To improve the treatment of patients with kidney disease, new renal replacement therapies are being developed. Prior to their use in humans with end-stage kidney disease (ESKD), these therapies need to be tested in animals with kidney disease. Goats seem particularly suitable because they are docile, have bodyweights comparable to humans and easily accessible neck veins to obtain blood access and tolerate frequent blood sampling, allowing for repeated monitoring. To obtain high blood concentrations of waste solutes that accumulate in patients with kidney disease and allow for the evaluation of solute removal by the new renal replacement therapies, we established kidney failure in five goats by partially blocking the blood supply of the kidneys via radiographic embolization. This resulted in stable moderate kidney disease. The administration of high-dose gentamicin caused a temporary further decline in kidney function. Although the response varied with animal, blood concentrations of waste solutes were representative of those found in ESKD patients. These animals can survive for more than ten months in good condition, allowing for the repetitive testing of new therapies in one animal, and therefore limiting the use of laboratory animals.A large animal model of (end-stage) kidney disease (ESKD) is needed for the preclinical testing of novel renal replacement therapies. This study aimed to create stable uremia via subtotal renal artery embolization in goats and induce a temporary further decline in kidney function by administration of gentamicin. Renal artery embolization was performed in five Dutch white goats by infusing polyvinyl alcohol particles in branches of the renal artery, aiming for the embolization of ~80% of one kidney and complete embolization of the contralateral kidney. Gentamicin was administered to temporarily further increase the plasma concentrations of uremic toxins. After initial acute kidney injury, urea and creatinine plasma concentrations stabilized 1.5 ± 0.7 months post-embolization and remained elevated  during follow-up (16 ± 6 months). Gentamicin induced temporary acute-on-chronic kidney injury with a variable increase in plasma concentrations of small solutes  and protein-bound uremic toxins representative of patients with ESKD. A uremic goat model characterized by stable moderate uremia was established via subtotal renal artery embolization with the induction of temporary severe acute-on-chronic kidney injury by the administration of gentamicin, allowing preclinical in vivo validation of novel renal replacement technologies. Novel renal replacement therapies (RRT) are under development to improve the treatment of patients with end-stage kidney disease (ESKD). These innovations include miniature dialysis machines for hemodialysis (HD) and peritoneal dialysis (PD), a bioartificial kidney and innovative dialysis membranes ,2,3. PriThe aim of the present study was to create a stable model of CKD in goats by performing a subtotal nephrectomy via transfemoral renal artery embolization. This method allows for the selective embolization of branches of the renal artery while sparing others, and is minimally invasive. Gentamicin, a drug with well-known nephrotoxicity, was administered to temporarily increase plasma concentrations of uremic toxins on demand, in order to study their removal during dialysis. Both HD and PD experiments were performed as proof of concept.n = 5) weighing 50–80 kg were selected, because these animals are docile, have easily accessible neck veins for placement of a central venous catheter and bodyweights (and distribution volumes) comparable to humans [The study was approved by the Animal Experiments Committee  and performed in accordance with national guidelines for the care and handling of animals. Clinically healthy female Dutch White adult goats (capra aegagrus hircus)  and PAH 6 mg/kg  dissolved in sodium chloride 0.9%  was administered, followed by continuous inulin (11.25 mg/min) and PAH (11 mg/min) infusion. Alternatively, a single intravenous bolus of iohexol 5 mL  was administered. Venous blood samples were collected before start and after 10, 60, 120, 180, 210, 240, 270 and 300 min, to measure inulin (or iohexol), PAH and hematocrit. Steady state plasma concentrations were used for the calculation of plasma clearanceGlomerular filtration rate  and effective renal blood flow  were measured by inulin and para-amminohippuric acid (PAH) clearances (Formulas 1 and 2), respectively, before and 1.5 ± 0.7 months after embolization, once urea and creatinine plasma concentrations had stabilized. Because the production of inulin by Fresenius Kabi was discontinued during the study, GFR was determined by iohexol clearance in two goats. Two venous lines were placed, one for blood sampling and one for inulin (or iohexol) and PAH infusion. An intravenous bolus of inulin 22.5 mg/kg .Arterial blood pressure was measured two months after embolization via cannulation of the a. auricularis in awake goats in standing position, and was compared to blood pressure in healthy goats.An important aspect of dialysis treatment is the release of bicarbonate  to neutralize the daily non-volatile acid production that is not sufficiently excreted by the kidneys in ESKD, and therefore limit metabolic acidosis. To study bicarbonate release during treatment, which depends on a transmembrane concentration gradient across the dialysis or peritoneal membrane, the plasma bicarbonate concentration of the experimental animal must be representative for patients with ESKD. Because plasma bicarbonate concentrations in goats were relatively high (28.9 ± 3.1 mmol/L) compared with maintenance HD patients (63% of HD patients have a plasma bicarbonate concentration below 23 mmol/L ), a combVenous blood samples were drawn before the start and once daily prior to medication administration in a lithium–heparin tube with gel-separator. The tubes were centrifuged immediately at 4 °C and left unopened until analysis. Analysis was performed within 2 h to assure bicarbonate stability .n = three samples) was collected from two female white goats in clot-activating tubes  and centrifuged at 2130 g for 10 min. Serum was separated and centrifuged again at 2500 g for 10 min. All reagents and samples were stored on ice during the assay to prevent the spontaneous activation of complement proteins. Sensitized human erythrocytes were prepared from the blood of healthy volunteers . The tube was centrifuged at 2130 g for 10 min, plasma was discarded and cells were washed with PBS-0.5 mmol/L EDTA and divided over two separate tubes. Cells were washed twice more with the assay-specific buffers (DGHB++ buffer was used for CH50 assay and DGHB-Mg-EGTA for the AP50 assay), which were prepared as described [8 erythrocytes/mL. Subsequently, human erythrocytes were sensitized with rabbit anti-human erythrocyte membrane  at a concentration of 100 µL in 10 mL of 108 erythrocytes/mL and incubated for 30 min at 56 °C. Cells were washed twice and the concentration was readjusted to 108 erythrocytes/mL. CH50 and AP50 assays were performed simultaneously in a Masterblock 96-well plate . An initial 2-fold dilution was performed, starting with 200 µL of goat serum (in triplo), followed by serial 10-fold dilutions with DGHB++ or DGHB-Mg-EGTA buffer, respectively. In addition, a blank well containing only buffer (no lysis) and a well containing distilled water  were included. A 200-µL sample of sensitized human erythrocytes was added to each well, followed by incubation in a water bath at 37 °C for 60 min. After incubation, a sample was taken from each well, centrifuged for 10 min at 2500 g and the degree of hemolysis was quantified by measuring the absorbance of the released haemoglobin into the supernatant at 405 nm using a spectrophotometer (Multiskan FC Microplate Photometer type 357). Complement-dependent lysis of erythrocytes was calculated as the percentage lysis relative to cells lysed in water (100% lysis) and cells incubated in buffer (0% lysis). Percentage lysis was plotted against serum dilution. CH50 and AP50 activity was expressed as the amount of goat serum necessary to cause 50% lysis.The complement system is a group of proteins that, when activated, cause cell lysis and facilitate phagocytosis through opsonisation. A hemolytic assay was used to test the functional capability of the classical (CH50) and alternative (AP50) complement pathway in the serum of uremic goats to lyse human erythrocytes pre-coated with rabbit anti-human antibodies, as described by Moreno-Indias et al. . Blood . Prior to dialysis, a central venous catheter  × 55 cm −3.1 mL V3.1 mL) was inserted into the external jugular vein under anesthesia with detomidine and propofol as described . This reTwo goats were instrumented with a straight Tenckhoff PD catheter  under general anesthesia. The catheter was tunneled to the back to prevent catheter manipulation and flushed daily with 50 mL NaCl 0.9%. After 379–382 days (goat 1) and after 4 days (goat 2), a standard peritoneal permeability analysis (SPA) was performed to assess peritoneal membrane transport status in terms of dialysate to plasma ratio (D/P) creatinine and the mass transfer area coefficient (MTAC) of urea and creatinine, as described by Pannekeet et al. . In briet-tests or Wilcoxon signed rank test, as appropriate. A p value < 0.05 was considered significant. Analyses were performed using IBM SPSS Statistics 25  and Graphpad Prism .Descriptive statistics are reported as mean ± SD or median (interquartile range), as appropriate. Linear interpolation was used for missing plasma concentrations of uremic toxins during follow-up. Comparison between two repeated measurements during follow-up were performed using paired Subtotal renal artery embolization was performed in five goats. In the first goat, subtotal nephrectomy of ~83% of total kidney tissue was performed in two stages. First, partial embolization of one kidney ~67%.  was perfPostoperative clinical recovery of goats was rapid, and no serious adverse events occurred. After 24 h, temporary signs of mild to moderate pain  were observed, which responded well to additional analgesic medication. One goat developed a groin hematoma post-operatively, located at the femoral catheter insertion site, which resolved spontaneously.Mean follow-up time was 16 ± 6 months. Renal artery embolization resulted in stable moderately elevated plasma concentrations of urea (12 ± 1.4 vs. 5.6 ± 0.8 mmol/L) and creatinine (174 ± 45 vs. 65 ± 5.6 µmol/L), without the need for maintenance dialysis . Apart fn = 1) and because of an intra-abdominal mass suspect for a liver cyst or abscess with signs of severe liver failure (n = 1).Two goats were euthanized after 15 and 27 months of follow-up because of unexplained severe acute-on-chronic kidney injury, which was not induced by gentamicin administration, and did not recover spontaneously. The first goat received one course of gentamicin (10 mg/kg twice daily for 7 days) at 8 months of follow-up, which caused severe acute-on-chronic kidney (requiring temporary HD) with partial recovery to stable severe uremia . The secn = 1–8 per goat). The administration of gentamicin 5–10 mg/kg twice daily for <7 days appeared to be insufficient to consistently induce severe acute-on-chronic kidney injury  were administered to five goats . In oney injury , which wAdministration of gentamicin 10 mg/kg twice daily for 7–10 days caused an initial decrease in phosphate plasma concentrations from 1.54 ± 0.29 mmol/L to 1.09 ± 0.38 mmol/L after 13 ± 3 days, after which plasma concentrations increased to 2.18 ± 0.28 mmol/L after 20 ± 5 days. Phosphate plasma concentrations were higher than 1.5 mmol/L from day 14 ± 7 for a duration of 10 ± 6 days. Potassium plasma concentrations