According to WHO report, 1,130 million people have hypertension worldwide, and less than 20% of people with hypertension have the problem under control. Further, 25% of men and 20% of women were reported to have hypertension in 2015 .P<0.05.Blood pressure and resting heart rate were measured after 10 minutes of sitting while at rest using an autonomic blood pressure measuring device . For measuring skin health conditions, participants were asked to not use makeup prior to conducting the analysis. For the analysis, participants were instructed to wash the face with only water; the hair was tossed backward and secured using a turban after 10 minutes of natural drying. The skin condition was measured using the JANUS facial analyzing system . The facial analyzer can measure pores (%), wrinkles (%), pigmentation with ultraviolet light (%), pigmentation with polarizing light (%), sebum level , porphyrin content (%), and skin tone (%). It can analyze multiple parameters of the whole face and extract the analyzed data using a 10 megapixel Digital Single-Lens Reflex Camera. All results are presented as mean ± standard deviation. Pearson-correlation analysis was performed to determine the association between blood pressure and skin health outcomes using SPSS version 18.0 . Statistical significance was set at The characteristics of participants are shown in P=0.038). Further, wrinkles were shown to have a significant correlation with systolic blood pressure  and diastolic blood pressure . However, there were no correlations between pigmentation with ultraviolet light, pigmentation with polarizing light, sebum level, porphyrin content, and skin tone with systolic blood pressure, diastolic blood pressure, and resting heart rate.The analyses revealed that pores have a significant correlation with diastolic blood pressure (r=0.271, In conclusion, pores and wrinkles are positively correlated with blood pressure. Future studies are required to examine the effect of blood pressure on pores and wrinkles.


The frequency of likely undiagnosed hypertension was 43.4%. The adjusted logistic model for sex, smoking habits and body mass index confirmed the association between continuous measures of high BP and continuous measures of tooth loss (odds ratio (OR) = 1.05, 95% CI: 1.03–1.06, p < 0.001). Age mediated 80.0% and 87.5% of the association between periodontitis with both systolic BP (p < 0.001) and diastolic BP (p < 0.001), respectively. Therefore, hypertension and tooth loss are associated, with a consistent mediation effect of age. Frequency of undiagnosed hypertension was elevated. Age, gender, active smoking, and BMI were independently associated with raised BP.We aimed to investigate the association between blood pressure (BP) and tooth loss and the mediation effect of age. A cross-sectional study from a reference dental hospital was conducted from September 2017 to July 2020. Single measures of BP were taken via an automated sphygmomanometer device. Tooth loss was assessed through oral examination and confirmed radiographically. Severe tooth loss was defined as 10 or more teeth lost. Additional study covariates were collected via sociodemographic and medical questionnaires. A total of 10,576 patients were included. Hypertension was more prevalent in severe tooth loss patients than nonsevere tooth lost (56.1% vs. 39.3%,  Hypertension is estimated to affect 1.56 billion 1.54–1.58) people in 2025 . Further–1.58 peoTooth loss may be seen as the worst-case scenario in oral health. In 2015, 4.1% of the world population (276 million) was reported to be edentulous . OverallSeveral lines of evidence have addressed the association between tooth loss and high BP ,8,9,12. With the present study, we intend to evaluate a relationship between measurements of BP and tooth loss and the mediation effect of age, on a large cross-sectional study from a national reference dental care clinic. As a secondary aim, we investigated the prevalence of potential undiagnosed hypertension patients.Ethics approval for this research was granted by the Egas Moniz Ethics Committee (Ref: 733) and under the Declaration of Helsinki, as revised in 2013. This primary cross-sectional study was performed following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines [This study uses data from the Egas Moniz Dental Clinic (EMDC) database, a university clinic, located in the southern Lisbon Metropolitan Area, that provides dental health services to the general public . This crTo be eligible to participate in the present study, the following inclusion criteria were determined: willing to participate and have signed informed consent; had a triage appointment; had a panoramic radiograph and had carried out blood pressure measurement. The exclusion criteria were as follows: being less than 18 years old and, for women, being pregnant, considering the risk of existing gestational hypertension in this case . ®, Grandate, Italy), BP readings were carried out as a one-single measure [Using an automated sphygmomanometer device  at the Radiology Department of EMDC. Participants were categorized for tooth loss severity based on how many teeth they had lost: 10 or more—severe; lower than 10—nonsevere ,12,28.2.Additional study covariates were collected via sociodemographic and medical questionnaires. Among these covariates were gender, age and active smoking (currently smoking). The number of self-reported medical conditions was calculated as numerical (including diabetes mellitus (DM) that was confirmed using WHO criteria ). Among n). After validation of data normality and homoscedasticity, we employed the t-Student test to compare mean values according to the severity of tooth loss. Additionally, the chi-square test was used for comparison of categorical variables. To illustrate the relationship between people suffering from hypertension with tooth loss, we created a graph using scatter plots from the “ggplot2” package for R v. 4.0; to calculate the trend, we used “geom_smooth”. Multivariate logistic regression analyses were used to model the influence of potential factors in the relationship between tooth loss and hypertension. Odds ratio (OR) and 95% confidence intervals (95% CI) were calculated within the logistic regression analyses; for different adjustment levels, by using multiple linear regression analyses, we investigated the possible linear relationship between SBP and DBP and age, BMI and missing teeth. The model adjustment was made progressively by including sex, smoking habits, BMI (continuous measure) and age (continuous measure), respectively.To proceed with the analysis of the data, we used IBM SPSS Statistics v. 25.0 . Continuous variables were represented in the form of mean and standard deviation (SD), and categorical variables were represented in the form of percentage (%) and frequency/cases  exposure to mediator, (2) mediator to outcome (direct effect), and (3) exposure to outcome . The total effect was obtained through the sum of a direct effect and a mediated (indirect) effect. Percentage of the mediated effect was calculated using the formula:  × 100. A significance level of 5% was set in all inferential analyses.2, and 25.7% (n = 2722) were active smokers. Concerning BP, mean SBP and DBP were 135.3 (20.1) and 83.0 (12.3) mmHg, respectively. This sample presented an average of 5.8 (7.2) missing teeth. In addition, patients had at least one self-reported medical condition. Furthermore, 18.1% (n = 1919) reported to have hypertension and 21.1% (n = 2230) to use antihypertensive drugs. Overall, 43.2% (n = 5470) were classified as hypertensive according to BP measurements, and 43.4% (n = 3504) were categorized as hypertensive without any previous medical history of the disease or medication.From an initial sample of 11,021 participants, 445 were excluded after applying the exclusion criteria . The final sample consisted of 10,576 patients, with an average of 44.9 (17.9) years of age and being predominantly female (59.7%) . The avep < 0.001) and had higher BMI (25.5 (4.7) vs. 25.0 (4.5), p <0.001), SBP (142.1 (21.0) vs. 133.2 (19.3), p < 0.001) and DBP levels (83.5 (12.7) vs. 82.8 (12.2), p = 0.008). Furthermore, self-reported hypertension  and usage of antihypertensive drugs  were more prevalent in patients with severe tooth loss. The prevalence of hypertension at examination was found higher in severe tooth loss patients . Of those, 34.0%, 15.6% and 6.6% were diagnosed with grade 1, 2 and 3, respectively. In contrast, cases of optimal and normal blood pressure were more prevalent in patients with less than 10 teeth lost .Specifically, participants with severe tooth loss were older  the presence of hypertension (odds ratio (OR) = 1.05, 95% CI: 1.05–1.06) and grade 3 hypertension  were associated with the number of teeth lost . This beThen, multiple linear regression analyses investigated the linear relationship between SBP and DBP with age, BMI and missing teeth, according to the use of antihypertensive medications both for the overall sample  and in ap < 0.001 and β =0.91, p < 0.001, respectively) and BMI with DBP . For patients reporting not using antihypertensive medications, a significant linear relationship of age, BMI and missing teeth with SBP was observed ; however, for DBP, this relationship was only confirmed for BMI . Finally, for patients reporting antihypertensive use, both SBP and DBP were found to be significantly linear related to age and BMI.In the global sample, the obtained linear regression models confirmed that age and BMI were significantly related to SBP . Age mediated 80% the link between missing teeth with SBP . Similarly, a significant model was obtained when age was included as mediation in the association between missing teeth and DBP , with a significant mediation effect of 87.5% .There was evidence that the association between tooth loss and blood pressure (SBP and DBP) was mediated by age . A signiWith the present study, we investigated whether the components of BP were associated with the number of missing teeth. Our results demonstrate an association between office BP and tooth loss. Furthermore, the prevalence of likely undiagnosed hypertension patients was 43.4%. Then, we confirmed that these associations were significantly mediated by age as previously confirmed in other fields of research .These results may have important implications: (1) our analyses are based on a consecutive large dataset from a dental clinic and may serve as reference information for future research; (2) the increase in BP may be associated with the number of teeth lost but is consistently age dependent; (3) the high prevalence of probable undiagnosed patients, detected in this national reference dental clinic, suggests a possible role of oral care providers in the surveillance of patients with apparent hypertensive levels and to refer them to seek proper care; (4) the average SBP of this population was high, which might be explained by the elevated average BMI observed.Despite the existence of an association, DBP did not exhibit a relationship with tooth loss. It seems implausible that the existence of a direct biological mechanism could explain the difference in the association between SBP and DBP. Nevertheless, hypertension is seen as a result of high values of SBP and/or DBP, though in this specific sample, the association between hypertension and tooth loss was seen only via SBP values. Interestingly, both components are strongly age related within the association with missing teeth; however, DBP demonstrated high association with BMI, as shown previously ,31,32,33The role of tooth loss as a possible risk factor for hypertension may certainly be the result of an indirect implication of oral health, rather than a direct influence, which is highly remote from a physiological point of view. Oral diseases such as caries and periodontal disease may participate in this equation, as they are the main responsible for tooth loss . On the one hand, the mechanisms by which periodontitis is a possible risk factor for hypertension were further debated . The maiOn the other hand, the association between caries and hypertension lacks biological foundation  and may For these reasons, future studies should gather a detailed history of how the patient lost their teeth, with blood sample testing to ascertain systemic values and to obtain a more detailed report of the individual’s diet. There is already evidence that demonstrates a relationship between hypertension and tooth loss. Hitherto, the vast majority did not employ accurate methods to measure tooth loss, for instance, self-reported measures ,11,12,28Furthermore, the effects of diabetes and smoking are important to consider in the hypertension/tooth loss association. First, hypertension is consistently linked with diabetes  and smokThe frequency of undiagnosed hypertensive patients has been reported to range between 15%–50% ,52,53,54Although our investigation presents some visible strengths, it also has particular limitations. As this report is based on a cross-sectional survey, we cannot make any conclusions regarding a temporal connection or the deduction of causality between hypertension and missing teeth. Furthermore, the nonspecification of ex-smokers and the number of cigarettes in active smokers may be viewed as a limitation to bear in mind in future studies. Another limitation is the fact that our analysis builds on one BP measure, with inherent reported bias limiting the validity of these results . HoweverAnother limitation is the patients’ inability to report, precisely, the cause of tooth loss. Recent studies in this regional area, but also at a national level, have demonstrated the serious ignorance regarding oral health, its consequences and oral hygiene habits ,66,67,68Further strengths regarding this investigation include a large number of participants, the comprehensive collection regarding medical history and the systematic clinical confirmation of missing teeth through clinical and radiograph procedures. Furthermore, this study assessed the mediation effect of age on this association, which can be seen as a novel result within the available literature. According to our data, office-measured BP and tooth loss are related, and age is a key mediator in this association. The prevalence of potential undiagnosed hypertensive patients was high, indicating the role of dental hospitals in the detection and referral to proper care. Age, gender, active smoking, and BMI were independently associated with raised BP. These results suggest that BP negatively impacts tooth loss rate.


