The relationship between renal function and clinical outcomes in patients with intracranial hemorrhage is controversial.We investigated the associations of blood creatinine and urea nitrogen levels with hospital death and 1-year mortality in patients with intracranial hemorrhage treated in the intensive care unit (ICU).A total of 2,682 patients with intracranial hemorrhage were included from the Medical Information Mart for Intensive Care III (MIMIC-III) database. Clinical variables, including admission creatinine, urea nitrogen, type of intracranial hemorrhage, underlying diseases and other blood biochemistry parameters, were collected. Multivariable correction analysis was conducted of the relationships between blood creatinine and urea nitrogen levels on admission with hospital death and 1-year mortality in the included patients with intracranial hemorrhage. Smooth curve and subgroup analyses were also performed for these associations.A total of 2,682 patients had their blood creatinine and urea nitrogen levels measured within the first 24 h after ICU admission, with median values of 0.80 and 15.00 mg/dL, respectively. We observed steeply linear relationships between creatinine and urea nitrogen levels and the risk of in-hospital death and 1-year mortality, but the risk of in-hospital mortality and 1-year mortality increased little or only slowly above creatinine levels > 1.9 mg/dL or urea nitrogen > 29 mg/d (the inflection points). Consistently, conditional logistic regression analysis suggested that these inflection points had significant modification effects on the associations between blood creatinine levels, as well as blood urea nitrogen, and the risk of in-hospital death  and 1-year mortality .Our results supported the hypothesis that elevated blood creatinine and urea nitrogen levels on admission are associated with an increased risk of in-hospital death and 1-year mortality in patients with intracranial hemorrhage. Interestingly, these independent relationships existed only for lower levels of serum creatinine (<1.9 mg/dL) and uric acid (<29 mg/dL). Some known chronic diseases, such as hypertension, cardiac disease and diabetes, and unhealthy lifestyles, including smoking, drinking and a high-fat diet, have been found to contribute to a high stroke risk . Renal dBlood creatinine and urea nitrogen, as the key indices used to evaluate renal function, play an important role in assessing the severity of the status of intensive care unit (ICU) patients, especially after cardiovascular events . For insGiven the current research evidence, we collected data from a total of 2,682 ICU patients from the Medical Information Mart for Intensive Care III (MIMIC-III) database. The MIMIC-III database included enough patients with intracranial hemorrhage, and data for clinical variables, including comorbidities and blood biochemical parameters, were collected. The present study investigated and further verified the associations of blood creatinine and urea nitrogen levels on admission with intracranial hemorrhage-associated in-hospital death and 1-year mortality in ICU patients with intracranial hemorrhage.The MIMIC III (v1.4) database was used for the present study. As a single-center critical care database, the MIMIC-III is publicly available and was approved for use by the Institutional Review Boards of the Massachusetts Institute of Technology  and Beth Israel Deaconess Insurance Center . Written informed consent was obtained from each patient based on the Declaration of Helsinki guidelines.The database contains detailed clinical information, including clinical variables such as demographic characteristics, vital signs, vital status and laboratory tests, on 46,520 patients admitted to various ICUs of the BIDMC from 2001 to 2012 in Boston, Massachusetts  was used. The first recorded value of clinical characteristics at baseline during the ICU stay were obtained, including age, sex, length of ICU stay, insurance status, ICU type, type of intracranial hemorrhage, head trauma, comorbidities, blood test parameters and medications.Blood test parameters, including creatinine, urea nitrogen, sodium, potassium, phosphate, magnesium, total calcium, chloride, glucose, partial thromboplastin time (PTT), prothrombin time (PT), international normalized ratio (INR), red blood cell count, platelet count, white blood cell count and bicarbonate, were tested within the first 24 h after ICU admission. If these blood variables were recorded more than once in the first 24 h, we used the first recorded value.The type of intracranial hemorrhage mainly included “intracerebral,” “extradural,” “subdural,” “unspecified intracranial,” “subarachnoid,” and “multiple.” Head trauma was defined as “yes” or “no”. ICU types included cardiology care unit (CCU), cardiovascular surgery rehabilitation unit (CSRU), insurance intensive care unit (MICU), surgical intensive care unit (SICU) and trauma/surgical intensive care unit (TSICU). Medications mainly included vasopressin, nitrate esters, β receptor blockers, benzodiazepines, statins and potassium. Additionally, data on comorbidities were obtained, including heart failure, hypertension, myocardial infarction, cerebral infarction, diabetes, chronic kidney disease and malignant tumor, according to the ICD-9 codes recorded in the MIMIC-III database.For the purpose of this study, the clinical endpoints were classified as in-hospital death and 1-year morality. In-hospital death was defined as “the patient died during hospitalization”. The definition of 1-year mortality was “the patient died within 1 year of ICU admission”.The normality of the data was examined for continuous variables by the Kolmogorov–Smirnov (KS) test. Values are expressed as medians [interquartile ranges (IQRs)] due to non-normal distributions of all continuous variables in our study. All categorical variables are expressed as total numbers and percentages. Comparisons between two groups  were made using the Mann–Whitney U test for continuous variables and the chi-square test for categorical variables.First, multivariate logistic regression models were used to characterize the associations between blood creatinine and urea nitrogen levels at baseline and the clinical outcomes . Other confounding factors (baseline variables) that were clinically relevant to the clinical outcomes, including age, sex, hypertension, heart failure, myocardial infarction, diabetes and cerebral infarction, were entered into a multivariate model as covariates. Then subgroup analysis using “type of intracranial hemorrhage” and “head trauma” as grouping variables was performed for these associations. Because malignancy and insurance status are important causes of all-cause death in elderly individuals, we also used “malignant tumors” and “insurance” as covariates in the sensitivity analysis.P-value < 0.05 was defined as statistically significant.Additionally, we performed a smooth curve analysis for relationships between blood creatinine and urea nitrogen levels and the risk of in-hospital death and 1-year mortality. A smoothed curve can fully demonstrate the non-linear associations of two variables. Stratified analysis was further performed on the associations of blood creatinine and urea nitrogen levels with the risk of in-hospital death and 1-year mortality through the inflection points (blood creatinine = 1.9 mg/dL and blood urea nitrogen = 29 mg/dL) of the smooth curves. In the stratification analysis, conditional logistic regression analysis was used, and the modification effect of the inflection points on the associations between blood creatinine and urea nitrogen levels with the risk of in-hospital death and 1-year mortality was assessed. All statistical analyses were performed by using Stata 13.0 and EmpowerStats 3.0. A After reviewing the data of 46,520 patients, a total of 2,682 ICU patients with intracranial hemorrhage were enrolled in the present study, as shown in the flow chart of the included study subjects . Among oP = 0.001] and 1-year mortality , as shown in P < 0.001) and 1-year mortality . These results remained consistent after adjusting for confounding factors, including age, sex, hypertension, heart failure, myocardial infarction, diabetes and cerebral infarction. Furthermore, we used “malignant tumor” and “insurance” as covariates in the sensitivity analysis. We observed that this independent relationship changed only slightly  = 1.14, 95% CI 1.05–1.22, slightly .P = 0.009] and 1-year mortality , as shown in We also used subgroup analysis to evaluate patients with different types of intracranial hemorrhage and head trauma for these associations. Our results showed that only in patients with subarachnoid hemorrhage increased blood creatinine levels were associated with an elevated risk of in-hospital death [adjusted odds ratio (OR) = 1.68, 95% CI 1.14–2.47, To further analyze the relationships between blood creatinine and urea nitrogen and clinical outcomes, we used a smooth curve to find potential “inflection points” of the relationships. Surprisingly, the smooth curve revealed a gradual upward trend in the association between blood creatinine and the risk of in-hospital death and 1-year mortality (According to the inflection point (blood creatinine = 1.9 mg/dL and blood urea nitrogen = 29 mg/dL) of the smooth curve, stratified analysis was further used to analyze the associations of blood creatinine and urea nitrogen levels with the risk of clinical outcomes, as shown in 2  was related to a poor prognosis within 6 months among patients with atherosclerosis stroke  Our study used intracranial hemorrhage data from the MIMIC-III database, which contains information from a large number of ICU patients with intracranial hemorrhage. This retrospective cohort study design could estimate the real-world prognosis of intracranial hemorrhage patients. (2) We observed a positive association between blood creatinine and urea nitrogen levels within 24 h of admission and a higher risk of in-hospital death and 1-year mortality in patients with intracranial hemorrhage only when their blood creatinine value was < 1.9 mg/dL or their blood urea nitrogen value was < 29 mg/dL. (3) Demographic characteristics, concomitant cardiovascular disease and malignant tumors were controlled in multivariate analysis, which eliminated the influence of relevant confounding factors. The present study also has several limitations. First, we did not use any information on accurate eGFR levels, which can reflect renal function well. Second, we only used the first value of the blood creatinine level measured on admission. We could not distinguish chronic renal dysfunction from acute renal dysfunction, potentially skewing the results. Third, 416 patients with intracranial hemorrhage were excluded due to missing information . WhetherIn conclusion, our results suggested that elevated blood creatinine and urea nitrogen levels contributed to an increased risk of in-hospital death and 1-year mortality in ICU patients with intracranial hemorrhage only when the blood creatinine value was <1.9 mg/dL or the blood urea nitrogen value was <29 mg/dL.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 Review Boards of the Massachusetts Institute of Technology  and Beth Israel Deaconess Insurance Center , and written informed consent was obtained from each patient based on the Declaration of Helsinki guidelines.HL and JX completed the data analysis and first draft. XY, KC, SL, and GL completed surveillance and data duplication. 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.


