These findings imply that XGBoost can be used to develop a reliable prediction model for minor amputations in patients with UT3 DFU, and that our online calculator will make it easier for clinicians to assess the risk of minor amputations and make proactive decisions.Minor amputations are performed in a large proportion of patients with diabetic foot ulcers (DFU) and early identification of the outcome of minor amputations facilitates medical decision-making and ultimately reduces major amputations and deaths. However, there are currently no clinical predictive tools for minor amputations in patients with DFU. We aim to establish a predictive model based on machine learning to quickly identify patients requiring minor amputation among newly admitted patients with DFU. Overall, 362 cases with University of Texas grade (UT) 3 DFU were screened from tertiary care hospitals in East China. We utilized the synthetic minority oversampling strategy to compensate for the disparity in the initial dataset. A univariable analysis revealed nine variables to be included in the model: random blood glucose, years with diabetes, cardiovascular diseases, peripheral arterial diseases, DFU history, smoking history, albumin, creatinine, and C-reactive protein. Then, risk prediction models based on five machine learning algorithms: decision tree, random forest, logistic regression, support vector machine, and extreme gradient boosting (XGBoost) were independently developed with these variables. After evaluation, XGBoost earned the highest score . For convenience, a web-based calculator based on our data and the XGBoost algorithm was established ( It is estimated that the number of diabetes patients worldwide will reach 300 million by 2025 . DiabetiDFU amputations can be divided into minor amputations below the ankle and major amputations above the ankle. Compared to major amputations as a life-saving alternative, minor amputations represent a larger clinical proportion about 90%) of patients undergoing amputation . Therefo0% of patMachine learning is a subfield of artificial intelligence that has brought revolutionary changes to the field of health care through fast, efficient, accurate, and cost-effective computing decisions . MachineIn this study, we collected data on University of Texas grade 3 (UT3) DFU patients from two tertiary hospitals in eastern China. The University of Texas classification is a commonly used grading system, which is detailed in Notably, the data collected by our team exhibits the class imbalance problem commonly associated with clinical data. To prevent its potential to lead to biased decision boundaries, we balanced the outcome variables using the synthetic minority oversampling technique (SMOTE) method, which has performed well in numerous studies –29. To aThe study design flow chart and data screening flow sheet are shown in All clinical data were selected from *** Hospital and the *** Hospital from January 2018 to December 2019. Both hospitals treated DFU under multidisciplinary cooperation. Only patients with UT3 DFU were included in the study while patients who received major amputation, gave up treatment, or had incomplete information were excluded. The demographic data, wound characteristics and laboratory indicators of patients were collected from the medical records. According to the Helsinki Declaration, our study was approved by the Ethics Committee of Nanjing Drum Tower Hospital (No. 2020–10901). Informed consent of the participants was waived because of the retrospective study design and the use of anonymized clinical data.A minor amputation is defined as any amputation distal to the ankle joint.A total of 21 variables that have been shown to have a prognostic impact on diabetic ulcers in the previous literature were collected , 31. AllUlcer location: The location of the ulcer was judged by the endocrinologist and the burn plastic surgeon at the first visit to the hospital.Wound duration: This period ranged from the first discovery to the first visit to the hospital.Diabetic peripheral neuropathy (DPN): Clinical symptoms, such as finger/toe symmetrical sensory disturbance or abnormal nerve conduction velocity, are noted on electrophysiological nerve examination. Two of the following diagnostic criteria of DPN must be met : (1) neuSmoking history: The definition refers to the standard recommended by the WHO in 1984, that is, smoking more than one cigarette a day for a continuous period of one month; otherwise, it is judged to be nonsmoking.Drinking history: The criteria for being classified as a drinker includes a long history of drinking lasting for more than 5 years and daily alcohol consumption ≥80 g.Hypertension: The criteria for determining hypertension are as follows: systolic blood pressure ≥140/90 mmHg or use of antihypertensive drugs with normal blood pressure.Peripheral artery disease (PAD): If one or more lower extremity artery occlusions are found by Doppler ultrasound, it is diagnosed as peripheral artery disease .Hyperlipidemia: Hyperlipidemia is known as lipid metabolism disorder and refers to total cholesterol, triglyceride, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol exceeding the standard value.To explore whether the variables were dose-dependent on the outcome of amputation of diabetic foot ulcers, we defined the abnormal values of variables according to clinical experience and guidelines –38. PatiOur dataset consisted of 75 (20.7%) patients with minor amputation and 287 (79.3%) patients without any amputation. A class imbalance exists in the original dataset, which is a common phenomenon in the field of data science.The class imbalance will cause “undo” effect because they cannot weaken the deviations of the majority class. Therefore, we used the SMOTE technique to alleviate the data imbalance problem, which synthesizes new minority instances from the nearest neighbors of a straight line connecting a small number of samples. These new instances are created based on the characteristics of the original dataset, so they become similar to the original minority class instances . The algFor each minority sample x, calculate its distance from the other samples in the minority class and get k-nearest neighbors.Randomly select a number of samples from the k-nearest neighbors.For each randomly chosen nearest neighbor x’, a new sample is synthesized according to the formula: xnew = x + rand*(x’-x).Determine the sampling multiplier based on the sample imbalance ratio and repeat the above process. Finally, a balanced dataset can be obtained.p-value <0.05 in the univariate binary logistic regression analysis were used as candidate factors to construct predictive models. In this study, machine learning algorithms were selected as the modeling methods for DFU minor amputation prediction. The whole dataset was randomly divided into the training set and the verification set according to the proportion of approximately 7:3, in which the training set was used to build the prediction models, and the verification set was used to verify and evaluate the performance of the models. Five machine learning algorithms were adopted to build risk prediction models, including DT, RF, LR, SVM and XGBoost. Among them, RF and XGBoost are integrated machine learning classifiers, and the remainder are single classifiers. In the process of training, the optimal parameters were determined by 10 cross-validations.Statistical analyses were performed using SPSS 26.0. The enumeration data were expressed as count (percentage) and processed with a Chi-square test, whereas the measurement data were presented as the means ± standard deviation and analyzed by t-test. Factors with a The evaluation indicators, including accuracy, precision, recall rate, F1-score, and AUC, were calculated to assess the constructed models. The closer the values are to 1, the better the performance of the prediction model. In addition, our experiment also used the receiver operating characteristic curve (ROC) to graphically represent the discernibility. As the most persuasive measurement for predictive analysis in machine learning, we also employed the confusion matrix (CM) for further model evaluation, which is a summarized table of the number of actual values and the predicted values yielded by the prediction model. Details of all these evaluation metrics are shown in From January 2018 to December 2019, a total of 362 patients with Texas grade 3 DFU were collected, including 257 males and 105 females aged 26–88 years. All the patient data, including demographics and disease and treatment characteristics, grouped by amputation are listed in P<0.05): random blood glucose, years with diabetes, cardiovascular disease, peripheral arterial disease, smoking history, albumin, serum creatinine, C-reactive protein, and DFU history.Univariate regression analysis was conducted based on 362 patients with minor amputation as dependent variables, and demographics, wound characteristics, and laboratory indicators served as independent variables. Significant results are shown in To solve the class imbalance of the binary variables, we adopted the SMOTE technique. We sampled both the training dataset and the verification dataset, and the sample distribution before and after oversampling is shown in Undergoing a minor amputation operation or not was set as the label, and 9 statistically significant factors in univariate analysis were set as features. The risk prediction models of minor amputation in DFU patients were established by DT, RF, LR, SVM and XGBoost.Firstly, we compared the prediction performance of five machine learning algorithms before and after oversampling as shown in https://dfuprediction.azurewebsites.net/). This web application enables the user to select nine variables to calculate the likelihood of minor amputation for DFU patients. Based on our dataset and the XGBoost algorithm, we constructed a web calculator using Microsoft Azure Web Sites. The address of the website is , the single classifier (DT and SVM), and another ensemble learning machine learning algorithm (RF). Thus, the XGBoost algorithm was best to predict minor amputation of DFU patients . XGBoostIn the results of our feature importance analysis, the top five important factors in our ranking were random blood glucose, DFU history and albumin. Random blood glucose accounted for three of the top five factors, emphasizing the importance of blood glucose control. Some studies have shown that intensive blood glucose control may lead to hypoglycemia –47. NeveP = 0.008, OR = 3.38) [The remaining top five important factors in our ranking were DFU history and albumin. Byung-Joon Jeon et al. demonstrated that a history of previous DFU increased the risk of LEA  = 3.38) . In our  = 3.38) . However . In ourP<0.001) and the incidence of major LEA (11.3% vs. 1.8%) in the malnutrition (GNRI<92) group was approximately 6-fold increased [Low serum albumin always indicates malnutrition, which is more common in patients with DFU given elevated flux and poorly controlled blood glucose. Adequate nutrition is essential for tissue remodeling. The GNRI score for assessing nutrition-related risks consists of serum albumin, body weight, and ideal weight. In a study on nutrition and DFU healing, foot prognosis deteriorated with the increase in the risk of malnutrition (GNRI score) . 3. Our study showed good results in small sample medical data using an oversampling approach (SMOTE) to balance the data. 4. Based on the results of the ranking of factors affecting the risk of minor amputation, we suggest that strict glycaemic control, active DFU follow-up including disease care education and regular review, and improved malnutrition are three key points to avoid minor amputation.Our research is characterized by the following points: 1. Our study provides a real-world dataset from two tertiary hospitals in East China, focusing on outcomes in patients with UT3 diabetic foot ulcers and minor amputations. 2. We compared five popular machine learning algorithms  to filter out the best-performing clinical models and ultimately provided a network calculator for use Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S1 Checklist(DOCX)Click here for additional data file.


