As the last link in the chain of cardiovascular events, chronic heart failure (CHF) has high morbidity, high mortality, and poor prognosis. It is one of the main causes of death and disability worldwide. As a new drug for the treatment of chronic cardiovascular disease, dapagliflozin, the efficacy, and safety issues are still the focus of attention. Therefore, we conducted a meta-analysis to evaluate the efficacy and safety of dapagliflozin in the treatment of CHF.According to the search strategy, regardless of publication date or language, randomized controlled trials (RCTs) of dapagliflozin for CHF will be retrieved from 8 databases. First of all, the literature was screened according to the eligibility criteria, and use the Cochrane Collaboration's tool to assess the quality of the included literature. Then, using Rev Man 5.3 and STATA 14.2 software for traditional meta-analysis. Finally, the evaluation of the quality of the evidence and the strength of the recommendations will adopt the Grading of Recommendations, Assessment, Development and Evaluation method.This study will evaluate the efficacy and safety of dapagliflozin for CHF, thereby providing more evidence support for clinical decision-making in CHF.Our research will provide more references for the clinical medication of patients with CHF.INPLASY202150046 CHF is the end-stage manifestation of cardiovascular disease and the main cause of death. It has a high recurrence rate and a poor prognosis, which seriously threatens people's physical and mental health. In developed countries, the prevalence of HF in adults is about 1% to 2%, and it gradually increases with age, and exceeds 10% in people over 80.,3 After being diagnosed with CHF, the rehospitalization rate was as high as 83.1%, and 42.6% were hospitalized >4 times. The Framingham Heart Study in the United States shows that within 5 years of the initial diagnosis of CHF, the mortality rate of patients is about 50%. In patients with acute myocardial infarction with CHF, the 1-year mortality rate is >50%. Therefore, extending the survival period of patients with CHF, reducing the mortality rate, and improving the prognosis are key issues that need to be resolved.Chronic heart failure (CHF) is a group of complex clinical syndromes caused by abnormal changes in cardiac structure and (or) function caused by various reasons, which make ventricular contraction and (or) diastolic dysfunction occur. Its effect of lowering blood sugar does not depend on improving insulin secretion and peripheral tissue resistance to insulin. It mainly inhibits the activity of proximal renal tubules SGLT-2, reduces the reabsorption of glucose by the renal tubules, thereby increasing the excretion of glucose in the urine, lower blood sugar. In addition, SGLT-2i drugs also have unique effects other than hypoglycemic effects. For example, empagliflozin and canagliflozin have been proven to have additional cardiovascular protection and can reduce the occurrence of cardiovascular events.,8 As a similar drug, dapagliflozin has also been proven to benefit cardiovascular disease in some studies, and this effect is independent of the hypoglycemic effect. In dapagliflozin and prevention of adverse outcomes in heart failure trial, dapagliflozin can reduce hospitalization rates and mortality from cardiovascular events in patients with and without type 2 diabetes mellitus (T2DM) who had HF with reduced ejection fraction (EF). However, some studies found that dapagliflozin can reduce the hospitalization rate of patients with CHF in the analysis of the baseline data and EF value of the DECLARE-TIMI 58 trial, regardless of whether the ejection fraction is normal or not. In addition, people may worry about the potential safety issues of this new drug in the treatment of CHF. Therefore, this study proposes a systematic review program to evaluate the efficacy and safety of dapagliflozin on CHF, and to provide sufficient basis for further guidance of clinical medication, so as to avoid unnecessary traps.Dapagliflozin is a new type of hypoglycemic agent belonging to the sodium-glucose transporter 2 inhibitors (SGLT-2i) class.22.1https://inplasy.com/inplasy-2021–5–0046/). We will be based on the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P), and strictly follow the requirements and conduct.Our protocol has been registered on the International Platform of Registered Systematic Review and Meta-Analysis Protocols (INPLASY). The number was INPLASY202150046  on the basis of routine western medicine of CHF. The control group was only given routine western medicine, or the same dose of placebo was given on the basis of routine western medicine. Routine western medicine mainly includes diuretics, ACEI, ARB, β-receptor blockers, ivabradine, digitalis and inotropic drugs, vasodilators, anticoagulants, etc.2.3.3The primary outcomes include mortality and HF rehospitalization rate; the secondary outcomes include New York Heart Association classification (NYHA classification), EF, N terminal pro B type natriuretic peptide (NT-proBNP), quality of life (QOL), etc; the safety indicators include hypovolemia, hypoglycemia, kidney damage, infections of the genitourinary system, and other adverse reactions.2.3.4Randomized controlled trials (RCTs) will be included in this study irrespective of language or publication category. Animal trials, review article and studies with incorrect RCT designs will be excluded.2.4Use endnoteX9.0 software to manage literature. After searching literature based on the above steps, import them into endnote software for literature screening. First, 2 independent researchers will conduct a preliminary literature screening based on the titles and abstracts of the included literature to eliminate duplicate and non-RCTs. Then read the full text of the remaining literature according to the previously designed principles of eligibility criteria, and finally determine the appropriate literature. When 2 researchers disagree, a third researcher will resolve it. The specific screening process is shown in Fig. According to the Cochrane Handbook for Systematic Reviews of Interventions, 2 researchers independently extracted and recorded the required information from all the included literature. When 2 researchers disagree, they will discuss to reach an agreement, otherwise they will work with the third researcher to resolve. The required information mainly includes the author, publication time, study design, participants number and demographic characteristics , treatment status , and outcomes . If any of the above information in the included literature is incomplete, we will contact the corresponding author via email to obtain the required data.2.5 The results of the quality assessment will be completed using software Review Manager 5.3.Two reviewers will independently assess the quality of the included literature according to the Cochrane Collaboration's tool for RCTs. If there is a disagreement between 2 reviewers, the third reviewer resolves the issue. According to Cochrane Handbook V.5.2.0, characteristics of each item will be evaluated in 3 categories: low, unclear, and high.2.62.6.1P < .05 is considered statistically significant. The heterogeneity among the included literature will be assessed using the Q test method and I2 statistic method. When the Q statistic corresponds to P ≤ .10 or I2 > 50%, it indicates that there is heterogeneity among the included literature, and assess the effect size by the random effect; on the contrary, a fixed effect model is used.We will execute Rev Man 5.3 and STATA 14.2 software for traditional meta-analysis. For dichotomous data, we will calculate a summary estimate with 95% confidence interval odds ratio value; for continuous data, we will calculate a summary estimate of standardized mean difference with 95% confidence interval, and 2.6.2Taking into account the issue of heterogeneity, we will conduct a subgroup analysis based on the specific circumstances of the included literature. If there is a problem of heterogeneity, we will conduct a subgroup analysis of age, sex, and interventions. In addition, in order to understand whether the left ventricular ejection fraction (LVEF) will affect the efficacy of dapagliflozin, it will be used for CHF patients with LVEF <40% and CHF with unknown LVEF the mortality rate and rehospitalization rate are analyzed by subgroups. In order to understand whether patients with CHF and T2DM affect the efficacy of dapagliflozin, the mortality rate and rehospitalization rate will be subgroups-analyzed on whether patients with CHF have T2DM.2.6.3This systematic review will use the method of eliminating each study one by one for sensitivity analysis. If the effective indicators  of dapagliflozin in the treatment of CHF have not changed significantly, it indicates that the study is robustness. On the contrary, it is not robustness. According to the specific situation, low-quality research is excluded.2.6.4Publication biases will be assessed by a funnel plot for meta-analysis and quantified by the Egger method. It should be noted that if the number of included literature is ≥10, it is appropriate to use a funnel plot to assess potential publication bias. However, if the included literature is <10, it may affect the overall test power because the included number is too small, and it is difficult to accurately evaluate the symmetry of the funnel plot.2.7The Grading of Recommendations, Assessment, Development and Evaluation used to assess the quality of evidence. The quality of evidence is divided into 4 levels from 5 aspects, namely high, medium, low, and very low.2.8This study is a systematic review, it does not involve medical ethics and patients’ informed consent. This study will publish the results of meta-analysis in journal papers.3As the aging of the population in various countries gradually accelerates, the incidence of various cardiovascular-related diseases is gradually increasing, such as coronary heart disease, hypertension, dyslipidemia, diabetes, Obesity, etc, and most of the end stages of these diseases end in CHF. However, in the current limited medical technology, the cardiac function and structure cannot be completely reversed temporarily. Some drugs and methods can only be used to improve or delay the deterioration of cardiac function, prevent further cardiac remodeling, reduce cardiovascular death, and improve long-term prognosis. With the discovery of neuroendocrine mechanism, early and comprehensive intervention of cardiovascular events can improve the prognosis, conventional treatments are mostly neuroendocrine antagonists, such as ACEI/ARB, β-receptor blockers, and digoxin, etc. Nevertheless, the mortality and rehospitalization rate of patients with CHF remains high. How to develop new drugs and therapies on the basis of evidence-based medicine to improve the prognosis of patients with CHF has become one of the health problems concerned by medical researchers all over the world.–18 But regardless of the mechanism of action, from the existing data, dapagliflozin is beneficial to improve the prognosis of CHF.,20 Perhaps it can bring hope to the treatment of CHF.Dapagliflozin is a new drug for cardiovascular diseases. Although the mechanism of SGLT-2i drugs for cardioprotection is still controversial, it may be that well-controlled blood sugar reduces the cardiotoxicity of blood sugar, or osmotic diuresis reduces water and sodium retention, thereby reducing blood volume, reducing cardiac preload, or lowering blood pressure and relieving arteriosclerosis, reducing the afterload of the heart, or improving the structure of damaged myocardial cells by adjusting oxidative stress, ion concentration and energy metabolism levels, delaying myocardial remodeling, and improving long-term prognosis.Although this systematic review has many advantages, such as statistical power and accuracy of effect size estimation, subgroup analysis of factors affecting treatment effects, a more objective evaluation of evidence and a more accurate and objective evaluation of effect indicators evaluation. However, it also has some problems. For example, this study is an evaluation of published literature, and there may be problems such as unscientific and non-strict RCT design, resulting in uneven quality of literature research, which affects the credibility of this study. Or the research results included in the literature have false negatives and false positives. In any case, this systematic review can provide reliable results for CHF, and provide strong evidence for the significant advantages of dapagliflozin in the treatment of CHF.Conceptualization: Xueyan Dong, Liming Yu.Data curation: Wulin Gao, Lili Ren.Formal analysis: Lili Ren, Xueyan Dong.Funding acquisition: Siyuan Cui, Liming Yu.Methodology: Xueyan Dong, Lili Ren, Xuewei Yin.Project administration: Liming Yu.Writing – original draft: Xueyan Dong, Yueli Liu, Liming Yu.Writing – review & editing: Xueyan Dong, Liming Yu.