The high number of patients with end-stage kidney disease (ESRD) on hemodialysis makes it necessary to conduct studies aimed at improving their quality of life.To evaluate brain compliance, using the Brain4care method for intracranial pressure (ICP) monitoring, among patients with ESRD before and at the end of the hemodialysis session, and to correlate ICP with the dialysis quality index (Kt/V).Cross-sectional study conducted at a renal replacement therapy center in Brazil.Sixty volunteers who were undergoing hemodialysis three times a week were included in this study. Brain compliance was assessed before and after hemodialysis using the noninvasive Brain4care method and intracranial pressure wave morphology was analyzed.Among these 60 ESRD volunteers, 17 (28%) presented altered brain compliance before hemodialysis. After hemodialysis, 12 (20%) exhibited normalization of brain compliance. Moreover, 10 (83%) of the 12 patients whose post-dialysis brain compliance became normalized were seen to present good-quality dialysis, as confirmed by Kt/V > 1.2.It can be suggested that changes to cerebral compliance in individuals with ESRD occur frequently and that a good-quality hemodialysis session (Kt/V > 1.2) may be effective for normalizing the patient’s cerebral compliance. Observational studies have demonstrated a relationship between Kt/V and mortality and morbidity. Patient survival is longer when Kt/V is greater than 1.0.9To assess the quality of dialysis, the dialysis quality index (Kt/V) is measured, which can be calculated in several ways.11 Approximately 30% of HD sessions have some type of complication,11 which may include hypotension, muscle cramps and post-dialysis complaints such as headache, fatigue and inability to concentrate.12Studies have focused on prevention of and intervention in frequent HD-related complications, given that these complications reduce patients’ quality of life and can contribute to mortality.13 DDS occurs due to a sudden drop in urea levels, which results in an osmotic imbalance, with consequent failure of self-regulation of the cerebral circulation, thus leading to cerebral edema. Its clinical presentations depend on the brain region involved: for example, edema in the occipitoparietal subcortical white matter can result in sudden loss of vision and other neurological symptoms.14Frequent symptoms that are present in dialysis patients, such as headache, nausea and muscle cramps, can represent milder forms of dialysis disequilibrium syndrome (DDS), and this often remains undiagnosed.13 Considering that cerebral edema and the consequent decrease in cerebral compliance are involved in the pathophysiology of DDS,17 assessment of intracranial pressure (ICP) could also contribute to a more positive outcome by helping to identify individuals with mild forms of DDS that are hard to recognize.13To prevent this syndrome, it is recommended that high-risk patients should be identified, rapid correction of metabolic acidosis using bicarbonate should be avoided and the urea clearance rate and decrease in plasma osmolality should be controlled.The aim of this study was to evaluate the brain compliance of patients with ESRD before and at the end of the hemodialysis session, and to correlate the results obtained with the dialysis quality index (Kt/V).This was a cross-sectional study at a renal replacement therapy (RRT) center in Brazil. It was conducted after authorization had been received from the Research Ethics Committee of Universidade Estadual de Ponta Grossa (UEPG) .Sixty patients aged 18 years or over, with ESRD, who were undergoing hemodialysis three times a week for 3-4 hours in each session, were included. To define the sample size, studies with similar variables were consulted. However, given that the intracranial pressure variable remains poorly studied, the sample size was defined according to the number of volunteers available. The exclusion criteria were presence of acute infections, chronic viral diseases and pregnancy. All the participants received information about the study and provided written informed consent.The clinical and dialysis characteristics of the participants were obtained through the computerized system of the RRT center at the Santa Casa de Misericórdia de Ponta Grossa Hospital.19 and it has been registered with the Brazilian National Health Surveillance Agency .Brain compliance was assessed through the Brain4care method, using equipment provided by Brain4care  for non-invasive ICP monitoring. The method is based on measuring volumetric changes in the skull that are detected by a sensor attached to a bandana that is kept in contact with the patient’s head. The equipment filters, amplifies and digitizes the signal coming from the sensor and sends it to a computer. This method has been patented and validated through comparison with the invasive method for monitoring ICP,21 On the other hand, if the cranial adaptive capacity decreases, there is an increase in the ICP, as well as a change in the ICP pulse waveform because the amplitude of the P2 peak becomes higher than those of P1 and P3.22The results are obtained through analysis on the ICP wave pulse morphology. The curve obtained has three peaks: i) P1 is a percussion peak that results from transmission of blood pressure from the choroid plexus; ii) P2 varies according to brain compliance; and iii) P3 is related to closure of the aortic valve in the heart. In situations of intracranial compliance, the amplitudes of the peaks P1, P2 and P3 decrease sequentially.To numerically represent the volunteers’ brain compliance, the ratio between the amplitude of the peaks P1 and P2 was defined as P1/P2 (ratio R = AmpP1/AmpP2). Ideally, the result from this relationship should be > 1.10. A ratio between 1.00 and 1.10 indicates that the patient is on the threshold of abnormality. Values < 1.00 indicate abnormality, i.e. P2 > P1.Pre-dialysis monitoring was performed before the patient started the hemodialysis session, and the patient was asked to remain immobile for 15-20 minutes of monitoring. At the end of the hemodialysis session, the same procedure was performed.2) for categorical variables and the Mann-Whitney test for continuous variables. The ICP was also evaluated through a classification and regression tree (CART) model using the dialysis quality index (Kt/V) as the dependent variable and the pre and post-dialysis ICPs as independent variables. In all analyses, the significance level was set at P < 0.05. The data were evaluated using the statistical program SPSS 20.0 .The Kolmogorov-Smirnov test was used to assess the normality of the data. Since most of the continuous variables did not present normal distribution, these were presented as the median and interquartile range. Categorical variables were presented as absolute numbers (n) and relative frequency (%). The paired parameters obtained pre and post-dialysis were analyzed by means of the Wilcoxon test, and the McNemar test was used to assess the significance of normal and altered ICPs. Possible differences between the groups were showed by means of the chi-square test  , it was In the present study, the main finding was that the alteration in pre-dialysis brain compliance that was observed in 28% of the volunteers showed a tendency to become normalized, as seen immediately after the dialysis. Moreover, this study presented the possibility that this result may have been related to HD quality.24 However, no studies had previously assessed the brain compliance of routine HD patients, because the technique most used is highly invasive.Previous studies that assessed the ICP of patients with renal failure did so through correlating the altered results with DDS.25 hydrocephalus,26 cryptococcal meningitis associated with HIV infection,27 traumatic brain injury,19 hemorrhagic stroke28 and assessment of cerebral compliance in the elderly,29 among others.Noninvasive assessment of cerebral compliance through the Brain4care method could be useful in monitoring patients with ESRD in HD. It would constitute an additional tool for clinical evaluation of these patients and would possibly help in early detection of complications. This method has already been used in several situations such as epilepsy,31ICP refers to the pressure inside the skull, which is influenced by blood and cerebral parenchyma and by the circulatory dynamics of cerebrospinal fluid (CSF). If there is an increase in the proportion of one of these components  and the cerebral adaptive capacity is exceeded, the ICP increases.32The aim of HD is to simulate the process of glomerular ultrafiltration. It is based on the principle of diffusion, in which clearance or removal of a high concentration of uremic toxins present in the blood is achieved by means of migrating the blood through a semipermeable membrane , to form a solution of lower concentration, called the dialyzed solution.A normal ICP waveform  was obse33 patients with intracranial hypertension often have elevated blood pressure due to sympathetic hyperactivity, especially in cases of head trauma. However, in the present study, patients with altered ICP parameters had lower systolic blood pressure (SBP). At the same time, it was found that patients with changes to their cerebral compliance had higher heart rate values, both pre and post-dialysis. Dimitri et al.34 suggested that there was direct interaction or communication between the heart and the brain, with