increased from 4.3 ± 0.3 mmol/L to 5.0 ± 0.6 mmol/L.At higher creatinine plasma concentrations during acute-on-chronic kidney injury (following gentamicin administration or prior to termination), plasma concentrations of indoxyl sulfate, p-cresyl glucuronide, p-cresyl sulfate and hippuric acid were within the range  or higher (p-cresyl sulfate) than uremic plasma concentrations , Table 1p = 0.16) and diastolic blood pressure tended to be lower .Systolic blood pressure measured two months post-embolization was not different compared with blood pressure in healthy goats  (Treatment with acetazolamide 500 mg/day and ramipril 1.25 mg/day for three days caused a decrease in plasma bicarbonate concentrations from 28.9 ± 3.1 mmol/L to 20.3 ± 0.9 mmol/L (< 0.001) . ContinuActivity of the classical (CH50) and alternative (AP50) complement pathway was determined during stable uremia  using a haemolytic assay . For botRepresentative kidney tissue sections of a goat that was euthanized after 16 months are presented in In total, eight 4-h HD sessions were performed in one goat to treat acute-on-chronic kidney injury (three sessions in five days for gentamicin-induced AKI and five sessions in nine days prior to euthanasia). The insertion of a CVC and the dialysis sessions were uncomplicated. Mean RRs of urea, creatinine and phosphate were 67 ± 5.2%, 66 ± 5.5% and 52 ± 2.2%, respectively, and eKt/V urea was 1.1 ± 0.04 per session. The CVC’s remained patent up to one month after which they were removed because HD was no longer required.Placement of the peritoneal catheter was uncomplicated. Peritoneal membrane transport characteristics, MTAC and D/P creatinine were low , correspIn the present study, a uremic goat model was established via subtotal renal artery embolization with the induction of temporary severe acute-on-chronic kidney injury by the administration of gentamicin.Adult white goats (Capra aegagrus hircus) were selected because they are particularly suitable for the evaluation of novel HD technologies, because of their long neck, which facilitates the placement of a central venous catheter . In addiRenal artery embolization resulted in stable moderately elevated plasma concentrations of urea and creatinine without the need for maintenance dialysis. This minimally invasive procedure was characterized by a short recovery time, reducing animal discomfort compared with open surgical techniques. Gentamicin induced temporary acute-on-chronic kidney injury on demand, with near complete recovery of kidney function to pre-gentamicin levels. We observed a more severe decline in kidney function after repeated exposure to high doses or prolonged therapy. In addition, the response varied per animal, which may be due to differences in residual kidney function ,25,26. WThe primary mechanism of gentamicin-induced nephrotoxicity is tubular necrosis. The drug is excreted by glomerular filtration and partially reabsorbed by the proximal tubular cells, resulting in tubular cell damage and necrosis, followed by cellular regeneration . GlomeruIn the ideal uremic large-animal model, all three classes of uremic toxins , middle molecules (≥500 Da) and PBUTs) should be quantifiable, with plasma concentrations representative of patients with kidney disease. Gentamicin-induced acute-on-chronic kidney injury resulted in a considerable increase in plasma concentrations of small water-soluble uremic solutes  to levels comparable to plasma concentrations in ESKD patients ,31. ConsBlood pressure was not increased in our model two months after embolization. Similarly, Misra et al. found that after an initial phase of hypertension post-surgery, blood pressure had returned to baseline values after two weeks in a uremic swine model induced by renal artery embolization, sparing ~25% of total kidney tissue . PossiblPlasma bicarbonate levels were relatively high in goats as compared to humans, and could be reduced to levels representative of patients with ESKD ) by the For medical devices that are in direct contact with circulating blood, such as HD machines, testing of complement activation is recommended by the International Organization for Standardization (ISO) 10993 standard 10993 “Biological evaluation of medical devices—Part 4”  and FDA HD was successfully performed in the uremic goats. Urea reduction ratios (URR) were comparable to URR in humans  and no cThis study has several limitations. First, a single intra-arterial blood pressure measurement was performed two months after embolization to evaluate blood pressure during CKD as continuous telemetric blood pressure monitoring was not available. However, for the purpose of monitoring blood pressure during HD, we demonstrated that the placement of a temporary intra-arterial catheter in the auricular artery is technically feasible in goats . Second,In conclusion, a uremic goat model characterized by stable moderate uremia was established via subtotal renal artery embolization with the induction of temporary severe acute-on-chronic kidney injury by administration of gentamicin allowing preclinical in vivo validation of novel dialysis technologies. The extent to which gentamicin increased uremic toxin plasma concentrations varied and may depend on residual kidney function. The animals can be maintained in good clinical condition for more than ten months without the need for maintenance dialysis, with on-demand aggravation of kidney failure if required, thus limiting the use of laboratory animals.


Both were provided with nutritionist-guided recommendations, a wearable tracking device and a dietary supplement that has previously been proven to help lose body weight and lower blood pressure. In addition, one of the groups (MTBAPP) used a mobile app specifically designed for the intervention. Blood pressure, body composition, triglyceride level, peak expiratory flow, forced expiratory volume in the first second and maximum oxygen volume were measured at different time points. In addition, participants were monitored with an activity bracelet throughout the intervention. As a result, both groups significantly lost body weight, while the group using the app additionally improved blood pressure levels and lowered fat mass. Furthermore, the app users significantly increased the number of daily steps and decreased sedentary time. In conclusion, the addition of a mobile app with daily reminders to follow healthy lifestyle recommendations increased physical activity and overall improved blood pressure and fat mass levels when compared with a group performing the same intervention but in absence of the mobile application.Consumer digital technology is rapidly evolving, allowing users to manage their health in a simple, non-invasive manner. However, there are few studies revealing if using digital technology as part of an intervention really has an impact in consumer health compared with traditional strategies. The objective of the current study is to compare two groups (MTB;  High blood pressure is one of the most common disorders in the world and is also the main cause for the development of cardiovascular diseases . There aWhen an individual is first diagnosed with raised blood pressure or pre-hypertension, the first recommended strategy is to change lifestyle habits, in the form of a healthy diet and physical exercise . In the Individuals are increasingly interested in adopting preventive strategies to avoid the onset of chronic disease. Therefore, besides improving their eating habits and increasing physical activity, there is an increased consumption of natural products that can help reduce body weight and blood pressure; thus, hopefully avoiding or delaying pharmacological treatment ,7,8.At the same time, the use of digital technology in the form of consumer wearables and mobile apps is on the rise, with one in six individuals worldwide using at least one device . ConsumeWhereas wearable devices allow tracking of physical activity, the use of a mobile app can contribute to increases in activity adoption, providing support and motivation . FurtherIn this vein, the development of health-related mobile apps for personal use has increased substantially in recent years, with over 325,000 apps in the stores . The mosIt is hypothesized that the combined use of this dietary supplement, along with the nutritional and lifestyle recommendations, product intake reminders, and behavior tracking provided by the app, as well as the monitoring of activity through the wearable device, will provide a holistic approach to help users manage their health and ultimately lower their blood pressure and lose weight. Therefore, the aim of this study was to evaluate the effectiveness of a mobile application to manage user behavior and potentially improve health outcomes in prehypertensive and overweight individuals.®. Group 1 (MTB) included all the aforementioned, while group 2 (MTBAPP) also installed in their cell phones an app specifically designed for the study. The subjects were randomized following the recommendations published by Mahmoud Saghaei, 2011 [This human intervention study comprised of two groups. Both groups were provided with dietary and activity recommendations, were controlled by a nutritionist monthly, and provided with a wearable device (Fitbit Charge 2) and the dietary supplement Metabolaidei, 2011 .L. citriodora) and hibiscus flower (H. sabdariffa), called Metabolaid®. This ingredient was provided by Monteloeder SL . Details on the composition and characterization of the blend can be found in previous publications [® and 120 mg of excipient .The dietary supplement used was a combination of purified extracts of lemon verbena leaves , how many portions of fruits and vegetables, and minutes of physical activity. Water and fruits/vegetable intake was inputted manually by the user, while physical activity was collected through the Fitbit account.Educational material was included in each section . The users were recommended to participate in a weekly challenge through the app, to motivate lifestyle changes. The challenges comprised of simple tasks, such as motivating to increase their water or fruit/vegetable intake or do more exercise. The users were recommended to take 8 glasses of water, 5 pieces of fruits/vegetables, and perform 30 min of physical activity per day. In addition, a tip on how to adopt that lifestyle change in their daily life was sent daily. The users were rewarded with points when reaching the daily recommendation and for complying with the weekly challenge. These points were then presented in a chart in the app where all the users were ranked. This was performed in order to incentivize and motivate the users .2, blood pressure of 120–140 mmHg/80–90 mmHg for systolic/diastolic measurements, no chronic medication or presence of any chronic disorder, and to also possess a smartphone where the mobile app can be installed. The subjects were informed of the study details and signed a written consent. Exclusion criteria included: the presence of a chronic condition related to obesity, blood pressure, or cholesterol; use of any medication for the before-mentioned disorders; medication/supplement for weight management or cardiovascular health; frequent consumption of alcohol; and in the case of women, being pregnant or lactating. A total of 40 subjects were initially recruited, 37 of which completed the full 3-month study (Subjects were recruited in a private clinic located in the city of Elche (Spain). The study commenced in September 2020 and ended in April 2021. The inclusion criteria were: adults over 18 years of age, BMI > 25 kg/mth study .The study was divided into various phases: (1) initial evaluation; (2) follow-up at 1 and 2 months; and (3) final evaluation at 3 months. During these phases, the subjects were