P < 0.001). PTT was significantly correlated to sleep efficiency  and oxygen desaturation index (ODI) . PTT drop index was strongly correlated to AHI , respiratory disturbance index (RDI) , ODI , arousal index , and periodic leg movement (PLM) index . Overall, the findings from this study indicated that the PTT drop index is a non‐invasive and useful marker for evaluating the severity of OSA and the effectiveness of treatment in patients with moderate to severe OSA.Airflow limitation in patients with obstructive sleep apnea (OSA) leads to arousal, increased sympathetic nervous system activity, and elevated blood pressure, which causes a decrease in pulse transit time (PTT). The present study aims to evaluate the effect of CPAP therapy on PTT in patients with moderate to severe OSA. This was a cross‐sectional study. Split‐night polysomnography (PSG) study was performed for each participant with apnea‐hypopnea index (AHI) ≥ 15 before and during CPAP therapy. The PTT was calculated as the time interval between the R wave of the electrocardiogram and the following arrival point in fingertip photoplethysmography. PTT drop was defined as a fall in the PTT curve of ≥15 ms lasting at least for 3 s and at most for 30 s. PTT drop index was defined as the number of drops in PTT that occur per hour of sleep. A total of 30 patients were included. PTT significantly increased, and PTT drop index significantly decreased during CPAP therapy  drop index before and during CPAP therapy in patients with obstructive sleep apnea. PTT drop index significantly decreased after CPAP therapy. PTT drop index was strongly correlated to AHI, RDI, ODI, arousal index, and PLM index. Polysomnography (PSG) is the gold standard diagnostic test for OSA.Pulse transit time (PTT) reflects autonomic imbalances and is a non‐invasive marker of respiratory effort and arousal in patients with OSA.Continuous positive airway pressure (CPAP) is the mainstay of therapy for adults with OSA, which reduces the frequency of respiratory events and improves blood pressure.22.1Adult patients (age ≥ 18 years) with moderate to severe OSA referred to our sleep clinic from November 2016 to October 2019 were eligible. The diagnosis of OSA was established according to AASM guidelines.2.2A split‐night PSG study was performed for each participant before and during CPAP therapy. PSG data were recorded using the SOMNOscreen PSG system. The standard PSG incorporated electrocardiography, electroencephalography, electrooculography, pulse oximetry, snoring voice recording, electromyography , thoracic and abdominal movements, thermal sensors, and oronasal airflow. Fingertip pulse oximetry and plethysmography were used to monitor oxygen saturation and the termination of the pulse wave. The PSG data were then interpreted automatically and revised manually according to the American Academy of Sleep Medicine criteria.2.3Respiratory PTT: PTT falls following respiratory events (apnea and hypopnea).Flow limitation PTT: PTT drops following a decrease in upper airflow (which does not meet the criteria for apnea or hypopnea) along with increased respiratory effort.Periodic leg movement PTT: PTT falls following periodic leg movement.Snoring PTT: PTT falls following snoring.Heart rate PTT: PTT falls following an increase in heart rate.Body position PTT: PTT falls following a change in body position.Spontaneous PTT: PTT falls without any recognized physiologic event.The PTT was calculated as the time interval between the R wave of the electrocardiogram (ECG) and the following arrival point in fingertip photoplethysmography.2.4t tests.Statistical analyses were performed using the SPSS software version 25. Shapiro–Wilk test was used to assess normal distribution. Normally distributed variables were expressed as mean ± standard deviation (SD). Median and interquartile range (IQR) were calculated for non‐normally distributed variables. Spearman's correlation analysis was applied to assess the correlation between PTT and PSG variables. Changes in PTT and PSG variables before and during CPAP therapy were assessed via paired samples 33.1A total of 30 patients with moderate to severe OSA were studied. The mean age was 53.4 ± 11.4 years. Nineteen patients (63.3%) were male. The mean body mass index (BMI) was 33.9 ± 5.3. Obesity (BMI ≥ 30) was detected in 25 patients (83.3%). The AHI ranged from 10.6 to 157.4 before CPAP therapy. Severe OSA was found in 28 patients (93.3%). The mean PTT and PTT drop index before treatment were 309.7 ± 19.6 ms and 34.7 ± 24.4, respectively.3.2P > 0.05). PTT drop index was strongly correlated to AHI, respiratory disturbance index (RDI), ODI, arousal index, and periodic leg movement (PLM) index   Figure . Among P) Figure . AHI, RD) Figure .4Obstruction of the upper respiratory tract during sleep in patients with OSA leads to arousal, increased sympathetic nervous system activity, and increased blood pressure, followed by a PTT drop. Therefore, measurements of the PTT drop index can, directly and indirectly, reflect the severity of OSA. In the present study, we observed a strong direct correlation between the PTT drop index and AHI, RDI, ODI, and arousal index, which may confirm this claim. We also monitored changes in PTT and PSG parameters before and after initiation of CPAP therapy. PTT [ms] increased significantly, and the PTT drop index decreased significantly following CPAP therapy. Among PSG parameters, AHI, RDI, sleep efficiency, sleep latency, REM, ODI, average SPO2, and arousal index improved significantly after CPAP therapy.Although associations between PTT and PSG parameters were evaluated in some previous studies,Investigating identifiable causes of PTT drop before and after CPAP is a unique feature of the present study. Not surprisingly, the majority of PTT drops occurred due to respiratory events, which resolved significantly after CPAP therapy. These findings may indicate that by preventing airflow obstruction, CPAP subsides respiratory events and autonomic overactivity, leading to a lower rate of PTT drops during sleep.PLM PTT and snore PTT indexes also improved significantly after CPAP therapy. PLM is characterized by repetitive stereotypical movements of the lower extremities during sleep.Snoring is a sound produced by the vibration of the upper airway's soft tissues during sleep and indicates increased upper airway resistance and pharyngeal collapsibility. Snoring is a common symptom among OSA patients and usually is associated with excessive daytime sleepiness and an increased risk of cardiovascular diseases.Spontaneous PTT was another important determinant of the PTT drop index, which did not change significantly following CPAP therapy. This finding may indicate that PTT drop may occur even without any recordable physiological stimuli during sleep. Spontaneous surges in blood pressure that normally occurs during sleep and/or spontaneous arousals might be responsible for these spontaneous PTT drops.The findings from the current study should be interpreted cautiously due to some major limitations. Small sample size, single‐night study, and lack of follow‐up are the most important limitations of this study. Since the PTT drop index reflects changes in blood pressure and autonomic nervous system, which are among the main risk factors of cardiovascular disease and mortality in OSA patients, the long‐term monitor of PTT drop index changes in OSA patients receiving CPAP therapy might be of great importance. Furthermore, due to the lack of a healthy control group, the importance of each subindex of the PTT drop index is undetermined.Here, we showed that the PTT drop index is strongly correlated to AHI, RDI, ODI, and arousal index, which may confirm the utility of the PTT drop index as a non‐invasive marker of OSA severity. We also demonstrated that CPAP therapy significantly improved PTT drop index and some PSG parameters, including AHI, RDI, sleep efficiency, sleep latency, REM, ODI, average SPO2, PLM index, and arousal index. Among subindexes of PTT drop index, respiratory, PLM, and snore PTT reduced significantly following CPAP therapy, but no change in spontaneous PTT was detected.None of the authors has any conflict of interest to disclose.All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The protocol of this study was reviewed and approved by the Ethics Committee of Tehran University of Medical Sciences. Written informed consent was obtained from all patients included in the study.EK contributed to conducting the research, interpreting data, and revising the manuscript, FK contributed to conducting the research and revising the manuscript, ME contributed to the ideas of this study and revising the manuscript, and BR contributed to the ideas of this study, conducting the research, interpreting data and revising the manuscript.


