Frailty is common in chronic kidney disease (CKD) patients and becomes more prevalent as kidney disease progresses. This study aimed to investigate the prevalence of physical frailty and quantify the relationship between frailty and mortality risk in patients with CKD.PubMed, Web of Science, Embase, Cochrane Central Register of Controlled Trials, Clinicaltrial.gov, and major renal academic conferences were systematically searched, and additional references to relevant articles were manually searched. The prevalence of physical frailty and the risk of mortality based on random-effects models were assessed using percentages and hazard ratio (HR) with a 95% confidence interval (CI).A total of 139 articles, including 1,675,482 participants, met the eligibility criteria for the meta-analysis. The results showed that 34.5% (95% CI 31.0 to 38.1%) of CKD patients showed signs of frailty, and 39.4% (95% CI 35.4 to 43.5%) had prefrail symptoms. Compared to non-frail patients, the risk of mortality was increased by 94.1% (95% CI 1.586 to 2.375) in frail patients and 34.5% (95% CI 1.231 to 1.469) in prefrail patients.The high prevalence of frailty and prefrail in adults with CKD and resulting in premature death emphasize the importance of measuring frailty, which provides important prognostic information and may provide opportunities for interventions to improve the prognosis of patients with CKD.The online version contains supplementary material available at 10.1186/s12882-023-03303-1. Chronic kidney disease (CKD) is one of the leading causes of increased cardiovascular morbidity and mortality,  which isFrailty is a state of increased vulnerability to stressors due to decreased physiological reserves and thus leads to a poor health outcome,  and it iPhysical frailty is common in patients with CKD, , 8 whichBetween 2017 and 2021, seven meta-analyses assessing the prevalence of physical frailty in patients with CKD or the impact of frailty on survival were published. –17 HowevTherefore, we conducted an updated, more comprehensive systematic review and meta-analysis with a larger sample size, and fewer overlapping cohorts, and its impact on survival. The primary goal of this study is to estimate the risk of mortality in patients with CKD who were affected by physical frailty. Our secondary objective is to assess the prevalence of physical frailty in patients with CKD, and to perform a detailed subgroup analysis to determine the distribution of frailty and the association of age and body mass index (BMI) with the risk of frailty-related mortality.https://www.crd.york.ac.uk/PROSPERO/) with a few modifications  [20 [20]  and the ns Table .Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.https://www.theisn.org/), European Renal Association (https://www.era-online.org/en/), and American Society of Nephrology (https://www.asn-online.org/) for the past five years to look for other potential studies. Finally, we manually investigated a relevant reference of systematic reviews to search for additional potential studies. [We searched PubMed, Embase, Web of Science, and two clinical trial registries-ClinicalTrials.gov and Cochrane Central Register of Controlled Trials (CENTRAL), from inception to May 8, 2022. The databases were searched independently by two authors (FZ and WH). We adopt a comprehensive retrieval strategy that combines medical subject heading (MeSH) terms, title/abstract, and synonyms to retrieve eligible studies fully. The search strategies for databases are available in Table studies. –17 Any dThe inclusion criteria for studies were as follow: (1) adults (aged 18 years or older) confirmed CKD, including predialysis , peritoneal dialysis, hemodialysis, kidney transplant recipients; (2) reported prevalence of physical frailty according to a validated tool , or sufficient data to calculate it; (3) study reported data on physical frailty and mortality outcomes; (4) study design was limited to observational studies, including cohort study, cross-sectional study, case-control study, and longitudinal studies; (5) articles published in English.Studies were excluded if any of the following exclusion criteria were met: (1) letter/comment/editorial, conference abstracts, and case reports; (2) studies of self-reported CKD; (3) reported other subtypes of frailty, like cognitive, psychosocial, or nutritional frailty.  For studRisk of bias of included studies was assessed using the Newcastle-Ottawa Scale (NOS).  The scalTwo independent authors (FZ and HW) extracted the data using an agreed form. We collected the following information from the included studies: (1) first authors; (2) publication year; (3) geographical location and country; (4) total sample size; (5) mean age and body mass index (BMI); (6) CKD stage; (7) the number of patients with physical frailty ; (8) assessment tool used to define the presence of physical frailty; (9) the number of deaths; (10) follow-up time; 11) hazard ratio (HR) and 95% confidence interval (95% CI) of patients with frailty CKD corresponding to non-frail patients.Where more than one study reported data from the same sample and outcome, only one study was selected based on a larger sample size or better suitability of data. When a study reported multiple instruments to assess physical frailty, we used only the results evaluated by the most used scales for inclusion in the primary meta-analysis to avoid the problem of non-independent data. If a study reported the prevalence of physical frailty at different stages of CKD, it was treated as two records included in the meta-analysis separately.Where a study used hierarchical categorization, for example, mild, moderate, and severe frailty, for the primary analysis, we classified those in the moderate and severe category as frailty and mild as prefrail. If a study appeared potentially eligible but did not report the required data, we contacted the authors by email to obtain additional information and maximize existing studies’ availability. Studies were excluded when they did not report data available for extraction, and the authors could not be contacted. If a study reported longitudinal data on the prevalence of physical frailty in patients with CKD, only baseline data were extracted. Any disagreement about data extraction was resolved by consulting a third author (LYH).meta [metafor package [2 and I2 statistics, and I2 > 50% was defined as significant heterogeneity. [We performed a meta-analysis using meta  and the  package  in R sof package  Since st package  In addit package  Heterogegeneity. We performed pre-planned subgroup