Aim of this study was to evaluate the associations of non-invasive central aortic and peripheral  blood pressure (BP) for Hypertension-mediated organ damage (HMOD) and atherosclerotic cardiovascular disease (ASCVD) risk.2.We evaluated associations of HMOD with 24-h ambulatory blood pressure monitoring (ABPM) of central aortic and peripheral BP indices in patients with primary hypertension and presence of several cardiovascular risk factors. BP measurements were performed by means of a non-invasive automated oscillometric device (Mobil-O-Graph). HMOD was defined as the presence of carotid intima-media thickness (IMT) above normal values and/or carotid plaque, left ventricular hypertrophy (LVH), and/or renal abnormalities as assessed by urine albumin/creatinine ratio above normal values and/or estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 mp = 0.029). Using ASCVD risk score as the independent continuous variable in multiple linear regression, 24-h central systolic pressure (SBP) , daytime central PP  and night-time PP  were all positively associated with ASCVD risk.In the study cohort of 273  patients with primary hypertension, documented HMOD was present in 180 (65.9%), LVH in 70 (25.6%), increased IMT in 129 (47.3%). Fifty-six patients (20.5%) had kidney organ damage . When accounting for confounding factors  only peripheral 24-h pulse pressure (PP) maintained statistical significance with HMOD indices (OR: 1.126, 95% CI: 1.012~1.253; Blood pressure obtained by 24-h ABPM was better correlated with HMOD than office BP. Whilst 24-h peripheral BP showed a stronger association with HMOD than 24-h central BP, the prognostic value of 24-h central BP for the 10-year ASCVD risk was superior to 24-h peripheral BP. With the change of lifestyle, the total number of hypertension patients in China has reached the alarming number of 245 million . As the Changes in large arteries and microcirculation play a role in the mechanism of BP and HMOD (hypertension-mediated organ damage) . The incHMOD is related to increased vascular risk and death, and their prevention should become the target of hypertension treatment and a surrogate sign of whether BP is well-controlled . It is tThe Chinese Hypertension Guidelines have pointed out that assessing HMOD is an important part of the diagnosis and evaluation of hypertension. After early detection and treatment, asymptomatic subclinical HMOD can be reversed, which helps to improve the prognosis of patients .In this study, we investigated the use different indicators to evaluate the correlation between different BP indices and HMOD such as heart, kidney, and large blood vessel damage, hoping to clearly distinguish the intervention targets for early detection, intervention and reversal of HMOD.In this cross-sectional study between July 2018 and July 2020, 273  inpatients enrolled in the Department of Geriatrics, Shanghai Ruijin Hospital, China, who suffered from primary hypertension with presence of several cardiovascular risk factors or complications involving clinical HMOD were recruited. The inclusion criteria were 3 consecutive measurements of office SBP ≥140 mmHg or consultation diastolic BP (DBP) ≥90 mmHg after resting for 5 min in the supine position, or the use of antihypertensive drugs without the diagnosis of secondary hypertension. Exclusion criteria were clinical or laboratory evidence confirming the acute cardiocerebrovascular disease within the previous 3 months before enrollment or any life-threatening disease.Patients' medical history, smoking habits, medication history, and auxiliary examinations  were collected in the form of standardized questionnaires. Cardiovascular risk was determined according to the American College of Cardiology/American Heart Association-Atherosclerotic Cardiovascular Disease (ACC/AHA-ASCVD) risk score .Current smoking was defined as having smoked in their lifetime or smoked in the past 7 days of BP measurement . DiabeteBoth office and 24-h BP measurements were performed by means of a non-invasive automated oscillometric device , validated for brachial BP measurement, according to the European Society of Hypertension International protocol .The monitor was fitted on a weekday between 8:00 am and 8:00 am. After 5-min rest, BP was measured four times consecutively at 1-min intervals. The mean of these measurements was settled as office(clinic) BP. The device was set to function under the manufacturer's inbuilt protocol number 11, namely: four BP recordings per hour from 0800 to 2,359 h and two recordings per hour from 0000 to 0759 h. In this mode of function, the device performs both brachial BP measurement and brachial pressure wave recording simultaneously. The aortic  BP is assessed by software analysis [with the application of validated generalized transfer functions ] after tAll patients included in the study had recordings of good technical quality . Otherwise, ABPM was repeated in 1 week.PPA was defined as the peripheral-to-central pulse pressure ratio and was calculated using the formula: PPA = /.2.HMOD was defined as the presence of carotid intima-media thickness (IMT) above normal values (0.9 mm) and/or carotid plaque, left ventricular hypertrophy (LVH), and/or renal abnormalities as assessed by urine albumin/creatinine ratio (ACR) above normal values  and/or an estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 mWe used high-resolution echocardiography Doppler ultrasound  with a broadband linear array transducer (multiple frequency: 4–12 MHz) to examine Carotid IMT.IMT was measured on both the left and right common carotid artery starting ~1.5 cm proximal to the carotid artery bulb. During the test, three records were collected from the left and right carotid arteries, and the average value of each side was calculated. When IMT> 1.3 mm, carotid plaque was diagnosed. When IMT ≥ 0.9 mm and/or carotid plaque was present, carotid artery abnormality was diagnosed.2 in men or ≥95 g/m2 in women and was calculated by means of echocardiography, performed according to the American Society of Echocardiography recommendations (LVH was defined as a left ventricular mass index (LVMI) ≥ 115 g/mndations .2) as calculated by the MDRD formula (The definition and the diagnostic criteria for chronic kidney disease (CKD) were proposed in the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines:  for statistical analysis. When t-test or Chi-square test were used for the comparison between patients with and without HMOD. Pearson correlation was used to assess the relations between brachial, central aortic BP and LVMI, ACR, eGFR, or IMT. The association of each BP estimate with the presence of HMOD was assessed by means of logistic regression analyses, with odds ratio (OD) calculation adjusted for age, sex, body mass index (BMI), antihypertensive treatment, smoking, TG, statin treatment, fasting glucose, glucose, hypoglycemic therapy, heart rate.Continuous variables are expressed as mean ± SD, and frequencies (percentage) are reported for categorical variables. Student's Furthermore, the relative impact of central vs. peripheral BP estimates was assessed by the simultaneous introduction of each pair of central and peripheral measurements  in the logistic regression models, and then calculating the adjusted ODs. The association of each BP estimate with the presence of ASCVD risk was assessed by means of linear regression with adjustment for baseline covariates including age, sex, BMI, antihypertensive treatment, smoking, TG, statin treatment, fasting glucose, glucose, hypoglycemic therapy, heart rate.The study cohort comprised 273 (71.8% men) patients with primary hypertension. A total of 180 (65.9%) patients had documented HMOD. LVH was present in 70 patients (25.6%), increased IMT in 129 (47.3%). A total of 56 patients (20.5%) had kidney organ damage . From them, 66 patients (24.2%) presented HMOD in more than one organ.r = 0.121–0.281, p < 0.001). ACR was significantly associated with both brachial and central SBP as well as PP parameters for clinic,24-h, day and night  except clinic aortic SBP and clinic aortic PP. It was also significantly associated with Clinic PPA and Night-time PPA  except 24-h PPA and Daytime PPA.There was a significant negative association between eGFR and the brachial and central PP for 24-h, day and night  except night-time aortic PP. It was also significantly associated with Clinic PPA and Night-time PPA  except 24-h PPA and Daytime PPA.IMT was significantly associated with both brachial and central PP parameters for 24-h, day and night .When PPA  were introduced in the same logistic regression model, none of PPA parameters were significant after adjustment for age, sex, BMI, antihypertensive treatment, smoking, TG, statin treatment, glucose, hypoglycemic therapy, heart rate.p = 0.014) after adjustment for age, sex, BMI, antihypertensive treatment, smoking, TG, statin treatment, glucose, hypoglycemic therapy, heart rate. Night-time central SBP is more relevant to LVMI than night-time peripheral SBP  when accounting for confounding factors, Using ASCVD risk score as the independent continuous variable in multiple linear regression, central but not peripheral 24-h SBP, daytime PP, night-time SBP and PP were all positively associated with ASCVD risk after adjusted for traditional cardiovascular risk factors (p = 0.008) and Night-time PPA were all negatively ssociated with ASCVD risk after adjusted for confounding factors except Clinic PPA and 24-h PPA.The left ventricular mass was further used as an independent HMOT index and analyzed as the independent continuous variable in multiple linear regression, we found that 24-h peripheral SBP was more relevant to LVMI than 24-h central SBP  BP did not increase significantly. This suggested that even for patients with normal clinic BP, we need to be vigilant and realize that clinic BP does not provide complete information.Although HMOD and non-HMOD patients had no difference in clinic peripheral and central PP and SBP, HMOD patients showed significantly higher BP levels on multiple indicators during ABPM. Furthermore, only central but not peripheral BP was associated with increased 10-year ASCVD risk.BP measurement is a fundamental means and method for evaluating BP levels, diagnosing hypertension, and observing the efficacy of antihypertensive treatment. In clinical and population prevention work, the main use of office BP measurement and out-of-office BP measurement, the latter includes ABPM and home BP monitoring (HBPM), can provide a large amount of BP data outside the medical environment .Clinic BP, recommend by most clinical guidelines , has beeWe found that different BP indicators have different correlations with HMOD: SBP and PP are better correlated with ACR, PP is better correlated with eGFR and IMT, and SBP is better correlated with LVMI.The increase of SBP will increase the vascular pressure at the end of systole, and the increase of PP will cause vascular endothelial damage and mechanical fatigue, leading to atherosclerosis. Kong MG et al. showed SBP and PP are better HMOD indicators .It showeJokiniitty et al.  suggesteIn general, PP is an independent risk factor for cardiovascular disease and mortality, and there is a clear link between PP and HMOD . In addiIt is well-known that SBP and PP are higher when assessed at the brachial artery compared to the aorta because of PP amplification across the arterial tree . TherefoIn most of the studies showing better predictive value of central BP, central and peripheral BP estimates were taken at clinic measurements of BP. In this study we investigated if ABPM might give the same result: whether it be assumed that 24-h central arterial pressure is superior to peripheral arterial pressure in predicting HMOD and long-term prognosis. However, seemingly contradictory results have been obtained in this study. The 24-h central BP did indeed show a greater predictive value for the 10-year ASCVD risk than 24-h peripheral BP. But when it comes to correlation with HMOD, the opposite is true: 24-h peripheral BP showed a stronger association with HMOD than 24-h central BP.This result is consistent with the findings of Spanish investigators .The conclusion appears paradoxical. Why is the central ABPM better than the peripheral in 10-year CV risk but poorer in HMODs? In fact, in the past few years, research in this area has consistently shown conflicting results. Studies have suggested that the correlation between central BP and cardiovascular events is better than peripheral BP , 36. OthThe finding of a lack of association with 24 h brachial BP and IMT is surprising and differs from several other findings in the general population  or in hyOur research results also show that if LVMI is analyzed as a stand-alone HMOD, 24-h peripheral SBP is more relevant to LVMI than 24-h central SBP. Night-time central SBP is more relevant to LVMI than night-time peripheral SBP. This is also contrary to what is generally accepted. It is generally believed that, compared with peripheral blood pressure, central BP is more closely correlated with LVMI . The parOur study also showed that the clinic PPA, 24-h 24PPA, day PPA, night-time PPA had no prognostic value for HMOD. As the day PPA increased, the ASCVD risk decreased, while the Night-time PPA increased, the ASCVD risk decreased. 