Insulin resistance (IR) has emerged as a risk factor for coronary heart disease (CAD), but there is currently insufficient data on the association of non-insulin-based IR indexes  with the presence and severity of CAD. Thus, the present study aimed to examine the relationship between these three non-insulin-based IR indexes and CAD, as well as to further compare the predictive values of each index.n = 149) and CAD group (n = 653) according to the angiography results. The triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio, triglyceride and glucose index (TyG index), and METS-IR were calculated according to the corresponding formulas. The severity of CAD was evaluated using the Gensini score (GS). The relationship of the TG/HDL-C ratio, TyG index, and METS-IR with CAD was analyzed, and the predictive values of the indexes were compared.In total, 802 consecutive patients who underwent coronary angiography for suspected CAD from January 2016 to April 2017 were included in this study and were divided into the control group  [95% confidence interval (CI)]: 1.32 (1.02–1.70) and 1.65 (1.32–2.05), respectively}, whereas only the METS-IR was an independent predictor of the severity of CAD [adjusted OR (95% CI): 1.22 (1.02–1.47)]. Further subgroup analysis indicated that statistical significance was observed only among men, younger patients (≤ 60), and patients with prediabetes mellitus (PDM). Receiver operator characteristic (ROC) analysis showed that the METS-IR had the highest predictive value for the prediction of both the presence and severity of CAD.The TG/HDL-C ratio, TyG index, and METS-IR are valuable predictors of the presence and severity of CAD, and the METS-IR has the highest predictive value among the three non-insulin-based IR indexes. Therechnique , but itsechnique . The mosechnique , which iechnique . In thisechnique –11. Thesechnique –16. To oThe present study complied with the Declaration of Helsinki and was approved by the Ethics Review Committee of Qilu Hospital of Shandong University. All patients provided informed consent.This was an observational study involving patients with known or suspected CAD who underwent coronary angiography at Qilu Hospital of Shandong University between January 2016 and April 2017. A total of 1,137 consecutive patients were examined. The exclusion criteria were as follows: history of previous coronary intervention or coronary artery bypass graft, severe valvular heart disease, decompensated heart failure, non-ischemic dilated cardiomyopathy, cerebrovascular disease, symptomatic peripheral arterial disease, renal or hepatic disease , acute or chronic infection and/or inflammation, chronic obstructive lung disease, thyroid and adrenal cortex dysfunction, malignancy, hematologic disease, autoimmune disease, or incomplete medical records. Finally, a total of 802 patients were enrolled in the present study. According to our pre-experimental results, we selected the research factor with the smallest OR (the TyG index) to calculate the sample size. Considering α = 0.05, β = 0.20, and OR = 1.30, a sample size of 603 was required. The sample size of the present study exceeded the calculated sample size.Clinical data, including patients’ demographic data, medical history, laboratory tests, and basic cardiovascular medication information, were collected from medical records by trained clinicians. Resting systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured three times on the right arm and the mean value was considered as the participant’s blood pressure. All blood samples of subjects were collected in the morning after overnight fasting (8 h minimum). The levels of fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), serum creatinine (SCr), and uric acid (UA) were measured using an automatic biochemical analyzer.2). Family history of CAD (FH-CAD) was defined as a history of CAD in a first-degree relative < 55 years  or <65 years . Hypertension was defined as either repeated blood pressure measurements of a SBP≥140 mmHg and/or a DBP≥90 mmHg at rest or the use of antihypertensive medication. According to the American Diabetes Association’s Standards of Medical Care in Diabetes (eGFR(mL/min/1.73m2) = 175×SCr(mg/dL)−1.234×age(year)−0.179×0.79. Non-insulin-based IR indexes were calculated by the following formulas: TyG=Ln[fastingTG(mg/dL)×FPG(mg/dL)÷2] (TG/HDL−C=TG(mg/dL)÷HDL−C(mg/dL) (ln[(2×FPG(mg/dL)) + fastingTG(mg/dL)]×BMI(kg/m2)÷Ln[HDL−C(mg/dL)] (Body mass index (BMI) was calculated as weight (kg) divided by the square of height ÷2] ; TG/HDL−C(mg/dL) ; and MET(mg/dL)] .n = 221); intermediate GS, 32–64 points (n = 215); and high GS, 32–64 points (n = 217).Standard Judkins technique was used for coronary angiography. At least two different plane images were taken for each coronary artery. The results were analyzed by at least two experienced interventional cardiologists. CAD was defined as the presence of obstructive stenosis of >50% of the vessel lumen diameter in any of the main coronary arteries, including the left main coronary artery (LM), left anterior descending artery (LAD), left circumflex coronary artery (LCX), and right coronary artery (RCA), or main branches of the vascular system. The severity of CAD was evaluated by the Gensini score (GS)  accordint-test or analysis of variance (ANOVA) was used to compare continuous variables with a normal distribution. For continuous variables with non-normal distribution, Mann–Whitney U test or Kruskal–Wallis H test was used. Categorical variables were analyzed using the chi-squared test or Fisher’s exact test. The association between GS and non-insulin-based IR indexes was assessed using Spearman’s correlation analysis. Variables were analyzed by univariate logistic regression analysis, and variables < 0.1 in univariate analysis were included in the multivariate logistic regression analysis. The variance inflation factor (VIF) of the variables included in the models was calculated to avoid the result deviation caused by multicollinearity. No evidence of collinearity was found in the models given a VIF≥1.32. We standardized the TG/HDL-C ratio, TyG index, and METS-IR using regression analysis to determine the relationships between the increase of non-insulin-based IR indexes per SD and the presence and severity of CAD. We also performed a subgroup analysis based on gender, age, and DM state to determine the association between the METS-IR and the severity of CAD differed across various subgroups, and p for interaction was calculated. ROC curves were generated for the TG/HDL-C ratio, TyG index, and METS-IR. The maximum Youden index was used to determine the optimal cutoff value. The area under the curve (AUC) was used to compare the diagnostic utility of the presence of CAD and a high GS. A p-value of less than 0.05 was considered statistically significant.Statistical analysis was performed using SPSS version 25.0  and R software version 4.1.3 . Receiver operator characteristic (ROC) curves were generated by MedCalc software version 19.6.4 . PASS version 15.0.1  was used for the sample size calculation. Continuous variables with a normal distribution are presented as the mean ± standard deviation (SD), and continuous variables with non-normal distribution are presented as the median with the 25th and 75th percentiles. Categorical variables are presented as the number and percentage. Independent samples p = 0.010; 8.63 (8.31–8.99) vs. 8.47 (8.16–8.90), p = 0.019; 40.06 (35.50–44.13) vs. 36.91 (33.35–41.20), p < 0.001, respectively].In total, 802 patients were enrolled