vein sampling. Among them, laboratory parameters including fibrinogen, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), total cholesterol (TC), triglyceride (TG), and HbA1c were subsequently analyzed by an automated analyzer .In this study, the diagnosis of PAD depended on the duplex ultrasonography examination in reference to Guidelines for the Assessment and Management of Patients with Peripheral Arterial Disease from the American Association in 2005 . Accordit-test was used for comparisons of the baseline characteristic in PAD subjects and non-PAD subjects, while 1-way analysis of variance (ANOVA) or the Kruskal-Wallis test for continuous variables and χ2 test for categorical variables were used for comparisons in different groups. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to present the relative risks for each category of fibrinogen level with the prevalence of PAD. Multivariable logistic regression analysis was performed to determine whether the association persists after adjusting confounding variables. A two-sided P < 0.05 was considered as statistically significant.Data analyses were performed with SPSS software (SPSS version 23.0 for Windows) and MedCalc software . In order to assess the correlation of fibrinogen concentrations and the influence of PAD, the study population was divided into quarters according to the fibrinogen concentration . Continuous variables are presented using mean with standard deviation (SD) according to the distribution of data, and categorical parameters were presented as number (%) for incidence rates. Student's Baseline clinical and biochemical measurements of 1096 subjects  are summarized in P < 0.001), waist circumference , fibrinogen , and HDL-C . Finally, fibrinogen was found to be the independent risk factor for the prevalence of PAD in T2DM subjects.All potential variables were initially evaluated in a univariate model to assess the functional relation with the prevalence of PAD. Parameters associated with PAD in the univariate analysis were male, age, smoking, alcohol use, diabetes duration, stroke hypertension, weight, height, BMI, waist circumference, hip circumference, waist/hip ratio, fibrinogen, TC, TG, HDL-C, LDL-C, and HbA1c as shown in P < 0.001), 2.738 , and 3.639 , respectively. In the adjustment for age and sex (model B), the ORs for PAD were 2.112 , 2.765 , and 3.651  for Q2, Q3, and Q4, respectively. After adjusting the full confounding parameters , the ORs for PAD were 1.993 , 2.469 , and 2.942  for Q2, Q3, and Q4, respectively , computed tomography angiography (CTA), and angiography. To our knowledge, the diagnosis of PAD was defined by the values of ABI ≤ 0.9 in almost all previous studies. The ABI test is a noninvasive method and is simple to perform . HoweverBased on these evidences, we performed a cross-sectional study to further assess whether the circulating levels of fibrinogen are associated with subjects with PAD measured by duplex ultrasonography in T2DM patients. The findings of our study reconfirm the positive association between serum fibrinogen levels and PAD. The strengths of this study include the assessment of PAD by a more accurate measurement-duplex ultrasonography and the exhaustive evaluation of biochemical and clinical parameters of atherosclerotic risk. Limitations of this study should also be acknowledged. First, the cross-sectional design limits the ability to establish a cause-effect relationship. Second, a selection bias could have been introduced because of the retrospective nature of the study. In order to minimize this issue, we maximized the sample size included in the study.In summary, our observation demonstrated that fibrinogen was positively correlated with the prevalence of PAD in T2DM patients, which should pay more attention to double lower extremity ultrasonic examination in diabetes patients with high fibrinogen level.


Asthma is a chronic disease affecting 30 million people in Europe under 45y. Poor control of Asthma is the main cause of emergency-department (ED) access, becoming the strongest determinant of the economic burden of asthma management.To examine the characteristics of adult patients admitted to ED for acute asthma attack, focusing on previous diagnosis of asthma (DA) and current therapy.During a one-year period, a structured questionnaire, assessing asthma diagnosis and management, was administered to all patients admitted for asthma attack, to the ED of a South-Italy town. Only patients with subsequently confirmed asthma were enrolled.The data on oxygen saturation (Sat.O2), heart and respiratory-rate, severity code ED-admission, hospitalization or discharge, had been obtained.p = 0.017).Two hundred one patients (mean 50.3ys), were enrolled. One hundred eighteen had a DA, made 17.5 ± 5.88 years before, and 35.6% had a specialist-examination in the last year. 53.3% of DA-patients used a self-medication before ED access with short-acting-beta-2-agonist and oral-corticosteroids, although none had a written-asthma-action-plan (WAAP). Almost all DA-patients were on regular therapy: inhaled-corticosteroids (ICS) in 61%, associated with LABA in 85%. 16.7% of DA-patients had previous DA-access. The overall hospitalization-rate was 39%, higher in DA compared to unknown asthmatic patients (UA)(p < 0.001), inability-to-complete a sentence  and the age .Significant risk factors for hospitalization were Sat-O2 ≤ 94% breathing ambient air  contains supplementary material, which is available to authorized users. Asthma is an important public health problem in Europe, affecting around 30 million children and adults under 45 years of age . EstimatMost emergency department (ED) visits for acute asthma are thought to be preventable , consideDespite the heavy economic burden of asthma-related ED visits, few studies have been designed to characterize the asthmatic patients who attend ED for acute asthma. According to a large epidemiological study, primarily focused on the quality of emergency asthma care, the proportion of asthmatic patients taking inhaled corticosteroids as long-term control medication was only 35%  and althAll patients (age ≥ 12 and < 65 years) admitted to the ED for suspected acute asthma attack (ICD-9-CM 2012 Diagnosis Code: 493 as primary diagnosis) since 1st January 2013 until 31st December 2013 signed an informed consent form to participate in this study, which had been approved by the Local Ethic Committee.A questionnaire was administered to all enrolled patients to obtain information about previous physician diagnosed asthma (DA) and current asthma medications, allergic rhinitis, outpatient visits for asthma and spirometry performed in the last 12 months, previous ED visits for asthma attack in the last 12 months, details of the medication used