24-h PPA and clinic PPA had no prognostic value for ASCVD risk. In other words, PPA only has a prognostic effect on ASCVD risk, and has no correlation with HMOD. The Northern Shanghai Study  showed tDue to the hypervagal function, night-time SBP decreased significantly (> 10%) so the day time peripheral PP was slightly higher than the night-time peripheral PP. Since the PPA of night time is less than the day time, day time SBP does not decrease significantly, resulting in a slightly higher night-time central PP than the day time central PP. Since the relation between central and peripheral PP is highly dependent on heart rate, is expected that changes in heart rate would result in different degree of amplification of PP from the aorta to the periphery.In future research, we will address the PPA effect of ABPM at different times, especially the prognostic value of nighttime changes to the risk of HMOD and ASCVD.2.In this study, HMOD was defined as the presence of carotid IMT above normal values (0.9 mm), LVH, and/or renal abnormalities as assessed by urine ACR above normal values  and/or an eGFR <60 ml/min per 1.73 mCarotid artery plaque was classified as abnormal carotid artery in this study, and ABI and PWV measurements were not considered to be a manifestation of target organ damage. We adopt this definition of target organ damage to refer to the definition in the 2018 Chinese guidelines for the management of hypertension . It was This study has some limitations. As a cross-sectional study with a small sample size, the results need to be further confirmed in prospective studies. The cohort of this study is a physical examination population and the risk factors such as antihypertensive treatment werenot collected, therefore it is unknown whether results are applicable for other disease populations. The study was conducted in an Asian population, and it is not known whether the results will hold true for other ethnic groups.Blood pressure obtained by 24-h peripheral ABPM was better correlated with HMOD than office BP and 24-h central BP. However, the prognostic value of 24-h central BP for the 10-year ASCVD risk was superior to 24-h peripheral BP.The data that support the findings of this study are available from the corresponding author, [Jl Z], upon reasonable request.Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.YH contributed to the concept and design of the study, the analysis and interpretation of data, and drafting and critically revising the manuscript. QW, JZ, HC, and BT were responsible for study design and analysis and interpretation of data. DC was responsible for the figure. IT contributed to interpretation of data and critically revising the manuscript. MB and AA contributed to the study design, the thorough reading of the manuscript and several revisions. JlZ and WW contributed to the conception and design of the study, interpretation of the data, and critically revising the manuscript. All authors approved the final version for publication and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.Project Supported by the National Natural Science Foundation of China (Grant No. 81500190), and Clinical Science and Shanghai municipal hospital new frontier technology joint project (SHDC12019X20), Shanghai Municipal Commission of Health and Family Planning (Grant No. 2020YJZX0124).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Near-infrared spectroscopy (NiRS) is a relatively new technology of brain imaging with its potential in the assessment of cerebrovascular health only recently discovered. Encouraging early results suggest that NiRS can be used as an inexpensive and portable cerebrovascular health tracking device using a recently proposed pulse relaxation function (PReFx). In this paper, we propose a new NiRS timing index,  The American Heart Association recommends that vascular stiffening be used as a predictor of cardiovascular disease risk1. Vascular stiffness is inversely proportional to compliance and reflects arterial resistance to stretching and recoiling in response to blood ejection from the heart. In a young or otherwise healthy vascular system, compliant arteries help smooth out the vascular pulsatility induced by blood pressure. As compliance decreases, blood pressure causes structural changes within the arterial walls that adversely affect their function3.Vascular stiffening is an important health indicator. It influences health in a manner that is independent of blood pressure4.PWV is the speed of the pressure wave traveling from the heart towards the periphery. Simultaneous measurement of arterial pulse in a proximal and a distal arterial sites e.g. common carotid and femoral gives the travel time of the pressure waveform. The distance between the measurement sites can be measured over the body surface. Hence, PWV is calculated as distance divided by travel time between two measurement sites using applanation tonometry5.Another change that occurs with reduced vascular compliance is increased pulse wave velocity (PWV)7. The reflection time can be measured using non-invasive technologies such as magnetic resonance imaging (MRI), transcranial Doppler (TCD) and photoplethysmograph (PPG). PPG utilises light emitters and detectors to measure blood volume changes in periphery . A PPG estimate of PWV, called stiffness index (SI), is calculated by dividing subject height by the reflection time11.When a pressure wave reaches a vascular bifurcation point, a portion of the wave is reflected back towards the heart. These reflected waves eventually augment the incident wave coming from the heart, thereby increasing the pulse pressure. While we often think of a single reflected wave, in reality many reflected and re-reflected waveforms are present in the signal. Due to the increased PWV in a stiff arterial system, the reflected waves travel faster, thereby reaching the incident wave earlier in systole and increasing the local pulse pressure even further. Both forward and reflected waves leave a peak or an inflection point on the pressure waveform, we will refer to these peaks as the systolic and the reflected peaks, respectively. The time difference between systolic and reflected peaks is the reflection time2. The brain, in particular, is highly vulnerable to SVD, as the blood flow to the sub-surface brain structures is compromised14. Based on a comprehensive review, cerebral SVD is believed to be one of the main causes of vascular cognitive impairments and accounts for a quarter of all acute ischaemic strokes15.In the brain, increased arterial stiffness can damage the arterial endothelium in small arteries and can, over time, produce a pathology known as small vessel disease (SVD)16, the method relies on estimates of vascular cross-sectional area, arterial inflow and venous outflow, which are not readily measurable. The TCD indices such as the pulsatility index, 19. Of these two, 20. The MRI pulsatility index  is the first NiRS based approach to the indexing of cerebrovascular compliance21. PReFx measures the deformation of the blood volume waveform during the systolic relaxation phase due to the presence of reflected waves. It has been demonstrated to correlate with CRF and inversely correlate with age24. PReFx is an area measurement in the averaged NiRS signal. We are motivated to use an index that can be easily applied to NiRS signals and also has evidence in other modalities.Near-infrared spectroscopy (NiRS) operates on same principals as PPG and its output is proportional to regional blood volume changes inside the brain based on the absorption of near-infrared light, mainly by oxygenated blood inside the arteries7. All these parameters are known to change with ageing and vascular health. Based on this model, we have introduced a new timing index (TI) as the inverse of the reflection time, similar to PPG SI but without the height parameter. In a previous experimental study we have shown that TI calculated using TCD blood flow velocity waveforms correlates significantly with vascular health factors such as age and CRF20. Here, we propose NiRS timing index  were recruited from the Newcastle, Australia. They provided informed consent prior to assessment. The study protocol was approved by the University of Newcastle Human Research Ethics Committee and is registered in the Australian and New Zealand Clinical Trials Registry (ACTRN12619000144112). All experiments were performed in accordance with relevant guidelines and regulations. TCD recordings from these participants were previously reported inTCD ultrasound  was used to record resting-state cerebral blood flow velocity from the right and left middle cerebral arteries. Participants were also scanned on a 3T MRI scanner , equipped with 64-channel receive only head coil, while a standard built-in dual channel body coil was used for RF transmission. Blood flow was quantified using a phase contrast flow quantification sequence . Participants assumed a sitting position for approximately five minutes during headpiece setup before recording commenced. During TCD recording, the heart rate was measured once per minute three times. The mean of these three heart rate measurements was used as the resting-state heart rate.14; i.e.,F indicates the flow and the bar sign indicates the mean value. Three subjects did not have an MRI scan and among the remaining 35 subjects, MRI phase contrast images were processed using the scanner software (Siemens Syngo) by manually placing a region of interest around the middle cerebral artery and quantifying the flow. The MRI pulsatility index, 18:Calculation of the augmentation index, 25. It involves a self-reported physical activity score, age, sex, body mass index and resting heart rate. See the supplementary materials for the physical activity questionnaire and cardiorespiratory fitness formula.The CRF was determined using the non-exercise test model proposed in21 using the “26 which is a MATLAB-based software module developed by the same group. Specifically, channels with source detector distances of 20–60 mm were selected and went through a quality-control process passing 1283 channels out of the original s. The rotation was performed so that the systolic peak would appear as a positive peak and the shape of the signal would look similar to that of a blood pressure, flow or volume signal. This facilitates understanding of the waveform. The arterial pulsation signals were visually inspected and channels that did not have a pulse shape were removed . Some 964 channels passed the pre-processing stage for further analysis. Channels with source detector distances between 25 and 50 mm proved to be most likely to