P < 0.05). Besides, intima-media thickness (IMT) of common carotid artery (465.84 μm), pulse wave velocity (PWV) (8.09 m/s), pressure of turning point 1 from isovolumic contraction phase to ejection phase (PT1) (126.5 mmHg), arterial enhancement pressure (AP) (6.14 mmHg), and arterial pressure enhancement index (8.58%) were all significantly higher than those of the normal control group (P < 0.05). In addition, the correlation between the coupling (E/A) of hearts and carotid artery of pregnant hypertension patients and PWV was not obvious . The results of the research indicated that intima-media inside carotid artery of pregnant hypertension patients thickened obviously, and it became less elastic compared with that of normal healthy pregnant women. What is more, cardiac morphological changes were manifested mainly as the enlargement of the left atrial chamber and the thickening of the interventricular septum. Volume load and blood flow velocity both increased, and left ventricular diastolic function was damaged. XGBoost algorithm-based ultrasound cardiogram images could improve the diagnostic effects of hypertension during pregnancy effectively.The research was aimed at analyzing the value of the optimized eXtreme Gradient Boosting (XGBoost) algorithm-based ultrasound cardiogram images in the diagnosis of pregnant hypertension patients. A total of 145 pregnant women  were selected as the reference to the comparison and analysis of ultrasound cardiac function parameter, common carotid artery parameter, and the coupling relationship between hearts and cervical vessels of pregnant hypertension patients. The results demonstrated ultrasound cardiac function parameter of pregnant hypertension patients as follows. The maximum volume of the left atrium (LAVmax) was 35.65 mm, left ventricular end-systolic volume (LVESV) was 31.07 mm, and left ventricular end-diastolic volume (LVEDV) was 88.73 mm. All the above indexes were obviously higher than those of the normal control group ( Pregnancy is a special physiological state. In this period, every system throughout pregnant women's body underwent a series of changes to promote fetuses' growth and development. The changes in cardiovascular system are especially obvious . HyperteRelated studies demonstrated that the pathological changes of hypertension during pregnancy of patients were caused mainly by arteriolar spasm throughout the body, which resulted in the changes of systemic hemodynamics. Its main change was the change of stiffness of vessel walls . PatholoIn terms of previous assessment methods of arterial structure, some imaging methods, such as computerized tomography (CT) and magnetic resonance imaging (MRI), were adopted to assess intima-media thickness (IMT) of carotid artery. Then, the blood pressure ratio between the ankle and arm was obtained based on the blood pressure values of body upper arm and ankle, which is called ankle-brachial index (ABI) . NeverthFrom August 2018 to March 2020, a total number of 145 pregnant women who experienced regular prenatal check in hospital were chosen as the research objects. Among these patients, 85 pregnant women with high blood pressure were in the experimental group while the other 60 healthy pregnant women were in the control group. The criteria of selecting pregnant patients with high blood pressure included (a) patients who met the diagnostic standard of high blood pressure disease during pregnancy, which was the constant increase of blood pressure 20 weeks before or prior to pregnancy, reaching or even greater than 140/90 mmHg; (b) patients with singleton pregnancy; and (c) patients who had diseases affecting the blood pressure level of human body, such as combined hyperthyroidism and pheochromocytoma. Exclusion criteria were as follows: (a) patients with basic heart disease before pregnancy; (b) patients with gestational diabetes mellitus, heart disease, and other complications during pregnancy; and (c) patients who had some systemic infectious complications. Patients in the research and their family members were informed and signed the informed consent form. Besides, this study was approved by the ethics committee of the hospital.Esaote color Doppler ultrasonic diagnostic apparatus  was used. The assessment of ultrasonic cardiac function parameters was as follows: the state of heart function of patients in the experimental and control groups was tested by color Doppler ultrasonic diagnostic apparatus immediately after being admitted to the hospital. Firstly, the searching unit was put at the apex part of the patients' heart and patients were asked to hold their breath, during which the position of the unit was adjusted to get the standard image of four chambers in the patients' hearts. After this, the image of the intima in the left atrium and related data were described and recorded. Finally, maximum volume of the left atrium (LAVmax), left ventricular end-systolic volume (LVESV), and the value of left ventricular end-diastolic volume (LVEDV) were all obtained. The method of measuring IMT in blood vessels and the elasticity index was that patients should lie on their backs and then rest silently for five minutes. In this period, the common carotid artery was presented and its image was acquired. All images were optimized by adopting XGBoost algorithm.Extreme gradient boosting algorithm, also called eXtreme gradient boosting (XGBoost), is one of the improved boosting algorithms, and its principle can be explained as a strong classifier attained by the concentration and synthesis of many weak classifiers. XGBoost can be seen as a kind of the improved tree-shaped model of a new stronger classifier, which is generated by gathering and synthesizing lots of decision-making trees. Also, XGBoost belongs to integrated algorithms.mth eigenvalue, and the samples of the eigenvalues less than n were viewed as left subtrees, while those greater than n were regarded as right subtrees. In this way, the first equation was obtained. XGBoost made use of classification and regression tree (CART) model, which assumed that the tree was transformed into a binary tree by keeping splitting features. It was assumed that the current node of CART was the manipulation over the direction of this tree by the The essence of CART's regression to the tree is that sample space was divided within this characteristic dimension, and the optimization of the division of sample space was a nondeterministic issue with polynomial complexity. Therefore, heuristic method was used to tackle with the problem in decision-making tree model. The function generated by the typical CART is shown below. n people calculated could be used to solve the following function:Consequently, optimal segmentation characteristic value and the function corresponding to optimal segmentation point As a result, people could acquire optimal segmentation characteristic and optimal segmentation point by viewing all segmentation points of all characteristics. The final result would be the transformation into a regression tree.q trees after continuous training, they would predict the score of a sample. In fact, there would be a leaf node corresponding to each tree and a corresponding score for every leaf node according to the features of samples. At the end, the predicted value of samples would be acquired only if the corresponding score of each tree was added.Keeping adding trees is the principle of XGBoost algorithm. To be specific, trees were generated one after another by constant split of characteristics. In essence, the appearance of each new tree is fitting the residual caused by the previous prediction by obtaining a new objective function. Once people got The objective function of XGBoost was defined as follows:A) and the score of leaf nodes (shown as w). Γ can regulate the number of leaf nodes, and λ can regulate leaf nodes to avoid its score becoming too large, which can prevent overfitting.The above objective function consists of two components, one of which is used to evaluate the gap between the predicted score and the true score. Regularization item is another component. Apart from the objective function, regularization item is also made up of two components, including the number of leaf nodes  in the above equation. In this equation, it was easy to figure out the values of optimal w and the objective function, which could be achieved by using vertex equation. Hence, optimal w value and the equation of the objective function are shown as equations w) in theThe gain equation of XGBoost was expressed asThe modelling process by XGBoost algorithm was explained as follows.D = {, , ⋯, }; A that represented the number of the iteration of weak classifiers was input and weak classifiers were CART used in the research. In the equation, z and y were samples and true labels matched by samples, respectively.Input: training dataset f(z).Output: strong classifier M,qbrowse through each characteristic zmq under the current feature q. Front node samples were divided into left and right subtrees by the split eigenvalues. Based on the equation, information gain was figured out, and then, the features and feature splitting values corresponding to the maximum information gain were selected to split nodes. When the maximum value of left subtrees (Lsplit) became less than 0, the splitting ceased. Γ could be seen as the split threshold that possessed the function of prepruning. The node splitting needed to be repeated. Optimal splitting value could be found out by scanning from left to right in the order