Hypertension is a chronic disease that has a major health problem over the centuries due to its significant contribution to the global burden. The objective of this study was to examine the association of survival time and longitudinal Systolic Blood Pressure (SBP) measurement and finding potential barrier that affects SBP measurement and the survival time of hypertension patients. The study considered a cohort of 318 hypertension patients who were aged 18 years or older and were under follow-up from January 1, 2012, to February 30, 2020, at Arba Minch General Hospital. To analyze the data we employed linear mixed effect model, Weibull model, and joint modeling approach for longitudinal and survival data. The results from joint model analysis indicate that systolic blood pressure measurement is significantly associated with survival time of hypertension patients. The results from the longitudinal sub-model reveals that alcohol use, Khat intake, smoking tobacco, stages of hypertension diseases, adherence to treatment, related diseases, and family history had statistical significant relationship with mean change in the  Recent researches indicate that 972 million people living with hypertension in year 2000 in the globe, and it will be increased more than 1.56 million in the year 20254. Globally the number of people with uncontrolled hypertension rose by 70% between in the year 1980 and 2008; the rising epidemic of hypertension is due to modernization, population growth and ageing5.Hypertension is one of major worldwide public health challenge and it is root cause of many body system and organs failure in both developed and developing counties. In 2008 Overall prevalence of hypertension in adult age 25 and above were 40% and it was cause for 7.5 million deaths worldwide6. The estimated number of hypertensive patients in Sub-Saharan Africa in 2025 will be 150 million7. Additionally, there is evidence which shows complications of hypertension such as stroke and heart failure are increasing at an alarming rate in this region8. Current disease assessments for Sub-Saharan Africa indicate that there is a wide disproportion (0.4–43%) in the prevalence of hypertension and obesity. The detection rates in most high-income countries vary from 32 to 64% although in many low-income countries, the reported detection rates are considerably lower9.Hypertension in sub-Saharan Africa is widespread of immense economic importance because of its high prevalence in urban areas, its frequency under diagnosis and the severity of its complications. Now a day it is transferred from a comparative rarity to the most important public health problem and cardiovascular disease is a unique double burden challenge for the whole of Africa10. The prevention and control of hypertension has not given attention in Ethiopia compared with other diseases like HIV/AIDS, Tuberculosis, malaria and nutritional deficiency diseases11.In Ethiopia, due to economic development and rapid growth of urbanization, non-communicable diseases and their related risk factors are growing and becoming a double burden12. Longitudinal observations such as square root of SBP are obtained from repeated measurements on the hypertensive patients at a series of time points. The related data on time-to-death event describe the length of time for occurrence of the event on each individual patient during a specified study period. So, Joint models analyses of such kind of data’s important to incorporate all information simultaneously and provide effective and efficient inferences13. The goal of this study was to examine the association of survival time and longitudinal SBP measurement and finding potential barrier that affects SBP measurement and the survival time of hypertension patients.In clinical and medical studies, longitudinal and survival data are considered important measures of health, and most of the time they arise togetherThe data for this study collected from hypertension patients under follow up at Arba Minch general hospital located in SNNPR Gamo zone Arba Minch town Ethiopia from January 1, 2012 to February 30, 2020. The data were taken out from the patient’s registration chart and cards with epidemiological, laboratory and clinical information of the patients under follow-up. Among 1020 hypertension patients under follow up 318 patients was selected with simple random sampling technique and the data was analyzed using R software version 3.6.2. The research proposal of this study was checked and approved by ethical clearance committee of Arba Minch University. So, Informed consent has been waived by Arba Minch University of the ethical committee. All study procedures were performed following relevant guidelines and regulations laid down by the Committee.The letter of ethical clearance was obtained from institutional review board of Arba Minch University, and Arba Minch General hospital gave permission to collect data of patients from recorded cards. For the purpose of confidentiality, there were no links with individual patients and all data had no personal identifier and were kept confidential and therefore Informed consent has been waived by Arba Minch University ethical committee.14; it measured at least three Blood Pressure measurements after the first report of hypertension diagnosis and the survival time of patients was the time in months of a patient to the associated death event. And it is time to death event of the patient under the follow up.Measurements of systolic blood pressure and survival time of hypertension patients were considered as response variable in this study. Systolic blood pressure measurement was measured repeatedly over time for each hypertension patient under the follow up. SBP has been a better indicator of risk than DBP.The predictor variables assumed to be determined the longitudinal systolic blood pressure (SBP) measurement and survival time of hypertension patients were visit time, Gender , Base line age The analysis consists; linear mixed effects model for the longitudinal data, Weibull regression model for the time to event data and joint model for both longitudinal and time to event data.15. Each person in the population is supposed to have his/her own mean response trajectories.In longitudinal data analysis, variations occurred from two sources, within-subject and between subject, within-subject arises during the measurements within each subject, and between subject variations arises during the measurement between different subjects. This variation among individuals arises because of unmeasured factors16:ith subjects, εi is distributed as A linear mixed model contains fixed and random effects. The fixed effect section of the model represents the mean response whereas the random effects section represents the individual level responses. The general linear mixed effect model for the longitudinal data defined as17.A model for the covariance must be chosen on the basis of some assumed model for the mean response. In order to reduce the number of parameters in the variance–covariance structure 15. The random intercepts model allows intercepts to vary across groups. In particular, a basic example of a random intercepts model which is included in order to illustrate the model fitting is formed by two clearly distinct parts,The random effects model or subject-specific model assumes that extra correlation arises among longitudinal responseui and within-subject error εi are independent for different subjects and independent of each other for the same subject. i.e.These are, a fixed part (which is the intercept and the coefficient of the explanatory variable times the explanatory variable) and a random part. The random effect In the mixed model formulation, the design matrices are replaced by:And the random effects model covariance structure, 15,An intuitive extension that allows a random shift in the subject-specific slopes is known as random intercepts and random slopes model. Consider the simple random intercepts and slopes modelui1 which represents the random slope effect of the coefficients and jth response on ith subject. As a result, actually two extra parameters should be estimated: the variance in intercepts between groups In this model, we have additional The most important characteristic that distinguishes the analysis of survival times from other areas in statistics is censoring. Subjects are said to be censored if they are lost to follow up, withdrawing from the study, or if the study ends before they have an outcome of interest.18. By far the most common type of censoring is right censoring, which occurs when observation is terminated before an individual experiences the event of interest. This could happen if a patient survives through the experiment and was still alive when the experiment ends.That is, observations are called censored when information about their survival time is incomplete. There are four kinds of censoring: right censoring, left censoring, interval censoring, and truncation19The Weibull regression model is employed frequently in modeling survival data. The Weibull regression model commonly used to handle survival data with monotonic hazard behavior. But, when a hazard function is non-monotonic, log-logistic and lognormal distributions are useful alternatives. Log-logistic and lognormal distributions have hazard functions that each reaches a peak and then decline over a period of timeith subject follows a Weibull distribution. Suppose the survival time T has Weibull distribution with scale parameter λi (t) and shape parameter ρ. Then under AFT model, the survival time Ti of the ith individual is distributed asIn this study, we assume that the survival time for the 20. Joint longitudinal-survival models can be formed where the association between the two endpoints is due to shared random effects.A use of joint models, which gains increasing interest in recent years, refers to the statistical analysis of the resulting data while taking account of any association between the repeated measurement and time-to-event outcomes21. The joint model consists of two linked sub-models, known as the longitudinal sub-model, and the survival sub-model.In joint model, the longitudinal and survival processes are assumed to be conditionally independent given unobserved random effects. That is, the key assumption of a joint model is that the random effects underlie both the longitudinal and survival processes. This means that these random effects account for both the association between the longitudinal and time to event outcomes, and the correlation between the repeated measurements in the longitudinal process. This type of joint model is also called a shared parameter model, as both processes share these random effectst. However, for each subject, we may have this longitudinal outcome occasionally at times ith subject. Normally distributed longitudinal outcomes and linear mixed effects (LME) model22 can be given by:We assume that the hazard function 23.The survival model in the joint model includes a latent association function 24. The distinction between ML and REML is the construction of the likelihood function. However, the two methods are asymptotically equivalent and often give very similar results except the difference becomes important only when the number of fixed effects is relatively large.In general terms, we use efficient estimation method using likelihood based models either ML or REML estimation to obtain estimates of the covariance parameters in linear mixed models with the remark that REML is usually better than ML, because it reduces the well-known finite sample bias in the estimation of the covariancei refer to the individual indicator and consequently, θ, the likelihood function is given by,In order to estimate the survival function, the parameter estimation and their estimated variances in the Weibull regression model can be found by maximizing the log-partial likelihood function with respect to the parameters. Let the sub-index 25, which is based on the following iterative procedure: Note that it takes to account for censoring information, by contributing with 22, thusThe main estimation method that has been proposed for joint models is ML. The standard ML method involves maximizing the log-likelihood, corresponding to the joint distribution of the time-to-event and longitudinal data processes. Strictly, both processes share the same unobserved random effects, and are conditionally independent given these random effectsi′th subject is expressed asBecause of the fact that the survival and longitudinal sub-models share the same random effects, joint models of this type are also known as shared random effects models. Under these conditional independence assumptions between longitudinal outcome and time-to-event given the random effects i′th subjects is given by,And, the survivor function for the The log-likelihood for the joint model is approximated using the Expectation–Maximization (EM) algorithm, because both the integral with respect to the random effects and survival function typically do not have an analytical solution, except in some special cases.The research proposal of this study was checked and approved by ethical clearance committee of Arba Minch University and data collected from Arba Minch General Hospital recorded cards, and Arba Minch General Hospital medical directors gave permission to use the patient’s data for this study. For the purpose of confidentiality, there were no links with individual patients and all data had no personal identifier and were kept confidential.From the total sample population, major parts (54.4%) were females and the remaining (45.6%) were males. Among those patients considered in the study we observed that (11%) died while the remaining (89%) were censored. The death proportion of female patients was (11%) which is greater than male patients are (7.58%). Regarding place of residence about 64.78% of patients were living in urban areas and 35.22% of them in rural areas with death proportion of 11.66%, 6.87% respectively. Regarding age proportion, the majority of the hypertension patients