Supplemental Digital Content is available in the text To understand the possible effect of a novel salt substitute with very low sodium in reducing blood pressure, salt intake and use of anti–hypertensive medications among patients on regular medications, to inform the future randomized trials.Single-arm pilot trial.A community health service center in Chongqing, China.A total of 43 patients with hypertension taking anti-hypertensive medications regularly.Patients received the salt substitute with 18% sodium chloride for 8 weeks.Patients were followed up weekly for the use of antihypertensive medications and measurements of blood pressure. We collected 24-h urine before and after the trial to measure sodium and potassium intake.P = .48; DBP change: 1.8 mm Hg , P = .38). For the rest patients, the mean SBP and DBP before intervention were 141.6 ± 16.9 and 74.6 ± 6.6 mm Hg but reduced significantly after the intervention , P < .001; DBP change: −5.5 mm Hg , P < .001). The 24-h urine sodium decreased (P < .001) and potassium increased (P < .001) among all patients. No severe adverse events were reported.Among 39 patients who completed the 8 weeks’ intervention, 30.8% patients stopped or reduced anti-hypertensive medications during the trial. For patients that stopped or reduced medication, the mean SBP and DBP before intervention were 122.1 ± 9.6 and 68.9 ± 9.4 mm Hg and both did not increase after intervention , The novel salt substitute showed potential in reducing blood pressure and use of antihypertensive medications. Further randomized double–blind controlled trial is warranted to validate these findings.http://www.clinicaltrials.gov. Unique identifier: NCT03226327.Clinical Trial Registration—URL: The World Health Organization recommends <5 g and Chinese Society of Nutrition recommends <6 g of salt per day for adults.As the most important risk factor for cardiovascular and cerebrovascular diseases, raised blood pressure is associated with the development of 47% coronary heart disease and 54% strokes. There have been many high quality randomized controlled clinical trials demonstrating that salt substitute could effectively reduce blood pressure among patients with hypertension.–9 However, such kind of salt substitutes is unable to reach the recommended level of <6 g/day for salt intake in Chinese population and may limit the effect of salt substitution to reach its highest possibility, since the current average salt intake is about 12 g per day in China.Among salt reduction strategies, salt substitute was developed to reduce blood pressure by taking advantages of the blood pressure reduction effect from addition of potassium and at the same time reduction of sodium in the salt while keeping the taste of saltiness unchanged as much as possible. In the composition of salt substitute, usually 30% to 50% of sodium chloride is replaced by potassium chloride plus or not other minerals.A novel salt substitute, named “Man Li Kang,” containing 18% of sodium chloride only, was developed to help people with difficulty in reduction of salt intake to reduce sodium intake by significantly a large amount so that the WHO recommended level of salt intake could be attained and its effect in lowering blood pressure can be maximized, without changing taste of food or habits of salt consumption.In this study, we aimed to preliminarily understand the possible effect of the novel salt substitute in reducing blood pressure, salt intake and use of anti–hypertensive medications as well as its safety among hypertensive patients who are taking anti-hypertension medications regularly. The information gained from this study would inform the design for a randomized controlled trial to confirm the efficacy and safety of the novel product.22.1This pilot study was designed as a single–arm trial with 8 weeks of intervention using the novel salt substitute among hypertensive patients taking antihypertensive medications regularly.2.2Patients and public were not involved in development of the research question or design of the study. They were also not involved in the recruitment to or conduct of the study. Besides, as an important and essential part of our procedure of obtaining patients and their family members’ written informed consent, sufficient time was ensured for them to give full consideration and assessment of the potential risks of the trial and burden of the intervention by themselves before signing written informed consent. After signing written informed consent, patients were assessed to verify whether they were eligible for inclusion and then entered into baseline investigation. General results, with all patients’ individual identifiable information  previously removed, of this trial will be available on reasonable demands.2.3From April to July in 2018, 69 participants were assessed for eligibility. After excluding 23 participants who did not meet the inclusion and exclusion criteria, a total of 43 patients with hypertension were recruited from a community health service center in Chongqing. To be included in the study, patients had to be diagnosed as hypertension and have taken antihypertensive medications without change in dose and types in past 3 months, and meet all of the following conditions:1.aged ≥50 and ≤75 years;2.not had plans to move out of the community in the next 3 months;3.not cooking at home <3 times or 1 day during the study; and4.provided written informed consent before enrollment in the trial.Patients will be excluded from the study if they were having:1.history of acute myocardial infarction or stroke in the past 3 months, history of malignancy or expected lifetime <1 year;2.hypercortisolism or aldosteronism;3.acute disease, such as upper respiratory infection, fever, and diarrhea;4.salt substitute use in the family;5.disease or disabilities that could exert potential influence on their adherence to the intervention, including deafness, dementia, as well as severe depression and other mental disorders;6.family members not willing to use the salt substitute;7.liver dysfunction;8.anyone with abnormal serum potassium in family;9.anyone using potassium-retaining diuretics in family.www.clinicaltrials.gov (NCT03226327).The study has been approved by the Institutional Review Board of Peking University (IRB00001052−17110). All patients and their families had signed informed consent which illustrated the study's purpose, benefits and risks. The trial was registered at 2.4Subjects and their families were given informed consent and then completed baseline investigation at the clinic including blood pressure measurements, questionnaires gathering data of demography, lifestyle, history of diseases, and anti-hypertension medications, as well as collection of 24 h urinary samples.2.5After baseline survey completed, research staff went to the patient's home and sealed all salt in each subject's household and replaced with the study salt substitute, Man Li Kang, which contained 18% of sodium chloride, 35% of potassium chloride, and 10% of calcium chloride. The study subjects were instructed to keep their habits of salt consumption unchanged. The intervention was implemented for 8 weeks for each patient.2.6We conducted follow up once a week at study participant's home to measure blood pressure and collect data on the use of antihypertensive medications, and incidence of adverse events.2.7 Blood pressure was measured three times at each visit with at least 1 min in between, and we used the average of three readings for data analysis.Sitting blood pressure, including systolic and diastolic blood pressure, was measured by trained staff in the clinic at baseline and patients’ home at each follow up visit, using electronic sphygmomanometer on the right arm, with appropriate cuff size. Patients were required to sit quietly for at least 5 min before the measurement and not to drink, eat, smoke, or carry out any physical activity in preceding 30 min.2.8 while urine creatinine and urine microalbuminuria were measured with the pyrogallol red molybdenum method.At baseline and end of this trial, 24-h urinary samples were collected and sent to the laboratory at the First Affiliated Hospital of Chongqing Medical University for analysis. The 24 h urinary electrolyte, including sodium and potassium concentrations, were measured using HITACHI 7600 with the ion selective electrode method,2.9Primary outcomes were changes in systolic and diastolic blood pressure from baseline to the end of follow-up. Secondary outcomes included the change in hypertension control rate, namely proportion of patients with SBP < 140 and DBP < 90 mm Hg; the change in proportion of patients reaching Chinese Society of Nutrition recommended target for salt reduction, which was defined as the average daily sodium chloride intake as measured by 24 h urinary sodium below 6 g/day; and the proportion of patients with anti-hypertension medication reduction, which was defined as stopping or reducing the dose or number of anti-hypertension medications during the trial including both physician-agreed and self-decided reduction.2.10Our main analysis was based on per protocol data set, including a total of 39 patients who completed both baseline and follow-up assessments. Mean and standard deviation were used for description of continuous variables with normal distribution, median, and inter-quartile ranges for data of skewed distribution, and percentages for categorical variables. We assessed effects of intervention on SBP by using linear mixed model, with SBP levels as the dependent variable and the time of blood pressure measurement (visits: baseline or follow-up) as the independent variable included as random effect. To account for potential confounding effects, we adjusted for covariates including sex, age, BMI, and use of anti-hypertensive medication, fitted as fixed effects. We repeated the same analysis for DBP and pulse pressure (PP), and for patients with and without reduction of anti-hypertension medications.For comparisons of urinary sodium and potassium excretion and the sodium-to-potassium ratio between baseline and end of intervention, linear mixed model was also used, with age, sex, and body mass index (BMI) adjusted.In addition, we performed intention to treat analysis as sensitivity analysis, which included a total of 43 participants, with missing data imputed using the method of last observations carried forward.P < .05 considered as statistically significant.All procedures of statistical analysis were performed using SAS version 9.4 software , with a two tailed 3We screened 69 participants for eligibility, among whom a total of 43 hypertensive patients meeting inclusion and exclusion criteria were enrolled, as was demonstrated in Patient Flow Diagram.2. About half were women and half had a history of diabetes, coronary heart disease, or stroke.Baseline characteristics were presented for patients included in the study in Table P < .001), −4.0 mm Hg , and −8.0 mm Hg , respectively. Meanwhile, significant reduction in SBP and PP appeared at the 1st week of intervention, while significant reduction in diastolic blood pressure appeared at the 2nd week of intervention. We did the same analysis for patients with and without reduction of antihypertension medications during the trial. Significant changes in SBP, DBP, and PP were only observed for patients who did not reduce medications. For patients who reduced medications, changes in SBP, DBP, and PP were not statistically significant. Interestingly, the baseline blood pressure level was lower for patients reducing than not reducing medications .Tables P < .001, Supplementary Table S1), −4.8 mm Hg for DBP , and −8.7 mm Hg for PP  at 8th week of intervention, respectively. We further analyzed changes in blood pressure according the type of anti-hypertensive medication, we did not find any significant differences in the changes in blood pressure between the groups (Supplementary Table S4). The trend over time in SBP was significant, after adjusting for sex, age, BMI, and use of antihypertensive medications, in both per protocol  and the sodium-to-potassium ratio decreased significantly from baseline to end of trial . Mean urinary creatinine and microalbuminuria did not change significantly.Table P = .01), the increase in proportion with salt intake <6 g/day was not significant .Proportion of patients with blood pressure controlled increased significantly from baseline to end of the trial  but decided by themselves to reduce medications during the trial indicated that the acceptability of the salt substitute for reducing blood pressure should be better than pharmaceutical treatments. That was the underlining reason why so many patients (over 30%) stopped or reduced their anti-hypertension medications during the trial when their blood pressure retuned to “normal” level by their own standards. In particular, mean blood pressure in these patients with reduction of medications did not increase during the trial, and there were four patients even reduced medications with agreement of their physicians. This phenomenon indicated that, with use of the study salt substitute, reduction of anti-hypertension medication use may be achievable for some patients without risking to increase their blood pressure. The observed contrast between patients who reduced and not reduced anti-hypertension medications in the effect of blood pressure reduction reinforced the effect of the study salt substitute on blood pressure lowering. were both statistically insignificant. Communications with study patients at weekly visits revealed that some of them