Reliable estimates of the absolute and relative risks of postoperative complications in kidney transplant recipients undergoing elective surgery are needed to inform clinical practice. This systematic review and meta-analysis aimed to estimate the odds of both fatal and non-fatal postoperative outcomes in kidney transplant recipients following elective surgery compared to non-transplanted patients.Systematic searches were performed through Embase and MEDLINE databases to identify relevant studies from inception to January 2020. Risk of bias was assessed by the Newcastle Ottawa Scale and quality of evidence was summarised in accordance with GRADE methodology . Random effects meta-analysis was performed to derive summary risk estimates of outcomes. Meta-regression and sensitivity analyses were performed to explore heterogeneity.Fourteen studies involving 14,427 kidney transplant patients were eligible for inclusion. Kidney transplant recipients had increased odds of postoperative mortality; cardiac surgery , general surgery  compared to non-transplanted patients. The magnitude of the mortality odds was increased in the presence of diabetes mellitus. Acute kidney injury was the most frequently reported non-fatal complication whereby kidney transplant recipients had increased odds compared to their non-transplanted counterparts. The odds for acute kidney injury was highest following orthopaedic surgery . However, there was no difference in the odds of stroke and pneumonia.Kidney transplant recipients are at increased odds for postoperative mortality and acute kidney injury following elective surgery. This review also highlights the urgent need for further studies to better inform perioperative risk assessment to assist in planning perioperative care. Patients with end-stage kidney disease (ESKD) derive a notable improvement in survival and quality of life compared to patients who remain on chronic dialysis , 2. HoweThe aim of this study was to perform a systematic review and meta-analysis of kidney transplant recipients undergoing elective non-transplant surgery to assess their odds of both fatal and non-fatal post-operative outcomes compared to patients with non-transplanted patients.This systematic review adhered to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) proposal for reporting  and PrefAll cohort studies comparing post-operative mortality and morbidity in adult (aged 18 years or older) kidney transplant recipients with non-transplanted patients in the general population were considered for inclusion. All types of surgery requiring a general anaesthetic were considered, including general, orthopaedic, cardiac, vascular and urological/gynaecological surgery. Kidney transplantation and related urological procedures were excluded. Studies in which more than 25% of the procedures were emergent  were excluded because they have an inherently higher odds of perioperative complications. Studies reporting aggregate outcomes for a mixed population of solid organ transplant recipients were included if > 70% of the population comprised kidney transplant recipients.We searched MEDLINE and Embase from inception to January 2020, without language restriction using a combination of relevant keywords including surgery, kidney transplant, postoperative, perioperative, mortality and their variants (see supplementary Table Database of Abstracts of Reviews of Effects (DARE), the Cochrane Database of Systematic Reviews (CDSR), National Institute for Health and Clinical Excellence (NICE) and the NIHR Health Technology Assessment (NIHR HTA) programme websites were all searched for existing reviews.Two researchers (D.P & K.K) independently reviewed all abstracts identified in the initial search to assess study eligibility. Any disagreements were resolved by a third reviewer (M.F). Type of surgery, patient numbers, summary statistics for baseline characteristics , and frequency of post-operative outcomes in each group were extracted from full-text manuscripts of eligible studies. An individually tailored data request form was used to obtain additional data from corresponding authors, including aggregated summary data of kidney transplant recipients baseline characteristics and outcomes.The primary outcome was all-cause mortality, defined as either 30-day mortality or death within the same hospitalisation as the index surgery. Secondary outcomes were postoperative myocardial infarction, stroke, congestive cardiac failure, pneumonia, surgical site infection , sepsis, acute kidney injury (AKI), thromboembolic events and return to theatre. Outcome definitions of complications were noted at the time of data extraction. The severity of each complication was measured using the Clavien-Dindo Classification, which was used to evaluate the implications of those postoperative complications on patients’ treatment courses and outcomes . The scaI2 using the t-statistic for degrees of freedom due to the small number of studies  and 95% confidence intervals (CIs) were calculated for both fatal and non-fatal outcomes reported in each study to ensure consistency using the absolute number of events in each group. Adjusted OR and 95% CI were recorded from studies that performed a multivariable analysis, adjusting for age as a minimum. As pre-specified in the protocol, odds ratio estimates were calculated using the DerSimonian and Laird (DL) method of random effects meta-analysis for each surgical discipline. Further meta-analysis using the Hartung-Knapp-Sidik- Jonkman method (HKSJ) was also performed for comparison due to small number of studies .Unadjusted and adjusted ORs for both primary and secondary outcomes in kidney transplant recipients versus non-transplanted patients were pooled by surgical disciplines, but not across disciplines due to differences in risks inherent to a particular discipline, potential for an interaction between surgical risk and transplant status, and inability to exclude differential bias in selection of surgical candidates. Meta-regression was performed using the random effects model to assess whether the unadjusted effect size was associated with important study level covariates, including age and pre-operative co-morbidity (ischemic heart disease and diabetes). Sensitivity analyses, excluding studies reporting aggregated outcomes involving other solid organ transplant recipients, were also conducted for all outcomes.L’Abbé plots were used to explore studies with divergent results and evaluate potential contributions of study group characteristics to such differences . Influenp-value < 0.05.Statistical analysis was performed with Stata 14.0 for Windows. Statistical significance was defined as a two-sided In total, 3448 abstracts were reviewed, from which 56 full-text articles were retrieved and evaluated See Fig. . FourteeSix of the 14 studies reported outcomes solely for kidney transplant recipients , 23, 25,All studies reported age and gender. Ten of the 14 studies reported baseline comorbidities including ischemic heart disease and diabetes mellitus –25, 27. p = 0.31). Inter-rater agreement between the two independent reviewers was very strong (κ = 0.83).As per the NOS, cohort selection was of good quality, but comparability was poor due to lack of multivariable adjustment in only 5 of the 14 studies. In addition, outcome reporting was also poor due to selective reporting of and differences in outcome definitions , and similar following general surgery . Fatal outcomes were not reported by any of the studies in the vascular or urological/gynaecological surgical disciplines. A single study of orthopaedic procedures reported an adjusted mortality risk ratio but did not provide absolute event rates  [2 85.6%, p for heterogeneity = 0.001, t = 1.9, Fig. 2 0%, p for heterogeneity = 0.75, t = 3.0). Meta-analysis results using the HKSJ method were very similar to those from the DL method. Results are summarised in Supplementary Table The incidence of all-cause mortality ranged between 0 and 16% in kidney transplant recipients, and between 0 and 5.7% in non-transplanted patients. Eight studies involving 8151 transplant recipients reported unadjusted mortality odds ratios Fig. a. ComparReporting of non-fatal complications was inconsistent across studies: acute kidney injury was the most frequently reported 11 studies), followed by pneumonia (8 studies), and stroke (7 studies). Thromboembolic complications were the least frequently reported 3 studies) . Pooling of adjusted analyses was not possible due to the fact that only one study in each of the other three disciplines reported adjusted analysis. The odds of surgical site infections was also not significantly different, irrespective of surgical discipline  followed by cardiac surgery . With the exception of two studies [2 = 48% p = 0.146, t = 12.8) and a single study involving general surgery (OR 2.02 95% CI 1.42–2.63).The incidences of postoperative AKI in kidney transplant recipients ranged between 7.0 to 37.4% following cardiac surgery, 10.0 and 11.7% after general surgery, and 0 to 26.7% after orthopaedic surgery. The odds of postoperative AKI was higher in kidney transplant patients than in their non-transplanted counterparts . L’Abbe plots did not identify any studies that exerted disproportionate influence on derived estimates of effect  [The other key finding of this review was that the odds of post-operative acute kidney injury in kidney transplant recipients was considerably higher than in non-transplanted patients in both unadjusted and sensitivity analyses. A single study reported a higher incidence of postoperative serum creatinine elevation in kidney transplant recipients with a preoperative serum creatinine greater than 176 μmol/L compared to those with lower values  . In the  = 0.04) . In the Although a comprehensive search strategy and rigorous assessment of methodologic quality using a validated tool were used, there were limitations which contributed to the low certainty of evidence. Firstly, observational studies and their subsequent meta-analyses are prone to bias due to the inability to quantify and adjust for known and unknown confounders. This was compounded by the incomplete reporting of patient comorbidities, preoperative kidney function, precise immunosuppressive regimens, selective reporting of clinical outcomes, and variation of outcome definitions between studies. In addition, assessment of publication bias using the funnel plot was limited by small number of studies . Meta-anPatients with a kidney transplant who undergo elective surgery are at increased odds of postoperative mortality compared to non-transplanted patients, with higher odds among patients with diabetes mellitus. Kidney transplant recipients are also at increased odds of postoperative acute kidney injury, but the odds of postoperative cardiovascular complications was no different between the two groups. The findings of this review also highlight the need for further studies to be more comprehensive in reporting patient baseline characteristics, including graft function and immunosuppression, as well as the use of consistent outcome definitions and recording of both short- and long-term graft outcomes. This will inform decision-making around the appropriateness of elective surgery in kidney transplant recipients and allow clinicians to adopt means to mitigate perioperative risk.Additional file 1 : Supplementary Table 1a: Search strategy for EMBASE. Supplementary Table 1b: Search strategy for MEDLINE. Supplementary Table 2: Methodological quality of each study assessed by the NOS scale. Supplementary Figure 1: L’Abbe plot for mortality event rates. Supplementary Figure 2: L’Abbe plot for post-operative AKI event rates. Supplementary Figure 3a: Funnel plot for bias assessment . Supplementary Figure 3b: Funnel plot for bias assessment (Acute kidney injury). Supplementary Table 3: Meta-analysis results using HKSJ method. Supplementary Figure 4: Unadjusted odds ratio estimate of post-operative stroke in kidney transplant patients compared to patients with non-transplant patients. Supplementary Figure 5: Unadjusted odds ratio estimate of post-operative pneumonia in kidney transplant patients compared to non-transplant patients. Supplementary Figure 6: Unadjusted odds ratio estimate of surgical site infection in kidney transplant patients compared to non-transplant patients. Supplementary Figure 7: Unadjusted odds ratio estimate of sepsis in kidney transplant patients compared to patients with non-transplant patients. Supplementary Figure 8: Meta-regression for post-operative mortality odds by prevalence of diabetes mellitus. Every circle represents a study; the circle size is representative of the weight of that study in the analysis. The relation between logarithmic mortality odds ratio and the prevalence of diabetes mellitus in kidney transplant patients and non-transplanted patients is significant . Supplementary Table 3: Meta-analysis of other non-fatal post-operative complications.


