Background: Cardiac collagen remodeling is important in the progression of heart failure. Estimation of cardiac collagen turnover by serum levels of serological markers is used for monitoring cardiac tissue repair and fibrosis. Peritoneal dialysis (PD) is used for the long-term management of refractory congestive heart failure (CHF). In this study, we investigated the effect of PD treatment on circulating fibrosis markers levels in patients with refractory CHF and fluid overload. Methods: Twenty-five patients with refractory CHF treated with PD were prospectively enrolled in the study. Circulating fibrosis markers procollagen type III C-peptide (PIIINP), matrix metalloproteinase 2 (MMP-2), and tissue inhibitor of metalloproteinases I (TIMP-1) levels were checked at baseline and after three and six months of treatment. Results: The clinical benefit of PD manifested by improved NYHA functional class and reduced hospitalization rate. Serum brain natriuretic peptide (BNP) levels decreased significantly during the treatment. Serum MMP-2 and TIMP-1 decreased significantly on PD. Circulating PIIINP showed two patterns of change, either decreased or increased following PD treatment. Patients in whom circulating PIIINP decreased had significantly lower baseline serum albumin, lower baseline mean arterial blood pressure, higher serum CRP, and a less significant improvement in hospitalization rate compared to the patients in whom circulating PIIINP increased. Patients in whom all three markers decreased demonstrated a trend to longer survival compared to patients whose markers increased or did not change. Conclusion: In refractory CHF patients PD treatment was associated with a reduction in circulating fibrosis markers. Cardiac collagen remodeling is important in the progression of heart failure. Progressive myocardial fibrosis in response to injury is a hallmark of pathological cardiac remodeling. It involves myocyte replacement with fibrosis or diffuse deposition of extracellular matrix (ECM). The cardiac ECM consists mostly of type I collagen and type III collagen. ECM turnover is determined by the net balance of collagen synthesis and degradation . During Previously, collagen content in the heart was directly measured in biopsies. Recently, noninvasive methods have been developed to detect cardiac collagen content, such as circulating biomarkers of collagen synthesis and degradation. PIIINP was found to be elevated in patients with advanced heart failure and a marker of poor prognosis ,7,8. CirTreatment of systemic congestion is one of the most difficult challenges in the management of severe congestive heart failure (CHF), particularly in patients with diuretic resistance. Peritoneal ultrafiltration (UF) is a simple choice for daily fluid removal with several advantages compared to ultrafiltration through hemodialysis: minimal impact on hemodynamics, slower decline in residual kidney function, sodium sieving with maintenance of normonatremia, possibility of draining of ascites, and avoidance of risks related to a vascular access and improvement of systemic inflammatory state ,17. It wThis study was designed to evaluate the net effect of peritoneal dialysis on circulating fibrosis markers levels in patients with refractory CHF and fluid overload.Twenty-five patients were enrolled into the study. The clinical, biochemical, and echocardiographic characteristics of the patients at baseline, prior to the beginning of PD, are presented in All patients continued treatment with oral furosemide. The median dose of oral furosemide remained stable for the duration of the study and was 160 mg per day (range: 120–240 mg). Patients were instructed to add 2.5 mg of metolazone when their body weight increased. Eleven patients were treated in a CHF day care center while on PD, where they received intravenous furosemide and vasoactive agents. p < 0.0001). p = 0.0008) and 12.42 ± 3.46 mg/l after 6 months of PD (p = 0.0020) (The average volume of PD solution the patients used was 3.28 ± 0.7 L per day. Fifteen patients (60%) were treated with one PD exchange per day, 7 (28%) with two exchanges, and more and 3 patients (12%) did only paracentesis. Four patients (16%) were on dialysis for 8 or more hours per day. Patients who needed only fluid removal did short PD exchanges 1–2 h each exchange. Those who had a substantial renal dysfunction were treated with longer exchanges or used cycler. At the three months of PD treatment point all patients reached a well-tolerated edema-free state. By three months of treatment body weight decreased significantly  and the  0.0020) . The 1-yn =7), improved (n =3), or aggravated (n = 4). Estimated SPAP was either stable (n =6), improved (n =6), or aggravated (n = 2).Fourteen patients performed a second echocardiography after PD has been started. LVEF was either stable (p = 0.0063) and 1052.55 ± 164.13 pg/mL at 6 months (p = 0.0110)  . p < 0.0001), compared to the second group, where PIIINP levels increased from 14.9 ± 1.6 micg/L at baseline to 19.7 ± 2.4 micg/L (p = 0.0052). At 6 months of PD treatment serum PIIINP decreased from 21.6 ± 3.9 micg/L at baseline to 16.9 ± 4.6 micg/L in the first group (p = 0.0228), compared to the second group, where PIIINP levels increased from 15.7 ± 2.3 micg/L at baseline to 21.6 ± 2.8 micg/L (p = 0.0022). At 3 months of treatment, patients in whom circulating PIIINP levels decreased demonstrated lower baseline serum albumin, lower baseline mean arterial blood pressure, and higher serum CRP compared to the patients whose PIIINP levels increased (p = 0.0438). Serum albumin was 3.15 ± 0.07 g/dL and serum CRP was 45.39 ± 11.07 mg/l in the first group compared to 3.49 ± 0.11 g/dL (p = 0.0171) and 12.17 ± 1.64 mg/l (p = 0.0057) in the second group, respectively. Hospitalization rate decreased from 22.6 ± 8.5 days to 14.1 ± 9.1 days (p = 0.0569) after 3 months of PD treatment in the first group compared to a decrease from 16.2 ± 5.3 days to 4.6 ± 2.7 days (p = 0.0096) in the second group. When diabetic and nondiabetic patients group were analyzed separately no significant changed in PIIINP levels dynamics were found between the groups at 3 and 6 months. Overall PIIINP levels did not significantly changed , yet a sncreased . Mean arp = 0.4237), and 16.07 ± 0.8 ng/mL after 6 months on PD (p = 0.0285).MMP-2 levels decreased following PD treatment  from 18.When diabetic and nondiabetic patients group were analyzed separately no significant changed in MMP-2 levels dynamics were found between the groups at 3 and 6 months. p = 0.0046), and 291.71 ± 21.9 ng/mL after 6 months on PD (p = 0.0107). There was a substantial decrease in serum TIMP-1 protein concentration during the treatment . Serum Tp = 0.0164) in diabetics compared to decrease from 387.1 ± 49.3 ng/mL to 338.0 ± 28.6 ng/mL (p = 0.1695) in nondiabetics. At 6 months no significant difference in TIMP-1 levels was found between diabetic and nondiabetic groups. When diabetic and nondiabetic patients group were analyzed separately a significant decrease in serum TIMP-1 levels at 3 months was demonstrated only in the diabetic patients group. TIMP-1 levels decreased from 380.1 ± 44.9 ng/mL at baseline to 330.1 ± 41.1 ng/mL at 3 months of PD treatment (p = 0.0288).Five patients who demonstrated a decrease in all three fibrosis markers following PD treatment demonstrated a trend to longer survival compared to the other patients . In thesNo significant differences were found in clinical or echocardiographic parameters between patients with or without a decrease in all three fibrosis markers.p = 0.0222) while serum MMP-2 and TIMP1 did not demonstrated any correlation with eGFR .Since serum fibrosis biomarkers can be cleared by the kidney the correlation of the PIIINP, MMP2, and TIMP1 with eGFR was analyzed. Serum level of PIIINP correlated inversely with eGFR  following PD treatment. A rise in TIMP-1 promotes fibrosis by inhibiting MMPs and their ECM-degrading function ,33. A noAngiotensin II stimulates collagen synthesis and regulates collagen degradation by enhancing TIMP-1 production in endothelial cells, thereby attenuating interstitial MMP-1 activity ,36. ChroWe assume that in some refractory CHF patients with fluid overload, PD treatment can lower the circulating levels of fibrosis markers adding benefit to already maximally tolerated traditional drug regimens. The possible explanations for PD benefits in cardiac fibrosis are neurohumoral activation resetting towards a more physiological condition after fluid removal, the decrease in mechanical pressure on the heart resulting in less remodeling, improvement in inflammation, and perhaps also the decrease in uremic toxins levels. All those factors are found to contribute to cardiac fibrosis ,39. We dThe limitations of the study include the small number of patients and their heterogeneity. An important question is, is the serum biomarker representative at the tissue level? Our analysis assumes that biomarkers are representatively excreted into circulation and that they actually reflect the myocardial accumulation of fibrous tissue. Further studies are needed to correlate the serum levels of the biomarkers with histology of cardiac biopsies and to define the precise timing of fibrotic deposition and degradation through the course of HF disease progression and treatment; this may facilitate temporal targeting of antifibrotic therapies and a better utilization of PD in this high risk population. Compared to cardiac biopsy, which is an invasive procedure with a risk of such complications as myocardial perforation with pericardial tamponade, arrhythmias, and pneumothorax , serum bAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Patients with refractory CHF referred by their cardiologists to our PD unit between March 2012 and July 2016 and completed at least a 3-month period of PD were enrolled into this study. The study protocol was approved by the Sheba Medical Center Institutional Human Research Board (19 January 2010). Written informed consent was obtained from all participants.All patients were in NYHA functional class IIIb or IV with symptoms and signs of severe cardiac failure and volume excess. They received optimal medical therapy according to the Heart Failure Guidelines . This inA PD catheter was implanted under local anesthesia by surgical dissection in the operating room. In patients with ascites, peritoneal centesis was started by a trained PD nurse one day after Tenckhoff catheter insertion. In patients with a significant volume overload, volume exchanges (~1500 mL) were performed in the recumbent position by a PD nurse starting the day after catheter placement. Dwell times were 1–2 h for one to three exchanges per day, 2–4 days per week. PD exchanges were performed by a PD nurse in the PD unit until training of the patient or a family member was satisfactory (approximately 2–3 weeks). PD solutions included both glucose- and nonglucose-containing (icodextrin) dialysis solutions . Data on the type and volume of PD solutions used and daily peritoneal UF volume were gathered.The following clinical parameters were collected; disease etiology, functional status (NYHA), preserved/reduced LV function, comorbidities and medications, body weight, and mean arterial blood pressure. Assessment of fluid status was based on clinical examination. The manifestations of volume overload were considered pulmonary congestion, peripheral edema, and elevated jugular venous pressure. Laboratory results included serum hemoglobin and leukocyte count, serum albumin, sodium, urea, creatinine, uric acid, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Estimated GFR (eGFR) was calculated using the Modification of Diet in Renal.Disease formula: Primary kidney disease was defined as urine protein >0.5 g/24 h, abnormal urine