the observation that when the ICP rose, the heart rate also increased. This is important information, because it can assist in validation of the ICP parameters for assessing cerebral compliance.According to Robertson et al.,Another important result from the present study was the relationship between cerebral compliance and the best-quality dialysis, as shown by Kt/V > 1.20. It can be suggested that good-quality dialysis can help to improve the post-dialysis ICP parameters of patients with ESRD who presented altered brain compliance before HD.In this study, one volunteer showed changes to his brain compliance only after dialysis. No complications were reported in this patient’s medical records during his HD session, and his Kt/V was 1.25. In addition, it was not possible to establish any relationship between this finding and the patient’s clinical and dialysis parameters.35 This volume can be more accurately estimated through an anthropometric equation that uses an individual’s gender, age, height and weight (e.g. the Watson equation).36 Based on the above, several factors can influence the quality of HD and be reflected in the Kt/V ratio, such as the duration of the session and the interdialytic weight gain, which needs to be controlled by the patient through dietary care.In the formula of the Kt/V ratio, K refers to the dialyzer urea clearance, which is multiplied by the treatment time (t) and divided by the patient’s urea distribution volume (V). K depends on the blood flow rate, size of the dialyzer and flow of the dialysate, t varies from three to four hours and the urea distribution volume of the patient (V) corresponds to approximately 55% of the individual’s body weight.12Inadequate hemodialysis (Kt/V < 1.20) can occur due to low adherence or non-adherence to treatment recommendations  and because of the clearance limitations of the conventional HD technique. It has been shown that not attending just one dialysis session is associated with a 25%-30% increase in the risk of death. This is a common problem with regard to HD.37 small changes in the way of conducting HD sessions, such as increasing the blood flow rate to 200 ml/min and the treatment time to four hours for some patients, can decrease the percentage of patients with Kt/V < 1.20, with a consequent increase in survival among these patients.According to Kimata et al.,38However, four-hour dialysis sessions do not guarantee good-quality dialysis. It is necessary to consider the residual renal function, the Kt/V ratio normalized according to body surface area and the expected ultrafiltration rate. In addition, it is important to consider the patients’ acceptance of the duration of dialysis to which they are subjected, since this directly impacts their quality of life and treatment adherence.39 questioned whether the hemodialysis procedure might be partly responsible for brain structural and cognitive changes, such as cerebral edema, which leads to increased ICP. However, our results suggested that an adequate hemodialysis session, with Kt/V > 1.20, may be effective in normalizing the ICP of individuals who have presented changes.Madero and Sarnak6 Thus, the importance of clinical assessment of cerebral compliance among patients undergoing HD can be emphasized.Lastly, it is worth mentioning that the clinical assessment is superior to any Kt/V formula and should serve as the basis for determining the adequacy of dialysis.® method, it could be seen that changes to cerebral compliance among patients on hemodialysis can occur frequently. Moreover, it can be suggested that good-quality hemodialysis (i.e. when Kt/V is greater than 1.20) may help to normalize the ICP parameters. Thus, the importance of maintaining a Kt/V ratio of at least 1.20 can be emphasized, in order to ensure good-quality dialysis for patients with ESRD.Through noninvasive assessment of the ICP parameters by means of the Brain4care


The purpose of this study was to investigate the relationship between homocysteine (Hcy) levels and cardiopulmonary exercise testing (CPET) in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI). We also explored the relationship between Hcy levels and cardiac ultrasonography.2), anaerobic threshold (AT), metabolic equivalents (METs), exercise load (load), oxygen pulse (O2 pulse), end-tidal CO2 partial pressure (PETCO2), ventilatory equivalents for carbon dioxide (VE/VCO2) and Oxygen uptake efficiency (OUES). Cardiac ultrasonography was used to evaluate the left ventricular end diastolic diameter (LVEDD), interventricular septal thickness (IVST), left ventricular posterior wall thickness (LVPWT) and left ventricular ejection fraction (LVEF). A serum Hcy level ≥ 15 µmol/L was defined as hyperhomocysteinemia (HHcy). The patients were divided into the Hcy < 15 µmol/L group (n = 189) and the Hcy ≥ 15 µmol/L group (n = 72).This study comprised 261 patients with ACS who underwent coronary angiography and PCI at Yulin First Hospital from January 2020 to June 2021. All subjects completed basic data collection, laboratory examination, CPET and cardiac ultrasonography. The CPET includes the peak oxygen uptake . Correlation analysis showed that Hcy levels were negatively correlated with METs, VO2/kg and PETCO2 and positively correlated with the VE/VCO2 slope (P < 0.05). Partial correlation analysis showed that Hcy levels were negatively correlated with METs and VO2/kg in the AT state. The correlation coefficients were − 0.172 and − 0.172, respectively (P < 0.05). Hcy levels were negatively correlated with METs, VO2/kg and PETCO2 in the peak state. The correlation coefficients were − 0.177, -0.153 and − 0.129, respectively (P < 0.05). After further adjustment for confounders, multiple linear regression analysis showed that Hcy levels were negatively correlated with METs and VO2/kg in the AT state and peak state. The standardized regression coefficients were − 0.035, -0.122, -0.048 and − 0.128, respectively (P < 0.05). Correlation analysis showed that Hcy levels were positively correlated with the IVST and LVPWT (P < 0.05), but after adjusting for confounding factors, partial correlation analysis showed that there was no correlation between them.The average age of the participating patients was 58.9 ± 10.1 years. The majority of participants were male (86.6%). The CPET indices of METs, load, VO2/kg and worse cardiopulmonary function in patients with ACS after PCI.A high Hcy level is associated with lower METs and VO Acute coronary syndrome (ACS) is a common cardiovascular emergency that includes unstable angina pectoris (UAP), non-ST elevated myocardial infarction (NSTEMI) and ST elevated myocardial infarction (STEMI). It has an acute onset, rapid progression and a high mortality rate, which endangers the lives, health and safety of people . PCI is 2) and carbon dioxide output (VCO2) can be obtained. Then, we can calculate indices such as the peak oxygen uptake (peak VO2), anaerobic threshold (AT), metabolic equivalents (METs), exercise load (load), oxygen pulse (O2 pulse), end-tidal CO2 partial pressure (PETCO2), ventilatory equivalents for carbon dioxide (VE/VCO2) and the oxygen uptake efficiency (OUES) [2 measured at peak and AT exercise are the most important indices to evaluate the patient’s cardiopulmonary function. We used peak VO2 and AT VO2 to evaluate cardiac function grading and exercise tolerance. It can also reflect the severity of heart failure (HF), coronary heart disease (CHD), pulmonary hypertension and cardiomyopathy [2 [2 using exercise tests. The exercise intensity load is calculated according to METs to guide the exercise program for patients. In the process of treadmill movement, the load increases with increasing oxygen consumption. We can calculate the exercise load (load) at peak and AT. The O2 pulse is the ratio of the VO2 and heart rate (O2/HR), which depends on cardiac output (CO) and the arteriovenous oxygen difference (A-VO2Diff). The O2 pulse plays an important role in the diagnosis of myocardial ischaemia [2 can evaluate ventilation perfusion and cardiac function to reflect the disease severity of patients with HF, cardiomyopathy, pulmonary hypertension, chronic obstructive ventilatory dysfunction (COPD) and other pulmonary ventilation disorders [2 slope is an important index of ventilatory efficiency and the severity of systemic disease [2 slope is negatively correlated with ventilation efficiency. It is related to age and ventilation. The more severe the degree of heart failure is, the higher the value of the VE/VCO2 slope [Cardiopulmonary exercise testing (CPET) is a noninvasive test method to evaluate cardiopulmonary function and exercise endurance. It can objectively and comprehensively evaluate cardiopulmonary function, which cannot be done by traditional equipment. During CPET, measures of pulmonary ventilation (VE), oxygen uptake VO and carbmyopathy , 4. The pathy [2 . METs arschaemia . PETCO2 isorders , 4, 7. T disease . In CPETO2 slope –11. The O2 slope . In concClinically, left ventricular hypertrophy (LVH) is a strong risk factor for the occurrence and development of cardiovascular disease, and it has been a focal point for cardiovascular physicians. LVH is highly prevalent in patients with ischaemic heart disease and increases the risk of myocardial infarction , 14. ThePrevious studies have shown that higher levels of homocysteine (Hcy) are associated with a higher risk of cardiovascular and cerebrovascular diseases . AbnormaIn