Background: Asthma is a heterogeneous syndrome with a broad clinical spectrum and high drug response variability. The inflammatory response in asthma involves multiple effector cells and mediator molecules. Based on asthma immunopathogenesis, precision medicine can be a promising strategy for identifying biomarkers. Biologic therapies acting on the IL-5/IL-5 receptor axis have been developed. IL-5 promotes proliferation, differentiation and activation of eosinophils by binding to the IL-5 receptor, located on the surface of eosinophils and basophils. This study aimed to investigate the expression of IL5RA in patients with several types of asthma and its expression after treatment with benralizumab, a biologic directed against IL-5 receptor subunit alpha.Methods: Sixty peripheral blood samples, 30 from healthy controls and 30 from asthmatic patients, were selected for a transcriptomic RNAseq study. Differential expression analysis was performed by statistical assessment of fold changes and P-values. A validation study of IL5RA expression was developed using qPCR in 100 controls and 187 asthmatic patients. The effect of benralizumab on IL5RA expression was evaluated in five patients by comparing expression levels between pretreatment and after 3 months of treatment. The IL5RA mRNA levels were normalized to GAPDH and TBP expression values for each sample. Calculations were made by the comparative ΔΔCt method. All procedures followed the MIQE guidelines.Results:IL5RA was one of the most differentially overexpressed coding transcripts in the peripheral blood of asthmatic patients (P = 8.63E-08 and fold change of 2.22). In the qPCR validation study, IL5RA expression levels were significantly higher in asthmatic patients than in controls (P < 0.001). Significant expression differences were present in different asthmatic types. In the biological drug study, patients treated with benralizumab showed a significant decrease in IL5RA expression and blood eosinophil counts. A notable improvement in ACT and lung function was also observed in these patients.Conclusions: These results indicate that IL5RA is overexpressed in patients with different types of asthma. It could help identify which asthmatic patients will respond more efficiently to benralizumab, moving toward a more personalized asthma management. Although further studies are required, IL5RA could play a role as a biomarker and pharmacogenetic factor in asthma. Asthma is a chronic inflammatory disease of the airways affecting more than 300 million people worldwide, and its prevalence is increasing, becoming a health and economic problem . It is dDespite the broad clinical spectrum of asthma, the presence of inflammation of the airway is a common pathologic feature and the primary treatment target. Nevertheless, the relationship between the intensity of inflammation and the severity of asthma has not been consistently established . The chaAsthma comprises different phenotypes with similar clinical manifestations but probably involving different underlying mechanisms . These pAsthma management aims to achieve and maintain control of the disease and reduce the risk of exacerbations. Understanding the underlying pathophysiologic mechanisms is necessary for stratifying patients toward individualized therapy. The implementation of precision medicine requires identifying specific biomarkers easily measurable in biological fluids, which can help in evaluating treatment effectiveness , 15. In In recent years, new drugs based on monoclonal antibodies have been developed against the action of IL-5 in eosinophilic-mediated inflammation. Benralizumab is a humanized IgG1κ monoclonal antibody that binds to IL-5RA via its Fab domain with high affinity and specificity, blocking IL-5 signaling . BesidesIL5RA in patients with different types of asthma and its role as a possible biomarker of response to treatment with benralizumab.The present study aims to investigate the expression of The study involved 347 unrelated Caucasian individuals, 130 controls and 217 asthmatic patients, from the Allergy Department of the University Hospital of Salamanca. The study was approved by the Clinical Research Ethics Committee of the Institute for Biomedical Research of Salamanca (IBSAL) (PI 2020-02-433) and all participants signed a written informed consent. Controls had to fulfill the following criteria: (i) no symptoms or history of asthma, rhinitis or other pulmonary diseases; (ii) no symptoms or history of allergic diseases; (iii) negative skin prick tests with a battery of locally adapted common aeroallergens; (iv) absence of family history of asthma, rhinitis or atopy; and (v) age >16 years old. Asthmatic patients were recruited if they met all the following criteria: (i) at least two symptoms consistent with asthma ; (ii) either a positive bronchodilator or methacholine test; and (iii) absence of other pulmonary disorders; and (iv) age >16 years old.Lung function was measured by spirometry according to the American Thoracic Society (ATS) criteria . Asthma TM-Blood kit . After Ambion DNAse I treatment , RNA was purified and concentrated with the RNeasy MinElute Cleanup Kit . All purification protocols were performed with the modifications indicated by the manufacturers. RNA was quantified by Nanodrop 1000 spectrophotometer . The RNA integrity number (RIN) algorithm was used to determine RNA quality on the Agilent 2100 Bioanalyzer using the Eukaryote Total RNA Nano kit . RNA samples with a RIN value above 8 were used. Globin transcripts and ribosomal RNA were removed, and RNA was cleaved to prepare RNA strand-specific libraries. Finally, the generated libraries were sequenced on the Illumina HiSeq 2500 platform .A total of 60 peripheral blood samples, 30 from healthy controls and 30 from patients with pollen allergic asthma, were selected for a transcriptomic RNAseq study. Total RNA extraction was performed using the Ambion RiboPureP-value <0.05 were considered as differentially expressed genes. Potential interactions between selected proteins were examined by cluster analysis using the STRING software . DNAse treatment was performed using Ambion DNAse I . Concentrations and RNA quality ratios were determined in a Nanodrop 1000 spectrophotometer . cDNA was generated from 500 ng of total RNA using Superscript III First-Strand Synthesis System for RT-PCR , in a final volume of 20 μl. Conditions for PCR included a single cycle and incubation periods of 65°C for 5 min, 25°C for 10 min, 50°C for 50 min, 85°C for 5 min, and 37°C for 20 min.IL5RA primers were designed using Primer 3.0 . The sequence of the primers used are shown in slope−1/ − 1) × 100. All efficiencies ranged from 90 to 110%. The reaction mixture in each well-contained a final volume of 15 μl based on 7.5 μl of Master Mix SYBR Green I , 10 μM of each primers and 20 ng of cDNA. All reactions were performed in triplicate. In each experiment, non-template controls and calibrator were included. The PCR conditions included 10 min at 95°C followed by 45 cycles of 10 s at 95°C for denaturation, 10 s at 60°C for annealing and 10 s at 72°C for polymerization. Finally, melting curve analyses were carried out to verify the specificity of the qPCR products. IL5RA mRNA levels were normalized to GAPDH and TBP expression levels using the formula 2−ΔΔCt by the comparative ΔΔCt method . imer 3.0  and the imer 3.0  softwaret method . All prot method .IL5RA expression in peripheral blood before and after 3 months of treatment with benralizumab was performed in five severe eosinophilic asthmatic patients. Benralizumab was administered at a dose of 30 mg by subcutaneous injection once every 4 weeks. Asthma control test (ACT), fractional exhaled nitric oxide (FeNO) and lung function parameters were performed before and after 3 months of treatment. Patients were considered responders in the ACT score if they achieved a score of 25 or an increase of 3 or more points after 3 months of treatment. Also, they were considered FEV1 responders if they achieved a FEV1.0 ≥ 200 ml or FEV1.0 ≥ 12% after 3 months of treatment. As only three doses were evaluated, exacerbations were not considered. Blood samples were collected and lung function tests were performed at each time point. All patients provided their informed consent to receive benralizumab therapy.A proof-of-concept study of the P-value <0.05 was considered statistically significant. All statistical analyses were performed using SPSS Statistics version 21 . Graphs were plot using GraphPad Prism version 6 .Descriptive analysis was carried out using central (mean and median) and dispersion tendency (standard deviation and interquartile range) measurements, followed by bivariate and multivariate analysis. The normality distribution was assessed by Kolmogorov-Smirnov test and the homoscedasticity was also tested before applying statistical tests. Continuous variables were evaluated using either ANOVA or Kruskal-Wallis test. Statistical significance was assessed by Wilcoxon's test for changes before and after treatment. A P < 0.001), except in the case of non-allergic and late-onset asthma groups, in which the disease had begun at older ages. According to the inclusion criteria, total IgE levels were significantly higher in all patient groups than in controls (P ≤ 0.001). Moderate persistent asthma was the most common type in both the RNAseq study and the validation analysis , followed by intermittent asthma . The most common aeroallergen sensitization in the validation analysis patients was pollen, followed by animal dander. No patient was receiving oral corticosteroids.The phenotypic characteristics of the studied subjects of the RNAseq study and the validation analysis are shown in P < 0.05). P-value and fold change. The main biological roles of these genes are described in IL5RA attracted our attention as a putative asthma biomarker because it was the best positioned when considering both fold change and P-value data, and because of its role in different immune processes.Significant differences between control and asthmatic patients were observed in the transcriptomic assay , PTGDR2 (prostaglandin D2 receptor 2), HRH4 (histamine H4 receptor), TIMP1  and IDO1 . Regarding the role of IL5RA in biological processes, the most significant terms were “immune system process” (FDR 1.74E-07) and “response to stimulus” (FDR 2.52E-06)  , as wellIL5RA expression than controls (P < 0.001). That also occurred in all subgroups except for non-eosinophilic asthma (P = 0.707). Interestingly, the lower increase in IL5RA expression levels was observed in patients with non-allergic asthma (NAA) without NP . Significant differences were observed when comparing these patients with the subgroup of patients who had NAA with NP (P = 0.047). These significant differences were not observed among the other subgroups, although IL5RA expression levels were significantly higher in eosinophilic asthma than in non-eosinophilic asthma (P < 0.001). Also, IL5RA expression levels were slightly higher in monosensitized patients to pollens.A validation qPCR analysis was performed to confirm the differences observed in the RNAseq study. Patients were classified according to the presence of atopy and nasal polyposis (NP), the severity of asthma and the age of onset of asthma. As summarized in IL5RA expression (IL5RA (12.0 ± 13.7), while patients with severe asthma had the highest levels . In addition, there was a statistically significant association between asthma severity and the number of eosinophils (P = 0.015).In general, there was an association between asthma severity and increased levels of pression . PatientIL5RA, patients receiving inhaled corticosteroids or allergen immunotherapy were compared with patients not receiving these treatments. One hundred thirty-nine patients were receiving therapy with inhaled corticosteroids; 54 patients were receiving allergen immunotherapy. No statistically significant differences in the IL5RA expression levels were observed between patients receiving corticosteroid treatment or allergen immunotherapy and patients not receiving these treatments.To discard a possible influence of anti-inflammatory treatments on the expression of IL5RA expression