microscopy, and/or abnormal renal sonography . Patients with urine protein <0.5 g/24 h, normal urine microscopy, and normal kidneys per sonography were classified as having cardiorenal syndrome. Echocardiographic parameters used in the study included LVEF and RVEF and systolic pulmonary artery pressure (SPAP). Peripheral venous blood samples were collected and immediately centrifuged, and the serum samples were stored at −80°C until assay. Serum was collected from the patients at baseline, i.e., before the first PD treatment, and at 3 and 6 months of therapy, when available. ® BNP Test, a rapid fluorescence immunoassay kit .BNP was measured using the Alere TriagePlasma levels of MMP-2 and TIMP-1 were assessed by enzyme-linked immunosorbent assay (ELISA) as per the manufacturer’s protocol . This assay employs the quantitative sandwich enzyme immunoassay technique. The cut-off or lower limit of sensitivity ranges from 0.014 to 0.082 ng/mL for MMP-2 and less than 0.08 ng/mL for TIMP-1. Plasma PIIINP level was assessed by ELISA assay per manufacturer protocol . This assay employs one-step sandwich colorimetric ELISA-type immunoassay. The cut-off or lower limit of sensitivity is 0.036 micg/L.t-test. Data presented in t-test for quantitative variables. Categorical variables were analyzed by Fisher’s exact test. Survival was assessed by Kaplan–Meier survival analysis. Pearson’s correlation test was used to analyze the association between circulating fibrosis markers levels and eGFR. p < 0.05 was considered significant. Statistical analyses were performed by GraphPad InStat 3 . Data are presented as mean ± SEM for continuous variables and as absolute numbers and percentages for categorical variables. Data presented in This study measured for the first time circulating fibrosis markers in severe congestive heart failure patients treated with peritoneal dialysis for fluid overload. A decrease in the serum fibrosis markers following PD treatment was demonstrated. Reduction in circulating fibrosis markers levels was associated with a trend to longer survival. This demonstrated that PD is a beneficial treatment, not just symptomatic but may increases survival and it is maybe also through its effect on cardiac fibrosis.


The development of a symptomatic lymphocele (SL) is a frequent postoperative surgical complication after kidney transplantation. It may lead to pain and discomfort and cause transplant malfunction or even secondary graft loss. A large cohort of renal recipients was investigated to identify the possible risk factors for SL.All renal transplant patients of a single centre were retrospectively analysed for SL between January 2010 and December 2017. The SL group was compared to a control group from the same cohort.45 out of 1003 transplanted patients developed an SL (incidence 4.5%), on average 50 days after kidney transplantation. SLs developed more in older patients, in those with a PD catheter and in ADKDP as primary diagnosis. Surgical predictors for SLs were venous anastomosis on the external iliac vein, concomitant PD catheter removal, perfusion defects, shorter operating time, splint > 7 days, double J stenting, discharge with drain, low initial drain production and ureteral obstruction. Opening of the peritoneum, re-operation for postoperative bleeding and previous nephrectomy seem protective for developing SL.We found multiple heterogeneous predictors for SL with a common denominator related to surgical management of the retroperitoneal space, peritoneum and the ureter. Future prospective studies are necessary to evaluate the influence of these variables on the development of SL. One of the most frequently observed postoperative complications of kidney transplantation is a symptomatic perirenal fluid collection, such as a haematoma, a lymphocele or lymphorrhea. A lymphocele in renal transplant recipients is a pseudo-cystic entity filled with lymph fluid, covered with a hard fibrous capsule, localized around the graft. The incidence of lymphoceles after kidney transplantation varies widely and is reported between 0.03% and 33.9% with a mean incidence of 5.2% –8. LymphMost lymphoceles are asymptomatic and resolve spontaneously or even go unnoticed. Symptomatic lymphoceles (SLs), however, cause pain and discomfort mainly due to the presence of a mass in the lower abdominal quadrant. More severe manifestations are ureteral obstruction, infection or renal vein thrombosis that may lead to secondary graft deterioration or even graft loss. Treatment consists of (repeated) aspiration or drainage of fluid, or more invasively, by open or laparoscopic intraperitoneal marsupialization or fenestration, which in turn may lead to complications as well –12. DespCurrent research has mainly focused on the treatment of choice for lymphoceles. There is no consensus about the risk factors for the development of an SL or how to prevent symptomatic lymphoceles from developing –15. We, We hypothesized that risk factors could be divided into three categories: patient characteristics , surgical characteristics  and postoperative characteristics .For this retrospective, observational, cohort study, the electronic medical records of all 1003 renal transplant recipients from a single academic centre  were reviewed for the development of a symptomatic lymphocele between January 2010 and December 2017. Symptomatic lymphocele was defined as a symptomatic fluid collection near the graft that required an intervention for the graft or patient. Postoperative or postintervention haematomas, urinomas and abscesses were excluded. Since lymphoceles mostly develop within 6 months after renal transplantation, patients needed to have a follow-up time of at least 6 months.The control group consisted of 520 patients who were randomly selected from the same cohort and evenly distributed over the cohort period from the beginning of 2014 until the end of 2017 (due to the use of an electronic patient system since 2014). According to regulation, no separate approval of the Medical Center Ethical Review Committee was necessary. Informed consent was waived.All operations were performed by a senior surgeon sufficiently trained for kidney transplantation. All recipients were given prophylactic broad-spectrum antibiotics (2 g ceftriaxone iv) 30 min prior to incision.A retroperitoneal approach via a Gibson incision was routinely used for the arterial and venous anastomoses onto the iliac vessels and to perform a ureteroneocystostomy according to Lich–Gregoir subsequently.If applicable a PD catheter was surgically removed at the end of the procedure. The ureteroneocystostomy was stented using an external splint for 5–7 days. To shorten the hospital admission time, from 2017 a double J stent was inserted and removed 2–3 weeks later at the outpatient clinic. At the end of the procedure, a wound drain was placed just beside the ureteroneocystostomy.All patients received triple immunosuppressive therapy consisting of tacrolimus (trough level 8–12 µg/l), mycophenolic acid and prednisolone. After 6 months, tacrolimus (trough level 5–8 µg/l), prednisolone (0.1 mg/kg/day) and mycophenolic acid dose was decreased and then discontinued, unless the patient had side effects of prednisolone. In these cases, prednisolone was decreased and stopped instead of mycophenolic acid. No induction therapy was given before July 2014, whereas thereafter basiliximab was given as induction immunosuppressant. If patients developed a symptomatic lymphocele, the immunosuppressive therapy was not adjusted.To assess risk factors for development of a symptomatic lymphocele, study variables were extracted from the electronic patient record. The study variables in this retrospective study were divided into patient characteristics, surgery related and related to the postoperative period. Patient characteristics were gender, age at day of transplantation, weight, body mass index, primary diagnosis for renal failure, cardiovascular history, smoking, diabetes mellitus, hypertension, kidney replacement therapy, type of kidney replacement therapy, duration of peritoneal dialysis previous to transplantation, PD catheter at time of surgery, side of the PD catheter, previous abdominal surgery, previous native nephrectomy (ADKDP patients), radiotherapy of pelvis, previous transplantation in same fossa, total kidney transplants, type of donor (living/deceased), AB0 incompatible donor, and need for anti-T cell therapy in case of rejection.Surgical characteristics were fossa sidedness, atherosclerosis of the iliac arteries, reconstruction of the iliac arteries, cold ischaemia time, anastomosis time, total surgery time, total blood loss, time on ventilation, whether the peritoneum was opened, removal and side of PD catheter, visible perfusion defects after reperfusion, diuresis and placement of splint or double J. Furthermore, for vascular anatomy of the graft and location of the anastomosis, high was defined as an arterial anastomosis on the common iliac artery or aorta, low arterial anastomosis was defined as an anastomosis on the external iliac artery and high venous anastomosis defined as an anastomosis on the common iliac vein and inferior vena cava and low venous anastomosis was defined as an anastomosis on the external iliac vein.Postoperative characteristics were defined as postoperative bleeding requiring re-operation, drain production and drain in situ at discharge, re-insertion of a drain, marsupialization or fenestration, splint in situ more than 7 days, transurethral catheter in situ for more than 9 days, ureteral obstruction, placement of nephrostomy catheter, any intervention done and mortality.t test to identify variables that were predominantly present in either the SL- or the control group, therefore being possible risk factors for the development of an SL. Data are expressed as mean ± standard deviation for continuous variables and as numbers and percentage for non-metric parameters. A P value < 0.05 was considered statistically significant. Statistical analysis was performed using statistical package for social sciences (SPSS) version 25.Univariate analysis was performed on all individual study variables using an unpaired Between January 2010 and December 2017, 1003 patients received a kidney transplantation and 45 patients developed a symptomatic lymphocele. The overall incidence of SLs in this study group was 4.5% (95% CI 3.6–5.8%). Incidence per year varied between 1.0% and 11.0%. SLs were detected after an average of 50 days post-surgery (range 11–244 days); this was on average 43 days after the first ultrasound.P = 0.017), more patients had a PD catheter at the moment of transplantation  and more patients in the SL group were diagnosed with ADPKD .Patients in the SL group had a higher age in comparison with the control group  and less patients with a PD catheter at the same side as the kidney transplantation . No significant differences were found in all other patient characteristics , removal of the PD catheter at the end of the kidney transplantation , perfusion defects of the kidney after completion of the anastomosis and reperfusion , and shorter surgery time .Comparing the SL group to the control group, more SLs were seen in patients that had a low venous anastomosis  and less opening of the peritoneum . No differences were found in all other surgical items , more usage of double J catheters , more drain requirement at discharge  and more ureteral obstructions .In the SL group, there were more patients that needed a splint for more than seven days  and less patients that needed re-operation for postoperative bleeding . No significant differences were found in the other postoperative parameters , which is below the mean 5.2% described in literature .0–11%, w. The mosA predictable but not less important