CNAP). We sought to validate the PPVCNAP-algorithm and investigate the agreement between PPVCNAP and arterial catheter-derived manually calculated pulse pressure variation (PPVINV). This was a prospective method comparison study in patients having neurosurgery. PPVINV was the reference method. We applied the PPVCNAP-algorithm to arterial catheter-derived blood pressure waveforms (PPVINV−CNAP) and to CNAP finger-cuff-derived blood pressure waveforms (PPVCNAP). To validate the PPVCNAP-algorithm, we compared PPVINV−CNAP to PPVINV. To investigate the clinical performance of PPVCNAP, we compared PPVCNAP to PPVINV. We used Bland–Altman analysis (absolute agreement), Deming regression, concordance, and Cohen's kappa (predictive agreement for three pulse pressure variation categories). We analyzed 360 measurements from 36 patients. The mean of the differences between PPVINV−CNAP and PPVINV was −0.1% (95% limits of agreement (95%-LoA) −2.5 to 2.3%). Deming regression showed a slope of 0.99  0.91 to 1.06) and intercept of −0.02 (95%-CI −0.52 to 0.47). The predictive agreement between PPVINV−CNAP and PPVINV was 92% and Cohen’s kappa was 0.79. The mean of the differences between PPVCNAP and PPVINV was −1.0% (95%-LoA−6.3 to 4.3%). Deming regression showed a slope of 0.85 (95%-CI 0.78 to 0.91) and intercept of 0.10 (95%-CI −0.34 to 0.55). The predictive agreement between PPVCNAP and PPVINV was 82% and Cohen’s kappa was 0.48. The PPVCNAP-algorithm reliably calculates pulse pressure variation compared to manual offline pulse pressure variation calculation when applied on the same arterial blood pressure waveform. The absolute and predictive agreement between PPVCNAP and PPVINV are moderate.The finger-cuff system CNAP  allows non-invasive automated measurement of pulse pressure variation (PPV Pulse pressure variation (PPV) caused by mechanical ventilation can predict fluid responsiveness , 2. PPV CNAP).In recent years, innovative finger-cuff technologies became available that allow continuous recording of the arterial blood pressure waveform and PPV calculation in a non-invasive manner –10. The CNAP-algorithm and (b) investigate the absolute and predictive agreement between PPVCNAP and arterial catheter-derived manually offline calculated PPV (PPVINV).We here sought to (a) validate the PPVThis was a prospective method comparison study comparing non-invasive finger-cuff-derived with invasive arterial catheter-derived arterial blood pressure as well as PPV in patients having neurosurgery. Here, we report PPV results. The arterial blood pressure results will be reported separately. The study was approved by the ethics committee  and conducted in operating rooms of the University Medical Center Hamburg-Eppendorf between April and October 2019. All patients provided written informed consent.−1 predicted body weight, respiratory rate ≥ 10 min−1, and positive end-expiratory pressure ≤ 5 cm H2O) were included.We included adult patients (≥ 18 years) who were scheduled for neurosurgery and required invasive arterial blood pressure monitoring using an arterial catheter as part of routine care. We excluded patients with vascular implants at the upper extremities, finger oedema, impairment in peripheral perfusion , cardiac arrhythmia, valvular heart disease grade 2 or above, excessive movement and/or seizures, or cardiac assist devices. For this analysis of PPV only patients with appropriate ventilator settings  and maximum PP (PPmax) undergo a plausibility check by using the average of previous verified PPmin and PPmax. After verification, PPV is calculated as: PPV = 200 × (PPmax – PPmin)/(PPmax + PPmin) (%). The PPVlgorithm  to the amax/PPmin pair corresponds to a half of a respiratory cycle. PPVCNAP is calculated by averaging six PPmax/PPmin pairs corresponding to the last three respiratory cycles. Additionally, outlier detection is used; PPV values higher than 40% are completely rejected. Further, if the difference between a new PPV value and the previous one is higher than a certain threshold, this new PPV value is used for calculation only with a 50% weight. If the PPV value is confirmed by the next measurement, the PPV value is then considered with a full 100% weight.Note that one PPmin or PPmax fail too often, all average and variance variables are reset. The PPVCNAP-algorithm is newly initialized and re-starts the calculation of average and variance variables from scratch.If plausibility checks of new beats or new PP−1 predicted body weight, a respiratory rate of ≥ 10 min−1 adjusted to end-expiratory carbon dioxide, and a positive end-expiratory pressure of ≤ 5 cm H2O. After insertion of the radial arterial catheter, the CNAP system’s upper-arm-cuff was attached on the ipsilateral arm. The CNAP finger-cuff was placed on the index and middle finger of the contralateral arm. CNAP finger-cuff arterial blood pressure measurements were calibrated to oscillometric arterial blood pressure measurements every 30 min in the first 27 patients. We changed this to the maximal calibration interval of 60 min during the study and calibrated every 60 min in the last 9 patients. Arterial blood pressure recording was started after positioning of the patient in the operating room and continued until the end of surgery. The continuous arterial blood pressure waveforms measured non-invasively with the CNAP system and invasively with the arterial catheter were simultaneously displayed and recorded on the patient monitor . Both waveforms were extracted to a personal computer  and beat-to-beat measurements were used for further offline analysis.After induction of general anesthesia, all patients were ventilated with a tidal volume of 8 mL kgWe randomly selected 10 60-s episodes of each patient. Within these episodes, we identified a period with at least three visible swings in PP in the non-invasive and invasive arterial waveform, which were used for further analysis.INV−CNAP by applying the PPVCNAP-algorithm to the arterial blood pressure waveform recorded invasively using the arterial catheter. PPVCNAP was automatically calculated using the PPVCNAP-algorithm based on the arterial blood pressure waveform recorded non-invasively with the CNAP system. PPVINV was calculated manually from the arterial blood pressure waveform recorded invasively using the arterial catheter (reference method).We calculated PPVDescriptive data are reported as mean ± standard deviation (SD) for continuous data and as absolute frequency and percentage for categorical data.INV−CNAP and PPVINV to validate the PPVCNAP-algorithm per se and (b) PPVCNAP and PPVINV to investigate the absolute agreement between PPVCNAP and PPVINV. For each comparison, we calculated the mean of the differences between the two methods (test method minus reference method), the SD of the mean of the differences, and the 95% limits of agreement  and the 95% confidence intervals (95%-CI) around the 95%-LoA to quantify the trueness and precision of agreement [INV−CNAP and PPVINV and between PPVCNAP and PPVINV by Deming regression for scattered plots with 95%-CI [CNAP and PPVINV. These PPV categories reflect PPV thresholds used for clinical decision making regarding fluid therapy in clinical practice [Using Bland–Altman analysis accounting for repeated measurements within individuals , 14, we greement , 16. We h 95%-CI , 18. We practice , 20. Thepractice . A CohenA total of 44 patients were available for this analysis, but eight were excluded. We excluded four patients due to cardiac arrhythmia, two patients because of technical failure of the CNAP system, and two patients because of study protocol violations Fig. . We thusINV−CNAP and PPVINV was −0.1 ± 1.2% (95%-LoA −2.5 to 2.3%)  and an intercept of −0.02 (95%-CI −0.52 to 0.47)   and an intercept of 0.10 (95%-CI −0.34 to 0.55) , we applied the PPVCNAP-algorithm to the arterial blood pressure waveform recorded invasively using an arterial catheter. The absolute agreement—i.e., the trueness and precision of agreement [INV−CNAP and the manually calculated PPVINV was high. The Deming regression analysis showed a significant correlation between PPVINV−CNAP and PPVINV and the predictive agreement was substantial according to Cohen’s kappa. Our results suggest that the PPVCNAP-algorithm reliably calculates PPV and that its measurements are interchangeable with the reference method—the manual offline calculation of PPV—when applied on the same arterial blood pressure waveform.To validate the PPVgreement , 16—betwCNAP to the reference PPVINV. The absolute agreement between PPVCNAP and PPVINV was lower than between PPVINV−CNAP and PPVINV and the Deming regression indicated a minor proportional difference between the methods. Nonetheless, the predictive agreement between PPVCNAP and PPVINV was moderate according to Cohen’s kappa.As a next step, we compared PPVINV) as the reference method. There are no consensus guidelines on how to perform PPV validation studies and interpret their results. Specifically, it remains undefined what constitutes clinically acceptable PPV measurement performance. The absolute agreement between PPVCNAP and PPVINV was similar compared with previous studies evaluating the measurement performance of PPVCNAP in critically ill patients [CNAP and arterial catheter-derived manually calculated PPV of −2.1% with 95%-LoA of −8.3 to 4.1% [-1, which were excluded in our study. In a cohort of 47 critically ill patients with acute circulatory failure, the mean of the differences between PPVCNAP and PPV calculated manually from a femoral arterial blood pressure waveform was −0.6% with 95%-LoA of −6.3 to 5.2% [CNAP and arterial catheter-derived manually calculated PPV before and after volume expansion [CNAP with PPVINV as no clearly defined thresholds for clinically acceptable PPV differences exist.In this study, we used arterial catheter-derived