were at age of above 50 was 51.13% which is greater than the age group below 50 which is 48.87%.The highest death proportion was observed from patients who use alcohol (16.176%) whereas the lowest proportion of death (6.87%) was observed among a patient who does not use alcohol.The proportion of death was varied by Khat intake of the patients. The highest proportion of death was observed from a patient who intake Khat (23.59%) whereas the lowest death proportion (5.28%) was recorded among patients who do not intake Khat. Regarding blood cholesterol level, Patients who have raised blood cholesterol level have highest proportion of death (22.43%) than patients those who have normal blood cholesterol level. In addition, patients who have practicing modification of life style change have low death proportion (8.84%) than patients those who have not practicing modification life style change (12.38%).1, stage2 and hypertensive crisis stage were (8.2%), (14.41%), (24.6%), (32.8%) and (20%) respectively; the risks of death proportion were increasing as compared to normal stages.Regarding hypertension disease stages those who was in the normal stage, elevated stage, stageThe risk of dying proportions of patients who have stroke, heart case, others and none related diseases were 30.95%,17.89%, 4.082% and 1.78% respectively. The highest part of dying was recorded from them with poor adherence (11.66%) whereas the lowest part of death (6.87%) was accounted among sample population with good adherence.In addition, (64.46%) patients had positive family history of hypertension disease and the remaining (35.53%) had negative family history of hypertension case, and their death proportion was 11.255%, 7.317%respectively. From the total sample subjects (61.32%) of them had diabetes mellitus case and the remaining (38.68%) of them had not diabetes mellitus disease.The patients were following up for the total 65 months. The median survival time of hypertensive patients was 38 months with mean and standard deviation of 37.74 and 19.97 months, respectively.Comparison of survival function is a good indication to see the event experiencing time of the groups. The estimation of survival function graphs in Fig. Looking in to survival function of base line age; less than and 50 had higher experience of lifespan probability than baseline age greater than 50.When compare subjects with alcohol use, the patients who do not use alcohol had better survival probability than those who use alcohol. Comparing the lifespan function of the sample population with cholesterol level, subjects who have the normal blood cholesterol level had higher experience of survival probability or lifespan than those who have raised blood cholesterol level. Also the survival function of patients taking Khat was lower survival probability or lifespan than patients does not taking Khat. In addition, subjects who have positive family history of hypertension disease had less experience of survival probability compare to patients with negative family history of hypertension cases. The patients who had good adherence have more favorable survival experience than patient who had poor adherence and they who have not diabetes of mellitus case had better survival experience than patients who have diabetes mellitus.χ2 = 2.3, p < 0.002), alcohol use , Khatintake , smoking tobacco , blood cholesterol level , adherence to treatment , related diseases , Status of stress ,and family history of hypertension patients and diabetes mellitus status at 5% level of significance. However, there was no significance difference in survival probability between the categories of gender, place of residence, stages of hypertension diseases and lifestyle change (modification) of hypertensive patients.The log rank test was used to check the significance of observed difference among categories of covariates using chi-square. The rank test results showed that there were significance differences in survival probability of patients in different categories of age  measurements with corresponding Shapiro–Wilk and Kolmogorov–Smirnov tests were used to check normality assumption of linear mixed effect model. The histogram of the SBP measurement in Fig. Similarly, Fig. Figure , the square root of SBP measurement was used in the linear mixed effect models. We fitted univariable marginal models to explore the relationship between the square root of SBP measurement and each of the covariates. In this analysis we considered eleven variables. Among the, variables those which are significant at 25% modest level of significance in the univariable analysis were used as a candidate for the multivariable analysis.To normalize SBP measurementThe variables alcohol use, Khat intake, smoking tobacco, status of stress, stages of hypertension diseases, adherence to drug treatment, related diseases, family history of hypertension and fasting blood sugar were found to be significant at 25% level of significance and they are considered in the multivariable analysis.25. From covariance structures, the one with the lowest AIC and BIC with convergence of the model in REML and ML were considered. In the analysis, four different commonly used covariance structures such as; Compound Symmetry (CS), Unstructured (UN), first Order Autoregressive (AR (1)) and Heterogeneous Compound Symmetry (HCS).In linear mixed effect model covariance structures should be carefully selected in order to obtain valid inferences for the parameters of fixed effects in the modelIn Table After fixing the covariance structure with UN, It is an important to determine the random effect to be included in linear mixed effect model.In Table Table 1, stage2 and hypertensive crisis stage were 2.28, 1.79 and 0.479 times higher compared to patients at the normal stage respectively; controlling for other variables. When we compare the two groups  in terms of SBP measurements, the patients those having stroke related disease have higher mean change in SBP measurement compared to patients none related diseases. The mean change in SBP measurement was 0.81 times higher for patients having stroke cases compared to none cases. The average change in SBP measurement was 0.64 times higher for patients those having heart disease compared to patients none related diseases controlling for the other variables.Regarding stages of hypertension disease, average change in SBP measurement for hypertension patients those were in Elevated stage was 0.140 times higher compared to the normal stage. Also, the SBP measurements of patients at stage26. All potential variables that are supposed to have significant impact  on the survival time of patients in univariable analysis were included in the multivariable cases.For each variable there is a univariable Cox proportional hazards model analysis that contains a single independent variable, which is used to know the significance of each variable with survival time. In the study, the variables that are significant in the univariable analysis in relation to time to the occurrence of event (or death) due to blood pressure were selected at 25% modest level of significanceχ2 = 3.53, p < 0.066), related diseases , diabetes mellitus status  and family history of hypertension disease  were not statistically significant that means the proportional hazard assumption holds at 5% level of significance but the covariates age and adherence to drug treatment  and  respectively were statistically significant, therefore the proportional hazard assumption does not holds at 5% level of significance. Finally global test was significant at 5% level of significant. Therefore the Cox proportional hazard model assumption does not hold.The proportional hazards assumption, which asserts that the hazard ratios are constant overtime and it, is important to use fitted PH model. Checking Cox PH model assumption is important to make inferences based on the models. The test of (PH) model assumption was done by applying formal test in the model by looking the estimated parameter over time. The regression coefficients were tested for each covariate and global test suggested strong evidence of non-proportionality (p < 0.025). The formal test for proportional hazard model was done. The analysis show that the time dependent covariates (interaction of covariates with logarithm of time) Khat (In the analysis of survival data parameters are estimated using Weibull Regression model.The Weibull model analysis in Table After having appropriate separate models for the mean change of the square root of SBP measurement and time to death of patients due to hypertension, the next step is to explore an appropriate joint model that associates the longitudinally measured SBP and time to death of patients.The analysis reveal that the association parameter (In Table The association parameter (27. However, this result was opposite to the research conducted in eastern Ethiopia by Ref.28.The purpose of this study was to examine the association of survival time and systolic blood pressure measurement and the survival time of the hypertension patients. The current study reveals that family history, stage of hypertension, related diseases, adherence to treatment; and smoking tobacco were potential barriers that affect both survival time and blood pressure measurements of the hypertension patients. This study found that an age was associated with survival time of the patients. The finding results are similar with findings from a study in Uganda by Ref.29. Current study reveals that family history is significantly affect systolic blood pressure measurement. However, finding from other research in Jima University specialized Hospital contradictory to this study finding30.We have also found a family history of hypertension was a statistically significant risk factor for death in hypertension patient; this result is in agreement with previous researchers32 identified Khat intake is one potential risk factor of hypertension.The study reveals that Khat intake was highly associated with survival time of hypertension patients. This findings are similar with previous research finding by Refs.9 identified smoking is one potential risk factor of hypertension. However, many researchers reported that there were no significant association between smoking and SBP of hypertension patients, and they concluded that there is no causal relationship34.The current study found that the patients who do not use alcohol had better survival probability than those who use alcohol. Similarly, Ayalew et al. indicated that Alcohol use is a potential risk factor of hypertension and they also found Hypertension was significantly higher in individuals who use alcohol than those who did not use33.This study identified the association between smoking tobacco and systolic blood pressure measurements of hypertension patients, and smoking tobacco was significantly associated with an increased risk of hypertension. This finding is similar with previous research finding by Ref.33In this study the finding regards the relationship between place of residence of hypertension patient and the survival time until hypertension-related death was no significant association between them. So, the current study reveal that place of resident have no significant effect on SBP and survival time of the patients. But, many researchers reported that place of residence has a significant effect on hypertension patients33. But other studies in Ethiopia and India have reported that the covariate gender does not have any association with hypertension36.Although this current study did not find any relationship between genders with patients a systolic blood pressure and the survival time until hypertension-related death; this finding is similar with previous research finding by Ref.37. Similarly, stages of hypertension disease and adherence to treatment were potential barriers that associated with both survival time and SBP measurement of the patients in the current study. The finding was consistent with the previous study finding38. The study found that there is strong dependence between a systolic blood pressure and survival time of hypertension patients, and suggests that joint model analysis rather than separate model analysis for such kind of dependence outcomes, clinical and medical studies. These findings are agreed with previous researchers finding23.The finding from the current study showed that related disease was significantly associated with both survival time and SBP measurements of hypertension patients. This finding was similar with previous researcher findingThe study concludes that the covariates with significant effects on survival time and longitudinal systolic Blood Pressure are the family history, stage of hypertension diseases, related diseases, adherence to treatments, and smoking tobaccos were potential barriers that affect both survival time and blood pressure measurements of the patients. Also, the patients with good adherence, with normal blood cholesterol level, patients did not intakes Khat, and patients with a positive family history had better survival probability compare with patients with poor adherence, raised blood cholesterol level, patients intakes Khat, and patients with negative family history respectively.The significance of the association parameter in the joint model indicates that there is a strong dependence of systolic blood pressure and survival time of hypertension patients. When evaluate the overall performance of the separate and the joint models, the joint model performs better for analysis of hypertension patient’s data.In conclusion, there are significant numbers of hypertension patients were found in the study area, and great attention and intervention should be needed on identified potential barriers. Aggressive work by stakeholders towards awareness creation about the effect of potential barriers; promotion of healthy lifestyle and improving health checkups among the community, implementation of community-based screening programs needed for early detection of hypertension and to treat hypertension related diseases are highly recommended.


