Briefly, 17-β-estradiol and progesterone concentrations were quantified via ELISA in all females. There were no differences in TMAO concentration between EFP (2.9 ± 1.7 μmol/L) and MLP (3.2 ± 1.1 μmol/L), between INACTIVE (3.3 ± 2.9 μmol/L) and ACTIVE (2.3 ± 1.1 μmol/L) days, or between men (3.0 ± 1.8 μmol/L), eumenorrheic women (3.0 ± 1.3 μmol/L) and contraceptive users (2.8 ± 1.4 μmol/L). Blood pressure was consistent across the menstrual cycle and pill days, but brachial systolic blood pressure was higher in males than females. There were no differences in brachial diastolic blood pressure or central blood pressure between the sexes. Repeated measures of TMAO, blood pressure, 17-β-estradiol and progesterone were consistent in all populations. These findings suggest that the link between TMAO and blood pressure is limited in healthy young adults.Trimethylamine N-oxide (TMAO), a gut-derived metabolite and marker of gut dysbiosis, has been linked to hypertension. Blood pressure is proposed to be elevated in hormonal contraceptive users and males compared to age-matched eumenorrheic females, but the extent to which TMAO differs between these populations has yet to be investigated. Peripheral and central blood pressure were measured, with the latter determined via applanation tonometry, and plasma TMAO concentration was assessed using liquid chromatography–tandem mass spectrometry. The following variables were assessed on two occasions in each of the following conditions: the early follicular phase (EFP) and mid-luteal phase (MLP) in eumenorrheic women ( The role of the intestinal microbiome in health and disease has garnered significant interest with recent research revealing sexual dimorphisms in the gut microbiome . As suchIt has been postulated that men may possess protective physiological mechanisms with respect to endogenous TMAO formation . HoweverThere is an absence of research exploring the reproducibility of circulating TMAO, 17-β-estradiol and progesterone hormone data, and blood pressure when measured on two separate occasions under the same control conditions. Replicate control studies are sparse within some scientific fields due to their time-consuming nature, but are needed to elucidate true response heterogeneity to interventions  from random within-participant measurement variability . At presThe aim of this study was two-fold. Firstly, to assess whether or not TMAO and blood pressure differ across the menstrual cycle, between pill consumption and pill withdrawal days in contraceptive pill users, and in males versus females. Secondly, to assess the reproducibility of TMAO, brachial and central blood pressure, 17-β-estradiol and progesterone under basal conditions..m2), 12 women taking oral contraceptive pills , and 23 men  volunteered to participate in this study. All participants were classified as being either recreationally active or trained [Briefly, 13 eumenorrheic women  surge, without the use of any hormonal contraceptives within the last 6 months) . Testing−1  being used to verify ovulation [In line with recently published methodological recommendations , calendavulation .® (n = 5), Lucette® (n = 2), Levest® (n = 2), Millinette® (n = 1), Cilique® (n = 1) and Lizinna® (n = 1). Contraceptive users were tested twice during the off-pill phase (INACTIVE) (days 1–4), i.e., when no exogenous synthetic hormones were ingested; and twice during the on-pill phase (ACTIVE) (days 17–21). Days 1–4 were chosen to ensure that endogenous concentrations of 17-β-estradiol and progesterone were low. Days 17–21 were selected as the end of the active pill phase where endogenous concentrations of 17-β-estradiol and progesterone are low but circulating concentrations of the synthetic, ingested hormones ethinyl estradiol and progestin concentrations are slightly elevated .Participants were required to rest supine for 10 min in a dark room. Thereafter, blood pressure of the brachial artery was measured using an automated sphygmomanometer . Five measurements were taken and the mean of the five measurements was used for analysis.Following 20 min of supine rest, pulse wave analysis was conducted on the radial artery using applanation tonometry methods . Pulse wave analysis calibrated to brachial blood pressure involves a validated generalised transfer function to derive corresponding central aortic pressures. All tonometry data were recorded by a single investigator, a minimum of two recordings were taken at each time interval and the two measurements with the highest quality index (>80%) were accepted for analysis. Pulse wave analysis indices of interest included aortic systolic and diastolic blood pressure.g at 4 °C for 10 min). Serum was then aliquoted into Eppendorf tubes and frozen at −80 °C for subsequent 17-β-estradiol and progesterone analysis.Following 30 min of supine rest, a tourniquet was applied around the upper arm and venous blood was subsequently drawn from an antecubital vein via venepuncture into EDTA and serum vacutainers. Plasma was subsequently extracted and stored at −80 °C for later TMAO determination. The serum tube was left to clot at room temperature before being centrifuged  from Cambridge Isotopes . Formic acid and ammonium hydroxide were purchased from Fisher Scientific.All solvents  were of LC-MS grade and purchased from Fisher Scientific  or VWR International . TMAO (98.9% purity) was purchased from Merck  and D9-TMAO) in methanol. Samples were then vortexed for 10 s and centrifuged at 21,100× g for 10 min at 4 °C. The subsequent supernatant was then transferred into vials for analysis.Plasma TMAO concentraiton was quantified using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Data were processed using MassLynx 4.1 software. An Acquity UPLC liquid chromatograph was coupled to a Quattro Ultima triple-quadrupole mass spectrometer  operated in multiple reaction monitoring (MRM) mode. Briefly, 20 μL of the plasma sample was mixed with 80 μL of 10 μmol/L deuterated TMAO  and 25 V (D9-TMAO) to monitor fragment ions of m/z 58.1 and m/z 66.1, respectively. Calibration standards (0–50 μmol/L) were prepared immediately prior to analysis. Samples were quantified using QuanLynx 4.1 software based on the ratio of peak areas for TMAO to D9-TMAO and compared to a calibration curve which was constructed by plotting the peak area ratio of the metabolites to internal standards against the concentrations. Based upon duplicate sample measurements, the intra-assay coefficient of variation (CV) was 3.0%.Chromatographic separation was performed according to a previously validated method  using a Briefly 17-β-estradiol and progesterone concentrations were determined in duplicate using competitive immunoenzymatic assays in accordance with the manufacturer’s instructions . The intra-assay CV for 17-β-estradiol was 3.6%, with a detection limit of 8.68–2000 pg/mL and 2.4%, with a detection limit of 0.05–40 ng/mL for progesterone.t tests were used for planned comparisons to compare EFP vs. INACTIVE  and MLP vs. ACTIVE . Paired-samples t tests were used to assess the reproducibility of biological repeats in males. To compare TMAO and blood pressure variables between eumenorrheic women, contraceptive users and males, data were averaged across the menstrual cycle (eumenorrheic women) and pill days (contraceptive users), and one-way repeated-measures ANOVAs were used. Significant main effects for groups were followed up with post hoc Holm–Bonferroni corrected independent-samples t tests. To calculate effect sizes, partial eta squared (p2n) was used for the omnibus tests, Cohen’s d (mean2 − mean1/SDpooled) was used for independent-samples t tests and Cohen’s dz (t/√n) was used for paired-samples t tests. Pearson’s product–moment correlation coefficients were used to assess the relationships between TMAO and blood pressure. To visualise the relationship between TMAO and continuous variables, a simple linear regression analysis was performed using GraphPad Prism 9.5.1. All data are displayed as mean ± SD unless otherwise stated. Statistical significance was accepted at p ≤ 0.05.SPSS version 27 was used for all statistical analysis. Shapiro–Wilk’s test was used to check data normality, and the Greenhouse–Geisser correction was used when sphericity was violated. Two-way repeated-measures ANOVAs were used to analyse the effects of phase (EFP vs. MLP and INACTIVE vs. ACTIVE) × biological repeat  in eumenorrheic women and contraceptive users. Independent-samples p2n = 0.06, p2n = 0.09), repeat  or phase × repeat interaction  in eumenorrheic women  or between MLP (3.2 ± 1.1 μmol/L) and ACTIVE . In males, there were no differences between visits . There was no main effect of group  between males, eumenorrheic women and contraceptive users , repeat  or phase × repeat interaction  in eumenorrheic women  or between MLP (106 ± 7 mmHg) and ACTIVE . In males, there were no differences between visits . There was a main effect of group , with brachial systolic blood pressure being higher in males compared to that in eumenorrheic women (d = 1.86) and contraceptive users (d = 1.81), both p < 0.001 , repeat  or phase × repeat interaction  in eumenorrheic women  or between MLP (67 ± 6 mmHg) and ACTIVE . In males, there were no differences between visits . There was no main effect of group  between males, eumenorrheic women and contraceptive users (There were no main effects identified for phase (ic women  or contric women . There wve users .p2n = 0.01) or repeat (p2n = 0.02), but there was a phase × repeat interaction (p2n = 0.36) in eumenorrheic women (p2n = 0.04), repeat (p2n = 0.13), or phase × repeat interaction (p2n = 0.12) in contraceptive users  or between MLP (93 ± 8 mmHg) and ACTIVE . In males, there were no differences between visits . There was no main effect of group  between males, eumenorrheic women and contraceptive users , repeat  or phase × repeat interaction  in eumenorrheic women  or between MLP (68 ± 7 mmHg) and ACTIVE . In males, there were no differences between visits . There was no main effect of group  between males, eumenorrheic women and contraceptive users , with higher concentrations of both hormones in the MLP vs. EFP  or phase × repeat interaction effects . In contraceptive users, there were no main effects of phase , repeat  or phase × repeat interaction  and the remaining 3 participants reported low 17-β-estradiol concentrations (ranging from 8.9–21.6 pg/mL). Additionally, 4/13 eumenorrheic women also demonstrated 17-β-estradiol concentrations that were below the lower limit of quantification in the EFP, with those above the limit of quantification ranging from 9.2 to 24.8 pg/mL, providing a positive confirmation of the menstrual cycle phase. In eumenorrheic women, there were main effects of phase on 17-β-estradiol and progesterone, respectively , and no correlations were observed between TMAO and oestrogen or progesterone . SimilarThere are large cyclic fluctuations in concentrations of 17-β-estradiol and progesterone throughout the menstrual cycle which is commonly divided into three phases: the EFP (low concentrations of 17-β-estradiol and progesterone), late follicular phase (high concentrations of 17-β-estradiol and low concentrations of progesterone), and MLP (high concentrations of 17-β-estradiol and progesterone) . EndogenOwing to the widespread utilisation of hormonal contraceptives amongst young women, assessing their side effects is an important public health consideration. Oral contraceptive pills downregulate endogenous concentrations of 17-β-estradiol and progesterone and have previously been shown to elevate blood pressure in young women in some ,20 but nAn interesting finding from the current study is that TMAO concentration was not different between similar-aged men and women. This contrasts findings from some previous human studies where men presented with higher TMAO concentration ,12,13, bn = 37) or pre-hypertensive . In line with previous observations, brachial systolic blood pressure was higher in males than females [All participants in the current study were normotensive  and following replicated 24 h food intake, allowing the confident assessment and reporting of the consistency of measures within and between individuals over time. Our replicated crossover study allowed, for the first time, the reproducibility between biological repeats to be quantified, and our data suggests that there is good reliability between biological repeats of the aforementioned variables.Despite a sex difference in brachial SBP, there were no differences in plasma TMAO concentration and central BP between males and females, throughout the menstrual cycle or between pill withdrawal and pill consumption days in oral contraceptive pill users. Plasma TMAO concentration was positively associated with brachial SBP in eumenorrheic women, but not female pill users or males, and was not correlated with central BP in any of these groups. All measured variables demonstrated acceptable between-day reproducibility. Therefore, while plasma TMAO, female sex hormones and brachial and systolic BP can be reliably determined in young healthy adults, the prognostic value of plasma TMAO concentration for cardiovascular health in these populations requires further research.