analyses according to the CKD stages, different assessment tools, geographical location , and study design. Possible publication bias was tested by examining the funnel plot and an Egger regression. , 32metafor package to assess the effect of the following moderator variables on the heterogeneity of the prevalence of physical frailty: mean age, the proportion of males (percentage), mean BMI, geographical location, CKD stage, and assessment tool. Moreover, using a bubble plot, we visualize the relationship between mean age, BMI, and prevalence of physical frailty and the association between frailty and mortality risk.To explain the significant heterogeneity observed, meta-regression analyses were conducted using the R We performed three sensitivity analyses: (1) to exclude studies with a sample size of fewer than 100 participants to verify the possibility that the results overestimated the severity of the problem due to the small sample size; (2) considering the recent debate on the meta-analysis of proportions, , 34 we uAfter removing duplicate articles from different databases, a total of 9,697 articles were included. These articles were first screened by title and abstract, and eventually, 369 articles and an additional seven articles were subjected to full-text review. A total of 187 articles were included after a rigorous screening process  with a total of 1,672,650 patients showed an overall prevalence of physical frailty in CKD patients of 34.5% (95% CI 31.0 to 38.1%), with significant heterogeneity between studies as expected Figure . The effAccording to the different scales for judging pre-frailty, 60 articles  reported data on prefrail in patients with CKD, with a combined prevalence of 39.4% (95% CI 35.3 to43.6%) and high heterogeneity between studies Figure . Leave-oFigure To explore potential heterogeneity sources in frailty prevalence, we performed univariate meta-regression analyses based on several study-level characteristics. The results identified disease stage and assessment tools as potential factors that could cause high heterogeneity Table . SpecifiFrom the 37 articles  that provided analyzable data, physical frailty was associated with increased mortality risk in patients with CKD. The pooled adjusted HR was 1.941 (95% CI 1.586 to 2.375), but heterogeneity was high Figure .Eleven articles  provided prefrail-related data. The pooled adjusted HR was 1.345 (95% CI 1.231 to 1.469), with moderate heterogeneity between studies Figure . In addiSensitivity analyses based on leave-one-out revealed no changes in the significance or direction of effects for these results Figure -S13. TheMeta-regression investigating potential sources of heterogeneity demonstrated that mean age, BMI, percentage of males, and CKD stage were not significantly associated with physical frailty and mortality risk, but geographical location explained between-study heterogeneity Table . FurtherFunnel plots for all meta-analysis outcomes are shown in Figure In this systematic review and meta-analysis of 1,672,650 CKD patients, approximately one-third (95% CI 31.0–38.1%) were physical frail, with a prediction interval pointing to a prevalence range of 3.2%–76.9%, which was a higher in older individuals and lower in those with higher BMI. Pre-frailty is defined as the transitional stage of transition from a normal clinical state to frailty. [On the other hand, with significant heterogeneity, the risk of mortality in patients with frailty CKD was nearly two times higher than in patients without frailty , and the results of subgroup analysis at different stages of CKD supported this association. Further analysis revealed a positive association between physical frailty and mortality risk in those with older age and higher BMI.In the past 20 years, frailty has been introduced in geriatrics as the aging population has rapidly expanded, highlighting the significant impact on patients and health services, clinical care, and chronic non-communicable diseases. , 6 StudiThe view in recent years has been that the assessment of frailty provides additional insight into the various phenomena that affect the physiologic status of patients with chronic diseases, including CKD. , 39 AlthAfter conducting a more comprehensive search and excluding overlapping populations, our current study provides a relatively reliable estimate of the prevalence of physical frailty in patients with CKD, documenting that approximately 30 of every 100 patients with CKD are frail and 39.4% are prefrail. This result suggests that up to 73.5% of CKD patients have some degree of physical frailty, compared to 63% in the general population.  It is imOn a national level, some countries reported sparse data, with India reporting a relatively higher incidence of frailty, as shown in Figure In the regression analysis, we observed an interesting phenomenon. The reality that the prevalence of physical frailty increases with age is unquestionable; after all, frailty is an age-related clinical condition.  However,The pooled adjusted HR associated with frailty for categorical and continuous indicators ranged from 1.291 to 1.941. In this case, the pooled adjusted HR was lower in kidney transplant recipients at 1.450 (95% CI 1.163 to 1.806) and higher in dialysis patients at 1.936 (95% CI 1.626 to 2.306). For dialysis patients, factors such as reduced physical activity and inadequate intake contribute to the high prevalence of frailty. , 54 In tIn patients with CKD, the “obesity paradox” has been reported, implying that higher BMI may be associated with better survival.  However,An unavoidable and challenging issue is the inclusion of studies using a variety of frailty assessment scales. Anderson et al. reported that the major frailty scales  were similar in assessing the prevalence of frailty in dialysis-dependent CKD patients.  