patient-related factor in the patient characteristics was age. Older patients receiving a kidney transplant were more at risk of developing an SL. Since more patients are treated at higher age, this effect should be addressed to the patient in light of the need for more invasive treatment and higher mortality risk if an SL occurs. In the literature, age as a predictor for lymphoceles has previously been described for prostatectomy. Older patients are prone to a decreased nutritional status accompanied by hypo-albuminemia and hypo-proteinemia, resulting in impaired tissue healing and prolonged lymphorrhea .High body mass index has been described in the literature to increase the risk of SL . We wereAutosomal dominant polycystic kidney disease (ADPKD) was the only end-stage renal disease (ESRD) that led to an increase of SLs in this study. Martinez-Ocana et al. also reported this correlation . They suOne of the surgical parameters that was found to increase the risk of an SL was the use of a low venous anastomosis. This effect has previously been described by Sansalone et al.; they pointed out that dissection around iliac vessels should be done with care . Proper A second predictor for SL was related to the presence of a PD catheter at the time of surgery as well as its subsequent removal, whereas removal of the PD catheter when it was located at the same side of the abdomen as the fossa used for transplantation as well as opening the peritoneum reduced the risk for SL. We are not able to explain why a PD catheter located at the same side as the kidney transplantation would be a protecting factor for the development of SL. PD catheters are often inserted from the midline of the abdomen into cavum Douglasi and subsequently tunnelled to the right or left side of the abdomen. Nevertheless, these findings point to an important role of the peritoneum in the development of SLs. It is well known that peritoneal dialysis changes the composition of the peritoneum. Opening the peritoneum by fenestration is a well-known treatment for symptomatic lymphoceles –25. InteAnother predictor for SLs was the presence of perfusion defects of the kidney after anastomosis and reperfusion, subsequently followed by partial ischaemia. Ischaemia and reperfusion affect many regulatory systems in the renal tissue and may trigger an immune response, resulting in a distinct inflammatory reaction of the kidney graft , 27. ThiAnother surgical predictor for SLs was the presence of a splint for more than 7 days and the use of a double J catheter (21 days in situ) when compared to standard 5-day splinting. Our theory is that a plastic or silicone tube leads to irritation of the graft ureter. This irritation may then in turn lead to an inflammatory reaction resulting in an accumulation of lymph fluid and hence more symptomatic lymphoceles –31. IrreThis study showed that drain production was inversely related to the development of SLs. Apparently, less drain production leads to more SLs. Our hypothesis is that improper drainage of the retroperitoneal space directly after the kidney transplantation not only leads to accumulation of the non-drained blood and lymph fluid, but also facilitates more lymph fluid production as reaction to it and thus leads to an SL. This idea is supported by the finding that less SLs were seen in patients requiring a second operation for a postoperative bleeding, wherein blood is removed from the retroperitoneal space, fluid leakages are managed and a drain is properly (re-) replaced. We also investigated the effect of a thin versus a thick drain, but no significantly differences in the outcome of SLs were found. We advocate proper drain placement, advise to keep the drain open and to not remove the drain too quickly to prevent possible formation of an SL.The slight increase in incidence of SLs over time might be attributed by the use of a double J as described earlier. Since the use of a double J was effectuated from 2017, this partly explains the increase. We, therefore, investigated other parameters that changed in time. A smaller drain diameter was used by May 2014, but no significant difference in SL formation was seen between the period prior and after the introduction. The same holds for the introduction of basiliximab as induction therapy starting July 2014. The trend towards more SLs is, therefore, unaccounted for.This is a retrospective study, which constitutes an important limitation. However, we obtained complete and detailed information from our database covering multiple years. Another limitation is the fact that these results are based on a single-centre study. Further research must show whether this applies to other settings as well.Furthermore, since our group of patients that developed a symptomatic lymphocele was relatively small, i.e. out of 1003 patients only 45 did develop a symptomatic lymphocele, we were unable to do an extensive multivariate analysis.This study showed that symptomatic lymphoceles develop in one out of 25 patients (4.5%) receiving a kidney transplant and cause significant morbidity and mortality.We found multiple surgical and non-surgical predictors for the development of a symptomatic lymphocele. The common denominators are the surgical management of the retroperitoneal space and peritoneum, management of the PD catheter at the moment of transplantation, wound drain production and the duration of stenting of the ureteroneocystostomy.A prospective study is needed to confirm the role of these risk factors in the development of symptomatic lymphoceles. This study may lead to a better awareness and hopefully prevention of development of symptomatic lymphoceles in the future.


Remote ischemic preconditioning (RIPC) are short episodes of ischemia and reperfusion applied to remote tissue to trigger responses in a specific organ or cardiovascular bed. This study investigates whether RIPC has a short-term effect on blood pressure (BP), heart rate, and arterial stiffness.From March 2018 to August 2018, we included 40 healthy volunteers  into this single-blinded randomized-controlled crossover trial. After measuring BP, heart rate, and arterial stiffness in supine position participants were randomized into intervention or SHAM group. The intervention group then underwent a RIPC protocol (3 cycles of 5 min of 200 mmHg ischemia followed by 5 min reperfusion) at the thigh. The SHAM group followed the same protocol just on the upper arm with 40 mmHg pressure inflation. Directly after this 30-min procedure a reassessment of hemodynamic measures was conducted.p = 0.672), and for diastolic BP Δ−0.69 ± 4.5 mmHg (p = 0.507). Heart rate shoed a Δ−0.8 ± 4.7 beats/min (p = 0.397). Regarding arterial stiffness measures, there was also no significant improvements thru RIPC. The mean difference between RIPC and SHAM for central systolic BP was Δ0.40 ± 7.2 mmHg (p = 0.951) and for PWV Δ0.01 ± 0.26 m/s (p = 0.563).There were no significant changes in all five outcome parameters when comparing the effect of RIPC to SHAM. In peripheral systolic BP the mean difference between groups was Δ1.14 ± 6.5 mmHg (This study could not find any short-term effects of RIPC on arterial stiffness, BP, and heart rate in a RCT in young healthy adults. Steady oxygen supply is the basic requirement for humans to survive. However, intermittent hypoxic  or ischeThe idea of RIPC was originally to protect from myocardial injury during coronary artery bypass grafting first shown in 1993 . In the Overall, the short-term effect of RIPC on BP, heart rate, and arterial stiffness is unknown. Therefore, the aim of this study was to evaluate whether a single RIPC procedure shows a short-term improvement of BP and arterial stiffness.From March 2018 to August 2018, we included 40 healthy volunteers without cardiovascular disease . Afterward they were randomized into an intervention or SHAM group using block method. The intervention group received a RIPC protocol of 3 cycles of 5 min each with occlusion to 200 mmHg with a special BP cuff on the right thigh followed by 5 min re-perfusion. The SHAM procedure consisted of a pressure cuff, inflated on the right upper arm for the same periods as the RIPC intervention but only to 40 mmHg as it has shown to mimic occlusion but not limiting blood flow. The study participants were thus led to believe that this study was a comparison between different occlusion techniques on the thigh and upper arm.After resting for 5 min in supine position the participants received a BP, heart rate, and arterial stiffness measurement on the left upper arm using oscillometric measurement device Mobil-O-GraphDirectly after this 30-min intervention or SHAM a reassessment of BP, heart rate and arterial stiffness measures was conducted. After a mean of 6.8 ± 1.0 days a crossover was performed and participants assigned to the other group and underwent the procedure again .The study was conducted in accordance with the Declaration of Helsinki (revision 2008) and the Good Clinical Practice guidelines. The study protocol was approved by the local ethical board (project number 209/18S) of the Technical University Munich. All participants gave written informed consent and agreed to anonymous publication of their data.Blood pressure and arterial stiffness were automatically measured on the left upper arm with the oscillometric cuff-based Mobil-O-Graph device in a supine position after 5 min rest. Cuffs were chosen according to the circumference of the left upper arm .Central systolic blood pressure and pulse wave velocity (PWV) were indirectly estimated with an ARCSolver Algorithmus  based on the recorded brachial pulse waves. This method includes the influence of arterial impedance and the aortic hemodynamics using a generalized transfer function and a mathematical model. It is confirmed that this non-invasive cuff-based method of the Mobil-O-Graph strongly correlates with the invasive measurement of central BP .t-test for independent samples.Data is described by mean ± standard deviation for all variables after proving normality for systolic, diastolic, central BP, and PWV by a Kolmogorov Smirnov test. To measure the effect of RIPC, differences between baseline and post-tests were calculated for intervention and SHAM procedures. Afterward the differences were compared with Student’s All tests were performed using SPSS . The level of significance for all two-tailed tests was set to <0.050.There were no significant changes and very low effect sizes in all of the four outcome parameters when comparing the effect of RIPC to SHAM.p = 0.672), and for diastolic BP Δ−0.69 ± 4.5 mmHg . There was also no significant change in heart rate .As shown in p = 0.951) and for PWV Δ0.01 ± 0.26 m/s .Regarding arterial stiffness measures there were also no significant improvements through RIPC. The mean difference between RIPC and SHAM for central systolic BP was Δ0.40 ± 7.2 mmHg . Only heart rate deceased in pre-RIPC with post-RIPC and pre-SHAM with post-SHAM significantly (both p < 0.001).Moreover, there were also no significant changes in systolic BP, diastolic BP, central systolic BP and PWV when comparing pre-RIPC with post-RIPC, and pre-SHAM with post-SHAM  measures should be performed to determine BP, and arterial stiffness. However, it should be considered that multiple pre- and post- BP assessments are also short bouts of RIPC and could therefore bias the data. The use of our oscillometric device for the assessment of arterial stiffness utilizes cuff inflation to measure PWV and central pressure and thus adds an ischemic stimuli to the sham group and an additional ischemic stimuli to the intervention group. Devices using applanation tonometry would be more appropriate for this study.The datasets generated for this study are available on request to the corresponding author.Human Subject Research: The studies involving human participants were reviewed and approved by the Technical University Munich project number 209/18S. The patients and participants provided their written informed consent to participate in this study.JM conceived and designed the study, sampled the parts of the analyzed data, and drafted the manuscript. MT sampled the data and provided important input for drafting and revising of the manuscript. RO conceived and designed the study and provided important input for revising of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