P < .001) and diastolic  blood pressure, total cholesterol , and weight . The educational intervention was found to be effective in reducing risk factors for cardiovascular disease.A pilot interventional quasi-experimental study without a comparison group was conducted to evaluate the effect of a 3-month educational intervention on clinical measurement changes among 50 patients with hypertension at the Bishoftu General Hospital in Oromia Region, Ethiopia. We measured blood pressure, weight, and total cholesterol at baseline and within a week of postintervention. We found significant decreases in systolic (−12.4 mm Hg;  Lowering and controlling blood pressure are crucial in reducing risk for cardiovascular disease. The burden of hypertension is increasing in Ethiopia, and evidence of educational and counseling interventions to lower the risk is limited.A 3-month educational intervention that focused on a healthy lifestyle among patients with hypertension was effective in improving systolic and diastolic blood pressure, weight, and total cholesterol.Establishing an educational and counseling program for patients with hypertension in health facilities and communities would promote a healthy lifestyle and help reduce their risk for cardiovascular disease.Hypertension is the leading cause of cardiovascular disease (CVD) and is also a modifiable risk factor . LowerinEducation and counseling interventions have been proven effective in preventing and controlling hypertension ,8. This A pilot interventional quasi-experimental study design without a comparison group was conducted at the outpatient department at Bishoftu Hospital in the Oromia Region of Ethiopia from January to September 2021.We included a convenience sample of 50 patients with hypertension at the pre-intervention assessment, which corresponded with the minimum sample size required to achieve 80% power. However, only 41 participants completed the postintervention assessments and were included in the analysis. Eligibility criteria required that patients be aged 18 to 65 years, have either systolic blood pressure (SBP) of 140 mm Hg or more or diastolic blood pressure (DBP) of 90 mm Hg or more, or be taking blood pressure medication. Pregnant women and patients with comorbidities  were excluded.The materials for the educational intervention sessions were adapted from the World Health Organization noncommunicable diseases model and modified according to the Ethiopian context . All parBaseline demographic characteristics were collected via an interviewer-administered questionnaire. All other measurements, including weight, blood pressure (systolic and diastolic), and total cholesterol were taken both at baseline and within 1 week after the pilot intervention. Body weight was recorded to the nearest 0.1 kg. Blood pressure was measured 3 times with the patient sitting down and the cuff placed on the left arm. Measurements were taken within 5-minute intervals, and the average of the 3 was calculated. The fasting blood samples were analyzed at the hospital using the end point Jaffe method to measure total cholesterol.t test assessed overall changes in measured outcomes; the 2-sample t test assessed outcomes by sex. The significance level was set at P < .05. Statistical analyses were performed using SPSS version 24 (IBM). Ethical clearance was obtained from the ethical review board of Oromia Regional Health Bureau and written consent was taken from all participants.Data normality for all continuous variables was checked and confirmed as normally distributed. Data were expressed as mean (SD) or as proportions. The paired Of the 50 participants, 41 completed both the pre-and post-intervention assessments for a response rate of 82.0%. The study sample was 63% female and patients had a mean age of 47.6 years. Approximately one-third (34%) of participants had no formal education, 61% were of Oromo ethnicity, 90% were Orthodox Christians, and 73% were currently married .P < .001). Mean weight of participants decreased from 67.9  kg to 65.3  kg (P < .001). Total cholesterol was reduced by 17.0%, from 205.5  mg/dl at baseline to 170.7  mg/dl at the 3-month follow-up (P < .001)  and mean DBP decreased 5%  ( < .001) .P < .001) and DBP , weight , and total cholesterol  at the postintervention follow-up among females. Similarly, males had significant reductions in the mean SBP  and DBP , weight , and total cholesterol . No significant differences between sex were identified in any of these measures (When results were stratified by sex, there were significant reductions in mean SBP (9.6%, measures .We found that a 3-month educational intervention promoting a healthy lifestyle among patients with hypertension resulted in significant reductions in SBP, DBP, weight, and total cholesterol. According to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, health-promoting lifestyle modifications are necessary to prevent the progressive rise in blood pressure and CVD . The lifThe strengths of this study included an acceptable follow-up of 82% of the study sample and objective measures obtained via a standardized protocol and results from a hospital laboratory. We anticipated explaining observed reductions in blood pressure and cholesterol as a function of weight loss. However, no significant associations were found between weight loss and blood pressure or total cholesterol, which could be because of the small sample size. Other limitations included a lack of a comparison group, a purposefully selected sample, and a short intervention duration. Hence, we cannot rule out the possibility that the changes observed from pre-intervention to postintervention were due solely to the intervention, as the improved outcomes could be attributed to one or more variables not measured.In conclusion, our pilot study demonstrated the beneficial effect of an educational intervention on changes in blood pressure, total cholesterol, and weight in a sample of patients with hypertension. We recommend that public health practitioners develop evidenced-based educational and counseling strategies appropriate for patients with hypertension in Ethiopia who seek treatment and control services at health facilities. However, supporting community-level educational interventions to reach a larger proportion of the high-risk population is equally important. Future interventions would benefit from including a comparison group or groups and a longer follow-up period with a larger sample size to examine whether positive changes would be sustained beyond the immediate educational intervention.


Type 2 diabetes mellitus is a major health problem worldwide with a steadily increasing prevalence reaching epidemic proportions. The major concern is the increased morbidity and mortality due to diabetic complications. Traditional but also nontraditional risk factors have been proposed to explain the pathogenesis of type 2 diabetes mellitus and its complications. Hyperglycemia has been considered an important risk factor, and the strict glycemic control can have a positive impact on microangiopathy but not macroangiopathy and its related morbidity and mortality. Thus, the therapeutic algorithm has shifted focus from a glucose-centered approach to a strategy that now emphasizes target-organ protection. Sodium-glucose transporter 2 inhibitors is an extremely important class of antidiabetic medications that, in addition to their glucose lowering effect, also exhibit cardio- and renoprotective effects. Various established and novel biomarkers have been described, reflecting kidney and cardiovascular function. In this review, we investigated the changes in established but also novel biomarkers of kidney, heart and vascular function associated with sodium-glucose transporter 2 inhibitors treatment in patients with type 2 diabetes mellitus. The prevalence of type 2 diabetes mellitus (T2DM) has been rising worldwide, reaching epidemic proportions in both high- and middle-income countries . MorbidiDiabetic nephropathy is the leading cause of kidney disease globally . AlbuminCVD, specifically ischemic heart disease, coronary artery disease (CAD), heart failure (HF), stroke and peripheral artery disease, accounts for 50% of deaths in patients with T2DM, a number that rises in the context of CKD [Multiple initiatives have been launched to prevent diabetes, achieve optimal glycemic control, and identify and treat diabetic complications as early as possible. Intensive blood glucose control and the management of body weight, blood pressure and lipid levels are all recommended for T2DM patients with tailored treatment objectives and plans . The funThe target-organ protective strategy has taken the place of the glucose-center approach since rigorous monitoring of glucose has failed to lower the frequency of complications, particularly macroangiopathy . ThroughSGLT2i remain the first line of treatment in HF and CKD since they have demonstrated remarkable outcomes in heart and kidney failure independent of diabetes, indicating that they act beyond glucose . SGLT2 iThe cardiovascular benefits of SGLT2i are thought to be caused by a number of processes, such as osmotic diuresis and natriuresis, which lower blood pressure, reduce arterial stiffness and vascular resistance, promote weight loss and reduce uric acid and oxidative stress. Elevated hemoglobin and hematocrit levels may also be involved, and glucagon’s control over heart glucose uptake is important for the beneficial inotropic and anti-arrhythmogenic effects ,24,25. AThe renal protection mechanisms of SGLT2i are also multifactorial. SGLT2i reduce sodium reabsorption in the proximal tubule, increasing sodium delivery to the macula densa. This restoration of tubular glomerular feedback results in reduced kidney blood flow, decreased glomerular hyperfiltration and lowered intra-glomerular pressure . These eAccording to the definition, a biomarker is “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention”. Biomarkers are used to detect subclinical disease before it manifests clinically. A biomarker should be easy to test in a non-invasive manner using a well-defined approach, and the measurement obtained should be capable of identifying those who are at risk . BiomarkThe non-hypoglycemic effects of SGLT2i have been extensively studied and documented in several publications, both in original research and review articles ,33,34. IHeart-related circulating biomarkers are proteins released into the blood either directly from the heart in reaction to tissue-specific damage, or from other cells as a systemic response to heart issues and can be easily detected .Natriuretic peptides (NPs) are hormones that regulate volume and pressure overload in the cardiovascular system, hence preserving homeostasis . Among tThe impact of SGLT2i therapy on NT-proBNP levels in patients with or without T2DM has been thoroughly investigated. Treatment with empagliflozin significantly reduced NT-proBNP levels in both diabetic and non-diabetic patients with HF with reduced ejection fraction (HFrEF) ,40. TreaMost studies report that canagliflozin significantly decreased the NT-proBNP levels in patients with T2DM, with either clinically stable HF ,45, or aAccording to Myhre et al., regardless of baseline NT-proBNP concentrations in HFrEF or HF with preserved ejection fraction (HFpEF), dapagliflozin improved outcomes, with the highest absolute benefit found in patients with higher NT-proBNP levels . PatientAlthough the majority of studies show a significant effect, some studies found no difference in the effects of empagliflozin or canagliflozin in patients with T2DM and clinically stable HF ,52,53,54Troponin (Tn) is a protein that exists in skeletal and cardiac muscle and has three isoforms, troponin C, troponin I and troponin T. The cardiac-specific isoforms of Tn  are exclusively expressed in cardiac muscle . Tn measNumerous studies have examined the effect of SGLT2i treatment on hs-cTn levels in patients with or without T2DM in various settings of underlying CVD. Vaduganathan et al. compared the effects of canagliflozin and placebo in diabetic patients with known CVD disease and showed that canagliflozin halted the rise in hs-cTnT over six years, while patients with increased hs-cTnT levels had a considerable advantage in terms of significant CVD events . This waRegardless of hs-cTnT baseline levels, empagliflozin had positive effects on CVD outcomes . DapagliOn the other hand, only some data such as that from Griffin et al. did not find a significant effect of empagliflozin on Tn levels in diabetic patients with stable HF .Soluble suppressor of tumorigenicity 2 (sST2) is a component of the interleukin-1 (IL-1) receptor family . It is gMatrix metalloproteinases (MMPs) are a family of enzymes that play a significant part in cardiac remodeling , being iCardiac imaging is used to evaluate the anatomy and function of the heart and is crucial in the diagnosis, treatment and monitoring of