Few studies have investigated the association of apolipoprotein B (ApoB) with the progression of diabetic kidney disease (DKD) and the risk of renal replacement therapy (RRT).In this retrospective cohort study, a group of 258 DKD patients with stage 3–5chronic kidney disease(CKD)were divided into low ApoB (<1.1 g/L) and high ApoB (≥1.1 g/L) groups and followed-up for 20.51 ± 6.11 months. The association of the serum ApoB concentration with RRT was determined by Kaplan–Meier and Cox regression analysis. ApoB was measured in the serum.p < 0.001). The presence of high ApoB increased the risk of RRT. Analysis of ApoB as either a categorical (<1.1 g/L or ≥1.1 g/l) or continuous variable by univariate and multivariate regression found that ApoB was an independent risk factor of DKD progression to RRT in this group of DKD patients with stage 3–5 CKD (p < 0.05).Ninety-three of the 258 DKD patients needed RRT during follow-up. Kaplan–Meier analysis showed that patients with high ApoB were significantly more likely to progress to RRT than those with low ApoB (log-rank = 16.62, Increased ApoB was an independent predictor of progression to RRT. A larger study is needed to confirm the unfavorable prognosis of increased ApoB in DKD patients. Chronic kidney disease (CKD) leads to loss of renal function. It is a public health problem worldwide, and the estimated prevalence in adults in the Chinese population is 10.8% . The ideThis retrospective cohort study evaluated the medical records of 258 adult DKD patients with stage 3–5 CKD who were patients at the Third Affiliated Hospital of Sun Yat-Sen University between December 2010 and December 2014. The patients were followed in the outpatient renal clinic of the Sun Yat-Sen University Hospital. The study protocol was approved by the institutional review board of the Third Affiliated Hospital of Sun Yat-Sen University (code: [2013]2–75). Written informed consent for each participant was waived.2. ApoB was assayed in the serum [Patients were diagnosed following the 1999World Health Organization diabetes criteria and the estimated glomerular filtration rate (eGFR) and urinary microalbumin DKD criteria included in the NKF-KDOQI Guidelines ,22. The he serum . RRT wasThe mean patient age was 66.13 ± 11.88  years of age, 156 were men and 102 were women. The cohort was divided into 165 non-RRT and 93 RRT patients. The study endpoint was the time from baseline to RRT. The average follow-up was 20.51 ± 6.11 months. The study cohort was also divided into low ApoB (<1.1 g/L) and high ApoB (≥1.1 g/L) groups, with 1.1 g/L as the upper limit of normal. Patients < 18 years of age, with type 1 diabetes, a history of donating or receiving a kidney, primary kidney disease, full or partial loss of a kidney, diabetic ketosis, hyperosmolar coma, fever, heart failure, infection, secondary hypertension, or severe hypohepatia were excluded from the analysis. The pathogenesis and factors affecting the progression of type 1 diabetes and primary kidney disease are different from those of type 2diabetes, so they are not included in our study. Patient variables retrieved from their electronic medical records included sex, age, race, and medical history. Laboratory values included hemoglobin, phosphate, cholesterol, triglycerides potassium, albumin, urinary albumin-to-creatinine ratio (UACR) and eGFR, and other the specific lab values. Physiological data included DKD-associated complications and comorbid diseases including diabetic retinopathy, hypertension history, and cardiovascular disease.p-values <0.05 were considered statistically significant.Statistical analysis was performed with SPSS 20.0 . Normally distributed data were reported as means ± standard deviation. Continuous variables with a normal distribution were reported as medians and interquartile range, and the significance of differences was determined by the Kolmogorov–Smirnov test. Categorical variables were reported as numbers and percentages. Continuous variables that were not normally distributed were analyzed with the Kruskal–Wallis rank-sum test. Categorical variables, including differences between the low ApoB and high ApoB groups, were analyzed with the chi-squared test. Cumulative risk of need for RRT was estimated by the Kaplan–Meier method. The significance of the association between ApoB and RRT was analyzed in univariate and multivariate Cox regression models with patient variables as covariates in high and low ApoB patients separately and also in models considering ApoB as a continuous variable. Differences with The characteristics and clinical data of the 258 patients are summarized in p < 0.001). Kaplan–Meier analysis found that patients with high ApoB were significantly more likely to progress to RRT than those with low ApoB . Model 1was corrected for gender, age, BMI, smoking history, history of hypertension, cardiovascular disease, retinopathy . Model 2 was corrected for, HGB, HbA1c, ALB, Ca, P, FBS, BUN, CYC, UA, TC, TG, HDL, LDL, ApoA, lysophosphatidic acid (LPA), UACR, and eGFR in addition to Model 1 . Model 3 was corrected for Model 2 variables plus diuretics and lipid-lowering drugs . The adjusted HRs were 2.157  for Model 1, 3.161  for Model 2, and 3.161 for Model 3.Ninety-three of the 258 patients (36%) required RRT during a mean follow-up of 20.51 ± 6.11 months, 54 (58%) in the high ApoB group and 39 (42%) in the low ApoB group  and a continuous variable, was a risk factor of DKD progression. An increase of serum ApoB was an independent predictor of DKD progression to RRT in this study group within 2 years of follow-up, and patients with high baseline ApoB had a higher risk of RRT than those with low baseline ApoB.DKD is a chronic microangiopathy of diabetes. The primary causes are renal arteriosclerosis, glomerular sclerosis caused by arteriolonephrosclerosis, and renal microvascular lesions. The impairment of renal function results from the effects of dyslipidemia on vascular mesangial and renal tubular cells . Lipid-lIn conclusion, increasing ApoB has until now not been correlated with the progression of CKD. In this study, increased and increasing ApoB were found to be independently associated with progression of CKD in diabetes patients until RRT was needed. The increase of ApoB had an unfavorable prognosis. The study was limited by its small patient enrollment. Although the relationship between ApoB concentration and progression to RRT remained strong after adjusting for relevant covariates in multivariate analysis, residual confounding and variables that were not evaluated may have contributed to this finding. Large-scale clinical confirmation is needed.