manually calculated PPV (PPVpatients , 23 and patients  or vascupatients . A pilot to 4.1% . Howeverxpansion . Even thCNAP to predict fluid responsiveness. PPVCNAP predicted fluid responsiveness very well according to receiver operating characteristics curve analysis [CNAP to predict fluid responsiveness, i.e., an increase in cardiac output after a fluid challenge. PPVCNAP and PPV calculated from an invasive arterial blood pressure waveform seem to have similar predictive value [CNAP predicts fluid responsiveness. Instead, we categorized PPV measurements considering clinical decision making based on predefined PPV thresholds for the prediction of fluid responsiveness [CNAP measurements falling in the same category as the respective PPVINV values would subsequently lead to the same decision regarding fluid therapy. The predictive agreement between PPVCNAP and PPVINV across the three categories was over 90% and Cohen’s kappa indicated a substantial predictive agreement. In line with the results of Bland–Altman analysis, the predictive agreement between PPVCNAP and PPVINV was slightly lower, but still over 80% and Cohen’s kappa indicated moderate agreement.When investigating non-invasively measured dynamic cardiac preload variables, their predictive capabilities regarding the prediction of fluid responsiveness may even be more important than absolute agreement with invasive reference measurements. In the before-mentioned study in vascular surgery patients, volume expansion was performed to investigate the ability of PPVanalysis . This wave value , 24. We siveness . PPVCNAPINV−CNAP and PPVINV as well as PPVCNAP and PPVINV suggest that the sample size was sufficient though. Additionally, the change of the calibration interval for the CNAP system during the study may have affected the results. We only included patients having neurosurgery and the results can thus not be generalized to other—especially critically ill—patients.We did not perform preload-changing interventions such as a fluid challenge or passive leg-raising test to assess fluid responsiveness. Nevertheless, we analyzed the agreement between the test and the reference method stratified by different PPV categories according to clinically established thresholds . Data paCNAP-algorithm reliably calculates PPV compared to manual offline PPV calculation when applied on the same arterial blood pressure waveform. The absolute and predictive agreement between PPVCNAP and PPVINV are moderate.In conclusion, the PPV


Multivariate logistic regression analysis demonstrated that LNSBP  was associated with heavy proteinuria. During the median follow-up of 23 months, 70 patients (19.7%) had a composite outcome; of these, 25 initiated dialysis, 25 had 40% eGFR loss, and 20 died. Cox analysis showed that the renal risk of LNSBP for CKD outcomes remained significant even after adjusting for background factors, including age, sex, medical history of hypertension and diabetes, smoking status, eGFR, 24-h proteinuria, and etiology of CKD . Concentrating on LNSBP could be valuable in guiding antihypertensive treatment to control heavy proteinuria and improve renal prognosis in elderly CKD patients.Ambulatory blood pressure monitoring (ABPM) can produce many variables, of which the lowest nocturnal systolic blood pressure (LNSBP) currently used in calculating morning surge is occasionally overlooked in recent kidney studies compared with other ABPM parameters. We explored the clinical effects of LNSBP in elderly patients with chronic kidney disease (CKD) in a multicenter, observational cohort study. A total of 356 elderly patients with CKD from 19 clinics were included in this analysis. We used multiple logistic regression and survival analyses to assess the associations between the lowest nocturnal systolic blood pressure and heavy proteinuria and kidney disease outcomes, respectively. The median age was 66 years, and 66.6% were men. The median eGFR was 49.2 ml/min/1.73 m It is well established that elevated blood pressure (BP) strongly indicates the progression of renal function and mortality in CKD or non-CKD populations5. In the past few decades, 24-h ambulatory blood pressure monitoring (ABPM) has exerted a better impact on evaluating the status of blood pressure throughout the day, distinguishing mask or white-coat hypertension in CKD patients more effectively than office blood pressure8. Hypertension management guidelines consistently have suggested ABPM as a better method to diagnose hypertension and can identify the proper time of antihypertensive drug administration10. ABPM also has a prognostic effect on the incidence and progression of renal damage11.Chronic kidney disease (CKD) can arise from heterogeneous diseases affecting 11–16% of the population worldwide12. Clinical and experimental data have indicated that heavy proteinuria is associated with the formation of renal interstitial fibrosis and contributes to the progression of renal failure13. The NHANES study showed that proteinuria was an independent risk factor for hypertension and independently associated with blood pressure (BP) control in CKD14. BP control reduces the incidence of albuminuria15. However, the association between 24-h proteinuria and 24-h ambulatory blood pressure in elderly CKD patients remains uncertain because of their cumbersome, time-consuming procedures, and expenditure in clinical practice. ABPM generates an abundance of data. Researchers have evaluated BP at different times, such as morning, daytime, and nighttime blood pressure. However, the lowest nocturnal systolic blood pressure (LNSBP), which is currently used to calculate the morning surge, is scarcely studied in CKD patients. We were particularly interested in the LNSBP whether it has an association with heavy proteinuria and can predict CKD outcomes, which has not been specifically addressed to the best of our knowledge.Heavy proteinuria is one of the essential diagnostic factors for nephrotic syndrome, which is commonly recognized as greater than 3.5 g measured by a timed 24-h urine collection method2. A great part of them (73.9%) had hypertension, and greater than one-third of the population had diabetes. As presented in Table Baseline characteristics are shown in Table We conducted logistic regression analysis to evaluate the relationship between LNSBP and heavy proteinuria Table . Higher During the median follow-up of 23 months, 70 patients (19.7%) had a composite outcome. Of those, 25 initiated dialysis, 25 had 40% eGFR loss from baseline, and 20 died. In Kaplan–Meier (KM) analysis  as a very high level of proteinuria instead of using a 24-h urine test, which is a method used to assess the quantity of all kinds of urine protein. In addition, we explored the lowest systolic blood pressure as either a continuous variable or a categorical variable to predict heavy proteinuria and obtained a positive result. Several studies reported that ABPM variables, particularly nighttime blood pressure, were strongly associated with the progression of microalbuminuria in individuals at high risk of CKD21, and our data added evidence that nighttime blood pressure was also associated with heavy proteinuria.A well-established association between ABPM and microalbuminuria has been reported in some previous studies22. Recently, a new viewpoint contrasting with previous thinking that elevated proteinuria is secondary to the development of high BP has been justified gradually26. Brantsma et al.21 conducted a longitudinal study with 4635 normotensive individuals at baseline to investigate the relationship between urinary albumin excretion and the new onset of hypertension. They found that participants with higher urinary albumin excretion at baseline were more likely to develop hypertension  change; 95% CI 1.03–1.36) after a mean 4.2 year of follow-up. In 2018, Haas et al.26 examined genetically bidirectional associations of proteinuria with blood pressure and suggested that elevated proteinuria and blood pressure could affect each other, which meant that increased proteinuria would lead to higher blood pressure and vice versa. It is reasonable for us to understand that sustained hypertension can lead to proteinuria. However, how can hypertension be explained by proteinuria? The mechanisms accounting for this interaction remain unclear. However, there are several speculations here. First, proteinuria was considered the result of kidney damage and seemed to be a major risk factor and pathological stimulus of renal inflammation-causing impairment in sodium homeostasis and overload, which led to hypertension28. Second, proteinuria might arise due to generalized endothelial dysfunction, which may also cause hypertension30. Third, urinary serine proteases aberrantly filtered into tubules, such as plasmin, activate the epithelial sodium channel in the distal tubule, with which sodium retention and volume overload may contribute to hypertension31. Combining with previous studies, we indeed think there is an underlying link between night blood pressure and heavy proteinuria, and a higher nighttime blood pressure level can be strongly associated with heavier proteinuria or the converse association.Hypertensive nephropathy is the second leading cause of CKD in the majority of countries33. However, studies illustrating the physiological meaning of LNSBP are rare. Cesare Cuspidi et al.34 reported that the LNSBP was predictive of new-onset left ventricular mass during a 10-year follow-up period. Combining our data with published literature, on the one hand, in terms of physical and mental activity as well as body position, LNSBP represents the minimal BP needed for adequate organ perfusion and physiological activity. On the other hand, in terms of arterial structure and elasticity, LNSBP reflects the degree of vascular stiffness. A higher LNSBP