patients with heart diseases . Lately,Left ventricular ejection fraction (LVEF) is a widely used biomarker for evaluating heart function. HF patients are classified into two categories based on LVEF: HF with reduced systolic contraction and thus decreased ejection fraction (HFrEF), and HF with diastolic dysfunction but preserved EF (HFpEF) .Studies examining the impact of SGLT2i therapy on LVEF have produced conflicting results. The EMMY trial investigated the effect of empagliflozin in the acute setting and found a significant improvement in LVEF in patients who underwent percutaneous coronary intervention (PCI) for acute MI . In a grLeft ventricular global longitudinal strain (LV-GLS) is one of the newest imaging cardiac biomarkers that examines longitudinal deformation of the left ventricle and is decreased in patients with hypertension and diabetes, despite normal LVEF ,87,88. TStroke volume, which represents the amount of blood that is pumped out of the left ventricle of the heart with each systolic cardiac contraction, does not appear to be affected by SGLT2i treatment ,81,83,85In individuals with HF, LV volumes are related to LV remodeling and deteriorate over time . The mosResults regarding SGLT2i’ impact on LV volume parameters are not entirely consistent, as an improvement in LVEDV was found with SGLT2i treatment mostly in nondiabetic patients. Empagliflozin significantly decreased LV volumes in stable HFrEF patients ,82, as wRegarding LVEDV, there are no data supporting an association with SGLT2i treatment in T2DM patients, regardless of their CVD status ,80,81,85Concerning LVESV, significant outcomes were primarily observed in non-diabetic patients on SGLT2 treatment ,73,82. LThe excessive growth of LVM is known as LV hypertrophy (LVH), and it has been noted as a significant risk factor for CVD and mortality .Several studies support a significant reduction in LVM in T2DM patients treated with different SGLT2i ,79,80,90Left atrial volume (LAV) depicts diastolic burden and is a reliable indicator of CVD outcomes . In T2DMLV diastolic function is evaluated using LV filling pressure parameters, expressed as the ratio of early mitral inflow velocity to early diastolic velocity in the mitral annulus (E/e′) .Treatment with various SGLT2i, in particular canagliflozin, dapagliflozin and empagliflozin, in patients who underwent PCI in the presence of an acute MI had a significant impact on E/e′ ,75,97. HUnlike LV parameters and function, one study in T2DM patients with CAD treated with empagliflozin did not report any change in the RV mass index (RVMi), RV end systolic and diastolic volumes  and RV ejection fraction (RVEF) .PV is an important element of CVD pathophysiology. Estimated PV (ePV) is calculated using several formulas based on anthropometric parameters and hematocrit and has been used as a prognostic factor for CV events and mortality .Multiple studies have demonstrated the significant impact of SGLT2i treatment on ePV. Empagliflozin was found superior in lowering ePV, compared to either placebo or conventional glucose-lowering treatment, in T2DM patients with HF or underlying CVD ,51, exhiA summary of both circulating and imaging biomarkers related to heart function affected by SGLT2i treatment is presented in The renoprotective effect of SGLT2i is largely mediated by osmotic diuresis and natriuresis-induced blood pressure (BP) reduction, local renin-angiotensin-aldosterone system inhibition and a reduction in body mass index (BMI) and arterial stiffness ,102. CliThe regulation of body weight also plays a role in the renoprotective effect of SGLT2i. Both the EMPA-REG OUTCOME trial and the EMPEROR-Reduced trial demonstrated a statistically significant weight loss when SGLT-2 inhibitors were used. In subgroups identified by glucose-lowering medication at baseline and follow-up, a 5 kg decrease in body weight was observed . PatientSeveral regulators of inflammatory response, including nuclear factor-B (NF-B), interleukin 6 (IL-6), monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor-a (TNF-a), enzymes such as matrix metalloproteinase 7 (MMP-7) and other molecular structures such as fibronectin-1 have been shown to decrease in response to SGLT2i therapy. Among these, TNF-a is considered essential for CKD patients’ ability to manage inflammation. TNF-a may bind to any of the several TNF-Receptor (TNFR) isoforms, including isoforms 1 and 2. Elevated TNFR-1 or TNFR-2, are signs of renal failure. Treatment with canagliflozin was found to reduce TNFR-1 and TNFR-2 levels . As the Biomarkers of tubular injury are proteins released in the circulation by the tubular epithelial cells as a response to injury. Among them, kidney injury molecule-1 (KIM-1) is located on the apical membrane of the proximal tubule. It is released into the tubular lumen and absorbed by the peritubular capillaries and is considered a predictor of kidney failure . CompareIn T2DM patients , SGLT2i Glomerular filtration rate (GFR) remains an ideal marker of kidney function. Due to the time-consuming nature of measuring GFR, it is typically estimated using equations that account for endogenous filtration markers such as serum creatinine (SCr) and cystatin C (CysC) .In a cross-sectional study, patients with T2DM who were treated with SGLT2i for at least 24 weeks were compared to those who had not in terms of their estimated glomerular filtration rate (eGFR), which was calculated using both CysC and the estimated glomerular filtration rate (eGFRcys) based on the former. The group receiving SGLT2i had significantly increased eGFRcr while eGFRcys remained the same. The SGLT2i group had a considerably greater difference between eGFRcr and eGFRcys (eGFRcr-cys) ,116. IndAt the start of the dapagliflozin treatment, fractional urea excretion was dramatically decreased, and free water clearance was also significantly decreased after four and 14 days . DapagliA minor but substantial decrease in HbA1c has been associated with SGLT2i therapy in CKD patients, but not with a decrease in urine fractional glucose excretion ,119.The urine albumin/creatinine ratio was dramatically decreased after SGLT2i treatment. Urine 8-hydroxy-2C-deoxyguanosine (8-OHdG), a marker of oxidative stress linked to kidney injury, decreased but urinary N-acetyl-b-d-glucosaminidase (NAG), urinary b2-microglobulin and urinary KIM-1 remained unaltered ,120. AccProteomics and metabolomics investigations have recently revealed new information about the discovery of novel biomarkers for the progression of diabetic nephropathy. Proteomics comprises methods for studying the urine proteome, whereas metabolomics identifies and quantifies urinary metabolites. The proteomic classifier CDK273 urine test was employed in the PRIORITY trial, and it was found that patients with T2DM had a 2.5-fold higher incidence of microalbuminuria .A summary of biomarkers related to renal function affected by SGLT2i treatment is presented in Arterial stiffness is one of the first indicators of morphological and functional changes in the arterial wall and it is caused by arteriosclerosis rather than atherosclerosis . It has The gold-standard method for the measurement of arterial stiffness is PWV, primarily carotid-femoral (cfPWV) or brachial-ankle (baPWV). In T2DM patients, PWV significantly decreased after treatment with either dapagliflozin ,126, canHowever, other studies that examined short-term or long-term treatment with SGLT2i as monotherapy or in combination with different non-SGLT2i agents did not find a significant change in PWV ,132. In Cardio-ankle vascular index (CAVI) is another biomarker that reflects arterial stiffness and, unlike PWV, is independent of BP. CAVI is now being used as a predictor of CVD .Sakai et al. found a significant reduction in CAVI in T2DM and HFpEF patients treated with SGLT2i , with no difference between the SGLT2i groups . In T2DMIt should be pointed out that these studies are heterogeneous, with different methodologies and populations. SGLT2i treatment was initiated in T2DM patients with or without CVD risk and/or hypertension, as monotherapy compared to placebo or in different combinations with other antidiabetic medications leading to different findings and somewhat conflicting results.The vascular endothelium controls all aspects of vascular balance in reaction to physical and chemical stimuli, through the production of various vasoactive mediators. Endothelial dysfunction plays a role in the formation and progression of atherosclerosis, as well as the rupture of atherosclerotic plaques .Independent of the existence of diabetes, SGLT2 inhibition has been proven beneficial for enhancing endothelial function, which emphasizes the cardioprotective properties of this class of medication even more .FMD is currently the most widely applied method of assessing endothelial function through ultrasound in the brachial artery, in response to changes in blood flow. Although primarily utilized as a research tool, it is considered a predictive factor for patients with both low and high CVD risk .FMD has been extensively studied as a treatment target of SGLT2i. Most studies note a significant improvement in FMD after treatment with different types of SGLT2i ,141,142,Peripheral microvascular endothelial function in the fingertip can be measured using an EndoPAT device. This approach involves pulsatile volume fluctuations at the fingertip and is non-invasive . The reaTreatment with dapagliflozin for six months managed to significantly improve endothelial function, as assessed by RHI in patients with uncontrolled T2DM, compared to non-SGLT2i treatment . HoweverCarotid ultrasonography is one of the most prevalent ways to detect atherosclerotic changes, and it is effective in both primary and secondary CVD prevention. Carotid intima-media thickness (cIMT) is calculated via carotid ultrasound using a specific reading software and is linked to a high risk of atherosclerosis .Treatment with SGLT2i has thus far been unable to reduce cIMT. In a randomized clinical trial of T2DM patients without CAD, tofogliflozin did not appear superior to conventional (non-SGLT2i) treatment, although antidiabetic medications in general (both SGLT2i and non-SGLT2i) reduced cIMT in a significant way . IpragliIn comparison to the arms, the lower extremities have greater systolic blood pressure. This connection is represented by the ankle-brachial index (ABI). A reduction in this ratio is used to detect peripheral artery disease and is related to greater CV risk .Both canagliflozin and luseogliflozin failed to affect ABI in a significant way when used in T2DM patients with stable chronic HF or suboptimal glycemic control, respectively ,132.Central hemodynamic indices are either measurements that estimate central BP parameters and derivatives , or parameters that evaluate wave reflections (augmentation index (AIx), forward and backward wave, wave intensity analysis). Wave reflection measurements have regularly been found to be reliable indicators of CVD events and death in high-risk individuals .Studies that examined the effect of treatment with SGLT2i on central BP and the AIx give contradictory results. Both empagliflozin and dapagliflozin reduced central BP and the AIx when compared to placebo for six and 12 weeks, respectively ,129. In Inflammation is a major factor in the development of vascular dysfunction in T2DM, which is a key contributor to the high cardiovascular risk associated with the disease. Chronic low-grade inflammation plays an essential part in the malfunctioning of vascular cells that underlies the onset and development of atherosclerosis in diabetes . SGLT2i Widely known as a biomarker of systemic inflammation, high-sensitivity C-reactive protein (hsCRP) has also been associated with the progression of atherosclerotic plaques, especially the more fragile ones ,155. ConSoluble intercellular adhesion molecule-1 (ICAM-1) is a component that has low expression in the endothelium under normal circumstances but is increased during inflammatory processes and may serve as an indicator of early atherosclerosis. Treatment with dapagliflozin gives conflicting results, as Zainordin et al. observed a significant improvement in ICAM-1 in diabetic patients, whereas Sposito et al. note no difference ,145.A summary of biomarkers related to vascular function affected by SGLT2i treatment is presented in SGLT2i constitute an important class of antidiabetic medications that also exhibit significant cardioprotective and renoprotective effects. Various biomarkers of renal, heart and vascular function, either conventional or novel, which are used to identify subclinical illness before clinical manifestation, are affected by SGLT2i treatment. Thus, it appears that a new area of research has been opened, aiming to use these drugs in subclinical disease to prevent the disease’s evolution or in an attempt to reverse any pathological changes that have already occurred before the disease onset.