did not use completely the study salt substitute and might add regular salt during cooking. In fact, there were 4 patients who withdrew from the study because they did not like the taste of the study salt. Hence, the study salt needs further improvement in this aspect in order to increase its acceptability and long-term adherence.The above conclusion was also supported by our observations in changes of sodium and potassium intake estimated by 24 h urinary sodium and potassium excretion, where potassium intake increased significantly by 8.8 mmol/day (17%) and sodium to potassium ratio decreased significantly by −0.8. However, salt intake reduction, estimated by change in 24 h urinary sodium excretion, from baseline to end of trial and change in proportion of patients with salt intake meeting the Chinese Society of Nutrition's recommendation,19 Chun Huang mixed regular salt with low sodium salt substitute in ratios of 3:1, 1:1, and 1:3, respectively and applied these combinations into intervention of 1 to 4 weeks. With gradual increase in amount of low sodium salt substitute, study subjects adapted to the taste of the salt substitute step by step. In contrast, our study replaced the regular salt completely and suddenly for study subjects, without leaving sufficient time for patients to adapt to the study salt substitute's taste, which might help to partially explain the withdrawal of the four patients.In the term of adherence of the study salt substitute, previous studies reported an acceptable attitude among most subjects. Nevertheless, the study successfully collected important information that could serve as basis for future randomized controlled trial to confirm our findings, with selecting study outcomes and estimation of study sample size in particular.Nevertheless, the study also bears important limitations. First, it had no parallel control group and was not blinded due to its pilot nature, and thus the placebo effect could not be entirely ruled out. Second, due to its very small sample size, we were also unable to conclude on the safety of study salt substitute, despite that we did not receive any reports of severe adverse events. Third, we did not measure body weight at the end of the intervention, which prevents us from understanding the possible impact of changes in body weight on our results. However, previous studies showed that salt substitution should had no effect on body weight in such a short period.In conclusion, the novel salt substitute presented potential effects in blood pressure lowering and reducing use of antihypertensive medications, without reporting incidence of any serious adverse events. However, the substitute's taste and compliance required further improvement. And future randomized controlled trials were warranted to confirm our findings in the study salt substitute's effects of reducing blood pressure, anti-hypertension medication use and salt intake, as well as safety.We thank all of the participants and their families for their understanding and strong support of our work, all of the patient advisers for their efforts in collaboration with the study group and all of the members in the study group for their generous contributions to the study, and Health Source (Chongqing) Cardiovascular Health Technology for supplying the study salt substitute.Data curation: Chenglong Li.Formal analysis: Chenglong Li.Funding acquisition: Yangfeng Wu.Investigation: Lihong Mu, Ting Liu, Ge Li, Meixian Wang, Ruoxi Wang, Huakun Rao, Qin He, Wen Wang.Methodology: Yangfeng Wu, Chenglong Li, Wuxiang Xie.Project administration: Lihong Mu, Ting Liu.Resources: Yangfeng Wu, Lihong Mu, Ge Li.Software: Wuxiang Xie.Supervision: Yangfeng Wu.Writing – original draft: Chenglong Li.Writing – review & editing: Yangfeng Wu, Lihong Mu, Ting Liu, Wuxiang Xie, Ge Li, Meixian Wang, Ruoxi Wang, Huakun Rao, Qin He, Wen Wang.


Bronchiectasis and asthma may share some characteristics and some patients may have both conditions. The present study aimed to examine the rationale of prophylactic inhaled corticosteroids (ICS) prescription in children with bronchiectasis. Data of children with radiologically established bronchiectasis were retrospectively reviewed. Episodes of dyspnea and wheezing, spirometric indices, total serum IgE, blood eosinophil counts, sensitization to aeroallergens, and air-trapping on expiratory CT scans, were recorded. The study included 65 children 1.5–16 years old, with non-CF bronchiectasis. Episodes of dyspnea or wheezing were reported by 22 (33.8%) and 23 (35.4%), respectively. Skin prick tests to aeroallergens (SPTs) were positive in 15 (23.0%) patients. Mosaic pattern on CT scans was observed in 37 (56.9%) patients. Dyspnea, presence of mosaic pattern, positive reversibility test, and positive SPTs were significantly correlated with the prescription of ICS. The prescription of ICS in children with bronchiectasis is more likely when there are certain asthma-like characteristics. The difficulty to set the diagnosis of real asthma in cases of bronchiectasis may justify the decision of clinicians to start an empirical trial with ICS in certain cases. Bronchiectasis is a complex and progressive respiratory disorder, characterized by chronic infection, inflammation, and abnormal dilatation of the bronchi. The loss of bronchial wall integrity, the mucus impaction and mucosal oedema may reduce the lumen opening and restrict the airflow especially during expiration when the bronchial walls appose. Bronchiectasis is a syndrome and not a disease per se, and several causative and associated disorders have been described .Children with bronchiectasis, apart from cough, may also develop wheeze and asthma symptoms. with reported rates ranging from 11 to 46% ,3, althoThe treatment of bronchiectasis is based mainly on antibiotics and chest physiotherapy. In cases of bronchiectasis and asthma coexistence, patients must receive treatment for both conditions ,8. NeverThe present study was conducted in the Pediatric Pulmonology Unit of the Attikon University Hospital in Athens, which is one of the main tertiary referral centres for pediatric pulmonary disorders, in Greece. Three consultants and four fellows had been serving in the Unit during the study period. Data of all the children attended in the Unit from 2013 to 2018, up to 16 years old, with chronic wet cough and radiologically established bronchiectasis on chest high-resolution computed tomography (HRCT) scan were retrospectively reviewed. All HRCT scans had been performed in the radiology department of our hospital and were evaluated by the same pediatric radiologist who was aware of the patients’ clinical history. The criteria for the diagnosis of bronchiectasis on HRCT were dilatation of bronchi, as determined by broncho-arterial ratio > 0.80 ; paralle, cypress, house dust mite, fungi, cat and dog dander). Nasal nitric oxide test and high-speed video microscopy analysis were performed only in patients who fit the clinical phenotype of primary ciliary dyskinesia. Spirometry was performed at the initial and the follow-up visits to all patients ≥5 years old who were able to cooperate. TH2-high status was defined as the combination of total serum IgE levels of ≥100 IU/mL and absolute blood eosinophil count of ≥140/mL [Investigations in all patients included a complete blood count, sweat test and/or cystic fibrosis (CF) gene mutation analysis, measurement of serum immunoglobulins, and skin prick tests (SPT) to the most common aeroallergens  or wheezing, and/or their spirometric indices or the shape of the spirometry loop were indicative of airway obstruction, and/or had positive SPT, underwent a bronchodilator response (BDR) test with salbutamol, during their first visit. The BDR test was performed with four actuations of salbutamol metered dose inhaler into a spacer device and interpreted as positive if the change in the forced expiratory volume in one second (FEV1) after bronchodilator administration was ≥ 12%. Spirometric indices were reported as percent predicted (pp) values using the NHANES III reference equations. All patients received antibiotics for 3–6 weeks, started daily chest physiotherapy, and some of them were also prescribed ICS with or without LABA. All were reevaluated in 2–3 months.Patients with CF were excluded from the study.The study protocol was approved by the Attikon University Hospital Ethics Committee.Variables are presented as mean with standard deviation (sd) or as median with interquartile range (IQR). Univariate analysis was performed with paired t-test, chi-square test, and Spearman’s rank correlation test with Bonferroni correction for multiple comparisons. Correlations were expressed as Spearman’s ρ with its corresponding 95% confidence interval (CI). The variables which in univariate analysis were significantly correlated with the decision to start ICS were included as explanatory variables in a multivariate logistic regression model. Results of multivariate analysis are presented as odds ratios (OR) with 95% confidence interval (CI). We further performed three linear regression models where ICS use was the explanatory variable and the differences in FEV1, FEV1/FVC, and the number of positive cultures, between the follow-up and the initial visit, were used as the response variables.Sixty-five children 1.5–16 years old, were diagnosed with non-CF bronchiectasis; 46 (70.7%) of them had been referred as cases of difficult asthma. Thirty-nine (60%) children had been referred by general pediatric practitioners, and 26 (40%) by pediatric departments and clinics. Sixteen (24.6%) patients had underlying disorders directly or possibly related with bronchiectasis: five had tracheoesophageal atresia, five had PCD, one had Crohn disease that was treated with infliximab, one had Job syndrome, one had congenital pulmonary airway malformation (CPAM), one had anhidrotic ectodermal dysplasia with immunodeficiency, and one had IgA deficiency. The remaining 49 (75.4%) patients had no identifiable cause. Apart from the child with the IgA deficiency, all children had normal for age serum concentrations of IgA, IgG, and IgM. Twenty-eight (43.0%) patients commenced daily treatment with ICS with or without LABA. Patients’ clinical characteristics and their correlation with the prescription of ICS are shown in p = 0.036, and OR:10.89; CI:2.21, 53.23; p = 0.003, and OR:12.55; CI:1.21, 121.61; p = 0.034, respectively). BDR test was not included in the model due to its small sample size and the lack of variation that did not allow a reliable estimation of model parameters. The three regression models showed that ICS use was not correlated with the differences in FEV1, FEV1/FVC, and the number of positive cultures, between the follow-up and the initial visit .The multivariate logistic regression model included as explanatory variables the presence dyspnea, positive SPT, and of mosaic pattern, and corroborated the correlations found in univariate analysis between these variables and the decision to prescribe ICS  ,12. HoweDyspnea and wheezing were the only clinical signs/symptoms that were included in our analysis as they represent the two most common characteristics reported by parents, or experienced by children, with asthma ; only dyH2-high status variable. This may have resulted from serum IgE and eosinophil count being less consistent markers of asthma and allergy due to the absence of specific cut off values and the considerable overlap between normal and allergic patients [Atopy, which is a considerable risk factor for asthma development ,18, was patients .Spirometry results were not a significant determinant of ICS prescription in our population. Indeed, spirometric values are usually normal in asthmatic children who are not in exacerbation and so they are not a reliable marker of asthma . On the The mosaic pattern in expiration HRCT scans reflects air trapping and it is a well-known radiological feature of bronchiectasis . HoweverThe present study has certain limitations. The data depict the prescription preferences of physicians from a single centre and so the results are neither free from bias nor can be generalized. Cough, one of the main features of asthma, was not assessed because it is also the cardinal symptom of bronchiectasis and as such it could not offer any discriminative information for asthma diagnosis. HRCT scans were evaluated by a single radiologist and were not blinded. All children received antibiotics and started chest physiotherapy at diagnosis. Because of this, we were unable to determine the net result, if any, of ICS in children with asthma-like features. We tried to examine whether the administration of ICS could result in any measurable clinical changes that would allow us to identify a group of children who could truly benefit from ICS. However, since the study was not designed to investigate this question, included only a few outcome variables, and the sample size was relatively small, the results were inconclusive.In conclusion, it was shown that the prescription of ICS in children with bronchiectasis is more likely when there are certain asthma-like features. The results should be conceptualized as a justification of the clinicians’ decisions in cases where the coexistence of bronchiectasis and asthma seems probable and not as evidence for the need for ICS in certain cases. Indirectly, the study stresses the importance of research data able to illuminate the issue of asthma and bronchiectasis coexistence and define the clinical characteristics of children with bronchiectasis who could benefit from the use of ICS.


