Kidney transplant improves patients’ survival and quality of life. Worldwide, concern about the equality of access to the renal transplant wait-list is increasing. In Iran, patients have the choice to be placed on either the living or deceased-donor transplant wait-list.n = 217 (52.2%) from living donors and n = 199 (47.8%) from deceased donors). Subjects were recruited from four referral kidney transplant centers across Tehran, Iran, during 2016–2017. The primary outcome was to identify the psycho-socioeconomic factors influencing the selection of type of donor (living versus deceased). Secondary objective was to compare the outcomes associated with each type of transplant. The impact of psycho-socioeconomic variables on selecting type of donor was evaluated by using multiple logistic regression and the effect of surgical and non-surgical variables on the early post-transplant creatinine trend was assessed by univariate repeated measure ANOVA.This was a prospective study performed on 416 kidney transplant recipients (p = 0.023), psychological status based on general health questionnaire (GHQ) , and lower monthly income . The waiting time was substantially shorter in patients who received kidneys from living donors (p < 0.001). The early post-transplant creatinine trend was more desirable in recipients of living donors , patients with an ICU stay of fewer than five days , and those with less dialysis duration time . Post-operative surgical outcomes were not different across the two groups of recipients (p = 0.08), however, medical complications occurred considerably less in the living-donor group (p = 0.04).Based on standardized coefficients, the main predictors for selecting living donor were academic educational level (adjusted OR = 3.25, 95% CI: 1.176–9.005, Kidney transplant from living donors was associated with shorter transplant wait-list period and better early outcome, however, inequality of access to living donors was observed. Patients with higher socioeconomic status and higher level of education and those suffering from anxiety and sleep disorders were significantly more likely to select living donors. Currently, there is a global concern regarding inequality of access to the renal transplant waiting list . SocioecIn Iran, patients in need of kidney transplants are placed on two separate wait-lists, based on the type of donor they select, living versus deceased donors. Thus far, studies have provided evidence that the outcome of living-donor transplant is superior to receiving kidneys from deceased donors –9. This Several factors contribute to this preference including psychological and socioeconomic factors. Among psychological variables, anxiety and depression pose unique challenges in the course and prognosis of a disease, as well as its management –14. The Although Iran was the first country to establish a living unrelated donor program in 1988 and living kidney donation has been performed frequently since then, a multicenter analysis comparing the psycho-socioeconomic status of recipients of living and deceased donors is not yet available –22. MoreThe primary outcome of this study was to identify the psychological and socioeconomic factors which influence the selection of type of donor (living versus deceased). The secondary objectives were to compare the early medical and surgical outcomes associated with each type of transplant, identify predictive factors of early post-transplant creatinine trend (as a marker of kidney function) and also estimate the mean waiting time for each type of kidney transplant while on the transplant wait-list.The center had to be a referral center located in Tehran, Iran.The center had to be a university hospital affiliated to one of the medical universities of Tehran, Iran.The staff of the center had to be willing to participate in this study and cooperate in sample collection.This was a prospective cohort study conducted on patients undergoing kidney transplant regardless of etiology. Patients were recruited from one of the four transplant centers across Tehran including; Labbafinejad hospital, Baqiatallah hospital, Sina hospaital and Modarres hospital, during 2016–2017. Selection of hospitals was based on the following criteria:Eligible subjects included patients aged ≥18 years old receiving a kidney transplant during 2016–2017, in one of the four centers mentioned above. A total of 416 recipients including 217 patients (52.2%) receiving grafts from living donors and 199 (47.8%) receiving deceased-donor transplants were included. The sampling approach was based on a three-month pilot study performed before the initiation of the actual study with the aim to estimate the number of transplants performed in each center and determine the dominant type of transplantation (deceased vs living) in that center. Then, based on probability proportional to size (PPS) sampling, the number of subjects required from each center was calculated. In the next step, sample recruitment started with both types of transplants. When the number of samples of the dominant type of transplant (in each specific center) reached approximately half of the required total sample size, no more samples of this type of transplant were included and recruitment would continue with the less frequent type of donor until the total sample size was reached. This ensured that within a particular timeframe, a proportionate number of living and deceased-donor transplant recipients would be included without intentionally or non-intentionally excluding any cases. Also, the adjustment of the proportion of living and deceased kidney transplant recipients allowed for a more reliable comparison.Medical files and questionnaires were used to collect demographic, psycho-socioeconomic, and clinical data of patients before kidney transplant. Data regarding post-transplant clinical outcome of patients  was collected by an independent investigator on day 1, 3, 5, 7, and 11 after transplant and eventually on the day of discharge based on history taking, physical examination, lab data, imaging and medical records. The indicators of socioeconomic position included employment status, health insurance, financial support, pre-dialysis income and education level of recipients one year before dialysis start. Time to kidney transplant was defined as time from placement on the waiting list to the date of the transplant. Income was calculated as individual (after-tax) disposable income including from work and benefits and was categorized according to the consensus of the Iranian Ministry of Cooperative, Labor, and Social Welfare. Financial support was considered as any financial assistance from family, relatives, or non-governmental organizations.The translated General Health Questionnaire-28 (GHQ-28) was used for assessing mental symptoms and psychosocial well-being of the recipients . Accordip-values. Also, the importance of variables was determined by computing the standardized coefficient. Univariate repeated measure ANOVA assessed the effect of surgical and non-surgical variables on the early post-transplant creatinine trend. Subsequently, variables with a p-value less than 0.05 entered the multivariable generalized estimating equation (GEE) model. Finally, to identify predictive factors on the difference between serum creatinine before transplant and on the day of discharge, multivariate linear regression analysis was performed. All statistical analysis was performed using the SPSS software version 14.0  and also the ‘reghelper’ package in R software. P-value less than 0.05 was considered statistically significant.Continuous variables were presented as mean (standard deviation) and categorical variables were reported as frequencies (percentage). The independent t-test or Mann-Whitney were used to examine the association between quantitative variables, and Chi-Square or Fisher’s Exact test were used for assessing categorical variables. The impact of psycho-socioeconomic variables on selecting the type of donor were evaluated using the multiple logistic regression with backward approach. Results are reported as odds ratio (OR) with 95% confidence interval (CI) and Written informed consent was obtained from participants before being enrolled in the study. The Ethics Committee of the Urology and Nephrology Research Center of Shahid Beheshti University of Medical Sciences (ethics code: UNRC.SBMU.931223.1) approved this study.n = 248) were male. There was no statistically significant difference between the two groups of recipients in terms of gender (p = 0.34). The mean age of the patients transplanted with living and deceased donors was 42.56 (SD = 15.87) and 40.45 (SD = 16.0) years old, respectively (p = 0.13). The mean duration of dialysis was 14.7 (SD = 17.1) months in recipients of living and 17.9 (SD = 22.6) months in recipients of deceased donors (p = 0.11). Also, the mean wait-list period for kidney transplant was significantly shorter in recipients of living compared to deceased kidney donors .Analysis was conducted on 416 recipients. Among the total participants, 68% . Regarding the four main areas covered by the GHQ-28 questionnaire [p = 0.044), while more patients receiving transplants from deceased donors suffered from depression symptoms (p = 0.045). Among the two distinct concepts of physical and mental health measured by the SF-36 questionnaire [p = 0.435 and p = 0.788, respectively). Also, there were no difference between social support of the family, friends and significant others in the two groups of recipients based on the SSQ questionnaire. Table As shown in Table 1ionnaire , anxietyionnaire , there wThe results of unadjusted analyses to determine predictive factors of donor type selection are presented in supplementary Table ). Post-operative clinical status of all recipients including medical and surgical outcomes and laboratory tests is presented in Table p = 0.08), however, medical complications occurred considerably less in the living-donor group (p = 0.04).The most common reasons for receiving kidney transplant among the total population were hypertension and diabetes mellitus   (Table p = 0.027). Moreover, patients who were on peritoneal dialysis experienced less improvement in post-transplant serum creatinine level compared to those without a history of dialysis, although this difference was not statistically significant (p = 0.076).In addition, the effect of non-surgical and surgical variables on the early postoperative creatinine trend was investigated Figs.  & 2. TheIn this study, we investigated the role of patients’ socioeconomic and psychologic condition on electing deceased or living donors. Our results revealed that patients with higher education and income tended to receive transplants from living donors more frequently. This was similar to the majority of studies showing that access to the kidney transplant waiting list is affected by higher level of education and socioeconomic deprivation –4, 30–32-donor transplant, since the donor who is either a relative or someone with an altruistic motive for donating is usually known to the recipient, somewhat different experiences have been reported [Generally, kidney transplant candidates are prone to significant psychological distress in the transplant wait-list period. Previous studies have shown that dialysis patients anticipating deceased-donor transplant suffer from anxiety and depression during the transplant wait-list period . Depressreported . Thus, treported . The finreported . There hreported , 19.In general, early post-transplant surgical complications are classified into three groups: vascular, urologic, and others. Vascular complications remain the major concern after kidney transplant with a reported incidence of 2 to 15%. In a study by Ayvazoglu Soy et al., the incidence of vascular complications on 2594 kidney transplants (76% living donors and 24% deceased donors) was 2.1% , with thAccording to previous studies, risk factors of failure to reduce early post-transplant serum creatinine level include gender, BMI, type of dialysis, duration of dialysis, length of ICU stays, cold and warm ischemia time, and type of donor –42. Our Ours study also estimated the waiting time for kidney transplant in recipients of living donors (7.05 months) to be significantly less than that of deceased donors (11.27 months). Also, it seemed that living donor transplant in Iran renders less waiting time compared to other countries, possibly due to the active living donor program and high rate of deceased donation. The transplant waiting time in the USA is almost 4.72 years for recipients of deceased donors and in European countries, this time is about 2 to 5 years . HoweverAlthough this was not the intention of our study, we found that hypertension and diabetes mellitus were the most common factors attributing to end-stage renal disease (ESRD) in our study population. In line with this finding, the United States Renal Data System (USRDS) has reported diabetes mellitus and hypertension as the major causes of , followed by glomerular diseases (14%) . HoweverOur socioeconomic data was based on self-reported questionnaires which may have been inaccurately reported.The reported psychological status of patients might be affected by the method of assessment, for example, results might have been different based on the person who interviewed the patients . In this study, the psychological questionnaires were filled in by an independent blind interviewer who were medical staff.Some outcomes required a greater number of patients to reach a more precise conclusion. For example, vascular complications are not common, thus for a better comparison of this outcome in the two groups of recipients, a larger sample size would have been beneficial .Data about human leukocyte antigen (HLA) matching was missing in our study. Since HLA- mismatch affects the outcome of transplant and the post-transplant creatinine trend, we could not reach a definite conclusion in this regard .There were some limitations to our study:This study reveals novel information about the existing psycho-socioeconomic disparities in Iran in terms of access to type of donor and the medical and surgical outcomes associated with each type of transplant. In summary, higher educational level, higher monthly income, and suffering from anxiety and sleep disorders (based on the GHQ-28) influenced the choice of selecting a living-donor transplant, which came with the benefit of less waiting time and better early post-transplant creatinine trend. Moreover, although post-operative surgical outcomes were not different across the two groups of recipients, medical complications occurred considerably less in the living-donor group. However, since the results associated with outcome of transplant might change over time in both groups, follow-up of these patients would be beneficial. Also, future studies to compare the psychological status of these two group of recipients after transplantation is recommended.The findings of this comprehensive multicenter study will provide evidence for policymakers to implement strategies and specific actions for providing support to susceptible individuals who are either socioeconomically or psychologically less advantaged. Hopefully, this will allow for an equal opportunity to choose between living or deceased-donor transplant.Additional file 1: Supplementary Table 1. Univariable logistic regression to determine predictive factors for selecting type of donor.