this single-centre observational study, 261 patients diagnosed with ACS aged 20 to 80 years who underwent coronary angiography (CAG) and PCI at the Sixth Affiliated Hospital of Guangxi Medical University from January 2020 to June 2021 were selected. They were divided into two groups according to their concentration of Hcy. One of the groups was Hcy < 15 µmol/L (n = 189), and the other group was Hcy ≥ 15 µmol/L (n = 72). All hospital in-patients were routinely screened for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov2) on admission to hospital. All the patients we included were SARS-Cov2 negative.The exclusion criteria were as follows: (1) incomplete medical records ; (2) severe renal insufficiency ; (3) pernicious anaemia, myocarditis, cardiomyopathy, valvular heart disease, congenital heart disease, rheumatic heart disease, malignant tumours, a recent history of surgery or trauma, pregnancy, and patients under 18 years of age; and (4) vitamin or folate supplementation within 3 months.This study was approved by the Ethics Committee of the Sixth Affiliated Hospital of Guangxi Medical University. All patients provided written informed consent to participate in this study. This study complied with the principles of the Declaration of Helsinki for investigations involving human beings.The basic information of each patient at admission was recorded in detail. These include age, sex, body mass index (BMI), smoking, diabetes, primary hypertension, hyperlipidaemia and chronic renal failure. We also collected laboratory indicators such as plasma levels of Hcy, triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), D-dimer, PT, Fibrinogen, uric acid (UA) and serum creatinine (Cr).First of all, Venous blood was drawn from the subjects in the fasting state (≥ 10 h). Hcy was determined by enzymatic colorimetry (DiaSys). The examination was conducted using Roche Cobas C 701/702 automatic biochemical analyzer  and Hcy test kit . The detection process and results were judged in strict accordance with the kit instructions by an experienced laboratory physician. All parameters of the instrument shall be kept constant during measurement.CPET was detected by MasterScreen CPX tester from German yeger. The procedures of CPET include: (1) patient preparation: the patient should wear loose and comfortable sports shoes, socks and clothing. Avoid full meals or long periods of fasting and smoking or drinking strong coffee before exercise before exercise. (2) Sign the informed consent: patients were informed of the purpose, significance, exercise plan, potential risks and normal reactions during exercise of CPET, and sign the informed consent. (3) Test preparation: inform the patient of the pedal speed (60r/min), adjust the height of the bicycle seat and handle to the optimal position, common reasons for stopping the movement and nonverbal communication methods that are obviously inappropriate during the movement. (4) Evaluation of the trial physician: according to the different severity of the patient’s disease, combined with gender, age and functional state, select the appropriate power increasing rate, and complete the maximum extreme exercise in about 10 min. Stop exercise in case of one of the following conditions: chest pain, dyspnea, pale face, fatigue, dizziness, lower limb pain and instability; ECG indicates myocardial ischemia; Severe arrhythmia; Systolic blood pressure > 250 mmHg, diastolic blood pressure > 115 mmHg or systolic blood pressure drop > 20 mmHg.2, O2 pulse, AT, PETCO2, METs, exercise load, VE/VCO2 slope and OUES were further calculated.CPET was arranged when the patient’s condition was stable after PCI and informed consent was obtained. Subjects wore appropriate masks and were connected to ECG monitors to dynamically monitor ECG, blood pressure and oxygen saturation. CPET was performed on a power bike, and AT was measured by the v-slope method. The changes in oxygen consumption, blood pressure, exercise load, pulmonary ventilation index and ECG were continuously monitored during exercise. Thus, the peak VOPatients underwent colour Doppler ultrasound during their hospitalization. Cardiac ultrasonography was used to evaluate the LVEDD, IVST, LVPWT and LVEF.P < 0.05 in a two-sided test was considered statistically significant.The survey data are entered by EpiData V3.1 software. Statistical software SPSS 19.0  was used for data analysis. Accordingly, continuous variables with normal distribution were expressed as mean ± standard deviation (SD) and compared between two groups using the independent samples t-test. The count data are expressed as number of cases and percentage (%). A chi-square test was used for the comparison between groups. Correlation analysis or partial correlation analysis was performed using Spearman correlation analysis. The relationship between CPET and Hcy was analyzed by multiple linear regression. A value of P < 0.05). There were no significant differences in age, sex, BMI, smoking history, hyperlipidemia, diabetes mellitus, triglyceride, total cholesterol, D-dimer, PT, Fibrinogen, resting systolic blood pressure (SBP), resting diastolic blood pressure (DBP) and resting heart rate (HR) between the two groups (P > 0.05). There were a significant difference in the creatinine, uric acid and plasma Hcy level between the two groups (P < 0.05). We found that all the patients have TIMI3 flow after PCI. In our study, 70.9% were STEMI patients and 29.1% were NSTEMI patients. There were more NSTEMI patients and in the Hcy ≥ 15 µmol/L group compared to the Hcy < 15 µmol/L group, but there were no difference between the two groups (P > 0.05). According to the angiographic data, we further analyzed the culprit vessel and there were no difference between the two groups (P > 0.05).A total of 261 participants, including 189 Hcy < 15 µmol/L patients and 72 Hcy ≥ 15 µmol/L patients, were enrolled in the study. Clinical characteristics and biochemical findings of involved participants are listed in Table 2/kg, PETCO2). while showed a significant increase in the CPET index (VE/VCO2 slope) and cardiac ultrasonography . The difference was statistically significant  and positively with VE/VCO2 slope, IVST and LVPWT. The difference was statistically significant  in AT state. The correlation coefficients were − 0.172 and − 0.172 (P < 0.05). Hcy was negatively correlated with  in peak state. The correlation coefficients were − 0.177, − 0.153 and − 0.129 (P < 0.05). Hcy was positively with VE/VCO2 slope, IVST and LVPWT. But the difference is not statistically significant (P > 0.05). Multiple linear regression analysis was performed with  as independent variables and Hcy as dependent variables. Model 1 no factors were adjusted; Model 2 adjusts for age, sex, BMI, hypertension, diabetes, hyperlipidemia, uric acid and creatinine. After further adjustment for confounders (model 2), Hcy was negatively correlated with  in AT state and peak state. The standardized regression coefficients were − 0.035, − 0.122, − 0.048 and − 0.128 respectively. (P < 0.05, Table After adjusting for age, sex and BMI, partial correlation analysis showed that Hcy was negatively correlated with (METs, VOHcy is a sulfur-containing amino acid metabolite that is synthesized in the process of methionine metabolism. A high Hcy level can lead to cardiovascular and cerebrovascular diseases. Studies have reported that an elevated level of Hcy is a risk factor for CHD, stroke and hypertension , 21. HHcCHD seriously threatens human health and greatly increases the risk of death. ACS is even more fatal. Previous studies have shown that CPET is helpful in the diagnosis of CHD , 29. Int2 and other related indicators, we can formulate the best indicators of aerobic exercise prescription [2/kg in the AT state and peak state. We speculate that the possible mechanism by which Hcy aggravates the damage to cardiopulmonary function in patients with ACS is that Hcy promotes myocardial hypertrophy and damages myocardial systolic function through oxidative reactions and the activation of sympathetic nerves. Hcy-lowering interventions should be considered to prevent cardiovascular events [In the process of the CPET, a gradual increase in the exercise load should gradually increase the cardiac output. The degree of myocardial ischaemia and prognosis can be detected and evaluated through CPET. The prognosis of patients with CHD can be improved by cardiac rehabilitation according to cardiac ultrasonography and a quality of life scale. However, it cannot replace the accuracy and objectivity of CPET indicators. By evaluating AT, peak VOcription , 33. We r events  and imprr events , 36.Previous studies have found that Hcy levels are associated with cardiac systolic function in patients with CAD . With anThis study is the first report the relationship between Hcy levels and CPET. However, due to the limited number of patients in this study, more evidence is needed to draw a conclusion about this issue. Moreover, this study included only ACS patients after PCI. More patients with other diseases should be studied in the future. These patients can be followed up for a long time to understand the improvements in cardiopulmonary function after further treatment.There was a correlation between Hcy levels and CPET. A higher Hcy level was associated with worse cardiopulmonary function in patients with ACS after PCI. Attention should be given to blood Hcy levels in patients with ACS.