To understand the related influencing factors of outpatient hypertension detection and control and self-test control compliance rate.  A total of 637 hypertensive patients who visited the outpatient clinic of our hospital from January 2021 to December 2021 were selected for investigation and research, and the relevant information such as blood pressure, treatment detection, and other related information of the patients were counted, and the detection and control of outpatient hypertension were explored through regression analysis and the related factors of the self-test control compliance rate. P > 0.05), and it can be found that there was no statistically significant difference in the age of patients who met the standard and those who did not (P > 0.05). The proportion of patients with self-test hypertension control at home was 64.68%, and the compliance rate of self-test blood pressure was 42.54%. The compliance rate of blood pressure control in outpatient testing was 61.85%. Heart rate, exercise, smoking, medication compliance, and other factors are important factors affecting the control of hypertension. Knowing hypertension-related knowledge, regular follow-up, office blood pressure compliance, smoking, excessive salt intake, and hypertension complications are important factors affecting the self-test control of hypertension in the family.  There was no statistically significant difference in the number of patients who met the standard or not under the gender difference ( By urging patients to do daily physical exercise, admonishing patients to quit smoking, and improving patients' medication compliance, the control rate of hypertension in outpatient clinics can be effectively improved. Understanding the knowledge of hypertension, controlling the salt content in the diet, and receiving regular follow-up surveys from doctors can effectively improve the effect of self-measurement and control of blood pressure at home and further improve the control rate of hypertension. At present, scholars have proved that bad habits such as smoking and drinking lead to poor blood pressure control in patients with hypertension. Family history of cardiovascular disease, long-term excessive drinking, smoking, diabetes, hyperlipidemia, and compliance with medical compliance are risk factors affecting blood pressure control in patients with hypertension. These factors should be paid attention to in clinical practice. But these studies are not in depth and need to be further explored.Hypertension is a common chronic disease, often accompanied by heart, kidney, and other target organ dysfunction or organic discoloration and is also a major risk factor for cardiovascular and cerebrovascular diseases such as stroke and coronary heart disease , 2. In rHypertension, as a common disease, seriously affected the physical condition of patients with hypertension. If the blood pressure of patients with hypertension is not well controlled, the increase in the range of blood pressure fluctuations can increase the cerebral perfusion pressure and lead to dizziness. Without timely treatment, it will even progress to small focal bleeding, causing amaurosis, or even fainting. Therefore, the common clinical symptoms of hypertension patients are dizziness, headache, blurred vision, blackening, and even fainting. Excessive drug dose in patients with hypertension may lead to low blood pressure. Similarly, insufficient cerebral perfusion can also cause transient ischemic attack, leading to dizziness, headache, and darkness. In severe cases, patients will also have symptoms of fainting. Low blood pressure caused by acute cerebral infarction will not only cause severe headaches but also cause coma .Hypertension is a long-term chronic disease that requires patients to maintain long-term medication treatment to maintain a stable blood pressure state. Even if the patient's blood pressure level generally reaches the safe standard, there is still a certain residual risk of cardiovascular events , 8. At pThrough the analysis of community outpatient hypertension detection control and self-test control compliance rate-related factors, we can more accurately grasp the blood pressure control of patients with hypertension to help patients with hypertension stable condition; normal life is of great significance.The study cases were 637 hypertensive patients who visited the outpatient department of our hospital from January 2021 to December 2021. The inclusion criteria of the surveyed patients were as follows: (1) meet the diagnostic criteria of hypertension in the “Chinese Guidelines for the Prevention and Treatment of Hypertension 2010” and meet the systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg. (2) Age >18 years old. (3) Have self-behavior, clear consciousness, and no communication barriers. The exclusion criteria are as follows: (1) patients with secondary hypertension. (2) Patients with severe cardiovascular and cerebrovascular complications in the past. (2) Suffering from mental illness and cognitive dysfunction. (3) Women who are pregnant or breastfeeding. All patients participated in the investigation and research voluntarily, and the patients and their families had signed the informed consent, and the research was approved by the ethics committee of our hospital. The general data of the study cases are shown in This study focuses on the analysis of the factors related to the compliance rate of hypertension detection control and self-test control in community clinics. On the premise of considering the age and gender factors of patients, the relevant evaluation criteria are measured by grouping patients in different groups. The effect of age on blood pressure control and the effect of gender on blood pressure control were also analyzed.The clinicians who have received unified training and passed the examination will conduct a questionnaire survey and physical examination on the subjects. They will learn about the age, disease, medication, physical exercise, family history, diabetes history, smoking and alcohol history, medication compliance, and other information of the subjects in the form of a questionnaire. After completing the questionnaire, they will review the questionnaire items in time and supplement the missing information. Physical examination included height, weight, and blood pressure measurements of the subjects. The height and weight of the subjects were measured according to standard methods. The subjects were required to take off their shoes and hats and wear single clothes. When measuring height, the subjects were required to stand barefoot close to the scale, keep their heels close together, and keep their shoulder blades, hips, and heels close to the scale. The height data reading was accurate to 0.1 cm. A platform scale was used to measure the weight of the subjects, and the weight data were accurate to 0.1 kg. The blood pressure of the subjects was measured according to the international common blood pressure measurement methods and quality control methods, and the standard mercury sphygmomanometer was used for measurement. Before the measurement, the subjects were required to sit and rest for at least 5 min and measure three times, ensuring that the interval between the two measurements was 1–2 min and taking the average value of the three measurements.In the examination of blood pressure in the consulting room, if the systolic blood pressure of the subjects under 60 years old is ≥ 140 mmHg or the diastolic blood pressure is ≥ 90 mmHg, the examination is unqualified. If the systolic blood pressure is ≥150 mmHg or diastolic blood pressure is ≥90 mmHg of subjects over 60 years old, the test is not up to the standard. In the family self-test, if the systolic blood pressure of the subject is ≥ 135 mmHg or the diastolic blood pressure is ≥ 85 mmHg, the test is unqualified. Salt intake ≥ 6G per day is considered as excessive salt intake. The study subjects who smoke or have quit smoking are smoking history, which refers to smoking and smoking more than 1 cigarette a day for more than 1 year or smoking more than 1 cigarette a day in the past but have quit smoking now. Drinking history refers to drinking more than 50 ml of baijiu, 150 ml of red wine, or 500 ml of beer every day. In the evaluation of physical exercise indicators, if the average number of exercises per week is ≥ 3 and the duration of each exercise is ≥ 30 min, it is judged that there is physical exercise. If the number of days of taking medicine according to the doctor's instructions exceeds 90% of the total number of days, it is judged that the medication compliance is good. Subjects with BMI ≥50 were obese, and BMI was the square of body weight divided by height.L in males and 124 umol/L in females. Left ventricular hypertrophy was diagnosed by the left ventricular mass index. If female ≥110 g/m2 and male ≥125 g/m2, left ventricular hypertrophy was judged. If there is atrial enlargement or left ventricular thickening in each atrium and ventricle of the study object, the study object is marked as cardiac enlargement and hypertrophy. If the carotid intima-media thickness of the subject is ≥ 1 cm, or there are single or multiple atherosclerotic plaques, the subject is marked as carotid artery thickening and plaque.If the study object meets one of the conditions of plasma cholesterol rise ≥5.7 mmol/l, low-density lipoprotein cholesterol >3.6 mmol/l, or triglyceride rise ≥1.7 mmol/l, it is judged that the study object is dyslipidemia. The subjects with a history of typical angina pectoris and coronary artery stenosis ≥50% shown by coronary CTA or coronary angiography, or a history of myocardial infarction, were recorded as coronary heart disease. Cerebral hemorrhage and cerebral infarction were recorded as stroke complications, and heart failure included acute heart failure and chronic heart failure. If the daily urine protein quantity of the study object is more than 150 mg, or the urine protein qualitative test result is positive, or the urine protein/creatinine is more than 200 mg/g, the study object is judged to be proteinuria. Serum creatinine was higher than 133 umol/The above are diseases that interact with hypertension, but they are not comprehensive. If other diseases occur during the survey, they can be listed separately for analysis.t-test is used for intergroup comparison, the count data are compared between the groups by the test, and the related factors are analyzed by binary logistic stepwise regression. P > 0.05 indicates that the difference is statistically significant.Statistical software SPSS22.0 was used for data analysis, and measurement data were expressed as the mean ± standard deviation P > 0.05). There were statistically significant differences between those who reached the standard and those who did not reach the standard under such indicators as BMI, heart rate, exercise, smoking, drinking, medication compliance, and excessive salt intake (P < 0.05).P value of the heart rate, exercise, smoking, and medication compliance was less than 0.05, indicating that factors such as the heart rate, exercise, smoking, and medication compliance were