To evaluate liver stiffness (LS) by real-time two-dimensional shear wave elastography (RT 2D-SWE) and to assess its correlation with the mean arterial pressure (MAP) in patients on maintenance hemodialysis (MHD). The secondary aim was to identify biological and biochemical parameters associated with elevated LS.This study enrolled patients treated with MHD in the Split University Hospital from December 2017 through February 2018. LS was measured after a HD session using RT 2D-SWE. Mean arterial pressure was measured before RT-2D-SWE was performed.P = 0.008). C-reactive protein , parathyroid hormone , and total bilirubin  were correlated with elevated LS.The study enrolled 47 patients with the mean ± standard deviation age of 68.48 ± 14.33 years. Arterial hypertension was diagnosed in 70.2% of patients. Liver stiffness >7 kPa, suggesting clinically relevant fibrosis, was found in 59.5% of patients. Arterial pressure was significantly correlated with LS (ρ = 0.38, Mean arterial pressure is correlated with increased LS in patients on MHD. Our results emphasize the importance of proper regulation of arterial blood pressure and indicate that LS should always be interpreted in combination with laboratory parameters. Further prospective studies with larger series are needed. Chronic kidney disease (CKD) is an important public health problem. The number of CKD patients in the world has increased from approximately 10 000 patients in 1973 to 703 243 in 2015 . The cliPercutaneous liver biopsy is still the gold standard for the evaluation and staging of LF . It is a2, and in patients with viral hepatitis, primary biliary cholangitis, alcoholic liver disease, and cholestatic liver diseases independent of the degree of fibrosis , patients with metabolic disease, autoimmune liver disease, or a history of liver steatosis caused by drug treatment  were excluded as well.This single-center study was conducted in the Department of Nephrology and Dialysis of Split University Hospital Center from December 2017 through February 2018. The study enrolled 47 patients older than 18 years treated with MHD due to ESRD for at least 3 months. The exclusion criteria were applied according to EFSUMB 2017 guidelines and included active malignant disease, acute infection, congestive heart failure, and biliary obstruction as revealed by dilated bile ducts and biochemical signs of cholestasis , weight (kg), body mass index (BMI), Kt/v, and urea reduction rate (URR). Data on comorbid conditions  were obtained from medical history. BMI was determined as weight (kg) divided by height (m) squared. Blood samples were taken before a HD session, prior to heparin administration. Laboratory tests performed are shown in Systolic and diastolic arterial pressures were measured before RT-2D-SWE with the patients in the supine position. MAP was calculated as follows: systolic arterial pressure +2 × diastolic arterial pressure/3.The patients received three to five hours of hemodialysis twice or three times per week. Ultrafiltration was evaluated volumetrically by the HD machine, depending on patients’ dry weight (ultrafiltration volume was from one to four liters per procedure). The temperature of the dialysis bath ranged from 35.5 °C to 36.6 °C. The bath contained 138-145 mmol/L of sodium, 2 mmol/L of potassium, 32-35 mmol/L of bicarbonates, and 1.25-1.75 mmol/L of calcium. Low flux polysulfone dialyzers were exerted.LS was measured with Toshiba Aplio 500, Platinum Series Ultrasound system .RT-2D-SWE was performed approximately 30 minutes after HD, following at least 3 hours of fasting. LS measurement values were expressed in kilopascals. The cut-off value for detecting LF was LS>7 kPa ,37. The 2, following the International Society of Renal Nutrition and Metabolism Panel recommendations, which state that for patients on dialysis, BMI<23 kg/m2 is a protein-energy wasting criterion . All procedures conducted are in accordance with the 1964 Helsinki declaration and its later amendments. The participants were informed about the study aim and gave informed consent before recruitment.2) were tested with the t test for independent data. The correlations between LS value and other variables were assessed with the Pearson (ρ) correlation coefficient. Multiple regression analysis including the variables that were shown to be significant was used to analyze the contribution of each variable to the change in LS. The level of significance was set at P < 0.05. Statistical analysis was performed with IBM SPSS Statistics for Windows, version 22.0. .The sample size was estimated with G*power 3.1.9.7 software for Windows with Cohen classification for effect size (ρ 0.5), with α 0.05 and power (1-β) of 0.95, indicating that it was necessary to include at least 42 participants. Quantitative variables are summarized using descriptive statistics. Normality of distribution was tested with the one-sample Kolmogorov-Smirnov test. The results are expressed as mean ± standard deviation. Differences between the groups . No significant difference in LS (P = 0.274), MAP (P = 0.899), age (P = 0.871), and other analyzed laboratory data was found between the groups with BMI<and >23 kg/m2. Baseline demographic data are summarized in The study enrolled 47 patients (68.1% men). The mean age was 68.48 ± 14.33 years. The most common etiology of ESRD was chronic nephritis. There was no significant difference in LS mean between men and women (P = 0.023) and LS and PTH  was found. In the group with BMI>23, a significant correlation was found between LS and total bilirubin . In the group with LS>7 kPa (n = 28), total bilirubin  and PTH  were significantly correlated with LS (P = 0.008)  , 36.1% o with LS . Arteria= 0.008) . Multipl= 0.008) .This study showed that in patients on hemodialysis MAP was positively correlated with LS. Elevated LS was also correlated with CRP, PTH, and total bilirubin. Arterial pressure was the strongest predictor of LS value. To the best of our knowledge, this is the first study evaluating the impact of factors on LS assessed using RT 2D- SWE in this specific population.Under physiological state, the liver receives one third of the blood flow through the hepatic artery and two-thirds through the portal vein. In advanced fibrosis, however, blood flow through hepatic artery increases . Our stuP values, low ALB, and increased LS are strong predictors of high mortality and probably interact with the MIA syndrome (Different factors can affect RT 2D-SWE detection of LS . As showsyndrome ,44,49.Previous reports have yielded heterogeneous results regarding the correlation of AST and ALT with LS. While Tapper et al  found a According to Cheng et al , lower PThe limitation of our study is the lack of liver biopsy performed in our patients, which prevented us from comparing LS values with histological characteristics.In conclusion, our results show that arterial pressure affects LS. Moreover, LS should always be interpreted in combination with laboratory parameters. Further prospective studies are needed to clarify the pathophysiological pathway of arterial pressure affecting LS and to allow an insight into the pathogenesis of LS changes and their influencing factors in the hemodialysis population.