for asthma attack and whether the patients had received a written asthma action plan (WAAP) and comorbidities including allergic rhinitis were also assessed , considering statistically significant only Three normality tests were performed , to establish the distribution of the data. Basing on the normal or not normal distribution, the comparisons between clinical data from UA and DA patients, were performed using Student’s t-test or Mann-Whitney U test.p < 0.10 on univariable analysis were included in the multivariate model. All tests were two-sided, and variables were considered significant for p-values < 0.05.The factors associated with a patient’s admission were assessed with the use of logistic regression analysis. All factors associated with Two hundred one patients had been admitted to the ED in 12 months, 126 (62.7%) male and 75 (37.3%) female, with a mean age 50.3 years (range 12–65 yrs).Of all the patients who were included, there were 118 (58.7%) with DA and 83 (41.3%) with UA. Clinical and demographic characteristics of the two groups are reported in Table p < 0.001). Concerning the time lapse between the onset of asthma attack and the ED access, a greater prevalence of ED access between the 6th and 24th hour was observed in DA patients (62.7%) compared to UA patients , while no differences were observed in early access (< 6 h), respectively 21,2 and 30,2%, and in late access (> 24 h), respectively 12.7 and 20.5%.In the group of DA patients, the diagnosis had been made 17,5 (95%CI 14.8–19.9) years before, and 42 out of 118 (35.6%) had a specialist examination in the last 12 months. Allergic rhinitis was reported by 54.2% of patients with DA and by 6% of patients with UA  used self-medication before the ED access, consisting of short-acting beta-2 agonist (SABA) in 57 of them (90%) and oral corticosteroids in 6 (10%), according to their physicians’ advice. No patient had a WAAP and none used peak flow assessment.Almost all the DA patients  were on regular therapy, consisting of inhaled corticosteroids (ICS) in 68/112 (60.71%), associated with LABA in 85% of them, SABA alone in 14 patients (12.5%), antihistamines for associated allergic rhinitis in 25 (22%), oral corticosteroids (OCS) in 4  and theophylline in one patient .Twenty DA patients (16.9%) had an history of previous ED access during the last 12 months. Among these patients, 14 (70%) had at least one specialist examination in the last 12 months, 18 (90%) received regular treatment with ICS, combined with LABA in 78%, while two patients (10%) were taking only antihistamine drugs for concomitant rhinitis.p = 0.017).The hospitalization rate after acute admission in ED was 38.8% (78/201) for the whole study population, significantly higher in DA compared to UA patients , had higher prevalence of previous diagnosis of asthma  and previous ED visits , lower SaO2 , higher respiratory rate  and pulse rate , and they were more frequently unable to complete a sentence .Clinical and demographic characteristics of hospitalized patients (HP) compared to patients who were discharged are reported in Table p < 0.0001), the inability to complete a sentence  and the age of the patients .Multivariate analysis Table  showed tA surprising result of our study was that 40% of patients presenting to the ED received the diagnosis of asthma for the first time. It is known that asthma may be diagnosed for the first time in a patient presenting to the ED, but, in the majority of cases, the patient will be aware of the underlying diagnosis of asthma .A confident diagnosis of asthma cannot be made on a single visit to the ED,  and the mis-diagnosis of asthma is also frequent in patients managed in primary care settings , 16. ManInhaled corticosteroids were regularly used by 60% of our patients with DA, a percentage higher than the percentage previously reported in patients admitted to ED for asthma, which had been reported as low as 35% in a US large epidemiological study primarily focused on the quality of emergency asthma care during exacerbation . Indeed,High use of health services, including ED visits, has been observed in patients with suboptimal asthma drug regimens in a Canadian population-based assessment study . In partIn conclusion, despite guideline recommendations about asthma diagnosis and treatment, up to 40% of patients presenting to the ED received the diagnosis of asthma for the first time, and ICS were regularly used only by 60% of patients with known asthma. Moreover, it is disappointing that none of the patients had a WAAP. This could explain why only 53% of the patients used self- administered medication before their attendance at the ED.Despite asthma guidelines-recommendation, up to 40% of patients received the asthma diagnosis in ED, only 61% of DA-patients were taking ICS. It is disappointing that DA-patients did not have a WAAP, which could explain the poor patient-self-medication at ED admission.Additional file 1:“Asthma questionnaire – Emergency Department admission due to asthma attack” Description of data: the questionnaire contains data assessing asthma diagnosis and management, primary vital signs and drugs administered in Emergency Department (ED) in patients admitted to the ED for an acute asthma attack. (DOCX 15 kb)


The aim of the current study was to evaluate the association between a decreased estimated glomerular filtration rate (eGFR) and accidental falling in elderly patients who visited the day clinic of the department of geriatric medicine of the University of Medical Center Utrecht (UMCU).2). Logistic regression models were used to evaluate the association between chronic kidney disease and falling.A cross-sectional analysis with people aged ≥ 65 years of the Utrecht Cardiovascular Cohort was performed. Patients were stratified into different stages of kidney disease ] of falling in the population with an eGFR < 45 ml/min per 1.73 m2 compared to patients with an eGFR ≥ 60 ml/min per 1.73 m2. After correcting for multiple potential confounders in the multivariate analysis, this association was no longer present.Our analysis included 1000 participants with a mean age 79.4 (± 6.6) years, of whom 38% had an eGFR of < 60 ml/min per 1.73 mIn geriatric patients ≥ 65 years, patients with a decreased eGFR fall more often than patients with a preserved kidney function. This seems to be related with the risk profile of patients with CKD and not with a decreased eGFR itself, as after correcting for potential confounders no association remained. Nevertheless, accidental falling is a highly prevalent problem in the elderly CKD population. Therefore, nephrologists should actively ask about accidental falling, and thereby screen for high-risk patients. Accidental falling is a common problem in the elderly