indicates a greater chance of target organ damage. In our study, one-third of elderly CKD patients had a nocturnal systolic blood pressure of greater than 120 mmHg, which far exceeds 90/60 mmHg, the lowest organ perfusion requirement in a healthy population. We confirmed that in elderly CKD patients, high LNSBP may be attributed to high basal systolic blood pressure or arterial stiffness free from interference of diurnal activities, hormone changes, sympathetic nervous tone, and the renin–angiotensin system. However, further research on relative explorations and comparison is warranted.The LNSBP is mostly used in calculating morning surges37. Although the pathophysiological mechanism of the association between nocturnal blood pressure and worsening renal prognosis has not been confirmed, our study demonstrated that higher LNSBP was associated with heavier proteinuria, which can accelerate renal function loss. In addition, LNSBP was independently associated with prognosis, indicating that higher organ blood perfusion or the degree of arterial stiffness can affect the hemodynamics of the kidney and lead to renal function loss.Our study suggested an increased risk of poor prognosis in elderly CKD patients with higher LNSBP independent of conventional CKD progression risk factors. Nighttime BP has been explored in many studies, and most of them have concluded that nighttime BP is superior in indicating ESRD or death than daytime BP and office blood pressure in CKD or non-CKD patientsGiven that heavy proteinuria and prognosis are the priorities for nephrologists, it is reasonable to measure the lowest nighttime blood pressure by ABPM devices. Proper administration of anti-night hypertensive treatment may help to control proteinuria and slow the progression of CKD in the elderly population.Several limitations should be mentioned. First, only elderly patients were enrolled in this study, and population representation was relatively limited. Second, 70 outcomes, including only 20 all-cause deaths, occurred during follow-up, which prevented us from detecting an association between LNSBP and all-cause death. Patient number did not provide sufficient power to evaluate the antihypertensive drug effects on LNSBP. Third, some of the day and night durations were defined by wide fixed-clock intervals (6:00 AM–10:00 PM for the day and 10:00 PM–6:00 AM for the night). Some patients may be asleep, whereas others may be awake, representing a source of data inaccuracy. Some sleep durations were self-reported, which was probably misreported by patients, resulting in potential errors in some ABPM values. Fourth, 24-h urine collection and ABPM were both performed only once at baseline, and changes in blood pressure and proteinuria during follow-up may influence the results. Finally, we did not analyze the association between LNSBP and proteinuria during follow-up due to the susceptibility of proteinuria to environmental factors, drugs, physical activities, and diets. Thus, the causal relationship between LNSBP and proteinuria has not been studied. In conclusion, higher nocturnal systolic BP was independently associated with an increased risk for heavy proteinuria and poor outcomes. Concentrating on the lowest nocturnal systolic blood pressure could be valuable in guiding antihypertensive treatment to control heavy proteinuria and improve renal prognosis in elderly CKD patients.38 and provided signed informed consent. We excluded participants if they (1) had received dialysis or renal transplantation; (2) were diagnosed with acute kidney injury; (3) had active malignancy within 24 months prior to screening or metastatic cancer; (4) had a life expectancy less than 6 months; (5) had severe heart failure (New York Heart Association function class III or IV); (6) had HIV infection; (7) had isolated hematuria; and (8) were unable to communicate with examiners, unable to complete the study procedure even if assisted or otherwise unable to comply with the study protocol. A total of 356 predialysis patients with ABPM records and basic information were enrolled until February 2019. The CKD Epidemiology Collaboration (CKD-EPI) creatinine equation39 was adopted to calculate the estimated glomerular filtration rate (eGFR). This study was approved by the Ethics Committee of the Chinese PLA General Hospital (No. S2016-100-02). All participants signed informed consent before they joined this study.This study was a multicenter, observational cohort study that was launched in February 2017 to investigate elderly Chinese CKD patients (greater than 60 years of age) recruited from 19 clinical centers in China. All the participants conformed to the following inclusion criteria: aged ≥ 60 years old, received a diagnosis of CKDOur patients started 24-h urine collections after their first voiding in the morning and to collect all urine continuously for 24 h, including the last void at the end of the 24-h period, or timely collected 24-h urine from 7:00 to 7:00 AM of the second day. Twenty-four-hour urine total protein was assayed by using the pyrogallol red method . Urine volume less than 500 ml was excluded.ABPM was performed by skilled physicians with validated devices  on a routine working day after the patients provided informed consent. The monitors recorded blood pressure at 15-min intervals in the daytime and 30-min intervals in the nighttime for a 24-h period. Different sized cuffs were used based on the arm circumference of the patients. Patients with monitors were suggested to maintain their usual activities. Valid measurements were those fulfilling ≥ 80% continuous recordings. Day and night durations were defined by wide fixed-clock intervals (6:00 AM–10:00 PM for the day and 10:00 PM–6:00 AM for the night) or according to self-reports of patients. The lowest nocturnal systolic blood pressure (LNSBP) was defined as the mean of the three nighttime SBP readings, the lowest reading, and the readings immediately before and after, centered on the time of the lowest nighttime values. Morning SBP (MSBP) was defined as the average of SBP values during the first 2 h after wake-up or the mean value obtained between 06:00 AM and 08:00 AM.Apart from 24-h proteinuria and ABPM, we also collected data, including age, sex, smoking status, body mass index (BMI), medical history of hypertension and diabetes, serum creatinine, eGFR, total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), blood urea nitrogen (BUN), uric acid, hemoglobin, and antihypertensive medication history.38. Specific causes of CKD were mainly dependent on pathologic diagnosis when the biopsy result was available or otherwise dependent on the clinical diagnosis made by nephrologists. All enrolled patients were categorized into the following subgroups: CKD with uncertain reason, membranous nephropathy, IgA nephropathy, diabetic nephropathy, hypertensive nephropathy, and others. The patients with other specific renal biopsy diagnoses were categorized as “others”. Hypertension was defined as office blood pressure (BP) ≥ 140/90 mmHg, self-reported hypertension history, or current treatment with antihypertension drugs. Diabetes mellitus was defined as a fasting glucose level ≥ 7.0 mmol/l, glycated hemoglobin ≥ 6.5%, self-reported diabetic history, or current treatment with antidiabetic drugs.CKD stages were consistent with the Kidney Disease Improving Global Outcomes (KDIGO) 2012 guidelines40. CKD progression and all-cause death were composite outcomes. CKD progression and all-cause death were ascertained through contact with patients or reports from next of kin, review of medical records and death certifications. Individuals should visit the clinics every 6 months. The allowance of the early and delayed visits would be 1 month from the scheduled visit date. Patients who were not able to show up in hospitals on time were followed up by telephone call or online contact until ESRD, death, withdrawal from the study, loss to follow-up, or January 2020. Greater than 90% of the patients kept in touch during this period. All methods were performed in accordance with the relevant guidelines and regulations.CKD progression was defined as ESRD (the initiation of replacement treatment therapy) or 40% eGFR decline, which ever occurred first. We selected a 40% eGFR decline over follow-up because this outcome was clinically significant and proposed by the National Kidney Foundation and the US Food and Drug Administration as a broadly accepted measure for kidney function declineWe summarized baseline participant characteristics across tertiles of baseline the lowest nocturnal systolic blood pressure with mean ± (SD) for normal distribution variables, median (interquartile range) for nonnormal distribution variables, number (%) for category variables. We categorized proteinuria as a binary variable [nonheavy proteinuria (< 3.5 g/24 h) part and heavy proteinuria (≥ 3.5 g/24 h)] because the data did not meet the requirement for normal distribution of linear regression. Multiple logistic regression analysis was used to investigate the association between ABPM parameters and heavy proteinuria. Kaplan–Meier survival curves were used to estimate the proportion of participants in different tertiles of LNSBP surviving without a composite outcome for specified durations. Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for time to renal outcomes with adjustment for traditional risk factors, including age, sex, smoking status, medical history of hypertension and diabetes, eGFR, 24-h proteinuria, and etiology of CKD in either death as an outcome or censored data models. The assumption of proportionality was tested using Schoenfeld residuals. No substantial deviations from proportionality were observed. Statistical significance was set at the level of P = 0.05. Analyses were performed with IBM SPSS 25.0 software .