We have designed a study to test whether PP and EtCO2 were efficient for the monitoring of NCO during VA-ECLS.Veno-arterial extracorporeal life support (VA-ECLS) results in cardiopulmonary shunting with reduced native cardiac output (NCO). Low NCO occurrence is common and associated with risk of thromboembolic and pulmonary complications. Practical tools for monitoring NCO during VA-ECLS would therefore be valuable. Pulse pressure (PP) and end-tidal carbon dioxide  curves.In this prospective single-center observational study, patients who underwent a VA-ECLS for cardiogenic shock from January 2016 to October 2017 were included, provided low NCO was suspected by a PP < 20 mmHg. NCO was measured with pulmonary artery catheter or echocardiography and compared to PP and EtCO2 relationships with NCO were nonlinear and showed strong correlations for NCO < 2 L/min (r = 0.69 and r = 0.78 respectively). A PP < 15 mmHg and EtCO2 < 14 mmHg had good predictive values for detecting NCO < 1 L/min .Among the 106 patients treated with VA-ECLS for cardiogenic shock during the study period, 26 were studied, allowing the collection of 196 study points. PP and EtCO2 may offer an accurate real-time monitoring of low NCO events during VA-ECLS support. Further studies are needed to show if their utilization may help to implement therapeutic strategies in order to prevent thromboembolic and respiratory complications associated with VA-ECLS, and to improve patients’ prognosis.PP and EtCONCT03323268, July 12, 2016 Peripheral veno-arterial extracorporeal life support (VA-ECLS) for severe acute cardiac failure is increasingly used in patients with refractory cardiogenic shock (CS) or persistent cardiac arrest, either as a bridge to myocardial recovery, or to cardiac transplantation, or to long-term mechanical circulatory support –3. Howev2) follows changes in cardiac output, provided CO2 production and removal are stable ) were compared with Student’s 2 with NCO were assessed graphically. The relationships of pulse pressure with stroke volume and PaCO2-EtCO2 gradient with NCO were studied to consider heart rate and PaCO2 confounders respectively. As these analyses showed nonlinear links for some variables, they were fitted in a regression model using a cubic spline ). Forty-seven (24%) of the study points were recorded while left VAD support was running (= missing data for pulse pressure), with a similar proportion between Th-NCO events and other study points  Th-NCO episodes were collected, mainly during the first hours (1 h [0–15]) of VA-ECLS. NCO ≥ 1 L/min study points (6% Th-NCOEighteen (69%) patients presented at least one episode of Th-NCO and 13 (50%) had Th-NCO at the first measurement. Respiratory and hemodynamic variables according to NCO < or ≥ 1 L/min are reported in Table p < 0.001 with positive coefficient), which means that the model fitted better for lower NCO values. A similar relationship was observed between PP and stroke volume, with the spline regression model error significantly increased with NCO (p < 0.001)  Fig. b.Fig. 2Since the relationship between PP and NCO < 2 L/min was covering the NCO values of interest, we also tested a linear fitting, which showed a correlation coefficient of 0.694 [CI 0.570–0.786].2 relationship with NCO also described a nonlinear regression curve. The spline regression model error increased significantly with NCO (p = 0.01 with positive coefficient), which means that the model fitted better for lower NCO values. Indeed, linear fitting between EtCO2 and NCO < 2 L/min found a correlation coefficient of 0.779 [CI 0.683–0.848].As shown in Fig. 2 and NCO (p = 0.15 and p = 0.1 for V/Q ECLS and V/Q lung respectively).Of note, uneven V/Q ratios at lungs and membrane did not affect the relation between EtCO2-EtCO2 gradient but in the opposite direction to EtCO2 .The best cut-off values for predicting Th-NCO were 14.5 mmHg for PP  and 13.5 mmHg for EtCO2 cut-off values are shown in Fig. 2 than for PP .ROC curve analysis of PP and EtCO2 are strongly correlated with NCO when it is lower than 2 L/min. PP < 15 mmHg and EtCO2 < 14 mmHg predicted Th-NCO (NCO < 1 L/min) with good accuracy. Monitoring these parameters may help to prevent the risks associated with low NCO during VA-ECLS.This prospective study shows that, during VA-ECLS, PP and EtCOn = 38, 75%) occurred afterwards, despite global NCO improvement over time.In the early phase of cardiovascular assistance in the case of severe CS, VA-ECLS is devoted to the restoration of blood flow to organs, a vital issue in avoiding multiple organ failure and death . TherefoNot surprisingly, Th-NCO was associated with higher VA-ECLS flow, lower blood and pulmonary artery pressures, stable heart rate, and higher inotropic and vasopressor support Table , a hemodIn this respect, ELSO guidelines recommend the use of a PAC to maintain mean PAP > 30 mmHg, echocardiography to avoid non-opening of the aortic valve, and continuous arterial monitoring to track the non-pulsatile arterial line . PAC is A continuous monitoring of the arterial pressure line can evidence loss of pulsatility, and echocardiography may then confirm absence or rare openings of the aortic valve. The loss of pulsatility is associated with blood stasis and a high incidence of stroke (41%) . However2 appears as a very pertinent parameter, even when PP is not reliable. EtCO2 monitoring is a routine and non-invasive measure in ventilated patients. Recent studies have found a correlation between NCO and EtCO2 in patients requiring LV venting during VA-ECLS [2 correlated strongly with NCO when < 2 L/min, and even that EtCO2 tended to have a better ability than PP to predict Th-NCO. This result corroborates Bachman and coworkers’ study, which showed in an experimental model of VA-ECLS that the variation of CO2 elimination from the lungs correlated strongly with the variation of pulmonary blood flow [2 was measured as a control of effective CO2 removal by both lungs and ECLS. Owing to the facts that PaCO2 was in normal range and that sweep gas-to-blood flow ratio at ECLS as well as ventilator settings were unchanged, the EtCO2 changes followed the NCO quite well at low NCO levels. Indeed, in physiological conditions, when CO2 production is stable, the venous return allows CO2 transport to the lung where CO2 is removed from the blood through the regulation of pulmonary gas exchanges. EtCO2 is closely related to PaCO2, and the PaCO2-EtCO2 gradient is low (3–5 mmHg) [2 decrease, with parallel increase of PaCO2-EtCO2 gradient, while CO2 production or gas exchanges are unchanged, reflects quite directly a decrease in venous return and pulmonary artery flow, generating alveolar dead space [2 removal depends on ventilator and ECLS settings, but even with very low volume ventilation, EtCO2 variation parallels the changes in alveolar dead space related to low pulmonary artery blood flow. In our series, minute ventilation was low , but median PaCO2-EtCO2 gradient was 30 mmHg, i.e., 6-fold the normal range, when NCO was < 1 L/min. The EtCO2 kept going up when NCO increased above 1 L/min but the relation between EtCO2 and NCO curved down significantly when NCO exceeded 2 L/min  . An EtCOad space , 31, 32.Taken together, the two parameters offer a real-time, complementary monitoring method and could guide medical interventions  for NCO optimization in situations of threatening NCO.2. The ventilator and ECLS settings were fixed according to guidelines, which are routinely used in most ECLS centers. A quarter of the measures were made with concomitant left VAD support that induced missing data for PP. However, the association of transient or durable VAD with VA-ECLS is frequent and source of low NCO events. NCO monitoring is crucial in these patients and PP is not reliable. Based on previous observations [Our study has several limitations. It is a single-center nature study with a small number of patients and a strict control of lung and ECLS ventilations, and thus PaCOrvations , we thourvations . Althoug2 are interesting parameters to monitor residual native cardiac output during VA-ECLS, specifically for detecting threatening NCO. Thresholds of PP < 15 mmHg and EtCO2 < 14 mmHg predicted NCO < 1 L/min with good accuracy. Further studies are needed to show if their utilization may help to implement therapeutic strategies in order to prevent thromboembolic and respiratory complications associated with VA-ECLS, and to improve patients’ prognosis.The study shows that PP and EtCO