generate usable waveforms.Optical light intensity NiRS signals were used to derive two different indices: the pulse relaxation function (PReFx) and the proposed timing index, mentclass2pt{minim21. In brief, s signal in the first and the second cardiac cycles and s signal between A and inserted intoB is the area of a rectangle formed by 21, channels with PReFx value outside the interval of The pulse relaxation function is calculated based on the methods explained ins, a completely automated algorithm is proposed (Sample data and codes available at https://github.com/Rashid-Afkhami). The algorithm uses the second derivative to locate key points in the signal. This is based on similar approaches that have been proposed for locating peaks and inflection points in the pressure and PPG signals28. Firstly, the second derivative, s is calculated. Next, the following time points are defined on the s and the s signal and s has a positive peak, s, are shown in this figure where the detected s is detected and the wave components shown in Fig. We define the timing index as the inverse of the time between the forward and reflected waveform peaks. In order to find the timing of these peaks, named corr function. Lilliefors test of normality with a 5% significance level was used to assess the data distribution. Age and Statistical analysis was carried out in MATLAB using the inbuilt The correlations of the proposed NiRS timing index and existing NiRS PReFx index with the indices derived from other imaging modalities, age and CRF are reported in Table 1 and cardiorespiratory fitness29. Thus, a common approach with any vascular index is to compare its relationship with age and CRF30 and here we have done the same. The PReFx correlation coefficient reported here for age is consistent with existing studies; however, the correlation with CRF is lower than previously reported. PReFx correlations with age and CRF in the adult population have so far been studied by the same research group using two different datasets23. Reported correlations with age are 21 and 23; a correlation of 24 for a combination of the two datasets. Our reported correlation, 21 and 23, however, our correlation with CRF of 25, it is common to remove the gender factor where the result is called eCRF21. 31). This notch can appear as a large deformation in the signal (see Fig. The NiRS indices are designed to measure vascular stiffness, which is well correlated with age20. That is, correlations of While no previous NiRS studies have reported a timing index, the correlations of 14, we expect NiRS indices to correlate with the MRI pulsatility index which is an indicator of vascular health. PReFx showed no significant correlation with Based on a previously proven association between 33. The AI captures the augmentation of the incident wave by the reflected wave, with smaller values reflecting no augmentation when the arteries are healthy and the propagation speed is low. TI indexes this delay between the incident and reflected waves directly, which is why 21 which is also supported by the use of light emitters in PPG and its morphological similarity to the arterial blood pressure waveform35. Thus, we believe that the proposed NiRS timing index is affected similarly by vascular health parameters in the same way as the timing index derived from the blood pressure waveforms7. As blood pressure can not be readily measured in cerebral vessels, a NiRS-based timing index can provide an alternative approach.Overall, NiRS blood volume waveforms are believed to closely resemble the changes in blood pressureIn this paper, we presented a novel NiRS based cerebrovascular stiffness index, Supplementary Information 1.


Background: Data on outcomes of renal transplantation in the Kingdom of Saudi Arabia (KSA) is limited. We describe renal transplant experience in one of the largest referral centers for renal transplants in KSA.Methods:This is a retrospective cohort study of patients who underwent kidney transplantation at King Abdulaziz Medical City (KAMC) from January 2016 to July 31, 2019, with at least one year of follow-up post-transplantation.2. The most common comorbidities were hypertension (77.3%) and diabetes mellitus (34.5%). The most common etiology of end-stage kidney disease (ESKD) was unknown (49.0%) followed by Lupus nephropathy (16.0%). Central venous catheters were the predominant dialysis access (56.2%). Living-related kidney donation was the commonest source of kidney transplantation (61.3%), followed by deceased donor renal transplantation (22.7%). Anti-thymocytes globulin (ATG) was the predominant induction agent (57.7%) and nearly all patients received tacrolimus-based maintenance immunosuppression. Mean serum creatinine at the time of discharge was 109 umol/l. Delayed graft function was observed in 6.7% of our patients. The most common medical complications were urinary tract infection (26.3%). Post-transplant surgical complications occurred at a low rate.Results: One hundred ninety-four individuals were identified and included in the analysis. The mean age of the renal transplant cohort was 45 years with an average pre-transplant body mass index of 26.1 kg/mConclusion:Our study demonstrated a successful renal transplant experience among a relatively healthy cohort and identifies potential gaps, particularly the high rate of central venous catheters, the frequent lack of clear etiology of ESKD, the low rate of pre-emptive transplant, and deceased donors. Further studies are needed to evaluate and close these gaps. The prevalence of chronic kidney disease (CKD) has been increasing globally and is associated with impaired quality of life, morbidity, mortality, and a significant burden on the health care system ,2. This A total of 11,509 renal transplantation surgeries has been carried out in the Kingdom of Saudi Arabia from 1979 to 2017 . From a The study was conducted at King Abdulaziz Medical City (KAMC) in Riyadh, Saudi Arabia. KAMC is a tertiary hospital and is part of a government-funded multispecialty health system in Saudi Arabia. The data were collected after obtaining the IRB approval from King Abdullah International Medical Research Center (RC20/386/R).We included patients who underwent kidney transplantation from January 2016 to July 31, 2019. All patients had to have at least one year of follow-up post-transplantation. Patients who had organs transplanted in addition to kidneys were also included. We excluded patients who were previously transplanted or underwent transplants outside of the Kingdom of Saudi Arabia.We collected the following variables: age, gender, pre-transplant, and one-year post-transplant body mass index (BMI), smoking, cause of ESKD, type of dialysis, hospital length of stay, comorbidities prior to transplantation such as diabetes, HTN, coronary artery disease, cerebrovascular disease, complications post-transplant such as post-transplant diabetes, HTN, malignancy, and fracture, immunosuppressive regimen, and kidney function at the time of discharge after transplantation. Delayed graft function was also collected and was defined as the need for dialysis in the first week following transplantation.Statistical Package for the Social Sciences  was used for data analysis. Categorical variables were presented as frequencies and percentages whereas continuous variables were presented as mean ± standard deviation.The demographics of our patients are shown in Table 2 and a one-year post-transplant BMI of 28.67 ± 5.82 kg/m2. Only 30 (15.5%) patients were smokers. HTN was the most notable comorbidity (77.3%), followed by DM (34.5%), dyslipidemia (22.7%), and coronary artery disease (12.9%). Only a few patients had a history of stroke (2.6%), malignancy (1.5%), or amputation (1.5%). Causes of ESKD were unknown in almost half of the patients (49.0%). Lupus nephropathy (16.0%), DM (14.9%), and HTN (11.9%) were the most common identifiable causes of ESKD  patients were males and 86 (44.3%) were females. The patients’ mean age was 45.01 ± 14.8 years with an average pre-transplant BMI of 26.13 ± 5.11 kg/mMost of the patients received dialysis through central venous catheters , and arteriovenous fistula/graft (28.4%). Focusing on data specific to renal transplant, we found that living-related kidney donation was the commonest source of kidney transplantation (61.3%), followed by deceased donor renal transplantation (22.7%) and living-unrelated donation (16.9%). The overall rate of pre-emptive transplantation, defined as renal transplant prior to initiation of dialysis, was low (7.2%). Pre-transplant serology testing showed that 83.5% of our cohort was positive for Epstein-Barr virus (EBV) and 50% was positive for CMV. Of note, our center uses universal antiviral prophylaxis therapy that consists of three to six months of Valganciclovir post-transplantation.Immunosuppressive induction therapy based on anti-thymocytes globulin (ATG) was the most prevalent (57.7%), followed by the Basiliximab-based regimen (42.3%). Most of our patients (99.5%) received maintenance immunosuppression that contained Tacrolimus along with prednisone and mycophenolate. It should be noted that our protocol uses a Basiliximab-based regimen for low immunological risk recipients and ATG for high immunological risk recipients. High immunological risk is defined as less than one haplotype match, previous kidney transplant, or high panel-reactive antibody (PRA) level. We do not use pre-transplant plasmapheresis, as patients with donor-specific antibodies (DSA) or blood group incompatibility is put through the kidney paired exchange program. Our maintenance regimen consists of low-dose prednisone, mycophenolate, and Tacrolimus, targeting a level of 7-10 ng/mL for the first three months after transplantation and 3-7 ng/mL for the subsequent months.The post-transplant length of stay was 9.8±6.4 days, with 11 (5.7%) patients requiring intensive care unit admission following the renal transplant surgery. The average serum creatinine at the time of discharge following the renal transplant surgery was 109.1±97.5 µmmol/L , followed by fracture (3.6%), psychiatric illness (3.6%), and malignancy (1.0%). Delayed graft function was observed in 6.7% of our patients. Graft rejection in the first year occurred in 14 patients (7.4%). Of note, our transplant program does not perform surveillance allograft biopsies and all biopsies in our paper were done for clinical suspicion of rejection.This study demonstrated a successful experience in renal transplantation at our center. Our cohort experienced a low rate of delayed graft function, rejection rate, and mortality. Surgical and medical complications were relatively lower than what has been reported in the literature -16 , similar to what has been reported in the literature . The secOur study has strengths and limitations. The strengths of this study are: 1) it provides a comprehensive descriptive analysis from a referral center for renal transplant the Kingdom of Saudi Arabia, 2) we have identified gaps and areas for further research and improvement, particularly early referral for pre-emptive transplantation, improving the deceased donor pool, transplantations of diabetic people, the need for special emphasis in identifying and treating the primary cause of ESKD, and 3) our study also calls for the better steroid-using strategies among renal transplant population. Limitations include it is an observational study, conducted in a single center, has relatively a small sample size, and did not include the serum creatinine level past the time of discharge.This study demonstrated a successful renal transplant experience among a relatively healthy cohort and identifies potential gaps, particularly the high rate of CVCs, the frequent lack of clear etiology of ESKD, the low rate of pre-emptive transplant and deceased donors. Prospective studies are needed to evaluate and close these gaps. The study also showed that our outcomes are comparable to the international reports.