Fulminant myocarditis has a sudden onset and rapid progress, which can easily cause multiple organ failure. Acute kidney injury is a common complication. ECMO  and CRRT  have been used in the treatment of fulminant myocarditis, but the combination of the 2 has an impact on the prognosis. There is still a big controversy. Therefore, the purpose of this randomized controlled trial is to evaluate the nursing effect and long-term efficacy and safety of ECMO combined with CRRT in the treatment of fulminant myocarditis.This is a prospective randomized controlled trial to study the effectiveness and safety of ECMO combined with CRRT in the treatment of fulminant myocarditis. Approved by the clinical research ethics committee of our hospital. Patients were randomly assigned to 1 of 2 treatment options:1.ECMO combined with CRRT group and2.ECMO group.Observation indicators include: basic vital signs, laboratory indicators, echocardiographic changes, complications, and outcomes. SPSS 25.0  version statistical software package was used to analyze the data.This study will evaluate the nursing effect and long-term efficacy and safety of ECMO combined with CRRT in the treatment of fulminant myocarditis. The results of this experiment will provide clinical evidence for the treatment of fulminant myocarditis with ECMO and CRRT.Private information from individuals will not be published. This systematic review also does not involve endangering participant rights. Ethical approval was not required. The results may be published in a peer-reviewed journal or disseminated at relevant conferences.DOI 10.17605/OSF.IO/PAQBZ. Patients can quickly develop severe hemodynamic disturbances, heart failure, and severe malignant arrhythmia, leading to multiple organs such as liver and kidney dysfunction, the early mortality rate is extremely high. It is believed that ECMO can be used as a first-line treatment option for fulminant myocarditis. Fulminant myocarditis often causes renal hypoperfusion, and in ECMO circulation support, hemolysis caused by red blood cell destruction can cause acute kidney injury (AKI), which seriously affects the prognosis of patients. Studies have shown that AKI and overload fluid occur in 70% to 85% of ECMO patients. Continuous renal replacement therapy (CRRT) is an extracorporeal blood purification therapy that can replace impaired renal function for a long time. It removes toxins and cytokines through diffusion and convection methods, and reduces cardiac load through ultrafiltration Maintaining hemodynamic stability well.Extracorporeal membrane oxygenation (ECMO) takes the venous blood in the body out of the body and injects it into the patient's arteries or veins through a special material artificial heart-lung bypass oxygenation device, which plays a role of partial heart-lung replacement. Therefore, this research program will study the effectiveness and safety of ECMO combined with CRRT in the treatment of fulminant myocarditis through randomized controlled trials.The impact of ECMO combined with CRRT on the prognosis is still controversial. Studies have pointed out that regardless of whether AKI occurs, and whether CRRT is performed, the difference in mortality of CF patients in the intensive care unit is not statistically significant.22.1This is a prospective randomized controlled trial to study the effectiveness and safety of ECMO combined with CRRT in the treatment of fulminant myocarditis. We followed the Consolidated Standards of Reporting Trials (CONSORT) guidelines for reporting randomized trials and provided a CONSORT flow diagram Fig.  and the 2.2This research program is in accordance with the Helsinki Declaration and approved by the Clinical Research Ethics Committee of our hospital. This protocol has been registered in open Science Framework (OSF)(Registration number: DOI 10.17605/OSF.IO/PAQBZ). All patients need to sign a written informed consent before they are randomly assigned to continue the trial.2.3 we set the minimum number of people in each group of studies to 40, and the final number will be based on actual recruitment.In order to draw reliable conclusions, this study will include as many qualified samples as possible, referring to similar studies,2.4②No previous serious underlying heart disease; ③A viral infection of the respiratory system occurred before the onset; ④After the onset, the condition deteriorated rapidly, the left heart function was severely impaired, the hemodynamics was unstable, and circulatory and respiratory support was needed; ⑤Be over 18 years old.Inclusion criteria: ①Meet the diagnostic criteria for fulminant myocarditis of the European Heart Collaboration Group;Exclusion criteria: ①Those who use ECMO for other reasons; ②;Severe irreversible multiple organ damage; ③Pregnant women with severe heart failure; ④Patients with congenital and acquired diseases that cannot be corrected after cardiac surgery; ⑤Cardiopulmonary Resuscitation (CPR) for more than 30 minutes; ⑥Thouse who are unable to understand the research plan after explanation or unwilling to participate.2.5Eligible participants were randomly assigned to the treatment group or the control group at a ratio of 1:1 using a random tool based on the central network. Randomization was performed without any stratification generated by an independent statistician who was not involved in trial implementation or statistical analysis using SAS 9.3 software . The clinical research coordinator entered the participant information on the tablet, and was given a random number. The research assistant gets the participant's assignment from the computer. Throughout the research process, the research assistant is responsible for screening, recruiting participants, and assigning random numbers to the included participants. The result assessor is responsible for the assessment of the scale.2.61.Establishment of ECMO: The surfaces of all connecting pipes of the ECMO system, the contact surfaces of the oxygenator and the centrifugal pump are all covered with heparin coating. After ultrasound assessment of blood vessel diameter and elastic plaque, the femoral vein (20–22 Fr) and femoral artery (16–20 Fr) were inserted percutaneously. If severe ischemia occurs in the lower extremities, place a 6F perfusion tube to increase blood supply to the lower limbs. The perfusion tube increases blood supply to the lower extremities. The femoral vein femoral artery catheterization was used to establish an ECMO  support model.2.ECMO management: ①Adjust pump flow according to cardiac function and hemodynamic parameters; ②Anticoagulation management: use unfractionated heparin for anticoagulation, monitor the activated coagulation time every 2 hours, and adjust the amount of heparin to maintain it between 160 and 200 seconds; ③Mechanical ventilation management: mechanically assisted ventilation according to protective lung ventilation strategies; ④Hemodynamic management: monitor heart rate, blood pressure of right upper limb, blood oxygen saturation of right hand. Measure blood gas and central venous oxygen saturation at 4 hour intervals; ⑤Management of vasoactive drugs: adjust the type and dosage of vasoactive drugs according to circulatory indicators such as blood pressure and heart rate.3. The current conventional method is to add the CRRT machine to the ECMO loop, which can avoid the risk of multiple tube placement. When ECMO is combined with CRRT treatment, the connection method of the pipeline is to join the CRRT loop in parallel on the ECMO pipeline. The inlet end (artery) of CRRT is connected to the back end of the centrifugal pump through a three-way connection, and the outlet end (venous) is connected to the other end is before the membrane lung. Choose continuous venous-venous hemofiltration or diafiltration mode, the replacement dosage is pre-dilution  1 to 2 L/hour, post-dilution 1 L/hour, replacement fluid and dialysate use modified port formula replacement fluid. The nurse adjusts the pump speed according to the doctor's advice according to the acid-base level of the blood gas analysis; adjusts the potassium chloride dosage according to the blood potassium level. Soak and flush the pipeline with 0.9% sodium chloride solution. No additional anticoagulant measures are added during CRRT.CRRT establishment: In ECMO combined with CRRT treatment, if the 2 loops are placed separately, it will inevitably increase the risk of bleeding and infection, and there are problems such as expensive and complicated operations.4. ECMO assisted flow rate is reduced to 1 L/min, no or only small doses of vasoactive drugs are used to maintain hemodynamic stability, mean arterial pressure >60 mm Hg (1 mm Hg = 0.133 kPa), Pulse pressure difference >20 mm Hg, LVEF(left ventricular ejection fraction)>35% to 40%, central venous pressure <10 mm Hg, left ventricular pressure <12 mm Hg, systemic central venous oxygen saturation >65% to 70%, lactic acid <2 mmol/L.ECMO weaning indication:5.Nursing intervention: The operation of the machine and the setting of parameters should be closely monitored in nursing. The nurse observes and records the speed and flow rate of the centrifugal pump every hour, and observes the pressure before and after the pump to avoid hemolysis caused by excessive negative pressure; observe the pressure before and after the oxygenator, observe whether the pipeline shakes, the color of the pipeline, and whether the flow rate is suddenly high suddenly low to prevent insufficient blood flow, thrombosis or pericardial tamponade, etc.; check the temperature setting of the water tank and actual water temperature, etc.; closely monitor heart rate, heart rhythm, blood pressure, urine output, bedside electrocardiogram, left ventricular systolic function and change trends; use blood purification A dedicated observation record sheet, which accurately records data such as arterial pressure, venous pressure, filtrate pressure measurement, transmembrane pressure, pressure drop, fluid flow in and out, and dehydration volume every hour. In any case, inform the responsible doctor as soon as possible.,13 All nurses and doctors involved in the treatment are experienced professionals.The treatment group adopts the combined treatment mode of ECMO and CRRT, and the control group adopts the ECMO treatment mode. Any emergencies during treatment will be dealt with according to the expert consensus opinion of fulminant myocarditis.2.71.Record the patient's basic vital signs changes , weaning time, hospital stay, etc.;2.2/fraction of inspiration O2), blood lactic acid (lac), liver and kidney function, coagulation function, arterial blood pH, etc.;Monitor changes in laboratory indicators before and after treatment: such as N terminal pro B type natriuretic peptied, high-sensitivity troponin I, myocardial enzymes, oxygenation index , left ventricular end-diastolic diameter;4.Complications and treatment outcomes: including weaning rate, in- and out-of-hospital mortality, complication rate .5. score is used to assess the patient's organ condition.Sequential Organ Failure Assessment (SOFA)2.8Observation indicators were collected before treatment, 24 hours, 48 hours, 72 hours, 96 hours after treatment, and 2 hours before weaning. At the same time, follow-up for 30 days to assess complications and treatment outcome. One or 2 assistants will collect and record the entire data. Personal information about potential participants and registered participants will be collected, shared and stored in an independent storage room to protect confidentiality before, during and after the test. The access to the database will be restricted to the researchers in this study team.2.9t test or Mann–Whitney U test was used for the comparison of measurement data, the paired t test was used for the comparison within the group, and the Chi-Squared test or Fisher exact probability method was used for the comparison of count data. All are two-sided tests, with P < .05 as the difference is statistically significant.The SPSS 25.0 software was used for statistical analysis. Measurement data are expressed as mean ± standard deviation or median (quartile), and count data are expressed as number of cases. The independent sample 3,15 It has been reported in the literature that the survival rate of mechanical assist devices for fulminant myocarditis is 57% to 80%.,16 Early and timely ECMO placement to maintain effective circulatory perfusion is the key to reducing the mortality of FM. However, for long-term use of ECMO treatment, it should be noted that the probability of complications of ECMO treatment such as limb ischemia, abnormal coagulation function, bleeding, and infection will be greatly increased. Some researchers believe that ECMO combined with CRRT avoids the risk of bleeding at the puncture site during ECMO-assisted systemic anticoagulation. At the same time, it can measure the pressure of the ECMO membrane before and after the membrane, reduce the pressure measurement device, and reduce the risk of infection. Studies have shown that during EMCO treatment, about 50% of patients may be combined with CRRT treatment, which may be related to ECMO oxygenated blood flowing backward through the renal artery, ECMO-related inflammation activation, high anticoagulation state, hemolysis, etc. These factors are related. The integrated use of ECMO and CRRT in parallel can achieve joint support of multiple organs such as heart, kidney, and lung in 1 cardiopulmonary bypass pathway. However, some scholars believe that the use of CRRT during ECMO may increase the risk of in-hospital mortality. Therefore, whether the early application of CRRT is beneficial to the prognosis of patients with fulminant myocarditis still needs clinical research to verify.Patients with fulminant myocarditis progress rapidly and are often accompanied by difficult to correct hemodynamic disturbances or stubborn fatal arrhythmias. Therefore, the early use of effective mechanical assist devices is the key to improving the prognosis of such patients.This study also has the following limitations: the sample size included in this study is limited, which may affect the results. The planned follow-up time for this study is short, and there is no assessment of the long-term efficacy and safety of the treatment plan. If necessary, we will extend the follow-up time and pay more attention to its long-term efficacy.Data curation: Juan Wu, Hui Zhang.Funding acquisition: Xihua Huang.Resources: Hui Zhang, Yongxia Gao.Software: Hui Zhang.Supervision: Yongxia Gao, Xihua Huang.Writing – original draft: Juan Wu, Hui Zhang.Writing – review & editing: Juan Wu, Xihua Huang.