population. Approximately one-third of people aged ≥ 65 years fall each year, increasing to around 40% for those ≥ 70 years of age . These rIn addition, CKD is a global public health issue and is associated with increasing age , 7. PatiA few studies have focused on the association between falling and end-stage kidney disease (ESKD), mainly in the population with renal replacement therapy (RRT)  –12. FallThe aim of the current study was to evaluate the association between a decreased eGFR and accidental falling in elderly patients who visited the day clinic of the department of geriatric medicine of the University of Medical Center Utrecht (UMCU).A cross-sectional study was performed using the Utrecht Cardiovascular Cohort. This is a cohort study conducted at the UMCU. All patients that visited one of the geriatric outpatients clinics at the department of geriatric medicine in the UMCU  in the period from January 1, 2011 to December 31, 2014 were included. As part of usual care, all these patients underwent a comprehensive geriatric assessment consisting of a physical examination, cognitive and mobility tests, and laboratory testing. In addition, patients filled out a questionnaire concerning their general health and history of accidental falls. Data of these outpatients were collected in a database by the nurses and physicians working at the day clinic. The study protocol was approved by the Medical Ethics Committee of the UMCU.For this analysis, patients were excluded if age was under 65 years, if no kidney function was available, when on RRT, or if no questionnaire about accidental falls was available.The following data were extracted from the database: age, gender, living situation, medical history, intoxications, history of falls, number of medications, comorbidity, postural hypotension, body mass index, physical function, cognition, symptoms of depression, data of functional assessment , and blood test results.Falls were defined as a fall in the previous year. Frequent falls were defined as two or more falls in the past year. Comorbidity was scored by using the Charlson comorbidity index (CCI) . This inCardiovascular disease was defined as a history of myocardial infarction, transient ischemic attack, stroke, or peripheral artery disease. Postural hypotension was defined as a fall in systolic blood pressure of at least 20 mmHg or diastolic blood pressure of at least 10 mmHg when a person assumes a standing position after lying down for a period of at least 10 min. Blood pressure was measured after 1 and after 3 min after assuming standing position. Physical function was assessed by evaluating if the patient walked with the help of a walking aid. Functional assessment was assessed by the Katz-15 questionnaire . This isCognition was based on the Mini Mental Examination (MMSE) . This isSymptoms of depression were measured by the short version of the Geriatric depression Scale (GDS-15) . If a pa2. Kidney function was categorized into three groups according to the cut-off values recommended by the US National Kidney Foundation Kidney Disease Outcomes Quality Initiative Guidelines (K/DOQI guidelines); ≥ 60, 45–59, and < 45 ml/min per 1.73 m2 [n = 38) of patients with an eGFR < 30 ml/min per 1.73 m2, no separate group was created for this kidney function.Measures of kidney function were calculated by the CKD epidemiology collaboration (CKD-EPI) equation . For the equation Caucasian race was assumed. An impaired kidney function was defined as an eGFR < 60 ml/min per 1.73 m 1.73 m2 . Becauset test for continuous parametric data, Kruskal–Wallis for non-parametric continuous data, and Chi-square for categorized variables. For differences between continuous parametric data in the different kidney groups, the One-Way Anova was used. Categorical variables were reported as proportions; continuous variables were reported as means with standard deviations or medians with interquartile range for non-parametric data.Data were analyzed using SPSSS software (IBM SPSS statistics version 21). Because the baseline dataset showed some missing data , we performed multiple imputation to replace missing data as implemented by SPSS, version 21. This procedure was repeated ten times, resulting in ten different ‘complete’ datasets. The final results were averaged across these datasets and were used for logistic regression. Differences between group results were evaluated using the unpaired p < 0.05 was considered statistically significant. Outcomes were calculated with a 95% confidence interval (95% CI).To investigate the association between falling and the different stages of a decreased eGFR, logistic regression analysis was performed. Potential risk factors were chosen a priori . Differen = 1385) who filled out the questionnaire about accidental falls (n = 1012). Patients with no available kidney function and patients on RRT were excluded (n = 12), leaving 1000 participants for analysis. Patients that were excluded from analysis because of a missing questionnaire about accidental falls are shown in Table 2. Of the total population, 38% of the patients had an eGFR < 60 ml/min per 1.73 m2 of whom 17% had a kidney function < 45 ml/min per 1.73 m2. Compared to patients with a normal kidney function, patients in the group < 45 ml/min per 1.73 m2 were older (82.2 ± 6.6 vs. 78.0 ± 6.3), used more medication (84.8% vs. 65.6%), and had a higher comorbidity burden with more cardiovascular disease (47.0% vs. 27.7%) and diabetes (34.9% vs. 23.0%). They were also more dependent in ADL and iADL. Moreover, there was a higher use of a walking aid (70.2% vs. 48.8%) and postural hypotension (47.1% vs. 37.2%). Compared to the other day clinics, patients that were referred to the general geriatric day hospital had the highest rate of impaired kidney function . On the other hand, patients that were referred to the memory clinic had a relatively low rate of impaired kidney function . There were no significant differences in gender, smoking status, alcohol use, cognition, and symptoms of depression between the different groups.This analysis includes all patients visiting the geriatric day clinic between 2011 and 2014, aged ≥ 65 years n = 185 who fip = 0.17)  patients had an accidental fall in the previous year. This rate was the highest in the < 45 ml/min group (70.8%). Frequent falling  was also more common in the < 45 ml/min group (49.4% vs. 41.8% in the population with a preserved kidney function) but this difference was not significant . More detailed baseline characteristics for the different outpatient clinics are shown in Table Additional subgroup analyses for the different geriatric outpatients are shown in Tables 2 had significantly higher rates of accidental falling  compared to patients with a preserved kidney