To analyze the benefit of color-coded summation images in the assessment of target lumen perfusion in patients with aortic dissection and malperfusion syndrome before and after fluoroscopy-guided aortic fenestration.Between December 2011 and April 2020 25 patients with Stanford type A (n = 13) or type B dissection (n = 12) and malperfusion syndromes were treated with fluoroscopy-guided fenestration of the dissection flap using a re-entry catheter. The procedure was technically successful in 100% of the cases and included additional iliofemoral stent implantation in four patients. Intraprocedural systolic blood pressure measurements for gradient evaluation were performed in 19 cases. Post-processed color-coded DSA images were obtained from all DSA series before and following fenestration. Differences in time to peak (dTTP) values in the compromised aortic lumen and transluminal systolic blood pressure gradients were analyzed retrospectively. Correlation analysis between dTTP and changes in blood pressure gradients was performed.Mean TTP prior to dissection flap fenestration was 6.85 ± 1.35 s. After fenestration, mean TTP decreased significantly to 4.96 ± 0.94 s (p < 0.001). Available systolic blood pressure gradients between the true and the false lumen were reduced by a median of 4.0 mmHg following fenestration (p = 0.031), with significant reductions in Stanford type B dissections (p = 0.013) and minor reductions in type A dissections (p = 0.530). A moderate correlation with no statistical significance was found between dTTP and the difference in systolic blood pressure .Hemodynamic parameters obtained from color-coded DSA confirmed a significant reduction of TTP values in the aortic target lumen in terms of an improved perfusion in the compromised aortic region. Color-coded DSA might thus be a suitable complementary tool in the assessment of complex vascular patterns prevailing in aortic dissections, especially when blood pressure measurements are not conclusive or feasible. Acute aortic dissection is a severe and life-threatening subtype of acute aortic syndrome that is characterized by significant mortality rates at 48 h . Beside Endovascular aortic fenestration is an established minimally invasive approach that might be the treatment of choice in patients with severe malperfusion syndromes with or without previous aortic repair surgery . By puncIntravascular pressure measurements in both lumina might provide important information about the severity of pressure gradients before fenestration and the extent of hemodynamic equalization after the intervention . NeverthColor-coded DSA is a post-processing technique that enables the visualization of hemodynamic information of a monochromatic DSA series within a single composite image. While its benefit has been demonstrated in the field of neuroradiological and peripheral artery interventions, its application in the context of aortic flap fenestration in aortic dissections has so far not been reported , 9. ThisA review of the archives in our interventional radiology division resulted in 25 patients  with aortic dissection and malperfusion syndromes who were consecutively treated by endovascular aortic fenestration between December 2011 and April 2020. 10 patients of the study population had been reported in another study series, in which the technique of fluoroscopy-guided balloon fenestration using a re-entry catheter was evaluated [All Stanford type A dissections had been treated with thoracic aortic repair surgery before an endovascular fenestration procedure was conducted. Dissections were classified as acute in 24 cases and chronic in one case with presence of aortic dissection for 11 months prior to the procedure. The chronic type B dissection was iatrogenic and occurred during percutaneous coronary intervention. All other dissections occurred spontaneously. All included patients were treated as part of routine care and gave informed consent for the procedure. The local institutional review board waived its approval before conducting this retrospective study. All patients received cross-sectional imaging before the intervention, including computed tomography angiography (CTA) in 22 cases and magnetic resonance angiography (MRA) in three cases.Branch vessel affection resulted in mesenterial (n = 4), renal (n = 5), spinal (n = 4) and iliofemoral malperfusion syndrome (n = 6). In six cases, a combination of different malperfusion syndromes was present, including mesenterial and spinal malperfusion in two cases, renal and iliofemoral malperfusion in two cases and spinal, renal and iliofemoral malperfusion in two cases. Clinical symptoms of spinal malperfusion were ischemic monoplegia or paraplegia. Signs of renal malperfusion were renal failure with high serum creatinine levels. Mesenterial malperfusion was associated with abdominal pain and elevated serum lactate levels and iliofemoral malperfusion with pain, pulselessness, paraesthesia, and poikilothermia of the lower extremities. Patient characteristics and procedural data are given in Table All procedures were performed by the same experienced board-certified operator in our local angiography suite . Vascular access depended on the extension of the dissection membrane into the iliofemoral vasculature based on cross-sectional studies. In 14 cases, vascular access was created via the right common femoral artery and in six cases via the left common femoral artery. In five cases, a bilateral femoral access was utilized. All procedures were performed under local anaesthesia . A 6 – 7F-sheath  was positioned within the true lumen whenever possible. For the acquisition of aortography, a pigtail-shaped catheter was placed in the aorta proximal to the level of maximum true lumen compromise. DSA parameters were: tube potential 70 kVp, body weight adapted tube current setting, 7.5 pulses per second, and a 480 mm field of view. In general, a 1:1 iodinated contrast medium (300 mg/ml)/saline dilution was applied.In all procedures, percutaneous balloon fenestration of the dissection membrane was performed utilizing a fluoroscopy-based re-entry catheter , as reported elsewhere .Systolic blood pressure measurements in the true and false lumen were introduced routinely during the study period and thus were not available in the first five patients of the study. In one patient, manometry was technically not feasible due to failure of the device. In total, complete systolic blood pressure values were available in 19 cases. Sufficient equalization between both lumina was defined as a pressure gradient after fenestration of 5 mmHg or less.The puncture direction depended on the degree of true lumen collapse. The favoured target lumen was the false lumen, with puncture direction from the true lumen towards the false lumen in 22 cases. In the remaining three cases, puncturing from the false lumen towards the true lumen was necessary because of the minor extent of true lumen compromise. When flow equalization and reduction of true lumen collapse were insufficient after the first dissection flap fenestration, the fenestration process was repeated. In this regard, two fenestration windows were installed in seven cases, and three fenestration windows in two cases. Subsequent iliofemoral stent implantation was performed in four cases in which compromise of iliofemoral blood supply persisted after successful fenestration.The acquired DSA series were transferred to the local picture archiving and communication system (PACS) . The generation of post-processed color-coded images was performed utilizing the commercially available software Syngo iFlow® . This software enables the demonstration of hemodynamic information extracted from a monochromatic DSA series as a single color-coded composite image . Blood fThe region of interest used in our study was determined by the region of malperfusion and subsequent fenestration site. The ROI placement was identical prior to and after fenestration. Each ROI was averaged out of three pixel markers Fig. . In mostStatistical analysis was performed using a dedicated software . Descriptive data are presented as means ± standard deviation (SD) for normally distributed variables or medians with ranges for non-normalized variables, if appropriate; categorical data are expressed as counts and percentages with n (%). With regard to the assessment of normality, the Shapiro test was used, rejecting the hypothesis of normality when the p-value was less than or equal to 0.05. Intergroup differences were calculated using the Mann–Whitney U test and unpaired Student´s t test, differences before and after the procedure using the Wilcoxon or paired Student´s t test. Correlation analysis of ordinal and metrical data was performed with the test according to Spearman for non-normalized variables.The mean aortic TTP prior to fenestration was 6.85 ± 1.35 s. Postinterventional, TTP values were shortened with significance, resulting in a mean TTP of 4.96 ± 0.94 s (p < 0.001) and a mean dTTP of 1.89 ± 1.43 s . After treatment, median systolic blood pressure gradients resulted in a value of 3.0 mmHg (range 0–15 mmHg). The median gradient reduction was 4.0 mmHg, reaching statistical significance  was found in 11 cases. In four cases, reductions in blood pressure gradients not reaching the predefined limit were observed. In the remaining four cases, fenestration revealed paradox results with an increase of systolic blood pressure gradients after the procedure.When comparing the systolic blood pressure measurements, a significant reduction of transluminal pressure gradients was observed following fenestration in Stanford type B dissections (p = 0.013) but not in type A dissections (p = 0.530). Regarding TTP values, both Stanford type A and B dissections revealed significant reductions after dissection flap fenestration (p = 0.001 vs. p = 0.0002).The relationship between dTTP and decrease of systolic blood pressure gradients was moderate and not statistically significant . The difference of dTTP in one or multiple fenestration windows was not statistically significant (p = 0.596).TTP represents the time until the maximal concentration of contrast within the region of interest and compromised blood flow due to stenosis or true-lumen collapse is likely to lead to prolonged TTP values. In this study we aimed to investigate TTP as a suitable parameter of technical success for the improvement of hemodynamics in the compromised vessel lumen after dissection membrane fenestration. This hypothesis is supported by the results of this study as treatment led to significant dTTP values.The