levels and peripheral blood eosinophil counts was also analyzed, observing some correlation with a Pearson's correlation coefficient of 0.520 (P < 0.001). Remarkably, as shown in IL5RA. In addition, an eosinophil count-dependent increase in both IL5RA expression levels and dispersion was observed when the eosinophil counts were divided into quartiles  of peripheral eosinophil count was observed in all patients (P = 0.042) (IL5RA expression levels were reduced between 70–96% after treatment (P = 0.043) . In addition, all patients achieved an ACT score >20 and a mean increase of 30% in FEV1, except patient 4. This patient had the highest pretreatment levels of IL5RA expression, and the improvement of FEV1 reached 50%  . IL5RA e= 0.043) . A stronreatment  with a Pched 50% .Novel biological therapies have increased clinical treatment options for asthma. The necessity of identifying biomarkers to achieve a proper selection of these expensive compounds has led to the application of transcriptomic methods as a starting point for discovering new genes involved in the disease. In a previous transcriptomic study, increased expression of interleukin-4 receptor (IL-4R) on B cells was observed in allergic asthma patients . In the IL5RA turned out to be one of the genes with the highest differential expression, which is also supported by its relevant role in asthma . Nevertheless, as shown by green arrows in IL5RA expression levels compared to their eosinophil counts and vice versa. Also, we found that patients with the same eosinophil counts can show very different IL5RA expression levels. For example, IL5RA expression values ranging from 4 to 32 were observed for counts of 200 eosinophils/μl. This distribution was also found in controls, as variability in IL5RA expression levels was observed at low eosinophil counts. However, the dispersion was considerably more significant in patients with high eosinophil counts. This dispersion was also observed in all subgroups according to asthma severity. It can be speculated that differences could be due to different levels of expression of the IL5RA by eosinophils, caused by unknown elements, such as genetic or environmental factors driving the expression of the receptor. Besides, differences could reflect the expression by other cell types, such as basophils .Following the results obtained in the RNAseq study, we decided to carry out a qPCR validation study to evaluate the performance of the peripheral blood f asthma . This rea r = 0.5. Neverthasophils . FurtherIL5RA expression levels were elevated in both allergic and non-allergic asthma. This finding is in agreement with the fact that responses to benralizumab are not influenced by the atopy status . Thus, we believe that IL5RA expression level could add value to peripheral blood eosinophil counts. Accordingly, the patient with the highest IL5RA expression levels showed the best lung function response and reached an ACT of 25. In a very recent study, Nakajima et al.  (PI 2020-02-433). The patients/participants provided their written informed consent to participate in this study.SE-P, DH-J, AG-S, ME, MM, JR-G, JT, MI-G, CS, and ID have contributed in designing research studies, conducting experiments, acquiring data, analyzing data, and writing the manuscript. All authors read and approved the final manuscript.ID declares having received honoraria for participation in speakers' bureaus or advisory boards from Astra-Zeneca, GSK, and Sanofi. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Background: Hypertension has gained global significance and risk of cardiovascular disease, and adiposity is the most important of the conditions associated with and considered responsible for hypertension in children. Therefore, the present study aimed to determine whether indices of adiposity independently predicted blood pressure at multiple points in gender-specific groups. Methods: This was a cross-sectional study involving 10 randomly selected primary schools within the Ellisras Longitudinal Study, and involved 1816 adolescents (876 girls and 940 boys) aged 8 to 17 years. All the anthropometric indices and blood pressures (BP) were examined according to the International Society for the Advancement of Kinanthropometry protocol. Results: In an adjusted linear quantile regression analysis of boys, waist circumference (WC) was associated with BP across all multiple points of systolic blood pressure (SBP). Furthermore, the triceps skinfold site was associated with high SBP. In girls, body mass index (BMI) was significantly associated with SBP after adjustment for potential confounders. Other anthropometric indices of adiposity, including WC, biceps, and triceps skinfold sites were not associated with SBP. Conclusions: The results of the present study suggest that in black South African children, variables such as WC and triceps skinfold site may provide stronger explanatory capacity to SBP variance and systolic hypertension risk in boys than other adiposity indices; whereas in girls, only WC and BMI predict diastolic blood pressure (DBP) and SBP, respectively. Hypertension is the most common risk factor for cardiovascular disease, the leading global cause of death . HyperteAlthough the large component of hypertension occurs in adulthood, hypertension is considered a lifelong problem that can be progressive from childhood into adolescence and adulthood, such that individuals who have higher blood pressure in early life may have higher blood pressure values in later life . ResearcHowever, information on this association is still limited in the Limpopo Province of South Africa, especially concerning rural children and adolescents, as more emphasis has been placed on the middle aged and elderly population. It is, therefore, in this context that the present study aimed to determine, in black South African children aged 8 to 17 years in the Ellisras Longitudinal Study, whether indices of central (waist circumference), general (body mass index), or subcutaneous (skin-fold thickness) adiposity independently predicted BP at multiple points. This is particularly pertinent, given that Ellisras is reported to be dominated by cardiovascular risk factors, including among others, overweight or obesity and hypertension [This was a cross-sectional study involving 10 randomly selected primary schools within the Ellisras rural area. A total of 1816 children (876 girls and 940 boys) aged 8 to 17 years participated in the study. Informed consent was obtained from all participants, and study protocols were approved by the Turfloop Research Ethics Committee (TREC). Only children who were part of the Ellisras Longitudinal Study and returned the consent form were eligible to participate in the study. Children who did not submit the informed consent form were excluded from the study, together with those who were pregnant.2). Waist circumference (WC) was measured to the nearest 0.1 cm at the midway between the lowest rib and iliac crest with flexible steel tape [All children underwent a series of anthropometric measurements according to the International Society for the Advancement of Kinanthropometry protocol . Height eel tape . Skinfoleel tape .r = 0.93) was found between the readings taken with the automated device and those taken with a conventional mercury sphygmomanometer [Blood pressure was measured using an electronic Micronta monitoring kit. At least three BP readings of systolic blood pressure (SBP) and diastolic blood pressure (DBP) were taken at an interval of five minutes apart, after the child had been seated for five minutes or longer ,11. The anometer .All training of anthropometric measurements was done following the standard procedures of the International Society for the Advancement of Kinanthropometry (ISAK) . The relThe parametric z-test was applied to test the significant differences between sexes at a 5% significance level. The parametric linear quantile regression approach was used in this cross-sectional study to examine the relationship between anthropometric indices and blood pressure subtype levels. The predictive variables included in the models, were age, waist circumference (WC), body mass index (BMI), triceps, and biceps skinfold sites. All the statistical analyses were performed using Stata 13 and R software.p = 0.548). There were significant differences between boys and girls with regard to SBP (p < 0.001), DBP (p < 0.001), BMI (p < 0.001), triceps skinfold site (p < 0.001), and biceps skinfold site (p < 0.001), but no significant differences between the sexes with regard to WC were found (p = 0.240). On average, girls had higher values for their SBP, BMI, and skinfold sites than boys did.The characteristics of the participants are described in p = 0,000 for low value of SBP, p = 0.001 for mid-SBP, and p = 0.009 for high value of SBP). Furthermore, the triceps skinfold site (p = 0.008) was significantly associated with high SBP (p = 0.008), whilst BMI and biceps skinfold site were not significantly associated with SBP in boys . In girls, BMI was significantly associated with mid-SBP (p = 0.009). Other anthropometric indices of adiposity, including WC, and biceps and triceps skinfold sites were not associated with SBP  in girls.p = 0.002) and high DBP (p = 0.031) in girls. Additionally, BMI, triceps and biceps skinfold sites were not significantly associated with outcome variable DBP after adjusting for confounder variable age .The present study presents a rare insight into rural-dwelling black South African children for multiple points change in the association of blood pressure subtypes with anthropometric indices of adiposity. The results revealed that there was a significant difference in the systolic and diastolic blood pressures of girls and boys. Girls had higher mean systolic and diastolic blood pressure than boys. This is inconsistent with the earlier findings , which sThe previous study by Al-Sendi et al., has found a strong association between anthropometric variables  with SBP in both genders . HoweverConsistent with the literature , the preThe mechanism linking anthropometric measurements with low BP in children is not clear. However, it is thought that different anthropometric measurements may have varied impacts on BP. The results of the present study showed that only WC and BMI were significantly associated with low SBP in both boys and girls, whereas WC was only associated with low DBP in girls, which suggests anthropometric gender differences in this population. Several reasons could explain anthropometric gender differences in this population. Firstly, findings similar to those in this study were noted among children, with hormonal changes occurring at puberty being attributed to the observed differences . SecondlAlthough the association between anthropometric indices of adiposity and BP are well established ,18,21, tThe study was affected by the following possible limitations, among others. Firstly, the study was a cross-sectional design, preventing the assertion of a causal association of anthropometric indices of adiposity and blood pressure. Secondly, the sampling technique used may limit the external validity of the study, in that results cannot be generalized to the greater community outside of this group or the total Limpopo Province population. The results of the present study suggests, that in boys, variables such as WC and triceps skinfold site may provide a stronger explanatory capacity to SBP variance risk than other variables; whereas, in girls, only WC and BMI predict DBP and SBP, respectively. Since, individually, BMI and biceps skinfold site were not associated with SBP in boys, whereas in girls WC, biceps, and triceps skinfold sites were not associated with SBP, future research may be needed to build on the results of the present study to investigate the combined effects of anthropometric indices of adiposity on BP. In an area dominated by cardiovascular risk factors, including, among others, overweight or obese and hypertension, there is a need for screening and monitoring of children’s anthropometric indices and blood pressures regularly so that an effective intervention for the prevention and management of chronic diseases may be developed.