function. Patients in this group also fell more frequently  than patients with a preserved kidney function. After correction for potential confounders there was no independent association between a decreased eGFR, accidental falling, and frequency of falling in the overall group. However, in sub-analysis, there was an independent association between an eGFR < 45 ml/min per 1.73 m2 and falling in the patients that were referred to the general geriatric day hospital .In this cross-sectional study involving 1000 community-dwelling geriatric subjects aged 65 years and over, the prevalence of accidental falling was high . Patients with an eGFR < 45 ml/min per 1.73 m2.The rate of accidental falling in our population is high compared to other studies in the elderly population as well as in dialysis patients. A review about falling in community-dwelling adults reported that 35–45% of persons over 65 years old fall every year, and up to 50% of those over 80 years old . A studyOur results suggests that a decreased eGFR does not make a direct contribution on accidental falling in the overall geriatric population. There are several possible explanations why patients with a decreased eGFR in our study population fall more often. Firstly, CKD (and treatment for optimization of CKD) can lead to risk factors of falling. In our study population, patients with a decreased eGFR were older, used more medication, had a higher comorbidity burden, were more dependent in daily life, had more postural hypotension, and were more immobile. These are all risk factors for falling , 22. Sec2) and serious fall incidents. However, not only the serious fall incidents have consequences. Minor fall incidents can also lead to fear of falling, depression, social isolation, and institutionalization. Patients in this study were also younger, and less frail than in our study population  [Similar to our main finding, previous studies also did not find an association between accidental falling and a decreased eGFR. One large prospective cohort study in the United States in a population with patients of ≥ 65 years found no relationship between a decreased eGFR  . The stuobility) , 15. The2) in the group of patients visiting the general geriatric day hospital. Since large population studies did find an independent association of mild-to-moderate CKD with gait disturbances and incident mobility [n = 5 in < 15 ml/min per 1.73 m2 and n = 33 in 15–29 ml/min per 1.73 m2). Further research in patients with more severely impaired kidney function is needed to explore this hypothesis.However, in the group that was referred to the general geriatric day hospital, we did find an independent association between a decreased eGFR and accidental falling. Our hypothesis is that this association is a consequence of a higher frequency of a severely impaired kidney function . As prior research has shown that elderly patients are often unable to recall falls over a longer period of time , it is pThe associations that we report in this study may have implications for the care of elderly patients with CKD. Previous research in the general population showed that less than half of the patients who experienced a fall reported this to a healthcare provider . TherefoIn conclusion, patients with a decreased eGFR have more accidental falling and tend to fall more frequently than patients with normal kidney function. This is most likely due to the risk profile of the CKD patient, and not due to the decreased eGFR. Further research should focus on the relationship between lower levels of eGFR and falling and risk factors in the CKD population to improve patient selection.


CNAP monitor is a continuous and noninvasive blood pressure (BP) measurement device that can be used in intraoperative monitoring. But whether its accuracy changes with age and its detectability of hypertension and hypotension are still unclear. This study was to investigate the agreement of CNAP and invasive arterial pressure (IAP) in different age groups, and the ability of CNAP to detect hypertension and hypotension.This observational study enrolled 48 Chinese patients undergoing surgery under general anaesthesia, including 25 relatively old patients (age between 50 and 70) and 23 relatively young patients (age between 18 and 49). IAP was monitored at the radial artery and CNAP was applied on the opposite arm simultaneously. Paired BP data in the entire surgery were recorded, and analyzed with Bland Altman plot and Spearman correlation. The ratio of the hypertension and hypotension episodes detected by IAP and CNAP was analyzed using chi-square test.7990 valid paired BP data were analyzed, wherein 4186 data were from 25 relatively old patients, and the other data were from 23 relatively young patients. Bias (SD) for relatively old patients was: systolic BP (SBP): − 6.5 (18.6) mm Hg; diastolic BP (DBP): 9.3 (7.8) mmHg; and mean BP (MBP): 4.2 (9.5) mm Hg. Bias (SD) for relatively young patients was: SBP: − 6.2 (12.1) mm Hg; DBP: 10.6 (6.9) mmHg; and MBP: 4.8 (7.3) mm Hg. The correlation between CNAP and IAP was higher in MBP than those in SBP and DBP, and it decreased with the increase of age. Comparing to IAP, CNAP tended to miss reporting a high SBP, low DBP and low MBP, and misinform a low SBP, high DBP and high MBP.CNAP showed acceptable agreement with IAP in MBP for all age groups, but reduced agreement with IAP in SBP and DBP, especially for relatively old patients. Ability of CNAP to detect hypertension and hypotension episodes was weaker than IAP. Therefore, CNAP monitor is suitable for young patients and hemodynamically stable surgery, but may not be recommended for old patients with arteriosclerosis and diabetes or surgeries expecting to have fluctuating blood pressure. Perioperative blood pressure is usually measured in two ways: invasive or noninvasive. The invasive arterial line provides continuous monitoring and high accuracy, but it is technically demanding and has risk of complications such as trauma, bleeding, infection, thrombosis, embolism, distal ischemia, and the formation of a pseudoaneurysm , 2. TherRecently, a new monitor CNAP™ Monitor 500  for continuous and noninvasive blood pressure measurement has been used in intraoperative and emergency monitoring –10. The Previous studies reported the comparison of CNAP monitor with arterial line and oscillometric pressure device in general anesthesia or spinal anesthesia –9. The rThe aim of this study was to investigate the accuracy difference of CNAP monitor in the relatively old and relatively young people, as well as the ability of the CNAP monitor detecting the hypertension and hypotension episodes, by taking arterial line as a reference.2 or > 30 kg/m2, a positive Allen’s test, severe cardiopulmonary disease, peripheral vascular disease or preexisting edema of the upper limb. 2 patients were dropped out due to failing to place the arterial line into the radial artery. 