assessed for body weight, blood pressure, height, body composition through electrical bioimpedance ; anthropometric measurements , lung capacity by spirometry, peak expiratory flow (PEF), triglycerides, and a physical test consisting in walking 1 mile. The participants were always appointed at the same time in all the visits to ensure they were in the same conditions .The present study was carried out in agreement with the standards of the Helsinki Declaration. The Ethics Committee for Human Research of the University of Alicante (Spain) approved the clinical trial (UA-2020-04-16). The researchers maintained the confidentiality of all personal data. The study was also registered in clinicaltrials.gov (Ref: NCT04828655).A single-arm blood pressure measurement was performed in each visit using the Omron RS2 wrist blood pressure monitor. The participants were seated and asked to relax for 10 min prior to performing the measurement. Both diastolic blood pressure (DBP) and systolic blood pressure (SBP) were measured at each review.Body composition was evaluated by bioelectric impedance with a Tanita BC-730F , as it is a non-invasive, low cost, and commonly used approach for BC measurements and assessment of clinical condition . The varRegarding anthropometric measurements, the data obtained from each subject were: weight, height, waist circumference, hip circumference, mean abdominal circumference, subscapular fold, biceps fold, triceps fold, mean abdominal circumference, hip circumference, and waist circumference. The standard protocol of the International Society for the Advancement of Kynanthropometry (ISAK) was followed . Height ® Plus. The Accutrend® Plus test uses capillary serum and is based on the retention of blood cells by filtration through fiberglass when a drop of blood is applied on the reactive strip. An enzymatic reaction on the strip occurs when exposed to oxygen, giving rise to a color. The reflectance of the strip is measured at 660 nm, and triglyceride concentration is calculated using a simple algorithm. The precision of the Accutrend® Plus, as indicated by the product information, is 3.4% [Blood samples were extracted and triglycerides measured using an Accutrend is 3.4% .As previously commented , all parA Rockport 1 mile effort test was performed , which iEach subject was provided with a Fitbit Charge 2 activity tracker  for the whole duration of the study. The activity tracker allows measurement of heart rate as well as various physical activity parameters: daily steps, distance, calories burned, minutes, and intensity of physical activity, as well as sleep duration and time in different sleep phases .A diet diary (dietary record) was provided during the first and last week of the study, to perform a quantitative analysis of the diets. This method consisted of asking the subjects to write down daily during those days the food and beverages they ingested. The intake of each participant was calculated by averaging the 7 days, using the DietoPro diet program. In addition, in each of the measurements, the participants gave feedback on their sensations.®. The questions included were: (1) how much do you like the app? ; (2) how much is the app helping you to remember to take Metabolaid? ; (3) how much is the app helping you to adopt a healthy lifestyle?; (4) what do you like the most about the app?; and (5) what behaviors have you changed since using the app?In order to determine the participants’ opinions about the application, a questionnaire was designed. The objective was to know the impact of the app on their behavior. There was also a question referring to the intake of MetabolaidThe statistical analysis was performed using the JAMOVI statistics program . Descriptive statistics (mean ± standard deviation) and inference analysis were calculated using the Shapiro–Wilk test to establish that the distribution was normal. Afterward, independent t-tests were performed to compare the baseline values between groups. An analysis of co-variance (ANCOVA)  × groups (MTB-MTBAPP)) was used to analyze the effects of the intervention on the results.2) was used for the interaction time × group. An η2 ≥ 0.01 indicates a small effect, ≥0.059 indicates a medium effect, and ≥0.0138 is a large effect. For the variables that presented a significant effect, post hoc Bonferroni tests were performed. The level of significance was established at ≤0.05.The covariability used was fat mass for blood pressure, since a previous analysis demonstrated that individuals with poor eating habits were those that did not improve, or improved to a lesser degree, their fat mass. The size of the effect Eta squared (ηn = 18) and MTBAPP (n = 19). The baseline characteristics are presented in The objective of the study was to evaluate if the use of a mobile app specifically designed to be used together with a dietary supplement for weight loss and lower blood pressure can have a significant impact on an individual’s health. A total of 37 subjects participated in the research, divided into two groups: MTB (p = 0.010), which was not observed in the MTBAPP group. All other parameters remained unaltered at the end of the study. Regarding diet quality, the MTB subjects reported no changes, during the follow-ups, they commented with the nutritionist about their sensations and indicated that they had noticed a decrease in their hunger. In the MTBAPP group, both in the dietary records and in the app perception questionnaires, they generally reported a higher consumption of water, a higher consumption of vegetables and fruits, together with a decrease in the consumption of processed foods, such as industrial pastries at breakfast and sugary desserts at dinner.Diet intake was inputted by the subjects during the first and last weeks of the study . No sign® helps to lower blood pressure, however, in subjects who used the application with nutritional recommendations the reduction in blood pressure was greater, particularly diastolic blood pressure, after 90 days of intake.The results of the blood pressure analysis were compared taking into consideration the sum of both study groups (as they both took the same dietary supplement), as well as each group independently. When analyzing the two groups independently, it was revealed that the MTB group significantly reduced their systolic blood pressure (SBP) after 30 days of intake compared with baseline values, however, at days 60 and 90 their levels increased back to initial levels . As for Analyzing body weight, BMI, fat mass, and visceral fat, it was observed that both study groups decreased their body weight and subsequently BMI. Regarding body weight and BMI, the combination of the two groups revealed significant improvement starting at the first month, which was also reflected in the MTB group . The MTBAs for body fat, the combination of both study groups revealed a significant decrease in fat percentage and visceral fat, starting at 2 months of treatment. When assessing each study group independently, a significant decrease in fat percentage was detected in the MTBAPP group starting at the second month, while the MTB group did not reveal any significant change. A similar behavior was observed for visceral fat. Therefore, it can be concluded that the ingredient helps reduce body weight and fat mass, particularly visceral fat, and that the app contributed to a greater extent in reducing body fat.Regarding anthropometric measurements, significant differences were observed in both groups in abdominal measurements and skin folds . Waist, As for the skin folds, the triceps fold was significantly decreased in the pooled data and in both groups individually, being significant from the first month in the MTB group and in month 3 in the MTBAPP group. In the biceps skinfold, a similar effect was observed in the pooled data and in both groups starting at 60 days. Finally, in the subscapular skin fold, significant differences were observed in the pooled data and MTBAPP group at the third month, while the MTB group revealed significant differences starting at the second month.Therefore, regarding anthropometric measurements, the pooled data and MTBAPP group revealed significant reductions in waist and hip circumferences, while the triceps, biceps, and subscapular folds were significantly decreased in both study groups and the pooled data.No significant differences were observed in any of these tests, neither comparing initial results from final, nor between groups .The level of physical activity was measured using the data collected from the Fitbit trackers. In the case of daily steps, a tendency to increase was reported in both study groups, being significant in the MTBAPP group at 30 days, which coincided with the pooled data . HoweverTherefore, the MTBAPP group presented more activity in terms of steps and sedentary time, although a general trend of increase was detected in all groups.Regarding the questionnaire carried out by the subjects in the MTBAPP group to find out their opinion on the use of the app, a positive response was observed A–D in teWhen asked what was the feature that they liked the most, behavior tracking was the most commonly named feature both after 1 month and 3 months of the study. The daily reminders, daily tips, and ease of use were evenly mentioned as their favorite features, where the reminders increased in importance after 3 months compared with the first month.Finally, when asked what lifestyle behaviors they had changed since using the app, fruit/vegetable and water intake were the most commonly mentioned behaviors, followed by exercise. This was corroborated by the manual input of intake in the app, where these values increased progressively throughout the study, being significant starting at day 60 of treatment.The current study reveals that the use of a mobile application, as part of a weight management strategy that includes lifestyle recommendations and daily tips on how to adopt them to the user´s everyday life, can contribute to an increase in physical activity and ultimately provide significantly better results compared with non-app users following the same intervention.A recent meta-analysis  of 41 stRegarding physical activity, the MTBAPP group significantly increased their daily steps during the first month of the study with an over 14% increase at the first and second month , but dropping in the third month (yet still 9.5% higher than baseline). This was also reflected in less sedentary minutes in the app users. The MTBAPP group overall gave positive feedback regarding the usefulness of the app throughout the whole study duration, with the behavior tracking considered as the best-liked feature. In the research conducted by Liliana Laranjo et al. in 2020 , they al®. In addition to the above, Metabolaid® also helps to reduce appetite levels, thus helping consumers to control their hunger [The current study included a mobile app specifically designed to be used alongside a dietary supplement that includes the ingredient Metabolaidr hunger ,35. InfoRegarding lifestyle modifications, the app users revealed that introducing more fruits and vegetables in their diet, and increasing water intake, were the most frequently adopted changes, which was reflected in the increased intake observed in the app. Pooling together the data from both groups revealed that Metabolaid significantly reduced systolic blood pressure, while diastolic blood pressure presented a noticeable, yet not quite significant decrease. The lack of significance in the MTB group could be due to the lower number of participants compared with the other studies ,16,27,36As previously mentioned, treatment adherence is a matter of grave concern, particularly in chronic conditions ,38. The Joshua H. West et al.  observedLastly, educational