Nepal has a high prevalence of hypertension which is a major risk factor for cardiovascular diseases globally. It is inadequately controlled even after its diagnosis despite the availability of effective treatment of hypertension. There is a need for an in-depth understanding of the barriers and facilitators using theory to inform interventions to improve the control of hypertension. This formative study was conducted to address this gap by exploring the perceived facilitators and barriers to treatment and control of hypertension in Nepal.We conducted in-depth interviews (IDIs) among hypertensive patients, their family members, healthcare providers and key informants at primary  and tertiary level  facilities in Kathmandu, Nepal. Additionally, data were collected using focus group discussions (FGDs) with hypertensive patients. Recordings of IDIs and FGDs were transcribed, coded both inductively and deductively, and subthemes generated. The emerging subthemes were mapped to the Capability, Opportunity, and Motivation-Behaviour (COM-B) model using a deductive approach.Major uncovered themes as capability barriers were misconceptions about hypertension, its treatment and difficulties in modifying behaviour. Faith in alternative medicine and fear of the consequences of established treatment were identified as motivation barriers. A lack of communication between patients and providers, stigma related to hypertension and fear of its disclosure, and socio-cultural factors shaping health behaviour were identified as opportunity barriers in the COM-B model. The perceived threat of the disease, a reflective motivator, was a facilitator in adhering to treatment.This formative study, using the COM-B model of behaviour change identified several known and unknown barriers and facilitators that influence poor control of blood pressure among people diagnosed with hypertension in Kathmandu, Nepal. These findings need to be considered when developing targeted interventions to improve treatment adherence and blood pressure control of hypertensive patients.The online version contains supplementary material available at 10.1186/s12889-021-11548-4. Hypertension is a major risk factor for cardiovascular disease (CVD) . It is rDespite clear evidence regarding the effective treatment of blood pressure using medication, global studies have reported that around half of diagnosed hypertensive patients remain untreated and more than half of those being treated continue to have uncontrolled blood pressure . StudiesSystematic reviews on barriers to management of high blood pressure have reported factors related to patients, providers and the health system , 13. SevNepal is a Low Income Country (LIC) where 25.2% of people are living below the poverty line . In NepaA qualitative study was conducted among patients and providers to explore their perspectives on barriers and facilitators to treatment and control among hypertensive patients in Nepal. Qualitative methods are appropriate for formative research where there is a need to explore determinant factors that are specific to a context and where literature is limited. Qualitative methods can provide deep insights into the problem being studied . The finTo obtain diverse views from all critical stakeholders, we included hypertensive patients, their family members, healthcare providers working at different levels of the health system and key informants. We included patients (ranging from 30 to 70 years old) who had been diagnosed with hypertension and were prescribed anti-hypertensive drugs by a qualified medical practitioner. To ensure maximum variability, we undertook purposive sampling of patients with diverse characteristics . We excluded hypertensive patients with serious complications  and those with co-morbidities requiring advanced care at a secondary or higher-level hospital as these limited their ability to participate in the study. However, we included patients with co-morbidities who were not serious and did not require immediate treatment. Patients with severe mental and physical disabilities and pregnant women were also excluded. Healthcare workers from PHCCs and HPs of Kageswori Manahara Municipality (primary level) and KMCTH (tertiary level) were interviewed.Healthcare workers distributed a study flyer containing information on the objectives, eligibility, and nature of the study to eligible hypertensive patients at selected health facilities. A list of those who agreed to participate was provided to researchers along with participant contact details. Participants, of both FGDs and IDIs, were asked to nominate and obtain consent from those family members who were involved in their care so that the researchers could contact family members purposively. The healthcare providers from selected sites were also invited for an interview to obtain their perspectives. To gather policy-level perspectives on challenges faced by the patients, key informants working in the Non-Communicable Diseases (NCDs) management  were interviewed in the study. Details are presented in the Tables Barriers to high blood pressure treatment and control were defined as any factors restricting the performance of recommended behaviours for patients to maintain optimum blood pressure control and treatment (medication and lifestyle) . The COMThe COM-B model Fig.  involvesWe used in-depth interviews (IDIs) and focus group discussions (FGDs) methods to collect data from March to July 2018. All IDI and FGD topic guides were translated into the Nepali language and were pilot tested  transcribed 25% of the transcripts, and a qualified transcriber, fluent in both English and Nepali transcribed the remaining audio-recorded FGDs and IDIs. Before direct English transcription, three interviews were transcribed in Nepali and translated into English by the qualified transcriber. The English language transcripts were back translated by BB, and translation reliability and accuracy were compared with the original Nepali transcript. This process ensured the presence of no significant differences in translation. The transcripts were checked against audio recordings, and pseudonyms were applied to participants to maintain confidentiality.QRS NVivo 12 software  was usedAll transcriptions were coded independently by the first author (BB). A random sample of three transcripts was shared with a co-author (RJ) for independent coding verification. Any discrepancies were resolved and agreed upon between investigators. We have used different methods of data collection like IDIs and FGDs and included the perspectives of diverse groups  in the study. Different methods and sources of data complemented the findings of each other. The initial codes generated from inductive coding were merged into subthemes and those emerging subthemes were mapped under the COM-B model using a deductive approach. For example, the codes that emerged inductively  generated the subtheme “Stigma of disease and fear of disclosure”. We then mapped out these subthemes to themes based on the COM-B model using a deductive approach. The Consolidated Criteria for Reporting Qualitative Studies (COREQ) 32-item checklist  was foll. The mean age of participants in IDIs was 50.2 years and in FGDs was 44.9 years. There were 44% males in IDIs and 56% in FGDs; 64 and 69% of patients were literate in IDIs and FGDs, respectively. The distribution of patients with blood pressure control was 60% in IDIs and 56% in FGDs.The characteristics of hypertensive patients who participated in IDIs and FGDs are presented in Table 1Detail characteristics of other participants  are provided in Table The themes and sub themes derived from the study are presented in Table Sub themes under psychological capability comprised of:Responses showed that many patients lacked necessary knowledge and understanding of various causes and risks associated with hypertension. Some were not aware of symptoms of hypertension and that it can be an asymptomatic disease. As one participant described:“If it is increased … what will happen... like... [Inaudible]... if increased may be unconscious or fall … may faint … I don’t know what happens.” .Many study participants did not have adequate knowledge about the complications of hypertension and were unaware of the consequences of uncontrolled blood pressure. They did express the need for more information about risk factors and treatment of hypertension.“Another thing is ... neither I know what exactly salt will do or how it will affect in my pressure... I don’t have exact information.” .Many were not aware of recommended behaviour modifications for blood pressure control. They did share their knowledge regarding the significance of exercise and salt reduction in their diet to control blood pressure; however, they did not know about the kind of exercises required for this and expressed their concern about salt intake. For example,“Yes, they are cooking food without salt and taking out vegetables for them, and they will add salt for the family members … They are not taking salt completely, and another problem will arise.” .Many study participants reported the misinformation that adding water to their diet would reduce the amount of salt in it. On the other hand, if they were advised to reduce salt, the health providers were worried that they would restrict salt to such an extent that there would be other issues like hyponatraemia. As one health provider explained:Some were aware that heart attack and sudden death could be a result of uncontrolled blood pressure."Half of the people I met said that I am too young to take medicine for pressure. They said that I should not be taking medicine before fifty years of age." Patients considered anti-hypertensive medication as the last option after trying other alternatives. Hence, they were taking the anti-hypertensive medicine after getting complications and at late stage. Moreover, they were worried about taking medicine for a long time. Participants also expressed that they do not need to take medication until and unless they felt symptoms such as pain or discomfort. Healthcare providers agreed that patients usually do not start their treatment on time, and if started, it was after trying all other alternatives. Patients were likely to discontinue the treatment when their pressure was under control. As one participant described:"I went to see the doctor (A-pseudonym) … Doctor checked my pressure, and it was 170/100. He gave me medicine… I took the medicine for 3-4 days and my pressure was in control, and I stopped that medicine." It was evident that deeply rooted perceptions were guiding the hypertensive patients’ behaviour, either they were not taking treatment or stopping them in between and not following recommended behaviour.Participants revealed many prevailing misconceptions related to the association between disease and age. Some stated that hypertension is a disease of old age, and therefore, medicine should not be started at a young age. They stated that if people get hypertension in their youth, they should delay the treatment until they reach fifty. One participant summed this approach up aptly:During analysis, the following sub-themes related to physical capability were identified:If there would be something to remind me, then that might be easy for me”.There were many barriers and challenges in taking the medication regularly. Among those related to physical capability were (i) forgetfulness, (ii) inconvenience, and (iii) being too busy with other commitments. Forgetfulness