Chronic kidney disease is one of the most common complications of type 2 diabetes mellitus (T2DM), causing an increased risk of cardiovascular morbidity and mortality. Matrix metalloproteinase (MMP) activity has been proposed as useful biomarker for diabetic renal and vascular complications.A cross-sectional study was conducted among T2DM patients who attended a public secondary hospital in Mexico. We performed clinical, biochemical, and microbiological assessments, as well chronic kidney disease diagnosis according to the KDIGO guideline. Urinary MMP-9 was quantified by ELISA and adjusted using urinary creatinine (UCr).A total of 111 patients were included. Most participants were women (66%). Mean age was 61 ± 10 years and median T2DM duration was estimated at 11 years. Through multivariate analysis, MMP-9/UCr was found to be associated with albumin concentration and albumin to creatinine ratio.Validation of non-invasive biomarkers of chronic kidney disease among T2DM patients is necessary. Here, we demonstrate MMP-9/UCr as a potential biomarker of albumin concentration and albumin to creatinine ratio in Mexican patients with T2DM. The prevalence in Mexico in 2016 of previously diagnosed type 2 diabetes mellitus (T2DM), and the combined prevalence of overweightness and obesity were 9.4% and 72.5%, respectively . ChronicIt has been proposed that a molecule involved in the remodeling process during the early pathology of diabetic kidney disease (DKD) would ideally provide the best marker of disease progression . An earlMmp-9 gene knockout diabetic mouse model, nephropathic changes such as hypertrophy, increased albuminuria and thickening of the glomerular basement membrane are significantly attenuated . Moreover, 48 proteases have potentially been involved in the generation of the most important peptides, including MMP-9 . In 24-htenuated . Here, wA cross-sectional study was conducted (November 2016- March 2017) among T2DM patients that were treated in the public second-level unit “Clínica Hospital del Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado 25 A 300 400” in Xalapa, Veracruz, Mexico. Criteria for inclusion in the study: ≥18 years of age and meet the clinical requirements to estimate the glomerular filtration rate glomerular filtration rate (GFR), according to the KDIGO guideline . ConditiTo randomly select subjects, sampling was conducted as previously described in . A conveThe research protocol was approved by the investigation committee of the “Clínica Hospital del Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado 25 A 300 400” (Register No. 001/073/0230). This study was conducted according to the principles of the Declaration of Helsinki and included subjects signed an informed consent.Blood samples collection, urine specimens collection, analysis of aerobic bacterial cultures using Cystine-Lactose-Electrolyte Deficient (CLED), anthropometric and vital signs were recorded as previously described in . GlucoseAliquots of urine samples were centrifuged and stored as previously described in . Human a2 (GFR categories G1 and G2) and ACR A1  present for >3 months, while “With CKD”: GFR ≤59 mL/min/1.73 m2 and ACR A1, A2 (moderately increased) or A3 (severely increased) or with GFR ≥60 mL/min/1.73 m2 and ACR A2 or A3 present for >3 months. Urinary tract infection (UTI) for women and men were according the SIGN guideline , failure to provide clinical samples (n = 14), hematuria (n = 58) and sperm in the urine sample (n = 2). GFR and ACR were estimated in 158 participants and, more than 3 months later, 137 patients returned for a second estimation of GFR and ACR. The study finally comprised a total of 111 patients with GFR and ACR categories in concordance.A total of 292 patients were invited to participate in the study, with signed informed consent obtained from 99% of those invited. Fifty-eight participants were excluded for not meeting the requirements for calculating GFR, antibiotic treatment, anuria, liver cirrhosis, rheumatoid arthritis, or cancer. Subsequently, 75 participants were excluded for having practiced vigorous exercise in the 72 h preceding the clinical sampling , adjusted (n = 101), and adjusted in participants without UTI (n = 94) models, urinary MMP-9/UCr was the only statistically significant variable in albumin concentration and ACR. BMI also showed a statistically significant association in most of the models. The remaining variables were not found to be significantly associated , waist size, systolic blood pressure, diastolic blood pressure and serum glucose were included in the models  and 4. Isociated  and 4.Through two indicators of CKD, our results show that urinary MMP-9/UCr is associated with albuminuria in patients with T2DM, although detection of MMP-9 was in 26% of the subjects, probably due to the sensitivity of the ELISA. A similar association has been reported by van der Zijl and colleagues between MMP-9 activity and incipient diabetic nephropathy . ThroughThe pathological mechanism of kidney fibrosis involves a series of complex molecular events that produce an excess of ECM deposition. In response to noxious stimuli, renal cells secrete pro-inflammatory and pro-fibrotic molecules that promote the recruitment of inflammatory cells. This inflammatory state can lead to the epithelial-mesenchymal transition (EMT), thus contributing to the progression of fibrosis . StudiesType IV collagen is the principal component of the glomerular basement membrane and mesangial matrix. Excretion of type IV collagen in urinary samples has been postulated as an indication of matrix turnover in diseased kidneys . Since Mβ-catenin accompanied by expression of mesenchymal markers such as vimentin and α-smooth muscle actin (β1, CXCL-16 and angiopoietin-2 have been shown as independent predictors of albuminuria and these molecular markers can improve renal risk models beyond established clinical risk factors (Mmp-9 can be upregulated by TGF- β1 in mouse renal peritubular endothelial cells, causing endothelial–mesenchymal transition (The EMT is characterized by the loss of epithelial markers such as cytokeratin and E-cadherin, and by nuclear translocation of le actin . In pati factors . Throughansition .No association was found between urinary MMP-9/UCr and BMI. Among reproductive-aged women, a positive correlation has been demonstrated between some serum MMPs, including MMP-9, and BMI, as well as significantly higher concentrations of MMPs being found in obese subjects, compared to patients of normal BMI . Plasma Given the pathophysiological processes that encompass DKD, such as hyperfiltration and pro-fibrotic, pro-inflammatory and angiogenic processes, it has been challenged whether albuminuria, or any other single biomarker, is individually capable of accurately forecasting the development and progression of renal damage in T2DM . MoreoveThe negative association found between BMI with albumin concentration and ACR is conflictive. Higher BMI has been positively correlated with higher ACR and an increased risk of major renal events in patients with T2DM . AlthougThis study presents some limitations related to the sensitivity of the ELISA kit, and the absence of MMP-9 found in urinary samples might be questionable. Another limitation of this study is the inclusion of patients that received renin-angiotensin system drugs, given their effect on the expression of some MMPs . The strNon-invasive biomarkers of urine are required to assess DKD development and progression. The present study demonstrated that MMP-9/UCr correlated positively with urine albumin concentration and ACR in Mexican patients with T2DM. We propose MMP-9/UCr as a possible early biomarker of CKD in T2DM patients.10.7717/peerj.10474/supp-1Data S1Click here for additional data file.


Firstly, it is mandatory in subjects with the suspicion of PH to confirm the diagnosis. Secondly, it is strongly recommended in the follow-up of patients with confirmed pulmonary arterial hypertension (PAH) to evaluate drug efficacy and in case of clinical deteriorationIn order to always perform a complete and correct RHC, clinicians carrying out the examination must be guided not only by technical recommendations, but also by the accurate knowledge of the different clinical issues which have to be addressed in these different situations .2.RHC can be a challenging procedure in patients with PH and requires expertise, attention to detail, and meticulous collection of data3,4, the femoral and internal jugular veins are most commonly used in clinical practice. The femoral access is easily compressible and complications  are more likely when arterial and venous access are both obtained. The main disadvantage is the need for bed rest after the procedure.Whenever possible, RHC should be performed in stable, non-acute clinical conditions. Although any systemic large vein may be used for venous accessThe internal jugular vein allows easy access to the pulmonary artery. Complications are uncommon using an ultrasound-guided approach which gives the possibility to minimize the risks of the procedure, visualizing the location of the jugular vein  and the direction of the needle.5. A zero-level set five cm above (or below) the midthoracic level results in underestimation (or overestimation) of all pressures by approximately four mmHg. This may significantly affect management of patients.A wrong zero-level set is among the most common mistakes and a major confounding factor during RHC. All pressure measurements are the difference between the pressure at the chosen zero level and the pressure within the cardiac chamber or vessel where the catheter tip is positionedThe zero reference defines the location in the circulatory system where changes in body position do not affect pressure measurements. The current consensus is that pressure transducer should be zeroed at the mid-thoracic level (midpoint between anterior sternum and bed surface) with the patient supine, which best approximates the level of the right atrium. These references should be maintained for the entire duration of the procedure.The thermodilution technique can be considered the preferred method of cardiac output monitoring, even among patients with very low cardiac output and/or severe tricuspid regurgitation. Thermodilution has in fact proven to be a reliable method when compared with the direct Fick measurement; on the contrary, the indirect Fick method is less reliable than the other techniques.6,7.In order to cope with the intrinsic random errors of pressure and flow determinations made with a fluid-filled pulmonary artery catheter, it is now clearly recommended that measurements should be repeated in triplicate to obtain values within a 10% agreement and averaged •Is PH present? •Is PH pre-capillary or post-capillary? •Does PH cause right ventricular failure?The hemodynamic definition of PH is based on the value of mean pulmonary arterial pressure (mPAP) which must be ≥25 mmHg at rest according to 2015 ESC/ERS Guidelines. This can only be obtained at RHC. Doppler echocardiography is used to estimate the right ventricular (RV) systolic pressure by estimating the pressure gradient between the right ventricle and the right atrium using the modified Bernoulli equation; an estimate of right atrial pressure obtained by the evaluation of dimensions and collapsibility of the inferior vena cava must be added to this number to approximate the RV systolic pressure, which coincides with the systolic pulmonary artery pressure (sPAP) in the absence of pulmonic stenosis.8,9, however, these have not gained clinical acceptance in international guidelines. In general, Doppler echocardiography allows for accurate measurements of the pulmonary circulation, but has only moderate precision, which explains why echocardiographic estimates of pulmonary pressures are valid for population studies, but cannot be used for the individual diagnosis of pulmonary hypertension10.Numerous methods have been suggested to derive non-invasively mPAP by sPAPIn addition, the relationship between the systolic and the mean pressure in a vessel is not linear but it is highly dependent on the stiffness of the vessels, which may vary from patient to patient and cannot be determined non-invasively.11. Including pulmonary vascular