material was added to the app. It has been observed that providing nutritional education with the objective of promoting lifestyle changes, through digital devices, has positive effects in both the short and long term in the treatment of chronic diseases such as diabetes , obesityOverall, the combination of these features in the app provides a more holistic approach to improve user lifestyle behavior. It reveals to the user that searching to lose weight and lower their blood pressure requires more than just taking a dietary supplement, and that lifestyle changes are necessary. This observation was demonstrated by the users’ questionnaire responses, where they reported the importance of using the app to reach their goals, as well as what features they found most useful. Taken together, having closer and more direct contact with subjects by offering them constant information on how to improve their diet, even in the form of a mobile application, can increase the success rate of adopting lifestyle behaviors.As a strength, it is possible to include the use of the app as such, since it has been seen to improve the health of the participants, improving their autonomy in the control of their eating habits and physical activity. All participants lived in the same geographical area, so the objectives, design, and environment were similar. There are some limitations to this study, firstly, the sample size and the short period of time the intervention was conducted (3 months). Future research should be aimed at improving the understanding of the time course of the effects of the intervention, both of Metabolaid intake and app use. In particular, a greater understanding is required for the timing of the peak effect size, the timing of the decline in user engagement, de-motivation, and the factors underpinning these phenomena. This may involve future studies with longer follow-up periods and with outcome measures taken at more regular and frequent time points. The relatively short-term nature of the positive effects suggests that additional efforts are required to design app features that help maintain user engagement with the app over time, for example, perhaps through modules, unlockable content, and rewards.p < 0.001) and localized fat (p < 0.005), the app users managed to lower their blood pressure (p < 0.005) and increase their level of physical activity . This provides further proof that mobile apps can be a valuable tool to help users adopt healthy lifestyle habits and improve their health.In conclusion, the study presented demonstrates that the use of a mobile application specifically designed to help users lose weight and adopt a healthy lifestyle can have a more significant impact on the subject´s health than non-app users following the same intervention. Specifically, where both study groups lost body weight (


It is of interest to evaluate the clinical characteristics, treatment patterns, clinical effectiveness, and safety of telmisartan as a monotherapy or as part of combination therapy in Indian adults (>18 years old) with hypertension. All patients werereceiving telmisartan as monotherapy, or as a combination therapy for hypertension management. Demographics, risk factors, existing comorbidity, and ongoing medical therapies were retrieved from the patients’ medical records. A total of 8607 patients withhypertension  were part of the study. The gender distribution suggested, 5534(64.3%) patients were male, and 3073 (35.7%) were female patients. The excess salt intake (39.0%) was the most common risk factor according to the results. Theanalysis revealed telmisartan dual therapy (57.9%) as the most prescribed therapy, followed by monotherapy (32.5%), and triple therapy (9.6%). Further, telmisartan 40mg (21.3%) and telmisartan 40mg plus amlodipine 5mg (17.6%) were the most commonly prescribedtherapies. The data suggested that only 17.2% of patients required dose titration. The mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) (mmHg) were significantly decreased with monotherapy (mean change: 19.8 [15.1] mmHg and 8.8[8.2] mmHg),dual therapy (mean change: 23.7 [16.6] mmHg and 10.3[8.5] mmHg), and triple therapy (mean change: 28.6 [19.0] mmHg and 12.1[10.8] mmHg) after the treatment (P<0.001). A total of 98.4% of the patients were compliant, and 97.6% achieved the target blood pressuregoal with telmisartan-based therapy. There were 157 adverse events reported altogether. The Physicians' global evaluation of efficacy and tolerability showed the majority of the patients receiving telmisartan-based therapy on a good to excellent scale. Telmisartanused as a monotherapeutic agent or as a part of combination therapy was successful and effective in reducing blood pressure and achieving the blood pressure target. Irrespective of the patient’s age, duration, and stages of hypertension, the study resulted in agood to excellent scale in efficacy and tolerability in the Indian patients having hypertension. Hypertension is one of the leading causes of the increasing global deaths due to cardiovascular diseases (CVDs) and chronic kidney diseases (CKDs)  230 millThis study was a retrospective, multicentre, observational, and real-world study conducted at 331 sites across Indian healthcare centers. Patients having medical records with diagnosed hypertension, and who were receiving telmisartan as monotherapy and/orcombination therapy for hypertension were included. The study was approved by the Independent Ethics Committee (IEC), Clinicom, Bangalore. The study procedure was in accordance with the principles of the Declaration of Helsinki,the International Conference onHarmonization Good Clinical Practices (ICH GCPs), and the applicable legislation on noninterventional studies.Patients of either sex, aged above 18 years, diagnosed with hypertension as per the American College of Cardiology (ACC) or American Heart Association (AHA) criteria (ACC/AHA guidelines 2017), and receiving treatment for hypertension with telmisartanmonotherapy and/or combination therapy, were included in this study. According to the ACC/AHA criteria, normal BP is defined as <120/<80 mmHg, elevated BP as 120-129/<80 mmHg, hypertension stage 1 as 130-139/80-89 mmHg,and hypertension stage 2 as≥140/≥90 mmHg . InvestiThe data was collected from the existing case record forms that included demographic data, lifestyle associated information,family history, treatment history, and therapy details. The demographic data was having information on age, gender,height, and weight.The lifestyle-related information included physical activity, smoking history, and alcohol consumption. The family history of hypertension, dyslipidemia, diabetes mellitus,stage or grade of hypertension, and duration of hypertension was recorded. The hypertensiontreatment history and current telmisartan therapy, dosage, and duration of telmisartan as monotherapy and/or combination therapy were also accounted for. Other crucial information, such as the current status of hypertension (controlled/uncontrolled) and anyadverse events related to telmisartan, were included in the study.Data were analyzed using Statistical Package for The Social Sciences (SPSS) software (version 23.0). Demographic characteristics included median and interquartile range (IQR) for the continuous variables and frequency and percentages for the categoricalvariables. A comparison of qualitative variables between the groups was done using the chi-square test, and the Mann-Whitney U test was used for the quantitative variables. A paired sample t-test was used for comparing the pre-and posttreatment systolic BP (SBP)and diastolic BP (DBP). A P-value less than 0.05 were considered statistically significant.A total of 8607 patients with hypertension were enrolled. The median age of the patients was 51.0 years. The number of male patients (64.3%) was higher than the number of female patients (35.7%). The majority of the patients (51.7%) were from urban locations.A total of 64.4% of the patients were diagnosed with stage II hypertension, and the remaining patients (35.6%) having stage I hypertension. The median systolic blood pressure (SBP) and diastolic blood pressure (DBP) were 155.0 mmHg and 94.0 mmHg, respectively(Table 1 - see PDF).It was observed that excess salt intake (39.0%) was the most common risk factor among the overall population. Other important risk factors were smoking (33.7%), obesity (32.9%),family history of hypertension (29.8%), sedentary lifestyle (28.6%), emotionalstress (20.7%), tobacco consumption (17.3%) and excess alcohol intake (16.5%) .The monotherapy and combination therapy of telmisartan was received by 32.5% and 67.5% of the patients, respectively. In combination therapy, dual therapy was the most commonly prescribed therapy (85.8%), whereas triple therapy was prescribed for 14.2% of thepatients only. The 65.5% of patients having monotherapy were prescribed telmisartan 40 mg dose. Other patients undergoing monotherapy, were on telmisartan 80 mg (20.1%) and telmisartan 20 mg (14.4%). In combination therapy, the majority of the patients wereprescribed telmisartan and amlodipine (39.1%). This was followed by other combinations such as telmisartan and chlorthalidone (25%),telmisartan and hydrochlorothiazide (18.7%), and telmisartan,and metoprolol succinate (17.2%). The most common treatment regime ofthe dual combination therapy was telmisartan 40 mg and amlodipine 5 mg dose (30.5%). Triple combination therapy was prescribed for 823 patients. The most commonly prescribed triple-drug combination therapy was telmisartan 40 mg,amlodipine 5 mg, and hydrochlorothiazide12.5 mg (79.3%) (Table 2 - see PDF).The median duration of the treatment was 12.0 months. The dose titration was done only for 1479 patients (17.2%). The majority of the patients (81.3%) had dosage up-titration and 18.1% of the patients had dosage down-titration during the treatment. Beforethe telmisartan-based therapy, a total of 22.4% of the patients were treated with other antihypertensive.Analysis of the patient compliance suggested that a total of 98.4% of patients were compliant, and 97.6% of patients achieved the target BP goal with telmisartan-based therapy . On the Hypertension is a growing serious health problem in India causing a significant burden on the existing health care system. Indians are prone to hypertension and related complications due to the early onset of hypertension, multiple CVD risk factors, lifestyleproblems, lack of awareness on health, treatment, and BP control . TelmisaWe have noted that the key risk factors for hypertension were excess salt intake, smoking, obesity, family history of hypertension, sedentary lifestyle, emotional stress, tobacco chewing, and excess alcohol intake. These findings were in agreement with theprevious Indian studies. According to the National Family Health Survey (NFHS) 2015-16, increasing age, obesity, overweight, male gender, urban lifestyle, and alcohol consumption were the crucial independent risk factors for Indian adults with hypertension .SimilarSeveral parameters such as the antihypertensive regimen used beforetelmisartan-based therapy; details of the concomitant medication, and time of previous visits could not be captured. Such information will have an indirect effect on the overall study results.Further, a large-scale, prospective, well-designed analysis will help to establish the efficacy and safety of telmisartan-based regimens in the Indian population.Analysis of 8607 hypertension patients suggested that telmisartan is efficacious and tolerable for BP control when used as part of monotherapy and in combination therapy for Indian patients. This is effective irrespective of age, duration, and stages ofhypertension; the therapies were tolerable by the study population with few minor adverse events.


Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly prescribed drugs to treat pain, and are easily available over the counter in lower dosages. NSAID use is associated with various side effects and elevated blood pressure is one of them. NSAIDs vary considerably in their effect on blood pressure with indomethacin being one of the NSAIDs associated with a significant increase in blood pressure. We present a case of a 58-year-old woman who developed a hypertensive crisis after a single dose of prescription indomethacin. Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used medications globally due to their easy availability, and effectiveness in resolving acute ailments like pain and fever, with a reported 29 million adults in the USA who are regular users of NSAIDs . In lighDue to the lack of reports on this topic, and to highlight the effect of NSAIDs on blood pressure, we present a case of a 58-year-old female who presented with a hypertensive crisis shortly after consuming indomethacin for her frozen shoulder. A 52-year-old female was prescribed indomethacin, 75 mg extended-release tablet for frozen shoulder. After she took the tablet of indomethacin, she developed severe blurring of vision around 1 hour later. She also complained of giddiness and had difficulty in writing as she developed tremor in hands. Her blood pressure (BP) measured immediately was 210/170 millimeter of mercury (mmHg) and the remaining vitals were within the normal range. The baseline BP of our patient was 100-110/60-70 mmHg. She had a history of migraine and was taking metoprolol for prophylaxis. She also had a past history of hepatitis B infection 33 years back. She has a family history of hypertension and diabetes mellitus in her father. She was immediately rushed for an MRI and developed a throbbing headache on the way. Her BP was measured to be 180/110 mmHg and the measurement 2 hours later was 140/90 mmHg. Similarly, BP measurement in the evening was 120/80 mmHg. She remained asymptomatic on the next day and her BP that day was 120/70 mmHg. She had not been prescribed NSAIDs or any other medications. However, she again developed a severe throbbing headache with an elevated blood pressure of 190/110 mmHg on the third day.She was monitored clinically and laboratory investigations were not performed. A CT scan of the head was done to rule out intracranial bleeding and it came out to be normal. On MRI of the head, T2-weighted images revealed subtle ill-marginated patchy high-signal-intensity areas in bilateral cerebellar hemisphere in posterior aspect involving cortical area Figure . The pat It is estimated that more than 29 million adults consume NSAIDs regularly and that 73 million prescriptions of NSAIDs are written every year ,7. In a Although indomethacin increases blood pressure in certain patients, those with pre-existing hypertension are at greatest risk ,10. IndoAseptic meningitis, psychosis, and cognitive dysfunction are the commonly reported neurologic side effects of NSAIDs ,17. Our NSAIDs are one of the most commonly used medications and the adverse effects of NSAIDs are raising concerns with the increasing use of these drugs and effect on blood pressure is one among them. The effect of NSAIDs on blood pressure is varied with a modest increase seen with most drugs and the effect is seen primarily in hypertensive patients. In our case, a normotensive patient presented with hypertensive crisis and neurologic manifestations like tremor, both of which are uncommon in the literature following the use of indomethacin, an NSAID.


The duration of hypotension and the maximal change in blood pressure were also greater in the epinephrine group. Conclusions: Perineural epinephrine for brachial plexus blockade does not reduce hypotension due to dexmedetomidine infusion and may actually augment the occurrence of hypotensive events.Background: Sedation using dexmedetomidine is frequently associated with hypotension. In contrast, epinephrine, a commonly used adjunctive agent in regional anesthesia, is a potent vasopressor. We hypothesized that perineural epinephrine used in brachial plexus blockade may reduce hypotension during dexmedetomidine infusion. Methods: Patients scheduled for upper extremity surgery were randomly allocated into a control and an epinephrine group. All patients received brachial plexus blockade, consisting of 25 mL of a 1:1 mixture of 1% lidocaine and 0.75% ropivacaine, with patients in the epinephrine group also receiving 125 μg epinephrine. Intraoperative sedation was induced using dexmedetomidine at a loading dose of 1 µg/kg and maintenance dose of 0.4 µg/kg/hr. The primary outcome was the incidence of intraoperative hypotension or hypotension in the post-anesthesia care unit (PACU). Results: One hundred and thirty patients were included (65 per group). The incidence of hypotension was significantly higher in the epinephrine than in the control group (80.6% vs. 56.9%,  Dexmedetomidine, an alpha-2 adrenergic agonist with a unique sedative effect, known as arousable sedation, is widely used in regional anesthesia due to its favorable clinical profile. Unlike other sedatives, it enables cooperative sedation while preserving respiratory drive ,2. IntraEpinephrine is another drug often used during regional anesthesia due to its vasoconstrictive effect, which may delay the systemic uptake of local anesthetic and prolong the blockade when used as an adjunctive agent for peripheral nerve blockade . Its chrBecause dexmedetomidine and epinephrine have opposing hemodynamic properties, the use of epinephrine as an adjunctive agent during peripheral nerve blockade may prevent the decrease in blood pressure caused by dexmedetomidine infusion. To date, however, no studies have assessed the hemodynamic interactions of these two agents when used together as adjuvants during regional anesthesia. The present study therefore evaluated the hemodynamic effects of perineural epinephrine during dexmedetomidine infusions in patients undergoing upper extremity surgery under a brachial plexus block.This randomized, controlled, double-blinded trial was conducted at the Chungnam National University Hospital, Korea, from May 2020 to January 2021. The study was approved by the Chungnam National University Hospital’s Institutional Review Board (CNUH 2020-03-100) and was registered prior to patient enrollment at cris.nih.go.kr KCT0004961). Study data were collected and managed using the REDCap (Research Electronic Data Capture) software hosted at Chungnam National University Hospital. The REDCap is a secure, web-based platform designed to support capturing of data for research studies . This st61. StudyPatients were evaluated for study eligibility, and written informed consent was obtained from all enrolled participants before surgery. Patients aged 20–65 years with American Society of Anesthesiologists (ASA) physical status I or II scheduled for orthopedic upper extremity surgery under regional anesthesia and sedation were recruited. Exclusion criteria included hypersensitivity to local anesthetic, epinephrine or dexmedetomidine; coagulopathy or local infection at the block site; hemodynamic instability, such as uncontrolled hypertension or tachy- or bradycardia; and patient refusal. Shoulder surgery was also excluded since it is commonly performed under general anesthesia with sitting position in our institution. Uncontrolled hypertension was defined as systolic blood pressure >160 mmHg, determined as the average of two or three available preoperative measurements.www.randomization.com, accessed on 11 May 2020). To conceal the allocation, the sequence was uploaded to REDCap , allowing access only to the researcher preparing the assigned drug for brachial plexus block. All other individuals who participated in the surgery, including the attending anesthesiologist, the