in the present study, including 653 patients with angiographically defined CAD (CAD group) and 149 patients with normal coronary angiography (control group). The baseline clinical and demographic characteristics are shown in n = 221); intermediate GS, 32–64 points (n = 215); and high GS, 32–64 points (n = 217). The baseline characteristics according to the tertile of the GS are summarized in p = 0.115 and 0.119, respectively). More importantly, the TG/HDL-C ratio and METS-IR were significantly different between the high GS group and non-high GS group , whereas the TyG index showed no statistical difference (p = 0.093)  .In addition, the baseline characteristics were described according to the glucose metabolism status. As shown in r = 0.087, p = 0.027; r = 0.151, p < 0.001, respectively). No significant correlation was observed between the TyG index and GS   .Univariate analysis demonstrated that the following factors were associated with the presence of CAD: age; gender; glucose metabolism status; hypertension; eGFR; UA; single antiplatelet therapy; use of statin, insulin, and other hypoglycemic drugs; TG/HDL-C ratio; TyG index; and METS-IR . MultivaThe results of multivariate logistic regression analysis for predicting high GS suggested that only the METS-IR was an independent predictor of the severity of CAD . For eacp-values for interaction≥0.306), the statistical significance was observed only among men, the younger age group (≤ 60), and patients with PDM  among the non-insulin-based IR indexes. In addition, the METS-IR of 38.2 was identified as the optimal cutoff point for detecting high GS with a sensitivity of 69.1% and a specificity of 48.2% : 0.636 (0.589–0.683)] demonstrated the highest AUC value compared to the TG/HDL-C ratio [0.567 (0.517–0.618)] and TyG index [0.562 (0.509–0.614)] . For theof 48.2% .Our current study demonstrated that the TG/HDL-C ratio and METS-IR were independent predictors of the presence of CAD, and only the METS-IR was an independent predictor of high GS. More importantly, the METS-IR had the highest predictive value for the prediction of both the presence and severity of CAD.Insulin resistance is a general term that characterizes a low response of adipose tissue, skeletal muscle, liver, and pancreas to insulin action. Theoretically, IR plays an important role in the pathogenesis of atherosclerosis, which is the most common cause of CAD. Several mechanisms describing the promotion of CAD by IR have been elucidated, including changes in classic CVD risk factors and alteration of insulin signaling pathways . The InsIn the present study, we found that the TG/HDL-C ratio, TyG index, and METS-IR were significantly higher in the CAD group than in the control group. The TG/HDL-C ratio and METS-IR were significantly different between the high GS group and non-high GS group, and both indexes were significantly positively correlated with GS. The proportion of current smoking was higher in the CAD group compared to the control group, but the difference was not statistically significant. Patients have different smoking characteristics, including years of smoking, the number of cigarettes, and secondhand-smoking exposure. All of these factors may affect CAD, which may have attributed to the lack of significance. The CAD group had a higher percentage of patients taking statins. The lack of significance in the TC, TG, and LDL-C between the groups may have been attributed to the higher usage of lipid-lowering drugs in the CAD group. There were more patients with hypertension in the CAD group, but the difference in SBP and DBP was not statistically significant between the groups. The use of anti-hypertensive drugs affects blood pressure, which may have attributed to the lack of significance. In the present study, patients with DM taking metformin had a lower GS. Previous studies have demonstrated that metformin improves cardiovascular functions and reduces cardiovascular risks , 31. In Further analysis showed that the TG/HDL-C ratio and METS-IR were independent predictors of the presence of CAD, whereas only the METS-IR was an independent predictor of high GS. The correlations between GS and these indexes were relatively low, and the clinical application value of these indexes needs further research. In the present study, no statistical significance was found in the prediction of CAD severity by the TG/HDL-C ratio and TyG index after adjusting for confounders, which was consistent with previous studies , 33. YunIn the present study, we found that single antiplatelet therapy was an independent predictive factor for the presence of CAD. However, dual antiplatelet therapy, instead of single antiplatelet therapy, was significantly associated with high GS. Single antiplatelet therapy is widely used for the prevention and treatment of CAD, whereas dual antiplatelet therapy is used for patients with acute coronary syndrome who may suffer from more severe CAD. The different indications of single and dual antiplatelet therapy may explain our findings.In the subgroup analyses, the significant association between the METS-IR and high GS was mainly observed among men, younger patients, and patients with PDM. The Tehran Lipid and Glucose Study (TLGS) has also reported differences in the association between the TyG index and CVD in different age and gender groups . The incPrediabetes mellitus is an intermediate metabolic state between normal glucose regulation (NGR) and DM. Previous studies have shown that patients with PDM have a higher rate of CAD and a worse prognosis . PatientBello-Chavolla et al. found that the METS-IR has a good and significantly higher diagnostic performance of incident T2DM compared to the TyG index and TG/HDL-C ratio in Mexican subjects . A studySeveral limitations of this study should be considered. First, this was a single-center retrospective study, indicating that potential bias may have been introduced. Second, as with many clinical studies, this cross-sectional study only showed association rather than causation. Third, the sample size was relatively small, which might influence our results. Fourth, the values of inflammatory markers were not measured in most patients, preventing the investigation of the associations between non-insulin-based IR indexes and inflammation. Finally, we did not record nutritional habits and physical activities, which may affect non-insulin-based IR indexes. Additional multicenter, large-size, and prospective studies may strengthen our conclusion.In conclusion, the present findings demonstrated that non-insulin-based IR indexes are valuable predictors of the presence and severity of CAD and that the METS-IR has the highest predictive value among the three non-insulin-based IR indexes. Thus, these findings suggested that the METS-IR is a simple, inexpensive, and timely index for the prevention and management of CAD.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethics Review Committee of Qilu Hospital of Shandong University. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.ZW, JY, and TZ drafted and revised the manuscript, contributed to the conception, and design of this manuscript. HC, WL, and YZ contributed to the case collection and database organization. LL, ZL, WZ, ZW, and JY performed the statistical analyses. All authors revised the manuscript critically for intellectual content, agreed to be accountable for the work and to ensure that any questions relating to the accuracy and integrity of the manuscript are investigated and properly resolved, and approved the final version.