important influencing factors for hypertensive patients to be controlled. It is a risk factor for hypertension control, and regular exercise and high medication compliance are protective factors for hypertension control.The multivariate analysis results of the influencing factors of hypertension detection and control are shown in The ROC curve is used to reflect the diagnostic performance of the heart rate, exercise, smoking, and medication compliance indicators in hypertension clinics. The OR value of the heart rate was 0.997, between 0.824 and 1.039, so heart rate block was a risk factor for high snow pressure control. Smoking is also a risk factor for blood pressure control. Conversely, exercise and medication adherence are protective factors for blood pressure control. The ROC curve of the heart rate, exercise, smoking, and medication compliance in the prediction of blood pressure control compliance in patients with hypertension is shown in The results of blood pressure self-testing in community outpatient clinics are shown in P > 0.05); hypertension, smoking, drinking, salt intake, follow-up, sleep quality, exercise, and hypertension complications were investigated; there was a statistically significant difference between the number of people who reached the standard and those who did not meet the standard of target organ damage and outpatient blood pressure (P < 0.05). Thus, education has a significant impact on home control of hypertension (P < 0.05), complications of hypertension also have a significant impact on home control of hypertension (P < 0.05), and the same history of hypertension in parents also has a significant impact on home control of hypertension. (P < 0.05).Logistic regression analysis was used to determine the main influencing factors that affect the self-assessment and control of hypertension. The multivariate analysis results of the self-assessment and control of hypertension are shown in The ROC curve is used to reflect the knowledge about hypertension, regular follow-up, meeting the blood pressure in the office, exercise, smoking, high salt intake, and suffering from hypertension complications. The ROC curve of the main factors controlling the compliance is shown in Hypertension is a common disease among middle-aged and elderly people. The occurrence of hypertension can lead to cardiovascular diseases such as myocardial failure and cerebral apoplexy in the middle-aged and elderly, which seriously endangers the normal life of middle-aged and elderly people , 15. ForThe study conducted an analysis of the compliance rate of hypertension outpatient testing and control in community outpatient clinics. The results showed that the blood pressure control compliance rate in outpatient testing was 61.85%. Through univariate analysis, it was concluded that BMI, heart rate, exercise, smoking, drinking, medication compliance, and excessive salt intake can affect the compliance rate of outpatient hypertension detection and control. Multivariate logistic regression analysis showed that the rapid heart rate and smoking were risk factors for hypertension control, while regular exercise and high medication compliance were protective factors for hypertension control. The increased heart rate can lead to an excited state of the sympathetic nerves, which promotes the production of thyroxine, which in turn causes the arterioles to constrict and raise blood pressure –23. SmokThe study showed that 64.68% of the experimental subjects took home self-measured hypertension control, and the self-measured blood pressure compliance rate was 42.54%. Through univariate analysis, the influencing factors of hypertension patients' self-measured blood pressure at home included hypertension-related knowledge, smoking, drinking, salt intake, follow-up, sleep quality, exercise, hypertension complications, and outpatient blood pressure compliance. Multivariate analysis was performed to determine the risk factors affecting the self-measured blood pressure control of patients. Using multivariate logistic regression analysis, the results showed that smoking, excessive salt intake, and suffering from hypertension complications were the risk factors for home hypertension self-assessment control. Knowledge of hypertension, regular follow-up, and meeting the standard of blood pressure in the office are the protective factors for the self-measured control of hypertension at home. It is known from numerous studies that increased salt intake can lead to increased water and sodium retention in the body, which in turn can lead to increased blood pressure. Hypertensive complications are malignant consequences of hypertension, and hypertensive complications can also feedback the status of hypertension, further aggravating the condition of hypertension –32. For To sum up, in the detection and control of hypertension, urging patients to participate in daily physical exercise, admonishing patients to quit smoking, and improving medication compliance can improve the control rate of hypertension in outpatient clinics. Blood pressure and regular follow-up surveys by doctors can effectively improve the control effect of blood pressure self-measurement at home in hypertensive patients and further improve the control rate of hypertension. There are still some limitations in the study. The selection of hypertensive patients is affected by regional and cultural factors, which makes the selection of relevant factors difficult to be universal. Therefore, in the follow-up research, the research scope needs to be gradually expanded, and the detection and control of hypertension should be discussed in depth.This study starts with a large amount of data and studies the factors related to the compliance rate of hypertension detection control and self-test control in community clinics under the premise of eliminating gender factors, age factors, complication factors, family history factors, and others. It has great research significance and has a significant effect on improving the self-behavior management and quality of life of patients with hypertension. There are still some limitations in the study. There are regional cultural factors in the selection of hypertension patients, which makes the selection of relevant factors difficult to have universality. Therefore, in the follow-up study, the scope of the study needs to be gradually expanded, and the risk factors and protective factors of hypertension detection and control are discussed in depth.


Patients with asthma use short-acting β-agonists (SABA) to relieve symptoms but SABA alone does not treat underlying inflammation. Thus, over-reliance on SABA may result in poor asthma control and negative health outcomes.To describe use of SABA and characterise the relationship with severe exacerbations in the Canadian provinces of Nova Scotia (NS) and Alberta (AB).via regression analysis.In this longitudinal Canadian SABA In Asthma (SABINA) study, patients with an asthma diagnosis were identified between 2016 and 2020 within two provincial administrative datasets . All patients were followed for ≥24 months, with the first 12 months used to measure baseline asthma severity. Medication use and the relationship of SABA overuse (three or more canisters per year) with severe asthma exacerbations were characterised descriptively and sd annual rate of 0.46±1.11 exacerbations, compared to 0.30±1.36 for those using fewer than three canisters of SABA. Patients in AB had mean±sd exacerbation rates of 0.31±0.86 and 0.17±0.62, respectively. The adjusted risk of severe exacerbation was associated with SABA overuse .A total of 115 478 patients were identified . SABA overuse was substantial across both provinces  and across all baseline disease severity categories. Patients in NS with SABA overuse had a mean±This study supports recent updates to Canadian Thoracic Society and Global Initiative for Asthma guidelines for asthma care. SABA overuse is associated with increased risk of severe exacerbations and can be used to identify patients at a higher risk for severe exacerbations. This longitudinal study supports the recent updates to the CTS and GINA guidelines for asthma care. SABA utilisation can be used to identify patients at higher risk of severe exacerbation, regardless of disease severity.https://bit.ly/3Nd3USz Asthma is a chronic disease affecting nearly 10% of Canadians and nearly 65 000 asthma exacerbations occur each year . It is eyrneet al. [yrneet al. [In 2017, O’Beet al.  highligheet al.  noted theet al. , little The SABA in Asthma (SABINA) study is a global programme to evaluate utilisation and clinical outcomes related to SABA use in asthma; this study is the Canadian contribution to that programme , 25. Thee.g. sex, date of birth) and administrative claims information on publicly reimbursed health resource use  and outcomes . Data from both provinces were analysed and reported separately to account for variability in content and coding as well as recognition of data security and privacy requirements from both health systems [This study is a retrolective cohort study  using ad systems .supplementary table S1), physician visits and exacerbations in the 12 months following the diagnosis meeting the case definition. The index date occurred at the end of the baseline period, or 365 days after the first date on which the patient had an eligible diagnosis, and was used to summarise the age and sex of the patient (supplementary figure S1). The remainder of the follow-up was designated the study period and was used to measure study exposures and outcomes. The study period began at index and ended at the time of censoring, the first occurrence of patients moving out of the province, death or by the end of the study in March 2019 in NS or March 2020 in AB.This study used the most recent available data at the time of extraction: from October 2016 to March 2019 for NS, and April 2016 to March 2020 for AB. Three time periods were defined within the study. The baseline period was used to assess case definition and to characterise baseline comorbidity, asthma disease severity, the frequency of asthma-related prescription claims (e.g. death) throughout the study period. Patients were excluded if they were ≥35 years with a diagnosis of chronic obstructive pulmonary disease, if they had <12 months of data available prior to the index date, if they did not have active asthma (no records of asthma diagnosis or treatment following the index date) or if they had severe asthma and were using biological therapies for disease management (supplementary table S2).Data were linked at the individual level to identify a patient cohort for analysis. Patients who were diagnosed with asthma and had at least two consecutive years of follow-up data were eligible for inclusion . We usedsupplementary material) [Asthma severity in the baseline period was determined using average daily dose for ICS  as per the Canadian Thoracic Society (CTS) guidelines . Baselinaterial) . Under ti.e. prescriptions dispensed) of ICS and SABA (see supplementary table S1 for included drug identification numbers). ICS in this study refers to all ICS-containing