resistance in the definition of pre-capillary PH is essential, allowing discrimination of elevation of PAP due to pulmonary vascular disease from those due to elevation of PAWP due to high cardiac output. This new definition reinforces the necessity of using the RHC for a precise definition of presence/absence of PH.A new hemodynamic threshold for PH has been proposed by the 6th WSPH Task Force on PH diagnosis and classification (combination of mPAP >20 mmHg and pulmonary vascular resistance (PVR) ⩾3 Wood Units)12,13. LVEDP direct measurement is only used when an accurate PAWP cannot be obtained14.Accurate measurement of left atrial pressure is essential for distinguishing pre-capillary from post-capillary PH, i.e., patients with left heart disease. In particular, heart failure with preserved ejection fraction (HFpEF) is most frequently misclassified as PAH and thus erroneously treated with PAH-specific therapy. Pulmonary artery wedge pressure (PAWP) is commonly used as a surrogate of left atrial pressure; in the absence of mitral stenosis, PAWP measured at end-diastole  more closely approximates left ventricular end-diastolic pressure (LVEDP)PAWP is obtained using a Swan-Ganz catheter with the balloon inflated in a branch pulmonary artery, preventing blood flow or the transmission of pressure from the proximal pulmonary arteries. The static column of blood transmits left atrial pressure to the catheter tip, allowing an estimate of left atrial pressure. Obtaining a reliable PAWP requires expertise and attention. It is important to achieve a stable balloon occlusion position, avoiding under-wedging or over-wedging.6.Pressure measurements are to be carefully recorded at end expiration, ensuring that the patient does not produce a Valsalva manoeuvre. All pressure values, including PAWP, are recorded as the mean of 3 to 5 measurements obtained at the end of normal expiration. This guideline recommendation may not be applicable in patients with chronic obstructive pulmonary disease (COPD), in whom there is often a prominent swing in intrathoracic pressure affecting intracardiac pressures. Averaging PAWP over several respiratory cycles may be the most reasonable compromise to compensate for respiratory fluctuations as positive expiratory and negative inspiratory intrathoracic pressures cancel each other outThere are several tricks to be sure that an accurate PAWP is obtained, including: PAWP value should be equal to or lower than diastolic pulmonary arterial pressure, the PAWP waveform must exhibit clear A and V waves, a respiratory swing should be visible, blood sampling from the distal lumen of the catheter should detect an oxygen saturation in the occlusion position similar or higher than the systemic saturations.15–19. The first randomized, multicenter trial comparing the effects of the continuous intravenous infusion of epoprostenol plus conventional therapy vs, conventional therapy alone in patients with severe primary pulmonary hypertension included patients with PAWP ≤12 mmHg16.However, expert clinicians must be aware of the fact that the optimal PAWP threshold for distinguishing pre-capillary from post-capillary PH remains a matter of debate. Although the 2015 ESC/ERS guidelines recommend a threshold of 15 mmHg, values between 10 and 18 mmHg have also been suggested19. In general, high cutoff risks misclassifying HFpEF patients as PAH, whereas a lower threshold carries the opposite risk. Therefore, most importantly, the hemodynamic values recorded at the diagnostic RHC must be in accordance with the clinical picture and with the non-invasive information20. This means that a complete and accurate diagnostic RHC is always preceded by a clinical evaluation of the patient and by a focused echocardiographic and Doppler examination to have a pre-test probability of PH due to left heart disease. The clinician performing the diagnostic RHC must correctly interpret the hemodynamic values recorded during the catheterization.In the REVEAL registry, a cutoff of 18 mmHg was used to avoid misclassifying older patients with PAH or patients with pulmonary vascular disease and a minor degree of left ventricular diastolic dysfunctiona priori probability of post-capillary PH is high (due to the presence of risk factors or to the presence of an enlarged left atrium and of diastolic dysfunction at echocardiography) and a low PAWP is recorded, RHC must include a fluid challenge test to uncover latent HFpEF21.Importantly, PAWP is not a constant value, but a dynamic parameter affected by the afterload of the left ventricle and by fluid balance. In many patients with left heart disease, PAWP can be lowered to less than 15 mmHg with intense diuretic treatment and vasodilator administration. Therefore, if the In the opposite situation, i.e., a high pre-test probability of pre-capillary PH and recorded PAWP values above 15 mmHg, the clinician should be prompted to re-check the zero level and to wedge the catheter in different positions.12.In case of post-capillary PH, this should be classified as: 1) isolated PH (IpcPH): PAWP >15 mmHg and mPAP >20 mmHg and PVR <3 WU; or 2) combined PH (CpcPH): PAWP >15 mmHg and mPAP >20 mmHg and PVR ⩾3 WU1.Finally, in patients with idiopathic, heritable or drug-related PAH, the diagnostic RHC must include an acute pulmonary vasoreactivity test in order to identify patients suitable for calcium channel blocker therapy. Vasoreactivity testing is usually performed with inhaled nitric oxide (10 to 20 parts per million). A positive test is defined as a reduction of mPAP ≥10 mmHg from baseline to an absolute value of mPAP ≤40 mmHg with unchanged or increased cardiac output16.In the 1980s, the National Institutes of Health (NIH) Registry on Primary Pulmonary Hypertension demonstrated that mortality in incident PAH patients best correlates with two hemodynamic variables obtained at the diagnostic RHC which describe RV function: i.e., one indicator of pump function  and one indicator of systemic congestion The latest recommended treatment algorithm for incident PAH patients foresees choice between two options. Patients at low or intermediate risk should be treated with initial oral combination therapy with an ERA and a PDE5i (monotherapy is limited to specific PAH subsets).In high-risk patients, combination therapy including i.v. prostacyclin analogues is recommended.2 and SvO2 <60% defines a situation of RV failure and thus characterize the highest risk patients.Although risk assessment in PAH is complex and must be based on a multidimensional evaluation of the patients, what is necessary in incident patients is only to identify the highest risk subgroup. This is easy using the hemodynamic parameters obtained at RHC: RAP >14 mmHg, CI <2.0 l/min/m •What is the risk of the patient? •Is pharmacological treatment effective?16. Over time, different tools have been proposed to predict outcome, but these two hemodynamic variables maintained a pivotal role in the assessment of prognosis in PAH22–26.The assessment of the prognosis has always been considered an important part of the evaluation of PAH patients since the publication of the NIH registry nearly three decades ago, demonstrating the strong association with mortality of a low CI and of an elevated RAPThe 2015 ESC/ERS PH guidelines introduced the recommendation of regular and comprehensive risk assessment at expert centers using a range of invasive and non-invasive parameters; the guidelines in fact stated that the goal of treatment in patients with pulmonary arterial hypertension (PAH) is to achieve or maintain a low-risk clinical profile.27–29.The complexity of the 2015 ESC/ERS chart for risk assessment was overcome in 2017, when novel abbreviated versions of the ESC/ERS risk stratification model were evaluated retrospectively in newly diagnosed cohorts of PAH patients demonstrating that it is possible to stratify patients into low, intermediate and high risk of events2 have worse long-term outcomes even when multiple low-risk criteria are present30,31.As expected, hemodynamic parameters play a relevant role in these tools. Importantly, haemodynamic parameters at the time of follow-up RHC are also independently associated with better long-term outcome. In particular, there is additional value in quantifying the stroke volume index (SVi) from a follow-up RHC; patients with a SVi <38 ml⋅m32,33. In the study from the French registry, brain natriuretic peptide (BNP) or N-terminal (NT)-pro-BNP measurements, NYHA functional class evaluation and exercise capacity at 6MWD allowed to identify a subgroup at low-risk, having a 100%, 99% and 97% survival at 2, 3 and 5 years, respectively.An intense debate is ongoing in the literature on the role of non-invasive markers of prognosis and whether these could eventually replace the invasive hemodynamic assessment34. However, a main issue is that only a small minority of patients meets all these noninvasive criteria during follow-up (9% in the COMPERA study and 19% in the French study). Thus, most patients (who are classified in an intermediate risk condition) should perform RHC to better elucidate pulmonary haemodynamics and right ventricular function, thus clarifying their risk.The usefulness of non-invasive methods to identify low-risk groups was confirmed in the COMPERA registry, with 1-, 3-, and 5-year survival rates of 100%, 100% and 95%, respectively35–37.One could argue that non-invasive imaging techniques, either magnetic resonance imaging (MRI) or echocardiography, being able to provide a direct evaluation of the right heart structure and function, should be superior to any indirect evaluation of the right ventricular function provided by hemodynamic parameters. As a matter of fact, the prognosis of PAH patients is determined by the impact of the elevated afterload on the function of the right ventricle38–40. The usefulness of echocardiography is more controversial, possibly because it is considered a less robust technique than MRI, despite the extensive literature reporting that a great number of echocardiographic variables may provide significant prognostic information41–46. Currently, the only echocardiographic parameters included in the risk assessment chart of the ESC/ERS 2015 guidelines are pericardial effusion and right atrial area. In summary, the weight of the evidence available at the current time favours the utility of RHC for routine follow-up of PAH patients.There is no doubt in the literature that assessment of right ventricular function with MRI is of great prognostic utility in PAHWe believe that in the future routine RHC may not be necessary during follow-up for specific subgroups of patients, possibly those who meet noninvasive low-risk criteria, but this has yet to be demonstrated.2.The issue of evaluation of drug efficacy is strictly linked with the issue of risk stratification. Treatment of PAH patients cannot be considered as a simple prescription of drugs, but it is a complex strategy that includes an initial multidimensional evaluation of severity of the disease and the subsequent response to treatment; thus, RHC is an important part in the evaluation of response. In fact, the goal of treatment in patients with PAH is achieving a low-risk status, which, hemodynamically, is characterized by a RAP <8 mmHg and a CI ≥2.5 l/min/mNot unexpectedly, RHC has been used to test drug efficacy in the seminal randomized, controlled trials for currently approved PAH therapies. In these trials the hemodynamic parameters used as end points (not necessarily primary end-points) were PVR, CI and RAP. Other additional hemodynamic parameters describing RV function have been occasionally used to define drug efficacy, such as RV stroke work, RV power or pulmonary arterial compliance but none has so far been validated.In PAH patients, RHC is mandatory to establish the presence and the hemodynamic type of PH. It is also extremely important during the follow-up of PAH patients to evaluate the risk of the patients, to guide therapy and to assess efficacy of treatments.Performing a correct and complete RHC in PAH requires not only knowledge and expertise in the procedure itself but, additionally, knowledge and expertise in the different clinical issues to be addressed in the different clinical situations in which RHC is necessary.