Diabetic kidney disease (DKD) is the most common microvascular complication of diabetes, which has been a major cause of end-stage renal failure. Diagnosing diabetic kidney disease is important to prevent long-term kidney damage and determine the prognosis of patients with diabetes. In this study, we investigated the clinical significance of combined detection of urine orosomucoid and retinol-binding protein for early diagnosis of diabetic kidney disease.We recruited 72 newly diagnosed patients with type 2 diabetes and 34 healthy persons from August 2016 to July 2018 at the First Affiliated Hospital of Henan Polytechnic University . Using the Mogensen grading criteria, participants were classified as having diabetes or diabetic kidney disease, and healthy persons constituted the control group. Urine orosomucoid and retinol-binding protein levels were measured and correlated with other variables.With the aggravation of renal damage, the level of urinary mucoid protein gradually increased. Urinary retinol-binding protein and microalbumin levels were significantly higher in the diabetes group than in control and nephropathy groups. Orosomucoid and retinol-binding protein might be independent risk factors for diabetes and diabetic kidney disease. Urinary orosomucoid significantly correlated with retinol-binding protein and microalbumin levels in the diabetic kidney disease group.Elevated urine orosomucoid and retinol-binding protein levels can be detected in the early stages of type 2 diabetic kidney disease. Both of these markers are important for diabetic kidney disease detection and early treatment. Diabetic kidney disease (DKD) is the most common and severe chronic vascular complication among patients with type 2 diabetes mellitus (T2DM) . It leadThirty-four healthy people who underwent physical examination at the First Affiliated Hospital of Henan Polytechnic University  between August 2016 and July 2018 were categorized as the normal control (NC) group, including 18 males and 16 females, with an average age of 47.9 ± 14.2 years. Seventy-seven patients with T2DM who were hospitalized at the same time were assessed according to the Mogensen classification criteria for the degree of kidney damage. We recorded the medical history and complications of all patients. Complications of diabetes include DKD and diabetic retinopathy (DR). These patients were categorized as those with T2DM  < 30 mg/24 h), which included 21 males and 17 females, with an average age of 48.7 ± 13.6 years, and patients with early DKD and combined DR , which included 19 males and 15 females, with an average age of 49.1 ± 14.4 years. Diabetes was diagnosed and classified according to the 1999 diagnostic criteria of the World Health Organization [We recorded the medical history and complications of all patients and measured their diastolic blood pressure (DBP), systolic blood pressure (SBP), height (cm), and weight (kg). The levels of total cholesterol (CHOL), low-density lipoprotein cholesterol (LDL), triglycerides (TG), fasting blood glucose (FBG), 2-hour blood glucose, serum creatinine (SCr) and urine orosomucoid, and RBP were measured using Applied blood biochemical detector . HLC-723 HbA1c Analyzer , i.e., high-pressure liquid phase ion-exchange chromatography was used to determine glycosylated hemoglobin (HbA1c) levels. The urine specimen was collected between 10 pm and 6 am, and the total urine volume (mL) was recorded after mixing. IMMAGE 800 protein chemistry analyzer  was used to detect urine MAL. The urine orosomucoid level was determined using the rate scattering immunoturbidimetric method performed on the Array 360 System . Orosomucoid reagents, calibration cards, and calibration were provided by the manufacturer. The detection temperature was 37℃, while the measurement wavelength of the instrument was 340 nm; the immunoturbidimetric measurement was performed after calibration. CV within and between batches was less than 5%. The CKD-EPI equation [For normally distributed data determined using the Shapiro–Wilk’s test, the indicators in each group were expressed as the mean ± standard deviation. The chi-square test was used to compare quantitative data between groups. The mean values for each of the three groups were compared using one-way analysis of variance. If there were significant differences between the groups, intra-group comparisons were performed using the least significant difference. A binary logistic regression model was used to determine the factors associated with T2DM and T2DKD, and correlation analyses were performed using Spearman’s rank correlation. The receiver operating characteristic (ROC) curve was used to analyze the diagnostic points and diagnostic value of orosomucoid and RBP in DKD. All statistical analyses were performed using SPSS version 23.0 . A two-tailed test with P < 0.05 was considered significant.There were no significant differences in age and gender among the three groups (P > 0.05). There were no significant differences in DBP, BMI, CHOL, TG, and LDL levels among the three groups (P > 0.05) Table .There were significant differences in SBP, HbA1c, FBG between the NC and the other two groups (P < 0.05). However, there was no significant difference in the general clinical data between the T2DM and T2DKD groups (P > 0.05). As renal damage increased in patients, urine orosomucoid levels gradually increased as well (P < 0.05) (Table Urine RBP and MAL levels in the T2DKD group were significantly higher than those in the NC and T2DKD groups (P < 0.001). The eGFR levels in the T2DKD group were significantly lower than those in the NC and T2DM groups (P < 0.001). There were no significant differences in RBP, eGFR, and MAL levels between the NC and T2DM groups (P > 0.05)  and the independent variables were the four variables  with differences between the two groups, as shown in Tables , No = 0 For the T2DM group and T2DKD group, the dependent variable was whether T2DKD had occurred Yes = 1, No = 0) and the independent variables were the five variables with differences between the two groups, as shown in Tables , No = 0 r = 0.489) and MAL (r = 0.513). RBP and MAL were significantly positively correlated with a correlation coefficient of 0.468. eGFR and urine orosomucoid, RBP, and MAL were significantly negatively correlated .Of the five factors that were included in the regression model (p < 0.05), SBP, orosomucoid, RBP, and MAL were all determined to be risk factors (OR > 1), and eGFR was shown to be a protective factor (OR = 0.948 > 1). Correlation analysis showed that in the T2DKD group, the urinary orosomucoid level was significantly positively correlated with RBP . The diagnostic point of orosomucoid was 22.43, sensitivity was 0.941, specificity was 0.842, and Youden’s index was 0.783. The diagnostic point of RBP was 0.53, sensitivity was 0.942, specificity was 1.000, and Youden’s index was 0.941.The diagnostic value of DKD had improved; however, no significance was observed  . Recent r = 0.489) and a significant negative correlation with eGFR (r = -0.577). The results also revealed an increase in orosomucoid in the early stage of DKD, suggesting that this increase may promote the occurrence and development of DKD.Orosomucoid protein is a non-specific acute phase reaction protein that is mainly synthesized and secreted by the liver; it is low in healthy body fluids but is significantly increased in a state of inflammation or during tumor growth. Orosomucoid can act in damaged areas, be released into the circulation and intercellular fluid, and become involved in the induction and regulation of body damage, immune, and inflammatory responses . Elevater = 0.468) and a significant negative correlation with eGFR (r = -0.474). Urine RBP may reflect early renal damage in DKD. In the area under the ROC curve for predicting DKD using orosomucoid and RBP, both factors had high sensitivity and specificity. Therefore, both orosomucoid and RBP can be used to diagnose DKD.RBP is filtered through the glomerulus and absorbed and degraded by proximal tubular epithelial cells. Therefore, it is generally stable in urine, difficult to decompose, and has a low excretion rate. An increase in RBP excretion may reflect the extent of damage , 18. StuThis study’s main limitation is that all the participants were residents of Henan Province, China, and the sample size was small. Further verification is needed through large sample-size studies and multicenter studies.Urine orosomucoid and RBP can serve as potential markers for the early diagnosis of DKD, facilitating timely treatment. However, the underlying molecular mechanisms and the clinically important levels of these potential biomarkers need to be studied further.