of eigenvaluesview every For each weak classification learner Ultrasound cardiac function parameters of patients in two groups were observed and compared, including LAVmax, LVESV, and LVEDV. Besides, the cardiac chambers and pericardium ultrasound images of patients in two groups before and after XGBoost algorithm optimization were also observed and compared. In terms of carotid artery parameters, IMT, pulse wave velocity (PWV), pressure of turning point 1 from isovolumic contraction phase to ejection phase (PT1), arterial enhancement pressure (AP), and augmentation index (AIx) were observed, and the coupling relationship between hearts and cervical blood vessels of pregnant hypertension patients was analyzed.x ± s. Data from several groups were compared by adopting one-way analysis of variance method, while q test was used for data comparison between two groups. As to the correlation analysis, Pearson-related test was involved and correlation coefficient r was calculated using the Spearman rank correlation. When P was less than 0.05, it was implied that the difference had statistical meaning.All data obtained by this work was analyzed and processed by Statistical Product and Service Solutions (SPSS) software in version 23.0, and measurement data passed the normality test and were manifested at the form of P > 0.05.The differences of data on age and average pregnancy weeks between pregnant women in two groups had no statistical meaning, and The comparison of ultrasonic heart function parameters between patients in the experimental groups and from the control groups, including the indexes of LAVmax, LVESV, and LVEDV, is shown in P < 0.05). (b) Heart chambers and echocardiogram of patients in two groups are shown in Figures 2P < 0.05). This difference was statistically significant. Meanwhile, some indexes, including LA diameter, interventricular septal diameter (IVSd), and LVEDD, were all apparently greater than those of patients in the control group (P < 0.05), which also reflected statistical meaning. E/A and of blood flow velocity E during color Doppler mitral systole and tissue Doppler left ventricular front wall and side wall e ; both of which are demonstrated in (c) Tissue Doppler showed the ratios of left ventricular front wall and side wall Figures 2E/A in tissue Doppler of pregnant patients with high blood pressure were significantly less than those of patients in the control group (P < 0.05). Besides, the ratio of blood flow velocity E during color Doppler mitral systole and tissue Doppler left ventricular front wall and side wall e  was evidently greater than that in the control group (P < 0.05). The difference had statistical meaning.IMT in common carotid arteries, PWV, PT1 from isovolumic systole to ejection period, augmented pressure (AP) on arteries, and augmentation index (AIx) of artery pressure of patients in two groups are shown in Figures P < 0.05). This difference had statistical significance.Figures The coupling relationship between hearts and cervical vessels of pregnant patients with high blood pressure is presented in E/A and PWV was not very apparent .P < 0.05). There was a statistical significance in this difference, which showed that dysfunction really existed in the left heart of pregnant patients with high blood pressure.Clinical ultrasonic cardiogram was applied in auxiliary diagnosis of high blood pressure during pregnancy, and the research of the application value of auxiliary diagnosis of high blood pressure during pregnancy by the imagological features of ultrasonic cardiogram, which was based on XGBoost algorithm, was the hot issue on the research about imagology . It was P < 0.05). The difference had statistical meaning. High blood pressure weakened the function of vascular endothelium of patients and vascular elasticity. What is more, it caused a great increase in the possibility of atherosclerosis in the future. PWV, a significant indicator associated firmly with high-risk factors of causing cardiovascular disease, had a much more superior predicative function of the possibility of cardiovascular disease than that of patients' age, gender, the value of blood pressure, and cognitive capacity [The change in the pressure on arteries was crucial for and even played a decisive role in the stiffness of blood vessels in arteries. Meanwhile, it was also an independent factor in predicting the occurrence of cardiovascular diseases and the organic damage. Related literature showed that IMT in carotid arteries was a key indicator reflecting whether earlier artery walls deteriorate. The damage caused by the increase of IMT resulted from the long-term influence of high-risk factors on artery walls, one of which was probably the rise of blood pressure of patients during pregnancy. If mean artery pressure (MAP) was equal to or greater than 85 mmHg, it was possible that patients would suffer from preeclampsia. If MAP was equal to or greater than 140 mmHg, cerebrovascular disease was likely to occur, which would make pregnant patients fall into a coma and even lose their lives , 17. Thecapacity . The pulcapacity . The rescapacity  proved tcapacity , 22. AnoE and the increase of peak A, namely, E/A < 1. In the experiment, 40 patients were featured with E/A > 1, 26 of which were characterized by E/A < 1 for front walls and for side walls in the left heart chambers. The number of patients with E/A < 1 was 17, whose E/A of both front walls and side walls of the left heart chambers were less than 1; the E/A value of two patients was greater than 2, which might be caused by the obvious weakening of the compliance of the left heart chamber, which referred to the failure of filling pressure to increasing along with left heart chamber expansion. The clinical manifestation of this feature was the increase of filling pressure at earlier diastolic stage, which resulted in the enhancement of peak E. At later diastolic stage of the left heart chamber, filling pressure rose so that ventricular filling rate decreased during atrial contraction and peak A weakened, even disappeared [It was found out in related research that the changes in cardiac morphology of patients with severe high blood pressure at the later stage of pregnancy mainly included hydropericardium, LA chamber expansion, and interventricular septum thickening, which caused damage to diastolic function of the left heart chamber. It was reported that the weakening of diastolic function of the left heart chamber preceded over that of systolic function for patients with preeclampsia . The bloXGBoost algorithm optimization-based ultrasound cardiogram images were adopted to examine and diagnose pregnant hypertension patients in this research. The results of analysis found out that XGBoost algorithm could obtain clearer and more accurate cardiogram images and data of patients quickly and effectively. Compared with normal healthy pregnant women, IMT in carotid artery increased obviously and intima-media became less elastic. The enlargement of the left atrial chamber and the thickening of the interventricular septum were the main changes of cardiac morphology. What is more, cardiac volume load and blood flow velocity both increased, which caused damage to left ventricular diastolic function. Ultrasound cardiogram images under XGBoost algorithm could obtain blood vessel IMT data and data related to blood vessel elasticity, which improved the diagnostic accuracy of hypertension during pregnancy effectively.


Asthma is a common disease characterized by chronic airway inflammation.Since airway inflammation is a cardinal feature of asthma, the main inflammatory phenotypes have been described using the inflammatory cell profile in induced sputum samples. However, sputum induction and analysis are not easy for the patient, require expensive special laboratory equipment, qualified and trained staff and is not widely available. On the contrary, complete blood count is an inexpensive and precise test, routinely performed in everyday clinical practice, has a great reproducibility and is widely available. Furthermore, complete blood count may allow an estimation of the type of airway inflammation, since circulating eosinophil number has been shown to correlate to airway eosinophilseBioMedicine, the study of Tsiavia T et al, reports the identification of asthma inflammatory phenotypes based on complete blood count using a French population based cohort.In The absence of a definite increase of any type of inflammatory cells in the airways of asthmatic patients, also called as paucigranulocytic phenotype, has been recognized as one of the most common phenotypes in optimally treated asthmatic patients with an incidence which varies between 31 and 47% in different studies.Importantly, approximately half of asthmatic patients included in the cohort of Tsiavia et al were overweight and approximately one third were uncontrolled.Overall, the study of Tsiavia et al shows that each inflammatory phenotype in asthma is associated with distinct clinical expression of the disease.AIP has received honoraria for presentations and consulting fees from AstraZeneca, GlaxoSmithKlein, Novartis, Boehringer Ingelheim, Chiesi, and ELPEN. SL has received honoraria for presentations and consultancy fees from AstraZeneca, Boehringer Ingelheim, Chiesi, ELPEN, GlaxoSmithKlein, Menarini, Novartis and Sanofi, Specialty Therapeutics. PB has received honoraria for presentations and consultancy fees from AstraZeneca, Boehringer Ingelheim, Chiesi, ELPEN, GlaxoSmithKlein, Menarini, Novartis, Sanofi and Gilead.