Neighbourhood characteristics are associated with several diseases, but few studies have investigated the association between neighbourhood and health in Jamaica. We evaluated the relationship between neighbourhood socioeconomic status (SES) and blood pressure (BP) among youth, 15–24 years old, in Jamaica.A pooled analysis was conducted using data from three studies , conducted between 2005–2008, with individual level BP, anthropometric and demographic data, and household SES. Data on neighbourhood SES were obtained from the Mona Geo-Informatics Institute. Neighbourhood was defined using community boundaries from the Social Development Commission in Jamaica. Community characteristics  were combined into SES scores using principal component analysis (PCA). Multivariable analyses were computed using mixed effects multilevel models.p < 0.001, for each standard deviation unit increase in PCA-SES1 score) in multivariable model accounting for age, household SES, study, BMI, fasting glucose, physical activity and diet. PCA-SES1 was not significantly associated with systolic BP among females  in a similar model. Associations for PCA-SES2 was assessed using linear splines to account for non-linear effects. The were no significant associations between systolic BP and PCA-SES2 among males. Among females, higher PCA-SES2 (i.e. lower SES) was associated with higher systolic BP at spline 2 [z-score -1 to 0] , but with lower systolic BP at spline 3 [z-core 0 to 1] . There were no significant associations between diastolic BP and PCA-SES1, but PCA-SES2 showed non-linear associations with diastolic BP particularly among males.Analyses included 2,556 participants  from 306 communities. PCA yielded two neighbourhood SES variables; the first, PCA-SES1, loaded highly positive for tertiary education and larger house size ; while the second, PCA-SES2, loaded highly positive for unemployment and population density . Among males, PCA-SES1 was inversely associated with systolic BP (β-1.48  mmHg, Higher neighbourhood SES was inversely associated with systolic BP among male Jamaican youth; there were non-linear associations between neighbourhood SES and systolic BP among females and for diastolic BP for both males and females. Neighbourhood characteristics, in particular conditions of the physical and social environment, have been shown to be associated with a number of health-related conditions . ResearcUnderlying mechanisms possibly include interactions between adverse environmental exposures, reduced sense of safety due to potential exposure to crime and violence, increase levels of adverse health behaviours and increased psychosocial stress . The effWith regards to blood pressure, associations have been reported for systolic blood pressure, diastolic blood pressure and hypertension , using iIn Jamaica, research on the association between neighbourhood and health is limited. Cunningham-Myrie and colleagues found associations between characteristics of the neighbourhood environment and physical activity and obesity, with significant differences by sex , while MTo our knowledge, no previous study on the relationship between blood pressure and neighbourhood characteristics has been conducted in Jamaica. Research on the neighbourhood effects on blood pressure is also limited in developing countries, among black populations and among youth. Studies have shown that social determinants of health often vary between countries and in different social context , suggestThis study therefore aimed to: 1.Evaluate the relationship between neighbourhood characteristics and systolic and diastolic blood pressure among Jamaican youth, 15–24 years old. 2.Evaluate whether the presence of elevated blood pressure or hypertension (BP ≥ 120/80 mmHg) is associated with neighbourhood characteristics.Estimates will adjust for potential confounders including age, sex and household socioeconomic status and will also evaluate the effect of possible intermediary variables and independent covariates. We hypothesized that lower neighbourhood SES will be associated with higher systolic and diastolic blood pressure and higher prevalence of elevated blood pressure or hypertension. We chose to assess elevated blood pressure or hypertension as our high-risk category since the study involved adolescents and young adults and prevalence of hypertension would be relatively low in this age-group.The study was conducted using data from three studies  which included measurements of blood pressure for youth aged 15 –24 years. We obtained data on neighbourhood characteristics from the Mona Geo-Informatics Institute Geographic Information Systems (GIS) Database. The studies included are (1) the 1986 Jamaica Birth Cohort Study 18–20 Follow Up (1986-JBCS), (2) The Jamaica Youth Risk and Resiliency Behaviour Survey 2006 (JYRRBS) and (3) The Jamaica Health and Lifestyle Survey 2007–2008 (JHLS-II). All studies were conducted by the Epidemiology Research Unit with one of the investigators (RJW) as the principal investigator for each study. All three studies were previously approved by the University of the West Indies Ethics Committee . Additionally, the proposal for this pooled analysis was reviewed and approved by The University of the West Indies Ethics Committee , prior to obtaining data on neighbourhood characteristics from the Mona Geo-Informatics Institute. Participants provided written informed consent at the time of data collection for the primary studies.Details on the methods used in these studies have been previously published . We therThe 1986-JBCS third follow up  was condJYRRBS  was a naJHLS-II  was alsohttp://www2.monagis.com/). For this study, MGI provided community data for anonymized participants from the three studies. We provided MGI with each participant’s address or electoral district, which were used to map them in communities as defined by The Planning Institute of Jamaica and the Social Development Commission (The Mona Geo-Informatics Institute (MGI) is an Institute of The University of the West Indies, Mona, and provides several GIS resources to the University and other stakeholders. MGI has an extensive human and social mapping database which includes geo-spatial data on environmental characteristics, infrastructure and social characteristics, at the parish, constituency, electoral division or community level. Data are derived from population censuses, government databases, non-governmental organizations, private sector partners and international organizations. These data are linked geo-spatially to MGI’s extensive mapping of the island. Additional information is available on the MGI website  for the JYRRBS. For each study, participants were classified as having high, moderate or low physical activity levels. Classification rules for the locally developed questionnaires have been previously published (https://sites.google.com/site/theipaq/scoring-protocol). We did not have data on salt intake and therefore frequency of fast food consumption was used as a surrogate for high salt diet. Data on fast food consumption was collected by questionnaire and categorized as less than twice per week, 2 to 4 times per week or five or more times per week.The study used previously collected data from the studies described above and from MGI databases. Data collection for all the included studies followed similar standardized protocols. In all studies, blood pressure was measured using a mercury sphygmomanometer  after the participant had been seated for five minutes. The mean of the second and third systolic and diastolic blood pressures were used for the analysis. Elevated blood pressure or hypertension was defined as systolic blood pressure ≥120 mmHg or diastolic blood pressure of ≥80 mmHg or being on medication for hypertension. This categorization includes persons classified as prehypertension or hypertension in The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and as elevated blood pressure or hypertension in the 2017 American College of Cardiology / American Heart Association Guidelines . This cuublished , while tAs stated above, data for neighbourhood characteristics were collated by MGI from population censuses, various governmental and non-governmental organizations, and private sector partners. We opted to use these data to evaluate neighbourhood socioeconomic status because there were no generally accepted measures for use in Jamaica. Previous studies have used indexes based on aspects of the built environment, services, poverty, education and crime , howeverhttps://sdc.gov.jm/) as geographic areas grouping people based on common ownership of resources or sharing of social, economic or cultural facilities. The country is thus divided into parishes, developmental areas, communities and districts. Jamaica has 14 parishes. In its most recent listing, the SDC social boundaries include 775 communities. For the communities included in this study, population ranged from just over 100 to over 60,000 community members. Further description of the community characteristics is shown in For these analyses, neighbourhood was defined as the community in which the participants lived. In Jamaica, community boundaries are defined by the Social Development Commission  we applied a design effect using the formula design effect = 1 + (M − 1) × ICC, where M = number of observations per cluster and ICC = intraclass correlation coefficient  and were performed for males and females separately. Correlation coefficients were −0.15 for females and −0.14 for males. Using Stata’s ‘fficient . The avep-value <0.05 was considered statistically significant.Analyses were performed using Stata 14.2 . Individual datasets were prepared for each study, and variables recoded to ensure that codes were the same for variables to be used for this analysis. The three datasets were then merged into a single dataset with a variable to indicate the study from which each participant came. Descriptive statistics were then obtained, initially stratified by study, and then stratified by study and sex. Summary statistics were also obtained for all participants stratified by blood pressure category. We also performed analyses to assess whether there was evidence for additive interaction by sex and by study in the relationship between systolic BP and neighbourhood SES and other covariates included in the models. For all analyses, a p < 0.05 (thus rejecting the null hypothesis that variables are uncorrelated). Based on these criteria, a final list of six community variables were chosen for inclusion in the PCA model . These variables were: percent poverty, percent unemployment, dependency ratio, population density, percent of houses with two or more bedrooms, and proportion with tertiary education. We believe that these six variables had good content validity, representing aspects of income, education, employment, crowding and wealth (size of house) which are all factors related to neighbourhood socioeconomic position. Horn’s parallel analysis method was used to select components to be used in the analysis; components having an adjusted eigenvalue greater than 1.0 used in the analyses  was used to derive composite socioeconomic status (SES) variables. We initially assessed the correlation between the available SES variables and used variables with significant correlations for consideration in the PCA. We then used the Kaiser-Meyer-Olkin (KMO) test for sampling adequacy and the Bartlett test of sphericity to select the variables for inclusion in final PCA model . We aimeanalyses . This meed knots .We used multilevel regression models to evaluate the association between community SES and blood pressure. Analyses with systolic and diastolic blood pressure as outcomes were done using mixed effect linear regression models with maximum likelihood (ML) estimation, while analyses with elevated blood pressure as the outcome were done with mixed effects logistic regression models. The multi-level model accounted for individuals nested within communities, and communities nested within parishes. The overall multilevel model structure was therefore: level 1—individual study participants; level 2—communities in which participant lived; level 3—parish in which community was situated. We report fixed effects coefficients adjusted for clustering by parish and community.