Background and Objectives: The effect of non-pharmacological aerobic exercise training on blood pressure in sedentary older individuals receiving social home care in Saudi Arabia has not been investigated. This study aimed to examine the effects of aerobic exercise on blood pressure in sedentary older Saudis with hypertension residing in these settings. Materials and Methods: A pilot randomized control trial was conducted with 27 sedentary individuals, aged 60–85, diagnosed with hypertension, and living in social home care in Makkah, Saudi Arabia. Recruitment took place between November 2020 and January 2021, and participants were randomly assigned to either the experimental or control group. The experimental group engaged in three 45 min sessions of low-to-moderate intensity aerobic activity per week for eight weeks. This trail was registered with the ISRCTN registry (ISRCTN50726324). Results: Following eight weeks of mild to moderate aerobic exercise training, the primary outcome of resting blood pressure showed a significant reduction in the experimental group  compared to the control group. Within the experimental group, there was also a significant decrease in systolic blood pressure  and diastolic blood pressure . Conclusions: This trial demonstrates the feasibility and potential benefits of low-to-moderate intensity aerobic exercise training in reducing resting blood pressure among sedentary older Saudis with hypertension residing in this aged care setting. Hypertension is strongly associated with age . ApproxiIn Saudi Arabia, hypertension affects 26% of the adult population and is a major cause of death ,8. ExistGiven the considerable risk associated with hypertension, the American College of Sports Medicine recommends regular aerobic exercise as a non-pharmacological treatment strategy for hypertension . SeveralClinical trials investigating the effect of aerobic exercise in older adults have reported divergent results . To our We conducted this pilot study using a nonblinded randomized controlled trial (RCT) design at the Medical Department of Social Home Care for older adults in Makkah, Saudi Arabia, from January 2021 to March 2021. The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of King Saud University (E-20-5451) and the Ministry of Human Resource and Social Development, Social Welfare and Family Agency (78891). This study was registered with the ISRCTN registry (ISRCTN50726324). We opted for a nonblinding RCT design based on the recommendation that blinding should not be a decisive factor in assessing bias in a rehabilitation context . We reviSedentary men or women, aged 60 to 85, with hypertension and living in social home care were eligible. We defined hypertension as systolic blood pressure ≥130 mmHg and diastolic blood pressure ≥80 mmHg . We descWe randomly divided participants who complied with the inclusion criteria into experimental and control groups, as shown in We assessed the primary and secondary outcomes at baseline and after the eight-week aerobic exercise training program. We determined the primary outcome of resting blood pressure by evaluating systolic and diastolic blood pressure using a conventional mercury sphygmomanometer . To assess systolic and diastolic blood pressure, we instructed all participants to cease smoking and drinking caffeine beverages 10 h before measurement and to empty their bladder. Participants were allowed to sit comfortably on a chair for at least 15 min with the back straight, supported, feet flat on the floor, legs not crossed, and arms supported on a flat surface. Blood pressure was measured twice, two minutes apart, and on two different occasions from both arms. We used the highest reading from the mean of the two readings as the blood pressure value. The mercury sphygmomanometer is valid, reliable, and considered the gold standard for measuring blood pressure .The secondary outcomes were heart rate, body fat, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and functional status. We assessed the resting heart rate using heart rate monitors when the participants were calm, relaxed, sitting, or lying. The term “resting heart rate” describes the heartbeat when it pumps the least blood required at rest. Heart rate monitors detect and measure heart or pulse rate and have proven to be accurate and valid tools . Body faAccording to the American College of Sports Medicine guidelines , we instIn the first week, participants started from 20 min with 30% of their heart rate and progressed gradually to 45 min with 50%. For the duration of each session, a 10 min warm-up and cool-down routine was included. We used a heart rate monitor to maintain aerobic exercise intensity during training and prevent excessively elevated heart rate of a maximum of 160 beats per minute (bpm) [The study sample size was calculated based on the inconsistent results of RCTs conducted on older adults in different settings and the divergent conclusions of the meta-analyses findings ,32, a rep-value < 0.05.We evaluated the dependent variables’ normality distribution and homogeneity of variance using the Kolmogorov–Smirnov and Levene’s tests, respectively. Descriptive statistics were presented as mean and standard deviation (SD) in total and for both experimental and control groups. The change in both the primary and secondary outcomes between the groups was analyzed using a nonparametric statistical test of the Mann–Whitney U test because of the limited sample size of this study. The change in the primary and secondary outcomes within groups was analyzed using a nonparametric statistical test of the Wilcoxon signed-rank test. Significance between groups was determined using an independent t-test, whereas a dependent sample test was used for within-group significance determination. The statistics were presented in mean and standard deviations (SD), along with 95% confidence interval (95% CI). All analyses were performed using IBM SPSS software . Statistical significance was defined as n = 1), older than 85 years old (n = 1), and with chronic obstructive pulmonary disease (n = 1) were also excluded. Finally, the study included a total of 27 participants. Due to 3 dropouts, only 24 of the 27 participants initially enrolled in the study—12 in each experimental and control group—were used in the final analysis. The reasons for dropping out were relocation, follow-up loss, and trial withdrawal  . Patientthdrawal .Participants in the experimental group were approximately one year older, overweight (26.1 vs. 24.6), and had a higher average LDL compared to the control group (103.2 vs. 79.3). Both groups had an average heart rate of 81 bpm .p = 0.001; and diastolic blood pressure: MD = 1.33 mmHg, p = 0.001). Within-group resting blood pressure was also significantly reduced . No significant changes occurred in the mean of systolic and diastolic blood pressures among the control group (p > 0.05)  .p = 0.002), 0.81 kg/m2 (p = 0.001), 40.9 mg/dL (p = 0.001), and 50.3 mg/dL (p = 0.001), respectively). No significant changes occurred between groups in the mean HDL and functional status . The mean heart rate, body fat, cholesterol, and low-density lipoprotein (LDL) cholesterol were significantly decreased within-group (MD = −3.67 beats/min (p = 0.005), −0.71 kg/m2 (p = 0.009), −34.0 mg/dL (p = 0.002), and−46.0 mg/dL (p = 0.002), respectively). No significant change occurred in the mean of HDL and functional status in within-group . No significant changes occurred in the mean of resting heart rate, BMI, cholesterol, LDL, HDL, and functional status from pre-to-post exercise among the control group (p > 0.05)  .Results indicated that resting blood pressure was significantly reduced between and within-group after eight weeks of mild to moderate aerobic exercise training. No significant changes occurred in the mean of resting systolic and diastolic blood pressure, resting heart rate, BMI, cholesterol, LDL, HDL, and functional status from pre-to-post exercise among the control group.In this study, the systolic and diastolic blood pressure reduction following aerobic exercise was less than expected . However, decrease in the systolic and diastolic blood pressures might be the underlying physiological process that occurs due to the increasing shear stress in the blood vessels, which increases the formation of nitric oxide (NOx) vasodilator and contributes to vascular vasodilatation . An earlThe findings of this study agree with those of a recent meta-analysis and systematic review of clinical trial studies . Accordi2 and 2.3 kg, respectively. Blumenthal et al. (2000) [The secondary outcomes of this study showed that aerobic exercise effectively reduces resting heart rate, BMI, cholesterol, and LDL. These findings are broadly consistent with previous studies. For example, Madden et al. (2009)  reported. (2000)  reported. (2000)  reportedIn this study, the results showed that aerobic training does not improve functional ability. This finding is similar to a previous study that reported no improvement in functional status after 12 weeks of aerobic exercise . This reThis study has several strengths. To our knowledge, this is the first study in Saudi Arabia investigating the beneficial effects of regular aerobic exercise on resting blood pressure in sedentary older adults with hypertension living in social home care. Nurse assessors who measured study participants’ blood pressure were blinded for allocation to avoid measurement bias. The physiotherapist and attendance supervised the exercise sessions, and the experimental group participants’ adherence was accomplished excellently. Additionally, all exercise sessions had the correct training time and amount of intensity being completed using heart rate monitors.However, this study has several limitations that should be acknowledged as well. Firstly, it is worth noting that the trial was conducted with a relatively small sample size of 27 sedentary older Saudis with hypertension residing in a social home care. While the study yielded significant findings, the limited number of participants may restrict the generalizability of the results to a larger population. Therefore, future studies with larger sample sizes are necessary to confirm and strengthen the observed effects. Additionally, it is crucial to account for attrition rates and consider the potential influence of the COVID-19 pandemic on participant dropout during the study period. Secondly, the study was exclusively conducted among sedentary older Saudis with hypertension residing in a specific aged-care setting in Makkah, Saudi Arabia. While this design allowed for a focused investigation, it may limit the generalizability of the findings to other populations, including individuals from different regions, cultural backgrounds, or socio-economic status. To ensure the external validity of the results, future research should aim to include a more diverse participant pool. Another limitation is the relatively short duration of the aerobic exercise training intervention, which lasted for eight weeks. While this duration was sufficient to demonstrate significant reductions in resting blood pressure, it is possible that longer intervention periods could yield different or more pronounced effects on blood pressure control. Future studies should explore the impact of extended exercise training durations to evaluate the sustained effects on blood pressure in sedentary older individuals. Moreover, it should be noted that this study focused exclusively on cycling as a form of aerobic exercise intervention. Although cycling is a popular and effective aerobic activity, the findings may not directly apply to other aerobic exercises or physical activity types. Incorporating interventions involving different forms of aerobic exercises, such as walking or swimming, would enhance the comprehensiveness and generalizability of the study. Future research should consider evaluating the effects of various aerobic exercise modalities on blood pressure in sedentary older individuals with hypertension. Additionally, another limitation of this trial is the need for long-term follow-up assessments. This study focused solely on the immediate effects of aerobic exercise training on resting blood pressure. The lack of long-term follow-up hinders our understanding of the durability of the observed reductions in blood pressure over an extended period. Subsequent studies should include long-term follow-up periods to evaluate the maintenance of blood pressure improvements and assess the sustainability of the intervention’s effects. Furthermore, despite efforts to minimize confounding factors, it is vital to acknowledge the possibility of other unmeasured variables influencing the observed outcomes. Factors, such as dietary changes, medication adjustments, and other lifestyle modifications were not explicitly controlled for, which may have influenced the results. Future studies should incorporate comprehensive assessments, including detailed dietary and medication records, to better understand and control potential confounders. Lastly, while the study demonstrated the feasibility and efficacy of aerobic exercise training, it is important to acknowledge that cycling may only be suitable or preferred by some sedentary older individuals. Factors, such as physical limitations, personal preferences, and accessibility to cycling facilities may impact the applicability of the findings to a broader population. Future research should explore and evaluate the feasibility and efficacy of different types of aerobic exercises to provide a range of options for sedentary older individuals with hypertension. Acknowledging these limitations is crucial for comprehensively understanding the study’s scope and potential implications. Future research endeavors should address these limitations to enhance the findings’ validity, generalizability, and clinical applicability in managing hypertension among sedentary older individuals residing in social home care settings.The findings of this study may have broad clinical implications because the results reflected a significant reduction in resting systolic and diastolic blood pressure, heart rate, BMI, and cholesterol in the exercise group. Physiologically, reducing cholesterol and LDL concentration in blood circulation may decrease vascular endothelial cell damage, thereby decreasing atherosclerosis and vascular stiffness, which are significant causes of hypertension and coronary artery disease , particuIn conclusion, our pilot trial provides evidence supporting the feasibility and efficacy of regular aerobic exercise as a non-pharmacological approach to reduce resting blood pressure and associated risk factors in sedentary older adults with hypertension in Saudi Arabia. It is essential to conduct further research on a national scale to enhance the generalizability of these findings. Future investigations should incorporate a more comprehensive statistical analysis, larger sample sizes, and explore alternative exercise modalities tailored specifically to this population. Additionally, long-term studies are necessary to establish the sustained impact of regular aerobic exercise on resting blood pressure. These findings significantly impact the development of targeted exercise interventions to reduce hypertension and improve cardiovascular health among sedentary older adults, particularly in nursing homes and in the post-COVID era.