products, i.e. including both ICS monotherapy and ICS/long-acting β-agonist (LABA) combination therapy. SABA dispensations were standardised to a 150-dose canister  androgramme , and 12 rogramme . An explrogramme . This alsupplementary table S3).Outcomes of interest included severe asthma exacerbations and all-cause mortality. Severe exacerbations were defined by dispensation of short-course (≤10 days) oral corticosteroids (OCS)  or by hoThis study received ethical approval from the Health Sciences Research Ethics Boards at Dalhousie University  and the Health Research Ethics Board of Alberta  for secondary use of information for research. All individual identifiable information was anonymised prior to data analysis and small number subgroups were not reported to prevent identification.Patient demographics and baseline characteristics including age, sex, comorbidity burden summarised using the Elixhauser comorbidity score  and healsupplementary figure S2). At index, patients from NS had slightly higher mean±sd age  and Elixhauser comorbidity score  than patients from AB (supplementary table S4).A total of 115 478 patients was included in the study   and 27% (AB) of patients had no asthma-related prescription use in the baseline period. In both cohorts, patients filled a mean±ectively .supplementary table S5, stratified by baseline disease severity defined using CTS and GINA, respectively.During the study period, most patients in both provinces received ICS-based maintenance therapy combined with a SABA rescue inhaler . In patiThroughout the study period, between 28% and 39% of patients met the definition of SABA overuse  across all baseline disease severity categories. In both provinces, the percentage of patients overusing SABA was associated with baseline severity of disease. Excessive use of SABA was also higher in NS  than AB  and this excessive use of SABA also increased with baseline severity of disease . In explsd estimates of annual exacerbations in NS increased from 0.30±1.36 among patients with appropriate use to 0.46±1.11 among those with SABA overuse and 0.60±1.31 among those with excessive use of SABA. In AB, annual estimates increased from 0.17±0.62 to 0.31±0.86 and 0.49±1.19, respectively. When stratifying by baseline disease severity, in NS, estimates increased from 0.27±1.09 among those with mild asthma (no prescriptions) to 0.81±2.23 among those with severe asthma. In AB, these estimates increased from 0.17±0.66 to 0.34±0.91. A similar trend was noted when baseline disease severity was classified using GINA Steps. Patients defined as GINA Step 5 demonstrated an annual rate of exacerbation six to nine times greater than found in patients of GINA Step 1 (supplementary table S6).Between 10% and 25% of patients experienced a severe exacerbation during the baseline period . The results of the present study are consistent with prior Canadian studies characterising SABA use nearly two decades ago  and thosdet al.  identifiiate use . In addiiate use . Thus, wiate use , the assInternationally, SABA overuse varies from 10% to ∼40% depending on study design , 17, 39.via prescription in Canada. Nonetheless, the use of administrative claims data in this context is also associated with several limitations. Prescription dispensation does not confirm actual use (and the timing of use) of study medications, e.g. patients may acquire new inhalers prior to fully utilising prior inhalers. As a result, while associations between SABA overuse and exacerbation outcomes were estimated in this study, causal inference of this relationship is not possible. In addition, claims data do not present additional clinical detail such as a measure of asthma control. As a result, medication and health resource use were used to characterise outcomes and baseline disease severity. Similarly, the dispensation of OCS used to define exacerbations would be subject to the same limitations. Therefore, in the absence of symptom or disease scores, the disease characteristics of these included patients is largely based on dispensed medication rather than actual use and clinical evaluation.The availability of comprehensive population-based data is a key strength of this study, adding to the generalisability of our results across Canada. In addition, asthma-related prescriptions are comprehensively captured in these data, because SABA can only be dispensed i.e. those patients who were overusing SABA to manage their asthma symptoms and who were at increased risk of severe exacerbation. As a result, these findings support the recent CTS guidelines for mild to moderate asthma: 1) patients with very mild and mild asthma may still be at risk of severe exacerbations and their disease control should be regularly assessed; 2) SABA use can be used as an indicator of partially controlled or uncontrolled asthma and three or more canisters of SABA in a year is considered overuse; 3) overuse of SABA is associated with a higher risk of exacerbation.Several randomised trials have already detailed a reduced risk of severe exacerbations in patients receiving budesonide/formoterol as needed compared to SABA alone, highlighting ICS/LABA as an advantageous combination relative to SABA in patients with mild asthma –45. AmonThese findings may also have implications for patients with moderate to severe asthma. For these patients, the CTS stratifies by risk of exacerbation and recommends escalation of ICS dose and/or consideration of biological therapy where appropriate. SABA use in these patients may provide a simple indicator with which to estimate asthma control. Indeed, the CTS now includes three or more doses of SABA per week as indicator of partial/uncontrolled asthma.Primary care providers and specialists may consider implementing these findings by reviewing with their patients the number of doses of SABA used in a week as a simple and objective way to identify patients who have partially controlled or uncontrolled asthma. This approach has also been highlighted by the Health Quality Ontario updated asthma quality standard, which recommends assessing SABA use at least annually with a recommended cut-off of three or more canisters .Physicians should regularly review SABA use with patients, regardless of disease severity. Pharmacists have a valuable opportunity to identify potential SABA overuse, provide education to patients and offer feedback to prescribing clinicians. Patients should be made aware of the implications of SABA overuse and use this simple metric to help manage their disease and advocate for better care.More than 25% of patients in this study overused SABA medication during the study period. SABA overuse was associated with increased risk of severe exacerbation outcomes. These findings support the recent updates to the CTS guidelines for asthma care , the Nat10.1183/23120541.00140-2022.Supp1Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.00140-2022.SUPPLEMENTSupplementary material 00140-2022.FIGURE1Figure S1 00140-2022.FIGURE2Figure S2


Both animal models and human observational and genetic studies have shown that immune and inflammatory mechanisms play a key role in hypertension and its complications. We review the effects of immunomodulatory interventions on blood pressure, target organ damage, and cardiovascular risk in humans. In experimental and small clinical studies, both non-specific immunomodulatory approaches, such as mycophenolate mofetil and methotrexate, and medications targeting T and B lymphocytes, such as tacrolimus, cyclosporine, everolimus, and rituximab, lower blood pressure and reduce organ damage. Mechanistically targeted immune interventions include isolevuglandin scavengers to prevent neo-antigen formation, co-stimulation blockade , and anti-cytokine therapies . In many studies, trial designs have been complicated by a lack of blood pressure-related endpoints, inclusion of largely normotensive study populations, polypharmacy, and established comorbidities. Among a wide range of interventions reviewed, TNF-α inhibitors have provided the most robust evidence of blood pressure lowering. Treatment of periodontitis also appears to deliver non-pharmacological anti-hypertensive effects. Evidence of immunomodulatory drugs influencing hypertension-mediated organ damage are also discussed. The reviewed animal models, observational studies, and trial data in humans, support the therapeutic potential of immune-targeted therapies in blood pressure lowering and in hypertension-mediated organ damage. Targeted studies are now needed to address their effects on blood pressure in hypertensive individuals.  In atherosclerosis, the role of inflammation is well defined,,,,,,+ and CD8+ T cells. Importantly, the selective isoLG scavenger 2-hydroxybenzylamine can prevent immune activation and lower BP in several animal models of hypertension.Table 1). These have targeted both the innate  and adaptive  immune system. Careful analysis of these studies helps identify potential therapeutic targets, but also highlights the impact of treatment protocol and animal model selection for BP and target organ damage outcomes .Inflammation and immune activation were first implicated as being involved in hypertension through the work of Grollman, Okuda, Svendsen,,,Epidemiological and observational human data supports a relationship between the immune system and hypertension, including the observation that humans with hypertension are at increased risk of COVID-19 infection-related death.++/CD16low monocytes to CD14++CD16+ intermediate monocytes. This seems to be mediated by STAT3 activation and associated with increases in IL-6, IL-1β, IL-23, CCL4, and TNF-α.Circulating leucocytes, which are important cellular components of the immune system, show significant perturbations in hypertension. Data from NHANES III demonstrate higher numbers of circulating leucocytes are associated with hypertension.+) in adults.et al.+ T cells. Even among hypertensive adolescents, a subset of pro-inflammatory CD4+ T cells is associated with SBP and arterial stiffness.