hemodynamic features prevailing in aortic dissections are difficult to study and remain only partially understood, to date . Unlike Interestingly, transluminal blood pressure gradients were differently influenced by the treatment in patients with Stanford type A and B dissections. While significant differences were documented in patients with type B dissection, patients with type A dissections presented with differences below the level of significance. An explanation for this result might be that all patients with type A dissection had undergone surgical repair treatment of the thoracic aorta prior to fenestration. Surgical repair of type A dissection seals the proximal entry of the aortic dissection, which is likely to result in alterations of hemodynamics prevailing in the distal aortic lumina. In this situation, the patency of the false lumen as well as the persisting extent of transluminal blood pressure gradient may highly depend on further existing entries and re-entries. Based on our results, we hypothesize that the parameters gained from color-coded DSA, including TTP, offer more stable and representative results in the evaluation of aortic lumen malperfusion, especially in type B dissections. All in all, both methods, blood pressure measurements as well as color-coded DSA, have weaknesses and it is unclear whether manometry is the correct gold standard at all.As shown in another study, the presented algorithm may serve as a periprocedural success control and might also influence the treatment strategy . For exaTo date, the utilization of quantitative color-coded DSA images has only been reported in a limited number of studies, predominantly in the field of neuroendovascular and peripheral artery procedures , 14, 15.Preinterventional cross-sectional studies should be available in most cases and support the investigation of hemodynamic and morphologic features in aortic dissections. Beside conventional CTA and MRA, more novel imaging techniques, such as four-dimensional flow MRI offer more precise characterization of blood flow while also enabling the color-coding of flow velocity or other parameters –20. NeveColor-coded imaging gained from DSA series is an implemented algorithm, neither necessitating additional amounts of contrast media nor the use of further radiation exposure. Its application is fast and simple and thus might be feasible to be employed intraprocedurally, even within the angiography suite . TherefoThe presented study underlies different limitations. First, the study was conducted in a retrospective design and the number of included patients is limited. Therefore, it must be recognized that although this study showed significant TTP changes before and after fenestration, the relationship between TTP and actual hemodynamic parameters is still unclear. Second, intraprocedural manometric measurements were introduced after the start of the study, and corresponding pressure gradients were available in 19 of 25 interventions. Third, catheter placement for manometry was not necessarily the same as placement of ROIs for hemodynamic analysis, which possibly might have influenced the measurement results.In conclusion, hemodynamic parameters extracted from color-coded DSA images may help to evaluate the procedures´ technical success in percutaneous fenestration of dissection flaps. Color-coded DSA images may offer a stable diagnostic tool, especially in cases of technically unfeasible or inconclusive manometry. However, the correlation with results from transluminal blood pressure measurements is limited. It is important to note, that due to the underlying technique, changes in cardiac output or blood pressure as well as the injection rate of contrast administration may lead to deviations.


Hypertension treated in secondary care settings was more likely to achieve the BP targets recommended by the ACC/AHA (1.31 times), ESC/ESH (1.32 times), NICE (1.41 times), and ISH (1.34 times) guidelines. (4) Conclusions: BP goal achievement was suboptimal. BP control efforts should prioritize improving cardiometabolic goals and lifestyle modifications.(1) Background: The present study aimed to assess the changes in blood pressure (BP) within the first 6 months of treatment initiation in a newly treated hypertensive cohort and to identify the factors that are associated with achieving the target BP recommended by the American , European , United Kingdom , and International Society of Hypertension  guidelines. (2) Methods: We analyzed 5308 incident hypertensive outpatients across Abu Dhabi, United Arab Emirates (UAE), in 2017; each patient was followed up for 6 months. Hypertension was defined as a BP of 130/80 mmHg according to the ACC/AHA guidelines and 140/90 mmHg according to the ESC/ESH, NICE, and ISH guidelines. Multiple logistic regression was used to identify factors associated with achieving the guideline-recommended BP targets. (3) Results: At baseline, the mean BP was 133.9 ± 72.9 mmHg and 132.7 ± 72.5 mmHg at 6 months. The guideline-recommended BP targets were 39.5%, 43%, 65.6%, and 40.8%, according to the ACC/AHA, ESC/ESH, NICE, and ISH guidelines, respectively. A BMI of <25 kg/m High blood pressure (BP) or hypertension is a leading risk factor for cardiovascular (CV) morbidity and mortality ,2. It isIn the last 4 years, four essential BP guidelines have been published, including the American College of Cardiology/American Heart Association  BP guidelines , the EurWith a population of 9.2 million in the United Arab Emirates (UAE), the age-standardized prevalence of hypertension was 33% in 2019, and less than half (47%) of patients were on treatment, and the control group comprised only 19% ,22,23. HThe study cohort, study population, inclusion and exclusion criteria, and baseline data including anthropometric and BP measurements were previously described in detail . BrieflyAll the SEHA facilities are equipped with automated unattended BP devices that give an average of several measurements. According to the SEHA protocol, each patient rests in a sitting position for 5 min in a separate room, and the measurement procedure yields three consecutive measurements. The mean of these three measurements obtained at baseline and at the 6-month follow-up examination was used in this study. Moreover, the physician should use the automated office BP measurements to initiate therapy or repeat the prescription for medication. Patients with prior use of antihypertensive medication or hospitalization due to elevated BP in the past 12 months of the index period were excluded.Hypertension is defined as an SBP/DBP of at least 130/80 mmHg according to ACC/AHA guidelines and 140/90 mmHg according to the ESC/ESH, NICE, and ISH guidelines, with current use of antihypertensive medications. The classifications of hypertension and the recommended BP targets according to the international guidelines are illustrated in 2), and diabetes status.Along with the BP parameters, the data collected at baseline and at 6-month follow-up included age, sex, healthcare center location , type of health facility , smoking status (smoker/non-smoker), body mass index .The baseline characteristics were presented as frequencies and percentages for categorical variables. Means plus/minus standard deviations (SD) were used for continuous variables. The chi-square test was used to compare the differences between the groups for categorical variables, and ANOVA or the Kruskal-Wallis test was used for continuous variables, as appropriate. Factors independently associated with changes in BP at 6-month follow-up were determined using Wilcoxon’s signed-rank test and the Mann-Whitney U test or Kruskal-Wallis test, as appropriate. Univariate and multivariate logistic regression analyses were performed to identify the factors associated with increasing the likelihood of achieving BP targets according to each guideline. Odds ratios (OR) with 95% CIs were calculated. A 2. The majority of patients were women (53.7%) and received care in primary care centers (60.1%). A higher baseline BP (≥140/≥90 mmHg) was significantly associated with higher BMI and treatment in primary care settings.In total, 5308 patients aged 18 years or above who registered for hypertension treatment across 54 SEHA facilities in Abu Dhabi, UAE, were identified. The baseline characteristics of these patients are summarized in At baseline, 28.4%, 29.2%, 29.2%, and 24.6% of the subjects had stage 1 hypertension according to the ACC/AHA, ESC/ESH, NICE, and ISH guidelines, respectively. More details on the distribution of BP according to international guidelines are shown in Among those newly diagnosed as hypertensive, different classes of antihypertensive drugs were prescribed as monotherapy (71.5%) or combination therapy (28.4%). The most frequently used antihypertensive drugs were angiotensin-convertase inhibitors/angiotensin receptor blockers (ACEi/ARBs) (31.4%), followed by calcium channel blockers (CCBs) (17.5%) and beta-blockers (15.4%). Furthermore, the proportion prescribed a combination of ACEi/ARBs with CCBs or diuretics was 18.1% and 10.2%, respectively. More details are given in p < 0.001), and a reduction in DBP of −1.15 mmHg  was observed in men. For women, a significant reduction was observed in SBP by −0.84 mmHg  but not in DBP (0.22 mmHg) . The average changes in DBP and SBP were significantly different between men and women . Moreover, significant differences in SBP (p < 0.001) and DBP (p < 0.001) were observed across healthcare settings. The hypertensive patients treated in primary care settings showed a significant reduction in SBP by −2.31 mmHg,  and in DBP by −2.15, ; however, no such differences in SBP were observed for patients treated in secondary and tertiary care settings, as shown in At 6-month follow-up, a significant average reduction in SBP of −1.68 mmHg , according to the ACC/AHA guidelines, 43% (95% CI: 41.6–44.3) for the ESC/ESH guidelines, 65.7% (95% CI: 64.4–66.9) for the NICE guidelines, and 40.9% (95% CI: 39.5–42.3) for the ISH guidelines. 