The main aim was to determine the acute responses on lung ventilation, gas exchange, and heart rate during exercise in patients with chronic obstructive pulmonary disease (COPD) with and without the use of FB. In this study, a randomized cross-over trial was performed with 18 men diagnosed with COPD . Each participant randomly conducted two trials with 30 min of rest between them with the same protocol on a treadmill for 10 min at a constant rate of 50% of VO2peak. Each test was performed randomly and in a crossover randomized design in two different conditions: (1) oronasal breathing; and (2) nasal breathing with FB . It was observed that FB had positive effects on dynamic hyperinflation, breathing pattern, and breathing efficiency, with higher expiratory and inspiratory time. Despite these differences, blood oxygen saturation percentage, oxygen uptake, and heart rate showed a similar response for both conditions during exercise. The results suggest that exercise performed with FB improved ventilatory responses compared to the oronasal mode in COPD patients. This new tool could be used during most daily tasks and exercise programs.A device called FeelBreathe (FB) Imax) and perception of well-being in COPD patients [Chronic obstructive pulmonary disease (COPD) is a pulmonary disorder characterized by the presence of inflammation, producing obstruction of the airways, deterioration of the quality of life, dyspnea, and intolerance to physical exercise , due in patients , and heapatients ,5. The mpatients , althougpatients . New comA nasal ventilatory flow restriction device called FeelBreathe (FB) was designed, developed, and patented to increase nasal airflow resistance . PreviouThe sample size needed was calculated using the G*Power version 3.1 software . Accordi1) between 30% and 70% of the predicted value, according to the criteria of the ATS [1 below 30% cannot perform the tests due to their clinical situation. Key exclusion criteria included COPD exacerbations that required treatment with antibiotics or oral steroids or hospitalization in the 8 weeks prior to inclusion, other medical conditions that contribute to dyspnea on exertion, or diseases that may interfere with the realization of the exercise test. Twenty-two patients were included in the study, although only twenty of them were randomized since two patients could not attend the day of the tests. Moreover, two patients were excluded: one of them due to intermittent claudication of the lower limbs and the other one for not finalizing the test due to disease. Therefore, eighteen patients completed all of the tests .2peak using Balke protocol . While performing the tests, an electrocardiogram and heart rate was measured every 10 s . Additionally, blood pressure was measured at the end of the test. Blood oxygen saturation percentage  and respiratory gas exchange were measured every 5 s and breath by breath, respectively, throughout the test.On the second day, the patients completed a health questionnaire, performed a resting electrocardiogram  and a spirometry  according to criteria published by the ATS . In addition, PImax was measured during a maximal, static inspiratory effort . PImax was recorded as the highest value averaged over 1 s from three maneuvers that varied by less than 10% and was measured based on three maximal reproducible respiratory efforts . Finally2peak on a treadmill after 1 min of warming up at 3 km/h, with 30 min of rest between sets in a sitting position [On the third day, each patient randomly conducted two identical walking exercise tests for 10 min at a constant rate of 50% position . Each teECO2); oxygen uptake (VO2); expiration time (Tex); inspiratory tidal volume (VTin); carbon dioxide production (VCO2); heart rate (HR); end-tidal partial pressure of carbon dioxide (PETCO2); fraction of expired oxygen (FEO2); expiratory time fraction (Tex/Tot); breathing frequency (BF); deadspace/tidal volume ratio (VD/VT); respiratory quotient (RER); ventilatory equivalent ratio for carbon dioxide (EqCO2); ventilatory equivalent for oxygen (EqO2); end-tidal partial pressure of oxygen (PETO2); and minute ventilation (VE).During each walking exercise test, the patients were connected to the gas analyzer with a Hans Rudolph nasal/oral, two-way and non-rebreathing face mask , which covered the subject’s mouth and nose. The inner seal of the mask was removed to ensure that the mask did not impinge on the nares during the tests. For ONB, the patients were asked to breath normally, freely. The following variables respiratory were collected during the walking exercise test: inspiration time (Tin); inspiratory time fraction (Tin/Tot); expiratory tidal volume (VTex); fraction of expired carbon dioxide  and those with higher values in the ONB trial . The proportion of responders and non-responders was calculated for each of the cardioventilatory variables using the typical error (TE) [Imax and rating of perceived exertion (RPE) post-tests were analysed by t-test for paired samples. The values of the cardioventilatory variables obtained from the maximal incremental exercise tests were analysed using Bayesian functional ANOVA [2 and VCO2 were log-transformed to compute the Bayesian functional ANOVA, thus the results of these variables are shown in log-scale. All the analyses were performed with the R software environment for statistical computing [https://github.com/JorgeDelro/COPD_1.3.Descriptive results are presented as mean ± standard deviation. Before any analysis, the cardioventilatory variables were classified according to our expected hypothesis as those with higher values in the FB trial  , and it al ANOVA . Since w of INLA . Once th of INLA , which iomputing  and can Imax and Borg’s scale recorded after the submaximal tests are displayed in p < 0.01, Cohen´s d = 0.61).The descriptive characteristics of the sample, pulmonary function, P2 and VCO2, which had differences only at the beginning of the test. The results showed that breathing patterns were more efficient when the tests were performed with FB compared to ONB.The Bayesian functional ANOVA results for each of the cardioventilatory variables are displayed in 2 were the variables with higher and lower proportion of responders respectively (72.2% and 11.1%). Additionally, the percentage of change by participants for each of the variables are displayed in The means, standard deviations and proportions of responders and non-responders for the cardioventilatory variables are shown in p < 0.05). Moreover, the variables related to breathing pattern  obtained responders in more than 44% of the participants, while breathing efficiency  obtained responders in more than 52% of the participants. Finally, the expiratory and inspiratory time  and the parameters of effort intensity (HR and RER) obtained responders in more than 56% and 47% of the participants, respectively.Considering the use of FB during the tests and all the outcomes related to dynamic hyperinflation , the number of responders was over 50% of the participants, but only in Tin was the proportion statistically significant  and RER (12/18 participants). Moreover, the variables Tin/Tot, Tex, BF, EqOThe main finding of the study was that the FB device is a possible effective tool for inspiratory muscle training, since this study shows that FB caused higher expiratory and inspiratory time and increased the efficiency of breathing patterns compared to ONB in a group of COPD patients.F and increased the inspiratory fraction, which may increase the effects of exercise on dynamic hyperinflation and the sense of breathlessness mentioned above [F and minute ventilation E , indicating an improved breathing pattern. In line with the results of Petrovic et al. [F/E in FB compared to ONB during exercise (0.66 versus 0.72). This could be explained by the fact that the patients adopted a slower, deeper breathing pattern during exercise due to the airflow restriction with FB. Moreover, FB causes nasal inspirations and mouth exhalations, improving the humidification, heating, and filtering of the air, as it represents a normal mechanism of heat and moisture exchange in the respiratory tract [Petrovic et al.  observedc et al. , our stury tract .E with FB and a light increase in 2 (2 dynamics (EqO2 and EqCO2) were lower with FB , which means an increase in expiratory effort, despite the fact that the amount of air was higher with FB (+12.5% for VTex), and this situation occurred during the entire test E. SimilaWe observed a significant difference in heart rate between FB and ONB test during the first five minutes I, but no2 and VCO2 kinetics during the test. A possible explanation is that VE in the FB trial was reduced compared to ONB, which could also reduce RER by slight changes on VO2 and VCO2.Differences in RER were observed between FB and ONB A, with l2, as variable of fatigue [2 in FB trial with differences from min 1:35 , so results must be taken with caution. However, there are several recent articles on exercise effects in COPD patients with a similar sample sizes ,37,38,39FB is a new device for training ventilatory muscles during exercise in COPD patients, since it produces lower dynamic hyperinflation and improved breathing patterns and efficiency, with higher expiratory and inspiratory time compared to natural breathing. Our findings provide a new tool that could be used during most daily tasks and exercise with a natural breath and simple shape, unlike other IMT devices.