+/CD8+ T cells and CD8+CD28 null T cells are also present at this early time point in hypertension.,130A causal role of lymphocytes in human hypertension is supported by large-scale Mendelian randomization genetic evidence.In summary, clinical studies identify greater proportions of activated pro-inflammatory monocytes and lymphocytes in hypertension. This may promote their infiltration into target organs, leading to perturbations in vascular and renal function, and ultimately modulating BP.,Data from Genome-Wide Association Studies (GWAS) and the transcriptome link hypertension with immune cellular defence and inflammatory responses.SH2B3/LNK gene in hypertension and myocardial infarction.,,,LNK knockout mice produce high levels of type I cytokines and these mice exhibit increased sensitivity to angiotensin II (Ang II), leading to hypertension, endothelial and renal dysfunction, increased inflammatory cell infiltrate, and oxidative stress.,Several GWAS have implicated Clinically available immunomodulatory drugs employ heterogeneous mechanisms of action, and hence their impact on BP regulatory systems is likely to be diverse. Agents reviewed below are selected to illustrate this breadth.Table 2). Study populations included those with RA, ankylosing spondylitis, psoriasis, and combined rheumatological diseases. Follow-up was from 2 weeks to 12 months and cohort sizes varied from 9 to 5408. Only 5 of the 20 studies were randomized and/or placebo controlled.,,,Figure 2): the combined estimate from 13 studies comparing average BP before and after TNF-α blockade was a 3.5 mmHg reduction in SBP (95% CI: –5.7 to –1.3), P = 0.001. Five randomized trials with placebo or other pharmacotherapy comparators produce a combined estimate of 4.1 mmHg SBP lowering (95% CI: –7.0 to –1.1), P < 0.001. Only two studies used the gold standard of ambulatory BP monitoring (ABPM), Yoshida et al.et al.,,,,,,,,,,,,,Figure 2). Observational data on incident rates of hypertension offer additional insight. In comparison with non-biologic anti-inflammatory medications, 4822 anti-TNF-α initiators demonstrated no difference in crude or adjusted rates of incident hypertension ,Using a systematized search, we identified 20 studies reporting BP in patients prescribed adalimumab, infliximab, etanercept, golimumab, and six papers with a mix of TNF-α inhibitors used .,,Considering other cytokine inhibitor approaches, we focused on pharmacotherapies with both animal study evidence and use in clinical practice: secukinumab and tocilizumab. We identified the FIXTURE trial of IL-17 antagonist secukinumab (150 and 300 mg groups) in patients with psoriasis. Despite BP being the primary outcome, this trial reported no change at 1 year, though patients were not hypertensive at baseline.,et al.P = 0.001), the other two papers reporting no change in BP with IL-6 blockade,,Three papers were identified reporting BP data with IL-6 antagonist tocilizumab, two used in combination with methotrexate (MTX).et al. demonstrated a reduction in average BP from 152/92 to 137/83 mmHg at 12 weeks in eight patients with psoriasis. Notably, BP increased following MMF cessation in this study. The authors also demonstrated a reduction in urinary TNF-α was during MMF therapy.,,P = 0.08) and diastolic BP by 3 mmHg (P = 0.02) at 6 months compared to transplanted patients receiving tacrolimus/sirolimus. Ninety percent of these subjects had hypertension at baseline.P = 0.88, baseline average 129/70 mmHg) whilst a group treated with tacrolimus/steroid showed an 8 mmHg rise in SBP.Figure 3); however, no data specifically pertaining to hypertensive patients are available.Mycophenolate mofetil (MMF) inhibits nucleotide synthesis and thus prevents lymphocyte proliferation. In an early study, Herrera Figure 3).,,,,et al.MTX is a chemotherapy agent and disease-modifying anti-rheumatic drug (DMARD). Five studies involving between 20 and 8065 participants were identified, reporting average baseline SBP between 121 and 137.5 mmHg. Only one of these employed ABPM. Average SBP lowering ranged from 1.4 to 5.9 mmHg, and diastolic blood pressure (DBP) reduction of up to 4.4 mmHg .,,Figure 4).Calcineurin inhibitors (CNIs) block the earliest steps of T cell activation, but also have substantial off-target effects, including stimulation of endothelin production, increases in sympathetic outflow, renal vasoconstriction, salt retention, and hypertension , and no change in DBP occurred from 2 weeks post-transplant to 12 months follow-up. This was dominated by reduction in nocturnal SBP in both the everolimus and cyclosporine arms.,,Mammalian target of rapamycin (mTOR) inhibitors such as sirolimus and everolimus regulate cellular metabolism, growth, and proliferation, offering alternative immunosuppression following transplantation. Of six studies we found reporting BP values, the three reporting an average baseline SBP >140 mmHg all suggested a reduction in BP of between 3 and 8 mmHg,,,P = 0.38 and 0.03, respectively).,P = 0.68).,Abatacept is composed of the Fc region of the immunoglobulin IgG1 fused to the extracellular domain of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). This agent targets T cell co-stimulation and is commonly used in transplant and rheumatologic diseases. In five studies of RA patients reporting BP outcomes with abatacept, specific values were not available for two and none of the others reported a statistically significant effect on BP.. Trials reporting BP that are not confounded by polypharmacy were sparse. We identified four such studies, and none involved patient groups with uncontrolled hypertension—the average participant baseline SBP being 131/83 mmHg or lower.,,,Rituximab is a monoclonal antibody against CD20, resulting in B cell apoptosis and depletion. It is used in lymphoid and blood malignancies and diverse autoimmune diseasesFigures 5). Data are however conflicting, and hypertension was rarely a pre-specified outcome measure. Trials often involved normotensive populations in which BP lowering is difficult to observe. A combined analysis of studies discussed in this paper shows that cohorts with higher average baseline SBP appear to achieve greater BP-lowering effect , an association also reported for anti-hypertensive drugs.In summary, trials in rheumatic, autoimmune, and transplant patients indicate a possible BP-lowering effect of selected anti-inflammatory therapies targeting diverse pathways previously identified by pre-clinical studies. The evidence appears to be most consistent in relation to anti-TNF-α agents, while other therapies such as hydroxychloroquine, MMF, and mTORs all suggest BP-lowering effect .Animal studies suggest that periodontal Physical activity has an established role in BP regulation, with 3 months of exercise lowering SBP by approximately 5 mmHg and DBP by 3 mmHg.,For dietary interventions, most research has focused on CVD risk reduction, though BP lowering has also been demonstrated in both normotensive and hypertensive cohorts,Dietary salt is another dominant driver of hypertension, primarily through activation of renin–angiotensin–aldosterone system,,,,The central nervous system regulates vascular and kidney function through sympathetic innervation but is also a potent modulator of immune responses. Animal and human studies demonstrate the role of neuroimmune axis in the pathogenesis of hypertension,+ effector T cells with a role in hypertensionAn alternative approach to sympathetic denervation is augmentation of parasympathetic activity through vagus nerve stimulation (VNS). This approach has proven effective in hypertensive rodent models.,Figure 5. Registry data of active RA, with 30% hypertension prevalence, suggested no difference in myocardial infarction rates in response to TNF-α inhibitors vs. DMARDs. However, 60% fewer events did occur in the TNF-α inhibitor responder subgroup vs. non-responders.P < 0.05.et al. reviewed 90 studies reporting cardiovascular risk outcomes in rheumatological conditions treated with abatacept, TNF-α inhibitors, rituximab, secukinumab, tocilizumab, and tofacitinib. They report a neutral effect on BP, on surrogate markers of cardiovascular risk, and on MACE, though authors emphasise the variation in quantity and quality of evidence.Hypertension-mediated organ damage (HMOD) correlates with BP values in hypertensionObservational data based on 13 000 matched pairs from Medicare and MarketScan patients with RA and newly treated with abatacept or a TNF-α inhibitor found benefit of abatacept in MACE restricted to the subgroup with diabetes [HR: 0.74 (95% CI: 0.57–0.96)].P = 0.02).P < 0.001).Colchicine is hypothesized to inhibit microtubular polymerization, assembly of the NLRP3 inflammasome, and IL-1β and IL-18 production. In acute coronary syndrome, colchicine abrogates local increases in IL-1β, IL-18, and IL-6 levels,Figure 5 for common immunomodulatory drugs.Overall, we would conclude that there is evidence of improvement in MACE for TNF-α inhibitors, MTX, tocilizumab, secukinumab, leflunomide and colchicine, though heterogeneity of study designs and outcomes limits the strength of this statement, and we have not explored the relationship between reduction in inflammation and MACE suggested by CANTOS and TNF-α inhibitor responders in the registry data above. HMOD outcomes beyond MACE are surmised in active inflammation. Hence, cardiovascular risk reduction with immune modulation is mediated not through BP alone, but via broader mechanisms of oxidative stress, endothelial function, vascular remodelling, and endocrine regulation, that are the ‘common denominators’ of a dysfunctional relationship. Secondly, we must target the optimal checkpoint in the inflammation–hypertension relationship to optimize benefit without adverse effect, and so far, this has remained elusive at a population level. Finally, it is important to consider that virtually all of the preclinical studies investigating the anti-hypertensive effect of immune interventions on hypertension have involved treatment of animals at the onset on hypertension, often concomitantly with the onset of the disease. In contrast, these agents are usually given to humans with long-standing hypertension. It is possible, and even likely that once hypertension has been established, there are chronic changes in renal and vascular function and structure that render such treatment less effective. In this regard, treatment of younger individuals with early onset hypertension might yield different results than those observed in the studies summarized here.While experimental, genetic, and clinical evidence supports the role of inflammation and immune system involvement in hypertension and associated vascular, renal, and cardiac pathology, immunomodulatory approaches are not currently considered therapeutic options in BP lowering and cardiovascular disease reduction. Indeed, clinical evidence reviewed in this paper shown a highly heterogeneous effect of immune targeting on BP and cardiovascular events across a wide range of patients mainly with various underlying immune-mediated diseases. Going forward, there are several important considerations. As is the case with traditional anti-hypertensive medications, the BP-lowering effects of anti-inflammatory agents appear to be limited to those with uncontrolled hypertension. This is not surprising as numerous compensatory mechanisms make lowering beyond normal BP difficult. It is also important to consider that the effects may be limited to patients with active pro-hypertensive inflammatory mechanisms. The lesson from CIRT, TNF-α inhibitor responders vs. non-responders, CANTOS, and the body of the evidence presented is that there must be Cardiovascular Research online.Conflict of interest: none to declare. This work was supported by the European Research Council (Project Identifier: 726318); the British Heart Foundation grants PG/19/84/34771, PG/21/10541, and RE/13/5/30177; the Marie Sklodowska Curie CIG Award 3631773; the Wellcome Trust grant 204820/Z/16/Z; and the University of Glasgow, Scottish Funding Council and the Global Challenges Research Fund.Data derived from sources in the public domain. Reference details are provided in full.cvab330_Supplementary_DataClick here for additional data file.