P < 0.05. One hundred forty patients were included in the analysis. Among these, 26 (18.4%) patients were controlled, 65 (46.1%) partially controlled, and 35% uncontrolled. Proportion of patients with uncontrolled asthma were higher among inefficient as compared to efficient, whereas patients with controlled asthma were higher among efficient as compared to inefficient. Asthma control status is significantly associated with inhalation technique (P=0.006). Since most of the patients were inefficient and it is significantly associated with asthma control status, the hospital tried to adopt video MDI teaching program, and the patient should ask healthcare professionals how to take medication and they should bring their device to receive demonstration during visit. Health professionals should re-evaluate the patient during their hospital visit and encourage bringing their device to give demonstration.Asthma is a heterogeneous disease which is characterized by chronic airway inflammation. It is a common chronic respiratory disease affecting 1–18% of population in different countries. It can be treated mainly with inhaled medications in several forms, including pressurized metered-dose inhaler (MDI). Patients encountered difficulty in using inhaler devices even after repeated demonstration and/re-evaluation. This could highly compromise patient treatment outcome/asthma control. To evaluate relationship between MDI use technique and asthma control among adult asthmatic patients who attend respiratory clinic in Jimma University Medical Center (JUMC), Southwest Ethiopia. A prospective observational study was conducted from March to August 22, 2018. All adult asthmatic patients who met the inclusion criteria were included in the study. Patient baseline assessment was conducted . Inhalation technique was obtained using a standard checklist of steps recommended in National Institute of Health (NIH) guidelines. Patient adherence using asthma inhalation test and asthma control status was assessed by 2017 GINA guideline. Independent predictors of outcome were identified, strength of association between dependent and independent variables was determined by using ordinal logistic regression analysis, and statistical significance was considered at  Asthma is a heterogeneous disease which is characterized by chronic airway inflammation. It is defined by history of patient respiratory symptoms such as wheeze, cough, shortness of breath, and chest tightness. Intensity and frequency of symptoms can vary from time to time and together with variable air flow limitation .An increasing number of risk factors have been linked to the development of asthma, particularly found in developing countries. These include indoor-like biomass, outdoor pollution, and occupational exposures .Based on previous reports, asthma has negative consequences, such as impairment of quality of life and reduction of daily living activities and direct and indirect costs related to emergency room visits, hospital admission, frequent outpatient visits, and school and work absenteeism , for botβ2 agonists, or both in combination are effective so as to achieve this outcome. However, achieving asthma control is not easy, and only a small number of asthma patients use the medications regularly as recommended or incorrect inhalation technique contributes for suboptimum treatment outcome [The goal of asthma treatment is to control the frequent symptoms of asthma and improve forced expiratory volume or pulmonary function. Different medications can be used for this problem such as inhaled corticosteroids, long-acting  outcome .A previous study showed that different factors were considered as predictors for asthma control status, such as the socioeconomic status, knowledge about the disease, and its triggering factors, poor perception about the pathophysiology of the disease/obstruction of bronchial tree, presence of comorbidities, fear of drug adverse effects, and ability to use different inhaler devices. Inappropriate inhaler devices and inefficient inhalation techniques can negatively affect the deposition of drugs in the target site (pulmonary) and increase the frequency of local and systemic adverse effects and prone to the patient with uncontrolled asthma .In Brazil, among patients using an MDI without a spacer, a large number of patients made mistakes in the steps of keeping the mouthpiece at a correct distance from the lips, exhaling fully before using the device .So this research will show the gab of patients' inhalation technique and its contribution for asthma control status and it can figure out the predictors. There is no study done before with this specific title in Ethiopia and so it could serve as baseline for further study.This study was done in JUMC, Jimma, Ethiopia. JUMC is located in Jimma town which is 346 km away from Addis Ababa, and it is found in southwest Ethiopia. It is one of the largest teaching university hospitals in Ethiopia. JUMC is offering diagnosis and treatment for approximately 10,791 patients per month. There are about 9 outpatient clinics located within the hospital which serve over 9592 visits/month . This stA hospital-based prospective study was used to evaluate the association of asthma control and metered-dose inhaler use technique among asthmatic patients attending respiratory clinics in JUMC. All adults of age 18 and above, patients with confirmed diagnosis of asthma and on controller medications for at least the last three months, and who are willing to participate and having follow-up at the outpatient respiratory clinic were included in the study. Patients who were on exacerbation during data collection period, patients who were handicapped, and whose age was >75 years old were excluded from the study. Finally, all adult patients who satisfied the inclusion criteria were chosen as subjects for the study.As shown in Relevant information like patient characteristics, inhalation technique, current medications, comorbidities, duration of illness, inhaler use, and adherence  was recorded using a structured questionnaire (adapted from different published literatures –13). A qAn empty and their own MDI were adapted to enable a patient's inhalation technique to be recorded and patients were asked to use their aerosol just as if they would be at home. Inhalation techniques were identified using a standard checklist of steps recommended by National Institute of Health (NIH) guidelines  with 1 pData were collected by two pharmacists after one day training. Supplementary information and clarifications on some patient's medical information were obtained through discussion with respective nurses and physicians.P value 0.156) was checked. Chi-square statistics was used to check adequacy of cells for ordinal logistic regression. Independent predictors of outcome and strength of association between dependent and independent variables were identified by using ordinal logistic regression analysis and P value <0.25 entered to multiple regression. P-value <0.05 was considered as significant. Descriptive statistics was used to characterize asthma control and independent variables. Results of the study were organized in the form of frequencies and percentages. The data are summarized and described using tables and figures.Data were entered into a computer using EpiData 3.1 software and analyzed with SPSS version 21. Before analysis, presence of collinearity between independent factors (having less than 3 variance inflation factor) and model fitness  were females. The overall response rate was 98%. The mean age was 47.8 (age range 19–74) years with the maximum number of patients being in the age group of 41–59 years. A majority of 110 (78.57%) patients were found to have isolated asthma. Fifty-seven (40.7%) patients had moderate persistent asthma, 35% had severe persistent, and the rest (24.3%) had mild persistent. Only 3 (2.1%) of the study subjects were currently smokers while 121 (86.43%) were nonsmokers.Seventy-seven (55%) and 72 (51.4%) patients drank alcohol and chewed khat, respectively. A majority of 88 (62.9%) patients were exposed to biomass fuels during cooking food, and other activities are shown in . Among tOne hundred thirty (92.85%) patients had errors in one or more steps of inhaler technique. The highest number of errors was found to be done in steps inhale slowly, simultaneously press canister, and breathing in slowly and deeply which is 97 (69.28%). The second most frequent error was lean head slightly back, 69 (49.3), and take inhaler out of mouth and hold breath for 5–10 sec was the third most missed step which accounts 54 (38.6%). In this visit, the most correctly followed step was shake the inhaler vigorously (5–10 times), only 3 (2.14%) patients missed this step. Only about 26% patients were efficient and the rest were not efficient.P=0.006, As shown in As shown in As shown in The proportion of patients with uncontrolled asthma was relatively higher among inefficient patients as compared to efficient, demonstrating that inappropriate use of the devices is one of the significant predictors of asthma symptom control. Correct performance of critical steps involved in using the devices was one of the factors affecting asthma symptom control. These steps which include inhaling slowly and deeply are crucial for fully delivering the drug to the lung, and, in the present study, this key step was the one with the highest proportion of errors. This might have contributed to the lack of asthma control among those who did not take a slow and deep inhalation correctly.The proportion of patients who had daytime symptoms more than twice per week, nighttime awakening, and activity limitations were higher in our study as compared to the study revealed in Addis Ababa which showed that 62 (34.6%) patients demonstrated improper inhaler technique . In our P=0.006). This study is consistent with the previous study done in India, Addis Ababa, Serbia, Italy, and France [Multivariate ordinal regression showed that three variables  were identified as independent significant predictors for treatment outcome/asthma control. Efficient patients were less likely to have uncontrolled asthma as compared to inefficient (d France –19 whichLimitation: our study relies on physician diagnosis of asthma and on small sample size.This study revealed that though majority of patients claimed to know how to use inhalation devices correctly, only few patients followed all the essential steps of inhalation technique of MDI before intervention. This study showed that there is significant association between inhalation technique and asthma control. Health professionals should educate patients about inhalation technique during their hospital visit to optimize inhalation technique and intern asthma control. Exacerbation, adherence, and inhalation techniques were identified as independent significant predictors for treatment outcome/asthma control. As there are still a lot of illiterate people in our patients, the need for proper counseling during their visit is even more important. Therefore, proper and regular training about error-free inhalation techniques needs to be conducted to optimize the patient treatment outcome.