In chronic kidney disease (CKD), plasma uric acid levels are increased because of the decrease in glomerular filtration rate. However, in addition to CKD, hyperuricemia is frequently associated with a number of other conditions such as hypertension, type 2 diabetes, obesity, and heart failure, overweight, and cardiovascular disease.It is now becoming increasingly clear that, in many clinical conditions, elevated levels of uric acid have a much greater role beyond just causing gout. The present review will summarize current knowledge on the relation between hyperuricemia, CKD, and existing comorbidities, as well as the mechanisms of uric acid–related renal damage. In addition, the role and evidence for urate-lowering therapy in prevention and cardiovascular protection in CKD patients is discussed with a focus on allopurinol and febuxostat. To date, several clinical studies have provided evidence that urate-lowering therapy may help to prevent and delay the decline of renal function in patients with CKD.Use of a xanthine oxidase inhibitor should be considered in patients who are at high renal risk and/or with declining renal function in the presence of hyperuricemia with and without deposition, although additional studies are warranted to define treatment targets. Notwithstanding, the possibility to delay deterioration of renal function in patients with CKD merits consideration. Uric acid is the end product of purine metabolism in humans. Two-thirds of uric acid circulating in the blood is excreted by the kidneys and one-third by the gastrointestinal tract. In the general population, results from the Framingham Heart Study have shown that, with age, serum uric levels remain relatively stable in men, whereas in women, serum uric acid levels gradually increase from the fourth to the seventh decades of life . Thus, tThe prevalence of hyperuricemia can be considered high worldwide. Using data from the NHANES survey 2007–2008, Zhu et al. reported a prevalence of hyperuricemia of 21% in the US general population, and this percentage appears to be increasing over the past two decades . Hyperur2 to 35.6% in those with eGFR < 30 ml/min/1.73 m2 [2 versus 64–78% among individuals with an eGFR between 15 and 29 ml/min/1.73 m2 [There is no doubt that hyperuricemia and gout increase in parallel with declining renal function. In the German Chronic Kidney Disease (GCKD) study, the overall prevalence of gout was 24.3% and increased from 16.0% in those with eGFR ≥ 60 ml/min/1.73 m/1.73 m2 . Numerou/1.73 m2 . The rel/1.73 m2 . In this/1.73 m2 . The pre/1.73 m2 . Hsu et /1.73 m2 . Similar/1.73 m2 . The pos/1.73 m2 . Hyperur/1.73 m2 . Taken t/1.73 m2 , 18–20.2, but not in those with eGFRs < 30 ml/min/1.73 m2, and that there was also a J-shaped curve considering uric acid levels and all-cause mortality. Some studies did not find any association between hyperuricemia and CKD progression. This was the case in the Mild to Moderate Kidney Disease study, in which patients with non-diabetic CKD (n = 177) were followed for a 7-year period and hyperuricemia was not an independent predictor of CKD progression after adjustment for GFR and proteinuria [The relation between uric acid and kidney failure has also been examined in individuals with existing CKD. As one example, Srivastava studied 3885 individuals with CKD stages 2–4 with a median follow-up of 7.9 years . In thatteinuria . In the teinuria .2 with normoalbuminuria and 14.1% had albuminuria with eGFR ≥ 60 ml/min/1.73 m2, while 2.0% had albuminuria with eGFR < 60 ml/min/1.73 m2 [2 increased with uric acid quintiles. Compared with the lowest quintile, relative risk ratios were 1.46, 1.44, 1.95, and 2.61 for the second, third, fourth, and fifth quintiles, respectively. It was thus concluded that mild hyperuricemia is strongly associated with the risk of CKD in patients with T2D.Several studies have also examined the relation between hyperuricemia and the development of CKD in patients with type 2 diabetes (T2D). A longitudinal study of 62,830 of patients with T2D using the database of the Italian Association of Clinical Diabetologists network found that, at a 4-year follow-up, 7.9% of patients developed GFR < 60 ml/min per 1.73 m/1.73 m2 . FurtherIn 2020, Kaewput et al. published the results of a study in almost 8500 patients with T2D and found that uric acid was among the risk factors associated with progression to CKD stage 5 with a hazard ratio of 1.24 per 1 mg/dl increase (95% CI 1.13–1.36) . A meta-The risk of developing hypertension is greater in subjects with hyperuricemia and the risk augments with age. Increased serum uric acid is significantly associated with the development of new-onset primary hypertension in children . In a laHyperuricemia has been further linked to an increased risk for stroke as well as other cardiometabolic risk factors including increased BMI and triglycerides in individuals with T2D . MoreoveHyperuricemia is common in renal transplant recipients . FollowiMultiple mechanisms have been related to renal damage caused by uric acid. The main mechanisms by which uric acid contributes to the development of renal and non-renal diseases have been summarized by Johnson et al. as shown in Fig. Uric acid is known to act as a mediator of hypertension through its effects on endothelial function and impaired production of nitric oxide ••. InitiToday, another hypothesis is arising suggesting that hyperuricemia is a contributor to hypertension, which leads to renal injury . InvestiUric acid has also been found to have a large variety of cellular effects in vitro. Soluble uric acid can enter cells via specific transporters where it stimulates signaling mechanisms that lead to the release of inflammatory mediators, vasoconstrictor molecules, growth factors, and oxidants as well as inducing mitochondrial dysfunction (reviewed in ). It hasOne of the main mechanisms through which hyperuricemia leads to hypertension and CKD may be via activation of the renin-angiotensin-aldosterone system (RAAS) . In thisInnate immune pathways are also increasingly recognized to be important in the pathogenesis of hyperuricemia with deposition, and in particular activation of the NLRP3 inflammasome, which leads to the release of IL-1β and other pro-inflammatory cytokines . The orcIn the German CKD study, only ~ 70% of individuals with self-reported gout were taking gout medications . Hence, A large number of studies have been carried out to investigate the effects of ULT on CKD progression n = 57) or to continue their usual therapy (n = 56); after 24 months, eGFR was decreased by 3.3 ± 1.2 ml/min/1.73 m2 in the control group and by 1.3 ± 1.3 ml/min/1.73 m2 in those treated with allopurinol (p = 0.018). However, the sample size was small, and this single-center study was not double-blind.Twelve randomized clinical studies have examined renal outcomes with allopurinol as ULT in hyperuricemic patients with CKD . The trin = 346), while it did abrogate increases in serum creatinine in 3 trials (n = 130). In another meta-analysis of 19 randomized trials in 992 patients with stage 3–5 CKD, allopurinol was associated with a modestly better eGFR compared with controls (mean difference 3.2 ml/min/1.73 m2) [In 2014, Bose et al. carried out a meta-analysis of 8 trials involving 476 participants, noting that there was substantial heterogeneity in baseline kidney function, underlying causes of CKD, and length of follow-up across studies . It was 1.73 m2) .2; 95% CI, − 1.62 to 6.33), but the difference was not significant. However, among patients with stage 3 and 4 CKD, significantly higher eGFR was found in those treated with febuxostat vs. placebo . The renal benefits of febuxostat were also significant in studies lasting more than 6 months. No significant differences in major complication or death were seen between the febuxostat and control groups. Considering these findings, the meta-analysis concluded that, in addition to lowering serum urate, febuxostat had a reno-protective effect in patients with CKD. The occurrence of renal events in patients with hyperuricemia treated with febuxostat and those treated with conventional therapy with lifestyle modification was also investigated in the FREED trial, a multicenter, prospective, randomized open-label, blinded endpoint study conducted in 141 hospitals in Japan [At least 11 studies have investigated the effects of febuxostat on renal function in patients with CKD •. Among in Japan . A total2 over the course of the study [In the review by Sato et al., clinical trials on ULT in CKD were classified as “interpretable” or “non-interpretable” based on whether the control group also showed evidence (or not) of clinically relevant progression of CKD, considering a threshold value of ≥ 4 ml/min/1.73 mhe study . Of the p < 0.001) and maintained significantly higher mean eGFR values for 4 years. Patients in the febuxostat group also had significantly longer renal survival time free from progression of renal disease than allopurinol and controls .More recently, several authors have compared ULT with either febuxostat or allopurinol in patients with CKD. Interestingly, most trials reported that febuxostat is superior to allopurinol in delaying progression of CKD. A retrospective review of medical records of adult patients was made by Lee et al. in 141 patients with stage 3 CKD and hyperuricemia who openly received either allopurinol or febuxostat and were followed from 2005 to 2018 . Patient2). The proportion of patients showing a ≥ 10% decline in eGFR from baseline at 6 months was also lower with febuxostat 17.9% vs. 34.1%). The retrospective study by Yang involved 83 patients on allopurinol and 233 patients on febuxostat and similarly reported that the long-term eGFR slope was positive in the febuxostat group and negative in the allopurinol group [Zhang et al. investigated the progression of renal impairment in a prospective cohort of 152 CKD stage 2–3 patients with hyperuricemia . In thisol group . Thus, tp < 0.0001). Multivariate Cox analysis showed febuxostat was associated with significant risk reduction for long-term dialysis compared with allopurinol . Considering a composite outcome of long-term dialysis or death, 52.72% of those on febuxostat reached that endpoint compared with 81.92% of those on allopurinol (p < .0001). Moreover, no significant increase in cardiovascular mortality was observed for patients on febuxostat , and febuxostat was associated with a lower risk of myopathy . As discussed above for earlier CKD stages, these interesting observations would need to be confirmed in a randomized controlled study.Lastly, febuxostat has been compared with allopurinol in pre-dialysis patients with stage 5 CKD in a large insurance database analysis from Taiwan in over 6000 patients  [Many studies have found serum uric acid to be an independent cardiovascular risk factor associated with a higher risk of events, although there is some debate about whether this relation is due to its association with established cardiovascular risk factors . In receThere is now increasing evidence to suggest that elevated levels of serum uric acid are associated with both CKD and cardiovascular risk. However, there is large heterogeneity in study designs, endpoints, and baseline characteristics making it very difficult to compare the results of multiple trials and to draw firm conclusions. For example, a recent study in patients with type 1 diabetes and early-to-moderate diabetes kidney disease found that there were no clinically meaningful benefits of ULT on renal outcomes •. AnotheIn a recent expert review, Sato et al. note that as ULT is not approved for treatment of CKD, any treatment decisions must be made following shared discussion with the patient . DietaryRegarding target levels, it has been proposed that ULT should be initiated in patients with serum urate ≥ 7 mg/dl (416 μmol/l), with a target of < 6 mg/dl 357 μmol/l). What should be done in those with intermediate values remains unclear . There i μmol/l. Considerations for the various ULT used with a focus on CKD stages 3–5 are shown in Table There is growing evidence that hyperuricemia with and without deposition is associated with high cardiovascular risk and a decline of renal function. Indeed, there is now an abundance of experimental and clinical data suggesting that hyperuricemia may promote and accelerate kidney damage through several well-understood mechanisms. Many clinical studies have provided support to the hypothesis that ULT may be beneficial in preventing and delaying a decline of renal function in patients with CKD. While the observed discrepancies in the outcomes of clinical trials on ULT in patients with CKD may indicate that not all patients will receive renal benefits of ULT, the discrepancies may also be due to a number of other factors, such as low sample size, short duration of follow-up, and lack of consistent definitions of CKD across studies as well as heterogeneity in study designs. Although current guidelines for management of CKD do not recommend treatment of hyperuricemia in the absence of a diagnosis of gout , there i