However,The results of our study have important clinical and public health implications. From a clinical perspective, assessment of frailty and consequent individualized care can improve physical condition before dialysis and awaiting kidney transplantation by assigning intervention strategies appropriate to the individual. It has been argued that the degree of frailty in ESKD is one of the critical decision factors for receiving renal replacement therapy. , 63 NephThe developmental benefits of reversing frailty are not limited to the patient level but may also positively impact public health. Based on our findings on the positive correlation between the prevalence of physical frailty and age in CKD and the progression of frailty with declining renal function, early detection, and intervention in predialysis stages and the provision of timely, accessible, and adequate affordable support for CKD patients through effective referral mechanisms to prolong the functional decline trajectory of older patients as much as possible, which is the concept of “healthy aging” advocated by the World Health Organization. This is the largest meta-analysis to date focusing on studies of the prevalence of frailty in CKD patients and its impact on the mortality risk in this population. We acknowledge the following limitations. First, statistical heterogeneity between studies remained high even after subgroup analysis of disease stage, geographic location, study design, and assessment tools. This suggests differences in the demographic characteristics of the included study populations that were not explained in this study . It may have partially contributed to the differences in reported clinical outcomes between studies. Nonetheless, high heterogeneity is a common problem in epidemiological meta-analysis and has been gradually accepted.  Second, In conclusion, this systematic review and meta-analysis suggest that frailty affects approximately one-third of patients with CKD. The current study also showed that frailty was associated with increased mortality risk among patients at different stages of CKD. Considering this, (1) frailty should be an essential consideration in decision-making, prognosis, and advance care planning for patients with CKD; (2) all patients with CKD, regardless of their degree of renal dysfunction, should be regularly assessed for frailty status with a standardized tool; and (3) more studies are needed to incorporate frailty into the prognostic scores of patients with CKD.Below is the link to the electronic supplementary material.Supplementary Material 1


To investigate the association between non-alcoholic fatty liver disease (NAFLD) and liver enzymes with the incidence of microvascular complications  in a cohort of Iranian patients with type 2 diabetes.For a total population of 3123 patients with type 2 diabetes, a prospective study was designed for 1215 patients with NAFLD and 1908 gender and age-matched control patients without NAFLD. The two groups were followed for a median duration of 5 years for the incidence of microvascular complications. The association between having NAFLD, the level of liver enzymes, aspartate aminotransferase to platelet ratio index (APRI), Fibrosis-4 (FIB-4) value, and the incidence risk of diabetic retinopathy, neuropathy, and nephropathy were assessed through logistic regression analysis.NAFLD was found to be associated with incidence of diabetic neuropathy and nephropathy  and 1.333 (1.007-1.764), respectively). Alkaline-phosphatase enzyme was found to be associated with higher risks of diabetic neuropathy and nephropathy ((Risk estimate: 1.002 (95% CI: 1.001-1.003) and 1.002 (1.001-1.004), respectively)). Moreover, gamma-glutamyl transferase was associated with a higher risk of diabetic nephropathy (1.006 (1.002-1.009). Aspartate aminotransferase and alanine aminotransferase were inversely associated with the risk of diabetic retinopathy (0.989 (0.979-0.998) and 0.990 (0.983-0.996), respectively). Furthermore, ARPI_T (1), ARPI_T (2), and ARPI_T (3) were shown to be associated with NAFLD (1.440 (1.061-1.954), 1.589 (1.163-2.171), and 2.673 , respectively). However, FIB-4 score was not significantly associated with risk of microvascular complications.Despite the benign nature of NAFLD, patients with type 2 diabetes should be always assessed for NAFLD to ensure early diagnosis and entry into proper medical care. Regular screenings of microvascular complications of diabetes is also suggested for these patients. Non-alcoholic fatty liver disease (NAFLD) occurs commonly in patients with type 2 diabetes mellitus, with a prevalence of 55%–68%  due to tThere is now growing evidence that independent of other known risk factors and especially in patients with type 2 diabetes, NAFLD, could be associated with an increased risk of macrovascular complications. Several observational studies and some meta-analyses have documented that NAFLD, especially its advanced forms, is strongly associated with fatal and non-fatal cardiovascular events, as well as with specific cardiac complications, including sub-clinical myocardial alteration and dysfunction, heart valve diseases and cardiac arrhythmias. Importantly, across various studies, these associations remained significant after adjustment for established cardiovascular risk factors and other confounders –7.Furthermore, It has been shown that NAFLD increases the risks for the development of type 2 diabetes and/or its progression , 9. TherSeveral population-based studies have revealed different types of associations between the incidence of microvascular complications of type 2 diabetes and NAFLD. A report from India revealed increased prevalence of microvascular complications including nephropathy and neuropathy in patients with type 2 diabetes and fatty liver disease . HoweverSince results of the previous studies are controversial, once again the present study aimed to investigate the association of NAFLD, liver enzymes, and Fibrosis-4 (FIB-4) index  witIn this prospective cohort study, 3123 patients with a history of type 2 diabetes enrolled and were followed for median of 5 years. The participants had all previously attended the endocrinology clinic of Vali-Asr Hospital, a medical center affiliated with Tehran University of Medical Sciences. The study group was chosen based on comprehensive exclusion criteria which consisted of having a history of glaucoma, vitreous surgery, cataract on eye examination, kidney disease (Creatinine (Cr)> 2 mg/dl) or low estimated glomerular filtration rate (eGFR) <30 cc/min), hypothyroidism, familial hypercholesterolemia, liver dysfunction, epilepsy, and hemoglobinopathy. Women taking oral contraceptives or hormone replacement therapy and pregnant women were also excluded. Additionally, patients with type 1 diabetes, gestational diabetes, diabetes due to pancreatic cancer, pancreatitis and other metabolic conditions were excluded. Patients with a history of alcohol use, viral hepatitis, hepatotoxicity-inducing drugs usage, autoimmune hepatitis, and/or rapid weight loss were excluded from the study. Baseline biochemical tests of the patients such as cholesterol levels and other lipid and glycemic indices were measured Table 1.NAFLD was defined as the presence of definite hepatic steatosis on ultrasound scan in the absence of a secondary