Although the important role of respiratory modulation of the cardiovascular system in the development of hypertension has been demonstrated in animal studies, little research has assessed this modulation in essential hypertensive patients. We aimed to explore whether respiratory-related variations in cardiovascular variables are changed in hypertensive patients and their potential relationships with the respiratory pattern.Respiration, ECG, and beat-to-beat blood pressure (BP) were simultaneously measured in 46 participants (24 hypertensive patients and 22 normotensive participants) during rest and a mental arithmetic task (MAT). Respiratory-triggered averaging and orthogonal subspace projection methods were used to assess the respiratory modulations of BP and heart rate (HR). Respiratory parameters including inspiratory time, expiratory time, respiratory rate and their variabilities were also characterized.The inspiratory time, expiratory time, respiratory rate and their variabilities were not different between hypertensive and normotensives. Additionally, the modulation of HR by respiration was also similar between the two groups. Hypertensive patients exhibited an amplified respiratory modulation of systolic BP (SBP), as assessed from the amplitude of respiratory-related changes and the percentage of the power of respiratory-related variation, and also reflected from the temporal pattern of respiratory modulation of SBP. The exaggerated respiratory-related variation of SBP in hypertensive patients accounted for ≈23% of the total power of SBP, producing an absolute change of ≈4.5 mmHg in SBP. MAT was characterized by decreased inspiratory time and increased variabilities of expiratory time and respiratory rate with no changes in the amplitude of respiratory modulations.Hypertensive patients had excessive respiratory modulation of SBP, despite having similar respiratory pattern with normotensives. These findings highlight the importance of respiratory influence in BP variation and suggest that respiratory modulation of SBP may have prognostic information for cardiovascular events in hypertensive patients. Hypertension remains a mounting threat worldwide despite the years of research and the significant advances in antihypertensive medication . Many syDespite the findings of the significant contribution of respiratory modulation of the cardiovascular system to the development of hypertension in animal models, there is a paucity of information about this modulation in hypertensive patients. One study  focusingA total of 50 participants, comprising 25 hypertensive patients and 25 normotensive controls between 40 and 60 years of age were recruited. All participants were screened by medical history, 12-lead ECG, and routine physical examination in the department of cardiology of No. 451 Hospital of Chinese People’s Liberation Army. The measurement of BP was taken at both arms with participants rested for 10 min at sitting position, using the auscultatory method with a mercury sphygmomanometer. The average of BP measured from both arms were documented. BP was measured at two clinic visits. Participants with systolic BP (SBP) < 120 mmHg and diastolic BP (DBP) < 80 mmHg during both visits were classified as normotensives, and hypertension was defined as SBP ≥ 140 mmHg or DBP ≥ 90 mmHg . ExclusiBefore the experimental visit, participants were asked to refrain from caffeine, alcohol, and vigorous exercise for at least 24 h. All experiments were performed in an environment-controlled room . Respiratory movements were measured by a strain-gauge pressure belt that placed stably around the chest . A 3-lead ECG (Lead II configuration) was also collected by the MP150 system. Beat-to-beat BP was measured through a photoplethysmograph finger cuff from Finometer . The Finometer cuff was wrapped around the middle finger of the participant’s non-dominant hand and referenced to the heart level. The raw pulsatile pressure data from the Finometer was input to the MP150 system in order to simultaneously record ECG, respiratory and BP signals. After the instrumentation and experimental setup, participants rested comfortably in a supine position for 20 min. Respiratory and cardiovascular signals were then recorded continuously throughout a 5-min baseline period followed by a 5-min mental arithmetic test (MAT). MAT involved continuous subtraction of seven from a four-digit number, and the participants were instructed to calculate as fast and accurately as possible. Throughout the procedure, participants lay comfortably and breathed spontaneously.SBP + 2DBP)/3. The time series of HR, SBP, DBP, and MBP were interpolated and resampled at 2 Hz for further analysis. Stroke volume (SV) was estimated from the pulse waveform using the Modelflow method embedded in Finometer . ECG signal was first bandpass filtered (5–15 Hz), and then Pan-Tompkins algorithm was used to detect R peaks . Beat-toinometer . Cardiacinometer , and theinometer .The respiratory-related changes in HR and BP were examined using the event-triggered averaging method. The inspiratory peaks were set as the triggering events in this study. For each participant, HR signal was segmented into epochs from his/her mean inspiratory time before to his/her mean expiratory time after the inspiratory peaks. These epochs were then averaged to generate the respiratory-related HR wave. The averaging process could dampen the irrelevant variabilities in HR and generate a distilled representation of the respiratory-related HR wave. The quantification of respiratory modulation on HR was then performed by measuring the difference between the maxima and minima of the averaged HR wave. Both absolute (ΔHR: maxima-minima) and normalized changes (Norm_ΔHR: maxima-minima/maxima) of HR caused by respiration were calculated in this study. Identical respiratory-triggered averaging procedures were performed for SBP, DBP, and MBP time series to assess respiratory modulation of blood pressure.The respiratory-related HR and BP waves derived from the event-triggered averaging method could also be used to identify the temporal relationship between respiration and cardiovascular variables. The individual duration of this HR (or BP) wave varied among participants due to their different durations of inspiration and expiration, which would make the direct inter-subject averaging impossible. In order to characterize the temporal respiratory modulation of HR (or BP) at the group level, a novel method based on respiratory phase was used in this study. For each participant, the HR (or BP) wave was resampled and interpolated with five-points from the onset of the inspiration to the inspiratory peak and five-points from the inspiratory peak to the end of the expiration using cubic spline interpolation. This approach was well suited to align the respiratory-related segments of cardiovascular variables within one respiratory period for multi-subject analysis, allowing the characterization of the temporal respiratory modulation at group level. After the interpolation, the HR (or BP) values were subtracted by the value of HR (or BP) at the inspiratory peak to represent a relative change during one respiratory cycle.One strategy to distill the respiratory-related variability from the total variability of cardiovascular signals is to decompose the signals into two components, namely the respiratory-related component and component related to other rhythms. Many methods have been proposed in the field of biomedical signal processing for this decomposition . A recenHRresp) and BP (BPresp) were then given by:The projected signal of HR  was performed by computing the ratio between the power of the respiratory-related component and the total power of HR (or BP) signal , express2 analysis was performed for comparisons of the categorical data. The distributions of continuous variables were examined by the Shapiro–Wilk test. For variables with normal distribution, between-group comparisons were carried out by the independent t-test and within-group comparisons between baseline and MAT conditions were done by paired t-test. For variables with skewed distributions, Mann–Whitney test and 1-sample Wilcoxon test were performed for between and within group comparison, respectively. A mixed-model ANOVA with respiratory phase and condition (rest and MAT) as within-subject factors and group (normotensive and hypertensive) as the between-subjects factor, was used to analyze the temporal regulation of respiration on HR and BP. Data are expressed as means ± SEM, and α level was set at 0.05.Participants’ characteristics were summarized as means for continuous variables and percentages for categorical variables. The primary outcome of the present study was a difference in respiratory modulation of BP between normotensive and hypertensive groups and we estimated a 50% difference between the two groups for the power calculation. Based on previous research, the respiratory modulation of SBP would be 2.5 mmHg in the control group . AssuminP = 0.067), and as a result, respiratory rate did not change significantly in hypertensives during MAT. In addition, the variabilities of expiratory time  and respiratory rate  were significantly increased during MAT in both groups.As shown in HRRESP), SBP (SBPRESP), DBP (DBPRESP), MBP (MBPRESP), determined by orthogonal subspace projection, are presented in P < 0.001; percentage of power in total variation: normotensives: 16.54 ± 1.36%, hypertensives: 23.52 ± 2.78%, P = 0.034). On the other hand, the two groups exhibited similar respiratory modulation of HR at rest . Additionally, resting modulation of DBP by respiration was also comparable between the two groups. The resting ΔMBP was significantly higher in hypertensive patients, but this difference became non-significant after the normalization. Similar to the baseline condition, hypertensives and normotensives showed comparable ΔHR, Norm_ΔHR, Norm_ΔDBP, and Norm_ΔMBP during MAT, whereas ΔSBP, ΔDBP, ΔMBP, and Norm_ΔSBP were significantly larger in hypertensive patients.P < 0.001, ANOVA main effect of respiratory phase). HR increased during inspiration, and reached the maximum at the end of inspiration, then decreased during expiration. BP decreased during most of the inspiratory period and expiration was associated with gradually rising BP as previously reported (P < 0.001) and MBP (P = 0.015), suggesting the degrees of inspiratory elevation and post-inspiratory attenuation of them were different between the two groups. The main effect comparing the rest and MAT conditions in the respiratory modulation of HR and BP were not significant.reported . The chaOur novel finding is that the respiratory modulation of SBP is exaggerated in hypertensive patients compared with age, sex, and BMI matched normotensive subjects. Additionally, different from our initial hypothesis, the changes in respiratory pattern and cardiovascular variables during MAT did not affect the respiratory-related variations in cardiovascular variables. An absolute respiratory-related change of ≈4.5 mmHg in SBP was observed in hypertensive patients with normal resting respiratory pattern, and the respiratory-related variation accounted for ≈23% of the total variability of SBP in those patients. These findings highlight the importance of respiratory influence on BP variation. Given that increased BP variability is significantly associated with cardiovascular and mortality outcomes , the exaIt has long been known that the cardiovascular and