Studies indicate a trajectory relationship between baseline blood pressure (BP) and outcome in patients with acute ischemic stroke (AIS) eligible for both intravenous thrombolysis (IVT) with alteplase and endovascular treatment (EVT). We determined whether baseline BP modified the effect of IVT in successfully revascularized AIS patients who participated in the Direct Intra-Arterial Thrombectomy to Revascularize AIS Patients With Large Vessel Occlusion Efficiently in Chinese Tertiary Hospitals (DIECT-MT) trial.The association of baseline systolic BP, trichotomized as high (141–185 mmHg), middle (121–140 mmHg), and low (91–120 mmHg), and the outcomes of any intracerebral hemorrhage (ICH), symptomatic ICH (sICH), and mortality and functional outcome on the modified Rankin scale at 90 days were explored. Logistic regression models determined the interaction between clinical outcomes and baseline systolic and diastolic BP, and mean arterial pressure (MAP), at 10 mmHg intervals. Data are reported as odds ratios (OR) and 95% CI.post-hoc analysis of DIRECT-MT, in 510 of the 656 randomized participants with successful revascularization underwent MT. The overall adjusted common OR of IVT and baseline BP on any ICH, sICH, and 90-day mortality and functional outcome were 0.884 (95%CI 0.613–1.274), 0.643 (95%CI 0.283–1.458), 0.842 (95%CI 0.566–1.252), and 1.286 (95%CI 0.772–2.142), respectively. No significant interaction between baseline blood pressure and intravenous thrombolysis with clinical outcome was observed.A In patients with baseline SBP under 185 mmHg, baseline blood pressure does not alter the risk of hemorrhagic transformation and clinicaloutcome in successfully revascularized patients, regardless of intravenous alteplase usage. Future studies are needed to confirm our findings.http://www.clinicaltrials.gov, Identifier: NCT03469206.URL:  Post-hoc analysis  alone is non-inferior to those who have had EVT after receiving conventional bridging thrombolysis, despite a higher likelihood of successful revascularization with the latter but no clear difference in the risk of symptomatic intracranial hemorrhage (sICH) . Howeveranalysis  of MR CLanalysis  and ETISanalysis  registri130 mmHg . BP-TARG130 mmHg . Moreovepost-hoc analysis, included patients were those who had achieved successful revascularization, defined by eTICI scores 2b/2c/3. Approvals were obtained from site ethics committees prior to any data collection and informed consent was obtained from all patients or their legal representatives prior to randomization.Details of the study protocol for the direct intra-arterial thrombectomy to revascularize AIS patients with large vessel occlusion Efficiently in Chinese Tertiary Hospitals: a Multicenter Randomized Clinical Trial (DIRECT-MT) are published elsewhere . In brie*DBP + 1/3*SBP. A routine automatic measurement of arterial BP was performed. Baseline BP exceeding 185/110 mmHg was a contraindication for IVT, therefore, patients with baseline BP exceeding this interval were excluded from this study.Baseline characteristics included demographic and clinical information, including neurological severity on the NIHSS scale and various time performance parameters in relation to EVT, which were extracted from the DIRECT-MT database. Baseline systolic BP (SBP) and diastolic BP (DBP) were measured at the time of presentation to the emergency department, and SBP was trichotomized into three groups as high (141–185 mmHg), middle (121–140 mmHg), and low (91–120 mmHg). The mean arterial pressure (MAP) was calculated with the following formula: MAP = 2/3The primary analysis focused on any interaction between baseline BP and the effect of IVT on the primary outcome of this trial, in which the functional outcome was measured by the modified Rankin Scale (mRS) at 90 days. A favorable functional outcome was defined as mRS 0–2. The investigated population was mainly successfully recanalized patients who were extracted from pooled data of DIREC-MT database. Secondary outcomes included favorable functional outcomes, defined as an mRS score of 0–2 at 90 days, and sICH. ICH was classified according to criteria. Symptomatic ICH was defined as a worsening of NIHSS with a score increased for 4 points or more within 24 h attributable to ICH.P-values were 2-sided, and conventional levels of significance  were used for interpretation. All analyses were performed using the SAS software, version 9.4 (SAS Institute).Baseline clinical variables are presented with descriptive statistics using frequencies and percentages for categorical variables and medians and interquartile ranges (IQRs) for continuous variables as appropriate. No imputation was performed for missing data since the missing data were minimal. The absolute benefit of intravenous alteplase for different BP values (trichotomized) was computed using the estimated probability of good functional outcome (mRS 0–2) for the intervention and control arm. The interaction between baseline BP and IVT was tested with multivariable ordinal logistic regression analysis with an interaction term. We computed (common) ORs per 10 mmHg SBP increase to assess the relation of SBP with the outcome on the mRS, mortality and ICH; as dichotomized . Adjusted odd ratios were reported as effect size estimates with their respective 95% CIs. All n = 314, 61.57%), who were older and more likely to have a hypertension history . Conversely, the occurrence of symptomatic ICH was lowest in the low BP group with a proportion of 1.89% (1/53). Symptomatic ICH occurred in 7.69% (11/143) and 4.78% (15/314) patients in the middle and high BP groups. A total of 47.17% (25/55) patients of the low BP group achieved functional outcomes at 90 days of follow-up and 13.21% (7/55) suffered death.The occurrence of any ICH was slightly higher in the low BP group with a proportion of 47.17% (25/53), compared with 38.46% (55/143) and 41.08% (129/314) in the middle and high BP groups, however, with no significance (P = 0.371) (P = 0.819). The effect of intravenous alteplase is comparable in three groups .The key prognostic covariables included baseline NIHSS score; baseline ASPECTS score; history of hypertension, diabetes mellitus, and atrial fibrillation. After adjustment, we found no interaction between baseline SBP and the effect of intravenous alteplase on the functional outcome (= 0.371) . The effP = 0.314) or any ICH (P = 0.338). However, lower baseline SBP showed a lower trend for better 90d functional outcome in both thrombolysis (46.2 vs. 40.0 vs. 38.8%) and non-thrombolysis patients (48.2 vs. 46.2 vs. 37.9%), however, without statistical significance (P = 0.371).Furthermore, baseline SBP did not influence the intravenous alteplase effect on the occurrence of sICH (P > 0.05). With baseline SBP 90–185 mmHg, no relationship was observed between baseline SBP per 10 mmHg and sICH  and any ICH . DBP and MAP were also not related to sICH and any ICH as shown in P > 0.05). Considering the improvement of NIHSS score from admission to day 5–7 or discharge, SBP, DBP, and MAP showed no influence . Functional outcomes of mRS 0 to 2 and mortality at 90 days were also not related to BP, as shown in As shown in post-hoc analysis was driven by uncertainty over whether baseline BP affects the benefit of intravenous alteplase before mechanical thrombectomy, given that the risk of thrombolysis-related intracerebral hemorrhage was relatively high in patients with high blood pressure  in recanalized patients and a J-shaped relationship with non-recanalized patients. In this study, we found no significant relationship between baseline BP and clinical outcome. The reason might be the “plateau effect," literally, in patients with baseline BP <185/100 mmHg, the trajectory effect is not significant. Furthermore, for patients eligible for IVT + EVT, neither baseline BP nor IVT usage affect the risk of poor functional outcome, and cannot be used as a predictor of clinical outcome. Nevertheless, patients with baseline BP exceeding 185/100 mmHg were excluded because of contraindications to intravenous alteplase. We assume that patients with baseline BP exceeding the normal range might suffer a higher risk of symptomatic ICH and poor clinical outcomes because of BP while not using alteplase.Successful or failed recanalization status influences the interaction between BP in the acute phase and functional outcome. In historical stroke cohorts, a U- or J-shaped relationship between baseline BP and clinical outcomes were identified. However, most of these studies predated current revascularization strategies, disregarding the recanalization state of the affected arterial territory. In the ETIS registry , high SBSystolic blood pressure at admission is an important predictive factor for clinical outcome after acute stroke. Higher baseline BP was associated with the better collateral flow after stroke onset, however, did not translate into better clinical outcomes. A meta-analysis recruiting 26 studies indicated that pre-thrombolysis systolic BP was significantly associated with poorer 90-day functional outcome  and increased incidence of sICH  and suggested that more aggressive lowering of BP below the current recommendations before thrombolysis might be beneficial . NeverthP = 0.35), and had a neutral effect on recurrent vascular events, disability or death, all-cause mortality, recurrent stroke, and serious adverse events. Further investigations were warranted to identify the optimal blood pressure post-MT treatment.Blood pressure control in the acute phase has a great benefit on clinical outcomes, with an SBP target of 140–150 mmHg being correlated with favorable outcomes in several previous studies , 14. Howpost-hoc analysis (P = 0.90). Forlivesi et al. .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. The handling editor DC declared a shared affiliation with the authors LS and CA at the time of review.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.