To quantitatively evaluate the impaired perfusion status of patients with symptomatic internal carotid artery (ICA) steno-occlusive disease and to explore the risk factors of impaired perfusion with computed tomography perfusion (CTP).n = 99 (52.9%)] and those without impaired perfusion [n = 88 (47.1%)]. Symmetrical bilateral internal watershed areas were selected as the regions of interest (ROIs). Statistical analysis was made on the status of impaired perfusion and the risk factors of impaired perfusion.The clinical and imaging data of 187 patients with ICA steno-occlusive disease were retrospectively analyzed. The ICA stenosis rate was divided into Grades I–IV , and the circle of Willis was classified as four types (types I–IV). According to the literature, the value of cerebral blood flow/cerebral blood volume (CBF/CBV) of 7.55/min was used as cut-off to predict symptomatic patients. All patients were categorized into two groups: those with impaired perfusion  and type IV  at admission were independently associated with impaired perfusion in the internal watershed areas.Univariate analysis revealed that systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), types of the circle of Willis, and clinical features at admission differed between the two groups (patients with or without impaired perfusion) (MAP and the type of circle of Willis at admission are independent risk factors associated with the impaired perfusion in patients with ICA steno-occlusive disease. Internal carotid artery (ICA) steno-occlusive disease is a leading cause of cerebral ischemia or infarction, especially in the internal watershed areas –3. WaterSeveral studies have identified that hemodynamic impairment of patients with severe stenosis or occlusion of ICA can predict the occurrence of stroke –6. SeverPrevious studies mainly focused on predicting the risk factors of stroke, but reports on risk factors affecting brain perfusion are relatively scarce. Moreover, the relationship between the circle of Willis and impaired perfusion had not been adequately investigated. Thus, we aimed to identify the independent risk factors of the impaired perfusion in the internal watershed areas induced by the occurrence of unilateral ICA steno-occlusive disease. This may help to determine the ideal candidates for further intravascular therapy.This retrospective study was approved by the Institutional Review Board of the General Hospital of the Northern Theater Command, and the study patients or their family members provided written informed consent. The clinical and imaging data of patients with unilateral ICA steno-occlusive disease from 1 January 2019 to 30 December 2021 were collected and reviewed. The inclusion criteria were specified as follows: (1) patients who underwent CTP within 24 h after admission and (2) patients with unilateral ICA stenosis or occlusion (stenosis ≥70%) diagnosed by digital subtraction anwwgiography (DSA). The following exclusion criteria were specified: (1) patients without DSA or with posterior circulation stenosis or bilateral anterior circulation stenosis or ipsilateral anterior cerebral artery (ACA) stenosis (≥50%); (2) patients with severe symptoms after massive parenchymal damage; (3) patients with previous intravenous or intra-arterial thrombolytic therapy, intracranial or extracranial arterial angioplasty, or stent implantation before CTP; (4) cerebral hemorrhage; and (5) patients with incomplete baseline data, such as blood pressure (BP). The following data were collected from each study patient: age, sex, the presence of hypertension, hyperlipidemia, or hyperhomocysteinemia (HHcy), history of diabetes, coronary heart disease (CHD), atrial fibrillation (AF), stroke, current smoking status, alcohol use, left ventricular ejection fraction (LVEF), and admission BP . According to the clinical features, patients were divided into two groups: those in the symptomatic group with TIA or contralateral limb dysfunction within 6 months, and those in the asymptomatic group with no definite symptoms of nervous system ischemia or only mild discomfort .Computed tomography perfusion examination was performed using a 64-slice spiral CT system , and the auditory-canthus-line was used as the baseline for scanning. A high-pressure injection indwelling needle was placed in the right cubital vein, and a high-pressure syringe was connected for plain CT and CTP. An injection of 40 ml iohexol  and 20 ml normal saline was delivered through a high-pressure syringe at 5 ml/s through the cubital vein for CTP imaging. The scanning parameters used included: tube voltage 120 kV, tube current 250 mA, matrix 512 × 512, tube ball rotation time ≤ 1 s, delayed scanning for 5 s, dynamic scanning for 50 s, a layer thickness of 10 mm, 14 layers, and finally 420 whole brain perfusion images were obtained. The NeroPerfusion software package  provided by the Perfusion Workstation was used to evaluate the data from perfusion imaging. The basilar artery and superior sagittal sinus were selected as the input artery and output vein, respectively. The dose length product (DLP) of a patient was 803.04 mGy·cm .Evaluation of ICA stenosis by DSA: According to the North American Symptomatic Carotid Endarterectomy Trial (NASCET) , the ICARegions of interest (ROIs): ROI measurements were based on the two types of internal watershed infarction (IWI) described by classical neuropathological studies, an infarction involving the corona radiata and the other involving the centrum semiovale . Because2) located within the centrum semiovale on the affected side were selected synchronously on the CBF and CBV parameter map, the midline of the brain was considered as the center line, and the symmetrical ROIs on the healthy side were automatically generated using the CTP software .–18.2) loIn contrast to CBF and CBV taken separately, CBF/CBV would be a more reliable indicator to evaluate the state of cerebral perfusion. The decreased CBF/CBV <7.55/min) in hemispheres with ICA steno-occlusive disease was categorized as impaired perfusion, which is consistent with the previous research results .55/min i. Based oThe computed tomography perfusion source imaging (CTP-SI) evaluation of the circle of Willis was based on the classification criteria reported by Hartkamp et al. . The claA fetal-type posterior (FTP) cerebral artery is defined as a PCoA originating from the ICA and extending directly to the posterior communicating segment of the ipsilateral posterior cerebral artery (PCA), and the diameter of the PCoA is larger than the P1 segment of the ipsilateral PCA originating from the basilar artery .According to a previous study , the vart-test was used for comparisons of measurements that were consistent with normal distribution. The Pearson chi-squared test and Fisher's exact test were used to analyze categorical variables. Univariate and multivariate logistic regression analyses were applied for CTP parameters in healthy and affected sides. Univariate and multivariate logistic regression analyses were applied for CTP parameters and clinical data in the symptomatic group and the asymptomatic group. Multiple logistic stepwise regression analysis was performed to identify independent risk factors associated with impaired perfusion. Univariate analysis of variance (ANOVA) was used to compare the differences of the CBF/CBV value among different vascular variants of the circle of Willis, and then the least significant difference (LSD) method was used for multiple pairwise comparisons. Interobserver agreement was assessed using a single measure statistic . ICC > 0.75 was considered as excellent . Normally distributed data were described as means and standard deviation (SD). Categorical variables were described as frequency or percentage. Independent sample xcellent . StatistIn this study, there were 187 patients  with unilateral ICA steno-occlusive disease . Among them, 88 were in the group without impaired perfusion (34 were symptomatic), and 99 were in the group with impaired perfusion (75 were symptomatic).Of 109 symptomatic patients, the mean CBF of affected and healthy sides was 10.30 ± 3.07 and 14.55 ± 4.07 ml/100 g/min; the mean CBV of affected and healthy sides was 1.54 ± 0.49 and 1.54 ± 0.49 ml/100 g; and the mean CBF/CBV of affected and healthy sides was 6.85 ± 1.44/min and 9.74 ± 2.07/min, respectively.Of 78 asymptomatic patients, the mean CBF of affected and healthy sides was 13.00 ± 3.93 and 15.23 ± 4.39 ml/100 g/min; the mean CBV of affected and healthy sides was 1.43 ± 0.34 and 1.50 ± 0.41 ml/100 g; and the mean CBF/CBV of affected and healthy sides was 9.22 ± 2.98/min and 10.43 ± 2.56/min, respectively.The degree of agreement between readers was excellent for CBF (ICC = 0.957) and CBV (ICC = 0.960)./with impaired perfusion), with respect to admission BP , types of the circle of Willis, and clinical features (p < 0.05). No differences in age, sex, hypertension, hyperlipidemia, HHcy, diabetes, CHD, AF, stroke, current smoking status, alcohol use, ICA stenosis rate, and LVEF were found between the two groups (p > 0.05)  .p < 0.001] and the type of circle of Willis [type IV ] were independently associated with impaired perfusion of the internal watershed  = 0.946, 