χ2 = 8.68, p = 0.013). Based on this we assessed the data to be missing at random (MAR)  had at least one missing value. om (MAR) . Using mom (MAR) . A stackom (MAR) . Given tom (MAR) . Multipl command . The imp’s rules . For mod’s rules .For multivariable analyses, we developed sequential models based on our hypothesized associations, in order to assess the effect of potential confounders, intermediary variables or independent covariates. Age, sex and household socioeconomic status were treated as potential confounders, while BMI, glucose, physical activity and diet were considered possible intermediary variables or independent covariates. A directed acyclic graph illustrating the hypothesized association is shown in Final analyses included 2,556 participants  from 306 communities. Mean age was 17.9 years (standard deviation 2.0). There was evidence for significant clustering of both systolic BP and diastolic BP within communities, with intra-class correlation coefficients of 10.7% (95% CI [6.8–16.6%]) and 10.9% (95% CI [7.0–16.6%]), respectively.z-scores for analyses. The first component, PCA-SES1, had an adjusted eigenvalue of 3.21 and explained 54% of the variance; this component loaded highly positive for tertiary education and larger house size . The second component, PCA-SES2, had an adjusted eigenvalue of 1.40 and explained 24% of the variance; this component loaded highly positive for unemployment and population density . PCA yielded two components with adjusted eigenvalues >1.0 and these were used to derive two neighbourhood SES variables. These two variables were standardized using z-score for PCA-SES 1 was highest in the 1986-JBCS (0.37) and lowest in the JYRRBS (-0.12), suggesting that participants from the 1986-JBCS had higher overall SES. This was supported by the distribution of individual community SES characteristics as shown in z-score for PCA-SES 2 was also highest in the 1986-JBCS. Prevalence of elevated blood pressure or hypertension was 29% overall and ranged from 21% in the 1986-JBC to 37% in JHLS-II (see S-II see . There wp < 0.001); we therefore used linear splines in the bivariate and multivariable analyses for PCA-SES2. We also assessed for interaction by sex and study. Tests for sex interaction were significant for the relationship between systolic BP and some covariates , therefore we present sex-specific analyses for bivariate and multivariable models. Details of the sex interaction effects are shown in As stated before, we assessed whether the relationship between systolic BP and the PCA-SES variables showed evidence for non-linear effects by adding a quadratic term to the model. This was non-significant for PCA-SES1, but significant for PCA-SES2 (p < 0.001) and 1.30 mmHg lower systolic BP among females (p = 0.003). For PCA-SES2 we report results for linear splines, given the evidence for a non-linear effect mentioned above. Among males, a significant association was seen only for spline 2 (z-score - 1 to 0) where a one standard deviation increase in PCA-SES2 (lower SES) was associated with a 2.6 mmHg higher systolic blood pressure. Among females, significant associations were seen for spline 1 (z-score <−1), spline 2 (z-score −1 to 0), and spline 4 (z-score >1). Coefficients were 2.7 for spline 1, −3.5 for spline 2 and −0.5 at spline 4. Age and BMI were directly associated with systolic BP among both males and females, while fasting glucose showed significant direct association among females only. Household possession categories was inversely associated with systolic BP for the middle third among males and the upper third among females. There was an inverse association with fast food consumption for the 3-4 times/week category compared to the to the ≤2 times/week category for females only. No association was seen for physical activity levels in these models.Bivariate analyses using mixed effects linear regression with systolic BP as the outcome are shown in p = 0.015).Results for bivariate analyses for diastolic BP are shown in p < 0.001) in the unadjusted model to −1.31 (p < 0.001) in model 1; however, addition of BMI to the model resulted in the magnitude of the coefficient increasing  to −1.49 (p < 0.001). There was no appreciable change in the coefficient when fasting glucose, physical activity and diet were added to the model. Among females, the significant association seen in the bivariate analysis was attenuated and no longer significant when age, household possessions and study were added in model 1. The coefficient reduced in magnitude from −1.30 (p = 0.003) in the unadjusted model to −0.46 (p = 0.423) in model 1. The addition of BMI (model 2) and other covariates (model 3) resulted in only very small changes in the coefficient. For PCA-SES2, the association seen at spline 2 in the unadjusted model among males was no longer significant in any of the sequential models, but a significant positive association was seen at spline 4  in model 2 only. Among females, PCA-SES2 was directly associated with systolic BP at spline 2 (z-score -1 to 0) with little change across the models. At this level a one standard deviation increase in PCA-SES2 (lower SES) was associated with a 4.09 mmHg increase in systolic BP in the fully adjusted model. At spline 3 (z-score >0 to 1), higher PCA-SES2 score was associated with lower blood pressure .Sequential multivariable analyses with systolic BP as the outcome are shown in z-score <−1) . There was a significant direct association at spline 2 (z-score −1 to 0) . Among females, there was a significant positive association between diastolic BP and PCA-SES2 at spline 1 .p = 0.051), suggesting that higher SES may be associated with lower odds of hypertension or elevated blood pressure, but did not achieve statistical significance in this study. There were no significant associations among females for thirds of PCA-SES1. Thirds of PCA-SES2 was not associated with elevated blood pressure in males or females.In order to assess whether our results could have been influenced by the multiple imputation, we re-ran the full models (model 3) with complete cases only  for systolic and diastolic blood pressure. These models are shown in We have shown from these analyses that lower community SES is associated with higher systolic BP among youth in Jamaica, particularly among males. This association persisted after adjusting for possible confounding by age and household SES and after accounting for the effects of BMI, fasting glucose, physical activity and diet (fast food consumption). Among females, the association with the first PCA-SES component was no longer significant after adjusting for confounders. Associations for the second PCA-SES component demonstrated non-linear effects. Diastolic BP also showed some non-linear associations for the second PCA-SES variable. However, while lower community SES may also be associated with higher odds of elevated blood pressure or hypertension among males, this did not achieve statistical significance.The findings from this study adds to the body of literature showing an important contribution of neighbourhood conditions to health and underscores the importance of including the neighbourhood context when evaluating the social determinants of health. It also highlights that the relationship between neighbourhood SES and blood pressure may be complex, with both linear and non-linear effects, thus necessitating a nuanced approach to our interpretation of these associations. A relationship between neighbourhood SES and blood pressure in adults is fairly well established, with several studies showing that lower neighbourhood SES was associated with higher BP . AdditioIn this study, the association between neighbourhood SES and diastolic BP was seen only for the second PCA-SES variable and showed non-linear effects. We have previously reported weaker associations between diastolic BP and socioeconomic variables in a longitudinal analysis from the 1986 Birth Cohort . AdditioThe finding of sex differences in the association between community SES and health have been previously reported in studies from Jamaica . CunningThe mechanisms underlying the relationship between neighbourhood SES and blood pressure has not yet been fully elucidated. Broadly speaking, neighbourhood SES may influence health through compositional effects , contextual effects (group level effects beyond those due to risk factors) or environmental effects . This inThis study had several strengths, including the fact that individual participant data for all three studies were available and therefore we were able perform pooled analyses in the study. The similarities in the source population, age range, and timing for each study the studies facilitated pooled analysis. While there was some evidence of heterogeneity between studies, this was seen only for specific splines of the second PCA-SES variable and therefore would have little effect on our conclusions. The studies in general had good response rates, and two were from nationally representative samples, so that the findings can be considered as generalizable to the Jamaican population. Another strength of this study is the use of PCA to derive socioeconomic status scores thus taking into consideration several SES variables rather than only a few select community characteristics.Limitations of this study include the cross-sectional design which limit our ability to make causal inferences. However, given the findings from other cross-sectional and longitudinal studies cited above, our findings add to the literature on this subject and strengthens the consistency of the associations reported. The study was also limited by the fact that we had missing data for some variables, however we were able to account for this by using multiple imputation analyses, assuming that data were missing at random. We assessed the effect of imputation on the findings by performing complete case analyses, which showed findings which were very similar to those found when imputation was used, thus increasing our confidence in the findings reported. Another potential limitation was the possibility of the same individual being included in two (or three) of the studies. While some communities were included in more than one study, we thought that the probability of the same individual being selected was low, given the differences in inclusion criteria for each study and the fact that households were selected based on a random starting point in the national surveys. It is therefore unlikely that such duplication would have had any meaningful effect on our estimates. Finally, we were unable to use survey weights to adjust for probability of selection of participants in communities as these data were available for only one of the three studies used; however, given the fact that we were more focused on the associations between neighbourhood SES and blood pressure rather than obtaining estimates of population prevalence, we believe that this would have very little effect on our findings. This position is supported by Carle who found that there were only minimal differences, which did not change inferences, when comparing weighted vs. unweighted analyses for multilevel models using survey data .Overall, we believe that the findings in this paper will make an important addition to the literature on the relationship between neighbourhoods and health, particularly in light of its focus on adolescents and young adults in an African origin developing country context. This will serve as a catalyst for further research in this area and will help to inform our strategy for reducing the adverse public health implications of hypertension.We have demonstrated that neighbourhood SES was inversely associated with BP among Jamaican youth and that there were sex differences in these associations. Findings from this study suggest that the neighbourhood context may be an important factor in the aetiology of hypertension and that interventions to address the growing public health challenges resulting from hypertension should include evaluation of neighbourhoods. Further research in Jamaica and similar populations is warranted to improve our understanding of the aetiology of elevated blood pressure and to help in the development of appropriate interventions.10.7717/peerj.10058/supp-1Supplemental Information 1Click here for additional data file.10.7717/peerj.10058/supp-2Supplemental Information 2Click here for additional data file.10.7717/peerj.10058/supp-3Supplemental Information 3Click here for additional data file.10.7717/peerj.10058/supp-4Supplemental Information 4Click here for additional data file.