2 achieved the ACC/AHA-recommended BP goal (<130/80 mmHg).The achievement of BP goals according to each set of guidelines was stratified by age, smoking status, BMI, and diabetes status, as presented in 2 is a significant predictor of achieveing the ACC/AHA-recommended BP goals . Similar findings were observed for the ESC/ESH  and ISH  goals. On the other hand, the ESC/ESH and NICE goals were associated with secondary care settings .The factors that are significantly associated with achievement of each guideline-recommended BP goal in hypertensive patients are shown in 2 were associated with achievement of the BP targets recommended by the ACC/AHA guidelines , the ESC/ESH guinelines , and the ISH guidelines . More details are shown in After adjusting for multiple covariates, the guideline-recommended BP goal was more likely to be achieved by those who maintained a normal BMI and were treated in secondary healthcare settings. Briefly, those with a BMI of <25 kg/m2 and ≥30 kg/m2, and people with diabetes was dramatically low. Those who had a normal BMI and were treated in secondary care settings were more likely to achieve the guideline-recommended BP targets.This is the first study to report contemporary data regarding changes in BP and the achievement of guideline-recommended targets for BP in newly diagnosed hypertensive patients. It also identified factors that could increase the likelihood of achieving the BP targets according to each guideline. After 6 months of treatment, the overall average reduction in SBP and DBP was only 1.23 mmHg and 0.4 mmHg, respectively. Moreover, the current study found that 60% of the subjects did not achieve the target BP recommended by the ACC/AHA guidelines, in contrast to subjects meeting the ESC/ESH guidelines (43%), the NICE guidelines (65.7%), and the ISH guidelines (40.9%). Notably, achievement of the guideline-recommended BP targets among young patients (≤40 years), smokers, those with a BMI of ≥25 kg/mThe primary analysis of this study focused on changes in BP after 6 months of antihypertensive treatment, starting from initiation. The results showed a broad difference in changes in SBP (−1.23 mmHg) and DBP (−0.4 mmHg) in 6 months. The magnitude of the BP changes in 6 months varied across the study population on the basis of age, sex, and healthcare setting. To the best of our knowledge, no studies in the UAE or the Middle East have used longitudinal data to date to investigate the changes in BP in the Arabian population. Prior studies from the Western countries demonstrated that greater visit-to-visit changes in BP over time were associated with an increased risk of CVD events, irrespective of the mean BP level ,26. A reAdopting a lower BP threshold for hypertension ≥130/80 mmHg) and setting stringent target BP goals emphasizes the importance of early preventive measures and non-pharmacological interventions. Despite this, studies continue to record inadequate control of BP ,29,30,31/80 mmHg The current study data revealed that achievement of the BP goals recommended by the four different guidelines across hypertensive patients in different age groups was substantially low. Furthermore, a marginal difference in the achievement of guideline-recommended BP goals was observed between the groups. These variations were also reflected across all the guidelines compared. Although the underlying reasons for the association between the groups and less improved BP control were unclear, this putative relationship warrants further elucidation. The improved BP control among these patients may be partly explained by the comprehensive promotion of a healthy lifestyle, such as adequate physical activity, low saturated fat intake, low-salt meals, and medical information provided by counselors regarding the CVD risks related to hypertension.The notable findings of this study are the overall high rate of BP goal achievement among patients maintaining a normal BMI. These patients are more likely to achieve the guideline-recommended BP targets (except for the NICE recommendations). As shown in the guidelines, the first step of intervention in newly diagnosed hypertensive patients is lifestyle changes such as consuming a heart-healthy diet (DASH), increasing physical activity, and weight loss for those who are overweight or obese ,17,18,19On the other hand, a recent Cochrane review observed that a 4.0-kg reduction in body weight reduced SBP and DBP by 4.5 mmHg and 3.2 mmHg, respectively, and significantly reduced cardiovascular mortality  in hypertensive individuals . A meta-In this study, about 15% of patients were managed in secondary care settings and were more likely to achieve the BP targets recommended by four different international guidelines. Additionally, the magnitude of the changes in BP in 6 months varied significantly for each setting. A study conducted by Billups et al. investigated the BP control among 86,512 hypertensive subjects in the USA by applying a BP cutoff of <140/90 mmHg . They obThis is the first study that investigated hypertension control and achievement of BP goals in a nationally representative sample of hypertensive patients in the UAE since the 1998 NASH-UAE study . TherefoThe current study has some limitations. First, the present study relied on automated office BP measurements from an electronic medical record; however, this method of determining hypertension has been widely applied in previous studies ,45,46, aThis study showed suboptimal BP control across the study population and identified variations in the BP goals according to the ACC/AHA guidelines vs. the ESC/ESH, NICE, and ISH guidelines in the UAE population. Furthermore, the overall average reduction in BP within 6 months was only 1.23 (SBP) and 0.4 (DBP) mmHg. We found that hypertensive patients with a normal BMI and those who were treated in secondary care settings were more likely to achieve the guideline-recommended BP targets. BP control efforts should also prioritize improving cardiometabolic goals and lifestyle changes at an early stage of hypertension.


Aim of this study was to explore whether differences in resting hemodynamic parameters may be associated with tilt test results in unexplained syncope. We analyzed age, gender, systolic (SBP), diastolic blood pressure (DBP) and heart rate (HR) by merging three large databases of patients considered likely to be of vasovagal reflex etiology, comparing patients who had tilt-induced reflex response with those who did not. Tilt-induced reflex response was defined as spontaneous symptom reproduction with characteristic hypotension and bradycardia. Relationship of demographics and baseline supine BP to tilt-test were assessed using logistic regression models. Individual records of 5236 patients  were analyzed. Tilt-positive  vs tilt-negative patients had lower SBP , DBP  and HR . In multivariable analyses, tilt-test positivity was independently associated with younger age (Odds ratio (OR) per 10 years:1.04; 95% confidence interval (CI), 1.01–1.07, p = 0.014), SBP ≤ 128 mmHg , HR ≤ 69 bpm , and absence of hypertension . In conclusion, among patients with suspected reflex syncope, younger age, lower blood pressure and lower heart rate are associated with positive tilt-test result. Thus, it is claimed that TT offers limited diagnostic value in those for whom it is most needed3. In this study we aimed to offer an alternative explanation for why some subjects with likely reflex syncope faint during tilt testing and others do not. The ISSUE 3  set out to identify patients with recurrent syncope, unexplained but thought likely to be of reflex origin in older patients who had received a dual-chamber rate-drop response pacemaker after documentation of an asystolic reflex episode4. Unexpectedly, patients with positive pre-implant-tilt were relatively unprotected against recurrent syncope during the pacing phase. In contrast, patients with negative pre-implant tilt-testing had a very low incidence of recurrent syncope5. The new interpretation of tilt-testing incorporated a susceptibility to vertical posture stress, possibly co-existing with any cause of syncope. This so-called ‘hypotensive susceptibility’ is caused by a vertically induced fluid shift, and is associated with the hypotensive (vasodepressor) aspect of reflex syncope3.Tilt-testing (TT) was first introduced for clinical diagnosis of reflex syncope in 19866. Other recent studies have emphasized the primary role of hemodynamic changes in the mechanism of impending reflex syncope during TT8. In this large 3 center series of consecutive suspected reflex syncope, we aimed to explore whether differences in resting hemodynamic parameters may be associated with tilt test results in patients with suspected reflex syncope.Recently, we have identified a specific cardiovascular profile in patients with reflex syncope, characterized by lower systolic blood pressure (SBP), elevated heart rate (HR), and diastolic (DBP) compared with the general population9.We analyzed individual values of resting supine BP and HR collected between 2003 and 2019 in three large databases of patients who had undergone TT for unexplained syncope, in tertiary syncope investigation units of hospitals in Lavagna, Italy (n = 2798), Florence, Italy (n = 805), and Malmö, Sweden (n = 1633). Consecutive patients who had undergone TT for diagnosis of syncope were included. Those with classical orthostatic hypotension (OH) and suspected postural orthostatic tachycardia syndrome (POTS) were excluded. Hypertension was defined as a clinical diagnosis of hypertension and antihypertensive medication reported by the patient. Despite the long study period, indications, methodology and interpretation of TT results remained unchanged during this time and were very similar to the recommendations of the current ESC syncope guidelines9. The protocol consisted of at least 10-min supine period, a 20-min passive phase at a tilt angle of 70°, followed by a 15-min nitroglycerine-potentiated phase  if syncope was not induced during the passive phase10. Positive response was defined as reproduction of spontaneous symptoms in the presence of bradycardia and hypotension9. In all three centers, baseline hemodynamic data were obtained in the supine position prior to TT, using validated non-invasive beat-to-beat hemodynamic monitors, Task Force Monitor  in Florence and Lavagna, and Nexfin  or Finapres Nova monitors  in Malmö12. The monitors were calibrated before measurement using brachial cuff and oscillometric method according to the manufacturer’s instructions. As the monitors render beat-to-beat data, an average value of a hemodynamically stable period of 10 (Florence and Lavagna) or 30 s  was recorded in the database. Data on baseline heart rate were unavailable in one of the three study-centers . The patient information was de-identified before merging databases. Ethical approval for original data collection was obtained by an appropriate institutional review board: "Comitato Etico Regionale" of Regione Liguria, Italy for Lavagna cohort, "Comitato Etico Area Vasta Centro, AOU Careggi, Florence”, for Florence cohort, and Regional Ethical Review Board in Lund, Sweden for Malmö cohort, and