patient, and the outcome assessor, were blinded to group assignment.Block randomization with sizes of 2 and 4 was performed with a random sequence generator , a high-frequency linear probe  and a nerve stimulator . The type of blockade  was determined by the attending anesthesiologist. Interscalene block was not included in the protocol since the blockade is not commonly used for upper extremity surgery other than shoulder surgery in our institution to avoid the risk of hemidiaphragmatic paralysis and ulnar sparing. When the surgical field extended to the medial side of the upper arm, an additional intercostobrachial nerve blockade was performed using 5 to 10 mL of 0.25% ropivacaine. Dexmedetomidine infusion was initiated only after confirming the onset of hypoesthesia in terminal nerve dermatomes  related to the operating field. Dexmedetomidine was infused at a loading dose of 1 µg/kg over 10 min and maintained at a dose of 0.4 µg/kg/h. Supplemental oxygen during the sedation was administered at a rate of 5 L/min via a simple facial mask. Dexmedetomidine was discontinued at the beginning of skin suture. In case of significant hemodynamic compromise such as severe bradycardia or hypotension, the infusion rate of dexmedetomidine was adjusted or small doses of vasopressors  or 0.5 mg atropine were administered. Although not prespecified, small doses of supplementary sedatives (2–3 mg midazolam or 20–30 mg propofol) or opioid (20–30 µg fentanyl) were allowed. The decision to intervene was made by the attending anesthesiologist.Except for heart rate, which was monitored continuously by pulse oximetry, all other hemodynamic variables  were measured at 5 min intervals with a non-invasive blood pressure cuff applied to the upper extremity not undergoing surgery. The primary outcome was the incidence of hypotension during and after surgery . Hypotension was defined as mean blood pressure <60 mmHg; a >25% reduction in mean blood pressure; systolic blood pressure <90 mmHg; or a >25% reduction in systolic blood pressure. The baseline hemodynamic variables were set by averaging two to three measurements obtained in the ward before arrival in the operating room.Secondary outcomes included the occurrence of bradycardia, defined as <75% of baseline and <50 beats per minute; maximum reduction of systolic, mean, and diastolic blood pressure; drug administration due to hemodynamic compromise; length of stay in the PACU; and first request for rescue analgesics.The sample size of this study was determined based on the results of a retrospective review of vital records of patients at our institution who underwent brachial plexus blockade and sedation using dexmedetomidine in 2019. The incidence of hypotension in these patients was about 30%. Based on the assumption that the incidence of hypotension in the epinephrine group would be 10%, each group should have 59 subjects to have a power of 80% and a risk of 5% for type I error. To account for potential dropouts and losses of data, this study aimed to recruit 130 subjects (65 per group).2 or Fisher’s exact (expected count < 5). A two-tailed p-value < 0.05 was considered statistically significant. Intergroup comparisons of time series data of hemodynamic variables were performed using a generalized additive mixed model with random intercept. This model included an interaction (smooth) term between time  and group as a fixed effect, and individual (smooth term) as a random effect.Results were analyzed on both an intention-to-treat (ITT) and a per-protocol (PP) basis using R software version 4.0.2 . Continuous variables were reported as the mean ± standard deviation (SD) and analyzed by independent sample t-tests or as median (interquartile range (IQR)) and analyzed by Mann-Whitney U tests, depending on the results of Shapiro-Wilk tests. Categorical variables were reported as number (%) and analyzed using χStudy eligibility was assessed in 141 patients; of these, 11 patients were excluded, and the remaining 130 patients were randomized into two groups of 65 patients each. All 130 patients were included in the ITT analysis, whereas 111 (60 in the control group and 51 in the epinephrine group) were included in the PP analysis. PP analysis was performed after excluding patients with significant deviations from the predefined study protocol. Significant deviations were determined at the analysis stage based on the following criteria: uncontrolled hypertension ; low dosage of dexmedetomidine ; supplemental opioid use; excessive use of another sedative (>30 mg propofol or >3 mg midazolam) due to patient discomfort or unexpected or uncooperative movements during the procedure; inability to use the contralateral arm for blood pressure measurements; or the use of drugs  that could affect hemodynamic parameters . The demp = 0.009). However, the difference in the PP population did not reach statistical significance (p = 0.050). Secondary outcomes are summarized in The results of the ITT and PP analyses of the primary outcome are summarized in The results of all four generalized additive mixed models for each hemodynamic variable are summarized in The results of the present suggest that the use of epinephrine as an adjunctive agent for brachial plexus blockade does not prevent hypotension induced by dexmedetomidine infusion. In fact, contrary to our hypothesis, the use of epinephrine actually increased the occurrence of hypotensive events. Because negative outcomes are associated with perioperative hypotension ,11,12,13Our primary hypothesis was based on the hemodynamic effects of epinephrine. As a widely used vasopressor, we assumed that perineural epinephrine could compensate for the hemodynamic changes caused by dexmedetomidine. Few previous studies, however, have assessed the hemodynamic effects of perineural injection of epinephrine during brachial plexus block. One such study reported that both heart rate and blood pressure increased when epinephrine was used as an adjuvant during axillary block . HoweverAlthough our results were unexpected, epinephrine has been reported to induce hypotension in both humans and rats ,16,17. TThe association of negative patient outcomes with perioperative hypotension ,11,12,13This study had several limitations. First, the infusion rate of dexmedetomidine varied among patients. Because the loading dose accounted for most of the total dose, there was no significant between-group difference in the total consumption of dexmedetomidine, measured as µg/kg. Second, other sedative and analgesic agents were administered to these patients to optimize patient comfort. Nevertheless, PP analysis found that the incidence of intraoperative hypotension was about twice as high in the epinephrine as in the control group, suggesting that the use of additional sedatives or analgesics did not alter our results. Third, hypotension was defined using both relative and absolute values, as previous studies suggested that an absolute target may not be sufficient to optimize individual blood pressure management. Thus, the incidence of hypotension may be dependent on the criteria used for its definition. Fourth, the use of vasopressor or atropine was not standardized due to the lack of a pre-specified threshold for the use of these drugs. However, since the incidence of the drug use was only 4 (6.2%) and 1 (1.5%) in the control and the epinephrine group, the effects of such non-standardized administration may not be significant.In conclusion, adjunctive use of epinephrine for brachial plexus blockade can increase the incidence of hypotension during dexmedetomidine infusion. When concurrent use is planned, a different dosing of dexmedetomidine, such as omitting the initial loading dose or slow titration, should be considered. Further research is warranted regarding the potential interactions between dexmedetomidine and epinephrine.