Laryngeal microsurgery (LMS) is often accompanied by a sudden increase in blood pressure (BP) during surgery because of stimulation around the larynx. This sudden change in the hemodynamic status is not immediately reflected in a casual cuff-type measurement that takes intermittent readings every 3 to 5 min.This study aimed to investigate the potential of pulse arrival time (PAT) as a marker for a BP surge, which usually occurs in patients undergoing LMS.Intermittent measurements of BP and electrocardiogram (ECG) and photoplethysmogram (PPG) signals were recorded during LMS. PAT was defined as the interval between the R-peak on the ECG and the maximum slope on the PPG. Mean PAT values before and after BP increase were compared. PPG-related parameters and the correlations between changes in these variables were calculated.P<.001), whereas PAT decreased significantly  in most of the cases. The change in SBP showed a significant correlation with the inverse of the PAT . Receiver-operating characteristic curve analysis indicated that an increase of 11.5% in the inverse of the PAT could detect a 40% increase in SBP, and the area under the curve was 0.814.BP surged because of laryngoscopic manipulation (mean systolic BP [SBP] from 115.3, SD 21.4 mmHg, to 159.9, SD 25.2 mmHg; During LMS, where invasive arterial catheterization is not always possible, PAT shows good correlation with SBP and may, therefore, have the potential to identify abrupt BP surges during laryngoscopic manipulations in a noninvasive manner. Laryngeal microsurgery (LMS) is often accompanied by a sudden increase in blood pressure (BP) during surgery because of stimulation around the larynx ,2. LarynPulse arrival time (PAT), measured as the interval from the R-peak on an electrocardiogram (ECG) to the peripheral arrival of the pulse wave, has been used as an estimate for pulse transit time and may be a noninvasive marker for BP -14. ReceWe previously reported that beat-to-beat changes in PAT can effectively detect decreases in systolic BP (SBP) during anesthesia induction in hypertensive patients undergoing renal transplantation . HoweverWe retrospectively analyzed the electronic records of 30 patients with vocal cord polyps or edema who were scheduled for an elective LMS under general anesthesia. Patients with cardiac arrhythmias or incomplete data were excluded.2 using a multiparameter monitor . All data were recorded simultaneously throughout the procedure. Volatile induction and maintenance of anesthesia were performed. Anesthesia was induced with 6% to 8% sevoflurane and rocuronium (0.5-1 mg/kg) and maintained with 2% sevoflurane and 50% nitrous oxide in oxygen.All patients were prepared for general anesthesia according to our institutional protocol. Premedication was not given. Cardiovascular medication, including antihypertensive medication, was administered until the day of surgery, except for angiotensin II receptor blocker or angiotensin-converting enzyme inhibitor. Routine monitoring included noninvasive intermittent BP (NIBP), ECG, pulse oximetry, and end-tidal concentration of CO50 (width at 50% height of each PPG wave peak), maximum slope, minimum slope, and area of each wave peaks [ECG and photoplethysmogram (PPG) waveform data were recorded with data acquisition software   at a samve peaks . These ft test or Wilcoxon signed-rank test was used to compare parameters before and after LMS. The correlation between the changes in BP and PAT and between the changes in BP and PPG-related variables at all time points were evaluated with a Pearson correlation coefficient or Spearman correlation coefficient, as appropriate. Receiver operating characteristic (ROC) curve analyses were performed to evaluate the ability of PAT and PPG-related variables to detect a 40% change in the SBP. R version 3.4.2 software  was used for all statistical analyses.All study data are presented as mean (SD), n (%), or median (IQR). A Shapiro-Wilk test was used as a test of normality. A paired This study was approved by the institutional review board at Asan Medical Center . The requirement for written informed consent was waived because of the retrospective nature of the study and the anonymity of the biosignals used in this study.All data generated or analyzed during this study are included in this published paper and After data processing, 60 sets of BP, ECG, and PPG values were analyzed. The demographic data of study patients are presented in r=0.582; 95% CI 0.281-0.779) than with changes in either mean arterial pressure  or diastolic BP . However, these differences in correlation coefficients were not statistically significant when compared with the coefficient between changes in the inverse of PAT and SBP using Fisher Z-transformation .During the abrupt BP rise because of laryngeal stimulation, changes in the inverse of the PAT showed better correlation with the changes in SBP . SBP changes also showed a good correlation with changes in the inverse of PAT  of 0.814 , whereas the model that used changes in the maximum slope of PPG showed an AUC of 0.679 . The combined ROC curve using the changes in both 1/PAT and PPG maximum slope showed an AUC of 0.819 (95% CI 0.650-0.988), which was not significantly different from the model with 1/PAT alone (Delong test, z=−0.114; We found that beat-to-beat PAT measurements using ECG and PPG are useful noninvasive indicators of BP surge in patients undergoing LMS. Specifically, changes in the inverse of the PAT and systolic NIBP show similar trends, and the inverse of the PAT changes shows a better correlation with the systolic NIBP changes than with those in the MAP or DBP. Moreover, beat-to-beat changes in the PAT reflect the BP surge 1 to 2 min earlier compared with cuff-type NIBP measurements.Laryngoscopic manipulation in our study is clinically similar to the endotracheal intubation phase in our previous study . PAT didAlthough changes in the maximum slope of the PPG showed a correlation with SBP changes, it did not increase the AUC of the ROC curve when it was combined with 1/PAT changes. Rather, the change in the 1/PAT value alone was sufficient to detect a 40% or greater change in the SBP, and the AUC of the ROC curve (AUC 0.814; LMS is a hemodynamically challenging procedure for anesthesiologists. Laryngoscopic manipulation and suspension of the larynx cause plasma catecholamine levels to rise and induce hemodynamic perturbation, including hypertension, tachycardia, bradycardia, and arrhythmias ,23-27. TDuring different surgical procedures, various kinds of biosignals can be used to monitor abrupt physiological changes or to predict outcomes. PPG signals, in particular, can be used to reflect various physiological changes such as vascular compliance during hepatic graft reperfusion period following liver transplantation  and the There were some notable findings from this analysis. First, we found that BP changes could be detected 1 to 2 min earlier with PAT than with NIBP, suggesting that PAT monitoring will facilitate earlier responses to BP changes than NIBP monitoring alone. Second, changes in PPG maximum slope also correlated with SBP changes. It is noteworthy that a feature of the PPG waveform alone correlates with BP, regardless of other signals, such as ECG. On the basis of the results of this study, we developed a built-in device, which is able to monitor BP surge using ECG and PPG signal in a continuous and noninvasive manner . Now we P values because both measurements have different scales and wide ranges of interpatient variability when they are converted to each other. Finally, as we conducted a retrospective analysis, selection bias or unknown confounders cannot be excluded. Well-designed prospective analyses and further device evaluation are warranted in the future.Our study has several limitations of note. First, we used PAT measured by ECG R-wave and PPG signal to estimate actual pulse transit time, which should be measured by the time delay between arterial waveforms from two different places. Although the measurement of PAT is noninvasive and is technically easy to perform at low cost, it has been suggested that the PAT may not be a proper surrogate for the correct pulse transit time ,38. To cThere is a clear correlation between BP and PAT, which demonstrates the potential of PAT as a useful and noninvasive means of continuous BP monitoring in situations where invasive monitoring is not appropriate. Further studies to adjust for confounding factors are needed to refine the BP-monitoring approach using PAT.