all participants gave their written informed consent. According to Italian and Swedish law, the use of anonymous patient data previously collected for patient care, as was the case here, did not require additional ethical approval.TT was performed according to the “Italian protocol” and endorsed by the most recent ESC guidelines on Syncope13, was calculated for merged Lavagna and Malmö databases.We retrieved the following data: age, gender, resting SBP and DBP, HR, and use of antihypertensive drugs although data on HR were not available in the Florence dataset. All the datasets were subsequently merged into one study population. Additionally, rate-pressure product (HR x SBP), a marker of cardiovascular fitness and myocardial oxygen consumptionContinuous data are shown as mean ± standard deviation, whereas frequencies are used to describe categorical data. The method of Kolmogorov and Smirnov was used to check the normality of distributions. Continuous variables were compared by means of the paired Student’s t-test. Paired and multiple proportions were compared by means of Pearson’s chi-square test. Stepwise multiple regression analysis was used to identify the independent factors associated with TT positivity. Multivariable logistic regression was adjusted for age, gender, SBP, and HR, whereas presence of hypertension was adjusted for age, gender and HR only. In addition, the results of the three centers were separately analyzed.https://www.sas.com/sv_se/home.html) and IBM SPSS Statistics software . Statistical significance was set at the 0.05 level and all p-values were two-sided.Analyses were performed using the Statistical Analysis System Software  were prescribed antihypertensive therapy. TT induced reflex syncope in 3129 (60%) patients and did not induce reflex syncope in 2,107 (40%) patients. Five-hundred-and sixty tests were positive during passive TT, and 2569 during drug-potentiated phase. TT was positive in 61% of males and 59% of females.Compared with TT-negative patients, TT-positive patients had lower baseline SBP , DBP  and HR . These differences were present both in males and females with small, but statistically significant, differences: baseline SBP was similar in males and females, but males had higher DBP whereas females had higher HR than males (p = 0.001 for DBP and HR)  logistic regression model (p = 0.083). Tilt testing results and resting hemodynamic parameters stratified according to the study center are shown in Table In this three-center analysis of syncope patients with high pre-test probability of reflex mechanism, we found a slightly different hemodynamic pattern among those who were tilt-test positive. Males and females who had induction of reflex syncope during TT had lower baseline SBP, DBP, and HR compared with those who did not. We propose that patients more resistant to orthostatic stress induced by TT, who have slightly higher BP and HR, may have greater hemodynamic reserve in the face of gravitational challenge.3. Its identification is thought to play a key role in the management of syncope and selection of effective therapy, such as guiding pacemaker therapy in reflex syncope14, as well as to be the reason for the good response to pacing in tilt-negative patients5. In writing of the European Society of Cardiology Guidelines on Syncope 2018, the concept of hypotensive susceptibility was further extended to anticipate that some patients with reflex syncope were constitutionally predisposed to reflex syncope based on presenting a low blood pressure—‘a low blood pressure phenotype’9.Our results suggest that patients with TT-induced reflex syncope may have increased resting vagal tone and/or lower sympathetic tone, both expressed by lower HR, and narrower hemodynamic margins in the face of orthostatic stress, expressed by lower initial BP. Hypotensive susceptibility is suspected to exist in most people, particularly in individuals with a history of syncope6. According to this study, patients who reproduce reflex syncope during TT have lower not only SBP, but also DBP and HR, and may thus represent a more vulnerable subset of syncope population. Recent studies have indicated that TT positivity is associated with neuroendocrine activation characterized by excess epinephrine and vasopressin release16, whereas adrenomedullin seems to play a protective role, probably reducing vessel permeability and acting against intravascular volume reduction during orthostasis15. Further, older age and higher resting SBP have been suggested to predict lower susceptibility to positive tilt-testing17. These findings were supported by Lindenberger et al. who observed upregulation of vasopressin release, reduced cardiac filling and cardiac output in women prone to reflex syncope18. It might be interpreted that vasopressin upregulation is a secondary effect of a relative hypovolemia, compared with non-vasovagal subjects, suggesting a key role of discrete water and electrolyte imbalance in increased tendency to syncope. There, also, remains a tenable possibility that the documented endocrine changes are precipitated by the developing adverse hemodynamic picture i.e. reduced venous return and cardiac filling. Combination of lower circulating blood volume and excessive blood pooling in capacitance vessels during orthostatic challenge may abruptly reduce stroke volume during TT, with a compensatory HR increase, as shown by Buszko et al.19.We have previously reported that individuals investigated due to unexplained syncope of likely reflex mechanism have in general lower SBP, but higher HR and DBP compared with normal population17. This may provoke response from the central nervous system, leading to reflex syncope in extreme situations21. As previously shown, this response occurs when cerebral tissue oxygenation is strongly compromised22.Those with a more pronounced TT sensitivity demonstrate increased epinephrine and vasopressin release during tilt testing and thus appear to be in greater need of circulatory compensation as their resting SBP and DBP are lower23, only younger age but not gender was independently predictive of TT positivity. The protective factors against TT intolerance were resting SBP above 128 mmHg, heart rate above 69 bpm and presence of hypertension, even while prescribed antihypertensive treatment.Although female gender, especially at younger age, is associated with higher syncope incidence24, higher SBP may suggest that those who are capable of tolerating TT have greater intravascular volume, better cardiac filling, and higher systemic vascular resistance compared with those who developed vasovagal syncope during TT. Interestingly, the association of combined heart rate and systolic blood pressure with TT positivity was markedly attenuated in younger women, who are genetically most predisposed to reflex syncope25, a fact that deserves more studies. Hypertension, on the other hand, implies chronic sympathetic activation with increased total peripheral resistance and elevated arterial tone in the precapillary vascular bed26. Arterial hypertension is detrimental for long-term cardiovascular integrity and promotes end-organ damage27, but hypertensive patients seem to be more resistant to orthostatic stress, either due to altered hemodynamic reserve, increased circulating blood volume, chronic neuroendocrine activation and arterial vasoconstriction or by baroreceptor resetting.Higher HR might indicate less vagal tone and more efficient chronotropic compensatory mechanisms. As SBP mainly increases with greater stroke volume, reduced arterial elastance, and, to a lesser degree, with elevated peripheral vascular resistanceThe differences in observed hemodynamic parameters between tilt-positive and tilt-negative patients were small, yet highly statistically significant. Despite these differences having limited clinical applications, they are important for clarifying pathophysiological mechanisms behind reflex syncope susceptibility in some individuals. Future studies might broaden the concept of hemodynamic prerequisite for reflex syncope by using Modelflow estimates of cardiac stroke volume and by applying prolonged and more accurate BP and HR assessment methodology such as 24-h ambulatory BP monitoring and heart-rate variability, as well as peripheral vascular resistance, blood volume, and venous return estimation.28. Thus, the inclusion of hypertensive patients was deliberate in order to pursue the population concept as hypertension is very common in the general population, although we accept that this inclusion constitutes a limitation.The strengths of this three-center study lie in the large number of patients included and almost identical examination protocol, thus minimizing potential inter-center variability. There are some limitations that should be mentioned. Data on baseline heart rate were unavailable in one of the study centers , however, despite this limitation, the results in the remaining two study-centers demonstrated consistency. The study is retrospective with all typical limitations for retrospective analyses. Lower overall stress and sympathetic drive could have contributed to the lower SBP, DBP and HR observed in patients with TT-induced reflex syncope. We are unable to confirm or refute this possibility, however, this does not contradict our study hypothesis of a hemodynamic phenotype contributing to reflex syncope susceptibility. Further, patients without induction of reflex syncope during TT may have suffered syncope due to competing mechanisms such as cardiac arrhythmia but the final diagnoses in this patient group were not available. Finally, in believing that the constitutional nature of a low blood pressure phenotype contributes importantly to hypotensive susceptibility, we found it necessary to include a wide range of ages and hypertensive patients, some of whom were likely to have a similar susceptibility prior to developing their hypertensive disease. Our clinical observations suggest also that some patients reporting a history of reflex syncope in youth that resolves in mid-life, sustain recurrence of syncope once effective hypotensive therapy is introduced and hypertension treatedPatients who develop reflex syncope during tilt testing have significantly lower blood pressure and heart rate compared with tilt-negative patients. In contrast, advanced age and hypertension are two important factors diminishing tilt-testing positivity. Our findings support the concept of a low heart rate and low blood pressure phenotype contributing to reflex syncope susceptibility during orthostatic stress.Supplementary Information.