BackgroundGlaucoma is a category of disorders that cause visual loss due to damage to the optic nerve. It is the primary cause of irreversible blindness around the globe. In diabetic individuals, intraocular pressure (IOP) was found to be higher than in non-diabetics, and this impact was linked to a rise in fasting blood glucose levels. In light of the foregoing findings, the current investigation was carried out with the goal of determining the prevalence and associated factors for primary open-angle glaucoma in people with diabetes in a tertiary care teaching hospital.MethodsThis cross-sectional study was carried out in a tertiary care teaching hospital. For a twelve-month period (2021-2022), adult patients (with type 2 diabetes and an age of 18 years or more) attending the ophthalmology out patient department (OPD) were included. Demographic information, socioeconomic data, and medical, familial, and ocular history were all gathered. All individuals with diabetes had an initial ophthalmological evaluation  by a senior ophthalmologist. Pearson's Chi-square test was used to compare variables on a nominal scale, whereas the t-test for independent samples was used to examine variables on a continuous scale.ResultsOur study enrolled a total of 1262 diabetic patients out of which 62.0% of subjects were male. Most of the enrolled subjects belonged to the 61-70 years of age group (35.8%). The eye examination of enrolled subjects showed that out of 1262 diabetic patients, 197 subjects (15.6%) were having primary open-angle glaucoma (POAG). The vision (in the better eye) was analyzed among three groups  and it was observed that no perception of light (PL) was noticed in 0.2% and 1.2% of subjects in the “no glaucoma or STDR” and “only glaucoma” groups respectively. In our study, the variables significantly associated with the increased prevalence of glaucoma among diabetic subjects included illiteracy, family history of type 2 diabetes mellitus (DM), being hypertensive, non-intake of anti-hypertensive medication, and >10 years duration of DM (p<0.05).ConclusionFrom our study, we came to the conclusion that there is clear-cut evidence of an increased incidence of POAG in diabetic patients, which was 15.6%. The study also showed a significant association between age, education, diet, hypertension, family history of diabetes and duration of diabetes, and; POAG. However, no significant association was found between gender and POAG. Glaucoma is a category of disorders that cause visual loss due to damage to the optic nerve. It is the primary cause of irreversible blindness around the globe. The most frequent types of glaucoma are open-angle and angle-closure glaucoma. Both can be separated into primary and secondary causes, as well as acute, subacute, and chronic stages of progression. The patient's quality of life, physical capabilities, and mental well-being are all affected by the group of diseases ,2.Primary open-angle glaucoma is a persistent, condition that affects both eyes. In the absence of recognized causes, the diseases are defined by structural abnormalities of the optic disc or retinal nerve fiber layer, as well as an open anterior chamber. Adults are affected by the POAG, and may or may not have vision loss. Higher intraocular pressure, advanced age, family history, and African heritage are all risk factors connected with the illness. Traditionally, increased IOP was assumed to be the primary cause of ocular neuropathy. In up to 40% of instances of open-angle glaucoma, the intraocular pressure is normal or low .The importance of early detection cannot be overstated, as it directly impacts the visual or functional outcome. Treatment approaches can assist reduce progression in both early and late stages of the disease; nonetheless, the visual impairment is permanent . IatrogePatients with diabetes have a higher risk of developing glaucoma than those who do not have diabetes. Patients who had been diagnosed for longer periods were at a higher risk. In diabetes individuals, IOP is found to be higher than in non-diabetics, and this impact is linked to a rise in fasting blood glucose ,6. In liThis cross-sectional research was carried out in a tertiary care teaching hospital. The approval of the Institutional Ethics Committee was obtained (IEC number: MMIMSR/2020/418). For a twelve-month period (2021-2022), adult patients (with type 2 diabetes and an age of 18 years or more) attending the ophthalmology out patient department (OPD) were included. All participants signed a written informed consent form. To detect the cases of primary glaucoma, all diabetic patients who were referred for cataract surgery or for the diagnosis and management of other ocular diseases such as glaucoma, diabetic retinopathy, age-related macular degeneration, pterygium, and secondary glaucoma underwent a detailed ophthalmological examination. Patients having congenital or juvenile glaucoma, as well as secondary glaucoma , were not included in the study.Demographic information, socioeconomic data, and medical, familial, and ocular history were all gathered. All individuals with diabetes had an initial ophthalmological evaluation  that included recording best corrected visual acuity (BCVA) using Snellen's chart at 6 m, slit-lamp biomicroscopy , assessment of peripheral anterior chamber depth (ACD) using Van-Herick technique, fundus examination using indirect ophthalmoscopy, stereoscopic optic disc evaluation using +78D lens (x16 magnification), and IOP measurement using Goldman’s applanation tonometer.Probable glaucoma patients were directed to a glaucoma specialist for additional glaucoma workup, including gonioscopy, disc evaluation, and visual field testing. A four-mirror Sussman gonioscope  was used to perform gonioscopy, and the angle was graded using modified Shaffer's classification. The vertical cup disc ratio (VCDR) was estimated, and glaucomatous optic neuropathy morphological abnormalities (including glaucomatous cupping) were identified. If the IOP was less than 21 mmHg or the VCDR was less than 0.7 in either eye, the visual field test was performed . Even ifThe patients were divided into three categories according to the International Society Geographical and Epidemiological Ophthalmology (ISGEO) classification system. Category 1 required structural and functional evidence i.e., 97.5th percentile of the VCDR (≥0.7) or VCDR asymmetry (≥0.1) in our normal population and visual field loss typical of glaucoma. Category 2 required advanced structural damage i.e., 99.5th percentile VCDR (≥0.75) or VCDR asymmetry (≥0.2) in the absence of visual field evidence i.e. when a useful visual field result was not possible or available. Category 3 applied when the optic disc was not seen and visual field testing was not possible and used: a) blindness (VA <3/60) with the 99.5th percentile IOP (≥28 mmHg), or b) diagnosed with/being treated for glaucoma. An additional level of evidence (level2b) was added where the optic disc was visualized but the VCDR was <99.5th percentile and visual fields were not available or if visual fields were interpreted as “unlikely glaucoma” but there was other compelling evidence such as RAPD, high IOP and/or corneal edema. If the glaucoma hemifield test graded “outside normal limits” and a cluster of three contiguous points at the 5% level on the pattern deviation plot, using the threshold test strategy with the 24-2 test pattern of the Zeiss-Humphrey field analyzer II, the glaucomatous visual field defect was considered to be present . The preA participant was classified as hypertensive if their systolic blood pressure was greater than 140 mmHg or their diastolic blood pressure was greater than 90 mmHg, or if they had a self-reported history of hypertension.Statistical analysisThe dataset of primary glaucoma patients at the hospital was evaluated, and descriptive statistics such as mean, standard deviation, and percentage for the study variables were calculated using the measuring scale. These tests were carried out based on whether the patients were glaucomatous or non-glaucomatous. Pearson's Chi-square test was used to compare variables on a nominal scale, whereas the t-test for independent samples examined variables on a continuous scale. The statistical significance was determined at a 5% level, and the full analysis was carried out with SPSS .Our study enrolled a total 1262 diabetic patients out of which 62.0% of subjects were male. Most of enrolled subjects belonged to 61-70 years of age group (35.8%). More than one fourth of subjects were illiterate (27.0%) and less than one fourth were educated up to high school or above (21.9%)  was analyzed among three groups  and it was observed that no perception of light (PL) was noticed in 0.2% and 1.2% of subjects in the “no glaucoma or STDR” and “only glaucoma” groups respectively. The vision of <3/60 to PL was observed among 3.8% and 6.1% of subjects in the “no glaucoma or STDR” and “only glaucoma” groups respectively. The vision (in the worst eye) was analyzed among three groups  and it was observed that no perception of light (PL) was noticed in 3.4% and 5.5% of subjects in the “no glaucoma or STDR” and “only glaucoma” groups respectively. The vision of <3/60 to PL was observed among 15.5%, 12.7%, and 18.8% of subjects in the “no glaucoma or STDR”, “only glaucoma”, and “glaucoma plus STDR” groups respectively  was found in 2.5 percent of the participants in our study. Studies have found a correlation between the severity of diabetic retinopathy and the later occurrence of POAG ,16. ManyLimitationsThe limitation of the study was that it was conducted in diabetic patients only, and there was no control group (non-diabetics), to compare the prevalence of POAG in diabetic and non-diabetic patients. Along with this, the study being single-centric might hinder the generalizability of the results to the non-diabetic population. Primary open-angle glaucoma is mostly asymptomatic until significant visual field loss has occurred. Patients usually present with significant visual field loss in one eye and advanced disease in the other eye. It is associated with irreversible blindness. Thus, the public health importance of detecting undiagnosed and treatable glaucoma, as blindness has economic and societal consequences for the rest of an individual’s life. Several studies have shown an association between POAG and diabetes. From our study, we came to the conclusion that there is clear-cut evidence of an increased incidence of POAG in diabetic patients, which was 15.6%. The study also showed a significant association between age, education, diet, hypertension, family history of DM type 2, and duration of DM type 2 and; POAG. However, no significant association was found between gender and POAG.