cause for hepatic steatosis. The participants were divided into two study groups based on the presence of NAFLD at the start of the study: 1215 patients with NAFLD and 1908 without NAFLD. The presence of NAFLD was diagnosed based on the observation of definite hepatic steatosis on abdominal ultrasound performed by an expert radiologist . Three hundred and fifty (350) patients who developed NAFLD over the duration of the study were excluded. During the study period, the status of possible chronic causes of non-NAFLD were constantly recorded. Patients with positive serology tests for hepatitis B, and C viruses surface antigens, and other causes of chronic liver diseases such as autoimmune hepatitis, hemochromatosis, Wilson’s disease, primary biliary cirrhosis, and sclerosing cholangitis were excluded from the current study, based on physical examinations and blood tests . After obtaining written informed consent from the participants, the incidence of microvascular complications was investigated in both groups. The study was reviewed and approved by the ethics committee of Tehran University of Medical Sciences.2). The subjects’ blood pressure was measured three times, after a ten-minute seated rest and within five-minute intervals. To measure blood pressure, a calibrated Omron M7 digital sphyg142 manometer  with appropriately sized cuffs which covered at least 80% of the subjects’ right arm was used. First reading was discarded due to possible imprecision and the second and third readings were averaged to calculate the mean value of systolic (SBP) and diastolic blood pressure (DBP). The participants were asked to stand still in a relaxed position, placing both feet together on a flat surface for waist circumference (WC) measurements; one layer of clothing was accepted. A non-stretchable measuring tape was used to measure WC as the smallest horizontal girth between the costal margins and the iliac crest at minimal respiration. During the interview process, demographic information, smoking habits, and medication usage status were obtained.For each participant, baseline demographic data such as weight, height, blood pressure, diabetes duration, the usage of anti-hypertensive and lipid lowering drugs were recorded by trained medical staff. Patients’ weight was measured using a portable digital scale with a precision of 0.1 kg, after they were asked to wear light clothing. An inflexible measurement tape with a precision of 0.1 cm was used to measure height with the subjects being asked to stand erect and remove their socks and shoes. Using the height and weight data, each individual’s body mass index (BMI) was then measured . The extracted serum was stored in the temperature of -70) . LaboratEmploying high-performance liquid chromatography , Glycated hemoglobin (HbA1c) was measured. Fasting plasma glucose (FPG) and two-hour postprandial (2HPP) glucose were measured using colorimetric methods by the glucose oxidase test. Serum lipid concentrations } ({age [years] × AST [U/L]/[platelet count (10/L)1/2]} To identify the microvascular complications associated with diabetes, the International Classification of Diseases, Tenth Revision (ICD-10) was used. Diabetic neuropathy was identified using specific codes E10.4, E11.4, E12.4, E13.4, and E14.4. Diabetes-related chronic microvascular complications were identified according to the International Classification of Diseases, Tenth Revision (ICD-10). The specific codes used were: E10.3, E11.3, E12.3, E13.3 and E14.3 for diabetic retinopathy; E10.2, E11.2, E12.2, E13.2 and E14.2 for diabetic nephropathy; E10.4, E11.4, E12.4, E13.4 and E14.4 for diabetic neuropathy , 25. BasTo statistically analyze the recorded data, version 25 of SPSS software was employed. Kolmogorov–Smirnov and Shapiro-Wilk normality tests, P-P plot, and histograms were used to test for the normality of the study population. The tested variables were discovered to be normal and the null hypothesis was rejected. Univariable analysis of potential categorical and continuous risk factor variables was performed using t-test and chi-square test, respectively. Mean ± standard deviation (SD) was used to report continuous, and proportions were used to report values for categorical variables. Logistic regression was conducted to ascertain the effects of NAFLD, liver enzymes and FIB-4 on microvascular complications and APRI on NAFLD. The results were adjusted for age, sex, and duration of diabetes, 2hpp, FBS, Cr, and BMI. Multifocal logistic regression and 4 models group of covariates used for evaluation of relationship between NAFLD and diabetic microvascular complications. A p-value < 0.05 was considered statistically significant.The level of ALKP, liver enzymes  as well as the presence of non-alcoholic fatty liver based on the ultrasound findings were assessed and statistically analyzed as possible predictors of microvascular complications. The baseline characteristics of the study population were summarized in Considering the importance of the role of gender in the occurrence of non-alcoholic fatty liver, statistical analysis was performed to investigate the role of gender in NAFLD determinants. In the group of fatty liver, females were older significantly , had lower SBP, DBP, drug duration, FBS, 2hpp, HbA1C, TG, Cr, uric acid, AST, ALT and higher Chol, HDL, LDL, BMI and ALKP, although there were no statistically significant in the prevalence of microvascular complications in fatty liver group based on gender Table 1.This prospective cohort study investigated the association of NAFLD and liver enzymes with the incidence of microvascular complications . After adjustment for confounding factors, NAFLD was a precipitating factor of nephropathy and neuropathy in patients with type 2 diabetes. On the contrary, NAFLD was not a risk factor of retinopathy in patients with type 2 diabetes after adjustment for confounding factors. Although it was found that alkaline-phosphatase increases the incidence risk of diabetic neuropathy and nephropathy and GGT is an increasing risk factor for the incidence risk of diabetic nephropathy. However, other liver enzymes as well as FIB-4 levels were not associated with microvascular complications.We observed that the incidence risk of diabetic neuropathy is significantly associated with NAFLD. In line with our study, a recent meta-analysis by Greco et al.  demonstrOur results showed that the incidence risk of diabetic nephropathy is significantly correlated with NAFLD. In line with our results Casoinic et al.  discoverIn contrast to our results, a cross-sectional study of the