Arterial stiffness (AS) has emerged as a strong predictor of cardiovascular (CV) diseases. Although increased AS has been described as a predictor of atrial fibrillation (AF), its role as a risk marker for AF recurrence has not yet been elucidated.Patients with AF who underwent pulmonary vein isolation (PVI) were included in this study. Presence of AS was evaluated by measuring aortic distensibility (AD) of the descending aorta by transoesophageal echocardiography.p = 0.03) and in those who had undergone prior PVI . AD was significantly reduced in patients with AF recurrence , as well as left atrial volume index (LAVI) . Multivariable analysis revealed LAVI (odds ratio (OR) 2.9, 95% confidence interval (CI) 1.2–3.4) and AS  as independent risk factors of AF recurrence.In total, 151 patients (mean ± standard deviation (SD) age 71.9 ± 9.8 years) were enrolled and followed for a median duration of 21 months (interquartile range 15.0–31.0). During follow-up, AF recurred in 94 (62.3%) patients. AF recurrence was seen more frequently in patients with permanent AF , DRKS00019007.The online version of this article (10.1007/s12471-021-01644-w) contains supplementary material, which is available to authorized users. In this study, arterial stiffness was not only a global parameter of cardiovascular damage, but it was also independently associated with recurrent atrial fibrillation.Aortic distensibility as a proxy for arterial stiffness was significantly correlated with left atrial size.Atrial fibrillation (AF) is the most commonly sustained cardiac rhythm disturbance. The prevalence of this age-related condition is still increasing , 2. Due Several predictors of recurrent AF have been identified, such as persistent AF, left atrial (LA) size or chronic kidney disease –7. TheseSince AS provides information on the overall CV risk, as well as on subclinical organ damage, noninvasive methods for the assessment of AS are becoming increasingly important in prevention and risk stratification .Measurement of aortic distensibility (AD) as surrogate of AS, by using transoesophageal echocardiography, permits a convenient assessment, which can be easily incorporated into clinical routine of patients with AF . This meThis monocentric observational trial was conducted at the First Department of Medicine (Cardiology), University Medical Centre Mannheim in Mannheim, Germany. Patients with AF who underwent PVI were included in the study. Written informed consent was obtained from all patients. Recruitment started in June 2015 and ended in December 2017. Patients were followed prospectively. Other results of this study population have been reported previously .Baseline demographic and clinical characteristics were acquired from a questionnaire and patient charts. Exclusion criteria at the time of transoesophageal echocardiography were acute myocardial infarction or stroke (within past 30 days), indication for aortocoronary bypass operation, minimal heart rate at rest <50 bpm, need for pacemaker stimulation, hypotension with blood pressure <90/50 mm Hg or uncontrolled hypertension with systolic blood pressure ≥160 mm Hg, history of aortic dissection/aneurysm and history of aortic prosthesis.The study was conducted according to the principles of the Declaration of Helsinki and was approved by the local ethics committee, the Medical Ethics Commission II, Faculty of Medicine Mannheim, University of Heidelberg, Germany. Data were analysed anonymously. Data protection was in accordance with the European Union’s Data Protection Directive.Recurrence of AF was based on electrocardiographic evidence, including 72-hour Holter monitoring. Classification of AF was performed in accordance with the current European Society of Cardiology (ESC) guidelines for the management of atrial fibrillation , whereby2DS2-VASc score: congestive heart failure or left ventricular systolic dysfunction, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischaemic attack, vascular disease, age 65–74 years, female sex [2, LA diameter ≥43 mm, ejection fraction <50% [Prior to PVI, clinical risk scores for prediction of thromboembolism , rhythmion <50% ) and AF ion <50% ) were asTransthoracic and transoesophageal echocardiographic examinations were performed at the time of study inclusion using Vivid E9  or iE33 .Cardiac chamber size and function were assessed using standard M‑mode, 2‑dimensional (2D) and colour Doppler imaging . Left veThe descending aorta was routinely imaged at the end of each assessment. Cross-sectional systolic and diastolic aortic diameters were measured with an electrocardiogram as a guide using 2D imaging techniques . If echoAoSD aortic systolic diameter, AoDD aortic diastolic diameter, SBP systolic blood pressure, DBP diastolic blood pressure.AD was calculated using the aortic diameters and brachial blood pressures as follows :\documenTo ensure reproducibility of AD assessment, a randomly generated set of 40 transoesophageal echocardiographic scans was analysed before study enrolment by one single experienced observer (TS-M), who was blinded to the data. Intraobserver variability for AD was determined using the calculation of intraclass correlation coefficient (ICC).A diagnostic quadripolar electrode catheter  was positioned in the coronary sinus with a femoral vein approach. Transseptal catheterisation was performed, and systemic anticoagulation was achieved with intravenous heparin to maintain an activated clotting time of 250–350 s.A multipolar Lasso catheter  was placed into the left atrium to map signals at the ostial sides of the pulmonary veins. A deflectable, quadripolar 7‑Fr catheter with 2‑5-2-mm interelectrode spacing and a 4-mm distal electrode with an embedded thermistor  was inserted into the left atrium, either through the same transseptal puncture site or through a second transseptal puncture, and was used for ablation. Bipolar and unipolar electrograms were filtered at bandpass settings of 30–500 Hz and 0.05–200 Hz, respectively, and were recorded digitally .Pacing was performed from the coronary sinus or left atrium with a stimulator . Complete isolation was verified as a reduction of all signals ≤0.2 mV and by pacing manoeuvres.Recurrence of AF after PVI, based on electrocardiographic evidence, served as primary endpoint.Patients with AF were followed up for a median duration  of 21 months (15.0–31.0). Periodical follow-up was performed during routine visits in our outpatient clinic. Three months after PVI, 72-hour Holter monitoring was performed.t-test for parametric and Mann-Whitney U test for nonparametric variables. Categorical variables were compared with a χ2 test.Data are presented as mean ± standard deviation, median (IQR) or frequency (percentage). Continuous variables were compared using a two-tailed Student’s p < 0.01 in univariate analysis. There variables were: eGFR (ml/min per 1.73 m2), heart failure, treatment with amiodarone, CHA2DS2-VASc score, APPLE score, left atrial volume index (LAVI) (in ml/m2) and AD. ICC was calculated to assess intraobserver variability for AD, providing a coefficient ranging from 0 to 1 and its 95% confidence interval (CI), with an ICC close to 1 indicating high similarity.Correlation analysis was performed with univariate linear regression analysis to test associations between AD as dependent variable and several clinical characteristics. Multivariable analysis with logistic regression analysis was performed using block entry of variables with p < 0.05 was considered statistically significant. All statistical analyses were performed with Statistical 1 Package for Social Sciences  or GraphPad Prism 8.0 .For all statistical analyses, In total, 151 patients were included in the study . The patients suffered from several cardiovascular comorbidities, such as hypertension (78%), diabetes mellitus (13%), chronic kidney disease (32%), coronary artery disease (29%), heart failure (43%) and obstructive sleep apnoea (13%). Stroke or transitory ischaemic attack had occurred in 12% of the patients and 18% had a history of smoking.Concomitant medical treatment was in accordance with the 2016 ESC Guidelines for the management and treatment of atrial fibrillation ; 72% of 2DS2-VASc score was 3.0 ± 1.7, while mean APPLE score was 1.9 ± 1.2. Prior PVI had been performed in 27 patients (18%). Hundred and thirty-five patients (89%) received anticoagulant therapy, consisting of vitamin K antagonists or direct oral anticoagulants.Persistent AF was diagnosed in 59 patients (39%). Mean CHA2) were elevated and outside of the normal range [−3 mm Hg−1) compared with normal values [Most patients had a normal systolic cardiac function (LVEF 56 ± 9%); impaired LVEF (<50%) was found in 25 patients (27%). Mean LA dimensions, both LA diameter measured by M‑mode (42 ± 7 mm) and LAVI , heart failure  and a higher CHA2DS2-VASc score . Chronic kidney disease was also more common in patients with AF recurrence , with significantly lower eGFR values . The presence of CV risk factors, such as nicotine consumption or diabetes, was similar. There were no differences regarding concomitant treatment with antihypertensive drugs, statins, diabetes medication or anticoagulant therapy. In contrast, treatment with amiodarone  or digitalis  was more common in the recurrence group. AF recurred more often in patients with persistent AF  and in those who had undergone prior PVI . Patients with recurrent AF had a significantly higher APPLE score .During follow-up, AF recurred in 94 patients (62.3%). We subsequently divided the cohort into two groups: patients without or with recurrent AF. Vital parameters  were not different between the groups. Patients with recurrent AF more often had hypertension , with a higher proportion of patients with impaired LVEF in the recurrence group . LA dimensions and volumes were significantly higher in patients with recurrent AF . AD was significantly reduced in patients with AF recurrence   2.9, 95% CI 1.2–3.4) and AS  were independent risk factors for AF recurrence. The other variables failed to reach statistical significance .Variables with p = 0.005), hypertension , as well as systolic blood pressure  and pulse pressure , eGFR , heart failure  and CHA2DS2-VASc score . Coronary three-vessel disease , use of vitamin K antagonists  and LVEF  showed less strong associations. In addition, a significant inverse correlation was seen for LA dimensions  and LA volumes   were also significantly associated with recurrences of AF in our study. However, it cannot be ascertained whether increased AS is an independent risk factor for the progression of AF or a global marker of overall CV risk and end-organ dysfunction. On the other hand, AF itself could promote negative vascular changes by promoting atherosclerosis and inflammation. Therefore, we believe that both increased AS and AF could promote each other, forming a vicious circle of adverse haemodynamic, structural and functional CV changes.2 is seen in several studies [Since the LA diameter does not reflect the correct size of the left atrium, measuring LA volume is a more correct approach . For thi studies , 48. In In hypertensive patients, AS is significantly correlated with LA size , which l2DS2-VASc score and APPLE score are composed of many of these parameters, which are used to assess the risk of AF recurrence. The implementation of AD in risk stratification of patients with AF could thus provide a simplified approach to reduce these complex scoring systems to a single value. Since AS may predict the risk of AF recurrence independently of traditional risk factors and is also likely to predict overall CV risk, its implementation in clinical practice could lead to both time savings and better prediction. Compared with established factors such as LAVI, AD was not inferior.For this reason, AS could be an interesting therapeutic target to break the vicious circle and to help identify patients at higher risk. AD, in contrast to LAVI, could be an early marker because increased LAVI indicates the terminal stage of cardiac remodelling, while AS reflects an ongoing process. On the other hand, AD is not a specific parameter and is influenced by various factors. In our cohort, AD was significantly correlated with age, blood pressure, kidney function, heart failure and LA size. Scoring systems such as the CHAOur study population consisted of patients with complicated AF who were treated at a university hospital and not by a general physician, which may have led to a higher proportion of AF recurrences. On the other hand, especially in asymptomatic patients, the incidence of recurrent AF may have been underestimated. Even though Holter monitoring was performed periodically, paroxysmal episodes may not have been detected.The current study evaluated the predictive role of AS in AF recurrence. Both AS, measured as AD, and LA size were independently positively associated with AF recurrence during follow-up. In addition, AD was significantly correlated with LA size, which leads to the assumption that increased AS promotes cardiac remodelling and hence maintains AF. For this reason, the use of AD measurements may help in the evaluation of the individual risk of AF recurrence after rhythm control therapy. However, further randomised clinical trials are needed to prove whether risk prediction by evaluating AD is not only time effective but also more accurate than conventional risk stratification. Our results should be verified in a larger and less complex patient population, in order to derive a recommendation for clinical practice.Table S1 Patients’ demographics, baseline characteristics, concomitant diseases and drug treatmentTable S2 Performance of a multivariable analysis to determine variables independently associated with an increased risk of atrial fibrillation recurrence during follow-up