Although the precise cause of obstructive sleep apnea (OSA) remains unknown, various anatomical or structural factors are thought to influence upper airway patency. Recent clinical studies show that OSA is frequently observed among patients with fluid‐retaining states, such as heart/renal failure and postsurgery. It is important to note that a cause–effect relationship is not yet established, and our understanding of the effects of fluid overload is limited. The goal of this study was to investigate an animal model that can characterize the physiological changes that occur in response to fluid overload.Acute nonsurvival experiments were conducted in 16 Sprague–Dawley rats. Rats were initially anesthetized by inhaled isoflurane, while the femoral vein was cannulated and urethane (1.2–1.5 g/Kg body weight) was gradually delivered intravenously to induce anesthesia. Additional doses of urethane were delivered as necessary to maintain a surgical plane of anesthesia. A surgical incision was made on the cervical area to catheterize carotid artery to measure blood pressure. A pair of stainless‐steel wires was injected into the tongue to measure genioglossus muscle activity (GGEMG). All physiological measurements were recorded as intravenous infusion of saline was provided to the rat (infusion rate = 22 ml/kg over 30 min).Acute saline overloading resulted in a 33% decrease in GGEMG, when compared to baseline. There was also a gradual drop in the respiratory rate (13% decrease) that reached statistical significance at 10 min after infusion was stopped. The blood pressure exhibited a 14% increase which subsequently returned to baseline within 40 min stopping infusion. There were no significant changes in the heart rate.The results of this study indicate that systemic fluid overload can affect significant changes in different physiological systems including reduction in genioglossus muscle activity, increase in blood pressure, and change autonomic nervous system function. In this study, the effects of acute intravenous saline infusion on multiple physiological parameters—such as respiratory, cardiovascular, and autonomic nervous system—which was conducted in urethane anesthetized rodents were evaluated. Our results showed that “fluid overloading” causes a significant decrease in upper airway dilator muscle activity, which is a characteristic biomarker observed in obstructive sleep apnea patients. Obstructive sleep apnea is a common and serious disorder affecting nearly 1 billion adults aged 30–69 years worldwide  therapy remains the gold standard therapy for treating patients with OSA. Despite the low morbidity and high efficacy of CPAP, up to 85% of patients find it difficult to tolerate  are responsible for movement of the tongue, soft palate, uvula, and pharynx and subserve multiple functions. Essentially, pharyngeal collapse occurs when the normal reduction in pharyngeal dilator muscle tone at the onset of sleep is superimposed on a narrowed and/or highly compliant pharynx. The resulting collapse of the upper airway underscores the interaction of anatomic factors  with neural state‐related factors. Accordingly, a better understanding of the pathogenesis of OSA might lead to new and better treatments.Although obesity is a commonly identified risk factor for OSA, it has been shown that approximately 60% of patients are in fact not obese , arterial blood pressure, heart rate, and heart rate variability. Preliminary results were presented previously in abstract form  within an induction chamber and subsequently maintained with a gas mask . Following completion of all surgical procedures (described below), the anesthesia was transitioned to urethane over a period of 1 hr . Anesthetic depth was monitored throughout the experiment by measuring blood oxygen level (98%–100%), heart rate (300–350 beat/min), respiration rate, and toe pinch. The animal was euthanized at the end of each experiment by intracardiac injection of 0.3 ml/Kg T–61™ .Experiments were conducted in 16 Sprague–Dawley rats . The protocol was approved by the Animal Care Committee at the University of Toronto and in accordance with the regulations of the Ontario Animal Research Act. Anesthesia was induced by inhaled isoflurane  to measure blood pressure (BP). The catheter was connected in series with a pressure transducer  and a syringe filled with the heparinized saline (0.5 IU/ml) that connected to an infusion pump . The heparinized saline and infusion pumped were used to maintain a consistent pressure signal. The signal from the pressure transducer was conditioned with a bridge amplifier unit (ADInstruments) and digitally recorded (sampling rate = 10 kHz) via the data acquisition system . The femoral vein was catheterized with PE‐50 tubing and connected in series with an infusion pump  to provide intravenous (IV) infusion of saline. The electrocardiogram (ECG) was measured by subcutaneously placing needle electrodes (23G × 1″ Needles) in both forepaws and the left hind paw. A pair of unsheathed stainless‐steel wires  was implanted into the genioglossus muscle to measure the electromyogram (GGEMG). Genioglossus muscle to measure the electromyogram signals were conditioned  and digitally recorded . A subcutaneous needle inserted in the lateral abdominal fat pad was used as the common ground.2.3All physiological parameters were measured continuously throughout each experiment. Once the anesthesia was switched to urethane, there was a 1‐hr acclimation period that was followed by the experimental protocol: (a) a 30‐min baseline (preinfusion) period, (b) a 30‐min infusion period , and (c) a 30‐min postinfusion period. The volume of infused saline was selected to achieve a state of fluid overload that was consistent with previous clinical experiments , and processed ) data. Analysis of the GGEMG involved Matlab (Mathworks Inc.), where the raw signal was rectified by applying a triangular Bartlett filter (window width = 300 msec) and then identified as muscle‐related activity with user‐specified adaptive threshold methods . The GGEMG signal was quantified by calculating the area under each detected peak. The respiratory rate was calculated by averaging the time interval between consecutive GGEMG signals within 10‐min windows .The HR was calculated by averaging the time interval between successive R‐peaks within 10‐min windows . Finally, the BP was quantified by calculating the average value within 10‐min intervals .Preprocessing of the RR interval time series and computation of time and frequency domain measures of heart rate variability (HRV) were performed using Kubios HRV software (HRV 3.1.0 software (University of Kuopio)  and a Fourier transform (Welch method) to the RR time series. The computed spectral measures were low‐frequency power (LF: 0.195–0.74 Hz), high‐frequency power (HF: 0.74–2.5 Hz), and the ratio of LF to HF (LF/HF) power . All data values presented were summarized as the mean ± SE.Quantitative assessment of the effects of fluid overload was based on statistical comparison of physiological variables between baseline and subsequent 10‐min intervals, defined within the infusion and postinfusion periods. A one‐way ANOVA was used to test the effect of fluid overload on individual physiological variables with a 95% confidence interval , electrocardiogram (ECG), heart rate (HR), and blood pressure (BP) were measured across three time intervals  or an increase in HR . In the HR− group, the initial baseline HR  decreased to 397.14 ± 10.53 bpm (range: 328.9–430.7) during saline infusion period and then to 387.7 ± 12.5 bpm (range: 321.8–438.8) during the subsequent postinfusion period  which increased to 367.8 ± 19.5 bpm (range: 323–469) and 373.3 ± 17.3 bpm (range: 332.5–463.2) during the infusion and postinfusion periods, respectively  during the infusion and postinfusion periods, but the changes compared to baseline not resulted in significant increase in BP, which reached statistical significance between 20 min and 40 min after infusion started Figure . In contd Figure . In conty Figure . It is n2O), the BP increased rapidly during infusion (128.3 ± 3.6 cmH2O) and remained elevated during the postinfusion period (127.5 ± 4.23 cmH2O). The observed increase in BP reached statistical significance  within 20 min of saline infusion, and remained at this elevated level for 10 min after infusion was stopped. The BP returned to baseline levels within 40 min after stopping infusion (data not plotted here).Acute saline infusion also resulted in an increase in BP across all 16 animals Figure . CompareR2 = .83) and the initial 10 min of the postinfusion period . By the end of the postinfusion period  revealed that saline infusion did not elicit any significant changes, we found there were significant changes in autonomic activity that occurred in the HR− and HR + groups. As shown in Figure − group (time = 30–40 min) and the HR+ groups (time = 10–20 min). In both groups, the SDNN returned to baseline levels within 20 min of stopping infusion. Analysis of the RMSSD , which subsequently returned to baseline by the end of the postinfusion period. Interestingly, this finding suggests that there was an approximately 30‐min delay between saline infusion and vagal‐mediated changes in cardiac function. Analysis of the mean RR interval showed there were no significant changes in either the HR− or HR+ groups (data not shown).Although time‐domain analysis of HRV using all experimental data , along with significant increases in HF power at t = 30 min (102% increase). The change in the LF/HF ratio was not significant  caused a significant decrease in upper airway dilator muscle activity, which is a characteristic biomarker observed in OSA patients  as the BP reached maximum values. Our findings are consistent with previous work which show that increases in blood pressure result in reduced diaphragm activity and total ventilation  along with signs of elevated sympathetic activity (LF/HF ratio) following saline infusion  which was consistent with the observed increase in HR.Another interesting outcome of this study was the identification of HRn Figure  and c. OPossible factors that may account for the differential changes in HR may include variability in the sensitivity to and metabolism of the injected urethane anesthesia among animals. Previous studies show that urethane anesthetized rats exhibit a HR in the range of 320–420 bpm, but dose and route of administration can have significant effects , rats in the HR− group exhibited similar cardiac autonomic regulation in the form of temporal and spectral measures of HRV. This study suggests that our HR− model could potentially be used to investigate the role of HRV in assessing risk stratification for cardiovascular events and mortality in sleep apnea patients. By incorporating upper airway obstructions into our animal model, future work may be able to predict the decreased cardiac vagal modulation that is observed in OSA patients during sleep  but nonsignificant decrease in HR  or fully awake animals—may provide significant insight into the pathological influence of fluid overload in OSA.The authors declare no conflict of interest.P. Sabetian, A. Yadollahi, and P. Yoo: designed and performed experiments, analyzed data, and co‐wrote the paper. P. Sabetian, P. Yoo: performed the experiments and data analysis, drafted the manuscript, and designed figures. A. Yadollahi, P. Yoo: provided essential guidance and aided in interpreting the results. A. Yadollahi, P. Yoo: supervised the research. All authors discussed the results and commented on the manuscript and co‐wrote the paper.