48 patients were eventually enrolled into this study, in which, 25 patients belonged to relatively old group (age between 50 and 70) and 23 patients belonged to relatively young group (age between 18 and 49).The observational monocentric study was conducted at department of anesthesia, Southwest Hospital in Chongqing, China, and followed the STROBE statements . This stAfter the patients were admitted to the operation room, ECG and SpO2 were measured routinely. Before induction of anesthesia, a 20 G, 32-mm-long catheter  was placed into radial artery, and connected to a disposable pressure transducer . The transducer was positioned at the patient’s midaxillary line and zeroed to atmospheric pressure. The damping coefficient and natural frequency were evaluated using the fast flush method as described by Gardner . After iFollowing pre-oxygenation, general anesthesia was induced with intravenous propofol 2 mg/kg, fentanyl 5 μg/kg and vecuronium 0.1 mg/kg. After tracheal intubation, the lungs were ventilated  to maintain SpO2 above 96% and PETCO2 between 32 and 38 mmHg. Anaesthesia was maintained with inhalation of sevoflurane and the minimum alveolar concentration (MAC) was kept between 0.8 and 1.2. Remifentanyl was infused with target effect-site concentration 3 ng/ml. Blood pressure was supported by pharmacological vasodilatation (nitroglycerine 0.5–1.0μg/kg/min) or vasoconstriction (ephedrine 5-10 mg/dose and norepinephrine 0.03–0.5μg/kg/min). The titration speed of the crystal solution during anesthesia was 8-15 ml/kg/h. Blood transfusion was performed when the hemoglobin concentration was less than 80 g/L.Blood pressure including systolic, diastolic and mean  from the CNAP™ device and the arterial line were automatically recorded into a computer using an anesthesia information acquisition system  every two minutes throughout the surgery (from anesthesia induction to skin suture). Before data analysis, blood pressure artifacts, such as arterial blood sampling and patient repositioning, were detected and removed from the data using Matlab software .The sample size was chosen based on the recommendations in the protocol of the Association for the Advancement of Medical Instrumentation (AAMI) that at least 15 patients should be included when comparing to arterial line . We inclP-value of 0.05 was considered statistically significant.Statistical analyses were carried out using Graph Pad Prism v5.0  and IBM SPSS Statistics 21 . Bland–Altman plots for repeated measures –17 were Patient characteristics are summarized in Table The Bland–Altman plots for SBP, DBP, and MBP were calculated for all the patients Fig. , the relFor DBP, the bias (SD of bias) was 9.9 (7.5) mmHg (limits of agreement: − 5.1 to 24.9 mmHg) for all the patients, 9.3 (7.8) mmHg (limits of agreement: − 6.3 to 24.9 mmHg) for the relatively old group, and 10.6 (6.9) mmHg (limits of agreement: − 3.2 to 24.4 mmHg) for the relatively young group, reflecting that CNAP overestimated IAP, and the degree of deviation was consistent in all age.For MBP, the bias (SD of bias) was 4.5 (8.5) mmHg (limits of agreement: − 12.5 to 21.5 mmHg) for all the patients, 4.2 (9.5) mmHg (limits of agreement: − 14.8 to 23.2 mmHg) for the relatively old group, and 4.8 (7.3) mmHg (limits of agreement: − 9.8 to 19.4 mmHg) for the relatively young group, reflecting that CNAP slightly overestimated IAP, and the degree of deviation was slightly higher for the relatively old group and slightly lower for the relatively young group.Spearman Correlation between CNAP and IAP for different age groups are summarized in Table Ratio of hypertension episode  and hypotension episode  detected by IAP and CNAP were shown in Fig. For SBP, the hypertension episode (SBP > 140 mmHg) detected by CNAP was significant less than that detected by IAP in all the patients (5.5% vs 10.4%), the relatively old group (7.2% vs 14.0%) and the relatively young group (3.7% vs 6.5%); but the hypotension episodes (SBP < 90 mmHg) detected by CNAP was significant more than that detected by IAP in all the patients (10.3% vs 5.5%), the relatively old group (11.3% vs 6.8%) and the relatively young group (9.1% vs 4.1%), which indicated that CNAP tended to miss reporting high SBP and misinform low SBP.For DBP, the hypertension episode (DBP > 90 mmHg) detected by CNAP was significant more than that detected by IAP in all the patients (6.3% vs 0.8%), the relatively old group (6.2% vs 0.5%) and the relatively young group (6.4% vs 1.2%); but the hypotension episodes (DBP < 60 mmHg) detected by CNAP was significant less than that detected by IAP in all the patients (11.4% vs 39.6%), the relatively old group (9.8% vs 32.3%) and the relatively young group (13.1% vs 47.8%), which indicated that CNAP tended to misinform high DBP and miss reporting low DBP.For MBP, the hypertension episode (MBP > 105 mmHg) detected by CNAP was significant more than that detected by IAP in all the patients (9.2% vs 5.2%), the relatively old group (9.7% vs 5.9%) and the relatively young group (8.7% vs 4.4%); but the hypotension episodes (MBP < 70 mmHg) detected by CNAP was significant less than that detected by IAP in all the patients (8.4% vs 15.6%), the relatively old group (7.2% vs 13.5%) and the relatively young group (9.8% vs 17.9%), which indicated that CNAP tended to misinform high MBP and miss reporting low MBP.We investigated the agreement of CNAP monitor with IAP in the relatively old and relatively young groups respectively, as well as the reaction capacity of CNAP monitor to hypertension and hypotension. The main findings of our study were: (i) CNAP showed an acceptable agreement with IAP for MBP, but a big positive bias for DBP, a smaller pulse pressure difference, and a high degree of deviation (SD of bias) for SBP; (ii) the biases for SBP, DBP and MBP displayed no age-related changes, but the degree of deviation (SD of bias) for SBP is higher in the relatively old groups than that in the relatively young groups; (iii) The correlation between CNAP and IAP was relatively higher for MBP but relatively lower for SBP and DBP, and it decreased with the increase of age. (iv) Ability of CNAP monitor to detect hypertension and hypotension was weaker than that of IAP, CNAP tended to miss reporting a high SBP, low DBP and low MBP, and misinform a low SBP, high DBP and high MBP.MBP, SBP and DBP have their respective roles and significance in clinical practice. MBP is an important index for clinical anesthesia in evaluating the perfusion of vital organs such as kidneys and heart . SBP hasThe reason for a larger SBP deviation in relatively old patients than that