Sodium glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) were initially approved to improve glycemic control in the treatment of type 2 diabetes. Clinical trials have also demonstrated beneficial effects with regards to cardiovascular and renal parameters. Beyond improving glycemic control, these therapies promote weight loss and lower blood pressure when used individually, and in an additive manner when used together. Accordingly, taking advantage of complementary mechanisms of action with the combined use of these two classes of agents to further improve cardiorenal outcomes is conceptually appealing, but has yet to be explored in detail in clinical trials. In this review, we discuss proposed mechanisms for renal protection, clinical benefits, and adverse events associated with the individual and combined use of SGLT2 inhibitors and GLP-1RA. The management of type 2 diabetes has significantly changed over the last few years, moving away from solely glycemic control towards the concurrent management of associated comorbidities in a patient population at significant risk of cardiovascular disease and progression of chronic kidney disease. It is from this perspective that we seek to outline the rationale for the sequential and/or combined use of SGLT2 inhibitors and GLP-1RA in patients with type 2 diabetes. Based on the results of recent cardiovascular outcome trials (CVOT) using newer glucose lowering therapies, diabetes clinical practice guidelines have had a renewed focus on cardiorenal protection in patients at significant risk for cardiovascular (CV) and kidney disease. In contrast to other anti-hyperglycemic agents, sodium-glucose contransport-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) have individually demonstrated CV and kidney benefits, as described below. Moreover, combined use of these medication classes in patients with T2D is appealing due to possible mechanistic and clinical synergies. In this article, we review the mechanisms and clinical benefits of SGLT2 inhibitors and GLP-1RA and outline the rationale for their sequential or combined use in people with type 2 diabetes (T2D).--,,---,,It is important to have a general overview of the main hypotheses that have been put forward to explain cardiorenal protection with SGLT2 inhibitors. Detailed reviews of mechanisms linked with cardiorenal protection have been published elsewhere.-,,--,GLP-1RA may similarly have “indirect” and “direct” effects contributing to their kidney protection. For indirect mechanisms, GLP-1RA therapies have a variety of effects on metabolism that may be cardiorenal protective, including reduced postprandial glucose levels by stimulating insulin secretion, reducing glucagon release and hepatic gluconeogenesis, and slowing gastric emptying,,,,,,,GLP-1RAs and SGLT2 inhibitors have beneficial clinical effects on glycemic control, blood pressure, and weight loss, when used alone or together. In terms of glycemic effects, GLP-1RAs reduce mean HbA1c by 0.55-1.2% versus placebo in patients with T2D, with exaggerated effects seen with longer-acting agentsBased on their distinct mechanisms of action and clinical effects, GLP-1RAs and SGLT2 inhibitors may have complementary renal and systemic effects, leading to interest in the potential for their combined use. There is, however, limited data on the combined use of GLP-1RAs plus SGLT2 inhibition on improving glycemic control, blood pressure, and weight. In the 28-week, phase three randomized control trial (RCT) DURATION-8, dual therapy with an SGLT2 inhibitor (dapagliflozin) and a GLP-1RA (once-weekly exenatide) was shown to reduce HbA1c by 0.4% more than either agent alone, in patients with a starting HbA1c of between 8-12%,,Further data comes from AWARD-10, a 24-week, phase three RCT of placebo versus add-on therapy with the GLP-1RA dulaglutide in patients on baseline SGLT2 inhibitionDespite what is known about HbA1c, weight, and blood pressure effects of combination therapy, less is known about other mechanisms associated with cardiorenal protection in response to combination therapy such as natriuresis and renal hemodynamics. In the following sections, we describe individual cardiorenal benefits of these agents before outlining a proposal for their combined used.Among large-scale clinical trials involving SGLT2 inhibitors and GLP-1RA, there exists only one dedicated renal outcome trial that has been published to date. The CREDENCE trial involved patients with T2D, macroalbuminuria, and eGFR 30-90 mL/min/1.73mPrior to CREDENCE, three CVOTs evaluated SGLT2 inhibitors in participant cohorts with varying degrees of CV and renal risk. EMPA-REG OUTCOME included 7020 patients with established atherosclerotic CV disease (ASCVD),,EMPA-REG OUTCOME first demonstrated significant reductions in primary 3-point MACE endpoint, CV mortality, overall mortality, and hospitalization for heart failure (HHF) in its entire cohort and in subgroups with varying baseline renal function and proteinuria,,Subsequent to the EMPA-REG OUTCOME trial being published, the CANVAS Program reported its results. This trial comprised an intermediate CV risk cohort and also demonstrated significant reductions in MACE, without individual improvements in all-cause or CV mortalityThe benefit of SGLT2 inhibition on HHF was further shown in the DAPA-HF trial, which importantly included participants with heart failure and reduced ejection fraction (HFrEF) with and without T2D-To date, seven CVOTs assessing GLP-1RA have been published, combining a total of 56,004 patients. Multiple meta-analyses certainly confirm a benefit in terms of reductions in MACE in patients with established ASCVD, and reductions in the risk of stroke,,-For kidney protection, benefits have been reported with GLP-1RA, though less substantial compared to those that have been established in the SGLT2 inhibitor literature. In pre-specified secondary renal outcome analyses in LEADER, new-onset persistent macroalbuminuria, persistent doubling of serum creatinine, need for renal replacement therapy (RRT), and death due to renal disease were reduced with a hazard ratio of 0.78 and an NNT of 67 Perhaps the most convincing data for kidney protection beyond albuminuria lowering stems from the AWARD-7 trial. This study evaluated dulaglutide against insulin glargine in 577 patients with moderate-to-severe CKD . The addition of eGFR neutral GLP-1RA to hemodynamically active RAAS inhibition or SGLT2 inhibition may be desirable under such circumstances given their possible direct renal benefits that are independent of acute GFR “dip” effects.,,,post-hoc analyses have shown that GLP-1RA is safe and well tolerated in patients with kidney disease,SGLT2 inhibitors are well tolerated, with mycotic genital infections the most common side effect and diabetic ketoacidosis, a rare but potentially serious complication-GLP-1RA have a glucose-dependent mechanism of action and low rates of hypoglycemiaThe use of SGLT2 inhibitors and GLP1-RA individually has significantly increased over the past several years. With the emergence of clinical trials in non-diabetic patient populations demonstrating benefits of these agents in cardiovascular and renal outcomes, use of these drugs is anticipated to expand into the arsenal of nephrologists, cardiologists, and neurologists. We expect their combined use to similarly increase, particularly in patients with multiple comorbidities. With respect to their individual use, important questions remain unanswered, including whether or not GLP-1RA reduces the risk of end stage kidney disease or doubling of serum creatinine in cohorts with DKD at baseline - a question currently being studied in the ongoing FLOW trial with semaglutide. In addition, it is not known if there is a lower kidney function limit for cardiorenal protection with either class of drug, especially in patients with non-diabetic conditions. Finally, patients with type 1 diabetes and solid organ transplant recipients, particularly kidney transplant recipients, are other populations in which ongoing investigation for use of these agents is warranted. Ultimately, based on data from studies using individual therapies, it is now of the utmost importance to elucidate the role of combination SGLT2 inhibitor-GLP-1RA therapy as a strategy to reduce cardiorenal complications.