Hypertension is the leading cause of morbi-mortality in our country. Thus, we conducted this national survey on hypertension to analyze the profile of the Tunisian hypertensive patient and to assess the level of blood pressure control.Nature HTN is an observational multicentric survey, including hypertensive individuals and consulting their doctors during the period of the study. Blood pressure measurements were conducted during consultation, using a standardized auscultatory or oscillometric sphygmomanometer after at least 15 min of rest. The diagnosis of new hypertension is based on the 2018 ESC/ESH criteria. The primary endpoint of our study was uncontrolled hypertension defined by a systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg.Three hundred twenty-one investigators participated in the study. We enrolled 25,890 patients with a female predominance  and an average age of 64.4 ± 12.2 years. Most individuals were treated in the public sector (74%), 39.4% of patients were diabetic, 25.8% were obese, 44.6% were overweight and 14% were smokers. Hypertension was controlled in 51.7% of cases if we consider 140/90 as a BP target, and only in 18.6% if we consider 130/80 as a target. The independent predictors of uncontrolled blood pressure were male sex , age > 65 year-old , Obesity , management in public sector , and Heart rate > 80 bpm . Contrarily, high educational level , salt restriction , drug compliance , and regular physical activity  are strong predictors of blood pressure control.NaTuRe HTN showed that blood pressure control was reached in more than half of the Tunisian people. The control remains low in patients with high cardiovascular profiles and in those treated in the public sector. A national health program based on therapeutic education, regular control and continuous support to the public institutions is needed to decrease the burden of hypertension incidence rate. Hypertension is the most common chronic disease in the world with a prevalence ranging between 30 and 50%. It is considered to be the leading cause of morbi-mortality in adults, especially in low- and middle-income countries. Treatment rates were at most 40% and control rates were less than 25% in most countries in all age and sex groups –9. The pNaTuRe HTN registry is an observational multi-centric national study, conducted in all the governorates of Tunisia, in both public and private health sectors. Patients were included between 15 April 2019 and 15 May 2019 (Ramadan in between). Different investigators ensured the enrollment and the clinical examination: Cardiologists, General Practitioners as well other specialists such as Nephrologists, Endocrinologists, and Internists. We included all patients with known or newly diagnosed hypertension who consulted their doctors during the enrollment period.During the office visits, we included patients with a history of or newly diagnosed elevated blood pressure and older than 18 years, after signing a consent form.High blood pressure was confirmed by clinic blood pressure measurements in all patients included in the analysis. Except when hypertension is severe , the diagnosis of new hypertension was confirmed according to the ESC/ESH guidelines as either Out-of-office Blood Pressure (BP) measurement above the recommended thresholds or repeated office BP measurements on more than one visit above 140 mmHg for the systolic pressure and/or 90 mmHg for the diastolic pressure .We excluded from the study patients undergoing hemodialysis, pregnant women, those classified as white coat hypertensive patients, and those who refused to sign the consent form.During the office visit, the physician had to complete the case report form of the registry after the patient’s interrogation and examination.Information on socio-demographic characteristics including age, gender, education level, health insurance, smoking, diabetes, pulmonary diseases, hypothyroidism, moderate renal failure history (defined by an MDRD creatinine clearance < 60 ml / min ), coronaThe interview included questions related to drug compliance and salt intake as well as sport practice. Physical activity was considered as regular when it was performed for at least 30 min three times a week .2). Obesity is operationally defined as a BMI exceeding 30 kg/m2 and is subclassified into moderate (BMI:30–34.9), morbid (BMI:35–39.9), and severe (BMI ≥ 40) [On physical examination, we measured weight and height to assess body mass index (BMI = weight/heightMI ≥ 40) . Blood pWe checked on electrocardiogram whether the patient had a sinus rhythm or atrial fibrillation and we searched for left ventricle hypertrophy (LVH) based on the definition recommended by the ESC/ESH guidelines  . We alsoWe also noted the last biology tests, performed during the last year before the office visit, especially creatinine, glycaemia, cholesterol, and kaliemia as well as microalbuminuria .To assess blood pressure control, we evaluated only patients with diagnosed hypertension for more than 6 months. The primary endpoint in our study was the rate of hypertension control.Uncontrolled hypertension was defined according to the ESC/ESH guidelines as average systolic blood pressure (SBP) above 140 mmHg and/or average diastolic blood pressure (DBP) above 90 mmHg .The secondary endpoints were the assessment of the profile of patients with hypertension in Tunisia .Validation of the study protocol and the consent form by a national ethics committee was also obtained.The data collected were managed by the Clinical Suite platform (Dacima Software), which complies with international standards including US Food and Drug Administration 21 Code of Federal Regulations Part 11, US Health Insurance Portability and Accountability Act, International Conference on Harmonisation, and Medical Dictionary for Regulatory Activities. The Clinical Suite platform allowed us to track the data entered and to check for inconsistencies and missing data. A steering committee was set up to monitor patient inclusions, verify data sources, perform the audit trail, and prepare the statistical analysis plan for the study.We confirm that all methods were carried out in accordance with relevant guidelines and regulations. All experimental protocols were approved by the ethics committee of the Hospital of the Internal Security Forces. Informed written consent was obtained from all subjects. In the case of illiterate participants, informed consent was obtained from legal guardians.All statistical analyses were achieved using the SPSS 23.0  statistical package. Continuous variables were presented as means value ± standard deviation in case of Gaussian distribution and as medians as well as extreme values in case of non-Gaussian distribution.Among patients with old hypertension for more than 6 months, we distinguished two groups according to the hypertension control (controlled group versus uncontrolled group). The comparison between the two groups was achieved by Student’s t-test and Chi2 test for continuous variables and categorical variables, respectively. Univariate logistic regression analyses were used to determine the crude odds ratio with the 95% approximate confidence intervals as estimators of the non-control of hypertension for various characteristics of the study population. To assess the predictors of hypertension non-control, we performed a multivariate logistic regression model. The significance threshold was set at p < 0.05.The factors associated with uncontrolled pressure were studied by calculating unadjusted  and adjusted (ORa) Odds Ratios after multivariate analysis using binary logistic regression. We retained a risk of error of 20% to include the indicator variables in the multivariate analysis.The NaTuRe HTN registry concerned 25,890 hypertensive patients, enrolled by 321 investigators from all the Tunisian governorates. The case report form was completed by Cardiologists in 71% of patients, a general practitioner in 25%, and other specialists in 4%. The patients were managed in the public and private sectors but the majority of patients were followed in public centers (78%). The hypertension was newly diagnosed in 2286 patients (8.8%) and in the medical history/record of more than six months in 23,601 persons.The majority of the patients  were included during Ramadan, especially for the private sector.The epidemiologic and clinical characteristics of the overall population are summarized in Table The mean age of our population was 64.0 ± 12.3 years (extremes: 18–108 years); half of our patients (49.3%) were more than 65 years old. There was a female predominance (sex ratio = 1.22). About 21.3% of the population was illiterate and only 9.4% got a university education. The rate of illiteracy was higher in women than in men . Most of the models had national health insurance (71.3%), private insurance was more frequently noted in patients treated in the private sector (5.8% versus 2.1%). The most associated risk factors were diabetes in 39.4% and obesity in 25.8%. Overweight or obesity was noted in 70.4%. The mean BMI of the study population was 28.1 ± 4.57, it was significantly higher in women than in men (p < 0.001), and obesity was more prevalent in female patients than in males (34.8% versus 17.6%). One patient out of four had a history of cardiovascular events (coronary disease or/and strokes), which means a very high cardiovascular risk.–3) and to salt restriction . Contrarily, men performed physical activities more frequently (p < 10–3).The mean SBP during the office visit was 138.8 ± 19.6 mmHg and the mean DBP was 79.03 ± 11.1 mmHg. Using the cut-point of 140/90 mmHg as a BP target, 51.8% of our patients had a controlled BP, but using the lower cut-off recommended by the ACC/AHA of 130/80 mmHg, only 18.6% were controlled. Both DBP and SBP were significantly higher in men compared to women, but there were no significant differences between the private and the public sectors. Women were also more likely to present atrial fibrillation  and hypothyroidism . Female patients were significantly more controlled than males . Generally, the male gender was found to be an independent predictor of uncontrolled hypertension. In fact, women were significantly more compliant to drug intake  and diabetics  compared to those treated in the private sector, but they performed less BP out office measurement. Moreover, they had less frequent physical activities . Thus, the rate of BP control was better in the private sector .The patients who were treated in the public sector were more frequently smokers  was higher in the private sector (42.9% versus 36.5%). An Antagonist of Conversion Enzyme (ACE) or Angiotensin Receptor Blockers (ARB) were used in two patients out of three. The ACE class was more frequently prescribed in the public sector whereas the ARB class was more frequently used in the private sector.On univariate analysis, patients with uncontrolled hypertension were significantly older, more frequently diabetic, obese, and smokers. They were followed in the public sector with a more frequent history of strokes and moderate renal failure antecedents. These patients also had a higher pulse rate . They practiced sports less frequently  and are less compliant to the drug intake and the salt restriction.Control of BP was better during the holy month (Ramadan), among 15,239 hypertensive patients included during this month, with HTN history > 6 months, 53.3% of individuals were on target.Contrariwise, patients with controlled hypertension had more frequently a history of coronary diseases than others , underwent more frequently electrocardiogram and echocardiography control, and showed less frequently left ventricle hypertrophy Table .Table 2CBased on multivariate analysis, predictors of uncontrolled hypertension were male gender, old age > 65 yo, diabetes, obesity, smoking, management in the public sector, and HR more than 80 bpm. Contrariwise, predictors of controlled hypertension were of high educational level (secondary/university), with a history of coronary disease, salt restriction, drug compliance, and regular physical activity Table .Table 3MHypertension is the most prevalent cardiovascular factor worldwide and is the main cause of death even in developed countries . RecentlThe second important finding of our registry is the improvement of BP control. In 2005, Ben Romdhane et al. conducted a Tunisian cross-sectional survey on 1837 adults aged between 40–69 years old, only 13.2% of hypertensive individuals were controlled . HyperteIn fact, controlling hypertension remains a health problem in not only low- and middle-income countries but also in high-income countries. Ikeda et al., in a comparative analysis of national surveys in 20 countries, showed that hypertension was treated in 13.8% to 80.5% of hypertensive patients in the different countries but was controlled only in 4.4% to 59.1% .In California, the implementation of a large-scale hypertension program has been associated with a significant increase in hypertension control compared to the other cities of the US. The control rate increased from 55% in 2001 to 64% in 2009. Key elements of this program included a comprehensive hypertension registry, development and sharing of performance metrics, evidence-based guidelines, medical assistant visits for blood pressure measurement, and single-pill combination pharmacotherapy .Recently the FLASH 2019 study, a national French study, has shown a rate of 54% of BP control . This raIn our population, BP control has improved; the reimbursement of Stage II and III hypertension costs, as well as the availability of generic molecules and the improvement of the education level of the Tunisian population, has certainly contributed to this achievement. The proportion of patients treated with monotherapy is still high (46.5%). The most prescribed monotherapy was ACE inhibitors. In fact, ACE inhibitors are available in hospital nomenclature but not ARB. In our study, 39% of the patients were diabetics, and 80% were treated in the public sector.Management of patients in the public sector was found to be an independent predictor of uncontrolled hypertension. Certainly, this could be explained in part by the discrepancy of drug availability between the two sectors, the quality of health insurance, and the lack of one single pill treatment in the public sector. However, it is worth noting that in our cohort we found that patients treated in the public sector seem to be at a higher cardiovascular risk with higher prevalence of obesity, diabetes, smoking with less frequent physical activity. All these factors were identified as predictors of uncontrolled hypertension in our population and were behind the bad control of BP in the public sector. Moreover, patients treated in the private sector underwent more frequent out-office measurements. They had a lower heart rate and better follow-up with more frequent lab tests. We also noted that ARB Class was more frequently prescribed in the private sector and this class is associated with better tolerance and persistence. In the public sector, the majority of patients take their drugs from the hospital. ARB class was not available in the public sector. All these findings should be considered by the health ministry to improve the conditions of management of hypertensive patients in the public sector where patients with the highest cardiovascular profile are treated.The reimbursement of stage I hypertension costs by the national security fund is another point to discuss and which is missing both, in the private and public sectors. There is an urgent need for a comprehensive integrated population-based intervention program to improve the serious problem of hypertension in Tunisia.Heart rate was another strong predictor of uncontrolled BP in our population and this could be related to the big prevalence of overweight and obesity as well as the low physical activity practice. One patient out of five has a heart rate > 80 bpm in our model. Recently, the ESC/ESH guidelines classified this clinical finding among the factors influencing cardiovascular risk , 27. ThePatients with a history of coronary disease were more on target in our model and ischemic cardiomyopathy was even identified as a predictor of controlled blood pressure. Many previous studies have confirmed these findings , 13, 32.The main limitation of our registry is the fact that it included only confirmed patients and did not aim to assess the prevalence of hypertension or the rate of undiagnosed and non-treated hypertensive patients. If all these groups had been considered, the control rate would be lower.Another limitation is the definition of hypertension control which was based on office measurements. We did not perform out-office measurements to check the white coat high blood pressure effect, therefore, the rate of uncontrolled patients could be over-estimated in this registry.Finally, this cross-sectional study did not evaluate the clinical follow-up and the impact of uncontrolled blood pressure on cardiovascular events.NaTuRe HTN is the largest national survey of hypertension in Tunisia. It would contribute to analyzing the burden of hypertension in a developing country, and highlight the important gaps in the treatment of hypertensive individuals. Certainly, it may help to guide the implementation of future interventions and to write national guidelines. The most important finding of this registry is that the control of hypertension has remarkably improved over the last years, despite the high cardiovascular risk of our population. Therapeutic education along with substantial support to and interest in the public sector are important preventive measures that can help improve public health in Tunisia.