in relatively young group may be the arterial compliance and structural changes caused by physiological or pathological arteriosclerosis and diabetes. Atherosclerosis increases measurement variability can be explained in two aspects. In the first aspect, the loss of compliance of the artery walls due to atherosclerosis increases the pulse wave amplification, which results in a higher SBP and a larger pulse pressure difference in distal artery than that in proximal artery , 21. In Compared with IAP, CNAP provided a lower SBP and a higher DBP, and thus a smaller pulse pressure difference (SBP minus DBP), which may be caused by the measurement principle of CNAP monitor. In the process of measurement, continuous pressure is applied on a finger by a ring cuff, as the time prolongs, venous blood backflow in finger is hindered, resulting in blood accumulating in the finger, which leads to a decrease in the amplitude of arterial pulse wave and the pulse pressure difference. Although CNAP monitor exchanged measurement fingers every half an hour and periodically calibrated the measurement value by oscillometry, the blood accumulation in finger caused by continuous pressure might still affect the accuracy of blood pressure measurement and the ability to respond to changes in blood pressure. This may be one of the reasons for the poor performance of CNAP in hypertension and hypotension conditions.Our study has some limitations: (i) We did not evaluate the results according to the recommendations of the protocol of the AAMI, because this standard is applied when comparing blood pressure measured from noninvasive intermittent devices such as oscillometry with invasive arterial pressure. So far, there has been no guideline or agreement regarding accuracy criteria of continuous and noninvasive devices compared with invasive blood pressure. (ii) The present study did not focus on the influence of anesthetics, analgesics and vasoactive drugs on the performance of CNAP monitor. However, the readings during pharmacological interventions, although not specifically identified, were included in the analysis. A different study design should clarify this issue. (iii) In this study, the calibration interval is 30 min according to the default set of CNAP monitor, but it seems too long to ensure the accuracy in CNAP. The optimal calibration interval in the course of general anesthesia has not been investigated, which requires further studies. (iv) The CNAP monitor was used on the opposite arm to the arterial line, the blood pressure difference between the left and right arms may contribute to bias. (v) Manual calibration was not performed in the case of repositioning of patients and special surgical procedures, which may contribute to bias. (vi) We did not evaluate the measurement results according to different types of surgery. A different study design with bigger sample size may clarify this issue.In conclusion, CNAP provides a beat-to-beat readings, a visual representation of the pulse wave, and an acceptable agreement with invasive arterial measurements in mean blood pressure for all age groups. Nevertheless, its precisions in systolic and diastolic pressures are reduced, especially in older patients with arteriosclerosis and diabetes. Also it is less capable of detecting hypertension and hypotension episodes in comparison to intra-arterial pressure measurement. Therefore, CNAP monitor may be suitable for relatively young patients with less arteriosclerosis and diabetes and hemodynamically stable surgery, but should be prudent to use in old patients with high risk or surgical patients who are expected to have fluctuating blood pressure.


Non-dipping nocturnal blood pressure (BP) pattern is a predictor of the future decline of renal function; however, it is unclear whether it is still a risk for chronic kidney disease (CKD) patients with normal BP. To solve this question, a retrospective cohort study was conducted, and 1107 CKD patients who underwent ambulatory blood pressure monitoring (ABPM) were enrolled. We divided patients into 4 groups based on their nocturnal BP dipping pattern (dipper or non-dipper) and average 24-hour BP (hypertension or normotension). The cumulative incidence of composite renal outcomes, including a 40% reduction in eGFR, the induction of renal-replacement therapy, or death from renal causes, was analyzed. Overall, 86.1% of participants were non-dippers and 48.2% of them were normotensive. During the median follow-up period of 4.72 years, the incidence of renal composite outcomes was highest in hypertensive non-dipper patients, and was similar between normotensive dipper and non-dipper patients. Multivariate regression analysis revealed that the 24-hour systolic BP, amount of urinary protein, and hemoglobin values were associated with the incidence of renal outcomes. In conclusion, our ABPM-based analysis revealed that a non-dipping BP pattern with normotension does not predict the future incidence of composite renal outcomes in CKD patients. Epidemiological studies have reported that high blood pressure (BP) is one of the strongest predictors of CKD onset in the general population and of altered kidney function in CKD patients6. Based on these findings, international guidelines have highlighted that the reducing the BP in CKD patients is essential to prevent the progression of CKD and cardiovascular diseases9. However, a target BP is still under debate due to the low reliability and reproductivity of conventional clinical BP measurements.The number of chronic kidney disease (CKD) patients is increasing worldwide because of the aging society12. Furthermore, a recent large scale cohort of 63910 patients demonstrated that ABPM was superior to home BP measurements for predicting mortality13. ABPM enables the detection not only of white-coat or masked hypertension, but also BP circadian rhythms14. In general, BP decreases during the night, termed the “dipper” pattern; however, some individuals exhibit less dipping in BP during the night, termed as “non-dippers”. Previous reports demonstrated that the non-dipper BP profile pattern, which is common in patients with CKD17 predicted renal damage, including urinary albumin excretion18, the doubling of serum creatinine, and end-stage renal disease (ESRD)19.BP measured outside the hospital, including ambulatory BP monitoring (ABPM), was more strongly correlated with the decline in kidney function and the incidence of cardiovascular diseases than that measured at the clinic23, it is currently unknown whether a non-dipper BP pattern with normotension can predict the future progression of CKD. Our recent observational report demonstrated that the decline in eGFR over 2 years was correlated with the 24-hour average BP, but not its circadian