Korean population reported that the prevalence of nephropathy was lower in patients with type 2 diabetes and NAFLD . In addiIn contrast to our findings Lv et al. reported that NAFLD negatively correlated with the risks of nephropathy, retinopathy and neuropathy . MoreoveThese discrepancies in the findings of the studies might be attributed to differences in baseline characteristics of the participants. Furthermore, the ethnic differences for pathophysiological characteristics of patients with type 2 diabetes might also be responsible for the differences between our findings and those of the mentioned studies.Our result showed ALKP had a significant association with incidence of neuropathy and nephropathy. Also, GGT had a significant association with nephropathy. An inverse association between ALT and AST were also observed with incidence of diabetic retinopathy. Similarly, Afarideh et al. , establiDespite the existence of conflicting studies on the relationship between microvascular complications of diabetes and NAFLD, several systematic reviews, meta-analyses and umbrella reviews have been conducted to investigate this relationship. It is concluded that NAFLD is a multi-system disease that does not only affect the liver tissue, but it causes many important complications in several organs and increases the mortality of diabetic patients, which is one of the important reasons for the increase in the mortality of coronary artery disease and also diabetic nephropathy . DiabetiIn the present study, APRI had significant association with NAFLD. In line with our results, a recent systematic review reported that APRI risk stratify morbidity and mortality in patients with NAFLD . Also a To the best of our knowledge, this is the first prospective cohort study with a population-based sample in Middle East and North Africa (MENA) region to identify the association of NAFLD and liver enzymes with the incidence risk of microvascular complications  in patients with type 2 diabetes. Another strength of the current study is the sufficient sample size, exact ultrasound grading by single expert operator, as well as the exclusion of other causes of liver disease to assess the presence of NAFLD in patients with type 2 diabetes related microvascular complications.However, there were some limitations to our study. First, since the present study population was a cohort of patients cared for at a single center, caution should be taken when extrapolating the results to all patients with type 2 diabetes. It should be considered that the majority of the participants were typical patients with type 2 diabetes commonly encountered in outpatient clinics and the present study granted a high degree of consistency regarding, ultrasonographic findings, laboratory data, and the assessment of microvascular diabetic complications. Second, estimated GFR was used rather than a more precise measure of kidney function, e.g., iothalamate clearance. Third, due to the NAFLD definition in the present study based on definite signs of hepatic steatosis , our results may not apply to patients with earlier hepatic steatosis stages on ultrasound or those individuals with sonographically undetectable NAFLD. Fourth, in our database one of the ignored data was consumption of some oral anti-diabetic agents like pioglitazone, so in the next studies, researchers should consider this issue. Moreover, the lack of a liver biopsy which is the gold standard method for diagnosis of NAFLD as well as differentiating it from non-alcoholic stetohepatitis (NASH)  can be dThe present prospective cohort study found that NAFLD, as diagnosed by characteristic sonographic features, was associated with an increased incidence of diabetic nephropathy and neuropathy. Additionally, according to our data, ALKP, GGT, were associated with increased risks of microvascular complication of diabetes, while ALT and AST were shown to be inversely associated with the incidence of diabetic retinopathy. Future studies are required to assess possible mechanisms related to the underlying pathophysiological basis of these associations.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethics Committee of Tehran University of Medical Sciences. The patients/participants provided their written informed consent to participate in this study.ND, FD, and FM performed the data analysis; AE conceived the article; NY, AP, MD, and MP drafted the manuscript; SR and IK provided manuscript revisions; and MN clinically revised manuscript. All authors contributed to the article and approved the submitted version.


The burden of diabetes continues to increase in South Africa and a significant number of diabetes patients present at public primary healthcare facilities with uncontrolled glucose. We conducted a facility-based cross-sectional study to determine the diabetes self-management practices and associated factors among out-patients in Tshwane, South Africa. An adapted validated questionnaire was used to collect data on sociodemography, diabetes knowledge, and summaries of diabetes self-management activities measured in the previous seven days, and over the last eight weeks. Data were analysed using STATA 17. A final sample of 402 diabetes out-patients was obtained (mean age: 43 ± 12 years) and over half of them were living in poor households. The mean total diabetes self-management of score was 41.5 ± 8.2, with a range of 21 to 71. Almost two thirds of patients had average self-management of diabetes, and 55% had average diabetes knowledge. Twenty-two percent of patients had uncontrolled glucose, hypertension (24%) was the common comorbidity, and diabetic neuropathy (22%) was the most common complication. Sex , race , marital status , social support , body mass index , diabetes knowledge , and uncontrolled glucose  were factors independently predictive of diabetes self-management. This study emphasizes that the self-management of diabetes was mostly on average among patients and was associated with the aforementioned factors. Innovative approaches are perhaps needed to make diabetes education more effective. Face-to-face sessions delivered generally during clinic visits should be better tailored to the individual circumstances of diabetes patients. Considerations should be given to the options of leveraging information technology to ensure the continuity of diabetes education beyond clinic visits. Additional effort is also needed to meet the self-care needs of all patients. Type 2 diabetes (T2DM) is one of the major global issues currently affecting 415 million people, and is projected to rise to 642 