95% confidential interval (CI) = 0.917–0.974, atershed .p < 0.001; OR = 0.408, 95% CI = 0.309–0.539, p < 0.001)  .p < 0.001) (p < 0.001)  . Univari< 0.001) .The CBF/CBV value of 7.55/min was the best cut-off value for predicting symptomatic patients as shown by the receiver operating characteristic : 0.800, sensitivity: 0.690, and specificity: 0.747) .F = 3.131, p = 0.010). Pairwise comparisons indicated that the CBF/CBV in patients with an ipsilateral FTP and patients with an ipsilateral FTP and incomplete anterior circulation was significantly lower than that in patients with a complete circle of Willis  (Univariate ANOVA showed that there were significant differences in the CBF/CBV of patients with different vascular variants of the circle of Willis (= 0.002) .The evaluation of the status of cerebral perfusion in patients with a stenotic or occluded ICA before treatment is essential. A few studies have shown that patients with impaired perfusion in the hemisphere ipsilateral to a stenotic ICA may have an increased risk of ischemic stroke than those with normal perfusion , 26. OurIn this study, impaired perfusion in the internal watershed area was associated with decreased MAP levels. This finding is consistent with that of Yamauchi's finding that effective BP management could facilitate reperfusion and play a protective role in ischemic brain tissue . As an iFrom the findings of our study, we think that impaired perfusion was not associated with the ICA stenosis rate, but impaired perfusion was associated with the type of circle of Willis (type IV) and FTP. Thus, we hypothesized that when the unilateral ICA was severely stenosed or occluded, the restricted ipsilateral carotid blood flow might be compensated by the circle of Willis and an adaptive expansion of cerebral vessels. The carotid stenosis rate may not fully reflect the cerebral perfusion situation or an ischemic event . As we kMedullary arterioles in the watershed areas showed insufficient self-regulation, and there was no compensatory dilation of pial vessels. If a patient had an incomplete circle of Willis, the redistribution of blood flow would be affected and result in a markedly negative effect .However, variants of the circle of Willis are diverse and the compensatory capacity of different variations also varies. Therefore, we also evaluated the effect of single-vessel variation on CBF/CBV. In this study, we suggest that the presence of an FTP, with or without an incomplete anterior circulation, was a risk factor for impaired perfusion in the internal watershed area. On the single side of the FTP, the ICA supplies blood to both MCA and PCA, which affects the onset of a secondary collateral flow between the ICA and vertebrobasilar arterial system. This leads to a bilaterally imbalanced CBF, and the perfusion pressure of the affected side is relatively lower than that of the opposite side.Patients with unilateral ICA steno-occlusive disease, combined with an ipsilateral FTP, have been reported to exhibit a marked reduction in the ipsilateral cerebral perfusion pressure. In addition, they are more likely to show decompensation and infarction involving watershed areas . BisschoPrevious studies have reported that ICA with severe stenosis or occlusion combined with elevated blood viscosity and an elevated risk of clotting may lead to a cerebral watershed infarction (CWSI) . HoweverOur results demonstrate that quantitative evaluation of the cerebral perfusion status and risk factors of impaired perfusion in patients with symptomatic unilateral ICA steno-occlusive disease is clinically relevant. If a subgroup of high-risk patients could be correctly identified by clinical doctors, the risk of irreversible cerebral infarction could be reduced. In addition, relevant studies have found that, when brain tissues have weak tolerance to ischemia and hypoxia, it is more likely to have more severe cerebral ischemia or infarction under the influence of ischemic intervention factors .This study had some limitations. The study's sample size was relatively small, and the enrollment bias could not be avoided. A large sample in multiple centers is needed in future studies. Moreover, this study did not consider the effect of mild cerebral vascular stenosis on cerebral perfusion. Finally, BP was measured once at admission and included in the analysis, making it difficult to exclude the fluctuation of BP. A 24-h ambulatory BP should be considered for future studies.In conclusion, admission MAP and the type of circle of Willis were found to be independent risk factors associated with the internal watershed impaired perfusion in patients with unilateral ICA steno-occlusive disease. Variants in the FTP were also associated with decreased CBF/CBV.MAP and the type of circle of Willis at admission may be independent risk factors associated with the impaired perfusion in patients with ICA steno-occlusive disease.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Institutional Review Board of General Hospital of Northern Theater Command. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.XQ, JD, and ZX conceived the project idea and wrote the manuscript. XW and YD provided critical suggestions for the design of experiments. YP, NZ, MQ, and JL collected the imaging and clinical data. ZX and BY supervised the project. All authors contributed to this article and approved the submitted version.This study was supported by Grant No. 202054044 from the Project of Natural Science Foundation of Shenyang and by Grant No. 201602768 from the Project of Natural Science Foundation of Liaoning province.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.


Total hip arthroplasty (THA) is a successful treatment for many hip diseases. Length of stay (LOS) and hospital cost are crucial parameters to quantify the medical efficacy and quality of unilateral primary THA patients. Clinical variables associated with LOS and hospital costs haven’t been investigated thoroughly.The present study retrospectively explored the contributors of LOS and hospital costs among a total of 452 unilateral primary THA patients from January 2019 to January 2020. All patients received conventional in-house rehabilitation services within our institute prior to discharge. Outcome parameters included LOS and hospital cost while clinical variables included patient characteristics and procedural variables. Multivariable linear regression analysis was performed to assess the association between outcome parameters and clinical variables by controlling confounding factors. Moreover, we analyzed patients in two groups according to their diagnosis with femur neck fracture (FNF) (confine THA) or non-FNF (elective THA) separately.P < 0.05). Variables including the American Society of Anesthesiologists classification (ASA), duration, blood loss, and transfusion among the elective THA while the approach, duration, blood loss, transfusion, catheter, and comorbidities (stoke and coronary heart disease) among the confine THA were associated with higher hospital cost (P < 0.05). The results revealed that variables were associated with LOS and hospital cost at different degrees among both elective and confine THA.Among all 452 eligible participants , 145 (32.08%) patients diagnosed with FNF and 307 (67.92%) diagnosed with non-FNF were analyzed separately. Multivariable linear regression analysis revealed that clinical variables including surgery duration, transfusion, and comorbidity (stroke) among the elective THA patients while the approach and comorbidities  among the confine THA patients were associated with a prolonged LOS (Specific clinical variables of the patient characteristics and procedural variables are associated the LOS and hospital cost, which may be different between the elective and confine THA patients. The findings may indicate that evaluation and identification of detailed perioperative factors are beneficial in managing perioperative preparation, adjusting patients’ anticipation, decreasing LOS, and reducing hospital cost. Total hip arthroplasty (THA) is a successful and effective treatment in pain relief and functional restoration for various hip diseases, and it might constitute financial burden for the healthcare system . Cases oPrevious literature already classified the clinical variables possibly affecting the surgical outcomes into two categories including patient characteristics and procedure variables, however, definitive conclusions were not reached among the literatures . Thus, fThe present study intended to investigate the possible impacts of available clinical variables on the LOS and hospital cost of THA patients in our institute and report the THA-relevant economic status in China. We hypothesize that specific patient characteristics and procedural variables are associated with the LOS and hospital cost among unilateral primary THA patients.The study was conformed to Declarations of Helsinki and approved by Ethics Committee of Peking University Shenzhen Hospital No.2020013), which was carried out from January 2019 to January 2020 in Peking University Shenzhen Hospital, a modernized and comprehensive general public hospital. The clinical data of the unilateral primary THA patients were retrospectively