rhythm24. However, the observation period in our recent study was insufficient to conclude that the 24-hour average BP, rather than its circadian rhythm, is an important predictor of the future incidence of ESRD. To overcome this limitation, we conducted a retrospective cohort study to elucidate the impact of actual BP values or its circadian rhythm on the long-term incidence of renal outcomes, including a 40% reduction in eGFR, the induction of renal-replacement therapy, or death from renal causes. In the present study, we divided CKD patients into four categories according to ABPM findings, i.e., 24-hour BP values and BP dipping patterns, and then compared the cumulative incidence of composite renal outcomes.However, due to the small number of interventional clinical studies with ABPM-based BP controls, the target BP in ABPM has not been established. Furthermore, in CKD patients, though the non-dipper BP pattern is regarded as a risk for the decline of kidney function and progression of cardiovascular diseases2 , blood urea nitrogen (BUN), and hemoglobin were measured by a standard procedure. eGFR was calculated according to the following formula26: “194 × [age (years)]−0.287 × [serum creatinine (mg/dl)]−1.094 × [0.739 if female]”. Urine was collected for 24 hours and daily protein excretion was measured. The co-existence of DM was defined as a history of glucose reduction treatment or HbA1c value above 6.5% by the National Glycohemoglobin Standardization Program (NGSP). The body mass index (BMI) was defined as [weight (kg)]/[height (meters)]2. The protocol for the present study was approved by the ethics committee of the Omihachiman Community Medical Center . The entire protocol of the present study was designed in accordance with the Declaration of Helsinki. Due to the retrospective design and its low risk to the patients, the ethical committee approved the use of the following opt-out methodology: The requirement for verbal informed consent was waived and informed consent was obtained by generally accessible information as well as easy methods to opt out, which were displayed on the website and at the outpatient clinic of Omihachiman Community Medical Center. Patient data were anonymized and de-identified prior to analysis.We conducted a retrospective cohort study at the Omihachiman Community Medical Center in Shiga Prefecture, Japan. We enrolled 1107 CKD patients who underwent ABPM from October 2006 to July 2016. CKD was diagnosed according to the criteria of the National Kidney Foundation defined as eGFR <60 ml/min/1.73 mABPM devices  were fit between 15:00 and 16:00 and removed at 15:30 the next day. The cuff size was selected based on the arm circumference and applied to the non-dominant arm. During the night (22:00–07:00), measurements were taken in 1-hour intervals, whereas daytime measurements (07:00–22:00) were taken in 30-minutes intervals. During the ABPM, patient activities were not restricted, but they were asked to stay motionless at the time of measurement. Diurnal and nocturnal BP were defined arbitrarily as 7:00–22:00 and 22:00–7:00, respectively.The average 24-hour BP was measured by ABPM. Nocturnal BP dipping was quantified as the difference between the average diurnal systolic BP (sBP) and average nocturnal sBP, and expressed as the percentage of average diurnal sBP. The non-dipper pattern was defined as an average diurnal sBP that was not 10% higher than the average nocturnal sBP. Hypertension was defined as an average 24-hour sBP higher than 130/80 mmHg , and death from renal causes , which were used in a recent clinical trialt-test for continuous variables and Fisher’s exact test for categorical variables. Multiple comparisons among the four groups were performed by the Steel-Dwass test for continuous variables and by Bonferroni corrections for categorical variables. We examined the relationship between the average 24-hour sBP and the nocturnal sBP dipping rate using a linear correlation model.Data are expressed as the median (interquartile range (IQR)). Comparisons of two groups were performed using Welch’s 28 and by a competing adjusted model. Significant differences among groups were assessed by Wilcoxon’s test.Death before the incidence of composite renal outcomes was considered to be a competing risk event. We compared the cumulative incidence of renal outcomes using Kaplan-Meier curves plotted according to previous recommendationsCox’s regression analyses were performed in order to assess variables associated with the incidence of composite outcomes using gender, age, the nocturnal sBP dipping rate, and factors considered to have a significant relationship. A P-value less than 0.05 was considered to be significant. Statistical analyses were performed using JMP version 9.0.3 for Windows .The mean (+SD) age of all participants was 69.2 ± 11.5 years, and 68.9% were men Table . The aveRegarding the clinical characteristics of participants, there was not significant differences in gender age, hemoglobin, or the usage rates of diuretics, or β-blockers among the groups Table . The perBased on BP profiles in each group Table , the ave20, our study suggested that the normotensive non-dipper BP profile is not a risk factor for the incidence of renal outcomes.During the follow-up period , 13.5, 32.5, and 46.1% of patients had the composite outcomes of a sustained 40% reduction in eGFR, renal-replacement therapy, or death from renal causes at 1, 3, and 5 years after recruitment, respectively Fig. . PatientTo investigate relevant factors for developing kidney disease, we performed a Cox regression analysis adjusted by gender, age, the nocturnal BP decline rate, and factors considered to have a significant relationship with the incidence of renal composite outcomes. The analysis identified average 24-hour sBP , proteinuria , eGFR at baseline , and hemoglobin values  as significant factors associated with the incidence of renal composite outcomes Fig. . We addiOne concern in our analysis was the difference in baseline eGFR among groups, and our multivariate analysis confirmed its strong correlation with the incidence of renal outcomes. In order to exclude the impact of baseline eGFR on the future incidence of renal composite outcomes, we performed a separate analysis on advanced eGFR < 30) and early (eGFR > 30) CKD patients. In early CKD patients, the baseline eGFR was not significantly different among groups (Supplementary Table 0 and earRegarding the BP profile in early CKD patients (Supplementary Table In the analysis of early CKD patients, renal composite outcomes were less frequent among patients with NDC or DC than among those with NDH or DH Fig. . Similar19, our clinical investigation was performed in order to clarify the impact of the non-dipping