An integrated study on the effect of renal diet on mineral metabolism, fibroblast growth factor 23 (FGF-23), total antioxidant capacity, and inflammatory markers has not been performed previously. In this study, we evaluated the effects of renal diet on mineral metabolism, oxidative stress and inflammation in dogs with stage 3 or 4 of chronic kidney disease (CKD). Body condition score (BCS), muscle condition score (MCS), serum biochemical profile, ionized calcium (i-Ca), total calcium (t-Ca), phosphorus (P), urea, creatinine, parathyroid hormone (PTH), FGF-23, interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-α) and total antioxidant capacity (TAC) were measured at baseline (T0) and after 6 months of dietary treatment (T6). Serum urea, P, t-Ca, i-Ca, PTH, FGF-23, IL-6, IL-10, TNF-α and TAC measurements did not differ between T0 and T6. Serum creatinine (SCr) was increased at T6 and serum PTH concentrations were positively correlated with serum SCr and urea. i-Ca was negatively correlated with urea and serum phosphorus was positively correlated with FGF-23. Urea and creatinine were positively correlated. The combination of renal diet and support treatment over 6 months in dogs with CKD stage 3 or 4 was effective in controlling uremia, acid–base balance, blood pressure, total antioxidant capacity, and inflammatory cytokine levels and in maintaining BCS and MCS. Chronic kidney disease (CKD) is considered the most common renal disease in dogs . Through2 blockers (ranitidine) every 8 or 12 h and sodium bicarbonate according to blood gas results. Two animals required 0.5–1 mg/kg BW appetite stimulants (cyproheptadine hydrochloride) every 12 h, and five animals were treated with 30–60 mg/kg BW/day phosphorus binder . One animal had an episode of acute decompensation of CKD and received medical treatment. Dogs were also closely monitored to detect dehydration and no parenteral fluid administration was needed, excepted for that dog that had acute renal dysfunction. Free access of tap water was assured.Ten client-owned dogs were enrolled with a mean ± SD body weight of 16.33 ±14.64 kg, a mean age of 8.89 ± 4.46 years, various breeds and seven out of 10 were females and three of them were sterilized. Diagnosis of CKD was based on persistent azotemia over 3 months as well as imaging (ultrasound) findings of chronic kidney abnormalities. CKD classification was according to IRIS and 80% of CKD dogs were in stage 3 at T0 . All anip = 0.045). However, BCS (T0: 5.70 ± 0.67 versus T6: 5.30 ± 1.05) and MCS (T0: 2.20 ± 0.42 versus T6: 2.40 ± 0.51) showed no significant differences  between T0 and T6.A reduction in body weight was observed between T0 (16.34 ± 14.64 kg) and T6 . No differences in urine specific gravity (USG) were found between the two time points, showing isosthenuria at both times (p = 0.384)  . Proteinp = 0.853) between T0 and T6 (138.4 ± 5.49 mmHg) (Systolic blood pressure was within the reference range  and show49 mmHg) .p = 0.704) and blood bicarbonate concentration (p = 0.072) showed no differences between the two time points and were within the reference range (Blood pH (ce range .p = 0.0350). Sodium , potassium , alanine aminotransferase (ALT)  and alkaline phosphatase (ALP)  were within the reference ranges at both time points. Moreover, serum total protein  and albumin  did not differ between T0 and T6 . The packed cell volume (PCV) showed a decrease between T0 (35.3 ± 6.83%) and T6  and was below reference values at both points (RI 37–55%). Notably, serum creatinine (SCr) was increased at T6  and serum cholesterol were slightly elevated at T0 and T6 , but only cholesterol was significantly different between assessment periods  and urea , and i-Ca had a negative correlation with urea . Urea and SCr were positively correlated , and FGF-23 was positively correlated with phosphorus .PTH concentration was positively correlated with creatinine , interleukin 10 (IL-10), and tumor necrosis factor alpha (TNF-α) and TAC showed no difference between T0 and T6  analysis, as well as different treatments that had to be initiated to control clinical and laboratory alterations. The best delineation would be the inclusion of a group of animals with CKD fed with a maintenance diet. However, the use of a maintenance diet in this situation may reduce the life expectancy of the dogs included in the control group. In advanced stages of CKD, finding animals with stable renal function and no appetite changes is difficult.In conclusion, feeding dogs with advanced CKD with a renal diet for 6 months in combination with support treatment was effective in controlling uremia, acid–base balance, blood pressure, antioxidant capacity, and production of inflammatory cytokines, as well as in the maintenance of BCS and MCS. Further studies are needed to better explore how a renal diet can improve the quality of life in CKD dogs.This study was conducted at the Veterinary Hospital of the School of Veterinary Medicine and Animal Science of the University of São Paulo (FMVZ/USP), São Paulo—SP, Brazil and approved by the Ethics Committee of the Veterinary Medicine and Animal Science School of the University of São Paulo (FMVZ/USP) on 4 September 2013, protocol number 3138/2013. The research was a prospective, 6-month longitudinal dietary trial utilizing a before (T0) and after (T6) design. Ten client-owned dogs with CKD at stage 3 or 4  were incNutritional contents of the diet were balanced and met all requirements for the maintenance of adult dogs ,63; howe® Model 811-B, Oregon, United States). Blood pressure was evaluated before any clinical examination or sample collection was performed. Six measurements were performed at each time point, and the mean value was recorded. The BCS was determined according to a nine-point scale . For analysis of PTH, FGF-23, cytokines and TAC, blood samples were collected and immediately placed on ice and centrifuged at 4 °C later. Serum aliquots of 1 mL were stored at −80 °C. Urine samples were obtained by cystocentesis for urinalysis , USG (by refractometry method), urine culture and sediment microscopic examination. Blood pH and bicarbonate measurements were performed using a blood gas analyzer —b; blood2+ is reduced to Cu+, and the resulting Cu+ forms colorful complexes. The color intensity at 570 nm is proportional to the amount of TAC in the sample, and the antioxidant concentrations were expressed in μm Trolox equivalents. FGF-23 was analyzed with a human-specific FGF-23 ELISA , the values at T0 and T6 were used for the statistical analyses. The data are expressed as the mean ± SD.Statistical analyses were performed using statistical software—Statistical Analysis System (SAS) —h (Stati


What are the mechanisms, risk factors, and outcomes associated with acute kidney injury (AKI) during pediatric diabetic ketoacidosis (DKA)?In this cohort study using data from 1359 DKA episodes in a large, multicenter, prospective study of fluid treatment during DKA, AKI occurred in 43% of episodes and was associated with greater acidosis and greater circulatory volume depletion. Children who had AKI were more likely to have subtle cognitive impairment during DKA and lower IQ at longer-term follow-up.These findings suggest that AKI is frequent in pediatric DKA and there is a pattern of multiorgan dysfunction during childhood DKA with the possibility of common pathophysiologic mechanisms. This cohort study examines the mechanisms, risk factors, and outcomes associated with acute kidney injury during pediatric diabetic ketoacidosis. Acute kidney injury (AKI) occurs commonly during diabetic ketoacidosis (DKA) in children, but the underlying mechanisms and associations are unclear.To investigate risk factors for AKI and its association with neurocognitive outcomes in pediatric DKA.This cohort study was a secondary analysis of data from the Pediatric Emergency Care Applied Research Network Fluid Therapies Under Investigation in DKA Study, a prospective, multicenter, randomized clinical trial comparing fluid protocols for pediatric DKA in 13 US hospitals. Included DKA episodes occurred among children age younger than 18 years with blood glucose 300 mg/dL or greater and venous pH less than 7.25 or serum bicarbonate level less than 15 mEq/L.DKA requiring intravenous insulin therapy.AKI occurrence and stage were assessed using serum creatinine measurements using Kidney Disease: Improving Global Outcomes criteria. DKA episodes with and without AKI were compared using univariable and multivariable methods, exploring associated factors.P = .03), higher initial serum urea nitrogen , higher heart rate , higher glucose-corrected sodium  and glucose concentrations , and lower pH  as variables associated with AKI. Children with AKI, compared with those without, had lower scores on tests of short-term memory during DKA  and lower mean (SD) IQ scores 3 to 6 months after recovery from DKA . Differences persisted after adjusting for DKA severity and demographic factors, including socioeconomic status.Among 1359 DKA episodes , AKI occurred in 584 episodes . A total of 252 AKI events  were stage 2 or 3. Multivariable analyses identified older age (adjusted odds ratio [AOR] per 1 year, 1.05; 95% CI, 1.00-1.09; These findings suggest that AKI may occur more frequently in children with greater acidosis and circulatory volume depletion during DKA and may be part of a pattern of multiple organ injury involving the kidneys and brain. In that study,10 AKI was reported to be more common in children with low serum bicarbonate levels, tachycardia, and hypernatremia, suggesting that severe dehydration and acidosis may play roles in triggering kidney injury. These risk factors are similar to those associated with cerebral injury during DKA,13 raising the question of whether factors associated with DKA severity are independently associated with increased risk of injury to multiple organs, or whether kidney and cerebral injuries during DKA might involve a single pathophysiological process. Isolated cases of severe multiple organ dysfunction syndrome during DKA have been reported14; however, a pathophysiological connection between DKA-related kidney injury and injury to the brain or other organs has not previously been established, to our knowledge.One recent study demonstrated that acute kidney injury (AKI) commonly occurs in children with DKA. In a 2017 retrospective cohort study of 165 children with DKA,15 Furthermore, in other childhood diseases, AKI is associated with increased risk of chronic kidney disease in adulthood, particularly when repeated episodes occur.17 Therefore, additional study of AKI during DKA is important to better understand how to prevent AKI during DKA and to consider possible associations with chronic diabetic kidney disease. In this cohort study, we evaluated the frequency of and factors associated with AKI using data from a large, prospective study of pediatric DKA. We hypothesized that subtle kidney injuries occur commonly in children during DKA and may be associated with cerebral injury.Long-term cognitive changes after DKA support the possibility that acute organ injury in DKA could lead to chronic organ dysfunction.18 The PECARN FLUID trial involved 13 emergency departments in PECARN and was approved by the institutional review boards of participating institutions, and informed assent was obtained for all patients. Our planned secondary analysis was included in approval and assent. The PECARN FLUID trial included patients younger than 18 years with episodes of DKA . We determined the presence of AKI during DKA in all episodes with height and creatinine data available. This study is reported following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.This cohort study was a secondary analysis of a multicenter prospective study comparing effects of fluid infusion rate and sodium content on neurocognitive outcomes in children with DKA, the Pediatric Emergency Care Applied Research Network (PECARN) Fluid Therapies Under Investigation in DKA (FLUID) trial.18 Exclusion criteria are described elsewhere19 and included conditions unrelated to DKA that affect mental status or cognition or substantial treatment for DKA before evaluation. Mental status during DKA was assessed hourly using Glasgow Coma Scale (GCS) scores, and short-term memory  was assessed every 4 hours during waking hours. Children 3 years and older returned for neurocognitive testing 2 to 6 months after the DKA episode, as described previously.19 This assessment included evaluation of long-term memory, IQ , and short-term memory .22The PECARN FLUID Trial compared 4 fluid rehydration protocols.23 Baseline creatinine values were not available for most episodes, and most previous creatinine values in medical records were measured during illnesses. We therefore used an estimated glomerular filtration rate (eGFR) of 120 mL/min/1.73 m2 to calculate expected baseline creatinine levels for all DKA episodes using the Schwartz estimating equation.26 An eGFR of 120 mL/min/1.73 m2 was chosen for consistency with other studies of pediatric AKI25; however, we conducted sensitivity analyses using