Right heart catheterization (RHC) and echocardiography are both routinely used for pulmonary artery systolic pressure (PASP) assessment in lung transplantation (LT) candidates, although this is not mandated by current guidelines. We aimed to explore the performance of echocardiographic PASP as an indicator of pulmonary hypertension in LT candidates, in order to assess the necessity of RHC.From a retrospective registry of 393 LT candidates undergoing RHC and echocardiography during 2015–2019, patients were assessed for the presence of pulmonary hypertension (PH), defined as mean pulmonary artery pressure (mPAP) above 20 mmHg, according to two methods—echocardiography and RHC. The primary outcome was the correlation between the PASP estimated by echocardiography to that measured by RHC. Secondary outcomes were the prediction value of the echocardiographic evaluation and its accuracy.p < 0.01). Echocardiography PASP measurements were moderately discriminative to diagnose PH, with an area under the curve (AUC) of 0.72 (95% CI 0.66–0.77). Echocardiographic overestimation of PASP of more than 10 mmHg was found in 35.0% of the patients, and underestimation was found in 11.6% of the patients.The mean value of PASP estimated by echocardiography was 49.5 ± 20.0 mmHg, compared to 42.5 ± 18.0 mmHg measured by RHC. The correlation between the two measurements was moderate (Pearson’s correlation: r = 0.609, In the pre-surgical evaluation of LT candidates, echocardiographic estimation of PASP had moderate correlation and limited accuracy compared to the PASP measured by RHC. We thus recommend performing routine RHC to all LT candidates, regardless of the echocardiographic estimation of PASP.The online version contains supplementary material available at 10.1186/s12872-022-02495-y. Lung transplant (LT) is a life-saving procedure for advanced stage of lung disease . PulmonaThe measurement of pulmonary artery systolic pressure (PASP) is the clinically relevant parameter since it is used in the pre-transplant lung allocation score. The latter aims to direct organs towards the 'right' patient on the waiting list based on a balance of short-term mortality and post-transplant survival, and it’s use has been to proven to decrease the number of deaths of patients on the wait list , 9, 10.Right heart catheterization (RHC) is the gold standard for measuring pulmonary artery systolic pressure (PASP), mean pulmonary artery pressure (mPAP) and other cardiac hemodynamic parameters , 11, 12.Whether non-invasive echocardiography is accurate enough to forego RHC and its complications in LT candidates is debatable. The Pulmonary Council of the International Society for Heart and Lung Transplantation (ISHLT) consensus document on LT candidates published in 2015 states that echocardiography is recommended in all LT candidates in their preoperative evaluation . The ESCThis observational study is based on a retrospectively cohort of 461 LT candidates evaluated for transplant by RHC at two campuses of Rabin Medical Center from January 2015 through December 2019. Of these, we analyzed 393 patients who underwent echocardiography within one year from RHC. For each LT candidate, we collected additional data about demographics (age and gender), medical history  systolic function, right ventricular function and valvular disease were recorded. Right atrial pressure was assessed according to the inferior vena cava (IVC) size and collapsibility  . PASP waThe study protocol and data collection was approved by Rabin Medical Center's human research committee, according to the ethical guidelines of the 1975 declaration of Helsinki. Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of the study.p value ≤ 0.05 was considered statistically significant for all analyses.The primary endpoint of the study was the diagnosis of PH in LT candidates, and the correlation between PASP estimated by echocardiography and PASP measured by RHC. Secondary endpoints were the prediction value of the echocardiographic assessment of PH and its accuracy. To examine the relationship between two quantitative variables, the Pearson correlation coefficient and the equation of the regression line were calculated. Comparison of quantitative variables was performed using the two-sample t-test for normally distributed variables or the Wilcoxon test for non-normally distributed variables. The association between two categorical variables was tested using either the Chi-Square test or the Fisher’s exact test as appropriate. ROC curves were plotted to study the diagnostic performance of echocardiography based PASP to diagnose PH (defined by RHC mPAP > 20 mmHg) and severely elevated pulmonary pressure (defined as RHC mPAP > 35 mmHg) . For eacTR jet, allowing estimation of the PASP during echocardiography, was recognized in 351 out of 393 LT candidates undergoing RHC (89.1%). Patients were predominantly males (63.6%) with a mean age of 61.5 ± 8.3 years Table . The avep = 0.021, and tended to have RV dysfunction . No other variables were found to be associated with elevated pulmonary pressure. The mean time interval between the echocardiography and RHC was 25 ± 372 days, and 78.3% of the patients have completed both tests within 90 days.Pulmonary hypertension mPAP > 20 mmHg) as measured by RHC was recorded in 251 patients (63.9%). The mean value of mPAP measured by RHC was 25.9 ± 11.5 mmHg and mean PASP was 42.5 ± 18.0 mmHg. Pulmonary vascular resistance (PVR) was elevated, with a mean value of 4.2 ± 3.5 Wood units. Mean PCWP was not elevated and the average cardiac output (CO) and cardiac index (CI) were both within the normal range (Table 0 mmHg asp < 0.001). A moderate correlation between the two values was found according to Pearson’s correlation: r = 0.609, p < 0.01  and overweight (mean BMI 28.3 ± 4.8 vs. 25.93 ± 5.63)  the mPAP on RHC was similar to those with measurable TR, meaning that the absence of TR does not predict absence of PH. This might be explained by technically difficult echocardiographic studies in those patients who were found to be obese compared to the group of patients with measurable TR. Regardless from the reason, our results and others , suggestSince the prediction value of echocardiography PASP measurements improved significantly when using it to diagnose severely elevated pulmonary pressure, we suggest using this noninvasive method as a reliable tool for follow up and assessment of treatment response when PASP estimation exceeds 52 mmHg. Results are consistent with recent publication suggesting that the specificity and the positive predictive value of echocardiographic estimation of PASP increases with high cutoffs .The study has a few limitations: First, it is based on a retrospective cohort. The echocardiographic interpretation and RHC measurements were not supervised or reviewed by a second physician and the two studies were not necessarily performed on the same day. Second, the echocardiographic estimation of PASP was based solely on the TR jet and other parameters used for the evaluation the right heart were not recorded. RHC related complications were not recorded as well. Nevertheless, to the best of our knowledge, this is the largest study of its kind which reflects the real-world data of LT candidates and their pre-surgical evaluation.In the pre-surgical evaluation of LT candidates, echocardiographic estimation of PASP had moderate correlation with the PASP measured by RHC, and tended to overestimate or underestimate RHC measurements. Echocardiography PSAP measurements were moderately discriminative to diagnose PH. The absence of TR did not preclude elevated PASP. Based on the study results, we recommend performing routine RHC to all LT candidates, regardless of the echocardiographic estimation of PASP or the presence of TR gradient.Additional file 1: Lung transplant etiologies.Additional file 2: Baseline characteristics of patients with measurable TR compared to patients with no measurable TR.