million by 2040 ,4. The gTo date, South Africa has experienced alarming rates of T2DM, which have tripled from 4.5% in 2010 to 12.7% in 2019, and are currently estimated at 4.58 million people (aged 20 and 79 years) living with T2DM, of which 52.4% are undiagnosed . HoweverThe literature documents that self-management, including lifestyle changes among patients with T2DM, may be a more efficient treatment strategy for patients due to a strong correlation between T2DM and unhealthy lifestyle, and may also assist health care providers in their duties ,14,15. SIt is worth noting that the strategic plans and policies for long-term care and self-management in South Africa are predominated by the self-responsibility of chronic disease patients, and adequate support from primary health care teams to teach and empower patients for appropriate disease self-management . HoweverNonetheless, poor self-management of diabetes continues to be a major public health concern in LMICs, SSA, and South Africa, implicating different contexts and factors ,40,41,42Additionally, emphasis has been placed on the qualitative aspects of diabetes self-management, instead of offering quantitative data. Lastly, this study investigated the self-management of diabetes at public PHC facilities; the first line of treatment for many South Africans, and not in the tertiary hospitals that have been well-researched in the past. According to the South African Statista Research Department , as of 2A cross-sectional study was conducted among diabetes out-patients seeking chronic care at Tshwane public PHC facilities in South Africa. The study was conducted between September 2021 and March 2022. The study was anchored on the conceptual frameworks of both Brown et al.  and SousThis study was conducted at the City of Tshwane (CoT) in the northern Gauteng Province, South Africa . CoT is Anecdotal information from the respective facilities estimates diabetes patients at 269,700 patients. The population seeking health care at these facilities is often of a lower to middle socioeconomic class and many present with poor to moderate literacy levels. Considering a confidence level of 95%, Cochran’s formula determined a minimum sample of 384 participants. A final sample size of 402 patients was eventually obtained after excluding eight questionnaires with more than 10% missing data. Cluster sampling was used to select PHC facilities in CoT and this allowed for widespread representative inclusion of out-patients to represent different areas. Ultimately, four public PHC facilities were used in this study . PHC facilities offer first line treatment for patients suffering from chronic diseases diagnosed by medical doctors and nursing staff , nonetheWhile sampling out-patients waiting in queues for services in the facilities, the difficulty of obtaining a random sample became evident. This led us to using convenience sampling to select patients who met the inclusion criteria. Although convenience sampling is a non-probability sampling method, it is the most applicable and widely used method in clinical research . After oA self-administered questionnaire see  was distA pilot study  was condA questionnaire was adapted from the revised brief Diabetes Knowledge Test (DKT2), summary of Diabetes Self-Management Activities Measure (SDSCA) , and Dia2). Underweight was BMI below 18.9 kg/m2, normal weight was BMI of 19–24.9 kg/m2, overweight was BMI of 25–29.9 kg/m2, and obesity was BMI of more than or equal to 30 kg/m2 , and adjusted odds ratio .Data were analysed using STATA version 17 . Missing data were identified through complete case analysis. Descriptive statistics was performed to generate the frequencies  out-patients diagnosed with diabetes; 210 (52%) females and 192 (48%) males participated in the study. The mean age of the patients was 43 ± 12 years, and 252 (63%) of them were aged 45 years and below, while 147 (37%) were above 45 years. Most patients were living in urban (72%) compared to peri-urban areas (28%). Most patients were black Africans (45%), followed by Coloureds (40%), and thirty-five percent (35%) of the patients were single, and 44% were married. Secondary school level (34%) and grade 12 level (48%) were the most frequently attained education levels. Most patients were living in households with monthly income between 83.11–276.85 $ (53%), while 70% reported good social support from family and friends. Forty nine percent (49%) of the patients indicated that they were diagnosed with diabetes with the past five years, whilst 51% were diagnosed for more than five years. About 8% of the patients had comorbid conditions, and hypertension and cholesterol were the most common coexisting conditions with diabetes. Common comorbidities among the patients were hypertension (24%) and high cholesterol (21%). The most prevalent complications were neuropathy (22%) and loss of eyesight (16%), while 23% of the patients reported to have been hospitalised at some point in time. The most common medication was oral hypoglycaemic tablets (49%), followed by insulin (28%), and combined oral hypoglycaemic tablets and insulin (21%). Half of the patients had access to a blood glucose machine to self-monitor at home. Over half of the patients [n = 222 (55%)] had an average diabetes knowledge. Significant differences of patients’ characteristics by sex were observed for marital status (p = 0.005), neuropathy complication (p = 0.029), ever hospitalised (p = 0.043), use oral hypoglycaemics tablets (p ≤ 0.0001), and insulin (p ≤ 0.0001) medication (Four hundred and two (dication .p≤0.001 (results not shown in table). Twenty-two percent of the patients (22%) had uncontrolled glucose levels, and females (27%) were significantly affected compared to males (17%), p = 0.012. The prevalence of hypertension was 29%, while overweight (30%) and obesity (63%) were high among the patients, with females (70%) being significantly obese versus males (55%), p = 0.007, and no one was under weight.n (%)], and categorised as poor (0–3 scores), fair (4–5 scores), and good (6–7 scores), and exercise on five or more days was categorized as good. Women who drink >1 drink/day were regarded as heavy drinkers, and those who drink <1 drink/day was regarded as light drinkers. Men who drink >2 drinks/day were categorized as heavy drinkers, and men who drink <2 drinks/day were light drinkers. Forty-seven percent of the patients had poor consumption of fruit and vegetables in the past seven days, while 49% consumed high fat foods, and 70% did not exercise. Furthermore, blood glucose self-testing (93%), foot