eGFRs of 90 mL/min/1.73 m2 and 110 mL/min/1.73 m2.26 For AKI stages 1, 2, and 3, we used Kidney Disease: Improving Global Outcomes creatinine cutoffs of 1.5-, 2-, and 3-fold estimated baseline creatinine, respectively.23 The maximum serum creatinine measured was used to define AKI. The first serum creatinine measured prior to initiation of DKA treatment was used to determine AKI at presentation.Episodes of AKI were defined by the Kidney Disease: Improving Global Outcomes serum creatinine criteria.z-scores,28 indicating the number of SDs a measurement differed from the mean for age and sex. Blood pressure z-scores were additionally adjusted for height. Concomitant medications were reviewed to identify medications with potential nephrotoxic effects . Clinically apparent cerebral injury was defined by a deterioration in neurological status leading to hyperosmolar therapy or endotracheal intubation or resulting in death.29Percentage dehydration was defined as the percentage difference between weight at presentation and discharge. Corrected sodium was defined as the serum sodium concentration (mEq/L) plus a factor derived using blood glucose (mg/dL) measured within 30 minutes (1.6 × [(Glucose − 100) / 100]). Heart rate and blood pressure were standardized as The primary analyses investigated factors associated with AKI during DKA using univariable comparisons and multivariable models. In secondary analyses, we investigated factors associated with AKI in specific patient subgroups, including those with previously diagnosed diabetes and patients for whom information was available on dehydration severity. Additional secondary analyses included sensitivity analyses varying the assumptions used to estimate baseline creatinine concentrations, and analyses exploring likelihood of AKI in repetitive DKA episodes among patients enrolled in the study with 2 episodes .We described DKA episodes with and without AKI using means and SDs for continuous characteristics and frequencies and percentages for categorical characteristics. We compared AKI to non-AKI groups using logistic regression models. Diabetes duration and previous DKA diagnoses were compared for patients with previously diagnosed diabetes. To account for delays in result reporting, AKI was considered prior to treatment if laboratory criteria were met within 2 hours of treatment initiation, if there were no results prior.co2, pH). Baseline heart rate z-score was included as an indicator of intravascular volume. Blood pressure was not included because blood pressure is often paradoxically elevated in children with DKA and is not a good indicator of intravascular volume.30 Diabetes duration and previous DKA episodes were not included because these data apply only to patients with previously diagnosed diabetes. The final model did not include dehydration severity owing to frequent missing data. Multivariable models were used for analyses of subgroups. Associations between AKI in initial and subsequent DKA episodes were analyzed using univariable and multivariable logistic regression adjusting for age, sex, and DKA severity (assessed by baseline serum bicarbonate) at the second enrollment.We used a multivariable logistic regression model to estimate adjusted associations of demographic, clinical, and biochemical factors with AKI. The model included covariate adjustments for age, sex, and new-onset vs previously diagnosed diabetes. Baseline laboratory measurements were included as indicators associated with DKA severity  to compare GCS declines  between AKI groups. We used a cumulative logistic model to evaluate differences in the magnitude of GCS declines between groups, adjusting for the same covariates. We tested for an association between AKI and clinically-apparent cerebral injury using a χA significance level of .05 was used for all statistical tests. We did not adjust significance levels for multiple tests; therefore, analyses of secondary outcomes should be considered exploratory. Analyses were performed using SAS statistical software version 9.4 (SAS Institute) from July to December 2019, with verification of results occurring as recently as October 2020.Of 1389 DKA episodes in the PECARN FLUID trial, 1359 were included in this analysis. A total of 30 DKA episodes (2.2%) with missing data were excluded, including 28 missing patient height and 2 missing creatinine level . The meaP < .001), and children with AKI were older than those without . Children with AKI were more acidotic and had higher initial glucose and sodium concentrations than those without AKI, and Pco2 levels in children with AKI were higher than those without AKI, although respiratory rates were also higher in the AKI group , higher initial SUN , higher heart rate , higher glucose-corrected sodium  and higher glucose concentrations , and lower pH  were associated with higher risk of AKI (2 or 110 mL/min/1.73 m2) found lower estimated AKI frequencies ; however, SUN, pH, glucose and heart rate continued to be significantly associated with AKI in all analyses  were repeat enrollments of patients presenting with more than 1 episode. When we compared AKI status at the first and second enrollments, the odds of AKI were 6.8-fold higher when the patient experienced AKI at the prior enrollment . After adjusting for illness severity and demographic factors , the AOR of AKI was even higher when the patient experienced AKI at the prior enrollment .P = .41). However, short-term memory scores during DKA were significantly lower in patients who experienced DKA episodes with AKI compared with those who did not  (P < .001). Additionally, patients who had AKI, compared with those without, had lower IQ scores after recovery  (P = .005) , and of 559 DKA episodes with AKI, GCS scores decreased below 14 in 33 episodes (5.9%), but these differences were not significant in multivariable analysis (P = .02) . In 11 D = .005) . These d = .005) .13 Of note, children with AKI had higher frequencies of subtle cognitive impairment during DKA, and deficits in IQ were evident in children with AKI after DKA recovery compared with children without AKI. Importantly, IQ differences between children with and without AKI persisted after adjusting for DKA severity and demographic factors. Although the observed IQ differences were subtle, cognitive deficits associated with DKA may become greater over time.1 Therefore, detection of any deficits in cognition shortly after DKA recovery is of concern. Our data suggest that AKI during DKA may occur as part of a pattern of multiple organ injury involving both kidneys and brain.The results of this cohort study agree with previous findings that AKI is common in children with DKA and that nearly half of children with AKI had severe AKI (stage 2 or 3), suggesting intrinsic tubular injury beyond prerenal azotemia. This cohort study found that AKI was associated with greater acidosis and circulatory volume depletion, similar to associations with cerebral injury during DKA.10 This difference might reflect differences in cohort inclusion between the studies, particularly more severe DKA  in the retrospective group compared with our prospective cohort. Regardless, both studies confirm a high frequency of AKI during pediatric DKA.The rate of AKI in our study was lower than the rate of 64.2% found in a smaller, retrospective single-center study by Hursh et al.31 Similar to cerebral injury during DKA, AKI can develop as late as 12 to 24 hours after initiating DKA treatment. The development or worsening of AKI during treatment, when hydration status should be improving, suggests that some AKI in DKA may not result from prerenal mechanisms.Most patients with AKI presented with AKI prior to DKA treatment; however, 4% of patients presented with normal kidney function and developed AKI during DKA treatment, and 3% of patients had worsening of AKI during treatment. A similar frequency of progression of AKI during DKA treatment was also found in a small clinical trial by Williams et al.10 More importantly, we found an association between AKI and signs of cerebral injury, both during DKA treatment  and several months later (lower IQ scores). To our knowledge, these data are the first to demonstrate this association during DKA in children. Although occurrence of hypotension in children with DKA might explain concurrent AKI and cerebral injury, previous analyses of the study database demonstrated that hypotension occurred rarely (0.2% of patients at presentation and 3.3% of patients during DKA treatment); therefore, hypotension is unlikely to be involved.30 Furthermore, the association between AKI and cerebral injury persisted after adjusting for multiple aspects of DKA severity, suggesting that concurrent kidney and cerebral injury were associated with a common process and not simply reflections of a higher risk of injury to both organs in children with more severe DKA.Our analyses indicate that AKI was associated with more severe acidosis and dehydration  similar to the study by Hursh et al.9 Decreased kidney perfusion likely contributes to AKI in DKA; however, evidence of cerebral inflammatory injury,7 and the association of AKI with cognitive dysfunction, raises the possibility of more diffuse inflammatory organ injuries, a physiological process that has not been studied in DKA, to our knowledge. Interestingly, in animal models, diabetes worsens kidney injury from ischemic events, and inflammatory mechanisms have been proposed to explain this association.32 Basal vacuolization of kidney tubular epithelial cells is a marker of ketoacidosis on autopsy, suggesting direct kidney injury in severe DKA.33 In addition, early diabetic kidney disease involves interstitial inflammation, including mononuclear cell invasion.34 These findings suggest a possible mechanism connecting acute and chronic kidney disease.34 Interestingly, among patients who enrolled in the study twice, AKI during the first DKA episode was significantly associated with the risk of occurrence of AKI during the second episode. These associations persisted after adjusting for severity of acidosis and demographic factors, suggesting either that AKI reflects specific inflammatory responses to DKA that vary among individuals or that prior episodes of AKI increase the susceptibility of the kidneys to further injury. Evaluation of factors associated with risk of AKI during DKA should be considered given these possible novel mechanisms.The cause of organ injuries in children with DKA is still poorly understood. Cerebral injury has been the most extensively studied. Although cerebral injury was previously assumed to be caused by osmotic shifts resulting from extreme hyperglycemia and rapid rehydration, recent data suggest that other mechanisms are more likely, including hypoperfusion and reperfusion injury, and damage resulting from inflammatory mechanisms.2 to be consistent with other pediatric AKI studies25; however, lower values have also been used. Sensitivity analyses using 110 mL/min/1.73 m2 and 90 mL/min/1.73 m2 yielded lower estimates of AKI frequency; however, clinical and biochemical associations were similar in all analyses. In addition, the frequency of clinically apparent cerebral injury in DKA is low and we relied on mental status and cognition as indicators of subtle cerebral injury. The extent to which subtle cognitive alterations during DKA were associated with more overt cerebral injury is unverified; however, the detection of deficits in IQ after recovery provides more convincing evidence of associations between AKI and cerebral injury. Additionally, use of potentially nephrotoxic medications prior to hospitalization was incompletely recorded; however, use of these medications in children with diabetes is uncommon. Furthermore, whether DKA influences development of chronic diabetic kidney disease is unknown. Data on urine microalbumin levels before and after DKA were not recorded, and periods longer than 2 to 6 months would likely be necessary to detect effects of DKA on chronic kidney disease.This study has some limitations. The timing of blood sample collection varied among sites, and creatinine level frequently was not measured after acidosis resolved. Therefore, some AKI episodes may have been missed or may have occurred earlier. In addition, baseline creatinine measurements were not available for most patients and were therefore estimated. The ideal eGFR to determine baseline creatinine is controversial. We used an eGFR of 120 mL/min/1.73 mThis cohort study of AKI during DKA using data from a large, multicenter, prospective study suggests new hypotheses around the development of kidney injury, and organ injuries in general, during DKA. Future investigations should focus on mechanisms associated with concurrent injury to the kidneys and brain. In addition, associations between AKI and long-term kidney dysfunction, including risk of chronic diabetic kidney disease, should be further investigated. More clearly defining the mechanisms of kidney injury resulting from DKA could have important implications for the development of new therapeutic and preventive strategies.