analyzed with patients’ consent, and the selection process of patients was illustrated in Fig. 3, which The postoperative patients then received personally tailored rehabilitation services from the rehabilitation experts within our department, rather than transferring to the rehabilitation department or hospital. Of note, per our standard protocol, we applied a conventional rehabilitation program for these patients, instead of the Enhanced Recovery After Surgery (ERAS) .Available clinical variables  were reviewed and collected from the electronic medical record (EMR) retrospectively. The patient characteristics including age, gender, body mass index (BMI), and American Society of Anesthesiologists classification (ASA) of each patient were recorded. Their diagnosis was categorized as hip osteoarthritis (OA), rheumatoid arthritis (RA), ankylosing spondylitis (AS), avascular necrosis (AVN), developmental dysplasia of the hip (DDH), and femoral neck fracture (FNF). Patients were separated into the confine THA (for FNF) and elective THA (for non-FNF) due to the characteristics of the THA . Relevan3 (m) + K2 × mass (kg) + K3,  [Procedural variables were defined as follows: Anesthesia type was categorized as general or regional ; Blood l 0.1833) ; Duratio 0.1833) .The outcome parameters were LOS and hospital cost. The LOS was defined as the period between the admitted date and the discharge date . The hosEven the discharge criteria varied worldwide , the dist-test was applied for normally distributed continuous variables while Mann-Whitney U test was performed for non-normally distributed continuous variables. Less than 1% of patients with missed information were deleted finally. We performed multivariable liner regression analysis to assess the association in LOS and hospital cost with patient characteristics and medical variables. The model was adjusted for gender, age, BMI, diagnosis, comorbidity, ASA, approach, duration, anesthesia, blood loss, transfusion, catheter, and drainage. Patients were analyzed in two groups per diagnosis as FNF (confine THA) and non-FNF (elective THA) separately. The results were displayed in the forest plots. Results are presented as regression coefficients, in companies with 95% confidence intervals (CIs) and P values. The level of significance was set at a 2-sided level of 0.05. All statistical analysis was performed on R version 4.0.2 .The distribution of data was evaluated with the Kolmogorov-Smirnov test. Normally distributed continuous variables were summarized by mean ± standard deviation (SD) while non-normally distributed continuous variables were expressed with median (interquartile range). Categorical variables were summarized by frequency and percentage. The baseline characteristics of participants were compared. Student 2). Patients’ demographic and procedure variables were listed in Tables and details were described as follows.Four hundred fifty-two (452) eligible participants were finally included , the surgery duration , transfusion , and comorbidity of stroke  were associated with the prolonged LOS while the blood loss  was associated with the shorter LOS (P < 0.05) , the approach  and comorbidities , CHD , and DM ) were associated with the prolonged LOS (P < 0.05) . The results were displayed in forest plots. For the elective THA (RP < 0.05) by multivariable linear regression analysis among the elective THA  , the approach , duration , blood loss , transfusion , catheter , comorbidities , CHD  and others ) were associated with higher hospital cost (P < 0.05) , surgery duration , blood loss , and transfusion  were associated with higher hospital cost, while the age , BMI , and drainage use  were associated with lower hospital cost  association between the LOS and currently available factors. Therefore, the additional nonlinear prediction would be considered in our future study. Finally, further prospective studies with more robust experimental designs and larger sample sizes are necessary to confirm the results of this study.The present study has several limitations. First, no casual relationships could be demonstrated in this observational and retrospective study. Second, even though the standard of discharge may be varied among institutions, the standardized discharge criteria used in this study were also well accepted by other Chinese hospitals, performing the in-house orthopedic rehabilitation services for the patients. Moreover, the patients in the present study received conventional in-house rehabilitation services (rather than the ERAS) within our institute prior to discharge, which extends their LOS and yields higher hospital costs. Therefore, our data should be interrupted with caution, especially for those institutes where the rehabilitation protocols are much different from ours. Thirdly, due to the limitation of our dataset and the retrospective nature of this study, we could not obtain all potential patient-relevant clinical variables, which may be the reason for the low ROur study demonstrates that patient characteristics and procedure variables might affect the medical efficacy and quality in terms of the LOS and hospital cost for unilateral primary THA patients. The impacts of these clinical variables are different for the elective and confine THA patients. The preliminary data from this study hint that the possible clinical benefits could be achieved if the practitioners precautiously identify surgical candidates at specific risk levels and modify specific clinical variables.


Advances in the Diagnosis and Treatment in Kidney Transplantation,” a great number of publications within these fields have been published and will be discussed in this Editorial.Kidney transplantation significantly improves patient survival and quality of life in patients with chronic kidney disease (CKD) stage 5 and is thus considered as the current optimal therapy for this patient cohort. More than 21,000 kidney transplantations have been performed in the EU in 2019 . We beliZulpaite et al. reviewed therapeutic potential and challenges of ex-vivo kidney machine perfusion techniques in this Research Topic. Furthermore, two original clinical studies and one experimental study have been published. Zeng et al. performed a small study comparing traditional antegrade perfusion technique with retrograde approach when they cannulated either renal artery or renal vein for hypothermic LifePort Kidney Transporter perfusion. Authors found that both approaches are associated with similar delayed graft function rates and eGFR at 6 months. Clearly, the study was underpowered and future studies are necessary to show this approach may have some advantages over the classical approach. Next, Weissenbacher et al. evaluated hemodynamic and metabolic parameters in normothermic kidney preservation. Normothermic machine preservation has been studied by several groups and this method is about to enter the clinical medicine. Normothermic machine perfusion may eliminate the effect of cold ischemia and allows evaluation of function and metabolic status of the graft and thus may help to decide whether the organ is still suitable for transplantation  of scores for gene sets and classifiers previously identified in various injury states, six injury groups were defined. Two classes of early AKI could be separated showing differences in function, parenchymal dedifferentiation, response to injury, inflammation and graft survival. The most important predictors of function (estimated glomerular filtration rate) and graft loss were injury-based molecular scores, not rejection scores.The molecular microscope developed by d organs . Using id organs  the actuVonbrunn et al. investigated in 26 zero-time biopsies gene expression profiles for different types of subsequent renal transplant complications. They could reveal significant differences between living and deceased donor kidneys mainly due to differences in the cold ischemia time. Genes encoding for immunoglobulins were differentially expressed in biopsies from transplants which later developed rejection corresponding to higher number of CD20+ and CD138+ cells. Acute renal failure before transplantation also had an influence on gene expression. Although transplant biopsies are still the gold standard in routine diagnostic, non-invasive diagnostic from urine or plasma can help to identify patients at risk for renal transplant rejection. Analysis of donor derived cell-free DNA (dd-cfDNA) has been shown to have the potential to detect cases of rejection episodes, with patients with rejection having higher plasma dd-cfDNA levels than patients with stable grafts without rejection . Previously Banas et al. developed a novel, non-invasive method to detect graft rejection via a characteristic constellation of urine metabolites by NMR spectroscopy -incompatibility have a high risk of developing antibody-mediated rejection (ABMR). The purpose of the study by Cucchiari et al. was to evaluate if residual B cell activity after desensitization could be estimated by the presence of circulating B cell-derived extracellular vesicles. In studies on patients before and after desensitization and controls they could demonstrate a significant drop in B cell-derived