respiratory systems are closely linked, and the respiratory modulations of HR and BP are two important manifestations of this physiological coupling . AlthougThe precise mechanism of the exaggerated respiratory modulation of BP in hypertensive patients remains unclear, but altered chemoreflex function in hypertension could be a potential major mechanism . EnhanceP = 0.067), and as a result respiratory rate did not significantly increase during MAT in hypertensive patients. From the analysis made in the present study, we cannot make meaningful interpretations about how this difference between groups might occur. One explanation is that variation in ventilatory response of individuals to mental stress is associated with cognitive function (As expected, MAT elicited significant changes in homeostatic control of the cardiovascular and respiratory systems . Changesfunction , which wfunction .Although MAT elicited significant changes in respiratory and cardiovascular parameters, our data showed that magnitudes of the respiratory regulation on HR and BP remained unchanged. The respiratory modulation indexes calculated by event-triggered averaging method were not changed during MAT, except the Norm_ΔSBP . ConsideIn a recent large population study, BP variability was significantly associated with increased risk of adverse cardiovascular outcomes in hypertensive patients, and a 5 mmHg increase in the within-visit standard deviation of SBP could increase the risk of cardiovascular events by 15% . We founThere are several limitations. First, as discussed, the event-triggered averaging method could not detect non-phase-locked responses of cardiovascular variables to respiratory regulation. Second, although orthogonal subspace projection could take non-stationarity of the signal into account by including wavelets as a basis when constructing the subspace of respiratory signal, this method only considers the linear relationship between cardiorespiratory signals. The non-linear characteristics of cardiorespiratory interrelationship should be further studied. Third, the present study was a case-controlled study with small sample size. Future multicenter population studies are needed.The present study demonstrated that respiratory modulation of SBP was exaggerated in patients with essential hypertension. Furthermore, this modulation remained unchanged despite significant changes in respiration and cardiovascular variables during mental stress. The larger SBP variation mediated by respiration in hypertensive patients may contribute to the heightened risk of adverse cardiovascular consequences. The prognostic relevance of respiratory modulation of BP, and whether it should be recommended as a BP control target are questions that warrant investigations in future studies.The datasets generated for this study are available on request to the corresponding author.The studies involving human participants were reviewed and approved by Ethical Committee of Xi’an Jiaotong University. The patients/participants provided their written informed consent to participate in this study.LX and JZ designed the study. LX, XD, and FZ performed the experiments. LX, XD, JY, BL, and XW processed the data and designed the figures. LX, JZ, ZL, and CL interpreted the data and drafted the manuscript. All authors discussed the results and contributed to the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Influential factor of RNFL defect in old group was ABI (p = 0.007). However, in young group (<50 yrs), HRV parameter (low-frequency/high-frequency ratio) determined the presence of RNFL loss (p = 0.040). Significant determinants of superior RNFL defect in old subjects were CAVI and ABI (p = 0.032 and p = 0.024). For young diabetic patients, autonomic dysfunction may have relationship with RNFL loss, but as patients get older, arterial stiffness could aggravate vascular autoregulation and diabetic RNFL loss. RNFL loss in diabetes may be correlated with systemic vascular conditions.Retinal nerve fiber layer (RNFL) loss in diabetic patients is especially common regardless of diabetic retinopathy (DR). The correlations between nonglaucomatous RNFL loss and systemic characteristics in diabetic patients have aroused interests in many aspects. 167 subjects with type 2 diabetes who underwent evaluation for arterial stiffness and cardiovascular autonomic function using heart rate variability (HRV) were included in this study. Arterial stiffness was measured using cardio-ankle vascular index (CAVI) and ankle-brachial index (ABI). Multivariate regression analysis was performed to determine factors influencing the presence of RNFL loss according to age. Factors determining the superior location of diabetic RNFL loss were also investigated. CAVI were worse in patients with RNFL loss, especially in those with old age (≥50 yrs) ( It is typically observed in glaucoma patients. However, it is also seen in nonglaucomatous retina of diabetic patients. RNFL loss in diabetic patients is especially common regardless of diabetic retinopathy (DR)2. This suggests that RNFL loss without DR can be a type of optic neuropathy in diabetic patients3.Retinal nerve fiber layer (RNFL) defect refers to the loss of retinal neuronal cell3, advanced glycation end products4, and blocked retrograde axonal flow of retinal ganglion cells5. Among these factors, oxidative stress could be influenced by systemic vascular conditions. Retinal vascular circulation is controlled through autonomic nervous system6, and it also could be impaired by arterial stiffness through narrowing vascular caliber7.Diabetic RNFL loss is influenced by multiple factors, including oxidative stress9. Shim et al.10 have reported that increased arterial stiffness is associated with existence of open-angle glaucoma in diabetic patients using brachial-ankle pulse wave velocity (baPWV) index. In addition, increased arterial stiffness can be affected by old age itself. Increased trend of arterial stiffness is even shown in healthy subjects with increasing age11. So, it is natural that the older the diabetic patient is, the more affected by the vascular stiffness.Several studies have evaluated the stiffness of vessel in diabetic patients and found that systemic vascular incompetence commonly occurs, wielding an influence on diabetic complications13. Worse heart rate variability (HRV) parameters could contribute to cardiac functional damage in diabetic patients, so we hypothesised that peripheral circulation might be influenced by compromised cardiac function, especially in retina of diabetes.Cardiovascular autonomic function could be another factor affecting systemic circulation in diabetic patients. Indeed, cardiovascular autonomic dysfunction has been widely reported using multiple indicesOur purpose of this study is to look into how systemic vascular changes of diabetes can affect retina, and to investigate the correlations between nonglaucomatous RNFL loss and systemic vascular characteristics in patients with type 2 diabetes according to aging.Of a total of 167 subjects, 105 had RNFL losses while 62 had no RNFL loss as age- and sex- matched controls. Baseline characteristics of both groups are summarized in Table 14, there was different criteria of considering antiplatelet agents to prevent atherosclerotic cardiovascular disease (ASCVD) based on age 50. So we determined the cutoff point of grouping subjects as age of 50. In young age group, there were no significant differences in mean value of CAVI, ABI, and ratio of patients with abnormal arterial stiffness index  2016 guidelinesP value was significant in CAVI value, but mean ABI and ratio of subjects with abnormal ABI showed marginal P values (0.051 and 0.051).On the other hand, in the old age group, there were statistically significant or considerable differences. In old patients who had RNFL loss, mean arterial stiffness indices were worse  and ratios of subjects who had abnormal CAVI or ABI results were also higher compared to subjects without RNFL loss . Values of autonomic functional evaluation, such as SDNN  and LF/HF (low-frequency/high-frequency), did not show any significant or meaningful effect. LF/HF ratio were statistically significant in multivariate model analysis in the young age group . In this group, HbA1c level was also meaningful for diabetic RNFL loss .Multivariate regression analysis including HRV parameters and arterial stiffness indexs was performed for subgroup analysis. Table p value was marginally insignificant (p = 0.054). ABI value or ratio of abnormal ABI patients was not significantly different between superior and inferior RNFL loss groups.Among patients with RNFL loss, the location of RNFL defect was also classified. Results on their correlations with arterial stiffness indices are summarized in Table As shown in Table 15. In the kidney, oxidative stress can cause endothelial injury, podocyte loss, albuminuria, and glomerular failure in sequence16. Similar microvascular endothelial structural impairment also occurs in retinal vessels. Therefore, this structural problem of vessel is a crucial factor that determines autoregulation of retinal circulation.Diabetic retinopathy and nephropathy can be caused by microvascular impairment due to oxidative stress with advanced glycation end products (AGEs)17. Activation of the AGE, protein kinase C (PKC), polyol, poly(ADP-ribose) polymerase, and hexosamine pathways can contribute to metabolic imbalance in hyperglycemic environment18. Because arteriovenous anastomoses of capillaries are usually under sympathetic control, compromised autonomic function in diabetic patients could affect microvascular circulation.Autonomic neuropathy in diabetes is also important complication. It can affect cardiovascular function and increase the risk of morbidity and mortality. Dysfunction of axon and dendrite of sympathetic ganglion has been identified by multiple experimentsWe have been focusing on the suggestion that retinal vascular homeostasis in diabetic patient is maintained through both autoregulation and autonomic regulation of vessel. To evaluate vascular autoregulation that is associated with structural changes of vessel, arterial stiffness indices such as CAVI and ABI were selected in this study. HRV parameters were also included to assess the autonomic functional status of vessels in diabetic subjects.19. Kim et al. have suggested that CAVI was related to smooth muscle contraction status of vessel20. In addition, ABI has been widely used to estimate vascular status as a simple and useful method21. ABI was known as a good index of atherosclerosis and lower ABI has been reported to be useful in the diagnosis of peripheral arterial disease23. Also, higher ABI was reported to represent medial artery calcification and to be related with the risk of cardiovascular event25.CAVI has been recently proposed as an indicator of arterial stiffness and arteriosclerosis independent of arterial blood pressure26. Changes of vascular structures in old age could affect retinal vascular autoregulation. Indeed, it has been reported that smooth muscle cells of arterioles have fibrosis, degradation and decreased cross-sectional area due to aging28.Autoregulation of retinal vessel can be attained by modulating vascular tone which could be achieved through multiple mechanisms affecting vascular structures including smooth muscle cells30. Compromised vascular responsiveness upon metabolic imbalance31 in diabetic patients could explain why microaneurysm, acellular capillary, and