After adjustment by EPTS  the association remained significant for medium hazards ratios (HR) 3.24 95%CI (1.2–8.8), p = 0.021 and high risk tertiles HR 4.3 95%CI (1.65–11.54), p = 0.003. GDF-15 improved the prognostic accuracy of EPTS at 1-year  and 3-year mortality . Our study suggests an independent association between higher GDF-15 levels and mortality after kidney transplant, adding accuracy to the EPTS score, an established risk prediction model currently used in kidney transplant candidates.Kidney transplantation implies a significant improvement in patient survival. Nevertheless, early mortality after transplant remains high. Growth differentiation factor 15 (GDF-15) is a novel biomarker under study as a mortality predictor in multiple scenarios. The aim of this study is to assess the utility of GDF-15 to predict survival in kidney transplant candidates. For this purpose, 395 kidney transplant recipients with pretransplant stored serum samples were included. The median GDF-15 was 5331.3 (50.49–16242.3) pg/mL. After a mean of 90.6 ± 41.5 months of follow-up, 82 (20.8%) patients died. Patients with higher GDF-15 levels (high risk tertile) had a doubled risk of mortality after adjustment by clinical characteristics ( Growth differentiation factor 15 (GDF-15) is a stress-responsive member of transforming growth factor β (TGF-β) cytokine superfamily. This pleiotropic protein has been linked to inflammation, metabolism, and oncogenesis regulation. Poorly expressed in healthy individuals, this molecule is upregulated in many pathological conditions such as following injury, ischemia, and other forms of oxidative and/or metabolic stress, raising interest in its potential utility as a biomarker in human disorders ,3. Several studies have demonstrated the connection between increased circulating GDF-15 concentrations and the development of cardiovascular pathologies. In patients with heart failure, GDF-15 has added value beyond the traditional risk factors that predict all-cause and vascular mortality ,4. IncreAlthough not so extensively studied, GDF-15 may be related to cancer diagnosis and tumor progression. Its relation with angiogenesis, proliferation, apoptosis, and growth remodeling support this idea. Elevated expression of GDF-15 has been demonstrated in different types of cancer including breast, colorectal, prostate, and head and neck, among others ,14,15,16Regarding nephrology, increased GDF-15 levels have been associated with higher risk of incident chronic kidney disease and more rapid decline in kidney function in different renal disorders, including diabetic nephropathy, IgA nephropathy, and primary membranous nephropathy ,18,19,20Cardiovascular disease is the most common cause of death in transplant recipients, followed by infections and cancer ,33. The We analyzed all adult renal transplants performed in our center from 2005 to 2015. As routine clinical practice in our hospital since 1985, serum samples were collected pretransplant and cold stored. Only pretransplant samples with at least 150 microliters available for GDF-15 testing were included in our study. The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the hospital’s Ethics Committee.The concentration of GDF-15 was analyzed using an enzyme-linked immunosorbent assay . All samples with an elevated level were diluted to provide quantitative results. We performed duplicate measurements for each sample with good repeatability. In this study, GDF-15 was analyzed as a continuous variable after log transformation  and as categorical, dividing our cohort in GDF-15 tertiles. Relevant information about recipient, donor, and transplant characteristics was extracted from the prospectively maintained database of renal transplant patients in our center. Clinical characteristics obtained from the medical records included age, sex, race, cause of CKD, dialysis, number of transplants, and history of other solid organ transplants, among others. Regarding CV events, we included coronary artery disease (based on imaging confirmation) and clinically significant  peripheral arteriopathy. Diagnosis of pretransplant diabetes was considered if the patient required hypoglycemic treatment prior transplant.https://optn.transplant.hrsa.gov/resources/allocation-calculators/epts-calculator/.Estimated Post Transplant Survival (EPTS) score was calculated in all first renal transplant recipients included in our study. The factors needed in the formula  were extracted from our database and calculated in the official webpage: Continuous variables were expressed as mean ± standard deviation or median with interquartile range (IQR) if not normally distributed. Categorical variables were described as relative frequencies. Univariate and multivariate logistic regression was performed to determine which clinical variables were associated with higher levels of GDF-15 in our population.p value of less than 5% was reported as statistically significant. Receiver operating characteristic (ROC) curves and area under the curve (AUC) were obtained to compare the predicted probability of logistic regression models using GDF-15, EPTS, and the combination of both to predict mortality 1, 3, and 5 years post-transplant. For our analysis, we used SPSS, version 22.0  and MedCalc® Statistical Software version 19.6 .The primary outcome of our study was all-cause mortality. Cox proportional hazards regression was used to test the association of GDF-15 (log GDF-15 and tertiles) with mortality. Covariates for adjustment were selected a priori based on previous literature. Statistically significant variables related to mortality in the univariate model were included in the multivariate Cox regression analysis. Hazards ratios (HR) were reported with 95% confidence intervals (CI 95%). A n = 76), the median peak PRA was 65% (IQR 36.7–93.3). The immunosuppression was based on anticalcineurin inhibitors (91.4%), mTOR inhibitors (4.6%), mycophenolate or azathioprine (93.9%), and prednisone (93.4%). Two hundred and seventy-five patients (69.6%) did not receive induction therapy, whereas 18 (4.6%) received basiliximab, and 100 (25.4%) received thymoglobulin. Regarding donor type, 5.8% of patients received a living donor transplant, while 94.2% were from deceased donors (92.4% brain death donors and 1.8% cardiac death donors).Four hundred and fifty patients were transplanted in our center from January 2005 to December 2015 (both included). Of them, 395 had stored serum samples obtained immediately pretransplant and were therefore included in our study. The samples were obtained after the short vintage in hemodialysis patients and immediately pretransplant in peritoneal dialysis and preemptive transplant candidates. Baseline characteristics of the study population are shown in p < 0.001), coronary artery disease (OR 2.66 CI95% (1.14–6.16), p = 0.02), peripheral artery disease (OR 2.51 CI95% (1.01–6.2), p = 0.048), and time of renal replacement therapy (RRT) (OR 1.04 CI95% (1.01–1.1), p = 0.02). GDF-15 was not associated with sex, race, diabetes, primary renal diagnosis, hemoglobin, albumin, creatinine, uric acid, C-reactive protein, phosphorus, parathyroid hormone, preemptive transplant, dialysis modality, or history of non-renal transplants. On multivariate analysis, only two variables were independently related to GDF-15 levels: Age (OR 1.04 (1.02–1.06) p < 0.001) and time of RRT (OR 1.04 (1.01–1.07) p = 0.02). The median GDF-15 in our cohort was 5331.29 (IQR 4071.83–6819.93) pg/mL. Only 6 patients (1.5%) had an GDF-15 level ≤2000 pg/mL  [p = 0.026). Survival was significantly decreased among the medium and high risk tertiles of GDF-15 compared to the low risk one: HR 2.16 CI95% (1.14–1.44), p = 0.018 for medium tertile and HR 3.28 CI95% (1.79–6.1), p < 0.001 for high risk tertile (p < 0.001), diabetes (HR 2.34 CI95% (1.49–3.67), p < 0.001), coronary artery disease (HR 2.99 CI95% (1.75–5.13), p < 0.001), peripheral arteriopathy (HR 2.24 CI95% (1.24–4.06), p = 0.008), other organ solid transplants (HR 1.97 CI95% (1.02–3.84), p = 0.044), and renal graft loss (HR 1.61 CI95% (1.03–2.53), p = 0.038). Additional variables considered in these analyses, but not significantly related to survival, included: Sex, race, time of RRT and modality, use of dialysis at the time of transplant, albumin, creatinine, uric acid, C-reactive protein, phosphorus, parathyroid hormone, hemoglobin, PRA (%), donor type, use of induction, and type of immunosuppression therapy. The mean follow-up post-transplant was 90.6 ± 41.52 months. There was no loss to follow-up during the course of the study. During this period, 82 (20.8%) patients died. By univariate Cox analysis, higher GDF-15 concentrations were significantly associated with mortality (log GDF-15 level HR 3.88 CI95% (1.18–12.78),  tertile . The folp = 0.009) after adjusting by age (HR 1.07 CI95% (1.04–1.09), p < 0.001), history of coronary artery disease (HR 2.2 CI95% (1.26–3.82), p = 0.005), censored graft loss (HR 1.95 CI95% (1.23–3.09), p = 0.005), and other organ solid transplants (HR 2.64 CI95% (1.32–5.28), p = 0.006). Variables associated with mortality by univariate and multivariate Cox regression analysis in our study are summarized in By multivariate Cox analysis, the relation between survival and GDF-15 remained significant for high risk tertile (HR 2.29 CI95% (1.24–4.24), n = 264). The EPTS value in our cohort was 31% (IQR 11.5–50.5). After including EPTS in the multivariate analysis, the association between GDF-15 and mortality remained significant. This relation was significant both considering GDF-15 as a continuous variable (logGDF-15 HR 9.46 CI95% (1.78–40.41), p = 0.008), or in tertiles (HR 3.24 CI95% (1.2–8.8), p 0.021 for medium risk tertile and HR 4.3 CI95% (1.65–11.54), p 0.003 for high risk tertile). EPTS score was calculated for all first kidney transplant recipients included in our study (n = 8), 5.7% (n = 15), and 7.2% (n = 19). By multivariate logistic regression, both EPTS score and high risk GDF-15 tertile were significantly associated with mortality after 1 and 3 years, while mortality at 5 years was only related with EPTS in our analysis. ROC curves based on predicted probability of logistic regression were obtained and compared, showing improved mortality prediction at 1 and 3 years using EPTS combined with GDF-15 tertile . Malignancy and its treatment complications were responsible for 22.0% of deaths (n = 18). By univariate Cox analysis, higher GDF-15 concentrations were significantly associated with cardiovascular mortality: HR 5.95 CI95% (1.32–26.88), p = 0.02 for medium tertile, and HR 7.91 CI95% (1.78–35.10), p = 0.006 for high risk tertile. Furthermore, this association remained significant (highest GDF-15 tertile HR 5.55 CI95% (1.24–24.7), p = 0.025) after adjusting by clinical characteristics associated with cardiovascular mortality in our study: History of coronary artery disease (HR 3.6 CI95% (1.52–8.43), p = 0.005), age (HR 1.06 CI95% (1.02–1.11), p = 0.007), and diabetes (HR 2.37 CI95% (1.09–7.15), p = 0.03). On the contrary, cancer-related mortality was not significantly related to GDF-15 in our analysis: Malignancy related mortality for high risk tertile HR 0.54 CI95% (0.16–1.76), p = 0.32.With regard to the causes of death, cardiovascular and cancer-related mortality were specifically evaluated. Cardiovascular mortality was responsible for 35.4% of deaths  adverse events ,46. Thisn = 18). It could also be possible that in chronic kidney disease patients, other conditions such as cardiovascular burden may have a greater influence in GDF-15 levels than carcinogenic factors.Additionally, we analyzed the causes of mortality in our patients and their relation with GDF-15. As it has been previously described, this biomarker is strongly related with vascular disorders, which remain the main cause of death after a kidney transplants ,33. In oIn healthy subjects, an increase in serum GDF-15 concentrations is observed with aging (the main determinant factor of GDF-15 in majority of studies) and smoking. A variable relation has been seen among GDF-15 and body mass index, with increased levels in both extremely high and low body mass index . Other sIn addition to this, there is still a number of unanswered questions regarding the pathogenesis of GDF-15. As mentioned before, this protein is poorly expressed in healthy tissues, and its production is induced after different forms of cellular damage. However, the source of production in patients with chronic kidney disease remains unknown, as most works have focused on its biomarker value and not on the role as a biological response modifier. Nair et al.  demonstrA large number of mortality markers after kidney transplant have been studied so far. Despite this, their utility remains unclear, as discussed previously . Given tThe strengths of our study include the following; first, a relatively large number of patients with a uniform collection of samples to analyze GDF-15 with measurements performed in a single laboratory. Second, the use of a prospectively maintained database of renal transplant patients, with a follow-up of at least five years after transplant in the same center and no loss of follow-up during the study. Third, the GDF-15 evaluation added prognostic value to a previously widely validated tool for kidney transplant candidates, the EPTS score. The limitations of our study also need to be considered. Our population is very homogenous, with a majority of recipients of Caucasian race and grafts obtained mainly from donors after brain death, restricting our external validation. Additionally, we could not compare the use of GDF-15 against other markers such as imaging  or anthropometric studies  as they are not routinely performed in all kidney transplant candidates in our center. Furthermore, GDF-15 concentrations were measured only once in each patient, so the evolution of the biomarker concentrations after transplant and the prognostic value of its change could not be assessed. In conclusion, our study supports an independent association between higher GDF-15 levels and mortality after kidney transplant, adding accuracy of EPTS score, a stablished risk prediction model currently used in kidney transplant candidates. As an emerging biomarker, further studies are needed to confirm our findings and improve the knowledge regarding this protein, including its exact mechanism of action and potential therapeutic targets, so this knowledge could lead to better outcomes in this population.