A model for predicting the prognosis of patients with heart failure with reduced left ventricular ejection fraction (HFrEF) is currently not available. This study aimed to develop an age-biomarker-clinical history prognostic index (ABC-PI) and validate it for the assessment of individual prognosis.A total of 5,974 HFrEF patients were enrolled and 1,529 were included in this study after excluding missing values and loss to follow-up. Variables that significantly contributed to prediction of all-cause mortality were assessed by Cox regression and latent trait analysis (LTA) was used to validate discrimination of variables.After Cox regression, the following seven most significant variables were selected: age, N-terminal pro-B-type natriuretic peptide, renal dysfunction, left ventricular mass index, percutaneous coronary intervention, atrial fibrillation, and New York Heart Association (C-index: 0.801 ± 0.013). After verification by LTA, discrimination of these seven variables was proven. A nomogram was used to form the ABC-PI, and then the total score was set to 100 points. A lower score indicated a higher risk. After verification, the 3-year mortality rate was 34.7% in the high-risk group and only 2.6% in the low-risk group.Our novel ABC-PI shows a good performance and does not require re-input in the original model. The ABC-PI can be used to effectively and practically predict the prognosis of HFrEF patients. Heart fPrevious studies on cardiovascular disease often focused on risk score systems to identify the risk of certain events rather than prognosis, such as using scores to predict the risk of bleeding in patients with atrial fibrillation . FurtherLatent trait analysis (LTA), which is a form of latent structure analysis, was first proposed in 1968 . LTA is This study aimed to develop a new age-biomarker-clinical history prognostic index (ABC-PI) and to validate it for predicting the prognosis of patients with HFrEF. Discrimination of the ABC-PI was tested by LTA. This study established a PI using a nomogram that was expected not to require re-input of the original model to achieve the purpose of improving practicability and effectiveness.22.1Patients with HFrEF were enrolled at the First Hospital of Shanxi Medical University and Shanxi Cardiovascular Hospital. The cohort was created in January 2014, and the cutoff date for analyses was August 2019. The inclusion criteria were an age of ≥18 years; diagnosis of HFrEF ; an ejection fraction of <40% or 40–50% with structural heart disease or diastolic dysfunction; and NYHA grade II, III, or IV. The exclusion criteria were the presence of a mental disease or another serious disease . Patients had data recorded at baseline and were followed up via cell phone and annual visits for 3 years. After each patient was discharged from the hospital, they were followed up via cell phone  to confirm survival status, and in cases of death, the exact date of death was recorded.n = 878) and another for verification of the PI (n = 651).A total of 5,974 patients were initially included. A total of 1,529 patients were finally included in the study after excluding incomplete variable data and loss to follow-up. The patients were divided into two groups, including one for development of the PI (2.2An HFrEF-electronic Case Report Form (HFrEF-eCRF) was established to collect baseline information during hospitalization, which include the following: (1) basic information, such as demographic characteristics, admission time, discharge time, and clinical diagnosis; (2) comorbidities and history of allergies; (3) results of a standard physical examination; (4) laboratory test results; (5) results of imaging, including electrocardiography and echocardiography; and (6) medication and surgery information. A total of 222 variables were included in this study.The HFrEF-eCRF was developed on the basis of clinical guidelines and clinicians’ opinions. Entry and follow-up personnel were trained, and data quality was controlled using dual entry. The study was reviewed and approved by the Medical Ethics Committee of Shanxi Medical University, China (No. 2013099), and written informed consent was obtained from all participants.2.3Mean values and standard deviations were calculated for continuous data, and numbers and percentages were calculated for categorical data. In the development stage, univariable and multivariate logistic regression was used to initially screen the variables. To improve predictive efficiency, the selected continuous variables were transformed into categorical variables via receiver operating characteristic (ROC) curve segmentation and re-introduced into model validation. A log-rank procedure was then used to verify the variables and the validated variables were included in Cox stepwise regression analysis.LTA was used to test discrimination of selected variables. LTA is also called item response theory in the field of psychometrics. This method establishes a functional relationship between latent categories and external variables. To date, there are at least 20 types of latent trait models. According to different data, different models can be used to estimate the parameters. In our study, the most common Rasch model and Ltm were used. The Rasch model is a special case of a one-dimensional latent trait model and the Ltm is a two-parameter logistic model . Parametα = 0.05, multivariate analysis: αentry = 0.05, and αelimination = 0.10). All statistical analyses were performed using SPSS 26.0  and R 3.6.1 (https://www.r-project.org/) software.Finally, the selected variables were input into a nomogram model. After a simple sum of the scores from the nomogram model, the ABC-PI was created   and written informed consent was obtained from all participants.3p < 0.05) are shown in In the development group, diseases of these patients included coronary heart disease , old myocardial infarction , unstable angina pectoris , arrhythmia , and others . There were 195 (22.2%) deaths during the 3-year follow-up period. In the validation group, diseases of these patients included coronary heart disease , old myocardial infarction , unstable angina pectoris , arrhythmia , and others . There were 108 (16.6%) deaths during the 3-year follow-up period. The 222 baseline variables were tested one by one, and the standard basic variables and all variables that showed significant differences (p < 0.05) in Variables that were significantly different , NT-proBNP levels >2,122 ng/L, a left ventricular mass index >137.9 g/mt-test. In the death group, the mean latent trait score was 5.847 ± 2.055 and that in the survival group was 3.086 ± 2.228 . This finding indicated that the selected seven variables with great discrimination could effectively distinguish the latent trait of HFrEF in patients.LTA was used to verify whether the selected variables could effectively distinguish the latent trait of HFrEF in patients and data were used from the validation group. Nomogram scores were examined using R software and the highest total score was 415. For ease of application, nomogram scores were converted to percentiles. The 3-year survival rate was >42% in patients with total scores >30 points and it was >82% in those with total scores >60 points . Table 5To further validate the ABC-PI, 651 patients in the validation group were tested. Higher scores were associated with lower 1-year, 2-year, and 3-year death rates . The 3-y4The prognosis of HFrEF differs substantially depending on subpopulations. Therefore, accurate assessment of this prognosis is important. In this study, we developed and validated the ABC-PI. The ABC-PI is a biomarker-based PI. The seven risk factors with the greatest capacity to predict risk of death in patients with HFrEF were NT-proBNP, renal dysfunction, age, left ventricular mass index, PCI, atrial fibrillation, and NYHA grade. After verification by LTA, the selected index was considered to be valid. The score was formed by a nomogram and then converted to a percentage system, and the ABC-PI was finally obtained. After external validation, the PI was found to be effective and practical.The ABC indicator had a high accuracy because of inclusion of age, a biomarker, and clinical history. A good prognostic indicator can be used in many aspects, especially to evaluate the effectiveness of medicine and precise treatment. Hijazi et al. used the ABC score to determine the effectiveness of anticoagulants in patients with atrial fibrillation . The ABCThe most informative predictor in the current study was NT-proBNP, which is a common biomarker of heart failure. Other biomarkers that have been identified include ST2 and galectin-3, but they are not routinely measured variables, and there is no evidence that their predictive capacity is better than that of NT-proBNP ,22. TherTraditionally, a PI that is generated on the basis of Cox regression is highly dependent on the model and requires re-input in the model. Based on the traditional Cox regression, this study used LTA to verify discrimination of the index. We then used a nomogram to form the ABC-PI, which did not depend on the original model, and it improved the practicability and applicability of the PI. LTA is commonly used in psychological tests and educational tests. LTA can distinguish different subpopulations of people . Our stuThe current study has some limitations. The main limitation is that because the study population was limited to China, the results cannot necessarily be directly extrapolated to other populations. In future studies, we will attempt to incorporate heart failure research centers in other countries to further improve the accuracy of the ABC-PI.5Overall, the PI developed in the present study shows good performance. The variables that constitute the ABC-PI include age, biomarkers, and clinical history. Therefore, the scope of this index is comprehensive. After external validation, the ABC-PI performed well for predicting 1-year, 2-year, and 3-year mortality. The 1-year, 2-year, and 3-year mortality rates in the high-risk group were 26.0%, 31.2%, and 34.7% compared with 1.7%, 2.3%, and 2.6% in the low-risk group, respectively. In the future, the ABC-PI could be used for evaluating the effect of intervention and individual risk prediction.ABC-PIage-biomarker-clinical history prognostic indexeCRFelectronic Case Report FormHFrEFreduced left ventricular ejection fractionLTAlatent trait analysisNT-proBNPN-terminal pro-B-type natriuretic peptideNYHANew York Heart AssociationPCIpercutaneous coronary interventionPIprognostic indexROCreceiver operating characteristic.