nerve fiber loss are common in superior retinal region. Under diabetic condition, impaired vascular response could bring about deficient homeostasis of blood circulation at superior retina which may have decreased blood volume due to gravitational effect32. In our study, when RNFL loss location was classified as superior and inferior in old age group, the subjects with superior RNFL loss presented worse CAVI values . Best corrected visual acuity was 20/40 or better and spherical equivalent was within ± 5.0 diopters in all subjects.36.Eyes without diabetic retinopathy (DR) or mild nonproliferative diabetic retinopathy (NPDR) were included. Stage of DR was evaluated by a retinal specialist (J.H.L) through fundus photography based on Early Treatment Diabetic Retinopathy Study (ETDRS) classification. Eyes with clinically significant macular edema were also excludedOnly well centered retinal photographs were used to evaluate the existence of RNFL loss. These photographs were obtained using digital fundus camera at 60° view Fig. . Two gla37. Hypertension was defined when systolic blood pressure was ≥140 mmHg and diastolic blood pressure was ≥90 mmHg, or any antihypertensive medication was used38.Patients were diagnosed as diabetes if fasting plasma glucose level was more than 126 mg/dl, or symptoms of diabetes appeared with random plasma glucose level of more than 200 mg/dl, or HbA1c was more than 6.5%After patients had fasted for 12 hours, blood samples were collected and blood glucose was measured using an automated enzymatic method. Glycated hemoglobin (HbA1c) level was measured to evaluate the controlled state of diabetes.39.Lipid profiles  were measured and glomerular filtration rate was estimated using the Modification of Diet in Renal Disease Study equationThe arterial stiffness was measured using cardio-ankle vascular index (CAVI) and ankle-brachial index (ABI). CAVI and ABI values were obtained with a VaSera VS-1000 device .40. ABI was calculated at each leg, dividing the higher pressure of posterior tibial or dorsalis pedis artery by systolic pressure at brachial artery41. The presence of plaque in carotid artery was distinguished using carotid sonography .CAVI was calculated using the distance from the level of aortic valve to the measured area and delayed time from closing of aortic valve to arterial pressure change at measure point42. Echocardiography signals of all patients were documented after 30 minutes of rest. They were then transferred to Medicore Heart Rate Analyzer, Model SA-3000P .Cardiovascular autonomic nervous function was evaluated with parameters of heart rate variability, including standard deviation of normal to normal intervals (SDNN) and ratio of low-frequency power to high-frequency power (LF/HF). HRV evaluation was done as follows44.Time domain methodologic evaluation was done through SDNN, the standard deviation of the normal rate-to-rate intervals mainly reflecting parasympathetic status. Frequency domain methodologic evaluation included LF/HF ratio. LF reflects both parasympathetic and sympathetic function while HF reflects parasympathetic dysfunction using vagal nervous compartment. Therefore, the ratio of LF/HF primarily reflects the imbalance of autonomic nervous systemP < 0.05 was considered statistically significant.All statistical analyses were performed with SPSS version 19.0 . Student t tests and Chi-square tests were used to evaluate clinical characteristics between RNFL loss group and the group without showing RNFL loss. Comparison was also done dividing subjects into age-specific groups. Patients with RNFL loss were also grouped according to the location of RNFL defect (superior and inferior). Univariate and multivariate logistic regression analyses were performed to determine significant factors influencing diabetic RNFL defect. In all analysis,


Guidelines recommend tight systolic blood pressure (SBP) control for favorable outcomes of type B aortic dissection (BAD) but are still limited by the optimal cut-off value of SBP. The purpose of this study was to evaluate the optimal cut-off value of SBP in BAD patients after thoracic endovascular aortic repair (TEVAR).From January 2011 to April 2017, 269 consecutive patients with BAD after TEVAR were included in the study. All patients were followed up according to a strict follow-up protocol. Cox regression analysis was used to examine the association between SBP at discharge and 90-day aortic related adverse events (ARAE).p = 0.020). Hybrid operation  and insertion of ≥2 stents  were demonstrated to be independently associated with poor SBP control (SBP > 130 mmHg) using Logistic analysis.All 269 patients completed 90 days of follow-up, and the unadjusted ARAE-free rates at 90-day was 95.1 ± 1.3%. The cut-off value of SBP at discharge identified by receiver operator curve was 130 mmHg for 90-day ARAE. In multivariable models, binary SBP at discharge was significant associated with 90-day ARAE (HR 3.780; 95% CI 1.236–11.556; The optimal cut-off value of SBP at discharge was 130 mmHg which can be used to predict short-term ARAE. Blood pressure in patients with hybrid operation and ≥ 2 stents should be given more focus. Stanford type B aortic dissection (BAD) is a life-threatening disease with high in-hospital and long-term follow-up mortality , 2. Guidp = 0.0003) ). Sex, the classification of BMI, tobacco abuse, alcohol abuse, hypertension, DM, PAD, CVD, CAD, dyslipidemia, stage of BAD, operative procedure, number of stentand medications at discharge were categorical variables and they were shown as counts and percentages. Independent samples There were 292 consecutive BAD patients who were initially treated with TEVAR in Wuhan Asia Heart Hospital. Among them, 1 patients who presented with other aortic lesions besides BAD, 1 with medical history of aortic diseases, 1 with Marfan syndrome, 1 with syphilitic aortic disease, 3 with iatrogenic or traumatic dissection, 5 with cancer, 3 with renal insufficiency, 2 patients who had CVD within 30 days of study enrolment, 4 patients who underwent surgical procedures within 30 days of study enrolment and 2 patients without follow-up records were excluded. Finally, 269 patients were enrolled.All 269 patients completed 90 days of follow-up, and the unadjusted ARAE-free rates at 90-day was 95.1 ± 1.3%. The mean age of all patients was 55 ± 10 years, and 84.0% of the patients were males. Patient demographics, clinical characteristics, treatment, blood pressure and medications at discharge are outlined in Table We constructed ROC curves of the SBP for the diagnosis of 90-day follow-up ARAE to find the optimal cut-off value with the highest Youden index. The optimal cut-off value of SBP at discharge for 90-day ARAE was 131 ≈ 130 mmHg. Subsequently, all the patients were divided into SBP ≤ 130 mmHg group and SBP > 130 mmHg group when the 90-day outcomes were analysed.p = 0.012), as shown in Fig. p = 0.020) was the only significant predictor of 90-dayARAE.Cumulative ARAE-free rate in all patients was 95.1 ± 1.3% at 90-day follow-up. The probability of 90-day ARAE-free as categorized by SBP using Kaplan-Meier analysis showed significant differences among the two groups  and insertion of ≥2 stents  were demonstrated to be independently associated with poor SBP control (SBP > 130 mmHg) by Logistic analysis (Table All patients were divided into 2 groups according to the significant cut-off value of SBP at discharge: SBP ≤ 130 mmHg group and SBP > 130 mmHg group. Table In the present, we examined the optimal cut-off value of SBP at discharge and the risk factors for poor blood pressure control. The main findings showed that lowering SBP at discharge to a target goal of ≤130 mmHg, compared with> 130 mmHg, resulted in significantly lower rates of 90-day ARAE. Logistic analysis demonstrated that significant predictors of poor blood pressure include hybrid operations and insertion of ≥2 stents.The results presented herein are consistent with hemodynamic mechanismsin patients with BAD to stabilize the aortic wall and prevent ARAE . A much The blood pressure target for patients with type A aortic dissection and BAD should be different. Type A dissections have the worst prognosis with an overall in-hospital mortality of 30%, whereas BAD tends to have a better prognosis than type A dissections, having an overall in-hospital mortality rate of 13% . A recenIn general, different treatments, including medical, TEVAR and surgery, are suitable for BAD patients with different serious conditions. For BAD patients with different therapies, the standard of decrease of blood pressure possibly shall vary. Theoretically, the cut-off value of SBP is more likely to need a lower level in BAD patients treated with simple medical than that after TEVAR, as the aortas of the latter are protected by stents. After the specific treatment plan, the level of blood pressure control should be regulated for BAD patients treated with variable surgery. In brief, multi-center, large sample studies are needed to clarify these problems in the future.In this study, we recorded blood pressure at discharge instead of at follow-up. We consider that blood pressure at discharge is inconsistence with the one recorded at follow-up, indicating different implication. Blood pressure at follow-up indicates the management of blood pressure among a period of time after discharge, while the one at discharge demonstrates a better state of blood pressure in BAD patients after regular management by clinicians in inpatient department. Recent years, several studies have confirmed that SBP at discharge was a significant predictor for long-term outcomes , 23. EveCVD was a risk factor of ARAE in BAD patients after TEVAR in the present study. Based on previous studies, CVD patients were older, more often had hypertension and atherosclerosis, and presented more frequently with symptoms such as syncope, hypotension, shock and pulse deficit . These fHybrid operation and insertion of ≥2 stents were risk factors for poor blood pressure. Hybrid operations were performed in patients involving the distal aortic arch. BAD involving the distal aortic arch are characterized by a high risk of rapidly expanding false lumens which may result in increments of vascular resistance and then effect blood pressure management. Patients with ≥2 stents presented with a large range of dissection, which mainly involved renal arteries, as described by a previous study . A studyAntihypertensive medications play a main role in the management of BAD. Current practice in the treatment of chronic BAD is the use of beta-blockers as first-line therapy to reduce the force of left ventricular ejection, decrease aortic wall stress and improve survival . ESC 201There are several limitations to the present study. First, the monitor of ambulatory blood pressure and blood pressure variability providng insight into overall blood pressure control for outpatient during follow-up were not performed. Second, the present study is a single-center study and multi-center studies in type BAD are required in the future. Finally, the choice of antihypertensive medications was leftat the physician’s discretion and subject to potential selection bias.The optimal cut-off value of SBP at discharge was 130 mmHg which can be used to predict 90-day ARAE. It may be difficult to control SBP at discharge for patients with hybrid operation and ≥ 2 stents. Further studies on blood pressure might provide new preventive and therapeutic strategies for aortic dissection.