Limited information exists about the nature of late-onset asthma (LOA) without medication intervention when compared to early-onset asthma (EOA). Our goal was to understand how EOA and LOA affect clinical and pathophysiological features.  A population-based cross-sectional study was carried out in Zhongshan Hospital . EOA and LOA were based on age of diagnosis . Clinical variables were collected with an emphasis on allergic features, analyzed, related, and compared using one-way ANOVA or Kruskal-Wallis test. Correlations between blood basophils and clinical data were evaluated by Spearman's rank test. Statistical analyses were conducted with SPSS v24.0. 1/FVC (%), FEV1% predicted, and FVC% predicted were all significantly lower in LOA compared to EOA (p < 0.01). The values of post-bronchodilator FEV1 in bronchodilator reversibility testing were higher in the LOA and EOA groups compared to subjects with COPD (p < 0.01). Among allergic features, mite sensitization was most common in EOA patients, followed by LOA and COPD, whereas mold sensitization was more prevalent in LOA than EOA. Moreover, blood eosinophils were a typical feature of asthma in both EOA and LOA compared to COPD and controls (p < 0.01), and there were no differences in blood neutrophils in LOA compared to controls. Interestingly, blood basophils were increased in both EOA (p < 0.01) and LOA (p < 0.05) compared to COPD and controls. This variable correlated with eosinophils in EOA  but not in LOA.  Of a total of 12,760 adults with cough, sputum, or chest tightness, 90 subjects with EOA (mean age ± standard deviation (SD):28.73 ± 5.89), 111 with LOA (mean age ± SD: 60.25 ± 9.85), and 106 with chronic obstructive pulmonary disease (COPD) (mean age ± SD: 61.58 ± 10.95) were selected. FEV LOA is a distinct clinical entity from EOA. In LOA, atopy was less frequent and spirometry values were lower when compared to EOA. In EOA, blood basophils and eosinophils were significantly correlated owing to pathophysiological differences between the two forms of the disease. Asthma is one of the major global health problems and contributes substantially to the worldwide burden of disease , 2. PrevDue to aging-related changes in respiratory pathology and immunity, LOA is frequently not diagnosed or is misdiagnosed . Unlike Most LOA patients enrolled in studies had been prescribed inhaled corticosteroids (ICS), oral corticosteroids (OCS), or leukotriene receptor blockers, which mask natural disease features and hamper research into the underlying mechanisms –15. It iA single-center, population-based, cross-sectional study was carried out in Zhongshan Hospital, Fudan University, Shanghai, China. This 2430-bed tertiary hospital is used by 10 million people in Shanghai and 150 million people in the surrounding Yangtze River Delta. More than 260,000 outpatients are referred to the Department of Pulmonary Medicine annually. All subjects signed informed consent forms and the study was approved by the Institutional Review Board, Human Subjects Research Protection Program Office (B2018-010R) at Zhongshan Hospital, Fudan University.Subjects were screened from the Screening and Monitoring for Obstructive Lung Disease project from February 2018 to October 2019. A total of 12,760 patients with cough, sputum, or chest tightness were referred to the Department of Pulmonary Medicine. We excluded 5085 patients with lung infection, lung shadow at chest xRay, or lung mass, and 3260 patients with previous diagnosis of asthma and/or COPD or already on medication with drugs for chronic obstructive airway disease. The remaining 1822 patients underwent pulmonary function and/or bronchodilator reversibility testing. If the spirometry results did not support the suspicion of asthma, the patients were subjected to peak expiratory flow (PEF) monitoring . Finally, 308 patients were diagnosed with asthma or COPD at the initial presentation by the pulmonologist or the attending physician according to the Global Initiative for Asthma (GINA) and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria . The stu1) of >12% and >200 mL from baseline, 10–15 minutes after 200–400 mcg salbutamol  or a change in PEF of at least 20% from baseline after 4 weeks of anti-inflammatory treatment, were considered as positive for diagnosis of asthma [Before performing spirometry examination and collecting blood samples, patients under medication for other indications were asked to stop the related medication for at least 7–10 days . Briefly, adults with respiratory symptoms, as indicated by an increase in forced expiratory volume in 1 second  < 0.7 with chronic respiratory symptoms [COPD was defined as any incidence of dyspnoea, chronic cough, or sputum production, with a history of recurrent lower respiratory tract infections and/or a history of exposure to risk factors for the disease and post-bronchodilator FEVsymptoms , 19. All1 ≥ 80% pred; moderate (GOLD2), 50% ≤ FEV1 < 80% pred; severe (GOLD3), 30% ≤ FEV1 < 50% pred; and very severe (GOLD4), FEV1 < 30% pred, based on post-bronchodilator FEV1values in the GOLD guidelines [Clinical information of all patients was carefully collected, including age, gender, weight, height, body mass index (BMI), smoking history (smoking ≥ 1 cigarette per day for 1 year), family history, related disease history, and asthma severity. Subjects with asthma were classified as mild, well controlled with step 1 and 2 treatments , moderate, well controlled with step 3 treatment , or severe with step 4 or step 5 treatment  based on the GINA criteria and National Institutes of Health guidelines . Accordiidelines , 21.1% pred, FEV1 (L), FVC% pred, FVC (L), FEV1/FVC (%), and bronchodilator reversibility testing in accordance with the American Thoracic Society guideline [All subjects underwent allergy testing for specific immunoglobulin E (sIgE) in serum , and blood cell counts were performed . Pulmonauideline . Fractio1% pred, FEV1 (L), FVC% pred, FVC (L), FEV1/FVC (%), FeNO, allergens, and sIgE were evaluated by Spearman's rank tests [p values < 0.05 were considered statistically significant. Statistical analyses were conducted with SPSS for Windows, version 24.0 .Clinical characteristics are reported as means ± standard deviation or percentages. Continuous variables were analyzed by one-way analyses of variance, and categorical variables were assessed with Kruskal-Wallis tests . Correlank tests . All tesAfter enrollment and screening, a total of 308 patients were diagnosed with asthma or COPD at their initial presentation . Based op < 0.05). Subjects with LOA were less likely to report a diagnosis of allergic rhinitis compared to those with EOA (52.7% vs. 80%), and COPD patients had the highest rate of smoking history (62.3%) among the three groups. With regard to asthma severity, LOA patients were more likely to be categorized as moderate (52.3% vs. 46.7%%) or severe (25.2% vs. 14.4%) compared to those with EOA. In the COPD group, most of the patients belonged to GOLD1class (39.6%) compared to the other subgroups .There were no differences in BMI among the groups. However, the subgroup of female patients with LOA had a higher BMI compared to female patients in the EOA group (1/FVC (%), FEV1% pred, and FVC% pred were all significantly lower in LOA compared to EOA (p < 0.01). The values of post-bronchodilator FEV1 in bronchodilator reversibility testing were higher in the LOA and EOA groups compared to subjects with COPD (p < 0.01). Moreover, although FeNO was lower in LOA compared to EOA, both groups showed significantly higher FeNO compared to the COPD group (p < 0.01). Respiratory physiology information is shown in The lung function test and allergic features were depicted in n = 74, 82.2%, p < 0.01), followed by LOA  and COPD . However, more subjects with LOA showed sensitization to mold compared to EOA . Furthermore, the LOA group exhibited more sensitivity to Aspergillus fumigatus than the EOA group .There was a marked difference in allergic sensitization between the LOA and EOA groups . Sensitip < 0.01). Interestingly, blood basophils  were also increased in both LOA and EOA. Blood basophil levels were the highest in EOA patients (p < 0.01), followed by LOA (p < 0.05), compared to COPD and healthy controls. There were no differences in blood neutrophils  among the LOA, EOA, COPD, and healthy control groups.As shown in r = 0.549, p=0.002) and the absolute value of blood eosinophils . Although blood basophils were increased in LOA (p < 0.05) compared to COPD and healthy controls, this was not correlated with any clinical parameter in the LOA group  Atopy was less common in LOA compared to EOA, but the antigen sensitization profiles were different. Sensitization to mites was most frequent in EOA patients, followed by LOA and COPD. Subjects with LOA were significantly more likely than those with EOA to exhibit sensitization to mold. (2) Spirometry values were lower in patients with LOA compared to EOA at their initial presentation. (3) Blood eosinophils were a typical feature in both the LOA and EOA groups. Number of blood basophils were also increased and correlated with eosinophils in EOA but not with LOA. There were no differences in blood neutrophils among subjects with LOA or EOA and healthy controls.Traditionally, LOA was considered to have less of an allergic component, as an incomplete response to bronchodilators , and is Aspergillus fumigatus sensitivity was increased in LOA compared to EOA. This suggests that sensitization to mold in patients with LOA may be related to their living and work environment [Our findings showed a major difference in the atopic sensitization between LOA and EOA. The Epidemiology and Natural History of Asthma (TENOR) study found that subjects with LOA had less allergic rhinitis and fewer patients with sIgE to at least one allergen , which iironment , and epiironment , 32.1values in bronchodilator reversibility testing were higher in both LOA and EOA groups compared to COPD. A reasonable explanation for this is age-related physiological changes that may act synergistically with asthma to worsen airflow obstruction, including less elastic recoil, increased airway remodeling in smaller airways, increased thickness of the central airway wall, and increased inflammation [Compared to younger cohorts, subjects with LOA have more severe asthma and higher rates of AHR. In our study, LOA patients were more likely to be categorized as moderate (52.3% vs. 46.7%%) or severe (25.2% vs. 14.4%) compared to those with EOA. Spirometry values were also significantly lower in patients with LOA compared to EOA at their initial presentation, which is similar to a previous report . Howeverammation .Eosinophilic inflammation is a typical feature of asthma. Many studies reported that levels of blood eosinophils were similar to those of airway eosinophils in asthma , 35. ThiThere are limitations to our study. Airway inflammation could not be assessed as sputum induction was not performed due to the high concentration of saline, which could exacerbate asthma symptoms in patients without medication-controlled disease . LOA witLOA is a distinct clinical entity from EOA. In LOA, atopy was less frequent compared to EOA and antigen sensitization differences may be related to their living and work environments. Spirometry values were lower for LOA patients at their initial presentation than EOA patients. In EOA, blood basophils and eosinophils were significantly correlated.COPD, chronic obstructive pulmonary disease; EOA, early-onset asthma; LOA, late-onset asthma.