extracellular vesicles after desensitization and that this paralleled the reduction in CD19+ cells in lymph nodes, while in peripheral blood B cells, this change was almost undetectable.Zero-time biopsies reflect the state of a donor organ before transplantation. In contrast to other organ transplants zero biopsies in kidneys are not routinely performed. ejection . In theiSchuller et al. investigated peripheral blood B cell composition before and after kidney transplantation. They could detect persistent and profound compositional changes within the B cell compartment. Low Transitional B cells, 1 year after KT, may account for the low serological response to SARS-CoV-2 vaccination in KTRs compared to dialysis patients.To unravel the finding why kidney transplant recipients show impaired immune responses to SARS-CoV-2 infection and a reduced efficacy of SARS-CoV-2 vaccination compared to dialysis patients, Osickova et al. found particularly high ABMR rates among recipients with a positive pre-transplant flow cytometric crossmatch (76 vs. 19% among crossmatch-negative recipients), demonstrating a 5-fold increased risk in multivariable analysis. These interesting results are of considerable clinical relevance, as they strongly support the systematic use of flow crossmatch testing in the context of DSA-positive deceased donor kidney transplantation. Moreover, Kälble et al. evaluated allograft outcomes in 38 DSA and/or crossmatch-positive recipients of a living donor transplant following an individualized algorithm of peri-transplant apheresis. Treatment, which included rituximab and/or thymoglobulin, was tailored according to careful immunological risk stratification, among others, based on single bead assay results and/or soluble CD30 (sCD30) monitoring. Patient and graft survival rates were found to be similar to those observed among standard-risk recipients, without differences regarding rejection rates. An interesting observation was that, following transplantation, 56% of the recipients had lost their DSA. ABMR rates in these patients were only 6%, but 60% in recipients with persistent and de novo DSA. In a retrospective study of 287 patients subjected to standard immunosuppression, Drasch et al. evaluated the impact of preformed DSA and sCD30 levels on renal allograft outcomes. In their study, graft survival was significantly lower in DSA-positive as compared to DSA-negative patients. While DSA-positive patients with increased levels of sCD30 had adverse 3-year graft survival, sCD30 levels were not associated with ABMR frequency, DSA persistence and long-term survival. Senn et al. studied a distinct risk constellation—husband-to-wife transplantations with mutual children—which may be complicated by the persistence of alloreactive T and B cells triggered by paternal HLA antigens. Analyzing 25 such transplants in comparison to women with prior pregnancies who received a kidney from other donor sources, they found numerically higher incidences of ABMR and inferior death-censored graft survival, despite the use of T cell-depleting induction therapy. Interestingly, in this cohort, DSA status, number of pregnancies, or the number of HLA-mismatches were not predictive for rejection or graft loss.In the last two decades, antibody-mediated rejection (ABMR) has become a major research focus in transplant medicine, and, today, our knowledge about molecular mechanisms and the manifold phenotypic presentation of this rejection type has improved substantially. Nevertheless, there are large numbers of unanswered questions, some of them now addressed in the context of our present Research Topic. One is the burden of recipient sensitization—a dominant risk factor of ABMR occurrence. Individualized risk assessment in this context may be of decisive importance to adequately guide organ allocation and tailor the composition or intensity of desensitization protocols , 10. TheNoble et al. present a single-center study including 40 renal allograft recipients who all received the anti-IL-6R antibody tocilizumab for chronic active ABMR. Six patients lost their graft within 12 months, but many patients showed stable eGFR, and there was no change in microvascular inflammation scores and the extent of interstitial fibrosis and tubular atrophy. Transplant glomerulopathy scores, however, increased. Even though limited by its uncontrolled retrospective design, this study may suggest that tocilizumab is able to stabilize the decline in renal function and histological rejection lesions, at least in some of the treated patients. There is now accumulating evidence for a role of DSA-negative ABMR, but there is not much known about its pathophysiology or responsiveness to rejection treatment. The latter issue was addressed by Koslik et al. Evaluating 102 renal allograft recipients diagnosed with ABMR, among them 61 with detectable DSA, the authors studied the impact of multi-compound treatment, primarily based on apheresis and intravenous immunoglobulin (IVIG) on allograft outcomes. In case of persistent ABMR increase in maintenance immunosuppression or long-term application of IVIG was used. While late rejection diagnosis and positive C4d staining turned out to be independent risk factors for allograft failure, DSA status did not relate to graft survival. An interesting finding was that DSA-positive recipients showed significantly better allograft survival after long-term IVIG than patients with DSA-negative ABMR. Conversely, the latter exhibited better responses to intensified maintenance immunosuppression. Moreover, there are individual histological and molecular phenotypes of ABMR that may respond differently to treatment. In this context, Sazpinar et al. provide a detailed evaluation of 16 patients presenting with pure chronic active ABMR. The authors evaluated the expression of predefined rejection-related transcripts using NanoString™ technology and evaluated biopsy results in relation to clinical outcomes. In this preliminary small study, treatment responsiveness of ABMR was associated with the extent of microvascular inflammation and transcriptome changes in NK cell and endothelial cell associated genes. Cell therapies treating late ABMR are emerging including the transfer of mesenchymal stem cells (MSC). Still, these therapies might be accompanied by serious side-effects in individual patients as described by Večerić-Haler et al. They describe a single patient case with late ABMR treated with autologous MSC within a study and the patient developed life-threatening symptoms mimicking capillary leakage syndrome, which only resolved after explantation of the kidney graft. The authors speculate that Parvovirus B19 might have mediated the life-threatening condition. These data point to the fact that viral infections might be transferred via cell therapies which result in life-threatening complications for the patient.Treatment of ABMR has remained a major challenge, and evidence for efficacy of currently available anti-rejection treatments is considerably low, especially in chronic rejection. One promising concept of ABMR treatment may be the use of antibodies directed against interleukin-6 (IL-6) or its receptor (IL-6R). Borski et al. confirmed a strong impact of late ABMR on renal allograft survival, demonstrating a 93, 64, 53, and 15% unadjusted overall allograft survival at 1, 3, 5, and 10 years after index biopsy, respectively. In search of surrogate endpoints that allow for accurate prediction of graft survival, they found a strong predictive value of early eGFR decline. An eGFR loss of 1 ml/min/1.73 m2 per year was thereby associated with a 10% (12-month slope) to up to 30% (24-month slope) increase in the risk for future allograft loss. These data strongly support the utility of calculating eGFR slope as a surrogate endpoint of graft failure in ABMR trials. Moreover, in search of biopsy findings that predict transplant outcomes after ABMR diagnosis, Piñeiro et al. studied a retrospective cohort of 90 patients treated for active ABMR, exploring the clinical relevance of persistent inflammation detected in follow-up biopsies. Following treatment with plasma exchange, IVIG and rituximab, microvascular inflammation persisted in 71% and tubulitis in 19% of the biopsies. Persistent inflammation, even despite not strictly meeting any of the Banff rejection categories, was found to strongly associate with graft failure. Retreatment of patients with persistent inflammation was thereby associated with a better prognosis than in untreated patients. Finally, Novotny et al. studied 72 renal allograft recipients exhibiting vascular rejection , in association with TCMR or ABMR features (microvascular inflammation). The authors found that intimal arteritis in conjunction with ABMR was a significant risk factor of transplant glomerulopathy in follow-up biopsies, regardless of DSA status. Among DSA-positive patients with intimal arteritis and microvascular inflammation, resolution of rejection was less frequent .There is definitely a need for well-designed randomized prospective trials to clarify the efficacy of new treatment approaches that are currently in the pipeline. Trial design in ABMR, however, is a challenge, partly because of the requirement