P = 0.006) and shorter time spent with hypoglycaemia . Conversely, no differences in body weight and blood pressure were observed between the groups. CGM in patients with type 2 diabetes mellitus could reduce HbA1c levels and time spent with hypoglycaemia. However, because few RCTs were included in this present study and heterogeneity was also noted, care should be taken when interpreting the results.In the present study, we aimed to investigate the effects of continuous glucose monitoring (CGM) on blood glucose levels, body weight, blood pressure, and hypoglycaemia in patients with type 2 diabetes mellitus using a meta-analysis of randomized controlled trials (RCTs). A literature search was performed using MEDLINE, Cochrane Controlled Trials Registry, and ClinicalTrials.gov. RCTs using CGM in patients with type 2 diabetes mellitus were then selected. Statistical analysis included calculation of the standardized mean difference (SMD) or risk ratio and 95% confidence intervals (CIs) using a random effects model. After literature search, seven RCTs (669 patients) satisfied the eligibility criteria established herein and were included into the meta-analysis. Compared with the self-monitoring blood glucose group, the CGM group exhibited significantly lower HbA1c levels (SMD, −0.35; 95% CI, −0.59–−0.10;  The number of patients suffering from type 2 diabetes mellitus is increasing worldwide, with estimates suggesting that approximately 300 million individuals could develop the disease by 2050 , 2. PrevSelf-monitoring blood glucose (SMBG) has been proven to be useful for long-term glycaemic control in patients with type 2 diabetes mellitus . HoweverContinuous glucose monitoring (CGM) allows for continuous measurement of interstitial glucose levels in subcutaneous tissues and evaluation of the detailed blood glucose profile of the patient. CGM includes retrospective CGM (r-CGM), which is used for retrospective examination of lifestyle problems and pharmacotherapy adjustment after understanding the blood glucose profile over several days, and real-time CGM (RT-CGM), which confirms the blood glucose profile in real-time. Studies have shown that utilization of such CGM approaches promotes favourable blood glucose control by changing patient behaviours or pharmacotherapy adjustment , 11.A 2013 meta-analysis that examined the influence of CGM on blood glucose levels in patients with type 2 diabetes mellitus indicated significant improvements in HbA1c levels . However∗ or T2DM or NIDDM or non-insulin dependent diabet∗) AND [continuous glucose and (monitor∗ or sensing or sensor∗)] or [continuous subcutaneous glucose and (monitor∗ or sensing or sensor∗)] or CGM or CGMS or real-time CGM or RT-CGM or flash glucose monitor∗ or FGM or sensor-augmented insulin pump or SAP AND .” The present study included RCTs that evaluated the effect of CGM on blood glucose levels, body weight, hypoglycaemic frequency, and other parameters in type 2 diabetes. Moreover, we included RCTs that compared CGM and SMBG regardless of diet/exercise therapy, oral hypoglycaemic agent use, and injectable formulation administration. The exclusion criteria were as follows: non-RCT studies, those involving animal experiments, those that targeted patients with gestational diabetes, those with insufficient data for analysis, and duplicate literature. Two authors (SI and RK) independently assessed whether each document satisfied the eligibility criteria established herein. In case of disagreements between interpretations by the two authors, a third reviewer (KM) was consulted.A literature search was performed on 1st February 2018 using MEDLINE (from 1960), Cochrane Controlled Trials Registry (from 1960), and ClinicalTrials.gov. The search strategy was “. Continuous variables were expressed as mean values, standard deviations, standard errors, or 95% confidence intervals (CIs), whereas binary variables were expressed as percentages (%). Studies comparing one SMBG group with two or more intervention groups were treated as two or more studies sharing an SMBG group. Two authors (SI and RK) independently evaluated the quality of research included in the present study. Accordingly, Cochrane's risk of bias tool was used for evaluating quality . Six domp values were described, standard deviation was calculated with reference to the method used by Altman and Bland .–24.18–24Among RCTs included herein, proportions of appropriate assessments for each domain were as follows: random sequence generation, 85.7% (6/7); allocation concealment, 85.7% (6/7); blinding of participants and personnel, 0% (0/7); blinding of outcome assessors, 14.2% (1/7); incomplete data, 71.4% (5/7); and selective reporting, 100% (7/7). The quality of the included RCTs varied considerably, with none of the included studies having a low risk of bias. Generally, the overall risk of bias was high, with most of the bias originating from blinding of participants, personnel, and outcome assessors. As there were <10 RCTs, a funnel plot was not created.I2 value of 64% (P = 0.01) confirmed the presence of heterogeneity. The CGM group had significantly lower HbA1c levels than the SMBG group , whereas the comparison between the r-CGM and SMBG groups resulted in an SMD of −0.43 . In addition, despite performing metaregression analysis because of heterogeneity, baseline HbA1c levels (P = 0.244) and age (P = 0.068) did not affect the impact of CGM on HbA1c.Seven trials regarding HbA1c were included in the meta-analysis –24, withI2 value of 47% (P = 0.13) suggested no heterogeneity. No difference in body weight change was noted between the CGM and SMBG groups , whereas the comparison between the r-CGM and SMBG groups resulted in an SMD of −0.33 .Four trials regarding body weight were included in the meta-analysis –20, 23, I2 value of 0% (P = 0.86) suggested no heterogeneity. The CGM group exhibited significantly shorter time spent with hypoglycaemia than the SMBG group  indicated no heterogeneity. No difference in time spent with hyperglycaemia was observed between the CGM and SMBG groups  confirmed heterogeneity. No difference in the systolic blood pressure was observed between the CGM and SMBG groups , whereas a comparison between the r-CGM and control or SMBG group resulted in an SMD of −0.63 . The same two trials were used for studying the diastolic blood pressure in the meta-analysis [P = 0.87; P = 0.96), whereas a comparison between the r-CGM and SMBG groups resulted in an SMD of −0.10 .Two trials regarding systolic blood pressure were included in the meta-analysis , 21, witDiabetes-specific scales used in the included trials were the Diabetes Treatment Satisfaction Questionnaire (DTSQ), Diabetes Quality of Life (DQoL), Diabetes Distress Scale (DDS), CGM Satisfaction Scale, etc. . AccordiIn this study, we examined the influence of CGM on blood glucose levels, weight, blood pressure, and frequency of hypoglycaemia in patients with type 2 diabetes mellitus using a meta-analysis of RCTs. Accordingly, our results revealed that HbA1c levels and time spent with hypoglycaemia were significantly lower in the CGM group than in the SMBG group. Conversely, no difference in body weight and blood pressure was observed between the CGM and SMBG groups.One 2013 meta-analysis involving four RCTs that collectively examined the effects of RT-CGM and r-CGM in patients with type 2 diabetes mellitus indicated that the CGM treatment group had significantly lower HbA1c levels than the SMBG group . SimilarWe showed no difference in body weight change between the CGM and SMBG groups. However, although the study by Beck et al.  showed tWith regard to influence on hypoglycaemia, we showed that the RT-CGM group spent less time with hypoglycaemia than the SMBG group. A previous study examining the utility of CGM for type 1 diabetes observed a shortening in the time spent with hypoglycaemia because of CGM intervention. In general, CGM intervention exhibits greater hypoglycaemic effect among patients with high hypoglycaemic frequency at baseline, such as those with type 1 diabetes . Among tOne study on the effect on blood pressure included herein showed that the CGM group had no reduction in systolic and diastolic blood pressure compared with the SMBG group. In another study included herein, Allen et al. found that the r-CGM group exhibited lower blood pressure during the collection period than the SMBG group. However, as indicated in a previous study , given tAlthough a meta-analysis regarding treatment satisfaction after CGM intervention had not been conducted, the present study included one trial , 24 thatLarge-scale clinical trials have shown that strict blood glucose management contributes to the reduction of the risk for vascular complications in patients with type 2 diabetes mellitus , 4. HoweThe present study had several limitations. First, given the few number of RCTs included, the present study might have had insufficient power to detect differences between groups. Second, although previous studies on RT-CGM interventions had indicated that the frequency of CGM sensor use influences its effects on HbA1c levels , this haThe present study examined the effects of CGM on blood glucose levels, body weight, blood pressure, and hypoglycaemia in patients with type 2 diabetes mellitus using a meta-analysis of RCTs. The results revealed that the CGM group had significantly lower HbA1c levels and shorter time spent with hypoglycaemia than the SMBG group. On the other hand, no difference in body weight and blood pressure had been observed between the CGM and SMBG groups. As previously mentioned, given the few RCTs included as well as the presence of heterogeneity, care may be needed when interpreting the results of the present study. Accordingly, further studies addressing the limitations presented herein may be necessary.