Adenosine stress perfusion cardiovascular magnetic resonance (CMR) is commonly used in the assessment of patients with suspected ischaemia. Accepted protocols recommend administration of adenosine at a dose of 140 µg/kg/min increased up to 210 µg/kg/min if required. Conventionally, adequate stress has been assessed using change in heart rate, however, recent studies have suggested that these peripheral measurements may not reflect hyperaemia and can be blunted, in particular, in patients with heart failure. This study looked to compare stress myocardial blood flow (MBF) and haemodynamic response with different dosing regimens of adenosine during stress perfusion CMR in patients and healthy controls.20 healthy adult subjects were recruited as controls to compare 3 adenosine perfusion protocols: standard dose (140 µg/kg/min for 4 min), high dose (210 µg/kg/min for 4 min) and long dose (140 µg/kg/min for 8 min). 60 patients with either known or suspected coronary artery disease (CAD) or with heart failure and different degrees of left ventricular (LV) dysfunction underwent adenosine stress with standard and high dose adenosine within the same scan. All studies were carried out on a 3 T CMR scanner. Quantitative global myocardial perfusion and haemodynamic response were compared between doses.In healthy controls, no significant difference was seen in stress MBF between the 3 protocols. In patients with known or suspected CAD, and those with heart failure and mild systolic impairment (LV ejection fraction (LVEF) ≥ 40%) no significant difference was seen in stress MBF between standard and high dose adenosine. In those with LVEF < 40%, there was a significantly higher stress MBF following high dose adenosine compared to standard dose . Non-responders to standard dose adenosine (defined by an increase in heart rate (HR) < 10 bpm) had a significantly higher stress HR following high dose , but showed no significant difference in stress MBF.Increasing adenosine dose from 140 to 210 µg/kg/min leads to increased stress MBF in patients with significantly impaired LV systolic function. Adenosine dose in clinical perfusion assessment may need to be increased in these patients. Stress perfusion cardiovascular magnetic resonance (CMR) is an accurate, non-invasive technique for the detection of myocardial ischaemia , 2. The Intravenous adenosine has been shown to induce near maximal hyperaemia  and is uConventionally, adequate stress is defined by a heart rate (HR) rise of ≥ 10 bpm or a systolic blood pressure (SBP) fall of > 10 mmHg , based oRecently developed techniques of inline myocardial perfusion mapping with CMR provide accurate, reproducible assessment of rest and vasodilator stress myocardial blood flow (MBF) following adenosine administration –13. ThisTwenty healthy subjects were recruited as controls to compare 3 adenosine perfusion protocols. Exclusion criteria were any known cardiovascular disease, hypertension, hyperlipidaemia, diabetes mellitus, smoking, body mass index (BMI) > 30 and any contraindication to CMR, adenosine or gadolinium-based contrast agents.Sixty patients with symptoms of angina or heart failure were recruited prospectively from CMR or coronary angiography waiting lists, for comparison of 2 adenosine protocols determined from the results in healthy subjects. Patients were divided into three groups for analysis consisting of; Group 1—Patients with coronary artery disease and left ventricular (LV) ejection fraction (LVEF) ≥ 40%. Group 2—Mild to moderate heart failure, LVEF ≥ 40% and no evidence of coronary disease, and Group 3—Moderate to severe heart failure, LVEF < 40% and no evidence of CAD. Exclusion criteria for patients were the presence of any contraindication to CMR, adenosine or gadolinium-based contrast agents. CAD was defined by either ischaemic  late gadolinium enhancement (LGE) on CMR, at least moderate stenosis on coronary angiography, previous percutaneous coronary intervention or previous coronary arterial bypass grafting.All CMR studies were undertaken on a 3 T CMR system . Participants were advised to avoid caffeine for 24 h before the study. The protocol consisted of cine imaging, stress and rest perfusion, and LGE.For perfusion imaging, adenosine was infused at a set dose for a preassigned time. Healthy subjects had three stress perfusion acquisitions; standard dose (140 µg/kg/min adenosine for 4 min), high dose (210 µg/kg/min for 4 min) and long dose (140 µg/kg/min for 8 min). Patients received standard dose and high dose for 4 min each. Doses were given in random order. A 10-min interval was kept between perfusion acquisitions, rest perfusion images were acquired 10 min after the final stress perfusion sequence in all participants.Participants were monitored for symptoms throughout the scan. SBP and HR were recorded prior to starting adenosine infusion and before acquisition. For each perfusion acquisition, an intravenous bolus of 0.05 mmol/kg gadobutrol  was administered at 5 ml/s followed by a 20 ml saline flush using an automated injection pump . Perfusion mapping was performed and implemented on the scanner using the Gadgetron streaming software image reconstruction framework as previously described , 13. MBFIschaemic segments were identified on visual assessment of perfusion images. Splenic switch off was assessed by comparing enhancement of splenic tissue at stress and at rest according to previously published methods , 15.Perfusion maps were analysed using cvi42 software . Endocardial and epicardial borders were drawn excluding papillary muscles, right ventricular insertion points marked, and a 16-segment American Heart Association model . MBF wasSubgroup analysis was carried out comparing patients with a HR change of < 10 bpm (non-responders) compared to those with a rise of ≥ 10 bpm (responders). Within Group 1, segments with ischaemia on visual assessment were compared with non-ischaemic segments.Analysis was performed using SPSS . Normality of distribution was assessed using Shapiro–Wilk test. Different dosing regimens were analysed using paired t-tests or Wilcoxson Signed Rank test in patients and analysis of variance (ANOVA) with repeated measures and post-hoc Bonferroni correction, or the Kruskal Wallis H test in healthy controls. Categorical data was analysed using chi-square test or Fisher’s exact test when expected numbers were < 5. All statistical tests were two-tailed and p < 0.05 was considered significant.Myocardial perfusion reserve (MPR) was calculated as stress MBF:rest MBF. Inadequate HR response was defined as < 10 bpm in keeping with Society for Cardiovascular Magnetic Resonance guidelines .20 healthy control subjects were recruited . One subject withdrew after the first dose of adenosine. Haemodynamic data were available for all three dosing regimens for 19 healthy subjects. In one case artefact on perfusion maps at standard dose meant these were not included in analysis of MBF response. The final cohort therefore consisted of 18 subjects.Haemodynamic data are shown in Table There was a significant difference in stress HR and between standard and high dose adenosine, but no difference between standard and long dose. No significant difference was seen in SBP or change in SBP between doses.Global stress MBF was 2.50 ± 0.74 ml/g/min with standard dose adenosine, with values of 2.66 ± 0.59 ml/g/min after high dose and 2.59 ± 0.64 ml/g/min with long dose, overall there was no significant difference between the three groups (p = 0.32).Although there was no significant difference in MBF, the largest increases in HR were seen following the high dose regimen Fig. , therefoSixty patients took part in the study divided into 20 in Group 1 (CAD), 16 in Group 2  and 24 in Group 3 . No significant differences were seen between the groups in incidence of diabetes mellitus, beta-blocker usage, age or sex , but no significant difference was seen in groups 2 or 3. Stress SBP was significantly lower following high dose adenosine compared to standard dose in group 2 . There was no significant difference in stress SBP between doses in the other groups.No significant difference was seen in absolute HR rise between the groups Fig.  and no sNo difference was seen in rest MBF between the 3 groups . No difference was seen in MBF or MPR between different adenosine doses in either Group 1 or 2. Within Group 3, MBF was significantly higher following high dose than after standard dose adenosine   and high dose adenosine . HR response with standard dose adenosine did not correlate with an increase in MBF or MPR with high dose adenosine.Five patients demonstrated failed splenic switch off with standard dose adenosine Table . AnalysiPatients were divided into groups of non-responders (n = 24) and responders (n = 36) based on a HR increase of < 10 bpm or ≥ 10 bpm. There was no significant difference in LVEF, age or incidence of diabetes or beta blocker usage between the two groups. Stress HR was significantly different between groups both with standard and high dose adenosine . There was no significant difference in rest HR or stress MBF between the two groups at either adenosine dose.In the non-responder group, stress HR was significantly higher with high dose adenosine than with standard dose Table . Those wWithin group 1, 11 patients had evidence of regional inducible ischaemia. On visual analysis, ischaemia was seen in the same coronary territories between the adenosine doses. A total of 60 ischaemic segments were visually identified following standard dose adenosine, and 63 segments following high dose. No significant difference was seen in MBF in between standard and high dose adenosine in either the ischaemic  or non-ischaemic segments  in these patients.The Society for Cardiovascular Magnetic Resonance Standardized (SCMR)  imaging protocols for stress perfusion recommend an adenosine dose of 140 μg/kg body weight/min for 2–4 min with an increase in the dose if there is inadequate HR and SBP response . Our resThe duration of adenosine infusion has not previously been studied for stress perfusion CMR but has been the subject of studies in nuclear cardiology. In Single Photon Emission Computed Tomography, a 3-min adenosine infusion showed better tolerability with similar diagnostic performance compared with a 6-min protocol. A PET sThe dose of adenosine infusion has been studied more extensively, using multiple modalities. Early invasive studies using intracoronary Doppler assessment of coronary blood flow velocity and total coronary resistance showed that intravenous adenosine at doses of 140 µg/kg/min resulted in maximal hyperaemia, defined by papaverine response, in 84% of subjects . SeveralIn patients with severe systolic impairment, previous studies have shown a blunted HR response to adenosine, with an increase in adenosine from 140 to 210 µg/kg/min more commonly required to achieve a sufficient haemodynamic response . In CMR,In non-invasive testing, response to adenosine and the achievement of hyperaemia is commonly assessed using haemodynamic response relating to peripheral vasodilation. Conventionally, an increase in HR by > 10 bpm and a fall in systolic SBP by > 10 mmHg are considered markers of adequate hyperaemia . A smallWithin our study, 61% of those patients with LVEF > 40% reached the threshold of 10 bpm, comparable to published results in other studies with a similar patient group . This reThis study showed no significant relationship between rise in HR at standard dose adenosine and an increase in stress MBF or MPR with high dose adenosine. This indicates that in patients