During the Covid-19 pandemic, we can lose sight of the fact that diabetes is also a pandemic, affecting 400 million individuals and causing approximately more than 1.3 million deaths in 2016, a burden of mortality similar to what has been reported from Covid-19 in one year [Sotagliflozin is a dual inhibitor of SGLT2 and SGLT1, the former dominating in the kidney and the latter in the small intestine . SGLT2 tSGLT1 transporters are located in the intestines, the kidney, the brain, the heart, the trachea, the testis and the prostate gland ,7. SGLT1Apart from controlling blood glucose levels, gliflozins have been shown to provide significant CV benefit in T2DM patients ,4. SeverOnly recently, Bhatt et al. have reported the results of two RCTs on the CV and renal effects of sotagliflozin. The first trial, Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure (SOLOIST-WHF), enrolled 1222 participants with T2DM, with a recent episode of decompensated heart failure (HF), in order to determine the efficacy and safety of sotagliflozin in preventing future HF events or CV death . The secIn the SOLOIST-WHF trial, sotagliflozin therapy initiated before or shortly after discharge in patients with T2DM and recent worsening HF, led to a significantly lower total number of deaths from CV causes and hospitalizations, and urgent visits for HF, which was the primary composite outcome of the study, than placebo . The ratIt is noteworthy that both trials were stopped early due to the loss of funding from the sponsor, and subsequently their original primary composite end points were defined again in order to gain statistical power. Nevertheless, this dual SGLT inhibitor performed almost equally well as the current selective SGLT2 inhibitors have performed until today, in terms of CV deaths and hospitalizations for HF .In particular, among more than 280,000 patients, who have been included in the major trials with selective SGLT2 inhibitors, significant reductions in the relative risks of individual adverse CV and kidney events, such as progression to end stage renal disease (ESRD), progression to macroalbuminuria and a two-fold increase in serum creatinine levels were reported, despite an increased incidence of urogenital infections, especially urogenital candidiasis. Notably, the frequency of diabetic ketoacidosis (DKA) associated with sotagliflozin in the SCORED trial was almost the same as that found in the former CV studies with selective SGLT2 inhibitors. Therefore, the addition of intestinal SGLT1 inhibition appeared to affect neither the beneficial effects nor the potential harms related to the use of sotagliflozin. Therefore, it seems likely that sotagliflozin will be added to the list of recommended SGLT2 inhibitors for T2DM. Sotagliflozin is authorized in the European Union only for treatment of patients with both T1DM and obesity ,11. SotaHowever, many questions arise on how these cardiac beneficial effects of SGLT inhibitors could be explained. In a 2015 study, Vrhovac et al. has used purified antibodies for human SGLT1 (hSGLT1) and SGLT2 (hSGLT2), and thereby identified locations of SGLT2 in the human kidney and SGLT1 in the human kidney, small intestine, liver, lung and heart . SGLT1 i++, which is a key regulator of energy production as well as mitochondrial morphology and apoptosis [++of cardiomyocytes in the left ventricle at rest has been related to an elevated increased cytosolic Ca++, mitochondrial swelling and reduced mitochondrial respiration [++ buffer capacity. A reduced cytosolic concentration of Na+ or Ca++ at rest could account for this effect [++ uptake has been demonstrated to contribute to the buffering of cytosolic Ca++ peaks in cardiomyocytes, whilst pharmacologic enhancement of mitochondrial Ca++ uptake has been related to a decreased sarcoplasmic reticulum concentration of Ca++ in catecholaminergic ventricular tachycardia models. An enhanced mitochondrial Ca++ buffer capacity has been suggested to contribute to decreased sarcoplasmic reticulum Ca++ levels and less ventricular arrhythmias. Moreover, mitochondrial swelling has been attributed to a Ca++ overload, thus leading to an opening of the mitochondrial permeability transition pore, mitochondrial depolarization, generation of reactive oxygen species and subsequent apoptosis [++ may account for the subsequent decrease in the size of the cardiomyocytes’ mitochondria by means of reversing mitochondrial swelling [Mitochondria are known to sequester huge amounts of Capoptosis . In the piration . Bode ets effect . Mitochopoptosis ,12. Bodeswelling .Moreover, sotagliflozin has also been demonstrated to provide beneficial effects on blood pressure and body weight, partially due to the glucosuria as well as the increase in the secretion of glucagon like peptide-1 (GLP-1) due to the delayed glucose intestinal absorption ,13.In conclusion, sotagliflozin has only recently been documented to prevent deaths from CV causes and hospitalizations and urgent visits for HF among patients with T2DM and recent worsening of HF, as well as among patients with T2DM and CKD, with or without albuminuria. Nevertheless, further large-scale studies are needed to confirm the molecular mechanisms behind the cardiac beneficial effects of dual SGLT inhibition. It is high time to focus on the heart of the problem. At last, it may be time to apply this dual SGLT inhibitor in our armamentarium against T1DM and T2DM, especially among patients with HF and CKD.


Elevated blood pressure is the leading cause of death worldwide; however, treatment and control rates remain very low. An expanding literature supports the strategy of task redistribution of hypertension care to nurses.We aimed to evaluate the effect of a nurse-based hypertension management program in Kenya.We conducted a retrospective data analysis of patients with hypertension who initiated nurse-based hypertension management care between January 1, 2011, and October 31, 2013. The primary outcome measure was change in systolic blood pressure (SBP) over one year, analyzed using piecewise linear mixed-effect models with a cut point at 3 months. The primary comparison of interest was care provided by nurses versus clinical officers. Secondary outcomes were change in diastolic blood pressure (DBP) over one year, and blood pressure control analyzed using a zero-inflated Poisson model.The cohort consisted of 1051 adult patients . SBP decreased significantly from baseline to three months , with no significant difference between groups. DBP also significantly decreased from baseline to three months with no difference between provider groups. Retention in care at 12 months was 42%.Nurse-managed hypertension care can significantly improve blood pressure. However, retention in care remains a challenge. If these results are reproduced in prospective trial settings with improvements in retention in care, this could be an effective strategy for hypertension care worldwide. Elevated blood pressure (BP), a major risk factor for ischemic heart disease , heart f58Recent literature suggests that health care worker density is significantly associated with hypertension treatment rates, and that nurse density in particular appears to be an important determinant . Given tIn 2011, Academic Model Providing Access to Healthcare (AMPATH) Chronic Disease Management Program initiated nurse-based hypertension management in rural western Kenya . The aimThe AMPATH program is an academic global health partnership between Moi Teaching and Referral Hospital, Moi University College of Health Sciences, and a consortium of North American universities led by Indiana University . AMPATH This study is a retrospective analysis of routine clinical data collected by the AMPATH Chronic Disease Management Program. All individuals enrolled in this nurse-based hypertension management program received the same care, according to standardized AMPATH protocols based on the contemporaneous evidence-based standards of JNC-7 and JNC-8 (Appendix A) 19, which21Community-based screening of all adults ≥18 years for systolic blood pressure (SBP) and diastolic blood pressure (DBP), using automatic BP machines, was initiated by AMPATH in both Kosirai and Turbo Divisions . The scrRoutine, de-identified, clinical data within the AMPATH Medical Record System (AMRS) were extracted without personal identifiers. Hence, informed consent from patients was not required. The clinical cohort was comprised of hypertensive patients over the age of 35 who initiated care between January 1, 2011, and October 31, 2013. The follow-up period was one year (+/– 3 months), and data were extracted from the electronic medical record system through December 31, 2014. Data extracted included: sex, age, encounter type, encounter date, SBP, DBP, facility type, provider type , and health center location (Kosirai or Turbo Division). BP measurements were conducted and recorded into the medical record by the clinical provider. Errant BP values per AMPATH Chronic Disease Management data management guidelines  were excluded from the analysis. In addition, clinical encounters with either a missing SBP or DBP value were also excluded, since it was unlikely that only one of the BP parameters was measured during the clinical encounter.The primary outcome measure was changed in SBP over one year, analyzed using piecewise linear mixed-effect models with random intercept and slopes. The response curve was divided into two segments with a linear model having different slopes fitted to each segment. The location where the two segments joined, called a ‘knot,’ was placed at three months to reflect clinical reality in terms of frequency of a return visit. The primary non-randomized intervention effect of interest was a comparison of SBP change among patients cared for by nurses versus those cared for by clinical officers. Within- and between-group changes before and after three months from baseline were assessed. Additional covariates included age, sex, and health center location. Age was mean-centered.The key secondary outcomes included change in DBP over one year and the frequency of BP control over one year. DBP was analyzed using the same method as described for change in SBP. BP control was defined as having both a SBP < 140 and a DBP < 90 during a clinical encounter. Only patients with more than one visit (and therefore opportunity for BP control) were included in all BP control analyses. BP control was analyzed using a zero-inflated Poisson model to account for individuals who never had their blood pressure controlled. The two-part modeling of the zero-inflated Poisson regression provided the effect of provider on lack of any BP control (a ‘zero’) and the effect of provider on the relative frequency of BP control over time among those who were ever controlled. Logistic regression was used to model the probability of lack of BP control and Poisson regression was used to model mean number of times BP was controlled. The Poisson model included a covariate for the (log) number of visits to account for variation in number of visits. Covariates included mean-centered age, sex, and health center location.As a sensitivity analysis, SBP and DBP analyses were run only on patients with more than one visit. All analyses were performed at the 0.05 (2-sided) significance level using SAS Version 9.4 .Of the 1432 patients enrolled in the Chronic Disease Management Program during the study period, 1051 individuals (65% women) were over age 35 and were confirmed as hypertensive by the clinician. Of these 1051 individuals, 753 (72%) had at least one follow-up clinical visit during the 12-month follow-up period and 446 patients (42%) were retained in care at one year (+/– 3 months). Women were more likely than men to remain in care at 12 months (45% vs. 38%).Of the entire clinical cohort, 180 individuals were cared for by a nurse and 871 were cared for by a clinical officer. The mean age was 60.6 years (SD 13.2), with no significant difference between those managed by a nurse versus a clinical officer . After adjustment for age, sex, and health center location, both nurse-managed and clinical officer-managed patients experienced significant reduction in DBP from baseline to three months , and the decrease was not significantly different between provider groups  . DBP remained relatively unchanged after three months . There was no difference between men and women with respect to DBP lowering. Older patients, relative to younger patients, tended to have greater DBP reduction over the follow-up period. Patients in the Turbo Division experienced