R = 0.375, p = 0.090). However, further studies with larger sample size are required to assess the direct association of UA level with major adverse cardiac events in patients with cardiovascular disease.The association between uric acid (UA) and cardio‐metabolic conditions has been recognized for a long time. However, recently, a body of evidence has highlighted the independent role of UA in a series of conditions, including renal and cardiovascular diseases. In this light, data regarding the prognostic role of UA in acute coronary syndrome (ACS) is scarce. A total number of 100 patients, 59 males and 41 females, diagnosed with ACS were recruited in this study. At the time of admission to the hospital, the serum level of UA was measured. In addition, the HEART score was calculated based on each patients' profile. Participants were on average 61.37 ± 12.08 years old. The most prevalent risk factors were hypertension (48%), a history of coronary artery disease (40%), and diabetes mellitus (33%). The average serum level of UA was 5.81 ± 1.81 mg/dl, and the calculated HEART score had a median of six (minimum of two and maximum of ten). A positive yet statistically insignificant correlation was found between the measured UA level and the calculated HEART score ( Our results suggest a modest positive yet statistically insignificant correlation between the serum level of UA and HEART score. However, further studies are needed to determine the exact correlation between UA and HEART score. Furthermore, all participants signed an informed written consent form prior to recruitment.2.2Z1−α2 = 1.96, Z1−β = 1.28, r = 0.346, C = 0.36, and N = 84. In this regard, 100 patients were included in the current clinical study due to a possible dropout rate of about 20%.The power (β) was set as 90%, and the significance level (α) was adjusted to 5%. According to a prior study  or lack of consent.2.4The HEART score, widely used as a prognostic marker to assess outcomes in ACS, was calculated for each patient Table . The HEAIn order to count the risk factors, a checklist including the following items was completed for each patient: history of diagnosed hypertension, diabetes mellitus, hypercholesterolemia, coronary artery disease, family history of coronary artery disease (parent or sibling with CAD before age 65), and smoking (current or cessation less than 1 month). Body mass index (BMI) was calculated using recorded height and weight; BMI > 30 was accounted as a risk factor. For patients with no risk factors, no points were given. Those with one or two risk factors were given one point, and those with more than two risk factors were assigned two points.Finally, the troponin I level was assessed: zero points were given if the Troponin level was within the normal range (<0.04 ng/ml), one point was given if it was one to three times of normal limit, and two points were assigned if it was more than three times of normal limit. The calculated Heart score was classified into three intervals: interval one with scores between zero and three, interval two with scores between four and six, and interval three with scores between seven and ten.In addition, a blood serum sample was obtained from patients at the time of admission in order to measure the level of UA (mg/dl). The UA level was used as an independent factor in the analyses.2.5p < 0.05 for all the statistical tests.Data were analyzed using the SPSS version. 23.0 statistical software . Data distribution was assessed using the One‐sample Kolmogorov–Smirnov test. Descriptive data were reported as mean ± standard deviation (SD) and median (interquartile range) for normally and non‐normally distributed data, respectively. As appropriate, the comparison between quantitative variables was performed using parametric one‐way analysis of variances (ANOVA) for normally distributed data or the Kruskal–Wallis test for the non‐normally distributed variables. In addition, for comparing the qualitative variables, the Chi‐squared test was used. Spearman's correlation coefficient was used to assess the association between the HEART score and UA level. Statistical significance was defined as 32. Our results revealed that 48 (48.0%) patients had hypertension, 33 (33.0%) patients had Diabetes Mellitus, 29 (29.0%) had hypercholesterolemia, and 40 (40.0%) patients had a history of CAD. Moreover, 23 (23.0%) patients were smokers, and 17 (17.0%) had a positive family history of CAD. The HEART score was with a median of six, a minimum of two, and a maximum of 10, and the average serum level of UA was 5.81 ± 1.81 mg/dl among the enrolled patients.Overall, 100 patients, 59 males and 41 females, were recruited in the study from 20th March to 20th September 2018. The mean age of patients was 61.37 ± 12.08 years old, and the calculated BMI was 24.31 ± 2.54 kg/mp = 0.002), higher prevalence of hypertension (p = 0.047), highly suspicious for ACS (p = 0.008), significant elevation of ST‐segment (p < 0.001), and higher troponin levels . Linear regression analysis also yielded a similar positive insignificant association  between the serum level of UA and HEART score. Considering other analyzed variables, we only detected a significant positive correlation between age and hypertension as a risk factor and the HEART score.We found a modest positive yet statistically insignificant correlation , renal diseases, and cardiovascular diseases   in patients with non‐specific chest pain or non‐ST‐elevation presentation of ACS  should be clearly defined and recorded. Then it will be possible to compare the predictive value of the HEART score and UA and ponder whether the addition of the serum level of UA to the HEART score system would increase the precision of anticipating short‐term MACE outcomes or not. Additionally, we evaluated 100 patients with ACS, and it is necessary to perform further studies with a larger sample size. Furthermore, the role of treatment with allopurinol to reduce UA and consequently prevent undesired cardiovascular events is another interesting subject to investigate.5In acute coronary settings, making accurate and cost‐effective decisions is critical. Thus, the most important factors should be incorporated to assess the situation better and predict the outcomes. While the HEART score is already in use for this purpose, the existing literature also suggests a promising role for UA. In fact, our results suggest a modest positive yet statistically insignificant correlation between the serum level of UA and the HEART score. However, further studies with a larger sample size are needed to determine the exact correlation between UA and HEART score.Ramin Khameneh Bagheri: Conceptualisation, Methodology, Funding Acquisition, Investigation; Mona Najaf Najafi: Formal Analysis, Data Curation; Mostafa Ahmadi: Conceptualisation, Methodology, Investigation; Mohsen Saberi: Investigation, Data Curation; Mina Maleki: Investigation, Data Curation, Writing—Original Draft, Vafa Baradaran Rahimi: Formal Analysis, Writing—Original Draft, Writing—review & editing.The authors declare no conflict of interest.


We aimed to determine the association between proton pump inhibitor (PPI) use and incident asthma in patients with coronary artery disease (CAD). This nationwide cohort study collected claims data from the Taiwanese Bureau of National Health Insurance from 2004 to 2013. The primary outcome, i.e., the risk of incident asthma, was assessed by estimating hazard ratios (HRs) and 95% confidence intervals (CIs). The adjusted HR of asthma development was estimated using the Cox regression model. Sensitivity and subgroup analyses were also conducted. A total of 8894 PPI users and 12,684 H2-receptor antagonist (H2RA) users were included in patients with CAD. Compared with H2RA use, an increased risk of incident asthma was found between PPI use and the risk of incident asthma in patients with CAD after adjusting for sex, age, urbanization, and low income . The sensitivity analysis results were consistent with the main analysis results. However, the subgroup analysis revealed no association of incident asthma in patients with diabetes mellitus, hyperlipidemia, stroke, allergic rhinitis, pneumonia, cancer, or depression in the PPI group compared with those in the H2RA group. In conclusion, PPI use increased the risk of asthma development in patients with CAD. Asthma is a major noncommunicable disease characterized by recurrent attacks of breathlessness and wheezing, which vary in severity and frequency from person to person. Globally, more than 339 million cases of asthma were reported in 2016 [Proton pump inhibitors (PPIs) are the primary agents for treating gastroduodenal ulcers and gastroesophageal reflux disease (GERD) and are effective in preventing nonsteroidal anti-inflammatory drugs/aspirin-associated peptic ulcers and ulcer bleeding . A studyTo date, the association between PPIs and incident asthma in patients with CAD remains controversial. In this regard, this retrospective cohort study aimed to evaluate the association between PPI use and the risk of incident asthma in patients with CAD based on the data from the National Health Insurance Research Database (NHIRD) of Taiwan.This retrospective cohort study used insurance claims data provided by the Taiwanese Bureau of National Health Insurance (TBNHI) from January 2004 to December 2013. The data from the NHI of Taiwan were used in this study, which is maintained by the National Research Agency for research purposes. The NHI data includes the data of more than 99% of Taiwan’s population. The database contains information on diagnoses, hospitalizations, examinations, and prescriptions.n = 25,082) who were diagnosed between January and December 2004 were identified. The index date was on the date of the first prescription for PPI between January 1, 2004 and December 31, 2012. At least one of the following inclusion criteria had to be met: (1) two or more outpatient visits within 6 months, (2) all prescriptions of PPI were continuously administered to the patients for more than 6 months within a 10-year follow-up period, or (3) one or more outpatients with a diagnosis of peptic ulcer disease and CAD.Patients with peptic ulcer disease  and CAD (ICD-9-CM code 410–414)  code first appeared in the outpatient claim records. We followed the PPI users or H2-receptor antagonist (H2RA) since their first prescription of PPI or H2RA, until the occurrence of asthma or the end of the study (December 2013).Comorbidity was defined as any diagnosis within a year after the index date. Asthma-related comorbidities of patients with hypertension were identified using ICD-9-CM codes 401–405, and hyperlipidemia was identified with ICD-9-CM code 272. Other selected conditions included diabetes mellitus (ICD-9-CM code 250), stroke (ICD-9-CM codes 430–438), allergic rhinitis (ICD-9-CM codes 477), pneumonia (ICD-9-CM codes 480–486), cancer (ICD-9-CM codes 140–208), and depression . Patients who had a prior history of asthma before the index date were excluded from the study. Finally, the study group comprised 8499 participants with peptic ulcer disease and CAD who were PPI users, and the control group included 12,684 participants with peptic ulcer disease and CAD who were H2RA users .Differences in demographic and clinical characteristics between PPI and H2RA users were examined using t-test for continuous variables, whereas chi-square tests were used for categorical variables. The asthma-free survival rates in the two groups were calculated using the Kaplan–Meier method and the log-rank test. The Cox proportional hazard regression model was used to compare the development risk of asthma between PPI and H2RA users. Adjusted HRs and 95% CIs were calculated. Their values were adjusted for important risk factors, such as sex, age, urbanization, and low income, for asthma development.We also conducted several sensitivity analyses to test the robustness of our primary findings. Initially, propensity score matching (1:1) and inverse probability of treatment weighting (IPTW) were conducted between the two groups using the SAS software. The PSMATCH procedure was used to perform greedy nearest neighbor matching. Logistic regression was performed to estimate the logit probability of exposure to PPI for each individual.p < 0.05. All statistical calculations were performed using statistical analysis software, version 9.3 .In addition, we conducted subgroup analyses stratified by sex, age, urbanization, presence of hypertension, diabetes mellitus, hyperlipidemia, stroke, allergic rhinitis, pneumonia, cancer, or depression at baseline for the primary outcomes of incident asthma. Statistical significance was considered at p < 0.05) at baseline. Inversely, patients with PPI use had lower rates of comorbid hyperlipidemia, allergic rhinitis, and depression. Simultaneously, PPI users used more oral nonsteroid anti-inflammatory drugs, aspirins, statins, beta-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers than those receiving H2RA . The characteristics at baseline are shown in ing H2RA . The folp < 0.001, The trends of results from the sensitivity and subgroup analyses were consistent with the main analysis. The sensitivity analysis for the multiple Cox regression model confirmed the risk of asthma in the patients with PPI use when they were assessed using IPTW and propensity score matching . Kaplan–An analysis of the listed comorbidities revealed that asthma prevalence was only higher among patients with hypertension in the PPI cohort  but did not differ among patients without hypertension  . Other sThis large population-based cohort study found a 1.41-fold risk of asthma development after adjusting for age, sex, urbanization, and low income in patients with CAD. The sensitivity analysis results were consistent with the main analysis results. However, compared with H2RA use, PPI use in patients with diabetes mellitus, hyperlipidemia, stroke, allergic rhinitis, pneumonia, cancer, or depression was not associated with increased risk of incident asthma in the subgroup analysis.A significantly higher prevalence of asthma has been previously reported in patients using PPIs compared with those not using PPIs, particularly in adults ,13,14. SIn the previous clinical observation study, the use of PPI to treat GERD was not associated with incident asthma ,20,21. RDaily low-dose aspirin is recommended for preventing cardiovascular events in adult patients with CAD, and PPIs are recommended for preventing or treating aspirin-associated gastrointestinal injury ,25,26. PA major strength of this study is that this was the largest population-based study to examine the association between PPI use and subsequent asthma development in adults. The national database used herein comprises a representative cohort of 1,000,000 people insured by the Taiwan NHI program, and the 10-year observation period ensured the power of our statistical analyses. This is also the first population-based study to suggest that PPI use is associated with an increased risk of asthma development in adult patients with CAD, although some risk factors for PPI are associated with asthma development.This study has some limitations. First, the data of all the patients in this study were collected from claim datasets of Taiwan NHI that were submitted by primary care clinics. Risk factors for asthma, such as body mass index, smoking status, family history, treatment adherence, environmental tobacco smoke exposure, and diet, were not available from these secondary data. However, considering that we used population-based data, we assumed that no differences existed between PPI users and H2RA users. Second, all the patients in our study had been diagnosed with CAD and peptic ulcer and had received PPI treatment. However, dosing, treatment adherence, and the severity of CAD with acid-related gastrointestinal tract disorders may have differed across patients using different PPIs. Thus, the association between PPI therapy and the risk of asthma may not reflect the effect of the prescribed drugs but rather the severity of the patients’ diseases and treatment adherence.To conclude, this large population-based cohort study showed PPI use increased the relative risk of incident asthma in patients with CAD. However, there was no association between PPI use and incident asthma in patients with diabetes mellitus, hyperlipidemia, stroke, allergic rhinitis, pneumonia, cancer, or depression. Future studies may help determine whether PPI treatment of at-risk patients with CAD could prevent the development of asthma in clinical practice.