Introduction: Mitral stenosis is associated with an atrial cardiomyopathic process, leading to abnormal atrial electrophysiology, manifesting as prolonged P-wave duration (PWD), larger P-wave area, increased P-wave dispersion (PWDmax—PWDmin), and/or higher P-wave terminal force on lead V1 (PTFV1) on the electrocardiogram.Methods: This was a single-center retrospective study of Chinese patients, diagnosed with mitral stenosis in sinus rhythm at baseline, between November 2009 and October 2016. Automated ECG measurements from raw data were determined. The primary outcome was incident atrial fibrillation (AF).Results: A total 59 mitral stenosis patients were included  males). New onset AF was observed in 27 patients. Age , systolic blood pressure , mean P-wave area in V3  were significant predictors of incident AF. On multivariate analysis, age  and P-wave area in V3  remained significant predictors of AF. Receiver-operating characteristic (ROC) analysis showed that the optimum cut-off for P-wave area in V3 was 1.45 Ashman units (area under the curve: 0.65) for classification of new onset AF. A decision tree learning model with individual and non-linear interaction variables with age achieved the best performance for outcome prediction .Conclusion: Atrial electrophysiological alterations in mitral stenosis can detected on the electrocardiogram. Age, systolic blood pressure, and P-wave area in V3 predicted new onset AF. A decision tree learning model significantly improved outcome prediction. P-wave duration of >120 ms. This condition results in delayed and asynchronous activation of the left atrium , is a measure of heterogeneous and discontinuous atrial activation. Secondly, P-wave terminal force in V1 (PTFV1) is a marker of left atrial disease independently of structural or pressure changes in the left atrium  results from impaired conduction of action potentials along Bachmann's bundle that connects the right and left atria . The ECG waveform data is captured at a sample rate of 4 MHz and reduced to 500 samples per second with 5 μV resolution. The mean, minimum, maximum, and standard deviation of different P-wave variables were calculated from values from all 12 leads  was defined as the area subtended by the terminal negative component of a biphasic P-wave in lead V1, with the area calculated by multiplication of the duration and depth of the waveform . The following parameters were manually measured by two investigators from the ECGs showing sinus rhythm. The following 12 leads . P-wave P < 0.05 was considered statistically significant. Non-linear interactions  play an important role in predicting the outcome. The consideration of non-linear interactions overcomes linear model's assumption that the dependent and independent variables are linearly related. In this study, the logarithmic form of the multiplication non-linear items formed by age  and other continuous variables were considered, i.e., log, log(age*diastolic blood pressure), log(age*diabetes mellitus), log, log, log, log, log, log(age*P-wave area in v3). For instance, for a patient whose age is 58 years old and has systolic blood pressure 110 mmHg, we generate the value of non-linear variable log(age*systolic blood pressure) by calculating log(58*110) = 3.8048. The values for the other non-linear variables are obtained in a similar way. Then these non-linear variables and the individual variables are together used as input in the risk prediction model. The reproduction of the non-linear variables can be obtained since there exists one-one mapping between the non-linear variables and the individual variable pairs that form them.Data were expressed as median [lower quartile to upper quartile]. Categorical data were analyzed by Fisher's exact test. Differences between study groups were tested using Kruskal-Wallis ANOVA. *systolic blood pressure), log(age*diastolic blood pressure), log(age*diabetes mellitus), log(age*hypercholesterolaemia), log(age*ischaemic heart disease), log, log, log, log, log(age*P-wave area in v3) together with individual variables  were used as input to the DTL model, in order to predict the new onset of AF outcome in mitral stenosis. In the DTL model, leaves represent class label of new onset AF and branches represent feature conjunctions  that lead to new onset AF. DTL uses Gini index to construct a decision tree, which is calculated by the formula c denotes the number of class (c = 2 for new onset AF classification in this study). The Gini index is used to create split points by considering a binary split for each variable in DTL. It varies between 0 and 1, where 0 denotes that all elements belong to a certain class or if there exists only one class, and 1 denotes that the elements are randomly distributed across various classes. A Gini Index of 0.5 denotes equally distributed elements into some classes.Decision tree learning uses a decision tree module (as a predictive model) to determine the outcome  of a sample based on the associated observations (represented by branches) for model classification and prediction. The principles of decision tree are illustrated in *(8/13)*(1–8/13) =0.4734, Gini index  = 2*(19/46)*(1–19/46) = 0.4849. In addition, the frequency table of ischaemic heart disease was considered: eight of 12 with ischaemic heart disease had new onset AF, and 19 of 47 without ischaemic heart disease had new onset AF. The corresponding Gini index was calculated by Gini = 2*(8/12)*(1–8/12)=0.4444, Gini index=2*(19/47)*(1–19/47) = 0.4817. In the same manner, the Gini indices of all the variables  was calculated. DTL splits the dataset on different variables by referring to the Gini indices, and the variable with the lowest Gini index value was selected as the decision node. DTL divided the dataset by its branches and repeat the same process on every branch. A branch with zero Gini index becomes a leaf node, while a branch with Gini index larger than zero needs further splitting. DTL is run recursively in a similar way on the non-leaf branches, until all data were classified.Here we present an example to show the construction process of DTL with Gini index. Firstly, the frequency table of new onset AF outcome (27 with “yes” and 32 with “no”) was considered: there are 19 of 46 females with new onset AF, while eight of 13 males with new onset AF. The Gini index for sex as a decision node to split the tree was calculated: Gini index  = 2n = 155) were screened. In this cohort, 96 had atrial fibrillation on admission to our hospital without prior ECGs in sinus rhythm available for analysis. The remaining 59 patients were in sinus rhythm and were analyzed further. A graphical representation of the different P-wave indices is shown in Electrocardiograms of patients with mitral stenosis (P-wave dispersion (84 [62–116] vs. 82 [57–110] ms), standard deviation of PWD (28 [17–33] vs. 24 [16–33] ms), mean P-wave amplitude (0.11 [0.09–0.15] vs. 0.11 [0.09–0.13] mV), minimum P-wave amplitude (0.05 [0.03–0.07] vs. 0.05 [0.03–0.06] mV), maximum P-wave amplitude (0.18 [0.15–0.25] vs. 0.19 [0.16–0.23] mV), dispersion of P-wave amplitude (0.14 [0.10–0.17] vs. 0.14 [0.11–0.19] mV), standard deviation of P-wave amplitude (0.04 [0.03–0.06] vs. 0.04 [0.03–0.06] mV), mean P-wave area (0.12 [0.09–0.14] vs. 0.10 [0.09–0.13] Ashman units [40 ms × 0.1 mV]), minimum P-wave area (0.05 [0.04–0.07] vs. 0.05 [0.03–0.06] Ashman units), maximum P-wave area (0.22 [0.17–0.26] vs. 0.18 [0.14–0.26] Ashman units), dispersion of P-wave area (0.16 [0.11–0.20] vs. 0.12 [0.11–0.16] Ashman units), standard deviation of P-wave area (0.05 [0.04–0.06] vs. 0.04 [0.03–0.04] Ashman units), Neither P-wave initial force in V1 (PIFV1: 7.6 [3.7–11.7] vs. 3.6 [1.7–11.0] ms.mV) nor P-wave terminal force in V1 (PTFV1: 2.7 [0–6.9] vs. 3.8 [0–8.3] ms.mV) differed between the groups. Similarly, no difference in left atrial diameter was detected . By contrast, P-wave area in V3 was significantly higher in the new onset AF group .A total of 27 patients developed new onset AF over a median follow-up of 58 [48–76] months. Patients with new onset AF had similar mean PWD (102 [95–118] vs. 101 [89–115] ms), minimum PWD (56 [40–68] vs. 52 [38–65]), maximum PWD (152 [132–164] vs. 136 [123–160] ms), P = 0.017), systolic blood pressure , mean P-wave area in V3  were significant predictors of incident AF. Variables that achieved P < 0.10 in univariate logistic regression were included in the multivariable model (P = 0.037) and P-wave area in V3  remained significant predictors of AF. Receiver-operating characteristic (ROC) analysis showed that the optimum cut-off for P-wave area in V3 was 1.45 Ashman units with an area under the curve of 0.65 for classifying new onset AF.The results of univariate logistic regression are shown in le model . On multn = 47) were randomly selected and the remaining 20% (n = 12) were used for validation. For the decision tree without interacting variables, P-wave area in V3 is the first predictor generated with a Gini index of 0.496 (P-wave area in V3 as the second most important variable with Gini index 0.278 (A decision tree learning (DTL) model was then employed to generate the decision rules based on only individual variables as shown in of 0.496 . In addiex 0.278 . Both deP-wave area in V3 and age was significantly predictive for classifying new onset AF outcome in mitral stenosis. We can also observe that several non-linear variables are more predictive than individual variables, indicating the importance of considering the non-linear patterns in clinical characteristics to improve the performance of predicting new onset AF.To determine the out-of-sample prediction ability of the model, five-fold cross-validation was adopted. The evaluation metrics evaluated are accuracy, precision, recall, and F-measure. Comparisons of the prediction performance of logistic regression and DTL are shown in P-wave area in V3 predicted new onset AF, and (iii) a stepwise improvement in the predictive performance after incorporation of interaction variables and machine learning using a decision tree approach.The major findings of this study are that (i) a high proportion of patients with mitral stenosis had IAB, (ii) age and P-wave morphologies and indices in non-valvular atrial fibrillation. Whilst some reports have dealt with the relationship between mitral stenosis and P-wave indices, few studies have examined whether these indices can predict new onset AF. Atrial electrophysiology in mitral stenosis is abnormal due to a complex process of electrophysiological remodeling. IAB is the conduction delay along the Bachmann's bundle between left and right atria, diagnosed by its characteristic ECG pattern , including P-wave dispersion and abnormal P-wave terminal force in V1 (PTFV1)  whether left atrial area, volume or volume index can predict incident AF and (ii) the potential effects on atrial reverse remodeling by drugs. Our main conclusion that Atrial electrophysiological alterations in mitral stenosis can detected on the electrocardiogram. Age, systolic blood pressure, and mean PWD predicted new onset AF. A decision tree learning model significantly improve outcome prediction.All datasets generated for this study are included in the article/The studies involving human participants were reviewed and approved by The Joint Chinese University of Hong Kong—New Territories East Cluster Clinical Research Ethics Committee. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.GT: conception of study and literature search, figures, study design, data collection, data analysis, data contribution, manuscript drafting, and critical revision of manuscript. IL: literature search, data analysis, data contribution, manuscript drafting, and critical revision of manuscript. JZ and KLi: data analysis, manuscript drafting, and critical revision of manuscript. SL, YL, KLe, and TL: data interpretation, and critical revision of manuscript. AB: literature search, data analysis, critical revision of manuscript, and study supervision. QZ: literature search, figures, study design, data analysis, manuscript drafting, critical revision of manuscript, and study supervision.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