greater DBP reduction than patients in Kosirai. SBP and DBP sensitivity analyses were also performed only on patients with more than one visit (n = 753), which produced very similar results .BP control analyses were also conducted on the subset of patients with more than one visit. After adjusting for age, sex, and health center location, there was no difference in the proportion of patients who never had their blood pressure controlled between nurses and clinical officers  , poor provider-patient relationship, the need for technical and mobility assistance to attend appointments, and general distrust of the medical enterprise . While tA central principle of this program was leveraging the existing infrastructure and task redistribution strategy implemented by AMPATH for the treatment and prevention of HIV . In addiOne of the primary limitations of this study was the lack of a controlled comparator group. The primary reason for this limitation is that, in the absence of this hypertension program, rural patients would otherwise have no access to hypertension care other than at the District and Referral Hospitals. Thus, the AMPATH Chronic Disease Management Program leadership felt that it would be unethical to monitor outcomes in a controlled comparator group without offering those individuals a care program that was geographically accessible and decentralized. In addition, the results of this impact evaluation can serve as the foundation to design and conduct a larger scale trial to rigorously test the hypothesis that BP control in hypertensive patients can be achieved by nurses as effectively as by clinical officers and physicians in this setting. Another limitation is related to the implementation of the hypertension management program; nurses were routinely mentored by clinical officers and physicians, in order to ensure quality of care. However, those mentorship sessions often evolved into the care primarily being driven by the mentors rather than the nurses. We therefore separated the cohort into individuals whose care was primarily by a nurse versus clinical officer, and were able to demonstrate that nurse-managed patients fared just as well and potentially even modestly better in terms of SBP and DBP. Finally, this analysis was limited to the initial implementation period of the program, and our team has been able to increase geographic decentralization over time in alignment with task redistribution. Future analyses will be necessary that take into account program scale-up, program maturation, and lessons learned.Hypertension is a growing risk worldwide, particularly in LMICs. This study has demonstrated that nurses working within a resource-limited setting can successfully manage hypertension and achieve significant reductions in BP. Although combating hypertension and other non-communicable diseases will require a multifaceted approach, the nurse management of hypertension model described here can serve as a model for similar non-communicable disease care delivery programs in other low-resource settings worldwide. If the findings of this study are reproduced in prospective trial settings with improvements in retention in care, nurse management and task redistribution could be an effective strategy for improving hypertension outcomes and addressing this growing global public health concern.The datasets used and/or analyzed during the current study are available on reasonable request to the corresponding author and the AMPATH Research Manager. This study complies with the NIH Public Access Policy, which ensures that the public has access to the published results of NIH-funded research, and therefore, all results have been (and will be made) available from final peer-reviewed journal manuscripts (including this one) via the digital archive PubMed Central upon acceptance for publication.The additional files for this article can be found as follows:10.5334/gh.856.s1Supplemental Figure.Loess plot of mean DBP over time, demonstrating early reduction in DBP in both the nurse and clinical officer groups, maintained during the follow-up period.10.5334/gh.856.s2Supplemental Table 1.Results of the piecewise linear spline model for DBP change over time, with knot at three months. The estimate values indicate the absolute change in DBP (mmHg) per month, except for the ‘other variables,’ which are for the entire follow-up period.10.5334/gh.856.s3Supplemental Table 2.Piecewise linear spline model for SBP change over time, using data for patients with more than one clinical visit.10.5334/gh.856.s4Supplemental Table 3.Piecewise linear spline model for DBP change over time, using data for patients with more than one clinical visit.10.5334/gh.856.s5Appendix A.AMPATH Chronic Disease Management hypertension management protocol.


Reports of different types of neurological manifestations of COVID-19 are rapidly increasing, including changes of posterior reversible leukoencephalopathy syndrome (PRES). Here we describe the first reported case of COVID-19 and PRES in Australia diagnosed on basis of MRI brain imaging and confirmed clinically by presence of confusion, delirium, headaches, also associated with hypertension and blood pressure variability and stable long-term kidney problems. He made full recovery as his blood pressure was controlled and clinical status was supported with appropriate supportive therapy. Although traditionally a rare condition, PRES is likely to be more common among patients with COVID-19 pathobiology there is Renin downregulation of ACE2 receptors, involvement of Renin-Angiotensin-Aldosterone system, endotheliitis, cytokine storm, and hyper-immune response. Thus we advocate clinical suspicion and early brain imaging with MRI brain among vulnerable patients with known co-morbidities, and diagnosed with COVID-19 given that hypertension and blood pressure variability are often exacerbated by acute SARS-CoV-2 immune reactions. Such acute hypertensive encephalopathy was able to be reversed with timely supportive therapy ensuring re-hydration and re-establishment of blood pressure control. A new β corona virus, severe acute respiratory syndrome coronavirus2 (SARS-CoV2) emerged as a novel cause of pneumonia in December 2019. Since then the SARS-CoV2 has spread to over 216 countries and is now regarded as a major world pandemic –5 as eviWe present, to our knowledge the first reported case of posterior reversible encephalopathy syndrome (PRES) associated with severe acute respiratory syndrome coronavirus2 (SARS-CoV2) in Australia. A comprehensive literature review revealed that 18 cases since December 2019 had been documented worldwide by late August 2020 though as shown in A 55-year-old man with known hypertension compliant with medications, obesity, chronic renal impairment secondary to hypertensive nephropathy [baseline eGFR 24 ], a 35 pack-year history of smoking, obstructive sleep apnea and hypercholesterolaemia was part of a family cluster of acute infections with SARS-CoV2 1 week prior to the admission to our hospital. The index case and the family (wife and four children) were positive for SARS-CoV2. In particular, he was experiencing headaches, fever, and dry cough for the prior 7 days. There was no report of nausea and/or vomiting during the preceding week. Prior to hospitalization, the family physician had prescribed oral dexamethasone 6 mg daily. On day seven, his daughter and wife found to him significantly lethargic, confused and disorientated and brought him to the Emergency Department (E.D) where he was admitted to hospital.Apart from his altered mentation, he appeared normal on examination in the ED. At the time of admission, his respiratory rate was 18 and his blood pressure was 171/85 mmHg, with a mean arterial pressure of 116. His blood pressure variability is shown in His blood examination displayed a total white cell count (WCC) of 11.5, a neutrophil count of 9.9 and a lymphocyte count of 0.6. His neutrophil-lymphocyte ratio (NLR) was 16.5 compared to expected value of <2 for his age group. C- reactive protein was also significantly elevated (132 mg/L compared to expected <5 mg/L) at admission. There was mild elevation in his creatinine levels from baseline. He was maintained on Moxonodine 200 mcg bid and his usual blood pressure medication, Prazosin 1 mg bid. He was found to be coherent on the third day after admission and was discharged home. On discharge, his total WCC had improved to 7.8, with a neutrophil count of 5.8 and lymphocyte count of 0.6. His NLR was thus 13.A CT scan of his brain on admission showed bilateral hypointensities around his posterior parietal-occipital regions see . A subseAlmost 25 years have elapsed since PRES was first described . InteresNormal clinical presentation of PRES includes altered mentation, headaches, visual disturbances, and seizures in patients with other underlying comorbidities. Fluctuations in blood pressure are a characteristic sign of PRES both in COVID patients and in other non-COVID associated diagnosis.A leading theory of the pathophysiology of PRES suggests that rising hypertension exceeding the upper limit of autoregulation of cerebral blood flow culminates in hyperfusion and blood- brain barrier disruption along with the extravasation of macromolecules and plasma to interstitial tissues , 21.Acute hypertension has been suggested to cause endothelial dysfunction in susceptible patients as multiple mechanisms lead to an eventual breakdown of the blood-brain barrier . The patFurthermore, it is known that COVID 19 attaches to ACE 2 receptors on endothelial cells (lung parenchyma as well as brain parenchyma) and brain microglia  inducingThere is no specific treatment for PRES, but symptoms are thought to be reversible once the underlying cause is removed . It is wWhile the pathophysiology of PRES or COVID induced VANDAL symptoms remains controversial, we advocate for tight blood pressure control and MRI imaging in all COVID-19 patients who show neurological symptoms from headaches to confusion and cognitive impairment, particularly in those with hypertension, as a matter of priority both at the time of the admission as well as during recovery prior to leaving hospital. We could not perform the repeat brain imaging due to the rapid recovery of the patient and difficult access to imaging in the middle of the pandemic related logistic issues. Uncontrolled hypertension and blood pressure variability alongside viral inflammation and excessive immune responses are both potential but not unexpected risk factors for worse outcomes involving COVID-19 and its effects on vulnerable kidney patients, given its propensity to attack the RAAS system and ACE2 receptors. We hypothesize that hypertension and potentially blood pressure variability exacerbated by acute SARS-CoV-2 action on the RAAS and associated inflammation may be additional risk factors for endothelial dysfunction and hypertensive encephalopathy with modest blood pressure changes during acute infection with SARS-CoV2 , 29–32.While most patients will fully recover from PRES, the extent of recovery and exactly how reversible symptoms of PRES or VANDAL are, is not known, given the definitions of both disorders are of a symptom of an underlying co-morbidity and particularly now in the presence of COVID. In a postmortem brain MRI study Coolen et al. , describMore research needs to be done into the specifics of both PRES and VANDAL disorders. COVID-19 is a very likely risk factor for PRES except the oedema seen is often more than that induced preferentially by the basilar artery. Thus, we argue that more vigilance is required to detect cognitive and neurological symptoms in these patients and to facilitate appropriate neuroimaging earlier enough and then again when symptoms dissipate. Surveillance neuroimaging is also necessary to determine radiologic outcomes. Tight control of blood pressure and reducing the risk of blood pressure variability and inflammation and hence potential for any further cytokine storms that are likely initiators endothelial cell damage allowing fluid leakage to the brain are likely to be helpful in this context.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical review and approval were not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Written, informed consent was obtained from the participant for the publication of this case report .TW conceived the idea and wrote the first draft of the manuscript. CW, CS, LK, and SC edited and contributed to the final manuscript. All authors approved the final manuscript.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.