or memory was also reported as a reason for not taking medicine on time. Though forgetfulness is a psychological factor, it resulted in challenges to the physical act of taking medicine. This was reported not only by elderly participants but even by young participants. For instance, a young participant expressed the need for a reminder to take his medication: “"And yes, sometimes I forget to take medicine as well. Medicine which needs to be taken in the morning, sometimes I forget and take that in the evening. Sometimes, I don't remember that as well." It was evident that most patients faced challenges in changing their lifestyles. They reported a lack of skills and difficulty in managing time for exercise, giving exercise a low priority, negligence to take medicine and not following the recommended behaviour as the main challenges. One patient briefly explains:"For physical activity, it would be good If I walk in the morning, but I don't feel waking up from the bed in the morning." Mostly female participants explained that they could not manage their time for the required physical activity due to their household commitments. Differentially assigned roles based on patient sex might also have affected their ability to modify behaviour in the study setting."But here people in rural areas are not able to get proper treatment. There is less amount of health posts in those areas and with very little manpower. There is also a problem related to the availability of drugs. First is the geographical barrier; second is transportation problem; third is lack of health-related infrastructure; the fourth is lack of manpower and the fifth is the cost factor." (KI 04)In Nepal, anti-hypertensive medicine is not provided free of cost through the healthcare system. In PHC level, even participants expressed the concern of non-availability of antihypertensive medicine/pharmacy in nearby places.We cannot buy these medicine (antihypertensive) around here. We must go there (city) for buying it. We must go till Chabahil (name of city -2-3 hr travel).Yes,must go that much far for buying it. I usually buy for a month for my mother. Medicine needs to be taken continuously for the patient’s life, so the issues of availability, cost of anti-hypertensive medicine and diagnostic tests were raised by the study participants. One of the key informants expressed that a “country like ours haven’t [sic] got the insurance policy and patient must buy the medicine from their own money and affordability is also one major barrier.”Access to health services and affordability of the treatment were expressed as important system-level challenges. Given the shortcomings in access to healthcare services for most patients in Nepal, there were many issues that pertained to a lack of appropriate medicine, no clear guidelines, a lack of skilled health workers, and a lack of training on NCDs at the primary healthcare level. A major barrier to treatment and follow up is a lack of universal access to health services and the requirement to access care at the tertiary level. Costs of medicine and diagnostic tests, lack of health insurance and heavy workloads of doctors at the tertiary level resulted in many participants discontinuing their treatment or inconsistent follow up.Poor communication between providers and patients was one of the most important sub-themes that was elicited during IDIs. Many patients complained that their provider did not tell them about their diagnosis, medicine, and recommended behaviour modification. Some patients learned about their high blood pressure status after taking medication for almost 2 years."Now … . in the hospital, they will not tell in detail … They say, "your pressure is high, so you have to take medicine and write the name of the drug directly without any explanation." Healthcare providers admitted their shortcomings in counselling to make the patient understand their disease and treatment. They stated that they could not give enough time to patients for counselling, due to heavy workloads.One is the patient-doctor ratio. Especially in the government sector, there will be much rush. Must give plenty of time but we are not able to give that time." "Key informants also expressed that “if the counselling is not done properly, they won’t start taking medicine.” (KI 02).Good communication plays a crucial role in enhancing the good relationship between the healthcare provider and patients. It helps patients to open-up about their problems, remove their doubts and enhance their trust in treatments.Is related to those cultural factors which determine a person’s behaviour . The sub"But I feel like … after knowing this my friend might tease me about this. Maybe there will be a difference in their behaviour regarding taking food, and there might be some limitation. I cannot tell other people... I feel ashamed." "They think that if they marry a person who has high pressure, they will be barriers to their marriage … Yes, people try to hide it also. They never say they have it even though they have pressure." Stigma attached to hypertension, may have influenced health seeking behaviours, and follow up of treatment leading to uncontrolled blood pressure and complications. This was more evident with younger participants.Participants expressed fear to disclose their disease due to the social stigma attached to hypertension in their vicinity. For example, people with hypertension are considered generally weak and unable to perform their duties properly. Moreover, young, and unmarried male participants shared that it would be difficult for them to find a bride if they disclose their hypertension status. Two patients have expressed this stigma in detail:good luck (Sagun), as an offering to God during worship, and is also consumed on special occasions. Such cultural norms encourage alcohol consumption. A healthcare worker describes this cultural practice:"In some community, it is like in their Sanskritic  program; alcohol is like necessary item. Drinks and alcohol should be there. Because of that, they are regularly consuming alcohol." Furthermore, oily, and fatty foods are considered to be superior and delicious items and are commonly provided in feasts and festivals and offered to guests as a mark of hospitality. Consumption of salt also holds cultural importance. When there is a death of a close family member, people restrict salt in their diet to express their grief.We have deeply rooted old superstition and tradition as if anyone left salt, they ...people will say ...look she is unfortunate  look she is not taking salt as if there is death in the family.aalacchini … look … . who died in your family, so you are not taking salt...? people will say like this." "The tradition and practice of salt intake during grief was a new insight for the researcher (BB) who is a member of the same society with the same cultural understandings of the process of death. Traditional and cultural norms associate obesity with good luck and wealth. These deeply engrained norms may discourage hypertensive patients from losing weight and negatively affect blood pressure control.In some ethnic groups in Nepal, alcohol is associated with In this study, two sub-themes of reflective motivation were identified.“I am taking medicine. If I left 1-2 days, then I get afraid that I might get paralysis. (Laugh)... … I get scared of dying … and if I don't take medicine, then I can’t sleep as well.” They feared consequences of complications of the disease. They were scared that if they were paralyzed, their social life would be disturbed, they will be a burden to the family and may not get enough care. Participants also expressed fears of side effects of the medication and developing addiction to the medicine due to prolonged intake. Some hesitated to start taking the medication and discontinued after commencement. One participant describes this hesitation as:“I left completely.... it would become my addiction and habit … it would be like Nasha (addiction) so, I felt sad about... that I had to take it always, so I left that medicine.” As for treatment, some participants believed that missing a single dose of anti-hypertensive medication could lead to instant death. Therefore, they preferred uncontrolled blood pressure over starting the prescribed medication.Beliefs about the consequences of disease were identified as a motivator for behaviour modification, especially in taking anti-hypertensive medicine. Several participants admitted that they were taking medication or following the recommended behaviour due to a fear of complications. For instance, participants thought that they might have a heart attack or suffer paralysis if they stopped the treatments prescribed by doctors.Participants stated that they had more faith in homoeopathy, ayurveda and other traditional herbs and bitter vegetables as remedies for high blood pressure as compared to allopathic (Western) medicine. Due to their strong trust in traditional medication, locally available remedies remained their first preference to Western medication. Some patients expressed their belief in the consumption of bitter substances as a supplement to cure or control of high blood pressure.“It’s been around one month that my pressure is little higher.... I used to drink the juice of bitter melon (karela) before … my children used to give me that. So, I did not take medicine.” While going to walk, he usually takes Jamara’s juice. That is only recently … and he also takesAloe verajuice. It’s like if he heard anything like that will have a good impact on his health not only for the pressure; he usually takes that …” “These kinds of practices were favoured because they were understood to have less side effects, were easily accessible, were low cost, were advocated by close relatives and had religious significance.The use of the juice of Jamara (green wheatgrass or barley sprouts) by Nepalese hypertensive patients was also reported during IDIs and FGDs. This is a recently introduced as a remedy for non-communicable diseases in Nepal. It also holds religious significance as it is used as a blessing during Dashain festival in Nepal.Participants also expressed behavioural inertia in changing lifestyles. For example, some were not following a recommended low salt and a low-fat diet. Participants also found it challenging to shift to a low-fat diet as oil was an integral part of their daily diet. In Nepalese society, a low salt and low-fat diet are considered to be diet for an ill person. These kinds of perspectives may shape their behaviour, choosing foods with high salt and fat to consider themselves healthy. Even family member admitted such challenges of changing in dietary practices.My wife (patient) loves eating fried meats and oily pickles  a lot. I told her there is no use in having oily foods; control it. But it is the same. Nothing has changed. Similarly, participants confessed to being unsuccessful in trying to change their habits of smoking and consuming alcohol. An older participant residing in a rural area stated that she has been smoking since her childhood. Due to her long-term addiction, she was unsuccessful in her attempts to quit smoking even after being diagnosed with hypertension. She said, “yes, I tried many times to stop smoking but could not.”