We apply a pattern-based classification method to identify clinical and genomic features associated with the progression of Chronic Kidney disease (CKD). We analyze the African-American Study of Chronic Kidney disease with Hypertension dataset and construct a decision-tree classification model, consisting 15 combinatorial patterns of clinical features and single nucleotide polymorphisms (SNPs), seven of which are associated with slow progression and eight with rapid progression of renal disease among African-American Study of Chronic Kidney patients. We identify four clinical features and two SNPs that can accurately predict CKD progression. Clinical and genomic features identified in our experiments may be used in a future study to develop new therapeutic interventions for CKD patients. It also helps to regulate the levels of minerals such as sodium, calcium, and potassium in blood. One suffers from chronic kidney disease (CKD), also known as renal disease, when kidney losses its function gradually and usually permanently. CKD, defined by reduced glomerular filtration rate (GFR), proteinuria, or structural kidney disease, is a worldwide growing public health problem2. Patients were randomized to the angiotensinogen converting enzyme inhibitor (ACEi) ramipril, the β-blocker (BB) metoprolol or the dihydropyridine calcium channel blocker (CCB) amlodipine, and to usual  or low (MAP African-American Study of Chronic Kidney disease with Hypertension (AASK) was motivated by the high rate of hypertension-related chronic kidney disease in the African-American population and the scarcity of effective therapies. The study involved 21-center randomized double-blinded treatment trial of 1,094 African-American patients with hypertension at ages ranging from 18 to 70 years. Patients had renal failure with GFR between 20 and 65 ml/min/1.73m effects , and the effects . Althougparation , AASK isor death .The initial AASK results were not conclusive . While tia/24 h) . The lowia/24 h) . Studiesia/24 h) ; howeveria/24 h) . Finallyia/24 h) . Most imia/24 h) . These dSeveral possible interventions such as blood pressure control , diabeteThe goal of our current study is to apply a pattern-based classification method to identify clinical and genomic features that may serve as prognostic markers for the progression of renal disease among AASK patients. Clinical and genomic features identified in our analysis shall be used in a future study to obtain comparison of the disease progression in white patients and African-American patients, both of those with and those without apolipoprotein L1 (APOL1) high-risk variants. The ultimate goal of our AASK data analysis, started in  and cont2Closer inspection of the data highlights the current dilemma: although there is a 00mg/day  and 2. I00mg/day , the Col00mg/day , RENAAL 00mg/day  and IDNT00mg/day .l/min/yr , althougl/min/yr . Based os, left) . This das, left) .2.1An avenue that has not been carefully explored is a data mining approach to detect the combinations of clinical features and/or single nucleotide polymorphisms (SNPs) that better determine the population at risk for progression of CKD. The goal of this section is to identify combinatorial patterns of clinical features and SNPs that can accurately predict progression of the renal disease among AASK patients. In order to achieve this, we perform a study on a selected subset of subjects from the AASK Clinical Trial based on the glomerular filtration slope (GFR) of all AASK patients presented in 2.2The resulting AASK dataset consisting of 138 rapid progressors, 75 slow progressors, 77 clinical features, and 113 SNPs, is further investigated to remove any features irrelevant for the recognition of a rapid progressor as opposed to a slow progressor. In order to obtain a classification model effectively and efficiently, we first apply a correlation-based feature selection procedure  to retai33.1-agonist (peripherol base), proteinuria, urine-protein/urine-creatinine, GFR value at G1 visit, where α-agonist represents the use of peripheral alpha-2 agonist blood pressure medication• four clinical features: α• two SNPs: CHGB-1, PLCG2 rs4399527.These six features were validated using 10 × 10-folding cross-validation experiments on seven commonly used and well-known classification methods, including Random Forest, Decision Trees, Nearest Neighbor, Support Vector Machines, Neural Networks, Logistic Regression, and Naïve Bayes . In thisAs can be seen in rapid prevalence: proportion of rapid progressors covered by a pattern to the total number of rapid progressors,• slow prevalence: proportion of slow progressors covered by a pattern to the total number of slow progressors,• rapid homogeneity: proportion of rapid progressors covered by the pattern,• slow homogeneity: proportion of slow progressors covered by the pattern,• degree: number of conditions appear in the description of the pattern of the C4.5 classification model are given in •  The pattern characteristics including3.2We remark that the C4.5 classification model given in As for the prevalence, patterns S4 and R8 are significant patterns, S4 covering Based on the 10 × 10-folding cross-validation experiments, the classification model correctly classifies Thus, we can conclude that the combinatorial patterns forming the classification model in https://repository.niddk.nih.gov/studies/aask-trial/.The datasets generated for this study can be found in the African American Study of Kidney Disease and Hypertension Study   ES, ML, and MMS are senior co-authors who designed and supervised the entire project and participated in writing the manuscript. MMM, TB, and MSM participated in the study design and performed the combinatorial analysis and participated in writing the manuscript. KC, EC, ZA, and RP were involved in various steps of the combinatorial analysis.ML, ES, and MMS’s work was supported by National Institutes of Health—Grant number: 5R21DK67468. KC and EC’s work was supported by National Science Foundation (NSF) Research Experience for Undergraduates (REU) Grant—Award number: 1,359,341.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Very low-calorie ketogenic diets (VLCKD) are an effective and increasingly used tool for weight loss. Traditionally considered high protein, ketogenic diets are often looked at with concern by clinicians due to the potential harm they pose to kidney function. We herein evaluated the efficacy and safety of a VLCKD in patients with obesity and mild kidney failure. A prospective observational real-life study was conducted on ninety-two patients following a VLCKD for approximately 3 months. Thirty-eight had mild kidney failure and fifty-four had no renal condition and were therefore designated as control. Anthropometric parameters, bioelectrical impedance and biochemistry data were collected before and at the end of the dietary intervention. The average weight loss was nearly 20% of initial weight, with a significant reduction in fat mass. We report an improvement of metabolic parameters and no clinically relevant variation regarding liver and kidney function. Upon stratification based on kidney function, no differences in the efficacy and safety outcomes were found. Interestingly, 27.7% of patients with mild renal failure reported normalization of glomerular filtrate after dietary intervention. We conclude that, when conducted under the supervision of healthcare professionals, a VLCKD is an effective and safe treatment for weight loss in patients with obesity, including those affected by mild kidney failure. The epidemic of obesity and its comorbidities represents an increasingly worrisome medical and economic burden according to WHO reports . SeveralAccording to the thrifty gene theory, obesity and its complications are due to the change in food type and availability. In fact, insulin resistance has been linked to the lack of fasting and fullness succession, leading to a reduced ability to safeguard glucose for the most important functions, such as cerebral activity and reproduction . Based oVery Low-Calorie Ketogenic Diets (VLCKDs), dietary interventions falling into the fasting mimicking ones, are characterized by a very low carbohydrate content (<20 g/daily), 1–1.5 g protein/Kg ideal body weight, 15–30 g fat/daily and about 500–800 caloric intake/daily . To favoA systematic review investigating renal outcomes reported that the kidney seems little affected by Very Low Calorie Diets, although the assessed studies only included adults with normal kidney function, and the diets were quite heterogeneous in macronutrient ratio, making results difficult to interpret . Little We therefore herein evaluated the effect of a VLCKD in terms of weight loss, improvement of metabolic syndrome markers and safety outcomes in a population with mild kidney failure and healthy control subjects.2, and NKF  subjects, with an eGFR ≥ 90 mL/min/1.73 m2. This was a real life observational prospective study conducted at the High Specialization Centre for the Care of Obesity, Sapienza University of Rome. Patients with obesity accessing the Centre had medical history collected, physical exam and laboratory work performed  as part of the routine all patients accessing the center undergo for initial evaluation. Those willing to undergo a VLCKD for weight loss purposes were enrolled, so long as they were in absence of contraindications according to national guidelines, such as known hypersensitivity to one or more components used in the meal replacement products; history of cardiac, cerebrovascular, or major gastrointestinal diseases; psychiatric disturbances; diagnosis of insulin-dependent diabetes mellitus (IDDM); pregnancy; lactation; CKD with an estimated glomerular filtration rate (eGFR) <60 . Based oThe study protocol was approved by the Medical Ethical Committee of Sapienza University of Rome (ref. CE5475). The study was conducted in accordance with the Declaration of Helsinki (1964) and subsequent amendments. All participants provided written consent before starting their participation in the study.All patients underwent a VLCKD with the use of replacement meals following a protocol consisting in 5 steps . During the first two steps, net carbohydrate intake was set between 20 and 50 g/day. Ketosis was confirmed every week with the use of commercially available urine reagent strips . Protein and lipid intake were approximately 1–1.4 gr/kg of ideal body weight/day and 15–30 g/day, respectively. Recommended water intake was at least 2 lt/day. Total caloric intake was between 450 and 800/day based on calculated ideal body weight. To avoid micronutrients deficiency, mineral and vitamin supplements were recommended throughout the dietary intervention as per current guidelines . During Body weight and height were obtained in fasting subjects wearing light clothing and no shoes with an empty bladder. The same calibrated scale and stadiometer were used for all patients. Waist circumference was measured in the same instance at the midpoint between the lower rib margin and the iliac crest, the patients had their waist uncovered and were asked to stand with their feet close together and their weight equally distributed on each leg. Systolic and diastolic blood pressure were measured at baseline and at the end of the intervention.Bioelectrical Impedance Analysis (BIA) was performed to evaluate indices of body composition : with Fat, Fat Free and Skeletal Muscle Mass  expressed in kg, and Total Body, Intra Cellular and Extra Cellular Water  expressed in lt. 2 [Blood samples were collected by venipuncture between 8 a.m. and 10 a.m. after an overnight fast. Samples were then transferred to the local laboratory and handled according to the local standards of practice. Insulin, Glucose, Glycosilated Haemoglobin A1C (HbA1C), lipid profile, electrolytes, uric acid, liver enzymes, and renal function were measured. Glomerular Filtration Rate (GFR) was calculated with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, that performs better than other equations at higher GFR, with less bias and greater accuracy, especially when actual GFR is >60 mL/min per 1.73 m2 . t-test. Between group differences were assessed by general linear mixed model analysis of end of diet variables of the NKF and MCKD groups. The variables of group, baseline values, age and gender were included in the model as fixed effects. Differences were considered statistically significant when p < .05. Statistical analysis was performed using GraphPad Prism Version 6.00 for Windows, GraphPad Software, San Diego California USA and SPSS Statistics for Windows, Version 25.0, Armonk, NY, USA: IBM Corp. Data are expressed as mean ± standard deviation (SD) for continuous variables and as percentage for dichotomous variables. Normality was assessed with the Shapiro–Wilk test and variables were Log transformed when the distribution was non-normal. Within-group analysis was performed by dependent sample Student 2. Baseline characteristics are summarized in Ninety-two patients with obesity (23 men and 69 women) were consecutively evaluated. The mean age was 51.3 ± 12.2 years; the mean BMI was 33.8 ± 5.8 kg/mp-value < 0.0001; and 3.53 ± 0.51 vs. 3.70 ± 0.46, p-value 0.005, respectively), whereas sodium and potassium were stable, as was PTH  levels. The mild but significant dehydration of the subjects at the end of the diet might justify the small increase in albumin and BUN levels. Calcium and phosphate levels showed a slight increase within normal ranges  subjects had a glomerular filtration volume (GFV) between 60 and 89 mL/min, corresponding to Stage 2 Chronic Kidney Disease, and 54 NKF  subjects had a GFV equal to or higher than 90 mL/min. MCKD subjects were then compared to NKF. Unsurprisingly, the MCKD group had a mean age that was higher than