Poor adherence to inhaled medication in asthma patients is of great concern. It is one of the main reasons for inadequate asthma control.The goal of the research was to determine if motivational messages using short message service  improved adherence to inhaled medication in patients with asthma.A prospective multicenter randomized parallel-group clinical trial was conducted in 10 asthma clinics in Spain. Adherence was assessed with electronic monitors  connected to inhalers. Patients in the SMS group received psychologist-developed motivational messages every 3 days for 6 months.P=.82). Significant differences between the study groups in morning and evening adherence to inhaled therapy, asthma control, exhaled nitric oxide levels, or improvement of lung functions were not observed.There were 53 patients in the SMS group and 88 patients in the control group. After 6 months, mean electronic adherence was 70% (SD 17%) in the intervention group and 69% (SD 17%) in the control group (Motivational messages were not useful to improve adherence to inhaled asthma medication compared with usual care. Epidemiological studies show a high prevalence of poor asthma control -3. Poor Adherence to inhaled therapy depends on multiple factors. Asthma education programs plus information and communication technologies could be more useful to improve adherence than using them separately. All cell phones can send or receive short message service  messages, which are a convenient, widely used mode of communication -32. It hSeveral studies reviewed the effect of reminders on asthma control and adherence to treatment -40. OnlyThe objective of this study is to measure the effect of motivational messages designed by a psychologist on treatment adherence compared with usual care in patients with moderate to severe asthma.We conducted a parallel-group randomized controlled trial in patients with moderate or severe asthma at 10 university hospitals in Spain. Patients were recruited from 2013 to 2014. Patients were randomized to an SMS group or a control group; follow-up was for 6 months.The eligibility criteria for participants were (1) aged 18 to 85 years, (2) asthma diagnosed according to the Global Initiative for Asthma (GINA) criteria , (3) allExclusion criteria were (1) inability to use inhaler devices ; (2) othThe SMS group received psychologist-developed motivational messages every 3 days for 6 months in addition to usual care recommendations according to GINA guidelines . SMS mesAll patients received a SmartTrack device . They also used albuterol pressurized metered-dose inhaler as rescue medication. Device reliability and precision have been reported according to other publications .Electronic monitoring via the Smartinhaler was used to assess adherence to inhaled asthma therapy. All patients received brief instructions on the use of the SmartTrack. Patients with adherence higher than 80% were considered regular adherents. Electronic monitors were attached to participant controller medications in the SMS and control groups.Patients assigned to the intervention group only received SMS communications about the importance of asthma medication every 3 days for 6 months; messages were not reminders to take a dose of medication. The messages, written by a psychologist in collaboration with pulmonologists, were randomly switched every 3 days and include the following:Remember that performing the treatment of inhaled medication keeps your asthma controlled.Inhaled medication helps to maintain asthma control.Remember to take inhaled medication; it keeps you well.Have you taken your inhaled medication?Do you take your inhaled medication in the morning and the evening?Maybe now is the time to take your inhaled medication.Remember to take inhaled medication as prescribed by your doctor.All patients were provided an asthma action plan on the first day written in accordance with the GINA guidelines. Inhaler technique was reviewed, and any problems were corrected. At each visit, inhaler technique and the asthma action plan were reviewed.Asthma control was measured using the Asthma Control Test (ACT) , and a sSpirometry with bronchodilator test was performed according to the European Respiratory Society/American Thoracic Society (ERS/ATS) guidelines . Values An FeNO level was measured before spirometry using the equipment available in each center. The test was performed following the ERS/ATS recommendations .Demographic data, ACT, lung function (spirometry), FeNO levels, and exacerbation history in the previous year were collected at the enrollment visit (V0). ACT, lung function, FeNO levels, and exacerbation history were also collected at V1, V3, and V6.The primary outcome was adherence to inhaled medication. SmartTrack devices were used to quantify adherence to control medication. The secondary outcomes were asthma control measured by the ACT, spirometry parameters , FeNO levels, number of asthma exacerbations, visits to the emergency department, and hospital admissions due to asthma.The sample size was calculated according to an adherence rate to inhaled asthma therapy between 30% and 70% . On the We generated the 2 comparison groups using simple randomization with an equal allocation ratio by referring to a table of random numbers. A mathematician, also in charge of randomization of the SMS sending, generated the sequences of random allocation, who enrolled participants, and who assigned participants to interventions and SMS sending.Blinding of patients was not possible. To avoid bias and with ethics approval, physicians were not notified about the SmartTrack recording function or SMS intervention until the study ended.t test or Mann-Whitney U test were used for the comparison of quantitative variables according to the standard or nonnormal distribution of variables. Tests were 2-tailed. Statistical significance was set at P<.05. Statistical analyses were performed using the SPSS Statistics version 20.0 (IBM Corp).Categorical variables were expressed as frequencies and percentages and continuous variables as means and standard deviations. The chi-square or Fisher exact test were used for the analysis of categorical variables, and the Student The clinical research ethics committees of the participating centers approved the study. All participants provided written informed consent. The study was classified by the Spanish Agency of Medicines and Medical Devices as a noninterventional imposed postauthorization safety study, and for this reason we were not required to register the clinical trial.Of patients recruited, 63.8% (97/152) were women. At the first data collection time point, the mean age was 48.9 (SD 16.7) years, and the mean duration of asthma was 16.5 (SD 13) years. A total of 6.6% (10/152) of patients were current smokers. Most patients were well controlled at enrollment, with a mean ACT score of 20.2 (SD 4.5) points. The mean FEV1 before the bronchodilation test was 79% (SD 17.9%) predicted, the mean FEV1 after bronchodilation test was 82.5% (SD 16.2%) predicted, and the mean FeNO level was 37.9 (SD 35.9) ppb. A total of 13.2% (20/152) of patients reported one or more exacerbations during the last 12 months, 15.8% (24/152) reported an episode of asthma-related urgent health care utilization and prednisone use in the previous year, and 5.9% (9/152) required admission to hospital.A failure with the randomization program unbalanced the number of patients in both arms. During the study period, 57 patients were assigned to the intervention group, and 95 to the control group. At follow-up, 11 patients were excluded because of the total failure of the electronic monitoring device. The final analysis included 53 patients in the intervention group and 88 in the control group. The flowchart of the study population is shown in Adherence data were recorded throughout the study starting from enrollment, and 92.8% (141/152) of patients had analyzable SmartTrack data. No adherence data were available for 7.2% (11/152) of patients due to device failure; 21.7% (33/152) of SmartTracks monitored adherence for at least 90 days, 11.2% (17/152) operated fine for between 90 and 179 days, and 59.9% (91/152) worked precisely until the study ended.P=.51).The data transmission software that communicated with the Smartinhaler platform failed throughout the study in most of the participating centers since it did not work with the hospital proxy servers. Due to this failure, the backup files generated during each visit were used for the analysis. Differences between the study groups were not found in SmartTrack failures (P=.82). Adherence to inhalers was higher in both groups in the morning  in the intervention group and 69% (SD 17%) in the control group (At the end of the study (V6), no differences were found between the SMS and control group in ACT, FEV1, FeNO levels, exacerbations, emergency department visits, or hospital admissions .In this study, motivational SMS was not associated with an improvement in adherence to inhaled medication. We also found no significant differences in secondary variables, asthma control, lung function, exhaled nitric oxide levels, or exacerbations due to asthma.P=.02). Changes in adherence in the SMS group, however, were not associated with clinical or functional improvement. Few patients were included in this study, and adherence may have been overestimated due to the possibility to take actions before the medical visit.Education strategies are useful to improve adherence to asthma therapy . Few stuP<.001). But, again, no improvements in clinical or lung functions were observed.In another study, Charles et al  used theP<.001) as well as with an improvement in the ACT but without differences between the study groups.In a 6-month cluster-randomized study, Foster et al  assessedIn a recent systematic review of interventions aimed at improving adherence to inhaled corticosteroids for asthma, 11 studies assessing electronic trackers or reminders versus control were analyzed . ElectroIn our study, a simple intervention based on motivational SMS sent every 3 days for 6 months was not adequate to improve adherence. Different reasons may account for this adverse finding. First, the messages sent were motivational; they were not reminders for taking medication. Second, the pattern of nonadherence behavior   was not An interesting finding of this study, in which all patients had twice-daily medication schedules, is that adherence rates were higher in the morning than in the evening. It is possible that in patients on single-dose inhaled medication regimens, SMS could have had a more significant impact on adherence.Although the Smartinhaler is accurate in recording and retaining actuation data ,49, poteIn our study, patients were recruited in specialized asthma units established in different hospitals throughout Spain for the management of patients with severe and difficult-to-control asthma . TherefoIn summary, in this prospective randomized clinical study, reinforcement of adherence to inhaled asthma medication using motivational SMS via cell phones was not capable of improving adherence. Mobile health interventions are increasingly popular for implementing on a large scale in different chronic health conditions -53, but