pattern of BP on the incidence of composite renal outcomes in normotensive CKD patients. A major result of this retrospective cohort study using ABPM was that the normotensive non-dipper pattern was not a risk for the future incidence of renal composite outcomes. Multivariate analysis demonstrated that a high average 24-hour BP more strongly correlated with the incidence of renal composite outcomes than the BP circadian rhythm.Based on previous studies demonstrating the non-dipping BP pattern to increase the risk of developing ESRD12, the number of large-scale cohorts using ABPM is limited due to its inconvenience for patients. The number of interventional trials conducted to date is also small, and only one study has used ABPM-based BP control for pediatric hypertensive patients29. Digital health innovations are emerging in the BP monitoring field by wearable devices using cuffless BP sensors, which facilitate the continuous monitoring of BP30. The reliability and reproductivity of these products are important for clinical practice12, and medical professionals, hypertensive patients, and the general public are interested in these technologies30. Therefore, based on the increased demand for clinical evidence of a relationship between long-term outcomes and ABPM, the present study suggested that patients should consider BP values over 24 hours, not its circadian rhythm, in order to prevent the progression of kidney disease.Although ABPM provides extensive information, including BP circadian rhythms and BP during sleep, which are not monitored by other modalities32. The BP of the study group with the non-dipping BP pattern in previous reports was often higher than that of dipping groups32, and it may have affected their results. Indeed, the impact of BP on renal outcomes was lost or diminished by adjusting for the BP value in some reports33 Regarding the impact of normotensive non-dipper pattern of renal outcomes, few studies including our previous one have been reported, but the results were not conclusive35. In contrast to our previous study24, a normotensive non-dipping BP can predict renal function decline in CKD patients35. However, the number of patients in these studies was small and the outcome was only the short-term renal function decline rate, not the incidence including ESRD. As we used composite renal outcomes, including ESRD and 40% eGFR reduction, in our study, our analysis provides stronger evidence for predicting the future renal prognosis, especially in normotensive non-dipping patients.In contrast to several previous investigations demonstrating the risk of the non-dipper pattern for CKD progression, our study revealed that the non-dipping BP pattern is not associated with the incidence of renal outcomes. One possible explanation for this discrepancy is that most previous analyses were performed by the categorization of dipper vs. non-dipper, not by the BP decline, as continuous variables36. In addition, normalizing the BP circadian rhythm by administering anti-hypertensive drugs reduced not only the urinary albumin excretion in diabetic kidney disease38, but also the incidence of cardiovascular diseases41. However, in our observational study, the circadian rhythm of the BP profile did not correlate with the future incidence of renal outcomes in both hypertensive and normotensive individuals, suggesting that the benefit of shifting from the non-dipper to dipper pattern to prevent the progression of kidney disease is limited.However, whether shifting the BP from the non-dipper to dipper pattern by the anti-hypertensive drugs administration has beneficial effects on renal outcomes is uncertain. In order to elucidate the impact of nocturnal BP dipping on renal outcomes, a prospective investigation of shifting the BP pattern by bedtime administration of antihypertensives may be ideal. Bedtime antihypertensive treatment for CKD patients reduced the average nocturnal BP and the percentage of non-dipper patients43. In addition, as we obtained no BP measurements at later time points, including ABPM or other methods, the impact of BP control on the future incidence of renal outcomes remains uncertain.The present study has several limitations. We only assessed single-point ABPM at recruitment. Sleep-disrupting cuff inflation during the night may increase the average nocturnal BP. The daily lifestyles of patients, e.g. food intake, may be affected during ABPM in order to obtain a better profile, resulting in a different BP from baseline. Previous studies demonstrated that some patients showed a different BP pattern in serial ABPM, even with short-term intervalsThe second limitation was the low prevalence of dipper patients, particularly hypertensive dippers. The small sample size in these populations may have influenced the significance of differences, particularly in the separate analysis according to eGFR. Therefore, the incidence of renal outcomes in DH and DC patients at a later time point needs to be carefully evaluated.44. Thus, these results need to be carefully applied to individuals of other races or countries.Furthermore, though we revealed that the non-dipping pattern with normotension was not a risk for the incidence of renal outcomes, we did not provide an actual value for the risk threshold for the 24-hour average BP. As this was an observational study on the prognostic value of ABPM, there was no direct intervention regarding the benefits of baseline patient treatments or BP control. In addition, we selected only the average 24-hour sBP, not diurnal or nocturnal average sBP for the analysis; therefore, which BP value among these is most strongly associated with the renal outcomes remains unclear. In order to establish a target BP, more substantial evidence from a large-scale prospective interventional study that includes multiple tests on ABPM is needed. In addition, this was a study on an Asian population at a single center, and a recent nationwide analysis demonstrated variations in ABPM profiles among races and countriesThe last limitation was the lack of data regarding the office BP and home BP measurement. We were unable to collect information on the situation when the BP was measured from patient records, which is essential for evaluating not only home BP but also office BP.In conclusion, our ABPM-based analysis demonstrated that a non-dipping BP pattern with normotension does not predict the incidence of renal composite outcomes in CKD patients. These results suggest that the control of BP, rather than its circadian rhythm, is essential to potentially prevent ESRD. A larger scale study to establish the target BP and interventional trials on ABPM-based BP control are required in order to obtain more conclusive evidence.Supplementary tables and figures