of large patient numbers and long periods of follow-up to demonstrate meaningful differences in allograft survival. In a retrospective monocentric study, Végh et al. showed nicely that blood pressure monitoring by 24-h measurements (ABPM) as well as vascular stiffness correlated with the GFR in the long term follow up of pediatric kidney transplantation recipients. Interestingly, there was no correlation of vascular stiffness and ABMR 2 years after transplantation, which points to the fact that CV health is of crucial importance for long-term function of grafts. Protection and/or of vascular calcification is an important step toward an improvement of cardiovascular survival in the chronic kidney disease population including kidney transplant recipients. Supplementation of magnesium has been proposed to be beneficial in treating vascular calcification in animal models (Lahav et al. show in their article in Frontiers in Medicine that serum-magnesium levels correlated inversely with all-cause and cardiovascular mortality in their cohort of kidney transplant recipients. Furthermore, magnesium supplementation did not show a benefit, but was rather associated with worse cardiovascular outcomes. Still, these outcomes might be biased by an improved graft function, which is associated with lower magnesium levels (Yin et al. published a study enrolling 105 kidney transplant recipients, who will be treated with placebo, metformin or empagliflozin. The two drugs will be tested for safety, effectivity, and tolerability in the kidney transplant population. The primary end point is the change in the visceral-to subcutaneous fat area evaluated by MRI as well as inflammatory parameters. This study critically addresses the problem of obesity and PTDM in the kidney transplantation cohort with the great opportunities of new therapeutic drugs such as SGLT-2 inhibitors, which have been shown to improve kidney function and cardiovascular mortality in the CKD cohort (Alloimmune responses are causative for kidney graft loss in a valuable number of our kidney transplant recipient. Still, cardiovascular events as well as infections are major causes of graft loss as well as death with a functioning graft after kidney transplantation . Thus, sl models . In linel models . Contrarm levels . ClearlyD cohort . Still, D cohort , 17.E. coli and Cryptococcus albidus. Both colonized in the transplanted kidney. Yan et al. further show that metagenome sequencing can be utilized as an additional diagnostic tool complementing pathogen detection especially in transplant recipients with unusual infections. In contrast, BK Polyoma virus infection is a frequent problem in kidney transplant recipients associated with an increased probability for graft loss. The study by Omić et al. showed that kidney transplant recipients with an insufficient decrease in BK Polyoma virus titers in the blood have a significantly increased risk for graft loss. Thus, not only patients with an initially high BK viral load, but also patients without a rapid decrease in BK viral load need to be closely followed. Omic also show that leflunomide did not improve GFR in their patient cohort but had the ability to fully clear the virus in a greater number of patients. Nevertheless, the only sufficient way to limit BK polyoma virus infection currently seems to be the reduction of immunosuppression. The COVID-19 pandemia put our kidney transplant cohort into severe risk for developing critical COVID-19 due to chronic immunosuppression and coexisting conditions (Dedinská et al. add to this evidence by providing retrospective, multicenter analysis of 186 kidney transplantation patients with COVID-19. Obese and patients >59 years are of high risk to develop critical COVID-19 illness. Corticosteroids more than 7.5 mg/day as well as HLA-DQ2 seem to be protective factors in their cohort of patients but need to be confirmed in larger trials.Infections are an important factor of graft and patient loss in the kidney transplantation population. Rare infections occur in our immune suppressed population such as shown in a recent case report of a patient developing malacoplakia due to the infection with a multi-resistant nditions . DedinskHödlmoser et al. show compelling sex disparities in both the US as well as in Austria with a significant higher chance for men to be listed for kidney transplantation. Even though the differences decrease over time, the gap persists especially for older women. Thus, we need to further understand the causes of sex disparities to set up ways to overcome them.Finally, a study on sex differences between start of kidney replacement therapy and inclusion on the waiting list for kidney transplantation has been published in this Research Topic of Frontiers in Medicine. KE, GB, MB, and OV: wrote, reviewed, and approved the manuscript. All authors contributed to the article and approved the submitted version.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.


Hypertension is a widespread condition when the blood’s force on the artery walls is extremely high to develop adverse health effects. This paper aimed to jointly model the longitudinal change of blood pressures (systolic and diastolic) and time to the first remission of hypertensive outpatients receiving treatment.A retrospective study design was used to collect appropriate data on longitudinal changes in blood pressure and time-to-event from the medical charts of 301 hypertensive outpatients under follow-up at Felege Hiwot referral hospital, Ethiopia. The data exploration was done using summary statistics measures, individual profile plots, Kaplan-Meier plots, and log-rank tests. To get wide-ranging information about the progression, joint multivariate models were employed.A total of 301 hypertensive patients who take treatment was taken from Felege Hiwot referral hospital recorded between Sep. 2018 to Feb. 2021. Of this 153 (50.8%) were male, and 124 (49.2%) were residents from rural areas. About 83(27.6%), 58 (19.3%), 82 (27.2%), and 25 (8.3%) have a history of diabetes mellitus, cardiovascular disease, stroke, and HIV respectively. The median time of hypertensive patients to have first remission time was 11 months. The hazard of the patient’s first remission time for males was 0.63 times less likely than the hazard for females. The time to attain the first remission for patients who had a history of diabetes mellitus was 46% lower than for those who had no history of diabetes mellitus.Blood pressure dynamics significantly affect the time to the first remission of hypertensive outpatients receiving treatment. The patients who had a good follow-up, lower BUN, lower serum calcium, lower serum sodium, lower hemoglobin, and take the treatment enalapril showed an opportunity in decreasing their blood pressure. This compels patients to experience the first remission early. Besides, age, patient’s history of diabetes, patient’s history of cardiovascular disease, and treatment type were the joint determinant factors for the longitudinal change of BP and the first remission time. The Bayesian joint model approach provides specific dynamic predictions, wide-ranging information about the disease transitions, and better knowledge of disease etiology. When the blood’s strain on the arterial walls is excessively high, a common ailment known as hypertension results , 2. AccoPoor hypertension management and a high incidence of hypertension are major risk factors for heart disease in underdeveloped nations like Ethiopia. Studies in Africa –6 such aThe high prevalence rates of hypertension are influenced by a variety of socioeconomic, demographic, biological, and behavioral factors. The prevalent significant predictors are drinking alcohol, genetics, a lack of access to health care, an unbalanced diet, and inactivity , 8. In lFor studying the development or evolution of patients over time, or to gauge the impact of treatment on patients, many clinical studies use repeated measurements data or longitudinal data. Following therapy modifications over time, the average systolic and diastolic blood pressure biomarkers of hypertensive patients were primarily reported . A separAt the follow-up appointment, conversion to normotensive status (SBP<140 mmHg and DBP<90 mmHg with no usage of antihypertensive medication) was considered remission of hypertension , 12.Numerous research , 4, 8 emThe study was conducted at Felege Hiwot Referral Hospital (FHRH), Bahir Dar, Ethiopia. The Hospital gives service to people who are living in Northwest Ethiopia. It is away 564 KM from Addis Ababa, the capital city of Ethiopia .A retrospective study design was implemented to extract all the necessary information from hypertensive patients receiving treatment in the hospital. The data was collected from all hypertensive patients who received treatment from their medical charts under the follow-up from September 2018 to February 2021. All the socio-demographic and medical data of the hypertensive patients under the follow-up was obtained from their respective registry cards.The sample size determination used in this study was based on  which isα is the level of significance and we take the value of 5%, 1−β is the power of the test which equals 80%, p