The direct correlation with baPWV existed in multivariable linear regression models with a β of 0.1 for hsTnT and 0.1 for Cathepsin D. The direct relationship between baPWV and CV biomarkers, particularly with hsTnT and Cathepsin D, may be helpful for risk stratification of hemodialysis patients.Brachial–ankle pulse wave velocity (baPWV) and cardiovascular (CV) biomarkers are correlated with clinical cardiovascular diseases (CVDs) in patients with kidney disease. However, limited studies evaluated the relationship between baPWV and CV biomarkers in hemodialysis patients. This study investigated the relationship between circulating CV biomarkers and baPWV in patients on hemodialysis. Hemodialysis patients were enrolled between August 2016 and January 2017 for the measurement of baPWV, traditional CV biomarkers, including high-sensitivity troponin-T (hsTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), and novel CV biomarkers, including Galectin-3, Cathepsin D, placental growth factor, Endocan-1, and Fetuin-A. The independent association was assessed by multivariate-adjusted linear regression analysis to control for potential confounders. The final analysis included 176 patients (95 men and 81 women) with a mean age of 60 ± 11 y old. After adjusting for age and sex, hsTnT ( Chronic kidney disease (CKD) is a prevalent global health issue, with a prevalence rate of 15%, and accounts for about 1.1 million deaths annually . PatientSeveral CV biomarkers are considered to provide more information regarding progressed kidney injury and cardiovascular risk to predict MACEs in managing patients with ESRD . High-seBrachial–ankle pulse wave velocity (baPWV) is an easily applied and noninvasive measurement using an independent cuff on four limbs based on an oscillometric approach. Increased baPWV correlates with a high tendency of arterial stiffness , one of CV biomarkers and baPWV are well-validated methods that can be easily measured in the hemodialysis unit. However, the significance of the relationship between CV biomarkers and baPWV in ESRD patients has not been well-clarified, and limited studies are focusing on the clinical efficacy of the combined use of baPWV with other biomarkers in the ESRD setting. Thus, the present study aimed to analyze the association between circulating CV biomarkers and baPWV in hemodialysis patients to investigate the underlying importance of CV risk prediction in ESRD patients.The study was conducted in the dialysis clinic of a provincial hospital in southern Taiwan between August 2016 and January 2017. In total, 193 patients who underwent hemodialysis 3 times a week using high-flux dialyzers were enrolled. Each hemodialysis session lasted 3.5–4 h, with a 500 mL/min dialysate flow rate and 250–300 mL/min blood flow rate. The Institutional Review Board of Kaohsiung Medical University Hospital approved the research protocol (KMUHIRB-E(I)-20160095), and all patients provided written informed consent. All clinical investigations were according to the Declaration of Helsinki’s standards and principles.All patients’ sociodemographic data , dialysis vintage, dialysis access (fistula vs. graft), medical history, and biochemical data were obtained from the electronic health care system records. BMI was calculated by dividing patient weight by height squared. A blood pressure of 140/90 mmHg or greater, or the usage of antihypertensive drugs, was considered hypertension, with diabetes defined as an HbA1C of 6.5% or greater or the use of antidiabetics. Physicians’ diagnoses were used to determine a patient’s history of hyperlipidemia, CAD, and cerebrovascular illness. Hemoglobin, albumin, low-density lipoprotein cholesterol (LDL-C), ion calcium, phosphate, C-reactive protein, and single pool Kt/V  were recorded. The chemiluminescence technique (Roche Diagnostics Instrument) was used to evaluate two classic CV biomarkers, hsTnT and NT-proBNP .BaPWV was measured using an automated waveform analyzer  10–30 min before the hemodialysis session . TransmiSerum levels of Endocan-1, PLGF, Fetuin-A, Cathepsin D, and Galectin-3 were evaluated using the MILLIPLEX MAP technology (Luminex) . Blood st-test for continuous variables with nearly normal distribution, or the Mann–Whitney U test for continuous variables with skewed distribution was used to assess differences between groups. Multiple CV biomarkers linked to baPWV were screened and assessed using linear regression adjusted for age and gender. The distribution of CV biomarker values and baPWV were plotted, and Spearman rank correlation coefficients were calculated. A multivariate-adjusted linear regression analysis was used to investigate the connection between serum CV biomarkers and baPWV by controlling for relevant confounders to find independent variables. Stepwise procedures were used to identify relevant demographic factors, comorbidities, and clinical laboratory data to control variables, with a p < 0.05 for model entrance and a p > 0.1 for model removal. SAS statistical software was used for all statistical analyses , and the data are presented as a β with 95% CI. Statistical significance was defined as a two-tailed p < 0.05.Descriptive data are presented as mean and standard deviation (SD) or percentages as appropriate. The Kolmogorov–Smirnov test was used to determine if the data were normally distributed. The chi-square test for categorical variables, the independent n = 5), patients with atrial fibrillation (n = 4), patients with bilateral below-the-knee amputations (n = 3), and patients who had been hospitalized for four weeks before research enrolment (n = 5), the final analysis included 176 patients (95 men and 81 women) -form system (1 women) .The patients’ baseline characteristics are presented in p < 0.01), NT-proBNP (p = 0.01), Galectin-3 (p = 0.03), and Cathepsin D (p < 0.01) were significantly directly associated with baPWV in hemodialysis patients  as well as Cathepsin D   and baPWV after adjusting for age and sex. Furthermore, an independent relationship was confirmed by the multivariable-adjusted linear regression model between baPWV and two biomarkers—hsTnT and Cathepsin D—indicating the link between peripheral vascular disease evaluation and proteins from cardiac origin. Thus, PWV not only represents a marker of peripheral vascular disease but is also a marker of cardiac disease in hemodialysis patients.p < 0.01), systolic blood pressure (p < 0.01), diastolic blood pressure (p < 0.01), hemodialysis vintage (p = 0.03), diabetes mellitus (p < 0.01), hypertension (p < 0.01), albumin (p < 0.01), ion calcium (p = 0.02), and C-reactive protein (p < 0.01) were significantly associated with baPWV  in predicting CV risk among hemodialysis patients were not significant.Galectin-3 is a β-galactoside-binding lectin (29–35 kDa) primarily released by activated macrophages, as well as other inflammatory cells in CV and renal systems ,41,42. AAnother novel CV biomarker is Cathepsin D, a cysteine protease enzyme released by macrophages, vascular smooth muscle cells, and endothelial cells in atherosclerotic plaques ,46. The The pioneered findings of the present study suggest that using baPWV combined with classical CV biomarkers such as hsTnT and/or novel biomarkers such as Cathepsin D may provide more predictive information on CV morbidity and mortality in the ESRD population requiring regular hemodialysis. Moreover, baPWV, hsTnT, and Cathepsin D can also be beneficial in managing chronic hemodialysis patients as therapeutic indicators of ameliorating arterial stiffness. Large population trials are required in the future to determine if combining baPWV, hsTnT, and Cathepsin D improve CV risk prediction and reduce MACEs in ESRD patients on hemodialysis.This study has several limitations. First, a causal association could not be determined due to the cross-sectional study design, so longitudinal investigations should be performed. Second, this study was limited to a single regional hospital, restricting the number of patients and their selection. Furthermore, because peritoneal dialysis patients were not included in this study, the findings may not be relevant to peritoneal dialysis patients. Third, the baPWV and bone turnover biomarkers were only measured once, which might have resulted in misclassification. Fourth, not all potential variables, such as food habits, genetic factors, medicines, and whole blood viscosity, were included in this study. For whole blood viscosity, in particular, Kobayashi et al.  applied This study demonstrated a significant direct association between baPWV and CV biomarkers, especially hsTnT and Cathepsin D, in hemodialysis patients. The clinical use of baPWV combined with these CV biomarkers may serve as effective CV risk predictors or therapeutic indicators for the ESRD population undergoing regular hemodialysis.