This study aimed to evaluate the value and feasibility of ultrasound multimodal score in the evaluation of endometrial receptivity in patients with artificial abortion (AA).Sixty-eight patients with AA (AA group) and 70 women of the childbearing age without any history of abortion (control group) were recruited between January 2018 and December 2018. All subjects received the examination of endometrium in the middle luteum phase (7–9 days after ovulation) with two-dimensional gray-scale ultrasound, two-dimensional color Doppler ultrasound, and three-dimensional ultrasound, and the quantitative scores were obtained and compared between two groups.p < 0.05).The quantitative score of endometrial receptivity was 10.46 ± 2.99 in the AA group and 13.49 ± 2.21 in the control group showing significant difference (Ultrasound multimodal quantitative scores can be used to evaluate the endometrial receptivity of patients with AA. Multimodal ultrasound can effectively evaluate some endometrium-related factors such as endometrial morphology, blood flow, and peristaltic waves.The ultrasound multimodal scoring is based on some features of the endometrium and may provide a more comprehensive reflection of endometrial receptivity.In the future, this scoring system has the potential to assist the reproductive physician to more accurately predict the outcome of pregnancy and plan the treatment.In recent years, the prevalence of artificial abortion is increasing and has become an important public health problem. Abortion can cause mechanical damages to the endometrium, which may lead to secondary infertility, seriously affecting the physical and mental health and quality of life . Studiesn=68) between January 2018 and December 2018. In addition, 70 subjects of the childbearing age who had not given birth and no history of artificial abortion were recruited as the control group in the same period. The inclusion criteria were as follows: Patients were ≥ 23 years, but ≤ 35 years; the menstrual cycle was regular within 1 year (28–35 days); the thyroid function was normal; patients were negative for abortion-related immune antibodies; the periodicity of sexual hormones was normal; the follicular hormone level was normal in the early follicular phase; the chromosomes of the father, the mother, and the infant were normal; ultrasonography of the uterus, uterine appendages, and pelvis showed normal; organic diseases and infectious diseases were excluded; there were no gynecological surgeries within prior 2 months; there were no medications affecting the hormones; and the semen analysis showed normal. The signed informed consent was obtained from each subject. The height and weight were measured for the calculation of body mass index (BMI). On the day of ultrasound examination, blood was collected to detect the estradiol, progesterone, testosterone, luteinizing hormone, prolactin, and follicle-stimulating hormone.Patients who had not given birth but received artificial abortion of one to three times were recruited as the artificial abortion (AA) group . If ovulation was not observed, the examination was abandoned. Implantation window phase was defined as 7–9 days after ovulation when ultrasonography was performed. In AA group, ultrasonography was performed at 3 months after the last artificial abortion.Color Doppler ultrasound system (GE Voluson E8) with vaginal probe (RIC6-12-D) at the frequency of 5–8 MHz was used for ultrasound examination. Patients lied in a lithotomy position. The vaginal probe was wrapped with a condom, smeared with coupling agents, and then placed into the vagina. Measurement was done at the vaginal fornix.Measurement of endometrial thickness: The distance between the interface of anterior wall muscle and the intima and the interface of posterior wall muscle and the intima was measured at 2 cm from the bottom of the uterine in the middle long axis view of the uterus. Measurement was done thrice and the mean was calculated. < 7 mm or > 14 mm was given 1 point, 7–8 mm was given 2 points, and 9–14mm was given 3 points.Observation of endometrial morphology: The echoes of the endometrium was observed. Then, the endometrial patterns were divided into three types based on the Gonen system: type A, trilaminar pattern , consisting of hyperechoic outer and middle layers, hypoechoic inner layers, and evident echo at the intrauterine midline; type B, relatively homogeneous hyperechoic endometrium, with unclear endometrial layers, obscure intrauterine midline echo, but clear interface between endometrial and muscular layers; and type C, homogeneous hyperechoic endometrium without intrauterine midline echo  Fig. 1)1). Type Observation of endometrial movement: In the middle long axis view of the uterus, the position of the probe was fixed, and the patient was asked to calmly breathe. The type and frequency (times/min) of endometrial wave peristalsis were recorded for 3 min. Ljland et al. divided the endometrial peristalsis into 5 types: (1) positive wave, the peristaltic wave from the cervix to fundus; (2) negative wave, the peristaltic wave from the fundus to the cervix; (3) static wave, the endometrium in a static state; (4) bidirectional wave, the endometrium at the fundus and the cervix contract simultaneously; and (5) local peristaltic wave, the wave with low amplitude, no obvious directionality and rhythm . NegativObservation of blood flow distribution in the intima and subintima: In the meddle long axis view of the uterus, the subintimal area was defined as the area 3 mm away from the intimal edge, and the endometrial and subendometrial perfusion was detected with CDFI mode and classified as 3 types: type I, blood flow is present in the endometrium and subendometrium; type II, blood flow is absent in the endometrium, but present in the subendometrium; and type III, blood flow is not observed in both endometrium and subendometrium  Fig. 2)2). Type 3 was given 1 point, EV of 2–4 cm3 was given 2 points, and EV > 4 cm3 was given 3 points. Unmeasurable VFI was given 1 point, VFI < 0.24 was given 2 points, and VFI > 0.24 was given 3 points.Measurement of endometrial volume and vascularization flow index: The energy Doppler blood flow imaging mode was used for measurement at a sensitive state. The branching of endometrial blood flow was assessed. Then, the 3D mode was set, VOCAL software was used for analysis, the endometrium was outlined, and then the endometrial volume (EV) and vascularization flow index (VFI) were determined –10. EV <As shown in Table p > 0.05 was observed. Data with normal distribution were compared with Tukey test between two groups. Data with abnormal distribution were compared with Kruskal-Wallis rank sum test, followed by Dwass-Steel-Critchlow-Fligner (DSCF) test between two groups. A value of p < 0.05 was considered statistically significant.Statistical analysis was performed with SAS 9.4 . Normal distribution of data was tested with one-sample Kolmogorov-Smirnov test, and normal distribution was defined once All the data acquired in two groups showed normal distribution.p > 0.05)  Table .Table 2p > 0.05)  Table .p < 0.05) , which reduces the total ultrasound multimodal score. This may be related to the pathological responses of the endometrium  after the mechanical injury to the endometrium –22. ThesThere were still limitations in this study. There are no widely accepted criteria or consensuses on the multimodal ultrasound assessment of endometrial receptivity. In this study, a new system was developed for the assessment of endometrial receptivity on the basis of previous findings and it might be subjective in the development of this system. Therefore, it is necessary to further investigate the clinical value and practicality and to improve this scoring system.In summary, multimodal ultrasound can effectively evaluate some endometrium related factors such as endometrial morphology, blood flow, and peristaltic waves. The ultrasound multimodal scoring is based on some features of the endometrium and may provide a more comprehensive reflection of endometrial receptivity. In the future, this scoring system has the potential to assist the reproductive physician to more accurately predict the outcome of pregnancy and plan the treatment. However, the relationship and interaction of various factors are still unclear, and more studies are needed to confirm our findings.


Repeated blood pressure (BP) measurements allow better control of hypertension. Current measurements rely on cuff-based devices. The aim of the present study was to compare BP measurements using a novel cuff-less photoplethysmography-based device to a standard sphygmomanometer device. Males and females were recruited from within the general population who arrived at a public BP screening station. One to two measurements were taken from each using a sphygmomanometer-based and the photoplethysmography-based devices. Devices were considered equal if the mean difference between paired measurements was below 5 mmHg and the Standard Deviation (SD) was no greater than 8 mmHg. Agreement and reliability analyses were also performed. 1057 subjects were included in the study analysis. There were no adverse events during the study. The mean (± SD) difference between paired measurements for all subjects was -0.1 ± 3.6 mmHg for the systolic and 0.0 ± 3.5 mmHg for the diastolic readings. We found 96.31% agreement in identifying hypertension and an Interclass Correlation Coefficient of 0.99 and 0.97 for systolic and diastolic measurements, respectively. The photoplethysmography-based device was found similar to the gold-standard sphygmomanometer-based device with high agreement and reliability levels. The device might enable a reliable, more convenient method for repeated BP monitoring. For over half a century it has been known that there is a strong relationship between abnormal blood pressure levels and the risk for health complications and death2. Higher levels of systolic and diastolic blood pressure have been associated with increased cardiovascular disease risk3. Currently used BP devices are usually based on the manometry method. This method is cumbersome, not always accurate and may have inaccurate measurements for different reasons, e.g. varying cuff size, accepted measurement guidelines not being followed, lack of routine calibration, and more9. There is a need to train both the operator and the patient on how to use these devices to allow valid measurements10. Despite these difficulties, and since hypertension is regarded as the world’s most common and modifiable cardiovascular risk factor12, BP measurements are still required in routine healthcare, with treatment often depending on imprecise measurements. Moreover, the new guideline issued by the American College of Cardiology and the American Heart Association (ACC/AHA) provides a substantially more stringent recommendation concerning out-of-office and self-monitored BP measurements, and recommends a more modern approach to out-of-office BP measurements using ambulatory or home BP monitoring to both confirm the diagnosis of hypertension and to titrate BP-lowering medications15.Blood pressure (BP) is one of the basic measurements taken to evaluate the physiological status of an individual, whether in the pre-hospital setting, in a community healthcare clinic or in the hospital16. This will also allow proper home care monitoring as well as pre-hospital and in-hospital care, providing early identification and prevention of cardiovascular morbidity.Thus, there is a need for simple, non-invasive, wireless monitoring systems that will enable health systems to implement future strategies, allowing a dramatic change in the way we gather physiological data, with an emphasis on BPThe aim of the current study was to compare non-invasive BP measurements between a commonly used manometry device and a new reflective photoplethysmography (PPG) device  and 591 females (55.9%)), for which the defined data set was available (Table p < 0.001), the mean ± SD Diastolic Blood Pressure (DBP) of the reference device was 68.2 ± 18.7 mmHg and with the BB-613WP 68.2 ± 11.5 mmHg (p < 0.001). Reliability of the BB-613WP device with regards to the reference sphygmomanometer device was excellent for both systolic and diastolic measurements and in both the first and second measurements, as indicated by an ICC of 0.96 and above (Table Table The mean deltas for the first (rest) measurement between the reference and the BB-613WP device for systolic and diastolic readings were -0.1 ± 3.6 mmHg and 0 ± 3.5, respectively. The delta for the second (exercise) diastolic measurement was statistically significant but the mean deltas for this second measurement were well below the 5 ± 8 mmHg threshold dictated by the ISO 81060-2:2013 Table . The perHigh agreement between the BB-613WP and the reference devices was demonstrated Table . 