that of NKF, but the groups were not different relative to anthropometric parameters other than fat mass, significantly lower in the MCKD, albumin (lower in NKF), and sodium, again lower in NKF. No significant differences in anthropometric parameters , blood pressure or biochemical parameters  were found between the two groups over time . MoreoveManagement of obesity is of constantly increasing concern nowadays, and chronic kidney disease is a possible complication that may require extra care. Among the available strategies for weight loss and maintenance, VLCKDs are an effective tool, but some concern is present with regard to the treatment of patients with renal failure due to the relative dietary protein excess.In our real-life observational study, we first assessed the entire enrolled population without taking renal function into account. We report a significant overall weight reduction as expected, with a mean body weight decrease of nearly 20%, and a significant reduction in fat mass  in less than 3 months of dietary treatment, consistent with previous studies . A statiIn fact, hepatic enzymes AST and ALT showed a tendency to decrease, despite not reaching significance, and triglycerides were profoundly decreased, all of which is consistent with reduced intrahepatic triglyceride content and liver size reduction, as previously described in patients with obesity undergoing a VLCKD before bariatric surgery ,20. No cWe also observed a significant but slight increase in calcium and phosphorus levels , that might be attributable to two possible reasons: First, mild dehydration, as observed by TBW reduction, and expected as a result of the significant diuretic effects of VLCKDs, might be responsible for the relative increase in calcium and phosphorus levels due to simple hemoconcentration. The observed elevation in albumin levels point in the same direction. Second, calcium and phosphorus levels could also be increased following bone loss, as it was previously observed in patients on severely calorie-restricted regimens with profound weight reduction . Of noteFerritin levels were also marginally modified by dietary intervention, with a significant reduction over time. As ferritin has been shown to be a marker of inflammation rather than iron deficiency in subjects with obesity , and ket2) of kidney function at the end of the dietary intervention, suggesting that not only is VLCKD an effective and safe weight loss tool in MCKD patients with obesity, but that it also could help ameliorate renal function.Subjects included in this study were then stratified in two groups based on renal function. No differences between groups were shown in anthropometric parameter changes  or metabolic profile improvement. Interestingly, a significant proportion of MCKD patients reported a full recovery (eGFR ≥ 90 mL/min/1.73mRelative protein excess typical of VLCKDs has been of major concern among clinicians for its kidney-damaging potential, preventing many to propose this intervention to patients with CKD in need of weight loss. In order to assess this safety outcome, creatinine, BUN, eGFR and urinary proteins were evaluated. Creatinine and eGFR were not affected by the dietary intervention and no differences were observed in the between group analysis. Conversely, BUN was slightly increased, most likely as a consequence of increased protein metabolism as previously described , with agThe major strength of our study is the real-life setting and the fact that—to the best of our knowledge—we stratified by renal function for the first time. However, our study also has several limitations. Ketosis was only assessed through urinary excretion of acetoacetate, and no capillary beta-hydroxybutyrate levels were measured due to technical obstacles. Markers of renal function that are unaffected by muscle mass—such as cystatin C—were not assessed, as the real-life setting did not allow so. However, previous evidence shows that creatinine is only very marginally affected by muscle mass , and we In conclusion, safety markers including kidney function were unchanged throughout the study and not differentially affected by intervention in the two groups, with efficacy outcomes confirming those of previous studies and—most likely—not depending on kidney function. VLCKD is therefore a safe and effective dietary intervention in patients with obesity affected by mild CKD when conducted under medical supervision in a real-life setting, although caution should be taken in screening for a lack of micronutrients and for altered bone metabolism, as well as in accurately monitoring protein consumption at all times.


To observe the changes of the retinal nerve fiber layer (RNFL) thickness and the optic disc vessel density (VD) in preclinical diabetic retinopathy (DR) and the relationship between RNFL changes and VD, as well as to investigate the influencing factors on peripapillary vessel density.  This was a cross-sectional study. Thirty-four eyes of 34 type 2 diabetes mellitus (T2DM) patients diagnosed with preclinical diabetic retinopathy (DR) were included in our study, with twenty-three eyes of 23 healthy subjects set up as normal controls. History of diabetes, hypertension, and dyslipidemia was recorded in detail. All participants underwent color fundus photography (CFP), RNFL around the optic disc, and OCT angiography (OCTA) over the optic disc. The 4.5 mm × 4.5 mm Angio Disc scan mode was performed with all participants by using the OCTA instrument. The relationship between changes of RNFL in the four quadrants  and VD changes was analyzed. t = −2.27) and temporal (t = −2.02) peripapillary sectors of diabetic eyes compared to normal eyes (P < 0.05). The retinal nerve fiber layer (RNFL) was significantly thinner in the temporal quadrant (P < 0.001) of diabetic eyes compared to normal eyes. Pearson correlation coefficient analysis showed a significant positive correlation between vessel density and RNFL thickness in the peripapillary region in the temporal  and superior  sectors. Multiple linear regression analysis showed that glycated hemoglobin (HbA1c)  and the duration of diabetes  were associated with peripapillary vessel density.  Vessel density was significantly lower in the superior ( Preclinical DR presented optic disc microcirculation changes. Temporal RNFL thinning is an early sign of retinal neurodegeneration and is associated with temporal peripapillary vessel density reduction. The duration of diabetes and HbA1c are risk factors for peripapillary vessel density reduction in patients with preclinical DR. Diabetic retinopathy (DR) was previously considered as a microvascular disease. The microvascular dropout of the macular area in preclinical and early-stage DR has been frequently reported in recent OCTA studies. And Liu et al.  found a Optical coherence tomography angiography (OCTA) has been considered as a useful tool to noninvasively investigate retinal microvascular changes and directly quantify the vessel density of the optic disc . This stThis was a cross-sectional study. The study was approved by the Ethics Committee of Changsha Xiangjiang Aier Eye Hospital  and was conducted according to the Declaration of Helsinki. Thirty-four preclinical DR eyes of 34 type 2 diabetes mellitus patients and 23 eyes of 23 healthy controls were included. The participants were recruited at Xiangjiang Aier Eye Hospital in Changsha, China, from January to September 2019. All participants were informed of the aims and procedures of the study and signed informed consent forms. Data on the participants' age, gender, blood pressure, course of diabetes, glycated hemoglobin, triglyceride, total cholesterol, high-density lipoprotein, and low-density lipoprotein levels were recorded.The inclusion criteria were as follows: (1) for the preclinical DR group, clinical diagnosis of type 2 diabetes; for the control group, no history of diabetes and high blood sugar. (2) No microaneurysm, bleeding points, or exudation in color fundus photography and fundoscopy after mydriasis induction. (3) Lens power spherical equivalent less than −6.00D. (4) OCTA image signal intensity ≥6. The exclusion criteria were as follows: (1) diabetic retinopathy in one eye. (2) History of eye trauma and surgery. (3) Intraocular pressure ≥21 mmHg and history of glaucoma. (4) Systolic pressure ≥140 mmHg or (and) diastolic pressure ≥90 mmHg. (5) Uveitis, retinal vein occlusion, age-related macular degeneration, or other retinal diseases.Each patient underwent a series of ocular examinations that included a biomicroscopy examination of the fundus, OCTA, color fundus photography, and intraocular pressure measurement using a noncontact tonometer. Preclinical DR was confirmed based on the clinical assessment by retinal specialists and color fundus photography. The less seriously affected eye of each patient was chosen. If neither eye of a patient had retinopathy, the eye with the higher image signal intensity was chosen.OCTA imaging of the optic disc was performed using the AngioVue OCTA system . A 4.5 × 4 .5 mm rectangle scan centered on the optic nerve head was performed. The newly developed, built-in AngioAnalytics software was used to measure vessel density and RNFL thickness. Vessel densities for the whole 4.5 × 4.5 mm scan area (whole image), optic disc area (inside disc), and peripapillary region (a 0.75 mm wide annular area extending outward from the optic disc boundary) , as wellt-tests. Pearson correlation analysis was used to analyze the correlation between the average RNFL thickness and the blood flow density. In the NDR group, some systemic factors and peripheral blood flow density were analyzed by multiple regression. P < 0.05 was considered statistically significant.SPSS software (version 19.0) was used for statistical analysis. All data were tested for Shapiro–Wilk normality. The measurement data were expressed as mean ± standard deviation. The difference between the measurement indicators between the two groups was compared using two independent sample All demographic data and general clinical characteristics are shown in t = −2.51, P=0.015), inside the disc area , and the peripapillary area   .t = −2.20, P=0.04). The vessel density in the superior and temporal sectors of the peripapillary area was significantly lower in the preclinical group than in the control group   .r = 0.344, P=0.047). The RNFL thickness in the upper and temporal discs positively correlated with blood flow density in the respective areas . The F-test results of the regression model showed that the linear relationship of the equation was significant . The Durbin–Watson test was used to determine whether the dependent variable values were independent of each other. The P value was not significant (P=1.72), indicating that there was no autocorrelation between the dependent variables and that the errors were independent of each other. The model's residual normal probability plot (P-P plot) shows that the points are basically scattered around the straight line, indicating that the residuals basically conform to the normal distribution , we speculate that decreased RPC vessel density results in insufficient nutritional supply to the RNFL in the corresponding area, leading to a decrease in RNFL thickness. This is consistent with the results of Cao et al. [Previous studies , 16 haveo et al.  who usedDiabetes duration and HbA1c have been shown to be high-risk factors for DR . Our resAccording to the level of HbA1c, Zhu  divided This study has some limitations. The main limitation is that we analyzed blood perfusion in an optic disc area of 4.5 × 4.5 mm. We did not include the vessel density of the macular area. The vessel density of the non-DR eye may change in the optic disc area and the macular area. Moreover, this study included only preclinical DR patients. We did not analyze optic disc vessel density in DR patients. Furthermore, there may be a relationship between the factors included in the multiple regression analysis, which requires further analysis. Although multiple regression analysis indicated that the duration of diabetes and the HbA1c and blood lipid levels are related to peripapillary vessel density reduction, the correlation was weak. One explanation may be that peripapillary vessel density may be affected by many other factors. Finally, the sample size of this study was small. Furthermore, studies with larger sample sizes are needed.In conclusion, vessel density in the peripapillary region and inside the optic disc decreases in diabetic eyes, suggesting changes in the optic disc microcirculation in preclinical DR. Temporal RNFL thinning is an early sign of retinal neurodegeneration and is associated with temporal peripapillary vessel density reduction. The duration of diabetes and HbA1c are risk factors for peripapillary vessel density reduction in patients with preclinical DR. Early management and effective blood glucose control in diabetic patients may be beneficial for preventing RNFL thinning in the temporal disc.