To investigate the correlation between the histopathology of the kidney and clinical indicators in patients with lupus nephritis (LN) using magnetic resonance imaging (MRI).A total 50 female participants were enrolled in the study. Thirty patients with LN were divided into types 2, 3, 4, and 5, according to their pathological features. The control group consisted of 20 healthy female volunteers. Serum creatinine, C3, C1q, and anti-ds-DNA were measured. Conventional MRI, DTI, DWI, and BOLD scanning was performed to obtain the FA, ADC, and R2* values for the kidney.P < 0.05). The overall comparison of the SLEDAI (Activity index of systemic lupus erythematosus) score, total pathological score, AI, and serum creatinine C3 showed that these were significantly different between the two groups (P < 0.05). FA and the ADC were negatively correlated with urinary, blood ds-DNA, and serum creatinine and positively correlated with C1q (P < 0.05). The R2* value was positively correlated with urinary NGAL, blood ds-DNA, and serum creatinine (P < 0.05). FA and the ADC were negatively correlated with the SLEDAI score, total pathological score, AI, CI, nephridial tissue C3, and C1q. The R2* value was positively correlated with the SLEDAI score, total pathological score, AI, CI, nephridial tissue C3, and C1q (P < 0.05).Compared with the control group, FA and the ADC were decreased in patients with LN, while the R2* value was increased (MRI examination in female patients with LN was correlated with pathologic test results, which may have clinical significance in determining the disease’s severity, treatment, and outcome. Systemic lupus erythematosus (SLE) is an autoimmune disease that involves multiple bodily systems. Based on the histopathology of the kidney, patients with SLE are often diagnosed with lupus nephritis (LN), and this condition is one of the leading causes of death in patients with SLE . Renal bThe LN group consisted of 30 female patients with LN and nephrology admitted to our hospital between January 2016 and December 2019. Inclusion criteria were (1) conformation to the diagnostic criteria of SLE, as revised by American College of Rheumatology in 1997, to obtain a SLEDAI score, and (2) diagnosis via renal biopsy pathology. The control group consisted of 20 healthy female volunteers who underwent examination. Inclusion criteria were (1) no history of diabetes mellitus, hypertension, and kidney disease; (2) no current kidney disease; (3) had not recently received any drug with obvious nephrotoxicity; and 4) acceptable kidney function according to various laboratory test indices. Before examination, all patients received no medicine for 8 h and fasted for at least 6 h. Water was withheld for 4 h before the examination [ acceptabConventional MRI and DTI, DWI, and BOLD scanning was performed on the kidney using the GE Singa HDxt GE3.0 T MR system. Post-image processing techniques were used to obtain the FA, ADC, and R2* values for the kidney.All patients with LN received 99mTc-DTPA (99mTc pentanoic acid) renal dynamic imaging in the Department of Nuclear Medicine of the hospital 1 week before and after the MRI test to obtain the SKGFR (the single kidney glomerular filtration rate). Levels of mALB and urinary NGAL were obtained from urine samples. Serum creatinine, C3, C1q, and anti-ds-DNA were obtained from blood samples.Subjects underwent renal biopsy under the guidance of color ultrasonography 7 days before and after the MRI test. Hematoxylin–eosin staining, periodic acid-schiff stain, Masson staining, and periodic acid-GMS were used for kidney tissues. For immunopathology, a fast, sensitive, direct immunization was utilized. The fluorescence intensity distribution of complement C3 and C1q was expressed with “ ± , + , +  + , +  +  + ” and replaced by “0.5, 1, 2, 3” when processed statistically. Based on ISN/RPS  (2003) criteria, patients with LN were classified as follows: type II (n = 4), type III , type IV , and type V (n = 8). The groups did not differ by GFR (glomerular filtration rate) or age. Using the semi-quantitative scoring method of the NIH , the AI (Activity index) and CI (Chronic index) were calculated for the patient group.Singa HDxt 3.0 T magnetic resonance scanner  is used. After routine T1WI and T2WI renal scanning, renal DWI imaging was performed. DWI adopts single shot echo plane imaging (SS-EPI) sequence, TR 6316 ms, TE 63.1 ms, matrix 96*180, FOV 340 mm*240 mm, NEX 8 times, b value is 800 s/mm2. The scanning center layer is located at the center layer of the kidney, with 6 layers. The surface phased array coil is used. The breath gating technology is used to eliminate the artifacts caused by the movement of abdominal organs, and the fat suppression technology is used to suppress the abdominal fat signal. Subjects received conventional double kidney T1W1 and T2W1 scanning using BOLD imaging.The scanning center level was in the center of the kidney. Six levels with a layer thickness of 8 mm were used. Using DWI images showing good corticomedullary demarcations, the central zone of renal hilum was selected to draw the regions-of-interest (ROI). ROI was drawn at the clearly demarcated level of renal skin and medulla, and the cortical contour was delineated with lines to avoid renal cysts and chemical shift artifacts as much as possible. Use a circular tool to draw three circular areas of about 15-25mm2 in the upper, middle and lower polar circles of the kidney. Average values were assigned for the ADC (apparent diffusion coefficient) and FA  of the corresponding renal medulla.BOLD imaging used the Functool 9.4.05a software package of ADW4.4 Workstation's Functool Workstation  for post-processing of the scanning data. The R2* post-process platform was selected. The software system automatically generated the R2* image. The R2* value was obtained using the same method as above.The images were measured and analyzed jointly by two MRI attending physicians, and they were discussed when they had different opinions.p value < 0.05 was considered to indicate a statistically significant difference.Data analysis was performed using SPSS Statistics 22.0. Measurement data conforming to the normal distribution were presented as “ ± s”. Comparisons between multiple groups were performed using ANOVA. The LSD (Least Significant Difference)—t test was used for pairwise comparisons, if there was the homogeneity of variance, while the Tamhane T2 test was used if there was the heterogeneity of variance. Data correlation was analyzed by Pearson correlation analysis. A p < 0.05 for all types) and were decreased significantly in the type IV group. However, the R2* value was increased, and this difference reached statistical significance in the type IV and V groups   Table .Table 1Cp < 0.05 for all groups), of which the mALB was the highest. Furthermore, urinary NGAL was increased significantly in the type IV group. However, the levels of creatinine, C3, C1q, and anti-ds-DNA showed no differences between the groups   Table .Table 2Cp < 0.05), with the biggest differences being seen for the SLEDAI score, total pathological score, AI, and serum creatinine C3 in the type IV group. CI and C1q deposits in renal tissues did not differ between the groups  , and significantly positively correlated with C1q . There was no correlation between the FA or R2* value and mALB or between FA and blood C3   Table .Table 4Cp < 0.05 for all comparisons) , advanced MRI including DTI, DWI and BOLD imaging was important in the evaluation of renal histopathology and kidney function change [n change . The kidn change –8. Our sn change . Pairwisn change . The FA n change . Becausen change , 13. Ourn change –16. Simon change  reportedn change . Xiao etn change .The comprehensive evaluation of LN activity is important for medication administration and outcome observation in clinical practice. The SLEDAI score is currently the most commonly used standard for evaluating SLE disease activity with the help of other indicators . When thPearson’s correlation analysis showed a strong correlation between advanced MRI and renal pathology. Thus, examination of the kidney by advanced MRI in patients with LN appears to be useful in the early recognition of the severity, treatment and prognosis of LN, particularly for patients who refuse renal biopsy or for whom it is contraindicated.This study establishes advanced MRI intervals in control subjects and patients with LN and identifies the correlation between renal advanced MRI values and pathological and laboratory activity indicators. However, this study has certain limitations. First, all patients included in the study were female, and male patients with SLE might present with more severe LN. The effect of gender on the activity of SLE and renal pathology has not yet been determined. In addition, none of the enrolled patients had serious complications such as neuropsychiatric or hematological system damage, and the effect of renal appearance was not defined. Therefore, further studies are required to define the clinical utility and broader indications of advanced MRI.There was correlation between MRI examination and pathologic test results in female patients with LN, indication clinical significance of advanced MRI including DTI, DWI and BOLD imaging in determining the disease’s severity, treatment, and outcome.