Cardiorenal syndrome (CRS) is a multi-organ disease characterized by the complex interaction between heart and kidney during acute or chronic injury. The pathogenesis of CRS involves metabolic, hemodynamic, neurohormonal, and inflammatory mechanisms, and atherosclerotic degeneration. In the process of better understanding the bi-directional pathophysiological aspects of CRS, the need to find precise and easy-to-use markers has also evolved. Based on the new pathophysiological standpoints and an overall vision of the CRS, the literature on renal, cardiac, metabolic, oxidative, and vascular circulating biomarkers was evaluated. Though the effectiveness of different extensively applied biomarkers remains controversial, evidence for several indicators, particularly when combined, has increased in recent years. From new aspects of classic biomarkers to microRNAs, this review aimed at a 360-degree analysis of the pathways that balance the kidney and the heart physiologies. In this delicate system, different markers and their combination can shed light on the diagnosis, risk, and prognosis of CRS. There is a close link between the heart and kidney: cardiovascular damage drives a worsening of kidney function; in turn kidney failure worsens cardiovascular injury . Heart FCardiorenal syndrome (CRS) is a multi-organ disease that includes a spectrum of disorders resulting from the close interaction between the heart and kidney during acute or chronic dysfunction of one of these organs.It was described for the first time by Robert Bright, in 1836, who found cardiac structural changes in a patient with advanced renal failure . Since tThe bidirectional nature of CRS has recently been highlighted, and the common pathogenesis identified in hemodynamic, neurohormonal, inflammatory mechanisms also involving the atherosclerotic degeneration.In 2008, the Acute Dialysis Quality Initiative divided CRS patients into two groups based on the primary organ failure driving the disease process  . This clMultiple processes are involved in the pathophysiological mechanism of CRS. Each of these plays a fundamental role in CRS development and cannot be considered an isolated entity but, on the contrary, a portion of larger multifaceted and complex pathophysiological pathways.In acute decompensated heart failure, the cardiac pump cannot maintain optimal blood flow, resulting in volume overload and increased central venous pressure (CVP). CVP is the thoracic vena cava’s pressure near the right atrium. It indicates the blood volume returning to the heart and its ability to pump the blood back into the arterial system. When this mechanism fails, consequent venous congestion results in renal dysfunction caused by reduced renal blood flow and glomerular filtration rate (GFR), and decreased urine output.p < 0.0001). In addition, on multivariate analysis, CVP remained associated with eGFR (p < 0.0001). Furthermore, they showed that CVP was an independent predictor of reduced survival rate (p = 0.0032). A recent meta-analysis included fifteen cohort studies, and showed that elevated CVP was associated with an increased risk of mortality , and acute kidney injury (AKI)  ; HR for highest versus lowest quartile, 2.98 ), and atherosclerotic events . Their results suggest that FGF-23 might influence a CHF mechanism that mediates at least a part of excess CV risk due to CKD. Scialla et al.  found in2 vitamin D synthesis that leads to a suppression of the intestinal phosphate reabsorption. The mechanisms of renal damage cause a decrease of α-Klotho, leading to FGF23 resistance and less efficient phospaturic action [At the kidney level, the interaction among FGF23, α-Klotho, and the fibroblast growth factor receptor (FGFR) induce phosphate excretion and a reduction of 1,25(OH)c action .2 vitamin D, which stimulates FGF23 creation through an endocrine feedback circuiting, modulating 1,25(OH)2 vitamin D production [The principal control on FGF23 is carried out by 1,25(OH)oduction .Notwithstanding the pleiotropic effects that vitamin D exerts to prevent different conditions leading to renal impairment ,59,60 toIn the last few years new biomarkers have been increasingly investigated to find an easy-to-perform and highly predictive tool for assessing, monitoring, and guiding choices for CRS treatment.(p < 0.001), while each 1 g/m2.7 increase in left ventricular mass index was associated with a 1.016-fold increase (p < 0.001). A promising connection between cardiac geometry and serum hepcidin in CKD patients was found by Kim et al. . On univp < 0.001) in the overall cohort and 2.56 in the acute coronary syndrome cohort (p < 0.001). The prognostic value of suPAR remained valid after adjusting for conventional CVD risk factors or conventional biomarkers such as C-reactive protein, NT-proBNP, and hs-cTnI a nd eGFR. In fact, a strong Spearman correlation coefficient was observed for eGFR, with a value of −0.27, (p < 0.001).Recently, Nikorowitsch et al.  identifip < 0.001).Galectin-3 is a recent biomarker belonging to the beta-galactosidase-binding lectin family, produced by activated macrophages and interacting with specific extracellular matrix proteins such as laminin, synexin, and integrins. The Ludwigshafen Risk and Cardiovascular Health (LURIC) study and German Diabetes Mellitus Dialysis (4D) study demonstrated that galectin-3 concentrations increase with progressive renal impairment . Iacoviep < 0.01) and CV death . Another promising biomarker proposed for CRS status assessment is the placental growth factor (PlGF), a member of the vascular endothelial growth factor family of cytokines; this molecule has a relevant role both in CRS and in CKD alone, predicting adverse events in the course of renal impairment. Nakada et al.  measured−10 for the control group, 49.0 ± 80.0 × 10−10 for the heart group, and 33.7 ± 18.0 × 10−10 for the kidney group. The UP/Cr in the heart and kidney groups was significantly higher than in the control group . An emerging biomarker of CRS is urine podocin/creatinine ratio (UP/Cr). Szczepankiewicz et al.  analyzedp = 0.031; overall accuracy 79.55%). Urinary cofilin-1 is another intriguing biomarker that acts as a modulator of epithelial-mesenchymal transition or de-differentiated renal tubular cells, which are essential for AKI and renal function recovery , and is r = 0.4889 p < 0.0001; ECP r = 0.6221 p < 0.0001; FETUB r = 0.4762 p < 0.0001; GDF15 r = 0.5570 p < 0.0001; GUAD r = 0.5549 p < 0.0001; and NOTCH1 r = 0.6493 p < 0.0001). This panel could be useful for foreseeing and preventing CRS features, even if dedicated study on these population should confirm its value. Another panel of urinary proteins, already used for CV risk, could be used in CRS population: Martinez et al.  posed anThe progressive affirmation of microRNAs (miRNAs) in clinical practice also involved CRS. MicroRNAs (miRNAs) are non-coding RNA molecules encoded in the human genome, 18 to 25 nucleotides in length, and responsible for post-transcriptional gene expression by binding to the 3’-untranslated region (UTR)/coding sequence (CDS) of mRNA of target genes. A number of studies have reported that microRNAs contribute either in a beneficial or negative way in mechanisms involving atherosclerosis and arterial remodeling, such as endothelial dysfunction, monocyte activation and migration in the arterial wall, and plaque constitution ,76,77. Sp = 0.001). The AUC of hsa-miR-21 based on ROC curve was 0.749, with a sensitivity of 55.95% and a specificity of 84.93%. Furthermore, combining hsa-miR-21with cystatin C enhanced the AUC to 0.902, with a sensitivity of 88.1% and a specificity of 83.6% (p < 0.001). These data indicate the utility of hsa-miR-21 in identifying risk factors for CRS and better monitoring the status of these patients, especially if combined with cystatin C.An miRNA that might play a decisive role in CVD management is the hsa-miR-21 that has been reported in all types of CRS and is associated with poor outcomes in most primary organ disfunctions . It is kOther miRNAs were found during CRS but their role is not yet completely understood. A panel of five circulating miRNA has been successfully tested by Keller et al.  in the cp = 0.034) and of 2.9  after adjusting for the FRS in a derivation cohort. They compared the hsa-miR-34a, -miR-223, -miR-378, -miR-499 and -miR-133 expression panel with the Framingham risk score (FRS), demonstrating a significant association with mortality given by a hazard ratio (HR) of 3.0 (95% (CI): 1.09–8.43; A recent meta-analysis demonstrated that hsa-miR-423-5p can be used as a marker of HF, with a higher specificity if used in combination with BNP , left veA recent in silico analysis aimed to identify crucial miRNAs and their associated target genes to pave the way for finding novel pathological mechanisms and biomarkers for CRS. Through this approach, the authors found that 5 miRNAs, namely, hsa-miR-122-5p, -miR-222-3p, -miR-21-5p, -miR-146a-5p, and -miR-29b-3p can be considered key regulators of CRS and correlate with it .The next goal could be the creation of a multivariable panel of miRNAs combined with other conventional biomarkers to conceive accurate diagnostic and prognostic algorithms for CVD patients .A summary of the biomarkers linked to CRS is represented in Previous valid papers aimed to enlighten the usefulness of classical CRS ,91,92,93In this setting, the use of microRNA, the ratio between well-known kidney and heart dysfunction parameters, and novel panels of multiple biomarkers were analysed with their strength and weakness..There is growing evidence regarding the validation and utility of recent serum and urinary biomarkers for acute and chronic CRS thanks to the harnessing of newer technologies or the development of dedicated protein panels. The use of high specificity and sensitivity tools with high prognostic values can help the clinician to overcome therapeutic limits and create new strategies for the treatment of complex clinical conditions ,91..The use of accurate and reproducible markers can be helpful in various aspects of CRS treatment, including prevention of CVD events, monitoring patients even at the onset of the disease complications. These biomarkers can help clinicians choose more accurately the timing of a specific treatment and study adequate prevention strategies. Further studies will be fundamental in developing the best tools for improving the diagnosis, predicting adverse outcomes, and choosing the right treatment for CRS.