The increasing access to antihypertensive medications has improved longevity and quality of life in hypertensive patients. Nevertheless, hypertension still remains a major risk factor for stroke and myocardial infarction, suggesting the need to implement management of pre- and hypertensive patients. In addition to antihypertensive medications, lifestyle changes, including healthier dietary patterns, such as the Dietary Approaches to Stop Hypertension (DASH) and the Mediterranean diet, have been shown to favorably affect blood pressure and are now recommended as integrative tools in hypertension management. An analysis of the effects of nutritional components of the Mediterranean diet(s) on blood pressure has therefore become mandatory. After a literature review of the impact of Mediterranean diet(s) on cardiovascular risk factors, we here analyze the effects of olive oil and its major components on blood pressure in healthy and cardiovascular disease individuals and examine underlying mechanisms of action. Both experimental and human studies agree in showing anti-hypertensive effects of olive oil. We conclude that due to its high oleic acid and antioxidant polyphenol content, the consumption of olive oil may be advised as the optimal fat choice in the management protocols for hypertension in both healthy and cardiovascular disease patients. Primary or essential hypertension can be currently defined, despite some variations across cardiovascular disease (CVD) societies, as the chronic elevation of blood pressure (BP) values over 130/80 mmHg, with no identifiable cause that, in the long-term, causes end-organ damage and results in increased morbidity and mortality . NeverthBeside genetic components , most ofdiets) is a more general descriptive term applied to dietary models traditionally adopted in several regions close to the Mediterranean Sea [Effective antihypertensive dietary strategies include reducing sodium intake, weight loss, limiting alcohol consumption, increasing potassium intake, and adopting an overall healthy eating pattern, such as the Dietary Approaches to Stop Hypertension (DASH) and the recently recognized potentially antihypertensive Mediterranean diet . While Dnean Sea . In geneWhat substantially differentiates the Mediterranean diets from the DASH diet is its fat content: a low intake of saturated fats but a relatively high consumption of unsaturated fats, mostly deriving from olive oil (OO), which is used daily in stews, fried foods, salads and even desserts .Already Ancel Keys, the father of Mediterranean diet, had identified OO as the key component of the healthful Mediterranean diet . PromotiOlea europaea) can be traced back to the Eastern and Middle East Mediterranean regions. From the Anatolian peninsula it spread out throughout the Mediterranean basin, initially by the Greeks  [In bromatological terms, OO nutritional components are divided into two fractions: a major saponifiable and a minor non-saponifying . The mosopa.eu/) Historically, the first clear epidemiological evidence correlating fat consumption to BP regulation dates back to the end of the nineteen eighties, when Williams et al., in a small cross-sectional study conducted in 76 middle-aged US men, highlighted the existence of an inverse relationship between systolic and diastolic blood pressure  and oleic acid consumption as evaluated by 3-day food records . These pIn the Multiple Risk Factor Intervention Trial, for example, data from 24-h dietary recalls gathered from 11,342 middle-aged men were used to evaluate the relationships between the consumption of various dietary macronutrients and BP regulation. Data analysis showed a clear inverse association between DBP and the intake of polyunsaturated fatty acids (PUFA), as well as with the PUFA/saturated fatty acids (SFA) ratio; unexpectedly, however, the analysis failed to show a protective effect for MUFA . In sharThe first cross-sectional study that investigated the association between specific fat consumption, including OO, and the incidence of hypertension in Southern Europe was conducted in Italy . BrieflyThese results agree with those that recently emerged from the International Study of Macro/Micronutrients and Blood Pressure (INTERMAP) trial, which evaluated the associations among SBP and DBP and an array of food and nutrient intakes in 4680 middle aged women and men enrolled in 17 geographically and culturally different cohorts in Japan, China, the United Kingdom, and the United States . Here, dAlthough from observational studies many positive evidences have emerged linking OO to lower BP, the modest validity of nutritional findings derived from research methods adopted  have pusTo identify and retrieve all potentially relevant articles on this topic, we performed the search utilizing the following expressions: “olive oil” AND “arterial pressure” OR “hypertension” OR “blood pressure” OR “diastolic pressure” OR “systolic pressure” AND “randomized controlled trial” AND “humans”. We searched for articles published in each database from its inception until September 2019. We also performed additional manual search by analyzing the reference list of original publications, reviews and meta-analyses on the same topic. In the final selection, we included and discussed 19 papers specifically addressing the role of OO in healthy subjects and/or in patients at cardiovascular risk, including hypertensive and diabetic subjects. From a chronological perspective, one of the earliest randomized clinical studies assessing the antihypertensive effect of OO dates back to the late 1980s . Here, tFrom this study forward , the numIn recent years, among the minor constituents of OO potentially responsible for the antihypertensive effect, the role of the antioxidant polyphenols has been largely assessed. This was first assessed in a sample of 40 coronary Spanish male patients . Here, pBeing BP the product of cardiac output and systemic vascular resistance, hypertension may follow from an increase in cardiac output, an increase in systemic vascular resistance, or both . Under nPathogenically, functional and structural changes eventually lead to increased vascular stiffness and atherosclerosis in the hypertensive arterial wall, including endothelial dysfunction, abnormal vascular smooth muscle cell (VSMC) growth and migration, inflammation, fibrosis, altered contractility, and vascular hypertrophic remodeling . The undInterestingly, many pro-hypertensive stimuli, including Ang II, aldosterone oscillatory shear stress, as well as pro-inflammatory cytokines and growth factors, exert their pro-hypertensive vascular effects through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived ROS . At the In spontaneously hypertensive rats (SHR), both BP and the vascular expression of the redox-sensitive transcription factors NF-κB and AP-1 were shown to be downregulated by a plethora of synthetic antioxidants , suggestAlthough all the aforementioned antihypertensive mechanisms have been attributed to the potential interference of EVOO antioxidant components within the redox-signaling pathways leading to hypertension , interesAccordingly, in a subsample from the EUROLIVE study , the admSince the first use of antihypertensive agents in the Veterans Administration Cooperative Study in the late 1960s , the incAs a consequence of recent studies showing benefits associated with more pronounced reduction of BP in the hypertensive population, the American College of Cardiology and American Heart Association Task Force have updated the guidelines for the management of BP in adults . BesidesA great deal of population-based nutritional studies have investigated and recognized several dietary components as promoting or protecting from hypertension . Among pTo this aim, we first reviewed all epidemiological evidence investigating the association between MUFA and/or OO and the incidence of hypertension. In agreement with Alonso and coworkers , we obseIn agreement with Nissensohn , more coThe heterogeneity in BP changes found across studies may depend on various factors, including intervention or exposure duration, OO amount and quality, and dietary and genetic background. For example, the CLOCK single nucleotide polymorphisms (SNPs) rs4580704 C > G has been associated with obesity, hyperglycemia, and hypertension . InteresTherefore, to decrease the within-group heterogeneity in terms of outcome, some important issues such as genetic stratification of hypertensive patients  as well Advances in understanding of the complex cellular and molecular pathophysiology of hypertension  have beeBoth experimental and human studies are overall robust in showing anti-hypertensive effects by OO, due to its high oleic acid and antioxidant polyphenols content. On the basis of reviewed results, it is difficult to establish which is the component that most efficaciously contributes to BP regulation. Rather, the whole range of EVOO components appears to express their maximal efficaciousness within the complex of their original matrix. This suggests that formulation of possible functional products should approximate as much as possible the natural environment in which active molecules are found. EVOO thus appears to be the optimal fat choice in management protocols for hypertension in both otherwise healthy and cardiovascular patients.