With advancing age, increased femoral vascular resistance positively correlated with aortic PWV and AIx (p < 0.01). No significant difference in endothelium function and arterial compliance for femoral and small peripheral arteries was observed between young and middle-aged groups. The serum Klotho levels were lower in young and higher in middle-aged pigs (p < 0.001), and a positive correlation was found between Klotho and aortic PWV, AIx, and femoral vascular resistance (p < 0.01). Our findings suggest that early-aged aortic stiffening has adverse effect on peripheral hemodynamics, independent of blood pressure levels. Elevated Klotho secretion was associated with increased aortic stiffness and peripheral vascular resistance with aging.The anti-aging function of Klotho gene has been implicated in age-related diseases. The physiological importance of Klotho in the progression of arterial stiffness with aging, however, remains unclear. The goal of this study is to determine the correlation of circulating Klotho with early age-related aortic stiffening and peripheral hemodynamics. We measured serum Klotho levels in a group of pigs with age ranges of 1.5–9 years and investigated the relationship between Klotho levels and biomarkers of aortic stiffening with aging, including aortic pulse wave velocity (PWV), augmentation index (AIx), and pulse pressure (PP). The effects of aortic stiffening on peripheral vascular resistance, compliance, and function were also evaluated. We found that increased aortic stiffness occurred at middle age (>5 years old), as evidenced by an increase in PWV and AIx ( It is well known that aging is a potent, independent risk factor for cardiovascular disease . In respKlotho gene was originally identified as an anti-aging protein, which encodes a single-pass transmembrane glycoprotein . It is pIn this study, we chose swine as the experimental subject since swine is considered an ideal preclinical model due to the anatomical and physiological similarities in the cardiovascular system between swine and human . We measn = 18) with age ranges of 1.5–5 years and a middle-aged group (n = 18) with age ranges of 5.5–9 years (defined as middle age according to a life span of 15 years for Yucatan miniature swine). All animals were fed a standard swine diet  twice daily, and the amount of diet provided was 1% of the body weight of the pigs. All animal experiments were performed in accordance with national and local ethical guidelines, including the Institute of Laboratory Animal Research guidelines, Public Health Service policy, and the Animal Welfare Act, as approved by the Institutional Animal Care and Use Committee at California Medical Innovations Institute, San Diego.A total of 36 female Yucatan miniature pigs were divided into a young group (2 was provided with a respirator and maintained PCO2 at approximately 35 mmHg. Under fluoroscopic guidance (Philips Fluoroscopy System), an introducer sheath (6 Fr) was percutaneously inserted into the jugular vein for administration of 0.9% saline and heparin (100 IU/kg). A sheath (5 Fr) was used to introduce a catheter into the aortic arch  via the carotid artery. Another sheath (5 Fr) was used to introduce a catheter into the abdominal aorta  via the right femoral artery. Those catheters were connected to a pressure transducer . The thoracic (aorta arch) and abdominal aortic blood pressure waveforms were recorded from these two locations simultaneously during the procedure. The femoral blood pressure waveform was also recorded with a catheter placement at the left femoral artery via an introducer sheath (4 Fr).Pigs were fasted for 12 h prior to surgery and pre-anesthetized with TKX . Pigs were then anesthetized with 2–3% isoflurane inhalation. Ventilation with 100% OPulse wave analysis was applied to determine aortic stiffness. PWV calculation is based on the difference in arrival times of the pressure wave at the proximal (aorta arch) and distal  locations. Since the tips of pressure catheters placed on the proximal and distal sites are visible on radiographs, the propagation distance was obtained by measuring the distance between the two catheters. PWV (m/s) was calculated by dividing the propagation distance by the difference between the two arrival times (transit time). AIx is expressed as the difference between the second and first systolic peaks of central aortic waveform calculated as a percentage of PP.The measurement of femoral blood flow velocity was obtained in all animals using an iE33 duplex ultrasonography  equipped with L15-7 transducer. The mean velocity waveforms were recorded continuously for 6 s for further analysis. The diameter of the femoral artery was also recorded by B-mode imaging. According to the flow velocity waveforms, femoral flow volume (ml/min) was calculated from the time-averaged mean flow velocity and the arterial diameter. Femoral vascular resistance (mmHg/ml/min) was calculated by dividing the mean arterial pressure by the flow volume. After flow measurement, the femoral artery and a small peripheral artery  were harvested for endothelial function and mechanical testing. Animal was then euthanized with a saturated solution of potassium chloride injection through the jugular vein to arrest the heart under deep anesthesia.4, 1.17 MgSO4, 2.79 CaCl2, and 5.5 glucose, solution gassed by 95% O2 plus 5% CO2). Both vessels segments were stretched to in situ length and preloaded at the physiological pressure of 80 mmHg. The pressure and external diameter were measured with a pressure transducer  and a digital diameter tracking , respectively. The vessel segment was pre-constricted with phenylephrine (PE) by a series of doses (10−10–10−5 mol/L in the PSS), and then relaxed with acetylcholine (ACh) by a series of doses: 10−10–10−5 mol/L. The endothelium-independent relaxation to sodium nitroprusside  was measured to verify the sensitivity of vascular smooth muscle to nitric oxide (NO). The overall contractility of vessel was tested with potassium chloride (KCl) at 60 mmol/L. Contraction was expressed as percentage of the response to KCl. Relaxation was expressed as percentage of pre-contraction to PE.An isovolumic myograph was used to evaluate the endothelium-dependent vasorelaxation . Briefly2+ free HEPES-PSS. The arterial segment was preconditioned with five cyclic changes in pressure from 0 to 180 mmHg. The pressure was then increased in 20 mmHg step increments from 20 to 180 mmHg in a staircase manner. The passive pressure (P)-diameter (D) relation was recorded. The lumen cross-sectional area (CSA) was computed from the lumen diameter (D), as CSA = πD2/4. The area compliance (CCSA) of the artery was determined by the slope of the pressure-CSA relationship, i.e., CV = ∆CSA/∆P as described in a previous publication  tubes for all experimental pigs. After centrifugation at 5,000 rpm and 4°C for 15 min, serum was immediately separated and stored at −80°C until analysis. The circulating level of Klotho in the serum was measured by a Klotho ELISA kit  according to the manufacturer’s guideline.t-test or one-way ANOVA. Multiple linear regression analysis was used to estimate the correlations between age and the study variables. Spearman’s correlation test was used to estimate the correlations between Klotho level and the study variables. Significant differences between the dose-dependent groups for endothelial function testing were determined by two-way ANOVA. The results were considered statistically significant when p < 0.05 (2-tailed).Results were shown as mean ± standard error of mean (mean ± SEM). Statistical analysis was performed using SigmaStat . The significance of the differences between young and middle-age groups was evaluated by either p < 0.001) by using linear regression analysis. Aortic PWV and AIx was significantly increased in middle-aged group as compared to young group (p < 0.001). No correlation was found between blood pressure and PP with age (data not shown).The mean age, body weight, hemodynamic parameters, and serum Klotho level were presented and compared between young and middle-aged groups in p < 0.01), whereas mean flow was significantly decreased (p < 0.01) in middle-aged as compared to young group. A linear relationship was observed between femoral vascular resistance and mean flow with age (p < 0.001). With regards to aortic stiffness, aortic PWV, and AIx were positively correlated with femoral vascular resistance (p < 0.01) and negatively correlated with femoral mean flow (p < 0.01) as shown in There was no significant difference in PP, SBP, DBP, and MAP in the femoral pressure measures between young and middle-aged groups . No diffCompliance of arteries was presented as the pressure-cross-sectional area (P-CSA) relationship of the femoral artery and small peripheral artery. Although the middle-aged group has lower values of CSA compliance in both femoral and small peripheral arteries as compared to the young group , the difp < 0.001). The Spearman’s correlation test confirms that the serum Klotho level was positively correlated with age within the age ranges of 1.5–9 years (p < 0.001). There was a significantly positive correlation between serum Klotho levels and PWV (p < 0.001) and AIx (p = 0.001) as shown in p < 0.001), but slightly inversely correlated with femoral flow (p = 0.005). There was no apparent correlation of Klotho levels with aortic and femoral blood pressure and PP (data not shown).ex-vivo PE pre-contractile endothelium-dependent vasorelaxation. No significant difference in the vascular contractions to PE for both femoral and small peripheral arteries was observed between young and middle-age groups as shown in p = 0.08, −5 mol/L between young and middle-aged groups for both arteries  aortic PWV and AIx had a significant positive correlation with age in a group of pigs 1.5–9 years old; (2) mean aortic and femoral blood pressure, and PP did not differ between young (≤5 years) and middle age (>5 years) groups; (3) with advancing age, increased femoral vascular resistance, and decreased femoral flow were associated with aortic stiffening but with no changes in femoral endothelium function and arterial compliance; and (4) serum Klotho levels were lower in young and higher in middle-aged pigs, and positively correlated with aortic PWV, AI, and femoral vascular resistance.Age-related arterial stiffening has emerged as an independent risk factor for cardiovascular events, including hypertension , myocardTo answer the question of whether early aortic aging affects the hemodynamics of peripheral vasculature, we measured the vascular resistance, mean flow, and arterial compliance of femoral artery (average of 4.04 ± 0.3 mm in diameter range 3.2–4.8 mm) for all experimental pigs. We also measured the arterial compliance of small peripheral artery (average of 410 ± 30 μm in diameter range 308–520 μm). In a previous large community-based population study, without established hypertension or advanced vascular disease, a modest rise in forearm vascular resistance was reported to be related to increased aortic stiffness . Here, wp = 0.08). There are emerging data that aortic stiffening may trigger remodeling, rarefaction, or hypertrophy in the microcirculation, leading to increased peripheral vascular resistance to blood flow  may be an early manifestation of aging. More research is required to investigate how Klotho interacts with the mechanisms of arterial stiffness in old swine. These studies serve as fundamental reference for the swine translational model in understanding human disease and testing of potential therapeutics.The raw data supporting the conclusions of this article are available on request to the corresponding author.The animal study was reviewed and approved by Institutional Animal Care and Use Committee at California Medical Innovations Institute, San Diego.XG conducted the experiments. XG collected and analyzed the data. XG and GK designed the experiments and revised the manuscript.GK is the founder of 3DT Holdings. GK had the involvementwith the study design and preparation of the manuscript.The remaining author declares that the research was conducted in the absenceof any commercial or financial relationships that could be construed as a potentialconflict of interest.