Evaluating the relationship between circulating metabolic biomarkers and semen parameters in obese, overweight and normal-weight patients.Patients were recruited at the “Andrology and Pathophysiology of Reproduction Unit”, in Santa Maria Goretti Hospital. Divided into three groups were 98 participants  according to BMI and were analyzed for three adipokines and six hormone peptides in blood serum and seminal plasma using Luminex assay. Standard semen analysis was performed for ejaculate volume, sperm concentration, total sperm count, motility, morphology and leukocytes.In all groups of subjects, we observed a higher concentration of blood serum c-peptide, GIP, PAI-1, leptin, ghrelin and GLP-1 in comparison to seminal plasma; differently, higher levels in seminal plasma were observed for insulin and visfatin. In comparison to the non-obese subjects, obese subjects showed a higher blood serum concentration of c-peptide, GLP-1, GIP and leptin and a higher concentration of seminal plasma of GIP and insulin. Total sperm count, progressive motility, motility, and atypical forms directly correlated with PAI-1 and visfatin, whereas GLP-1 directly correlated only with total progressive motility.Obese men showed a different pattern of blood serum and seminal plasma adipokines and hormone peptides concentrations in comparison to normal-weight men. Furthermore, these molecules correlated with functional seminal parameters. Our findings support the option to consider these molecules as new biomarkers and pharmacological targets for a new therapeutic approach in male infertility. However, further studies identifying other potential biomarkers of male infertility with important clinical implication and characterizing their mechanisms of action are mandatory. Obesity has several impacts in society, especially in industrialized countries and is largely associated with other pathological conditions such as atherosclerosis, depression, sleep apnea, type 2 diabetes mellitus (T2DM), cardiovascular and orthopedic disease. A possible relationship between obesity and male infertility has been suggested as well, since the normal function of hypothalamic–pituitary–testicular axis (HPA) depends on the balance of energetic intake and expenditure . StudiesAdipokines are cytokines specifically released from adipose tissue to communicate with other organs such as brain, liver, muscle, the immune system and adipose tissue itself , 8. The 6 leukocytes/ml were excluded as an objective sign of reproductive tract inflammation. Moreover, we excluded from our study five non-obstructive azoospermic samples and one criptozoospermic sample. The remaining 98 participants were divided into three groups according to Body Mass Index (BMI): 34 normal weight (nw) subjects (BMI ≥18.5 ≤24.99 Kg/m2); 30 overweight (ow) subjects (BMI ≥25 ≤29.99 Kg/m2) and 34 obese (ob) subjects (BMI ≥30 Kg/m2). Waist circumference was measured in centimeters at the narrowest point above the hips with the man standing straight. All patients provided informed written consent for personal data treatment in accordance with standard laboratory procedures. Ethical approval was not needed since blood and seminal samples were supplied for clinical assistance and laboratory analysis.We recruited 124 consecutive subjects from the Andrology Unit of Santa Maria Goretti Hospital  for analysis of seminal fluid and andrological evaluation, between February 2017 and February 2018. A clinical history was performed to collect personal information including lifestyle factors, sexual and reproductive status and medical history. Eligible patients had not been treated medically or surgically in the previous three months. Exclusion criteria included past medical history of endocrine, oncological or andrological  diseases and genital tract infections. FSH, LH and total testosterone were requested by the physician as diagnostic tool of the clinical andrological evaluation while semen examination was performed in our lab. Twenty semen samples containing >1 × 106/ml), total sperm count (n × 106/ejaculate), progressive motility (%) and morphology . Sperm concentration was examined in a Mackler counting chamber ; sperm motility and morphology were evaluated in duplicates according to standard WHO guidelines. To provide evidence for compliance with WHO recommendations, our andrology laboratory participates in an accreditation program of the Italian Society of Andrology and Sexual Medicine (SIAMS). For each semen sample 1.0 ml of the whole semen was recovered after semen analysis and it was centrifuged at 800g for 10 min and then the supernatant was centrifuged again at 3,000g for 10 min; the final supernatant was immediately stored at −80°C until adipokines and peptides assays have been carried out.Semen samples were collected by masturbation directly into a sterile plastic container after 3–5 days of sexual abstinence. All samples were left to liquefy at 37°C for 60 min and were then analyzed by the same biologist (LC) by light microscopy according to the World Health Organization criteria . The folvia venopuncture of superficial vessels by a trained nurse using color-coded Vacutainer tubes. Blood samples were collected after at least 8 h of fasting. To perform adipokine and hormone assay, blood samples were divided according to BMI patients into 26 nw, 30 ow and 26 ob men and were separated by centrifugation at 800g for 10 min; 1.0 ml of BS was stored at −80°C until adipokines and peptides assays have been carried out.In the same morning of semen analysis, 82 of the 98 subjects have had a blood draw as part of the routine clinical procedure to analyze antisperm antibodies. Venous blood samples were collected Adipokines and peptides were measured as previously described  in all SP value <0.05 was considered significant. Data were expressed as the mean ± standard error (SE). Kruskal–Wallis non-parametric test was used for semen parameters. Data were expressed as median, minimum and maximum. The Pearson correlations among adipokines and serum testosterone data were calculated whereas Spearman correlations among plasma adipokines and semen parameters were calculated.The statistical analysis was performed using GraphPad Prism 5 software  and SPSS 12.0 software package . The Kolmogorov–Smirnov test for normal distribution of the data, one-way analysis of variance (ANOVA), and T-test were applied. A Demographic and anthropometric characteristics in obese, overweight and normal weight subjects were reported in P <0.01 and 0.286, P <0.05 respectively) and visfatin , while GLP-1 positively correlates with the number of spermatozoa with progressive motility .Regarding semen analysis, we did not evidence statistical differences in sperm parameters among the three groups , a strong controller of glucose homeostasis , seems ain vitro studies demonstrated that visfatin increased testosterone production in rat  and oxidative stress (as i.e. interleukin (IL)-6 and IL-8)  could beThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical approval was not needed since blood and seminal samples were supplied for clinical assistance and laboratory analysis. The patients/participants provided their written informed consent to participate in this study.CA: wrote the manuscript. ML: revised the manuscript. LC: performed experiments. PiS: performed experiments and recruited the patients. CM: performed experiments. FB: revised the manuscript. LL: revised the manuscript. PaS: conceived of the presented idea and wrote the manuscript. LS performed the experiments and wrote and revised the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Major vascular complications of T2D include cardiovascular disease and chronic kidney disease (CKD). Results from several cardiovascular outcome trials (CVOTs) with these drugs have highlighted benefits in reducing major adverse cardiovascular events by 11%, reducing the risk of cardiovascular death or hospitalization for heart failure (HF) by 23% and reducing the risk of progression of renal disease by 45%. Their cardiorenal benefits are apparent across a range of eGFRs (within CKD1-3 groups) and the presence or absence of ischaemic heart disease, HF or T2D. In patients with HF with reduced ejection fraction (HFrEF), similar risk reductions in cardiovascular death and HF events are also seen; results from studies in patients with HF with preserved ejection fraction (HFpEF) are awaited. Cardiorenal benefits have been recently reported in patients with CKD, regardless of the presence or absence of T2D. Indications for use of SGLT2 inhibitors have extended beyond glucose-lowering to a central role in cardiorenal protection. This review will first explore the mechanisms by which glycaemic control, weight loss and cardiovascular risk factors are modulated therapeutically with SGLT2 inhibitors. Subsequently, we outline putative mechanisms underpinning the cardiorenal benefits seen, including in HF and CKD, in the context of completed and ongoing clinical studies. Treatment strategies with SGLT2 inhibitors in individuals with CKD or HF, with and/or without T2D are increasingly appealing. Combination therapy with complementary therapeutic agents is also explored.The kidney plays a major physiological role in glucose homeostasis but also contributes to the pathophysiology of type 2 diabetes (T2D), mediated by renal sodium glucose cotransporters (SGLTs). This recognition led to the development of SGLT2 inhibitors that inhibit proximal renal tubular renal glucose and sodium reabsorption. The glucoretic and natriuretic effect of SGLT2 inhibitors is associated with reductions in HbA The various roles of the kidney include the excretion of metabolic waste products, maintenance of intravascular volume and serum osmolality, regulation of blood pressure, acid-base and electrolyte balance through filtration, secretion and selective reabsorption of key ions. The kidney also has a major physiological role in regulating glucose homeostasis constantly supplying glucose to the brain despite diurnal changes in nutrient availability. The involvement of the kidney in gluconeogenesis was first described in 1938 in rabbits, where the amount of glucose required to maintain euglycemia was considerably higher after hepatectomy plus nephrectomy versus hepatectomy only   .The implications of the findings of these studies are that SGLT2 inhibitors appear to reduce the risk of hospitalization for HF in patients both without a pre-existing diagnosis of HF and in those with established HF; applicable for non-diabetic patients and those with T2D. In May 2020, dapagliflozin was the first SGLT2 inhibitor to be approved for the use of HF with reduced ejection fraction