“I know everything... it will harm my pressure as well, but I am drinking . It is like my challenge. I am taking medicine and taking alcohol, as well. It’s all due to my habit.” Hence, participant behaviours were guided by their entrenched lifestyles which are not easily modified.We conducted a formative qualitative study guided by an evidence-based tool, the COM-B Model of Behaviour Change Wheel , to undeUnder the ‘capability’ theme, inadequate knowledge and various misconceptions about hypertension and its treatment were identified as barriers. These findings are consistent with previous studies conducted in Nepal , 18 and Our study has identified forgetfulness and being too busy as barriers for medication adherence under the component of physical capability, where the former was reported even by younger patients. This may explain the findings of quantitative studies from other LMICs, where old age was associated with higher adherence . SeveralAdditionally, a strong belief and trust in locally available herbs and bitter foods was identified as a barrier to the initiation and maintenance of allopathic medicines. Similar finding, where traditional medicines were preferred as a perceived cure for hypertension was reported in a study from Ghana . A qualiThe elicited theme ‘beliefs of consequences of disease and treatment,’ fits reflective motivation, another COM-B Model component. Participants identified fears of complications related to the disease as a prime motivator in starting medication and adhering to treatment. On the other hand, fear of the side effects and long-term usage leading to addiction resulted in either delaying initial treatment or stopping treatment shortly after commencement. Similar findings have been reported in Nepal , 18, MalThere were various physical opportunity barriers  elicited in our study. Previous reviews have often classified these under availability, affordability and accessibility barriers . SimilarThe most significant barriers to behaviour change reported under the physical opportunity theme is “communication between providers and patients”. Thus, demanding workloads, a lack of time, a lack of counselling skills, and negligence were primary factors that resulted in poor doctor-patient relationships and led to mistrust in treatment and non-adherence to medicine. This finding is consistent with previous studies in Nepal , 18 and Social influence was identified as both a barrier and facilitator for hypertension control in a systematic review . Our anaAll the barriers identified in the study are interrelated, so a holistic approach is required to address it at multiple levels such as patient, health system and community. It demands a policy-level action and commitment from the government and multiple other stakeholders such as civil society, academia, the private sector, and international organizations, in line with the recently endorsed Multi-sectoral Action Plan for the Prevention and Control of NCDs in Nepal (2014–2020) . PrimaryThis study’s strength lies in the data collection and analysis, which was informed by a behavioural model. It is the first formative study on hypertension management in Nepal to our knowledge. The study included participants from different healthcare systems and providers, unlike similar previous studies in Nepal , 18. Add. One limitation is, as the researcher was a professional working in a tertiary centre, some participants may have assumed that she was familiar with the issues being discussed. However, to overcome this bias, the researcher probed each question. The finding of the study is not representative as it was conducted in one part of the country. It might not reflect the perspectives of the participants from the geographically disadvantaged parts of Nepal who depend on available local health facilities.All interviews were conducted by the first author (BB), a native researcher sharing a similar cultural and linguistic background to the participantsThis formative study, using the COM-B model of behaviour change, allowed the confirmation of several known and unknown barriers and facilitators that influence poor medication adherence and lifestyle change for control of blood pressure among hypertensive patients in Kathmandu, Nepal. This included stigma attached to hypertension, misconceptions about lifestyle change, and perceptions that low salt intake is bad luck, and that obesity is a sign of wealth. The findings can be a reference for academics, researchers, and policymakers of related fields for planning intervention programs to address the identified issues and for further research for better management and control of blood pressure among hypertensive patients.Additional file 1. IDI and FGD guides. Description: It contains the IDI guides for patients with high blood pressure (I), health care workers (II) and FGD guide for the patients with high blood pressure (III).


Chronic kidney disease (CKD) represents a public health problem because it is characterized by several comorbidities, including uremic sarcopenia (US), and a poor quality of life. Currently, there are no standardized treatments available to counteract the onset of US but only some possible therapeutic approaches to slow its progression. The aim of this pilot study is to collect descriptive data in order to design a clinical trial based on the power analysis and simple size. The purpose of this pilot study was to evaluate the possible beneficial action induced by the functional anti-inflammatory and antioxidant bars in combination with the adapted physical activity (APA), on the onset and progression of US and other related-CKD comorbidities. We enrolled 21 CKD patients under conservative therapy, divided into four groups: (A) the physical exercise program (PEP), three times a week, in combination with the daily consumption of the two functional bars group; (B) the PEP group; (C) the daily consumption of the two functional bars group; (D) the control group. The duration of the study protocol was 12 weeks. We observed an improvement trend of body composition, blood pressure levels, lipid metabolism, and functional test in A and B groups. These preliminary data would seem to confirm the effectiveness of APA and to demonstrate the additive role of the natural bioactive compound’s assumption in countering US and other CKD comorbidities. Chronic kidney disease (CKD) has become a significant and increasing problem for world public health in the last years, as it strongly impacts on global morbidity and mortality and because it represents an important cardiovascular (CV) risk factor . After SCKD is characterized by a series of comorbidities that significantly impact on the quality of life (QOL) of nephropathic patients . Among tSarcopenia, according to the updated guidelines of the European Working Group on Sarcopenia in Older People (EWGSOP2), drawn up in 2019, is defined as a decrease in lean mass and muscle strength, in association or not with a decline in physical performance, a parameter used to stage the severity of the pathology .In CKD patients, the sarcopenia is particularly frequent, and it is triggered by hormonal and nutritional disorders, alterations of peripheral oxygenation, metabolic acidosis, electrolytes alterations, physical inactivity, and alteration of the composition of muscle fibers ,12. VariInsulin resistance is often associated with CKD, and its incidence increases linearly with the decline in renal function . In respCKD induces, from the early stages, a chronic low-grade inflammatory state, which can be evaluated by monitoring its typical biomarkers, such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) . In partIn CKD patients, angiotensin II is activated by muscle catabolism, and it is able to further increase proteolysis, reducing blood levels of insulin-like growth factor-1 (IGF-1) and activating the transforming growth factor-β (TGF-β) pathway, which leads to the loss of muscle mass . It has CKD patients show a decrease in appetite due to various factors, including physical inactivity, high levels of uremic toxins, chronic inflammatory status, and underlying hormonal disorders, such as reduced production of ghrelin and neuropeptide Y and increased leptin levels, which stimulates satiety and mediates inflammation ,17,18.To date, there are no specific and standardized treatments available to counteract the onset of US but only some possible therapeutic approaches to slow its progression, such as adapted physical activity (APA), nutritional supplements, drugs to counteract metabolic acidosis, and insulin resistance. In particular, the cornerstones of the treatment seem to be diet-nutritional therapy and physical exercise, two approaches without relevant side effects ,19. Amon2max, muscle strength and muscle mass, physical performance, self-reported physical function, and QOL [In CKD patients, not only in conservative therapy but also in renal replacement therapy (RRT), physical exercise is recommended due to its positive influence on VO and QOL ,27. Acco and QOL . Most of and QOL , few dat and QOL .The aim of this pilot study is to collect descriptive data in order to design a clinical trial based on the power analysis and sample size. The purpose of this pilot study was to evaluate the possible beneficial action induced by the combination of the functional bars assumption, characterized by high anti-inflammatory and antioxidant activity, with the APA, on the onset and progression of US and other related-CKD comorbidities. In particular, we have examined the possible benefits induced by the two therapeutic approaches on body composition, oxidative stress, muscle strength, physical performance, and other comorbidities and metabolic dysfunction  ,32,33.At the Hypertension Unit and Nephrology Centre of the University Hospital of Rome Tor Vergata, we enrolled 21 CKD patients under conservative therapy  guidelines , 10 maleThe study population was divided into 4 subgroups . In particular, group A carried out the physical exercise program online at home, three times a week in combination with the daily consumption of the two functional bars; group B carried out only the physical exercise program online at home three times a week; group C daily consumed the two functional bars; group D represented the control group.At the time of the enrolment (T0) and in subsequent controls, namely after six weeks (T1) and after twelve weeks (T2), patients underwent the following evaluations, as reported in Routine blood and urinary parameters were monitored in each time point of the study. In particular, we evaluated azotemia, creatinine, uric acid, electrolytes , sideremia, glycemia, lipid profile, chemical–physical urinary examination, and albuminuria on morning urine. Moreover, inflammatory parameters such as CRP, erythrocyte sedimentation rate (ESR), IL-6 and TNF-α were also evaluated. All laboratory parameters were analyzed by Dimension Vista 1500 , while the lipid profile was detected by standard enzymatic colorimetric techniques . The IL-6 and TNF-α were monitored by IMMULITE 2000 XPi Immunoassay System . All parameters were analyzed according to standard procedures in the Clinical Chemistry Laboratories of the University Hospital of Rome Tor Vergata.All patients also underwent capillary sampling using CR4000 tool for the oxidative stress evaluation and for the assessment of antioxidant defense mechanisms. In particular, the free oxygen radical test (FORT) and the free oxygen radical defense (FORD) were performed. The former test measures the levels of circulating oxygen, free radicals, and the second one indirectly determines the organisms’ antioxidant capacity by measuring the concentration of ascorbic acid, glutathione, and albumin ,36.At T0 and at