with a low HR response at standard dose adenosine, a higher dose does not increase myocardial perfusion—a finding that questions the validity of current guideline recommendations and widely used clinical practice.Further, we saw no significant difference in SBP change between groups of patients, or adenosine doses and < 3% of patients had a decrease in SBP of ≥ 10 mmHg as described in standard protocols. SBP even increased in healthy subjects over baseline. These data suggest, in keeping with previous studies, that in particular SBP response should not be used as a marker of adequate vasodilator response, possibly due to an adrenergic response to adenosine symptoms, which overcomes the vasodilator effects on blood pressure.Our data suggest that those with reduced LVEF should have higher dose adenosine to achieve maximal hyperaemia, regardless of haemodynamic response. Our data also question the use of HR and SBP response to standard dose adenosine as criteria to increase the adenosine dose as it does not appear to increase MBF. However, due to low numbers of patients with inducible ischaemia in this study we have not been able to assess the diagnostic impact of our observations although we observed a small, non-significant, increase in the number of ischaemic segments identified following high dose adenosine.Our data may be influenced by physiological variation, although we have tried to minimise this. It is possible some effects may not have been controlled for, although we have previously demonstrated no significant difference in serial measurements of stress MBF within a CMR study . CaffeinIncreasing adenosine dose is well tolerated and related to increased stress myocardial blood flow in patients with significant LV impairment. Achievement of adequate myocardial vasodilator response, assessed by quantitative perfusion, is not significantly related to peripheral haemodynamic measurements SBP and HR. These observations may impact future practice guidelines for stress perfusion CMR. Dosage of adenosine in clinical perfusion assessment should be carefully considered and may need to be increased in subsets of patients, in particular those with severely impaired LV function, or alternative stress agents considered.


Digital health tools  provide opportunities for new methods of hypertension management for hypertensive patients. However, the willingness of these patients to use social media and mobile health apps for hypertension management remains unclear. This study explored the characteristics and requirements of patients willing to use digital health (WDH) tools to manage hypertension.From February to March 2018, we administered questionnaires to 1089 patients with hypertension at eight Chinese primary medical units. We assessed independent risk factors of WDH and requirement among WDH patients.P < 0.0001). After adjusting for other risk factors, higher education , good medicine adherence  and blood pressure self-monitoring  remained significantly associated with WDH . WDH patients responded that digital health tools should try to provide a platform for blood pressure monitoring (42%), medication reminders (41%), hypertension knowledge (39%) and doctor-patient communication (32%).Overall, 43% (465/1089) of participants were WDH patients, who were younger (58 ± 12 vs 61 ± 13 years) and had a greater proportion of employed individuals (31% vs 14%) and higher education levels (65% vs 52%) than the non-WDH patients  in the future. Hypertension has become the leading cause of cardiovascular death due to its low control rate  in both Digital health interventions, such as email, text messages, smartphone applications like facebook, have been explored to assist in the self-management of hypertension and some other chronic diseases . Many trA sample of 1089 individuals from eight primary medical units in Guangzhou and Dongguan, China, participated in this survey. Data were collected in February and March of 2018. Participants had to meet the following inclusion criteria: (1) community resident with hypertension and (2) age 18 years and older. There were no exclusion criteria. All of the interviewed individuals finished the survey, and the mean time required for participants to finish the survey was 20 min. This study was conducted in compliance with the Declaration of Helsinki; the study was also approved by the Ethics Research Committee of Guangdong Provincial People’s Hospital, and written informed consent was obtained from all patients .Sex, age, height, weight, education , occupation, and medical care were evaluated by standard survey items.  from high blood pressure were asked. Next, patients’ usual systolic blood pressure fluctuation, the frequency of blood pressure measurement and antihypertensive dosing were surveyed to understand participants’ blood pressure monitoring status and medical adherence. Last, the total time of participants’ daily activities  and smokThe definition of “good BP monitoring” is that the patient’s blood pressure is under 140/90 mmHg in their daily life. Adherence was assessed by asking participants how often they forget to take medicine. The answers “never” and “less than once a week” were defined as good adherence. The answers “more than one time a week” and “Don’t take medicine when blood pressure is under control” were defined as bad adherence.In the final part of the questionnaire, we surveyed participants’ willingness and requirements for the use of digital health tools from the following three questions: (1) Have you used WeChat or health applications in the last 1 year? (2) Would you like to use a digital health tool to manage your blood pressure? (3) What help would you like to get from the health apps ?p < 0.05. The statistical analysis was conducted using SAS V.9.4.We analysed the entire sample as well as specific subgroups, and we mainly compared WDH patients and non-WDH patients. Binary logistic regression models were applied. Baseline characteristics of the cohort were summarized using descriptive statistics. Continuous variables were reported as the mean and SD and were compared using linear regression models. Potential confounders and baseline values of the dependent variables were entered as covariates. Categorical variables were described as frequencies and percentages and compared using the χ2 test. The criterion for statistical significance was set at The total number of people participating in this community survey was 1089 . Majority of participants have a good habit in smoking (76.8%) and exercise (63.0%). Out of all participants, 42.7% reported that they were willing to use digital health tools to manage hypertension.P < 0.05) and that they were more likely to have good medicine adherence  and blood pressure self-monitoring . WDH was not associated with sex, age, BMI, marriage status, working time, knowledge of hypertension, SBP fluctuation, or the health behaviours of smoking and physical activity. Differences of baseline between patients with controlled hypertension and uncontrolled hypertension can be found in the Supplement Table The results from binary logistic regression  indicated that they were eager to engage in one-week blood pressure monitoring, and a similar percentage (41%) wanted feedback on 1 week of medical adherence. Thirty-nine percent of WDH patients wished to obtain some simple knowledge of hypertension, and 32% of them needed doctor-patient communication. In addition, 28% of WDH patients thought that self-control of blood pressure was needed, and 27% reported that they would like to communicate with other patients.This is a relatively new cross-sectional survey on the willingness of patients with hypertension to use digital health tools, which covered 1089 people with hypertension from different economic backgrounds, revealing a certain representativeness. Our survey found that 42.7% of hypertensive patients were willing to use digital health tools, and WDH was associated with higher education, good medicine adherence and blood pressure self-monitoring. Also, the results showed that most WDH patients wanted to receive scientific blood pressure monitoring, self-administration of medical adherence and common knowledge about hypertension.We searched a large number of articles about social media for health care, which show the organic combination of social media and medical health. A systematic review reviewed 45 social media use improvements in chronic disease management, showing that social media, especially Facebook and blogs, provides social, spiritual, and empirical support for chronic diseases. These platforms are thus highly likely to improve patient health . ResearcIn a recent longitudinal survey, Levine et al.  found thWe contributed to the preliminary evidence of the correlation of WDH with blood pressure self-management and medical adherence. Patients with poor blood pressure management and medical adherence are relatively reluctant to use digital health tools, which may be the result of a combination of factors such as age, smartphone maturity, personal income, tool trust, and so on. The relationship between blood pressure management and WDH may be explained by socioeconomic variables. Indeed, we found that possession of university degrees and employment were related to the use of WeChat and mobile health tools, and further research on this correlation is needed. More studies are needed on the features of effective digital health tool programs. Social media and health application effectiveness information based on evidences from rigorous research designs should be provided to users. Given the sheer number of applications available, the market transparency will be increased. Not only government guidelines and regulations, but also WHO recommendations could help people choose effective and appropriate applications . The firWe found differences in age and literacy rates in the use of mobile technology. Therefore, application developers and researchers should consider the needs of older people and those with lower education levels, for example, to provide customized features that are tested in intervention studies , 24. SimDue to the cross-sectional character of the survey, changes could not be checked, including associations of digital health tools and their characteristics with actual blood pressure and behavior management. The patient’s economic situation has not yet been included in the questionnaire, making the association of income with blood pressure management and digital health tools impossible to determine at this moment. Previous studies have found that the use of apps is associated with higher incomes . AnotherFurthermore, a large number of analyses were conducted which could have increased the probability of type I errors . However, our research is exploratory. Nonetheless, in addition to the uncorrected results, we decided to report the multiplicity corrected results following a recommendation by Streiner , who disOur survey suggested that among patients with hypertension, willingness to use digital health tools was significantly associated with higher education, good medicine adherence and blood pressure self-monitoring. In addition, we need to focus on WDH patients’ requirements for blood pressure monitoring, medication reminders, and hypertension education to improve the technology of digital health tools and research in the future.Additional file 1: Table S1. Questionnaire for community hypertension patients .Additional file 2: Table S2. Differences of baseline between patients with controlled hypertension and uncontrolled hypertension.