care (60%), and shoe checks (70%) among the patients were poor in the past seven days. At least 67% of the patients adhered to medication in the seven days, although 33% of the patients reported heavy drinking, while 25% reported heavy smoking.As displayed in In p ≤ 0.20). After controlling for potential confounders , the final hierarchical logistic regression showed significant associations of self-management of diabetes with sex , race , marital status , social support  and good: AOR = 4.49, 95% CI: 1.61–7.57], BMI , diabetes knowledge , and uncontrolled glucose [AOR = 2.97, 95% CI: 1.47–5.98).Self-management among diabetic patients to achieve glycaemic control is one of the South African goals on Diabetes Implementation Strategy at the PHC level, developed in response to the African Diabetes Declaration and Strategy, yet the country still has the highest incidence of diabetes in the African continent ,64. We cDespite diabetes being a major public health concern, patients’ knowledge of various components of diabetes care, such as dietary practices, glucose testing, exercise, insulin use, complications identification, and screening, has been reported to be low in South Africa  and in cMost of the patients in this study were married and had attained secondary school education, but were from poor households with a monthly income between 83.11– 276.85 $. Socioeconomic inequalities are known to influence the prevalence of diabetes . In highThen again, the importance of self-monitoring of blood glucose as an essential component of diabetes self-care and prevention of hypoglycaemia  can neveComplications arising from diabetes are detrimental to the wellbeing of the affected individuals including medical and rehabilitative costs that come with hospitalisation, and financially demanding on the health system ,35,36,87In this study, the self-management of diabetes was significantly associated with sex, race, marital status, social support, BMI, diabetes knowledge, and uncontrolled glucose. Differences in diabetes-related factors may be due to variations in the study designs and the characteristics of the study populations . For insRegarding other factors such as BMI, social support, diabetes knowledge, and uncontrolled glucose, the results of this study indicate that patients who are obese are less likely to participate in diabetic self-management practices. Obesity poses a significant risk for the development of insulin resistance, diabetes, and its subsequent complications . Thus, dIn summary, our study reported more on the sociodemographic context, considering the person, place, and social risk factors implicated as obvious determinants of health ,118. ThiFirst, the use of a cross sectional study design gives only inferences and limits any casual interpretations. This is coupled with the fact that this study was conducted within a short period of time (six months), although all the diabetes patients who came to the facilities at the time of data collection satisfied the inclusion criteria. Therefore, prospective cohorts are necessary to follow a larger number of patients with time and investigate causality. Second, although the facilities were randomly selected, they were not treated as a unit of analysis. The use of convenience sampling to select patients might have introduced bias, which we mitigated by obtaining a larger sample size. Third, we acknowledge a limitation regarding the classification of the duration of treatment into two groups, which does not account for the variability within each group. The duration of treatment was supposed to be collected as a value for proper classification and for the consideration of different experiences and outcomes. Fourth, the findings from this study are based on data collected from the four PHC facilities in Tshwane, and thus, may not be applicable to the whole of South Africa. In addition, the study was conducted among out-patients who had sought care in these facilities, and it might not be representative of the general population of diabetes patients. Fifth, data on diabetes knowledge were self-reported, which might have the disadvantages of recall and social desirability biases, leading to over or under estimation of some of the results. Furthermore, we did not establish whether the patients in the study had received health education on diabetes, which might have impacted their level of diabetes knowledge. Social desirability might also have been the case when obtaining information on self-management activities and practices. Sixth, considering that we did not measure diabetic control using glycated haemoglobin, all of the information that we received was self-reported by the patients. Future studies should assess glycated proteins in detail, primarily haemoglobin and serum proteins tests, which can quantify average glycaemia over weeks and months, thereby complementing day-to-day testing. Finally, future research, in particular, qualitative studies, or mixed method research, are necessary to respectively explore or understand the in-depth factors influencing diabetes self-care, considering facilitators and barriers within the context of diabetes patients. Nonetheless, our study provides insight into the self-management of diabetes among patients seeking chronic care in the selected PHC facilities in Tshwane, South Africa.Diabetes knowledge among patients was average amidst prevalent uncontrolled glucose, obesity, hypertension, and high cholesterol comorbidities, as well as amidst neuropathy, eyesight problems, and amputation complications. A high proportion of diabetes patients achieved average self-management when diet, exercise, blood sugar self-testing, medication, foot care, smoking, and alcohol consumption were jointly evaluated. Factors associated with self-management were sex, race, marital status, BMI, social support, diabetes knowledge, and uncontrolled glucose. This calls for a better understanding of the contextual determinants to facilitate the development of culturally appropriate interventions to modify beliefs and support self-management in this population. Innovative approaches are perhaps needed to make diabetes education more effective. Face-to-face sessions delivered generally during clinic visits should be better tailored to the individual circumstances of people living with diabetes. Considerations should be given to the options of leveraging information technology to ensure the continuity of diabetes education beyond clinic visits. Additional effort is also needed to meet the self-care needs of all people living with diabetes.