Stigma is an important psychological concept that is being studied in many diseases. However, there have been few studies on stigma in renal dialysis patients in China. This study aimed to investigate the level of stigma and its potential influencing factors among Chinese renal dialysis patients.A cross-sectional study was conducted among renal dialysis patients in two Chinese dialysis centers between April 2022 and July 2022. Two hundred four renal kidney patients were interviewed with a questionnaire on demographic variables using the Social Impact Scale (SIS), Resilience Scale-14 (RS-14), Herth Hope Index(HHI), Multidimensional Scale of Perceived Social Support (MSPSS), Revised Life Orientation Test(LOT-R), Perceived Stress Scale (PSS-4) and Fear of Progression (FoP). T-test/univariate one-way ANOVA, Pearson’s R, and hierarchical linear regression analysis were used to investigate the factors that influence stigma.P < 0.001), social support , perceived stress , and fear of progression  were found to be associated with stigma among the renal dialysis patients. All four variables in the model could explain 34.6% of the variance in stigma among renal dialysis patients in China.Renal dialysis patients in China experienced a moderate level of stigma (52.36 ± 8.16). Stigma was negatively correlated with resilience, hope, and perceived social support, whereas it was positively associated with perceived stress and fear of progression. However, it showed no significant relationship between optimism and stigma. Hierarchical linear regression analysis showed that hope (β = -0.318, According to this study, renal dialysis patients in China face a moderate level of stigma. Stigma was found to be negatively related to hope and social support but positively associated with perceived stress and fear of progression. Future research on the stigma of renal dialysis patients should include hope-based interventions, proper and specific social support strategies, stress management interventions, and more disease-related information. End-stage kidney disease, which is the fifth stage of chronic kidney disease, is the most severe stage of chronic kidney failure caused by various factors . The patRenal dialysis is the most commonly used treatment for patients with end-stage kidney disease, with more than 90% receiving it. The therapy provides those patients with a potentially longer life span. However, the adverse effects of therapy include low quality of life , fatigueStigma describes a deeply discreditable attribute or characteristic, conveying a spoiled social identity and a sense of disgrace in a particular social context, disqualifying the individual from social recognition . Stigma Stigma is an important concept in psychology and has been a research topic for many diseases. Surprisingly, little information is currently available about stigma in renal dialysis patients. Considering such immense pressure and its effect on renal dialysis patients and its importance, stigma should be approached from different perspectives. Therefore, the present study aimed to fill this knowledge gap. Studies examining the stigma associated with other diseases have revealed that, in addition to demographic and clinical characteristics, resilience , optimisThis is a cross-sectional designed study that was carried out at two renal dialysis centers in China. Data was collected between April 2022 and July 2022. The Ethics Committee of China Medical University approved this study (2022PS153K).2/1.52 = 191.1. The sample size was increased by 10%∼20%, considering invalid questionnaires, resulting in a final sample size of 211∼230.Patients receiving renal dialysis therapy who understood and completed the questionnaire were invited to participate in the study under their consent, while patients in severe conditions were excluded. The study size was arrived at following the below formula: The entire research process was anonymous, and the patients were voluntary. The researchers of the study uniformly trained the five investigators. After the patients agreed to participate, the paper questionnaires were filled out in a separate and undisturbed space in the hospital to prevent patients from influencing each other while filling out questionnaires. The investigator is responsible for interpreting the questionnaire items without any incentive. Another trained investigator performed quality control on site. Epidata software (version 3.1) was used for data entry and review.Questionnaires including demographic and clinical characteristics were self-developed in the study. The demographic section included age, gender, education level, job status, religious belief, income, family structure, and medical payments. Also, the clinical variables section included the approach and the course of dialysis of the patient .The stigma of the respondents was measured using the Social Impact Scale (SIS) . SIS conResilience was assessed using the Resilience Scale-14 (RS-14) . The RS-The level of hope was assessed by the Herth Hope Index (HHI) . The HHIThe Chinese version of the Multidimensional Scale of Perceived Social Support (MSPSS) was used to assess perceived social support . The MSPThe 10-item Revised Life Orientation Test (LOT-R) was used to assess optimism . The LOTThe 4-item Perceived Stress Scale (PSS-4) was used to assess perceived stress . PSS-4 iThe Fear of Progression Questionnaire-Short Form (Fo P-Q-SF) was used to assess the Fear of Progression (FoP) . The Fo P < 0.2 was entered as the control variable in the first step of the hierarchical regression analysis , R2-change, and F value.Data analysis was performed using the statistical software package for social sciences (SPSS 20.0). The significance for all statistical tests was 0.05 (2-tailed). Each continuous variable is first tested for normality and homogeneity of variance. Independent-samples t-tests and one-way ANOVA were used to describe the distribution of stigma for categorical demographic and clinical variables in renal dialysis patients. Pearson’s R-test was used to assess the correlations between resilience, hope, social support, optimism, stress, fear of progress, and stigma. Hierarchical linear regression analysis was used to assess the research hypotheses. To avoid overfitting the regression model, the one-way ANOVA/t-test variable with analysis . Then, tA total of 230 questionnaires were distributed in this study. Twenty patients refused to participate in the survey, and six invalid questionnaires. There were 204 valid questionnaires with an effective response rate of 88.7%.Out of the 204 respondents, 126 (61.8%) were male, and 78 (38.2%) were females. Nearly half of them (46.1%) were above 60 years old. All the patients had medical insurance. Only 12 (5.8%) patients had a regular employee. In terms of clinical variables, most respondents (96.1%) used an autogenous arteriovenous fistula to access dialysis. More than half of the respondents had dialysis for less than five years. r = -0.386, P < 0.001), hope , perceived social support , and positively associated with and perceived stress , fear of progression . Besides, it showed no significant relationship between optimism and stigma (P > 0.05).P < 0.001), social support , perceived stress , fear of progression  were associated with stigma in renal dialysis patients, with all four variables in the model explaining 34.6% of the variance in stigma in renal dialysis patients. There is no collinearity between the variables . The influencing factors of stigma in renal dialysis patients were investigated using hierarchical linear regression analysis. Multiple regression analysis included variables significantly related to stigma in univariate analysis and variables related to the psychological status of renal dialysis patients. This study included demographic variables , resilience, hope, perceived social support, perceived stress, and fear of progression in the regression analysis. Hope . The patients/participants provided their written informed consent to participate in this study.BL and PX were responsible for conception and design of the study. BL, DL, and YZ performed data extraction. BL did the data analysis and wrote the manuscript. PX contributed to the revision of the manuscript. All authors have reviewed the manuscript and given final approval of the version to be published.