BackgroundLiraglutide has pleiotropic effects beneficial to patients with cardiovascular and renal risks. These effects have been linked to weight and blood pressure reduction in type 2 diabetes (T2D) patients. However, whether this reduction is similar in all patients regardless of their ethnicity, baseline demographic, or clinical characteristics is unknown. This study aimed to identify the efficacy of liraglutide on weight, glycated hemoglobin (HbA1c), and blood pressure in Saudi patients with T2D who attended King Fahad Hospital of the University and received liraglutide as add-on therapy to other antihyperglycemic agents. The study also aimed to describe the pattern of change in these clinical parameters before and after the treatment and assess whether sex differences affect liraglutide's efficacy.MethodsWe conducted a retrospective longitudinal study reviewing medical records of 220 Saudi patients with T2D treated at King Fahad Hospital of the University (KFHU), in Al-Khobar city in the Eastern Province of Saudi Arabia, from December 2016 to November 2021. Patient cases were included if the patient was Saudi, aged 18 or older, and received liraglutide in a dose of at least 0.6 mg/day for at least three months in combination with other antihyperglycemic agents/diabetes medications. We recorded the effect on patient HbA1c, systolic blood pressure (SBP) and diastolic blood pressure (DBP), body mass index (BMI), and body weight at baseline, during, and after treatment. We used the paired t-test and repeated measure analysis of variance to compare the mean study parameters before and after treatment. Furthermore, an independent t-test was used to compare the mean study parameters among men and women.ResultsTreatment with liraglutide from 0.6 mg/day to 3 mg/day for three to 18 months had optimal results across the outcomes measured in our cohort study. There was a significant reduction in weight from baseline to 18 months from a mean weight of 97.9±20 kg to 96.51±18.45 kg with (p<0.001). Mean HbA1c at baseline was 9.34%±1.95%, dropped to 7.67%±1.11% (p<0.001) at 18 months. Moreover, mean SBP also significantly decreased from 126.61±10.4 mmHg to 122.48±7.29 mmHg by the last follow-up (p<0.001). Mean DBP was 76.54±8.37 mmHg at baseline and decreased to 74.29±6.22 mmHg at last follow-up (p<0.001). Men treated with liraglutide had greater reductions in weight than women throughout the study (p<0.05), and while men had greater reductions in SBP and DBP than women early in treatment (p<0.05), by the end of treatment, there were no significant differences in blood pressure between men and women. Likewise, we saw no significant difference between HbA1c reductions in men and women treated with liraglutide.ConclusionLiraglutide effectively reduces HbA1c, weight, BMI, SBP, and DBP in T2D patients. These study results reflect real-world liraglutide clinical practices from KFHU and can be beneficial for physicians when considering using liraglutide as add-on therapy in this population. It was approved by the United States Food and Drug Administration in 2010 to boost glycemic control in adult patients with type 2 diabetes (T2D). In 2015, it was approved in higher doses than those used in T2D management for treating obesity and high body mass index (BMI) in patients with a BMI≥30 kg/mBoth medically approved versions of liraglutide are instrumental in reducing the risk of cardiovascular factors, including high blood glucose, overweight and obesity issues, high blood pressure, and other severe heart complications like stroke and heart attacks in adults -4. LiragThe approval of liraglutide was a significant medical breakthrough considering that the risk of cardiovascular complications is the primary cause of death and morbidity globally ,8. EstimObesity is widespread across the Kingdom of Saudi Arabia (KSA), and it increases the likelihood of hypertension, certain types of cancer, osteoarthritis, cardiovascular disease, various non-communicable diseases, and T2D . These dFor people with diabetes and obesity, modest weight loss is important. When people with T2D lose weight, their body's glucose tolerance can improve, allowing them to utilize insulin better . MoreoveWe conducted a retrospective longitudinal review of the medical records of 220 patients treated at KFUH in Al-Khobar city in the Eastern Province of Saudi Arabia from December 2016 to November 2021. The study included Saudi 18 years or older patients with T2D who received liraglutide in a dose of at least 0.6 mg/day for at least three months. Patients were excluded from the study if they were non-Saudis, received liraglutide in a dose <0.6mg/day for less than three months, had bariatric surgery during the treatment course or were diagnosed with thyroid disorders, iron deficiency anemia, or hypertension treated with medication. Figure Sample sizeThe minimal sample size required to represent the whole population was calculated using Epi Info™ for mobile software . The calculation included the total number of patients treated at KFUH and received liraglutide (n=359), the prevalence of weight reduction was assumed to be 50%, the confidence interval was assumed to be 95%, the margin of error was assigned to be 4.1%, the design effect was 1.0, and the cluster was 1.Data collection techniques and toolsWe reviewed relevant electronic health records (EHRs) at KFUH for patients receiving liraglutide during the study. We documented patient sex, sociodemographic data, use of liraglutide (doses and duration), weight before and after liraglutide use, height, HbA1c, systolic blood pressure (SBP), diastolic blood pressure (DBP), comorbidities, history of bariatric surgery, lifestyle, diet, smoking status, and use of other medications. Patient records that met the inclusion criteria were imported to a Microsoft Excel  spreadsheet, then transferred to IBM SPSS Statistics for Windows, Version 28.0.  for analysis.Data processing and analysisFrequency tables were drawn to explore the findings. Measures of central tendency and measures of dispersion were calculated for quantitative data. We used frequency and percentage tables for categorical variables' descriptions to assess relationships. We used paired t-test and repeated measure analysis of variance to compare the mean study parameters before and after treatment. Furthermore, an independent t-test was used to compare the mean study parameters among men and women. We considered p<0.05 as statistically significant.A pilot study performed on a random sample of 10 EHR cases confirmed the feasibility and accessibility of the main study design. A reliability test was conducted using Cronbach's Alpha test . We maintained patient confidentiality, and no identifying information was collected or divulged.2, mean HbA1c was 9.34%±1.95%, mean SBP was 126.6±10.4 mmHg, and the mean DBP was 76.5±8.3 mmHg. The study population consisted of 131 women (59.5%) and 89 men (40.5%). Most participants were married  and unemployed . We noted a significant decrease in mean HbA1c from 9.34%±1.95% at baseline to 7.67%±1.11% at the last follow-up (p<0.001). Mean SBP also significantly decreased from 126.61±10.4 mmHg to 122.48±7.29 mmHg by the last follow-up (p<0.001). Mean DBP was 76.54±8.37 mmHg at baseline and decreased to 74.29±6.22 mmHg at the last follow-up (p<0.001).We recorded changes over time in clinical parameters, including weight, BMI, HbA1c, SBP, and DBP in Table The differences in liraglutide effects on clinical parameters, weight, HbA1c, SBP, and DBP according to patient sex are presented in Table This study aimed to identify the efficacy of liraglutide on weight, HbA1c, and blood pressure in Saudi patients with T2D who attended KFUH and received liraglutide as add-on therapy to other antihyperglycemic agents. While similar studies have been conducted on other ethnic populations ,15, this2, and given that obesity is highly associated with T2D, this finding is not surprising [Most of the 220 patients included in our study were women (59.5%), which aligns with previous reports that T2D is more common in female patients , includirprising . The higWeight reduction has a significant impact on the cardiovascular outcomes of patients with diabetes . Sanjoy Previous studies have reported that liraglutide is effective in helping to control hyperlipidemia, with a reduction in total cholesterol of 5.01 mg/dl from baseline after liraglutide treatment . While oLiraglutide effectively reduces HbA1c as monotherapy and in combination with oral antihyperglycemic agents, as demonstrated in the LEAD 2 and LEAD 3 studies ,25. TreaMean SBP and DBP significantly decreased in our study, which was likely due to the positive effects of weight and diabetes control on blood pressure or the direct antihypertensive effect of liraglutide. This supports findings reported by Robinson et al. in their meta-analysis, who noted that GLP-1 receptor agonists significantly decreased SBP in patients with T2D compared to placebo and active controls . HoweverFinally, liraglutide had a significantly greater effect on weight (p=0.003) in men than women. Liraglutide affected SBP and DBP differently in men and women; however, no significant difference in efficacy between the sexes was seen at the end of the study period. This finding of a difference in weight reduction between men and women using liraglutide has not been previously reported and needs further exploring in future studies.Limitations and strengths of the studyOur study had several important limitations. This was an observational study, which results less solid than those from randomized controlled studies; however, it does not impact its reliability. This study targeted a small part of the Saudi population, limiting our results' generalizability. However, it is the only study thus far to report on the use of liraglutide in the Saudi population and reflects real-world clinical practice in this region. Another limitation of this study is the loss of follow-up for some patients, which reduced the sample size. This study was not designed to look at the safety and tolerability of liraglutide, two facets that would have added value to the study.This study aimed to elucidate the effect of liraglutide therapy as an add-on to other antihyperglycemic agents on weight, blood pressure, and diabetic control in patients with T2D. Liraglutide as an add-on therapy is significantly effective in reducing weight, HbA1c, and blood pressure in Saudi patients with T2D. Moreover, liraglutide has a significantly larger weight reduction effect in men than women. Our results provide further insight into the benefits of liraglutide in this part of the world, a medication that might eventually improve the overall health of T2D patients and enhance their cardiovascular outcomes.