T2 (after twelve weeks), Prevención con Dieta Mediterránea (PREDIMED), short form-36 (SF-36), and Baecke questionnaires were administrated to assess, respectively, adherence to the Mediterranean diet, patient’s QOL and the baseline levels of PA. All the listed questionnaires were administered face to face with patients, at all-time points of the study. The PREDIMED questionnaire was able to assess through 14 items the adherence to Mediterranean diet (MD). In fact, each item corresponded to 1 point up to a maximum of 14 points. According to the scoring, patients should be divided into 3 MD adherence groups: minimal adherence (5 or less points), medium adherence (points comprised between 6 and 9), maximum adherence  ,38. The SF-36 is a questionnaire that assessed the patient’s QOL through a visual score. It is composed of 36 items that investigate 9 symptoms spheres: physical functioning, role limitations due to physical health, role limitations due to emotional problems, energy/fatigue, emotional well-being, social functioning, pain, general health and, health change . For eacFinally, the Baecke questionnaire evaluated the subject’s PA degree in three spheres: job, sport, and other free time activities .2). For the assessment of body composition, all nephropathic patients underwent bioelectrical impedance analysis (BIA). Resistance, reactance, impedance, and phase angle at 50 kHz frequency were measured using a BIA 101S instruments (Akern/RIL System-Florence). Patient’s anthropometric parameters were detected. Body weight (kg) was measured to the nearest 0.01 kg using a balance scale . Height (m) was measured using a stadiometer to the nearest 0.1 cm . Body mass index (BMI) was calculated as body weight divided by height squared , extracellular water (ECW), body cell mass (BCM), fat free mass (FFM) and, fat mass (FM) ,42. quadriceps rectus femoris thickness (QRFT) and quadriceps vastus intermedius thickness (QVIT) as this ultrasound approach seemed useful in the detection of muscle loss in CKD patients [At T0 and at T2 (after twelve weeks), the patients underwent ultrasound evaluation of patients ,44. Thispatients ,46,47. Ahandgrip strength (HGS) test, a dynamometer that evaluates the handgrip force (Jamar Plus). The cut-offs of HGS are <30 kg for men and <20 kg for women [per side were performed, considering the average value.For the assessment of muscle strength, we used the or women . The patshort physical performance battery (SPPB), the stair climb power test (SCPT), and the six-minute walk test (SMWT), which measure balance, gait speed, and dynamic elongation [To assess physical performance, patients executed the ongation ,49. The At the beginning of the study (T0), all patients underwent a medical examination carried out by a specialist in Sports Medicine, including the anamnesis, a 12 leads electrocardiogram (ECG) at rest, and monitoring of systemic arterial pressure, in order to obtain the eligibility for the practice of recreational-motor activity and to exclude possible complications related to the training.per bar, is shown in The composition of the two functional organic bars, weighing 32 g each, with a caloric intake of 122 kcal and average potassium content of 200 mg Olea europaea L., the organic extra virgin olive oil (EVOO) was present in both bars, while the organic olive leaf powder was present only in bar 2. These two products were selected for their high content in minor polar compounds (MPCs) and for their biological activities linked to molecules such as hydroxytyrosol, oleuropein aglycone, oleuropein, oleocanthal, oleacin, and verbascoside [Vitis vinifera L. (micronized grape pomace and grape seeds), they come from grapes rich in antioxidant compounds such as proanthocyanidins, anthocyanins  and flavonols (mainly quercetin and its derivatives) [The two bars selected for the study are based on organic fruit and vegetables, and they were added with secondary raw materials from the wine and oil supply chain. In particular, grape micronized pomace and grape seeds, and olive leaf powder were chosen for their content in antioxidant compounds, as reported in the study by our research group concerning the innovative production of these functional ingredients and their related chemical characterization made by high-performance liquid chromatography–diode array detector–mass spectrometry (HPLC-DAD-MS) . Regardiascoside ,51,52,53vatives) .Two parameters of the two functional organic bars were evaluated: the total antioxidant capacity by Folin–Coicalteu analysis, expressed in mg of gallic acid (GAE)/32 g, and the percentage antiradical activity (% AA) using the DPPH radical method . The resPatients randomly placed in groups A or B followed an online and supervised combined PA protocol, with an aerobic phase and a strength-focused phase lasting about 60 min, performed at home, three times a week. The training session was carried out entirely online, through video lessons, under the supervision of a Graduate Specialized in Motor Sciences at the University of Rome Foro Italico. In detail, the tailored exercise protocol included a general warm-up lasting about 15 min, with exercises aimed at improving joint mobility and balance. The central phase, lasting about 30–35 min, involved 3 sets composed by 3 strength exercises for both upper and lower limbs using elastic bands and an aerobic activity at ≃65–70% of patient heart rate reserve, evaluated through the Karvonen formula. Regarding the strength part: during the first four weeks the trainer proposed exercise for the anterior/posterior chain, where patients performed 2 sets of 2 circuits composed by 4 multi-joint exercises, bodyweight or using the resistance band Core training, which included exercises aimed to improve abdominal, lumbar, and pelvis muscle strength, was incorporated in the session, as well. In the last eight weeks, exercises were focused on the upper/lower chain, patients started with 2 sets of 4 exercises during the weeks 4–8, then in weeks 8–12, they performed 3 sets of 3 exercises. The last part of the protocol, lasting 10 min, focused on cooling down and stretching of the main muscle groups involved during training, such as abdominal, quadriceps, pectoralis muscles, etc. At the end of each phase, patients’ heart rate and perceived fatigue were monitored by the trainer using patients’ personal heart rate monitor and the Borg Scale. All patients completed the protocol and no adverse events related to exercise were experienced.All data were entered into an Excel spreadsheet  and the analysis was performed using the Windows Social Science Statistics Package, version 25.0 .The descriptive statistics considered the mean ±standard deviation for the parameters with normal distribution (after confirmation with histograms and the Shapiro–Wilk test), while for the non-normal variables, it was considered the median and the interval (minimum–maximum). The primary aim of the study was to assess the descriptive statistic of the size, which concerned the central tendency, variability, symmetry, and kurtosis. The comparison for the non-normal variables were obtained with the Pearson’s first skewness. The aim of this statically evaluation was to set the power analysis (sample size) for a subsequent randomized clinical trial and to estimate the effects size.Currently, a total of 21 CKD patients were recruited in this study. Patients were divided in four subgroups . Laboratory and body composition parameters as well as physical performance tests were assessed at T0 (baseline) and T1 (after 12 weeks).In At time of enrolment (T0), eight patients  presented a pre-sarcopenia condition, due to a decrease in the musculoskeletal mass index (SMI) obtained by BIA ,56 or a The main laboratory findings are resumed in Blood pressure parameters showed a reduction for diastolic blood pressure in Group A  vs.  and Group B  vs. . Systolic blood pressure did not show any relevant difference .Inflammation and oxidative stress parameters are reported in Body composition parameters are reported in As it is reported in In our study, we observed a positive impact of PA on lipid metabolism. In particular, total cholesterol showed a reduction in groups A and B, confirming how PA alone should be useful in ameliorating lipid metabolism and highlighting, for the first time, that physical exercise in combination with the assumption of functional bars improves the lipid profile in CKD patients ,58. The In group C patients, we did not observe a trend of reduction of total cholesterol, probably due to the lower baseline levels of total cholesterol in these patients compared to other study groups.Moreover, the data obtained from our study showed a relevant increase in azotemia and creatinine values in the control group (group D), compared to other groups. Probably, these negative data are related to the natural progression of CKD.In the literature, it is well-known that a higher level of arterial blood pressure is a factor related to the faster progression of CKD to end-stage renal disease (ESRD) . FurtherIn our study, we observed a reduction in diastolic blood pressure and in ECW% in patients of groups A and B, speculating that the combination of APA with the intake of functional bars should inhibit the renin–angiotensin–aldosterone system (RAAS) ,67,68,69Regarding the body composition assessment, in groups A, B, and C, we observed a substantial increase in phase angle values. Phase angle is a BIA-measured parameter that reflects the integrity of cell membranes . The redMoreover, BIA showed a decrease of FM% in groups A and B and an increase of FFM% in the same groups.Some of these data could be explained by considering the composition of the functional bars administered in this study. As previously mentioned, the bars are based on EVOO with a high content of active MPCs with antioxidant power. Some studies have shown how the intake of EVOO rich in MPCs, in particular hydroxytyrosol, can exert positive effects on health, including the reduction of total cholesterol and the protection of blood lipids from oxidative stress, as also described from the health claim of European food safety authority (EFSA) EU 432/2012 ,76,77. TVitis vinifera L. also explains the improvement of some parameters examined in our study. In particular, the proanthocyanidins have shown beneficial effects on health, including the reduction of total cholesterol and of blood pressure and exerting cardiovascular protection [The presence of micronized otection ,81.In this study, as already demonstrated in previous studies by our research group, the intake of products based on fruit, vegetables, EVOO, and natural extracts rich in antioxidant compounds belonging to the class of polyphenols, showed an improvement in the clinical status of CKD patients ,22,23,25Our preliminary data indicate the healthy effect of APA in CKD patients. For the first time, we evidenced the possible additive role of natural bioactive compounds with high antioxidant and anti-inflammatory action on the slowing and on the management of related-CKD comorbidities, in addition to APA. In fact, these two innovative approaches, free from side effects, seem to empower each other, ameliorating the metabolic alterations due to CKD itself. In particular, the body composition improvements characterized by an increased phase angle and FFM% and a decreased FM% and ECW%, seem to be encouraging. The data obtained in this pilot study need to be confirmed by a randomized clinical trial, conducted on a larger population.