Post hoc analysis of most studies with T2 biologics suggests that chronic rhinosinusitis with nasal polyps (CRSwNP) and, to a lower extent, allergic rhinitis may help in predicting clinical response. Considering that T2 biologics are now also approved for the treatment of severe CRSwNP, diagnosis of upper airway disease is a key step in determining eligibility for such therapy.Asthma is a heterogeneous disease sharing airway instability but with different biology, risk factors, and response-to-therapy patterns. Biologics have revolutionized the one-size-fits-to-all approach to personalized medicine in severe asthma (SA), which relies on the identification of biomarkers that define distinct endotypes. Thus, blood eosinophils and, to some extent, exhaled nitric oxide (FeNO) can predict the response to approved anti-type 2 (T2) biologics , whereas age at onset and comorbidities such as anxiety/depression, obesity, reflux, and upper airway disease (UAD) also influence therapeutic responses in SA. In this article, focusing on the predictive value of biomarkers for the therapeutic response to biologics in SA, we first summarize the level of prediction achieved by T2 biomarkers  and then review whether data support the predictive value of upper airway diagnosis on such outcomes.  Most patients with asthma may be well controlled by the ICS-LABA therapy, but 5–10% of patients have a more difficult, sometimes severe disease . The therapeutic paradigm has recently  Biomarkers Definitions Working Group defines a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” . The WHOThe biomarkers that are currently validated in asthma relate to type 2 (T2) immunity, namely blood (or sputum) eosinophils and exhaled nitric oxide (FeNO), which are elevated in more than half of patients with severe asthma –9. In adTheragnostic is an emerging field of medicine that combines therapeutic and diagnostic purposes with the intention to simultaneously or sequentially diagnose and treat medical conditions. In SA, blood eosinophils and exhaled nitric oxide (FeNO) can predict the response to approved anti-T2 biologics . In addition to biology, age at the onset and comorbidities, such as anxiety/depression, obesity, reflux, and upper airway disease (UAD), also influence therapeutic responses to this disease.In this article, after summarizing the predictive value of validated T2 biomarkers, we review clinical data on the potential predictive value of upper airway disease (UAD) diagnosis on the response to biologics in SA, as well as discuss its potential positioning in the current landscape of asthma-related biomarkers.Several biomarkers are available to phenotype asthma, some of which may predict clinical response to corticosteroids and T2 biologics; these include blood (or sputum) eosinophils, FeNO, serum total IgE (tIgE) levels, and periostin , 16.The prevalence of increased eosinophils is observed in ~ 50–60% of patients with mild-to-moderate asthma, and probably a larger proportion in SA , 18, as First, airway eosinophilia is a prognostic biomarker as it correlates with the degree of airway hyperreactivity, exacerbation rate, poor symptom control, as well as small airway dysfunction –24. In aOne important issue in clinical practice relates to the variability of blood eosinophils. Blood eosinophils may also vary due to disease activity as well as intrinsic day-to-day (and even within-day) changes. In contrast to oral steroids, which influence blood eosinophil counts, inhaled corticosteroids (ICS) impact airway eosinophils but only slightly influence blood eosinophils , 52. It Nitric oxide (NO) is a gas that can be measured in exhaled breath and is increased upon the activation of the airway epithelium by IL-4/IL-13, which upregulates iNOS expression, whereas eosinophilia is primarily increased following IL-5 upregulation , 55. Recpost hoc analysis found the greatest treatment response to dupilumab in patients with FeNO ≥25 ppb and blood eosinophils ≥150/μl  biologics  do not alter significantly FeNO. High FeNO may, however, predict a better response to mepolizumab, as “super-responders”  have a higher FeNO (41 vs. 23 ppb) at baseline . A stron ≥150/μl . For oma ≥150/μl , based o ≥150/μl . In contThe first biologic that was developed and demonstrated efficacy in severe asthma is omalizumab –4, whichPeriostin is an extracellular matrix protein produced by airway epithelial cells and fibroblasts upon activation by IL-4 or IL-13, which is implicated in tissue remodeling  and corrIn addition to markers related to airway immunobiology, late (adult) vs. early (childhood) onset of the disease is associated with non-allergic, eosinophilic vs. allergic asthma, respectively . Subsequ+ T cells into Th2 cells that release IL-4 and IL-13 interacting with B cells to produce IgE that may activate mast cells. IL-5 is also released by Th2 and innate lymphoid cell (ILC)-type 2, acting as a pivotal factor in the differentiation, survival, and activation of eosinophils, basophils, and mast cells (Upper airway diseases (UADs) are mainly represented by allergic rhinitis (and rhinoconjunctivitis), non-allergic rhinitis, and chronic rhinosinusitis with (CRSwNP) or without nasal polyps (CRSsNP), all of which are highly prevalent comorbidities that impact disease control in asthma. Thus, it is estimated that 80% of patients with asthma have allergic rhinitis, while 22–42% have CRS . Similarst cells .post hoc analyses of randomized, placebo-controlled trials (RCTs) by stratifying a posteriori enrolled patients according to the presence (vs. absence) of UAD, specifically allergic rhinitis or CRSwNP. This will be discussed separately for each biologic that is currently approved for the treatment of SA. Interestingly, the same biologics—namely anti-IgE, anti–IL-5, and anti–IL-4Rα–have been recently approved for the treatment of severe CRSwNP , further increasing the relevance of integrating UAD in the management of (severe) asthma.Data on the potential predictive value of upper airway disease (UAD) diagnosis on the biologic response in severe asthma emerged from post hoc analysis of a phase 3 RCT conducted in Chinese patients with moderate-to-severe persistent allergic asthma showed that asthma symptoms (ACQ score) and asthma-related quality of life (QLQ score) were significantly improved after 24 weeks of treatment with omalizumab compared to placebo in patients with perennial allergic rhinitis, in contrast with those without rhinitis. Unfortunately, the level of blood eosinophils according to the presence (or not) of rhinitis was not reported; the mean level is 296/μl in the total cohort (p = 0.027). The same finding was seen when considering CRSwNP, 72% of patients with FEV1 normalization had CRSwNP compared to 29% in the PAL group (p = 0.031). It is important to notice that the mean levels of blood eosinophils and FeNO were higher in the group of patients with reversal of airway obstruction than in those with persistent obstruction   for asthma treatment, before other indications such as chronic rhinosinusitis with nasal polyposis (CRSwNS) and chronic urticaria. Few studies evaluated the impact of allergic rhinitis as a biomarker of response to omalizumab. One l cohort  (Table 1ctively) .In an Australian prospective observational study of patients with allergic SA, 15% had CRSwNP, and the benefit of omalizumab on asthma symptoms (ACQ-5 score) and lung function (FEV1% predicted) after 6 months of treatment was similar whether or not patients had NP   Table 1Table 1.p = 0.012 and p = 0.007, respectively) (Mepolizumab was the first registered (in 2004) anti–IL-5 biologic for the treatment of severe eosinophilic asthma (SEA), before validation in other conditions including CRSwNP, hypereosinophilic syndrome (HES), and eosinophilic granulomatosis with polyangiitis (EGPA). A few studies showed that CRSwNP may predict the response to mepolizumab in SA. A first retrospective single-center study of patients who received mepolizumab for SEA (>300/μL in the preceding 12 months) and classified as responders , super-responders (absence of exacerbation for the 52 weeks of follow-up and discontinuation of mOCS), or non-responders showed that CRSwNP at baseline was associated with the responder and super-responder status. Indeed, 54.2% of responders and 67.9% of super-responders had CRSwNP compared to 25.9% of non-responders (ctively)  . In this last meta-analysis, patients with CRSwNP had a higher mean blood eosinophil count than those without CRSwNP (440/μl vs. 209/μl)  was associated with a significantly higher benefit in terms of exacerbations  and change in FEV1 from baseline . A trend favoring mepolizumab (vs. placebo) in patients with CRSwNP was shown when evaluating effects on ACQ-5 and St George's Respiratory Questionnaire. The presence of allergic rhinitis was also evaluated as a predictor of response but showed no beneficial effect in terms of exacerbations, FEV1, ACQ-5, or on the St George's Respiratory Questionnaire (In a  209/μl) . A post ionnaire . Mean leionnaire .post hoc analysis of two duplicate RCTs in which patients with eosinophilic (≥400 cells/μL) asthma and who remained inadequately controlled on at least medium-dose ICS were randomized to placebo or reslizumab (3 mg/kg every 4 weeks) for 52 weeks and categorized by use of maintenance OCS. As a secondary outcome, the post hoc analysis assessed biomarkers that predicted response in terms of exacerbations  in OCS-dependent patients and showed that the presence of CRSwNP did not impact the benefit on asthma exacerbations, although there was a trend toward higher reduction in patients with CRSwNP. The mean blood eosinophil count was 607/μl in those patients at baseline, but blood eosinophil counts in patients with or without CRSwNP were not reported . A reported  (Table 1p = 0.012), whereas only a trend was observed for the overall population . In contrast, the benefit of lung function was not increased in patients with CRSwNP. The median blood eosinophil count was 600/μl in the CRSwNP group and 400/μl in the group without CRSwNP : ≥10% FEV1 improvement, or ≥5% predicted FEV1 improvement, no exacerbation during the 52 weeks of study, or >1.5 improvements of ACQ-6. They found that compared to non-responders, super-responders to reslizumab were more likely to have CRSwNP (The benefit of reslizumab on asthma symptoms (ACQ-5 score) was significant in patients with CRSwNP  (A recent vs. 70%) .post hoc analysis of the SIROCCO and CALIMA trials on annual exacerbation rate in the overall population and in the ≥300/μl blood eosinophil population, the presence of CRSwNP increased the benefit of benralizumab every 8 weeks vs. placebo compared to the overall population, with CRSwNP ranking second as a predictive factor after OCS use at baseline. In patients with <300 eosinophils/μl, the effect of CRSwNP was not significant although a trend to a higher reduction of AER was observed. Similar findings were observed for lung function (pre-bronchodilation FEV1), with the greatest impact of CRSwNP observed with benralizumab vs. placebo. Similar results were also achieved in the ≥300 eosinophils/μl population and for asthma symptoms, compared to the overall population  biologics , but this was probably biased by the fact that complete control of comorbidities  was required to define such response . In thisDupilumab is a monoclonal antibody targeting IL-4Rα and subsequently inhibiting IL-4 and IL-13 activities. It was recently approved (in 2019) for asthma treatment, and it is also indicated in severe CRSwNP and severe atopic dermatitis. However, only a few data are available to assess whether UAD may predict response to dupilumab in asthma. A French study reported a greater improvement in lung function in patients with CRSwNP than those without . In contBlood eosinophils and FeNO have emerged as biomarkers capable of predicting the response of patients with asthma to ICS and T2 biologics. They are easy to measure, in both in- and out-patient settings and are non-invasive, but they suffer from variability  and/or multiple interfering factors such as environmental exposures, e.g., to cigarette smoke or allergens (mainly for FeNO). This article provides a comprehensive review of the data collectively indicating that UAD, in particular, CRSwNP and, to a lower extent, allergic rhinitis, predict the response to T2 biologics in severe asthma, as well as being improved by such therapies. Moreover, CRSwNP could be viewed as a stable biomarker that does not suffer from intrinsic variability, at least in Western countries, as CRSwNP displays a different inflammatory phenotype in Eastern countries . Since mAltogether the data reviewed in this article support that the diagnosis of UAD in patients with SA with the indication of biotherapy is a key step in refining the clinical profile and has added value to T2 biomarkers (blood eosinophils and FeNO) to predict the clinical response. As there is no published head-to-head trial comparing biologics for CRSwNP or for severe asthma and, although some studies are ongoing , only inSC and VD drafted the manuscript. CP designed and revised the manuscript and made the figure. All authors contributed to the article and approved the submitted version.