by the Federal Drug Administration (FDA).There are several ongoing studies of SGLT2 inhibition in patient cohorts with different phenotypes of HF . The EMPIn a recent analysis of DECLARE, dapagliflozin was shown to decrease the incidence of reported episodes of atrial fibrillation/atrial flutter (AF/AFL) adverse events in high-risk patients with T2D. This effect was consistent regardless of the patients’ prior history of AF, ASCVD, or HF .Several observational, population-based, retrospective cohort studies have examined the effects of SGLT2 inhibitors on rates of death and/or hospitalization for HF in patients with T2D ,53. In tanti-atherogenic effects. Proposed cardiac mechanisms include cardiac remodelling, improved contractility and a shift in myocardial and renal substrate utilization from fat and glucose oxidation towards an energy-efficient “super fuel” like ketone bodies, which improve myocardial/renal work efficiency and function [The mechanism by SGLT2 inhibitors mediates this reduction in CV death and HF remains unknown, although many theories have been proposed . The finfunction ,58. PresThe collective CV data and clinical trials context are summarised in 2) for 3 months, is classified into stages based on the level of GFR [a > 11-fold increased risk of end-stage renal disease compared with patients who did not have CVD [CKD, as defined by the presence of kidney damage or glomerular filtration rate . Furthermore, fewer than 1/6 of participants have eGFR <60 ml/min/1.73 m2 with only a small proportion with baseline eGFR <45 ml/min/1.73 m2. Recognizing the need to study the participants with the highest risk of adverse renal outcomes (i.e. those with the lowest eGFR), and thus the group who would derive the most benefit, studies of SGLT2 inhibitors have been conducted or are underway. Currently, SGLT2 inhibitors are not approved for use in patients with eGFR < 45 ml/min/1.73 m2 based on the diminished glycaemic efficacy with impaired renal function.In recent decades despite attempts to achieve optimal glycaemic and blood pressure control, and widespread use of ACEs/ARBs, there remains a high residual risk for patients with CKD to progress to end-stage kidney disease (ESKD) which highlights the need for additional renoprotective therapies to preserve eGFR and prevent ESKD. The renoprotective effects of SGLT2 inhibitors were first demonstrated in EMPA-REG, DECLARE and CANVAS ,37,66 al2 with UACR >300–5000 mg/g with all patients receiving renin-angiotensin system blockade with stable doses of ACEs/ARBs. Mean eGFR was 56.2 ml/min/1.73 m2 with 60% had an eGFR of 30–60 ml/min/1.73 m2. The primary outcome measure was a composite of ESKD , a doubling of serum creatinine or death from renal or cardiovascular causes. Secondary outcomes included cardiovascular outcomes. This study was terminated early after reaching the pre-specified efficacy criteria. The relative risk of the primary outcome was reduced by 30% in the canagliflozin group relative to placebo with a 20–30% lower relative risk of deleterious cardiovascular outcomes. It also provided reassurance about the risk of amputation/fracture with similar rates between the two groups. This study demonstrated benefit for patients of all eGFR groups including those with a low baseline eGFR (eGFR 30–45 ml/min/1.73 m2 in whom SGLT2 inhibitors would not currently be recommended).The only currently published RCT designed to evaluate the renoprotective effects of an SGLT2 inhibitor in 4401 people with T2D, CKD, and macroalbuminuria, compared with a placebo, is the CREDENCE study  . This st2.A further systematic review and meta-analysis which pooled data from the 3 CVOTs and CREDENCE, including a total of 38,723 participants, demonstrated consistent reductions in all the major kidney outcomes including acute kidney injury  Figure . Signifi2), consisting approximately two-thirds of the population with and one third without T2D, and demonstrated that the SGLT2 inhibitor, dapagliflozin, conferred kidney protection in patients with CKD. The occurrence of the composite primary outcome measure of a sustained decline in eGFR of at least 50%, end-stage kidney disease or death from renal/cardiovascular causes was reduced by 44%. Similarly, the risk of a composite of death from cardiovascular causes or hospitalization for heart failure was reduced by 29%.[The results of the DAPA-CKD trial have extended these findings to the broader population of patients with CKD (including participants with an eGFR 25–75 ml/min/1.73 md by 29%..A short-term (6 week) randomized double-blind, placebo-controlled, cross-over study (the DIAMOND study) has examined the effects of dapagliflozin on proteinuria in non-diabetic patients with CKD and on stable RAS blockade. Although this did not show a difference in mean proteinuria change from baseline between dapagliflozin and placebo, this may reflect the short study duration and the outcomes of longer-term clinical trials are awaited .EMPA-KIDNEY evaluating empagliflozin in patients with CKD, with or without T2D, is currently underway. Results from this study, with the results from DAPA-CKD, will likely pave the way for their application in patients with CKD, irrespective of a background of T2D.In clinical practice, there is a more heterogeneous population of patients that receive SGLT2 inhibitors than those randomized in placebo-controlled clinical trials and thus real-life studies assess whether clinical trial data extends to patients treated in routine clinical practice. CVD-REAL 3 was a multi-national, observational cohort study examining new users of SGLT2 inhibitors with other glucose-lowering drugs with measurements of eGFR before and 180 days after initiation . During In another such study, using nationwide data from routine clinical practice in Scandinavia  Pasternak et al., demonstrated that initiation of SGLT2 inhibitors, compared with dipeptidyl peptidase-4 inhibitors using propensity matching, was associated with a significantly reduced risk of renal events reflecting a composite including renal replacement therapy, death from renal causes and hospital admission for renal events  . These rOur understanding of the underlying mechanisms through which SGLT2 inhibitors achieve renal protection is evolving . Good glThe collective renal data and clinical trial context is summarised in Recently, a consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) provided updated recommendations on the management of hyperglycaemia . IncorpoGiven the increased transport capacity of SGLT1 for glucose following SGLT2 inhibition and the significant role of SGLT1 in intestinal glucose uptake, optimizing dual SGLT inhibition is an appealing strategy. As well as being identified in the human kidney and intestine, SGLT1 is expressed in the liver, heart, skeletal muscle, lung, and possibly brain, indicative of several extra-renal functions of this transporter . MechaniThe therapeutic potential of phlorizin was limited, due to poor oral availability, and effects on gut glucose absorption that resulted in diarrhoea. Sotagliflozin is the first dual SGLT inhibitor licenced for the treatment of T1D, in combination with insulin, in Europe. Compared to selective SGLT2 inhibitors, sotagliflozin has similar efficacy in terms of glycaemic control and weight loss and despite its increased selectivity for SGLT1 is well tolerated without severe gastrointestinal side effects, most likely due to incomplete SGLT1 inhibition .p < .001) in patients with obesity, and favourable increases in incretin hormones and urinary glucose excretion (∼100 g) in patients with T2D [In a small, proof of concept randomized controlled trial, lucagliflozin, a selective and potent dual SGLT1/SGLT2 inhibitor, demonstrated significant weight loss (5.7%) versus placebo (with T2D . A higheThe glucose-lowering effects of SGLT2 inhibitors are attenuated due to increased endogenous (hepatic) glucose production, partially explained by hyperglucagonaemia. Combined with the concept of compensatory hyperphagia with SGLT2 inhibitor therapy, a clear rationale for the co-administration of an SGLT2 inhibitor with a GLP-1 receptor agonist is provided. The aim of combination treatment would be to offset the compensatory metabolic changes and attenuate the central hyperphagic drive and ideally achieve additive, even synergistic, weight loss and metabolic changes. Two clinical trials have examined the glucose-lowering efficacy and weight change when an SGTL2 inhibitor is combined with a GLP-1 receptor agonist in T2D ,79. MechIn the EXSCEL study, open-label SGLT2 inhibitor use, in parallel with, or shortly after once-weekly exenatide, occurred in 8.7% of participants. Those on combination therapy were propensity-matched to those on placebo only and those on once-weekly exenatide only. The risk for MACE and all-cause mortality was numerically lower, and the estimated eGFR slope improved, with combination therapy compared with placebo or once-weekly exenatide only alone supporting the hypothesis that combinatorial therapy may provide benefit on cardiovascular outcomes and mortality .DPP-4 inhibitors are less potent than GLP-1 receptor agonists with an average HbA1c reduction of −0.74%  and theyThe DELIGHT study examined the albuminuria-lowering effect of dapagliflozin, with and without saxagliptin, in patients with T2D and moderate-to-severe CKD . DapagliData is continually emerging around the adverse effects and risks associated with SGLT2 inhibitors from a variety of sources including extensive clinical experience, case series, post-marketing surveillance and regulatory websites . The mosDKA, the triad of hyperglycaemia (blood glucose >11 mmol/l), acidosis (venous bicarbonate <15 mmol/l) and ketonuria/ketonaemia, represents the most common and serious hyperglycaemic emergency in patients with diabetes . Most coThere are multiple biologically plausible mechanisms by which SGLT2 inhibitors cause ketosis or DKA in T1D or T2D  . BiologiSGLT2 inhibitors have become an indispensable part of the therapeutic armamentarium in T2D with useful metabolic effects in all patients with little or no risk of hypoglycaemia. Their role in T1D is emerging with a need for careful patient selection and a need for ongoing pharmacovigilance. In T2D, they have a very clear role emerging in high-risk patients with atherosclerotic CVD, HF and CKD and their use is expanding to other patient groups who do not have diabetes, particularly those with HF of chronic kidney disease. Results of further ongoing randomized controlled trials will, no doubt, expand the clinical indications for these drugs in diverse patient populations and we can continue on this exciting journey of discovery.