Background: CO2-derived parameters are increasingly used to identify either low-flow status or anaerobic metabolism in shock resuscitation. However, the performance of CO2-derived parameters in cardiac surgical patients is poorly understood. This study aims to compare the performance of lactate and CO2-derived parameters in predicting major postoperative complications after cardiac surgery with cardiopulmonary bypass.Methods: This is a prospective, single-center, diagnostic accuracy study. All patients who receive elective cardiac surgery involving cardiopulmonary bypass will be screened for study eligibility. Blood samples will be taken for the calculation of CO2-derived parameters, including the venous-arterial difference in CO2 partial pressure (PCO2 gap), venous-arterial difference in CO2 content to arterial-venous O2 content ratio (Cv-aCO2/Ca-vO2), and venous-arterial difference in CO2 partial pressure to arterial-venous O2 content ratio (Pv-aCO2/Ca-vO2) at ICU admission, and 3, 6, and 12 h later. Baseline, perioperative data will be collected daily for 7 days; patients will be followed up for 28 days to collect outcome data. The primary endpoint is the occurrence of major postoperative complications. Receiver-operating characteristics (ROC) curve analysis will be carried out to assess the predictive performance of lactate and CO2-derived parameters. The performance of the ROC curves will be compared.Discussion: The performance of lactate and CO2-derived parameters in predicting major postoperative complications will be investigated in the non-sepsis population, which has not been extensively investigated. Our study will compare the two surrogates of respiratory quotient directly, which is an important strength.Trial Registration: ChiCTR, ChiCTR2000029365. Registered January 26th, 2020, http://www.chictr.org.cn/showproj.aspx?proj=48744. Complications after cardiac surgery  are associated with high morbidity and mortality –3. One cLactate is the most widely adopted biomarker of tissue hypoxia. The occurrence rate of hyperlactatemia is ~10–20% in patients receiving cardiac surgery . It has 2-derived parameters have attracted both clinicians' and researchers' attention (2) and the central venous oxygen saturation (ScvO2) reflect the oxygen exertion rate. However, they are often in a normal range or even in a supra-normal level in septic shock despite the presence of tissue anaerobic metabolism, partly due to microcirculatory shunting or the inability of the tissues to use oxygen , or both  is a useful index of the adequacy of cardiac output (CO) for the global metabolic conditions. In other words, a decrease in CO results in an increased PCO2 gap and vice versa. However, it fails when it serves as a marker of tissue hypoxia and anaerobic metabolism  could serve as a marker of global anaerobic metabolism . Thus, Cv-aCO2 can be estimated at the bedside by PCO2 gap, where the κ is the factor defining the relation between CO2 partial pressure and CO2 content.Recently, a series of COttention –15. Curr or both , 17. CO2lsewhere ; one cantabolism . In conttabolism . Due to 2-derived parameters are increasingly used to identify either low-flow status (PCO2 gap) or anaerobic metabolism (Cv-aCO2/Ca-vO2 and Pv-aCO2/Ca-vO2) in shock resuscitation, particularly in septic shock  in predicting major postoperative complications after cardiac surgery with cardiopulmonary bypass.The above-mentioned COic shock , 22. Howk  will be approved by the Ethics Committee.The study protocol and consent forms were approved on January 21st, 2020, by the Ethics Committee of Fujian Provincial Hospital . The study was registered on January 26th, 2020, at the Chinese Clinical Trial Registry (ChiCTR2000029365). Details including the items from the World Health Organization Trial Registration Data Set can be found on A study coordinator will be introduced to the family after the eligibility screen. The ICU physician will ensure that the family is aware of the study coordinator's credentials. The study coordinator will describe every relevant aspect of the project. Meanwhile, the study coordinator will frequently pause to ask if there is any question or request and ask the family to repeat the topic being discussed in their own words to ensure that they understand. It will be emphasized that the participants are free to decline consent without consequences and that they can withdraw consent at any time. Written consent will be obtained in the presence of a witness.2 is O2 consumption, CO is cardiac output, CaO2 is arterial O2 content, CvO2 is venous O2 content, VCO2 is CO2 production, CaCO2 is arterial CO2 content, CvCO2 is venous CO2 content.According to Fick's equation, we have:2/VO2 represents the respiratory quotient, and therefore, the right part of the equation (Cv-aCO2/Ca-vO2) serves as a surrogate of the respiratory quotient.From Equations (1) and (2), we have:2 partial pressure and CO2 content:2 gap expresses that, to a given VCO2 and κ , the PCO2 gap inversely correlates with CO.The following formula can describe the relationship between CO2 related variables are calculated as follows:2 = (Hb × SaO2 × 1.34) + (PaO2 × 0.0031)CaO2 = (Hb × SvO2 × 1.34) + (PvO2 × 0.0031)CvOThe O2 contents is calculated according to the Douglas formula (2 content = plasma CO2 content × (1 – 0.0289 × Hb) ÷ (3.352 – 0.456 × SO2) × (8.142 – pH)Blood CO2 content = 2.226 × plasma CO2 solubility × plasma PCO2 × (1 + 10pH−pK′)Plasma CO2 solubility = 0.0307 + 0.00057 × (37 – T) + 0.00002 × (37 – T)2Plasma COpK′ = 6.086 + 0.042 × (7.4 – pH) + (38 – T) × [0.00472 + 0.00139 × (7.4 – pH)]CO formula :Blood CThe study setting is the cardiac intensive care unit (ICU) (20 beds) and the department of cardiac surgery (118 beds) at a tertiary teaching hospital.All patients who receive elective cardiac surgery involving cardiopulmonary bypass (CPB) will be screened for study eligibility.The inclusion criteria are (1) Age ≥ 18; (2) Receive elective cardiac surgery involving CPB; (3) Admitted into ICU after the surgery; (4) With an arterial line and a central venous catheter in place. Exclusion criteria are: (1) Acute or chronic kidney disease prior to surgery (2) Acute or chronic hepatic insufficiency prior to surgery; (3) Malpositioning of the central venous catheter (4) History of alcohol abuse; (5) Pregnant; (6) Unwilling to provide consent.via the internal jugular vein or subclavian vein. The initial tidal volume will be ~8 mL/kg, and the respiratory rate will be adjusted to maintain an arterial CO2 pressure (PaCO2) of 35–40 mmHg during the surgery. Sufentanil or remifentanil will be used for analgesia. The neuromuscular blockade will be induced by using rocuronium, cisatracurium or atracurium. Continuous administration of propofol or sevoflurane will be used for anesthesia maintenance. After attaining an activating clotting time (ACT) > 480 s via heparin administration, CPB will be initiated by using an occlusive roller pump  and a membrane oxygenator . The pump flow will be around 2.0–2.6 L/min/m2 during CPB. The mean arterial pressure (MAP) will be maintained at 60–80 mmHg. Cephazolin will be administered as perioperative antibiotic prophylaxis. Patients will be transmitted to and monitored in the ICU after the surgery.The induction will consist of propofol, etomidate, or ketamine as appropriate. Patients will be intubated, and a central venous catheter will be placed 2 or a mixed venous saturation of >60%; analgesics will include sufentanil or remifentanil; sedation will consist of propofol or midazolam; ventilation will be continued until patients are awake, hemodynamic stable and with no bleeding, after that patients will be wean from the ventilator and extubated.The postoperative ICU management will be as follows: fluid infusion ; red blood cells will be transfused to maintain hemoglobin concentration; fresh frozen plasma and platelets will be given when bleeding was suspected; vasopressors and inotropes will be continuously infused to achieve the hemodynamic targets: MAP ≥65 mmHg, urine output ≥0.5 mL/kg, cardiac index ≥2.5 L/min/mvia both arterial line and central venous catheter for blood gas analysis  at ICU admission (T0), and 3 (T3), 6 (T6), and 12 h (T12) later. No personal information will be collected.Once admitted into ICU, demographic data, history of past illness, diagnosis, preoperative ejection fraction, and the New York Heart Association (NYHA) functional classification will be collected. The type of surgery, duration of operation, CPB and aortic clamping, intra-operative transfusion, net fluid balance, and the doses of vasopressors and inotropic agents during the operation will also be recorded. The sequential organ failure assessment score (SOFA) and Acute Physiology and Chronic Health Evaluation (APACHE) II score at enrollment and the daily highest score during the follow-up period will be recorded. Blood samples will be drawn Patients will be followed up for 28 days. The occurrence of major postoperative complications (see below) will be recorded. The duration of mechanical ventilation and length of ICU stay will also be recorded. Daily fluid balance and the highest vasoactive-inotropic score (VIS) will be calculated. VIS will be calculated as dopamine dose (μg/kg/min) + dobutamine dose (μg/kg/min) + 100 × epinephrine dose (μg/kg/min) + 100 × norepinephrine dose (μg/kg/min) + 15 × milrinone dose (μg/kg/min) + 10,000 × vasopressin dose (U/kg/min) .2/FiO2 <300 mm Hg); (3) stroke, defined as an embolic, thrombotic or hemorrhagic cerebral event with persistent residual motor, sensory or cognitive dysfunction; (4) delirium identified using the Intensive Care Delirium Screening Checklist  and the European Society of Intensive Care Medicine (ESICM) guideline  and Socihecklist ; (5) myohecklist ; (6) cirhecklist ; (7) sevhecklist ; (8) abdThe secondary endpoints include the duration of mechanical ventilation, length of ICU stay, ICU mortality, and hospital mortality. Data will be collected and analyzed from all patients, even if they cannot finish the full-term follow-up .The incidence of major postoperative complications in a recent study with a similar definition was 56.5% . Considet-test for normally distributed variables or Mann-Whitney U-test for non-normally distributed variables. Categorical variables will be presented as numbers and percentages and analyzed by using χ2-test or Fisher's exact tests as appropriate. Ordinal variables will be analyzed by using the rank-sum test.EpiData  will be used for data entry and data quality control. Multiple imputations will be used to handle missing data. Perioperative characteristics will be compared according to the occurrence or not of major postoperative complications. Continuous variables will be assessed for normal distribution and presented as means and standard deviations or medians and inter-quartile ranges as appropriate; the inter-group comparison will be performed by using Student's 2-derived parameters. The optimal thresholds for predicting major postoperative complications will be determined by maximizing the Youden index. Sensitivity, specificity, predictive values, and likelihood ratios will be calculated. The performance of the ROC curves will be compared by using DeLong's method (p < 0.05 (two-tailed) will be considered significant. Analyses will be performed by using SPSS Statistical Software  and MedCalc Statistical Software (for the comparison of ROC curves).ROC curve analysis will be carried out to assess the predictive performance of lactate and COs method . A p < 0Only members of the research team will have access to the research data. All data collected will be kept in a patient file and stored in a locker. At the completion of the study, all case report forms will be collated and archived. All electronic files will be password protected. All patient files (hard copy and electronic) will be handled consistent with the regulations of the hospital regarding the retention and disposal of patient records. No interim analyze is planned. The results of this study will be submitted to an international peer-reviewed journal. The results will also be disseminated via national and international scientific meetings. The datasets obtained from the present study will be available from the corresponding author on reasonable request.2-derived parameters are increasingly used to identify either low-flow status and/or anaerobic metabolism in shock resuscitation, they are not extensively investigated in cardiac surgery patients. Most studies focused on the predictive value of the PCO2 gap . The patients/participants provided their written informed consent to participate in this study.All authors edited the manuscript and approved the final manuscript.This study received funding from Fujian Puruikang Medical Equipment Co., Ltd. HC was supported by the High-level Hospital Foster Grants from Fujian Provincial Hospital (Grant Number: 2020HSJJ02). The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.