Background: Irreversible worsening of cardiac function is an adverse event associated with significant morbidity among patients with acute decompensated heart failure (ADHF). We aimed to develop a parsimonious model which is simple to use in clinical settings for the prediction of the risk of irreversible worsening of cardiac function.Methods: A total of 871 ADHF patients were enrolled in this study. Data for each patient were collected from the medical records. Irreversible worsening of cardiac function included cardiac death within 30-days of patient hospitalization, implantation of a left ventricular assistance device, or emergency heart transplantation. We performed LASSO regression for variable selection to derive a multivariable logistic regression model. Five candidate predictors were selected to derive the final prediction model. The prediction model was verified using C-statistics, calibration curve, and decision curve.Results: Irreversible worsening of cardiac function occurred in 7.8% of the patients. Advanced age, NYHA class, high blood urea nitrogen, hypoalbuminemia, and vasopressor use were its strongest predictors. The prediction model showed good discrimination C-statistic value, 0.866 , which indicated good identical calibration and clinical efficacy.Conclusion: In this study, we developed a prediction model and nomogram to estimate the risk of irreversible worsening of cardiac function among ADHF patients. The findings may provide a reference for clinical physicians for detection of irreversible worsening of cardiac function and enable its prompt management. Approximately 4 million people in China were estimated to have heart failure, with a prevalence of 0.4–1.3% . Some paRisk prediction models are often used to classify patients and simplify treatment decisions. They help physicians predict prognoses and interpret the results of prognostic studies to improve the level of care for inpatients with heart failure.To date, many death prediction models for ADHF have been developed and verified –7. HowevWe, therefore, aimed to develop a practical risk prediction model for irreversible worsening of cardiac function among ADHF patients.The Transparent Reporting for Individual Prognosis or Diagnosis (TRIPOD) recommendation was used as the guideline for the development and validation of the multivariable prediction model .This study was approved by the ethics committee of the Aerospace Center Hospital, Beijing, China. Written informed consent was waived owing to the use of anonymous retrospective data. Demographic, clinical, and laboratory data were retrieved from the electronic hospital database. A team of experienced clinical cardiologists reviewed and cross-checked the data. Each record was independently verified by two clinicians.A total of 1,222 patients diagnosed with ADHF who were admitted to the Aerospace Center Hospital  between January 2017 to December 2020 were recruited retrospectively. ADHF was diagnosed following the guidelines of the European Society of Cardiology .We excluded patients according to the following criteria: <18 years old, pregnant women, sudden cardiac death before admission, those who underwent surgery, reversible cardiomyopathy  .Consistent data for each patient were collected from the medical records, and all candidate predictors were selected based on a detailed literature review and clinical evidence within the confines of data availability.Demographic variables included sex, age, height, and weight values. Medical history included the presence of diabetes, hypertension, coronary artery disease, previous heart failure, atrial fibrillation, previous renal dysfunction, cerebral infarction, cancer, and cirrhosis. Clinical signs and symptoms included categorical and continuous variables as follows: New York Heart Association (NYHA) functional class, paroxysmal nocturnal dyspnea, orthopnea, heart rate, systolic blood pressure, diastolic blood pressure, rales (>1/2 lung fields), jugular venous distension, peripheral edema. Imaging results consisted of left ventricular ejection fraction (LVEF) by two-dimensional transthoracic echocardiography, and laboratory findings included evaluation of levels of B-type natriuretic peptide, troponin I, hemoglobin, C-reactive protein, alanine aminotransferase, blood urea nitrogen, creatinine, albumin, serum sodium, serum potassium, uric acid, and glucose. We recorded the baseline values of these tests, with the first value taken within 2 days of onset admission. The treatment regime included administration of aldosterone antagonists, loop diuretic, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACE-Is/ARBs), beta-blockers, anticoagulants, aspirin, ADP-P2Y12 antagonists, and/or vasopressors. Detailed and specific definitions of the variables included are listed in Irreversible worsening of cardiac function included cardiac death, implantation of a left ventricular assistance device, or emergency heart transplantation within 30-days of hospitalization.We considered the events per variables (EPV) ratio between 5 and 10 acceptable, with EPV of 10 as the optimal number to minimize the overfitting of the regression model . AccordiBefore data analysis, predictor variables were inspected for missing values. Among the predictors, the proportion of missing data was 0.34–6.2%. To include these data in the analyses, we imputed missing data through multiple imputations using chained equations of the mice package in R, in which predictive mean matching is embedded with the cases (k) = 5 as the default. Baseline clinical characteristics before and after imputations are listed in t-tests when the data were normally distributed; else, the Mann-Whitney U test was used. Proportions of categorical variables were compared using the χ2 test; the Fisher exact probability test was used when the data were limited. The statistical significance level for all tests was set as α = 0.05; P <0.05 (two-tailed) was considered statistically significant.Data were presented as frequencies (percentages) for categorical variables and as mean (standard deviation) or median (interquartile ranges [IQRs]) for continuous variables. Means for continuous variables were compared using The least absolute shrinkage and selection operator (LASSO) regression is a compression estimation used for collinearity estimates between covariates. When there are several collinear predictors, LASSO selects only one and ignores the others or zeroes out some regression coefficients. The glmnet package in R was used for LASSO regression analysis, the lambda values were selected after 10-fold-cross-validation; the larger the lambda value, the more compact was the model. Briefly, for cross-verification, the data were divided into 10 equal parts. First, the whole data were fit to generate a lambda sequence. Second, one data point was excluded each time, and the remaining nine were used for verification. The averages and standard deviations of the deviance obtained after 10 time-verification were calculated. Finally, two models were obtained as the output. One was based on lambda.min, that is, the lambda whose deviance mean was the smallest; the other was based on lambda.1se, that is, the maximum lambda corresponding to the deviance mean within one standard deviation of the minimum value.The results of the analysis were considered in conjunction with clinical evidence, sample size, and statistical ability . FinallyWe performed internal validation of the model development processes using the bootstrap resampling method (500 bootstrap samples per model) to obtain an unbiased estimate of model performance . Then thGiven the heterogeneity in sex , 20 and http://www.r-project.org; version 4.0.5).Data were analyzed using statistical packages in R  patients were male. Sixty eight patients had irreversibly worsened cardiac function, which implied that the incidence was 7.80%.P <0.05). Unlike other patients, those with irreversible worsening of cardiac function were older  +0.53645 × NYHA class +0.30738 × NYHA class = 4 +0.06832 × Blood urea nitrogen (g/L) −0.11930 × Albumin (g/L) +2.56681 × (Vasopressor = 1).The bootstrap analysis showed a good discriminative ability for the prediction model  . The calThe discrimination of the prediction model was consistent for the sex and coronary artery disease history subgroups  .The point in Based on the LASSO regression, we found four predictive risk factors for irreversible worsening of cardiac function, including NYHA class, high blood urea nitrogen, hypoalbuminemia, and use of vasopressor, in this retrospective study. Since age was an important factor affecting the prognoses of patients, this variable was also added .We took many steps to minimize the potential bias . This moThe discussion on variable screening has been an ongoing one. The analysis results, clinical reasons, sample size, and statistical power are simultaneously considered. The predictive variables in the nomogram model are convenient for clinical acquisition and thus, the construction of these models is feasible. We performed LASSO regression analysis to select variables. This parsimonious model showed sufficiently stable applicability. Sometimes machine learning algorithms are used to construct models and most of them are non-parametric. However, owing to the absence of parameters like regression coefficients, the clinical interpretation of such non-parametric models is difficult . TherefoInterestingly, although B-type natriuretic peptide is a widely recognized prognostic factor for patients with heart failure , it has Consistent with previous studies, the renal function also was an important predictor of outcomes . Serum uIn addition to these findings, some limitations exist in this study which should be addressed in the future. First, this was an observational study, and thus, we could not draw direct causal conclusions. Second, we excluded the patients with reversible cardiomyopathy and those who underwent surgery. Hence, the findings of this study cannot be extrapolated to the general population. Third, the non-linearity and interaction of variables were not analyzed. This may need to be investigated in the future. Finally, as this study was based on patients from a single center in China, there existed an inevitable sample selection bias, and external validation of the findings was lacking. As such, prospective validation to examine model stability, reproducibility, and external verification in independent samples is needed.We evaluated ADHF cardiac function in patients using the irreversible worsening prediction model. This would allow for early prediction of the patient's clinical course, and allocation of appropriate resources, including transplantation and mechanical circulation auxiliary equipment.In conclusion, an irreversible worsening of cardiac function is an adverse event associated with significant morbidity among patients with ADHF. Currently, there is no effective practical tool for estimating its occurrence likelihood. In this study, we developed a risk score-based prediction model and nomogram to estimate the risk of irreversible worsening of cardiac function among ADHF patients. The findings may provide a reference for clinical physicians to detect irreversible worsening of cardiac function and manage it promptly.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Ethics Committee of the Aerospace Center Hospital, Beijing, China. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.Y-TZ and LW made contributions to data collection, drafted the manuscript, and made contributions to the analysis and interpretation of the data. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.