Elevation of the head of bed (HOB) increases intra-abdominal pressure (IAP), but the effect of body position on abdominal splanchnic perfusion is not clear. The current study aimed to evaluate the effect of body position on the superior mesenteric artery (SMA) and the celiac artery (CA) blood flow by Doppler ultrasound in mechanically ventilated patients with intra-abdominal hypertension (IAH).This prospective cohort study included 53 mechanically ventilated patients with IAH. IAP, hemodynamic variables, and Doppler parameters of the SMA and CA were measured in the supine position. The measurements were repeated after the HOB angle was raised to 15° for 5 min and similarly at HOB angles of 30° and 45°. Finally, the patient was returned to the supine and these variables were re-measured.The median  superior mesenteric artery blood flow (SMABF) decreased from 269 (244–322) to 204 (183–234) mL/min and the median (IQR) celiac artery blood flow (CABF) from 424 (368–483) to 376 (332–472) mL/min (both p<0.0001) while median (IQR) IAP increased from 14(13–16) to 16(14–18) mmHg (p<0.0001) when the HOB angle was changed from 0° to 15°. However, SMABF and CABF were maintained at similar levels from 15° to 30°, despite median (IQR) IAP increased to 17(15–18) mmHg (p = 0.0002). Elevation from 30° to 45° further reduced median (IQR) SMABF from 200(169–244) to 164(139–212) mL/min and CABF from 389(310–438) to 291(241–383) mL/min (both p<0.0001), Meanwhile, median (IQR) IAP increased to 19(18–21) mmHg (p<0.0001).In mechanically ventilated patients with IAH, progressive elevation of the HOB from a supine to semi-recumbent position was associated with a gradual reduction in splanchnic blood flow. However, the results indicate that splanchnic blood flow is not further reduced when the HOB is elevated from 15° to 30°.This study confirms the influence of head-up angle on blood flow of the splanchnic organs and may contribute to the selection of the optimal position in patients with abdominal hypertension.The online version contains supplementary material available at 10.1186/s12871-023-02046-8. Intra-abdominal hypertension (IAH) is a frequent cause of morbidity and mortality among critically ill patients –3. IAH lThe available reports on the influence of body position have focused on monitoring distinct pressure indicators, such as IAP and APP. According to Poiselle’s law, flow = pressure/resistance. Therefore, a decrease in APP does not necessarily lead to the completely consistent decrease in blood flow of abdominal organs . AlthougThis study evaluated whether elevation of the HOB reduces blood flow in the celiac artery(CA) and superior mesenteric artery(SMA) using Doppler ultrasound.This prospective study was performed based on the Declaration of Helsinki. All experiments were performed in accordance with relevant guidelines and regulations. All the study protocols were approved by the Institutional Research and Ethics Committee of the Peking Union Medical College Hospital for human subjects (Ethics certificate number: ZS-3088). Informed consent was obtained from the next of kin or patients before enrollment in the study.The prospective cohort trial was performed in the Critical Care Department of Peking Union Medical College Hospital in China. Mechanically ventilated patients who were in the intensive care unit (ICU) were enrolled upon being diagnosed with IAH.The inclusion criteria were as follows: (1) tracheal intubation with mechanical ventilation and sedation; (2) bladder pressure ≥ 12 mmHg; (3) age 18–80 years; (4) sinus rhythm.The exclusion criteria were as follows: (1) coronary heart disease, severe mesenteric stenosis, or celiac artery stenosis; (2) patients in a fixed position ; (3) patients for whom IAP measurements were contraindicated ; (4) patients who had underwent abdominal surgeries involving the intestine, the descending thoracic or abdominal aortic procedures; (5) poor quality of abdominal ultrasound images; (6) pleural fluid or ascites.This study was initiated to determine the specific head of bed angle elevation that had the least impact on the blood flow of the internal organs compared to that measured in the supine position. In the pre-experimental stage, the blood flow of the CA (CABF) and superior mesenteric artery (SMABF) was measured at HOB angles of 0° and 15° in 18 patients with the same demographics, and the blood flow difference between two HOB angles was calculated. The study was designed with 80% power to detect a minimum blood flow difference between two angles with a two-tailed alpha of 0.05. A power calculation indicated that 21 patients were required to detect a difference in CABF and SMABF, and 53 patients were included in the study.Epidemiological data pertaining to the patients were studied upon admission. The patients were sedated to a Richmond Agitation Sedation Score (RASS) of −4 during the time of acquiring the measurements as per the World Society of the Abdominal Compartment Syndrome consensus recommendations . Only sePulse index continuous cardiac output (PiCCO)  was used to monitor cardiac output. The peripheral perfusion index (PPI) is an indicator of peripheral perfusion derived from the photoelectric plethysmographic signal of a pulse oximeter. It is defined as the ratio between the pulsatile and non-pulsatile portions of the plethysmographic waveform. The PPI was assessed using a Philips Medical Systems Viridia/56S monitor.IAP, systemic hemodynamic variables, and the Doppler parameters of the SMA and CA were measured at the HOB of 0°, 15°, 30°, 45°. Parameters were measured 5 min after each angle elevation, in order to stabilize the hemodynamic parameters. The time interval between each head up movement is 5 min plus the measurement time, which is about 15 min.Thereafter, the HOB angle was restored to 0° and measurements were conducted . Central venous-to-arterial carbon dioxide tension difference(Pv-aCO2) was calculated as the difference between the central venous CO2 tension and arterial CO2 tension.Standard blood samples of 2 mL were collected from the central venous catheter and the line of radial artery concurrently. All blood samples were examined by a Radiometer ABL800 FLEX analyzer . The central venous blood sample was analyzed to measure central venous oxygen saturation with a standard instillation volume of 20 mL of sterile saline according to the recommendations of the World Society of the Abdominal Compartment Syndrome consensus [Doppler ultrasound was performed with an ultrasound system consisting of a 2–5 MHz C60xp Probe . Blood flow parameters of each vessel were measured by two ICU physicians, and the average value was recorded. Each of the two ICU physicians had more than four years of experience in point of care ultrasound and obtained their certification from the Chinese Critical Ultrasound Study Group.The CA flow was obtained 1 cm proximal to the abdominal aorta before its division into the hepatic and splenic arteries. SMA flow was measured 1 cm proximal to the abdominal aorta. The angle of insonation was < 60°.The Doppler parameters were measured in the longitudinal section of the vessel, and the diameter(D) of the vessel was measured in cross-section at the same location.To reduce the error, the average of three measurements was taken in the zoomed state and the cross-sectional was calculated.The time–velocity waveform readings were used to measure time-averaged mean velocity(TAMV), and blood flow , according to the calculation software carried by the ultrasound. BF = π(D/2)²×TAMV×60. The calculation formula of APP: APP = MAP-IAP.A descriptive analysis was performed. Continuous variables were expressed as the means ± standard deviation or median and interquartile range. Normal distribution was evaluated by Kolmogorov-Smirnov test. Repeated measures one-way ANOVA was used to evaluate variables with normal distribution, and if the test was significant, paired t-tests were used to evaluate changes between different angles of the HOB with Bonferroni correction for multiple comparisons. Variables with non-parametric distributions, the Wilcoxon matched-pairs signed rank test and Friedman test was used. The 2-tailed significance level was set at p < 0.05. Statistical analysis was performed using SPSS Statistics 25.0 .A total of 66 patients with IAH between December 2020 and February 2022 met the inclusion criteria. Among these patients, six were excluded as they had underwent abdominal intestinal surgery, three due to cardiac arrhythmias emerging during the study, and four because of poor quality of abdominal ultrasound images. Thus, 53 patients were finally included in the study.The demographics, basic hemodynamic parameters, and causes of abdominal hypertension are presented in Table The results showed that cardiac index (CI) significantly decreased with each elevation of HOB while MAP and NE infusion rate were maintained at all angles Table .The IAP increased progressively when the HOB was elevated from 0° to 45°. HOB elevation was associated with significant decreases in PPI.p<0.0001). However, from 15° to 30°, SMABF (p = 0.2032) and CABF ( p = 0.0533) remained reduced at the same level. The elevation of the HOB angle from 30° to 45° was associated with a further decrease in SMABF and CABF (both p<0.0001) (see Table SMABF and CABF both decreased when the HOB was raised to 15° from the supine position(both BF p = 0.032 and CThe diameter of the SMA(SMA-D) and the time-averaged mean velocity of the superior mesenteric artery (SMA-TAMV) decreased with an elevation in the HOB angle  decreased significantly. At the same time, the ratio of CABF of CO (CABF/CO) was generally stable until 45°  The elevation of the HOB caused an increase in IAP and a decrease in the blood flow of the SMA and CA, particularly at an elevation of 45°. (2) There was no significant change in SMA and CA blood flow between 15° and 30°.Although the semi-recumbent position is recommended to reduce the incidence of VAP , some stAccording to the present study, the degree of HOB elevation is related to the increase in intra-abdominal pressure. Cheatham et al.  found thThe present study confirms that elevation of HOB in patients with IAH reduces splanchnic blood flow. Interestingly, our study indicated that SMA and CA blood flow was unaffected when the HOB was elevated from 15° to 30°.This phenomenon may be due to the fact that there was no statistical difference in APP between HOB 15° and 30°, suggesting no changes in perfusion pressure of the abdominal organs. This study supports that the IAH patient should be placed in the supine position and that if elevation of HOB is required it should not exceed 30°.As mentioned above, most of the studies on head-up positioning of critically ill patients monitored pressure indicators such as IAP or APP –6, 12. HDoppler ultrasound can monitor the blood flow of the splanchnic arteries at the bedside in real-time and non-invasively. As an important digestive and immune organ, the intestine plays an important role in the pathophysiological process of sepsis or multiple organ dysfunction syndrome. Further studies on intestinal blood flow and function are required.(1) The standard deviation of the data was large owing to the large individual differences in the SMABF. This may have affected the statistical results. (2) Doppler measurements could have been affected by subjective factors of the person performing the measurement although one previous study has reported that the blood flow of SMA measured by Doppler ultrasound has good repeatability . (3) TheIn mechanically ventilated patients with IAH, progressive elevation of the HOB from a supine to semi-recumbent position was associated with a gradual reduction in splanchnic blood flow. However, the results indicate that splanchnic blood flow is not further reduced when the HOB is elevated from 15° to 30°.This study confirms the influence of head-up angle on blood flow of the splanchnic organs and may contribute to the selection of the optimal position in patients with abdominal hypertension.Below is the link to the electronic supplementary material.Supplementary Material 1Supplementary Material 2Supplementary Material 3