100% se97 subjects (9.15%) had reported a previous diagnosis of hypertension. They were significantly older and weighed more than the general subject population . They also had more background diseases such as diabetes, hypercholesterolemia, CVA and COPD. ICC showed high reliability for both the systolic and diastolic measurements in subjects with or without reported hypertension. The average difference and the SD between the reference cuff-based device and the BB-613WP in subjects with and without diagnosis of hypertension were within the required limits, according to the ISO 81060-2:2013 .15. The change in the guideline’s definitions of hypertension resulted in an abrupt surge in the proportion of hypertensive adults in the United States18. Moreover, the new target of treatment for BP is accordingly lower.The 2017 guidelines published by The American College of Cardiology/American Heart Association (ACC/AHA) encourage changes in the management of hypertension. They recommend a holistic approach including the use of team-based care, routine use of home and ambulatory blood pressure monitoring (out-of-office BP measurements), and they stress the importance of consistent, accurate, and standardized measurements of BP19.Known discrepancies between office and home BP values, defined as white-coat hypertension and masked hypertension, together with the narrower BP goals now recommended, require closer BP monitoring and a need to frequent the use of out-of-office BP measurements. Recent estimates are that more than 800 million adults worldwide have an SBP of 140 mmHg or higher. Hypertension’s association with stroke, cardiovascular disease, heart failure, and chronic kidney disease places it with other leading preventable causes of death in the United States, and its consequences are projected to increase18. Ambulatory Blood Pressure (ABP) measurement is now acknowledged as the preferred method for predicting the risk of cardiovascular events relative to an individual’s BP level20. Following these perceptions, questions have been raised on the accuracy, and consequently the role, of manual BP measurement in routine clinical practice21 . Routine office BP measurements  are not only more susceptible to a “white coat effect”, but are also less accurate, correlate quite poorly with ABP, and are associated with approximating readings to the nearest zero value24.Expanding the use of home blood pressure measurements is important yet challenging. The quality of measurements among hypertensive patients varies, and teaching people to perform good-quality and reliable blood pressure measurements necessitates dedicated resources and is challenging, particularly in demanding clinical settings23.Reducing human involvement in the measurement of BP in the office, especially if considering that proper measurement techniques are rarely followed, is suggested to improve the quality of readingsThe above-mentioned insights and findings emphasize the importance of having a device that allows better practice and compliance by users by being non-invasive, cuffless, and wireless, enabling multiple measurements without disrupting the user’s daily routine.The subject population in this study was heterogenous and represented both genders. 26.7% had background chronic diseases Table  includinA first blood pressure measurement was recorded in 1057 subjects. The average difference between the cuff-based reference device and the BB-613WP was 0.1 mmHg (SD of 3.6) for systolic BP measurements and 0 mmHg (SD of 3.5) for diastolic BP measurements, i.e. statistically insignificant and below the threshold levels defined by different regulatory protocols such as the ISO 81060-2:2013.The Intraclass Correlation Coefficient (ICC) presents high reliability of the BB-613WP device with a 0.992 value for systolic BP and a 0.975 value for diastolic BP.In the 491 subjects for whom a second measurement was taken, the average systolic BP in the reference device increased from 117.1 to 135.0 mmHg, without any change in the average diastolic BP. The BB-613WP device detected these changes with high reliability—ICC = 0.989 for systolic BP and 0.957 for diastolic BP. This means that the novel PPG-based device can detect and follow changes in BP along time and not only when the BP is stable and without any changes. Consistently, the average changes and the SD are well under the required by the ISO 81060-2:2013.The agreement percentage between the reference device and the BB-613WP in identifying high and normal blood pressure was high . In 15.2% of the non-hypertensive subjects the reference cuff-based device showed a high BP value, while the BB-613WP device showed similar high BP values in 92.8% of these subjects. Bland–Altman plots demonstrate that the agreement between the BB-613WP and the reference device is within the limits of the ISO 81060-2:2013 definitions, suggesting good/acceptable agreement in all subjects. A subgroup analysis of subjects with or without reported hypertension demonstrated similar results.In conclusion, when comparing BP values measured by the standard cuff-based device to the novel BB-613WP device in subjects with both normal and high BP levels, we show that the mean value of the differences in systolic and diastolic measurements for all subjects is less than 5.0 mmHg and the SD is less than 8.0 mmHg, as required by different regulatory protocols such as the ISO 81060-2:2013. This indicates that the PPG-based BB-613WP device can be used as an accurate and reliable BP measurement device.Beyond its accuracy and reliability, a PPG-based device is simpler to place and use than the cuff-based device, reducing the involvement needed by health personnel. These findings may change the way these parameters will be monitored in the near future, both in pre-hospital and in-hospital settings, as well as in home care scenarios over prolonged periods of time. Further studies should be undertaken to strengthen this data.This was a short-term study with only one or two measurements collected and being compared between the two devices, minutes after the reference baseline value  took place in the BB-613WP device. As such, a prolonged protocol with more measurements per subject is needed to substantiate our findings. That said, already in this setting we were able to show the accuracy and the usability of such a wearable, wireless and non-invasive device. We are now in the process of concluding several other clinical studies addressing this limitation.Based on the ISO 81060-2:2013, measurements of BP should be taken by two investigators, with the reference value being the average of these measurements. This was not performed in the study as we could not interfere and change the way the designated hypertension screening stations operate. This also is being addressed in several other clinical studies using the BB-613WP.When EMS personnel take measurements with the cuff-based device, they round the numbers to the nearest 5 mmHg value. This has an influence on the comparison and is seen in the Bland–Altman plots. The research team decided not to change this pattern, with the intent to prevent any influence and allow the EMS personnel to continue with their tasks as usual.When using any sort of physical exercise to increase the BP, it will decay back to normal rapidly upon cessation of the exercise, therefore methods for standardization should take no more than few seconds of measurement. The research team did not want to change and interfere too much with the routine measurement of BP. Thus, despite this challenging environment, subjects that performed the 5 min exercise had the BB-613WP on them during the session, and upon completion of the exercise session BP measurement using the cuff-based device was immediately taken and in parallel the value in the BB-613WP device was recorded, as detailed in the methods.ISO 81060-2:2013 was replaced by ISO 81060-2:2018. By the time the study was conducted, ISO 81060-2:2013 was still valid. Importantly, ISO 81060-2:2013 is still accepted by regulators.This comparative prospective study was approved by the institutional review board (IRB) of the Tel-Aviv Medical Center, Tel-Aviv, Israel (0032-15-TLV).Male and female volunteers were recruited with no age restrictions. Each came for a BP checkup provided by the Israeli Emergency Medical Services (EMS) in designated BP measurement public screening stations deployed across the country. Each signed an informed consent form as defined by the Institutional Review Board (IRB). Informed consent was provided by the parents of subjects under the age of 18 years. The research team received coded numbers of the participants without any personal identifiers. Recruitment of subjects lasted for a period of two months, aiming to recruit more than the minimal sample size defined by the ISO 81060-2:2013 .The BB-613WP is a wrist-worn or skin attached device indicated for use in measuring and displaying functional oxygen saturation of arterial hemoglobin (%SpO2) and pulse rate using photoplethysmography (PPG) technology. Most commercially available devices transmit light in specific red (~ 650 nm) and infrared (~ 880 nm) wavelengths through the tested tissue, and a detector on the other side absorbs the transmitted light. These wavelengths have a unique absorbance pattern upon interaction with oxy- and deoxyhemoglobin. The detector measures the changing absorbance at each of the wavelengths allowing it to determine the absorbance resulting from the pulsating arterial blood alone excluding venous blood, skin, bone, muscle, and fat. The BB-613WP uses a unique reflective PPG technology, where, unlike most devices, the light source  and sensor array are placed on the same side (backside) of the device. As the LEDs transmit light into the subject’s skin, part of this light is reflected from the tissue and is detected by a photodiode detector. The high temporal and quantitative resolution of the device allows it to capture minute changes in tissue reflectance, calculating numerous vital signs derived from pulse contours, including advanced hemodynamic parameters such as tracking changes in blood pressure. This is based on Pulse Wave Transit Time (PWTT) which is obtained utilizing pulse measurements from the integrated SpO2 sensor, following a calibration process using an oscillometric blood pressure monitor. Once a calibration measurement is taken using the cuff-based BP device, the values are entered into a user’s application. The calibration is valid for three months, after which a new calibration measurement should be taken and introduced into the application using the same method.The results are displayed on the LCD screen of the wristwatch device as well as on the mobile application installed on the user’s smartphone. From there, the data is transmitted in real-time to a web application used by health care providers.25), which is considered by the FDA as a relevant protocol for regulatory use.Comparison between the devices was performed based on the International Organization for Standardization (ISO) guideline for non-invasive sphygmomanometers  was taken and used as the baseline calibration value for the PPG-based wearable device . Those who agreed and signed were included in this sub-group. The aim was to change the BP and to show that the BB-613WP can detect this change between the two measurements. Adverse events were recorded by the research team, such as local wrist irritation (where the wristwatch was placed), or any other complaint by the user.26. Correlation analysis was also performed using Pearson correlation, and agreement was evaluated based on the Bland–Altman method using 95% limits of agreement (LOA). The agreement in the classification (detection) of hypertensive cases (defined by the European Hypertension Society to be > 140 mmHg systolic pressure or > 90 mmHg diastolic pressure) was evaluated using Kappa agreement. Hypertension (SBP > 140 mmHg or DBP > 90 mmHg) detection ability was evaluated using ROC curves analysis. Pre-specified subgroup analysis of patients with and without previously diagnosed HTN was also performed. P values were set at 0.05. Data analysis was performed using the IBM SPSS Statistics for Windows, Version 23.0, IBM Corp , released 2015 and GraphPad Prism, version 8.0.2  released 2019.According to ISO 81060-2:2013 the PPG device can be considered as equal to the reference when the mean value of the differences in paired systolic and diastolic readings between the reference and the PPG device is equal to or less than 5 mmHg and the Standard Deviation (SD) is no greater than 8 mmHg. The PPG device reliability was determined by the Interclass Correlation Coefficient (ICC) in which an ICC ≥ 0.9 indicates “excellent reliability”All procedures performed in this clinical study were in accordance with the ethical standards of the local IRB  and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.Informed consent was obtained from all individual participants included in the study. Informed consent was provided by the parents of subjects under the age of 18 years.Supplementary Information.