Although metabolic acidosis is known as a potential complication of chronic kidney disease (CKD), there is limited information concerning the association between metabolic acidosis and clinical outcomes.3−) levels and clinical outcomes using Kaplan-Meier methods after the matching of baseline characteristics by propensity scores.Five hundred fifty-two patients referred to renal division of Iwata City Hospital from 2015 to 2017 were included as a retrospective CKD cohort, and finally 178 patients with CKD stage III or IV and 20 to 80 years of age were analyzed. We examined the association between serum bicarbonate (HCO3− levels (N = 94), as compared with patients with higher HCO3− levels (N = 84), were more likely to be male (P < 0.05), had more severe CKD stages (P < 0.05), more frequent use of renin-angiotensin system inhibitor (P < 0.05) or uric acid lowering agent (P < 0.001), heavier body weight (P < 0.001) and lower estimated glomerular filtration rate (P < 0.05). In Kaplan-Meier analysis after propensity score matching, the incidence of composite outcome as the doubling of serum creatinine level from baseline, end-stage kidney disease requiring the initiation of dialysis, or death from any causes was significantly fewer in the higher HCO3− group than the lower HCO3− group .Of 178 patients with CKD, patients with lower HCO3− level is significantly associated with the doubling of serum creatinine level, end-stage kidney disease or all-cause mortality in patients with CKD.Lower HCOhttp://www.umin.ac.jp/, study number: UMIN000044861).This study was registered with the Clinical Trial Registry of the University Hospital Medical Information Network ( In paons (H+) .3− levels and adverse kidney outcomes [3− levels in patients with CKD [Observational studies have shown an independent association between serum HCOoutcomes –7, and swith CKD –10. On tIn this study, we examined the effects of metabolic acidosis on kidney disease progression and mortality in patients with CKD using the method of propensity score matching analyses.We conducted a retrospective observational cohort study. We included all patients referred to Iwata City Hospital  from January 1, 2015 to December 31, 2017. Eligible patients were adults (more than 20 years of age), although patients over 80 years of age were excluded due to their life expectancy.http://www.umin.ac.jp/, study number: UMIN000044861).This study was approved by the institutional ethics committee  and conducted in accordance with the Declaration of Helsinki. Because of its retrospective nature, informed consent was waived. This study was registered with the Clinical Trial Registry of the University Hospital Medical Information Network . Normal range of serum HCO3− levels were generally from 22 to 29 mEq/L [Clinical information including comorbidities and laboratory findings was collected by the access to patient’s records. Complete blood count was measured using XN-3000™ hematology analyzer  and serum electrolytes, albumin, low-density lipoprotein (LDL) cholesterol, creatinine, and C-reactive protein (CRP) levels were measured using Ci16200 auto-analyzer . Serum HCO29 mEq/L , 12.3− level. Urine parameters included spot urine proteinuria score by dipstick .The demographic characteristics included age, sex, chronic kidney disease (CKD) stage, original kidney disease, the history of cardiovascular disease (CVD), medication, systolic blood pressure and body weight. Blood parameters included hemoglobin, albumin, LDL cholesterol, CRP, estimated glomerular filtration (eGFR), albumin-corrected calcium (Ca)-phosphorus (Pi) product and serum HCOThe all patients were followed until January 1, 2020 or the incidence of the composite outcome, whichever occurred first. The outcome, assessed in a time-to-event analysis, was a composite of the doubling of serum Cr level from baseline, end-stage kidney disease requiring the initiation of dialysis, or death from any causes.P < 0.05. Comparisons between two groups were performed using the Mann-Whitney U-test for continuous variables or the chi-squared test for categorical variables.Data were expressed as the mean ± standard deviation (SD) for continuous variables with normal distributions or the median and interquartile range (25th to 75th percentiles) for data with skewed distributions. The threshold for statistical significance was set at 3− level was set at 25.3 mEq/L based on its median value. The probability to over this threshold, as the propensity score, was determined by a multivariate logistic regression using the aforementioned 16 baseline characteristics including age, sex, CKD stage, original kidney disease, the history of CVD, medication, systolic blood pressure, body weight, hemoglobin, albumin, LDL cholesterol, CRP, eGFR, albumin-corrected Ca-Pi product and urinary protein score. A nearest-neighbor matching algorithm was used to match patients within a caliper width of 0.03 of the logit of the propensity scores. Outcome curves were constructed with Kaplan-Meier method and compared with the log-rank test. For Kaplan-Meier method, we analyzed the composite outcome as the doubling of serum Cr level from baseline, end-stage kidney disease requiring the initiation of dialysis, or death from any causes by the time to the first event. All statistical analyses were performed using IBM SPSS statistical software, version 26.0 .To adjust the differences in the baseline characteristics and perform the following analyses, propensity score matching was employed , 14. To 3− levels. Finally, 178 patients were included in the following analyses  were male. The original diseases were as follows: overt diabetic nephropathy in 18 patients (10.1%), chronic glomerulonephritis in 55 patients (30.9%), nephrosclerosis in 81 patients (45.5%), and polycystic kidney disease in 3 patients (1.7%). The mean eGFR was 41 ± 13 mL/min/1.73 m3− groups according to the median value of serum HCO3− levels , had more severe CKD stages (P < 0.05), more frequent use of renin-angiotensin system (RAS) inhibitor (P < 0.05) or uric acid lowering agent (P < 0.001), heavier body weight (P < 0.001) and lower eGFR (P < 0.05).Next, we divided those 178 patients into lower and higher HCO3− groups under the similar background, we employed the method of propensity score matching. After the propensity score matching, the differences of patient’s characteristics at the baseline between lower and higher HCO3− groups were adjusted , the incidence of composite outcomes as the doubling of serum Cr level from baseline, end-stage kidney disease requiring the initiation of dialysis, or death from any causes was significantly less in the higher HCO3− group than the lower HCO3− group, occurring in 2 patients (3.5%) and 10 patients (17.5%), respectively  supplementation can slow the rate of kidney disease progression [Experimental studies in animals have showed that metabolic acidosis contributes to progression of CKD , 16, andgression , 17.3− synthesis in response to metabolic acidosis leads to calcium precipitation in the kidney [Several mechanisms how metabolic acidosis accelerates the progression of CKD are proposed. Nath et al.  have repe kidney .3− levels in some patients of lower HCO3− group were within the normal range (22–25.3 mEq/L). At present, the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommends to start the administration of alkali when serum HCO3− levels are < 22 mEq/L, to maintain the value within the normal range [+ retention of variable severity has already occurred even if serum HCO3− levels are within the normal range in patients with CKD, which is referred as subclinical metabolic acidosis [3− levels have higher risk of eGFR decline and mortality than those with high-normal HCO3− levels [3− levels has also showed that sodium bicarbonate (NaHCO3) treatment preserved their kidney function after 10 years compared with sodium chloride (NaCl) administration or usual care [3− levels remain to be clarified. Further studies are needed to clarify these issues.One of key findings in this study is that serum HCOal range . On the acidosis . Epidemi− levels , 25. A rual care . Therefo3− levels within the normal range are associated with better survival [3− levels had poorer prognosis might be reasonable. Further interventional studies are needed to identify the relationships between metabolic acidosis and mortality in patients with CKD.Another key finding in this study is that all-cause mortality was included in the composite outcomes we set. In accordance with our result, epidemiological studies have showed that higher HCOsurvival , 25. On survival . Becausesurvival , 28, 29,Our study has several limitations. First, due to the retrospective study design, a longitudinal causal relationship cannot be established. However, to minimize this limitation, we employed the method of propensity score matching analyses in this study. Second, because of the relatively small number of patients in our cohort, the generalizability of our conclusions remains unclear.3− levels, as compared with those with higher HCO3− levels, were more likely to progress their kidney disease and have poorer prognosis. Therefore, metabolic acidosis may be a modifiable risk factor for the progression of CKD.In conclusion, we showed here that CKD patients with lower HCO