is the probability of patients expected to have good control of blood pressure (first remission) with the value of 0.504, and θR = ln(ψ) is the log of the hazard ratio of patients to remission who had no DM with a value of 0.4121 based on [Where n is the required number of patients to be included in the study, based on . The totInclusion and Exclusion Criteria: All hypertensive outpatients whose age is above 15 years old and received treatment and had more than one visit from their medical charts under the follow-up from September 2018 to February 2021, were included in the study.Ethical clearance was obtained from the ethical review of Felege Hiwot Referral Hospital with the Science College Research and Community Service Committee (SCRCSC) of Bahir Dar University, with reference number SCRCSC/102/02/13. As the data was obtained from a secondary source informed consent was not required by the ethical review board.The variables involved under this study were determined based on the patient registry card. Variables which are not fully accessible in the patient registry card were excluded.The dependent variables; bivariate longitudinal measure SBP and DBP in mmHg, and time to the first remission of hypertension outpatients. Remission of hypertension was defined as conversion to normotensive status (SBP < 140 mmHg and DBP < 90 mmHg and no use of antihypertensive medication) at follow-up visit, and reduction of ≥30% of antihypertensive medications while maintaining an office SBP <120 mm Hg at 12 months .The list of independent variables and their description, categories, and coding were presented in The data were explored using individual profile plots, mean profile plots, and the Kaplan-Meier curve. Then, the longitudinal measures from SBP and DBP were taken within follow-up, and the time to the first remission of patients was analyzed separately to identify the determinant factors for both models, and jointly to assess the influence of the longitudinal change of SBP and DBP on survival time till to the first remission among hypertension outpatients via Bayesian approach.γ of the survival model, we assume independent normal priors with mean zero and variance 1000. The association parameters α have a global-local ridge-type shrinkage prior. More specifically, for the sth element α, we assume:Modeling the joint longitudinal-survival data using the Bayesian approach is more effective as the parameter estimation computation is easier and flexible as compared to frequents approach . Besidesτ has sufficient mass near zero to ensure shrinkage, while the local smoothing parameter ψs allows individual coefficients to attain large values. The motivation for using this type of prior distribution, in this case, is that we expect the different terms behind the specification of f(.)  to be correlated and many of the corresponding coefficients to be non-zero [The global smoothing parameter non-zero .The goodness of fit of the joint longitudinal survival model was checked using the novel decomposition of AIC and BIC .In the Bayesian approach, the posterior distribution of the data is obtained from the conjugate of the likelihood of the current data and some prior distribution. The two components sub-models of the joint model are the longitudinal measurement model and the time to remission model which share one or more common parameters.θ is then given by [f is the posterior probability distribution, f is the likelihood function and π(θ), and π(b) is the prior probability distribution. In this framework, all the inference is carried out using the posterior distribution. In this study MCMC algorithm was used to draw samples from the posterior distribution [The joint posterior distribution for parameters given by :f time-varying covariate matrixi, b is a vector of random slope effects of Zi(tij) time-varying covariate matrix. ui is a vector of time-invariant covariates contained in some larger set Ui(ui∈Ui), and corresponding regression coefficients, δ. The model assumed the measurement error, ϵij(tij) is normally distributed with variance cov(ϵij(tij), ϵik(tik)) = 0 (where j≠k).Where PHs survival sub-model. The joint model aims to link the component processes together using shared parameters. Let mi(t) indicate the true unknown patient-specific longitudinal trajectory, and let Mi(t) = {mi(s), 0≤s≤t} indicate the corresponding true unknown longitudinal profile up to time t. Therefore, the PHs time-to-event sub-model is given by [h0(t) is the baseline hazard function, and ui∈Ui is the set of time-invariant variables, ψ indicates the associated vector of log hazard ratios, ρ indicates the association parameter. The exp (ρ) quantifies the hazard ratio for a one-unit increase in mi(t), at time t. Including the true unobserved trajectory function, mi(t), into the linear predictor of the PHs model provides a way to link the component sub-models to form the joint modeling framework. It is used to combine the longitudinal with the survival sub-model.given by , 27:h were male, and 124 (49.2%) were residents from rural areas see . About 8At the baseline, the average age of hypertensive patients with its corresponding standard deviation was 51.77 (Sd. = 13.88) years, and the mean SBP and DBP of hypertensive patients with their corresponding standard were 152.18 (Sd. = 18.68) mmHg and 92.79 (Sd. = 11.92) mmHg respectively.The average progress of both SBP and DBP was revealed in The Kaplan–Meier survival curves in The profile plot in The estimated standard deviation of random intercepts of SBP and DBP was 10.8131 and 6.7399 respectively, which is larger than the estimated standard deviation of the random slope of SBP 0.8605 and DBP 0.5223. This indicates that between-subjects variability at baseline is larger than longitudinal trajectories.The evolution of association was used to find the marginal correlation between the two responses SBP and DBP at different visit times. i.e., for the first three visit times, the marginal correlation between the two BPs was 0.260 (at the first visit), 0.246 (at the second visit), and 0.244  and 0.03 mmHg (0.0004) respectively see . The aveραSBP) was −0.1128 (HR = 0.89 (0.86 to 0.92)); there is a 0.89-fold decrease in risk of the first remission, per doubling of SBP. i.e., for a unit mmHg increase on the SBP the rate of first remission time of patients will be decreased by 10.67%.The hazard of the patient’s first remission time for males was 0.63 times less likely than the hazard for females see . The timThis study attempted to jointly model the longitudinal change of blood pressures (SBP and DBP) and time to the first remission of hypertensive outpatients receiving treatment. The data were explored using several approaches such as mean plot, profile plot, and Kaplan-mier estimates. To estimate the effects of the socioeconomic, demographic and biological characteristics joint longitudinal and survival models using the Bayesian approach were employed.According to the results of the study conducted at Jimma University Specialized Hospital, Ethiopia, there was a high correlation between BPs evolution and the association of evolution approximates one , 31. TheHR = 0.9987).The majority of hypertension patients (80.7%) experienced a brief period of disease remission, but later, their blood pressure may rise again. It was greater than other studies conducted at Adama Hospital Medical College Ethiopia (43.6%) , northweThe patient’s residence area was significantly associated with only the average SBP, not with the average DBP. This finding was in line with a study in . PatientAccording to research done in northwest Ethiopia , female The posterior estimates of the association parameters in the joint analysis are significantly different from zero, confirming that the two sub-models are associated and in line with research using the Bayesian joint model, even though the estimated parameters of the separate longitudinal model and the longitudinal sub-model under the joint model are exactly equal . In the Patients receiving both nifedipine and enalapril treatments have significantly higher SBP and DBP compared to patients receiving only enalapril, which may translate into a lower risk of first remission through the association. On the other hand, there is no evidence of a significant difference in SBP and DBP levels for patients receiving "other" treatments compared to patients receiving only enalapril in the longitudinal models but their risk of first remission is significantly increased. Therefore both the longitudinal and survival sub-models bring some piece of information about the treatments effect, which justifies the use of a joint model. The patients who had a good follow-up, lower BUN, lower serum calcium, lower serum sodium, lower hemoglobin, and take the treatment enalapril showed an opportunity in decreasing their blood pressure. This compels patients to experience the first remission early. Besides, age, patient’s history of DM, patient’s history of CKD, and treatment type were the joint determinants of longitudinal change of blood pressure and the first remission time. The findings of this study are supportive for the health authorities and legislators, and it will help as a reference for other researchers.