Debates continue about the cricoid pressure, which has been used for many years to prevent gastric aspiration during intubation. Using ultrasound, the effects of this maneuver and alternatives like paralaryngeal pressure are revealed. The aim of this observational study was to determine the effect of paralaryngeal pressure with an ultrasound probe on the oesophageal diameter in patients with different body mass indexes and neck circumferences.r value.After measuring the neck circumference at the level of the cricoid cartilage, the oesophagus was visualized by ultrasonography. Compression was applied medially at a 45° angle toward the vertebral column by the ultrasound probe and oesophageal anteroposterior outer diameters were measured. Correlations between body mass index, neck circumference, oesophageal diameter, and oesophageal diameter change ratio were evaluated with Pearson’s −2 were recruited. The oesophagus was located 78.18% partially to the left, 4.54% completely to the left, 1.81% to the right of the cricoid ring. In 15.45%, oesophagus could not be displayed. The mean diameter of the oesophagus was 7.6 ± 1.1 mm before pressure and 5.6 ± 0.09 mm after pressure (P < .001). There was no significant correlation between diameter change percentage and body mass index . However, weak correlation was found between diameter change percentage and neck circumference .One hundred ten volunteers (52 women and 58 men) with mean age 33.7 ± 8.02 years and mean body mass index 25.6 ± 4.65 kg mParalaryngeal pressure with an ultrasound probe has the potential to occlude the oesophagus and may be effective in all patient groups. Contrary to popular belief, the oesophagus lies down most often to the left of the trachea, then behind and to the right, respectively.Paralaryngeal pressure can be applied more standardized by visualizing by ultrasound and decreases the diameter of oesophagus.Regardless of body mass index and neck circumference, a significant narrowing of oesophagus occured with paralaryngeal compression.1 However, its effectiveness in preventing aspiration is still controversial.3Cricoid pressure (CP), known as Sellick’s maneuver, which is one of the important components of rapid sequence anaesthesia induction, has been used for years to seal the oesophagus between the cricoid cartilage and the body of the fifth cervical vertebra to prevent aspiration of gastric contents.4 In addition, it has been reported that adequate closure of the oesophagus cannot be achieved with CP and the main closure is mostly in the hypopharynx.6Computed tomography (CT) and magnetic resonance imaging (MRI) studies have shown that the oesophagus is located lateral to the cricoid ring in more than 50% of subjects and this rate rises to 90% with CP.7Due to the lateral location of the oesophagus, paralaryngeal pressure (PLP) is suggested as an alternative to CP. In terms of functional effect, it has been shown by ultrasonography (which can be easily reached in the operating theater) that PLP decreased the anteroposterior (AP) diameter of the upper oesophagus significantly in conscious volunteers.In this context, the primary aim of this study was to investigate the effect of PLP with the ultrasound probe on the oesophageal AP diameter in patients with different body mass indexes (BMI) and neck circumferences. During evaluating the neck anatomy by ultrasound, we also aimed to assess the correlation between anthropometric measurements (BMI and neck circumference) and the oesophageal diameter.This prospective observational study was performed in accordance with the Declaration of Helsinki. After ethical approval and informed consent, 110 adult volunteers, who were the staff of operating theater, enrolled in the study. Demographic data, height, and weight of patients were recorded. Afterward, the neck circumference was measured at the level of the cricoid cartilage while volunteers were in the supine position with the head extended. Prior to ultrasound evaluation, all participants were monitored with three-lead electrocardiogram and pulse oximetry. In all volunteers, the oesophagus was visualized in the paralaryngeal area by ultrasonography by the same physician using GE Logiq E with a 3.3-10 MHz linear probe with a footprint length of 53 mm . The images were recorded without measurement. By the same physician, compression was applied medially at a 45° angle toward the vertebral column by the ultrasound probe and the images were recorded again. For the 30 N compression force standardization, at least 50 compressions of a weighing scale were performed before the study. Competence in the application of the desired PLP was assured by 20 consecutive successful applications of a 30 N force (within a range of 2 N). Oesophageal AP outer diameter measurements on all recorded images were performed by another independent and experienced physician, who was blinded to the study. The AP measurement was performed in the middle of the transverse diameter, between the external layers of the walls of the oesophagus.Correlations among BMI, neck circumference, oesophageal diameter, and oesophageal diameter change ratio were evaluated.d = 0.50), and an alpha of 0.05. Results showed that a total sample of 54 participants was required to achieve a power of 0.95. This number was inflated to 60 to account for possible losses in image acquisition. Continuous values are shown as mean (standard deviation [SD]). The distribution of the groups was evaluated with the Kolmogorov–Smirnov test. The correlation between normally distributed parameters was evaluated with Pearson's r value. P < .05 was considered statistically significant.An a priori power analysis was conducted using G*Power  to test the difference between 2 dependent group means using a two-tailed test, a medium effect size  had esophagi positioned partially to the left of the cricoid ring, 4.54% (5) completely to the left of the cricoid ring, 1.81% (2) right of the cricoid ring, and in 15.45% (17) oesophagus was not visualized due to posterior placement during the ultrasound examination . When PLP was applied using the ultrasound transducer, the oesophagus was visualized completely to the left in 58.18% (64), partially to the left in 30.90% (34) and partially to the right in %1.81 (2). In 9.09% (10) of the volunteer’s oesophagus was not visualized after compression  Table 1Table 1. Diameter measurements could not be made in 17 volunteers with the oesophagus located behind the trachea before the PLP. In addition, 3 volunteers, whose oesophagus was behind the trachea after compression, although it was lateral at the first evaluation excluded.P < .001). The mean diameter of the outer oesophagus was 7.6 ± 1.1 mm in the neutral position and 5.6 ± 0.09 mm after pressure with the transducer . Any correlation between oesophageal diameter and BMI cannot be found . The correlation between neck circumference and oesophageal diameter was weak . There was no significant correlation between diameter change percentage and BMI . However weak correlation was found between diameter change percentage and neck circumference  (There was a strong positive correlation between BMI and neck circumference ( = .016) .This study demonstrated that, in all patients regardless of BMI and neck circumference, a significant narrowing in the oesophagus occurred with paralaryngeal compression. The neck circumference was negatively correlated with the diameter change percentage throughout PLP via ultrasonography. As expected, a strong positive correlation between BMI and neck circumference in adult volunteers was demonstrated. However, there was no correlation between BMI and any oesophageal measurement for this study.Rapid sequence anaesthesia induction still maintains its importance. Standardization of different components of this application  is very important in terms of providing common approaches and will provide convenience for practitioners. Ultrasonography, which is used frequently in the operating room, may also be a part of this technique. In this article, the objective effect of a different application of ultrasonography in anaesthesia practice is shown.8 Afterward, it is revealed that this relationship was dynamic and the location of the oesophagus changes with pressure. Even with CP, the rate of positioning completely laterally is up to 70%. Tsung et al.9 determined by ultrasound that this positioning is up to 80% to the left of the trachea, to a lesser extent in the posterior of the trachea. Also, Kei et al.10 reported that without CP, the oesophagus laid 20% directly behind the trachea, 60% partially behind the trachea, and 20% completely lateral to the trachea. Similarly, in our study, it was observed that the oesophagus laid 78.18% partially left, 4.54% completely left, 15.45% posterior, and 1.81% partially right to the trachea without any pressure. It has been demonstrated with the previous CT and MRI studies that the oesophagus usually lays partially or completely next to the trachea.5 stated in an MRI study that the effective application of CP resulted in incomplete occlusion of the oesophageal lumen. Inadequate oesophageal occlusion with CP conceived the emergence of the concept of PLP. Andruszkiewicz et al.6 found that the PLP creates a much more significant narrowing of the oesophagus than CP in healthy volunteers. This study appears to be the first to use ultrasound to evaluate oesophageal occlusion with CP. They reported that despite CP does not reduce the anteroposterior diameter of the oesophagus; PLP of 30 N by an ultrasound probe with a footprint length of 23 mm decreases this diameter and has the potential to occlude the upper oesophagus. Since the value of 30 N was taken as a cut-off for both cricoid and paralaryngeal compression in previous studies, we aimed to apply this pressure in patients with different demographic characteristics.11 These findings led us to apply PLP with the ultrasound probe. However, differently, we worked with the standard linear probe with a footprint length of 53 mm, which would be more acquirable in all centers. This standard probe was placed obliquely because it is oversize in the short axis placement and does not create an effective compression in the long axis placement. As in similar studies, we detected a significant reduction in oesophageal anteroposterior diameter with PLP.This anatomy and dynamic relationship led to the idea that adequate closure of the oesophagus cannot be achieved with CP. Boet et al.To our knowledge, the effects of PLP on different body sizes have not been studied before. The frequency of obesity, one of the most important problems of today, is constantly increasing. We aimed to reveal the effect of PLP, which is still controversial in the literature, on volunteers with different physical characteristics.A strong positive correlation was found between BMI and neck circumference. Nevertheless, any relation between BMI and oesophageal diameter was not found. More importantly, there was not any correlation between BMI and diameter change percentage. These findings may prove that PLP can be effective in patients regardless of BMI. Also, negative weak correlation between neck circumference and diameter change percentage shows that physical status does not interfere with this application. 7 emphasized that the CP acts by closing the post-cricoid hypopharynx, not the oesophagus. Afterward, Zeidan et al.12 demonstrated using video laryngoscope that the main effect of CP is at the level of the oesophageal entrance at the hypopharynx level. They published that CP administration closed the oesophageal entrance and prevented gastric tube placement in all patients under general anaesthesia. In a recent study comparing the effects of CP and PLP, Kim et al.13 reported that both manipulation decrease the diameter of the upper oesophageal entrance but the occlusion of the oesophageal entrance is achieved more frequently with CP than PLP during direct laryngoscopy. From these studies, the idea of using both maneuvers in combination may arise in patients with high aspiration risk. In contrast to these views of the current study, Rice et al.Cricoid pressure and PLP will often be needed under emergency conditions. Although it has become easier to access ultrasound in emergency rooms or operating theaters lately, it may not be possible to find a suitable ultrasound probe. However, in correlation with previous studies, it has been found that the oesophagus often lies on the left side of the larynx. Even if there is no ultrasound probe in patients with high aspiration risk, in addition to cricoid compression, paralaryngeal pressure applied to the left side with the finger can reduce the oesophageal diameter and decrease the risk of aspiration.This study has several limitations. First, the volunteers who participated in the study were mostly young people with mean age of 33.7 ± 8.02 years, without the concomitant disease. This sample will not adequately reflect the population of patients in the operating room, especially in emergency situations. In order to minimize this probability, more volunteers were enrolled in the study than in similar studies.Secondly, an investigator performed at least 50 compressions of a weighing scale for the 30 N compression force standardization before the study, and competence in the application of the desired PLP was assured by 20 consecutive successful applications of a 30 N force (within a range of 2 N). However, the paralaryngeal force applied continuously could not be monitored. Possible errors in the amount of applied force cannot be excluded.Third, the evaluations were made in volunteers who were not under general anaesthesia and muscle relaxant effect. Therefore, performing the same measurements after induction of anaesthesia can lead to some differences due to the dynamic relationship between trachea and oesophagus.Paralaryngeal pressure decreases the diameter of the oesophagus and has the potential to occlude the oesophagus. This pressure can be applied more standardized by visualizing using the ultrasound probe. Although there is a relationship between BMI and neck circumference, this may not be reflected in the oesophageal diameter change percentage, which may lead to the idea that PLP by an ultrasound probe or a finger may be effective in all patient groups. In patients with a very high risk of aspiration, both maneuvers, CP and PLP, can be performed together.