Post-stroke depression (PSD) is a common complication of stroke that can damage patients’ brains. More and more studies have been conducted on PSD in recent years, but the exact mechanism is still not understood. Currently, animal models provide an alternative approach to better understand the pathophysiology of PSD and may also pave the way for the discovery of new treatments for depression. This study investigated the therapeutic effect and mechanism of aloe-emodin (AE) on PSD rats. Previous studies have shown that AE positively affects PSD in rats by improving depression, increasing their activities and curiosities, enhancing the number of neurons, and ameliorating damage to brain tissue. Meanwhile, AE could up-regulate the expression of brain-derived neurotrophic factor (BDNF) and neurotrophic 3 (NTF3), but it could also down-regulate the expression of aquaporins , glial fibrillary acidic protein (GFAP), and transient receptor potential vanilloid 4 (TRPV4), which is helpful in maintaining homeostasis and alleviating encephaledema. AE may be a prospective solution in the future for the treatment of PSD patients. Post-stroke depression (PSD), which is a psychological disorder, usually happens to paralytic patients, which is one of the main reasons why patients ,2 sufferIn brain tissue, brain-derived neurotrophic factor (BDNF) and neurotrophic 3 (NTF3) bind with their respective receptors , tyrosinAstrocytes are the most abundant cells in the central nervous system (CNS)  and playAloe-emodin  is a naturally occurring anthraquinone derived from aloe or rhubarb . It has p < 0.01), while the sham and other administration groups show a downward trend. On day 21 of administration, the neurofunctional scores in the sham, positive-drug, and aloe-emodin groups are significantly lower than those in the model group (* p < 0.05), (** p < 0.01).Neurological function and behavioral scores were used to monitor the depressive status of the rats. Neurofunctional score (NDS) can directly reflect the recovery of neural function in MCAO rats: the lower the score, the better the recovery of a rat. As shown in p < 0.05), while the sham and other administration groups show an increasing trend. On day 21 of administration, the rats’ preference for sucrose in the sham group, the positive-drug group, and the aloe-emodin group increases compared to the model group (* p < 0.05).The sucrose preference test (SPT) can assess an animal’s hedonic capacity by measuring the amount of sucrose solution consumed. The more sugar water a rat takes, the better it recovers. As shown in p < 0.05).Forced swimming tests (FST) measure the sensitivity of animals to negative emotions under the threat of drowning. The more negative emotions a rat has, the longer it stays still while swimming. As shown in p < 0.05), (** p < 0.01).Movement reduction in the open field test  reflects reduced activity and curiosity, which are common symptoms of depression. As shown in The above results may indicate that AE could achieve the same effect as positive drugs that promote nerve function reparation, improving the activity and curiosity of rats, reducing their sensitivity to negative emotions, and relieving their symptoms of depression after cerebral ischemia.p < 0.01).Cerebral water content was used to evaluate the severity of brain edema in the rats after having a stroke. As shown in p < 0.01).TTC staining can detect the area of cerebral infarction in rats, as shown in H&E staining was used to observe the structural damage of the ischemic penumbra in the brain tissue after cerebral ischemia. p < 0.01) (* p < 0.05), intact structure (black arrow), and smaller cell gaps (yellow arrow). Therefore, the neuronal apoptosis in the PSD rats is reduced, and the neuronal function damage is alleviated.Cerebral ischemia-reperfusion injury can lead to neuronal apoptosis in a pathological environment, thereby exacerbating PSD. Nissl staining can be used to observe the number of Nissl bodies and the number of neurons in the ischemic penumbra. As shown in p < 0.01) (*** p < 0.001) (* p < 0.05). Moreover, the effect of AE is similar to that of the positive drug. Compared to the model group, although the expression of AQP11 in the brain tissue of the rats in each drug group is slightly decreased, it is not statistically significant. All of these indicate that AE can reduce the expression of aquaporins  in PSD rats’ brain tissue and alleviate the damage status of depressed rats after cerebral ischemia.ELISA was used to detect the expression of aquaporins  in the PSD rats’ brain tissue. As shown in p < 0.01) (* p < 0.05).For rat brain tissue sections, immunohistochemical staining was performed using AQP3, AQP4, and AQP5 antibodies. By using positive staining grayscale analysis, the area ratio of positive reaction of the brown-stained part in the ischemic penumbra was analyzed. As shown in p < 0.01) (* p < 0.05). However, the positive reactions of GFAP and TRPV4 decrease (** p < 0.01) (* p < 0.05).The brain tissue slices of the rats were subjected to immunohistochemical staining using BDNF, NTF3, GFAP, and TRPV4 antibodies. The positive staining grayscale was analyzed to compare the area ratio of positive reaction of the brown-stained part in the ischemic penumbra. As shown in p < 0.05), and the effect is similar to that of the sham group. However, the regulation of AQP5 in each treatment group is not statistically different.Western blot (WB) can be used to detect protein expression in the brain tissue of rats with PSD. As shown in p < 0.05). Meanwhile, the protein expressions of GFAP and TRPV4 in the brain tissue of the rats in each treatment group significantly decrease (* p < 0.05).As shown in PSD may have a detrimental effect on the recovery of stroke patients and form a vicious cycle, reducing patients’ cognitive function and autonomy, and even increasing the risk of suicide . CurrentPrevious study suggests that AE can protect the brain from damage and exert antioxidant and anti-neuroinflammatory effects by activating the PI3K/AKT/mTOR and NF-κB pathways . HoweverTherefore, this study investigated the therapeutic effect of AE on PSD rats by regulating both mood disorders and reducing brain damage. The results showed that AE improved the neurological function and depressive symptoms of PSD rats and produced neuroprotective effects, providing new insights into the relationship between stroke and PSD.It has been reported that neurotrophic factors are closely related to the condition and prognosis of PSD. BDNF is a type of neurotrophic factor that is involved in the survival and plasticity of neurons. BDNF and NTF3 are widely distributed in the central nervous system and are crucial for the growth and differentiation of the nervous system . BDNF an2+ channel, which can act as an osmotic sensor to respond to cell reactions in the brain and regulate changes in osmotic pressure in the brain [2+ enters cells through these TRPV4 channels, increasing the cell’s osmotic pressure and causing water to enter the cell through the water channel protein, ultimately leading to cell swelling and Ca2+ overload [2+ triggers the massive release of Glu at the synaptic terminals, and the release rate is much higher than the uptake rate, leading to the accumulation of extracellular Glu [After cerebral ischemia occurs, astrocytes undergo changes, such as cell body enlargement, cell swelling, increased protrusions, and proliferation , and thehe brain ,50. Whenoverload . The lar2+ influx into cells, lowers the Glu level in brain tissue, inhibits the expression of aquaporins, reduces water entry into astrocytes after cerebral ischemia, improves cell swelling, and treats cerebral ischemic edema. We hope that the dual therapeutic effects of AE on PSD can provide a new pharmacological basis for its clinical application in PSD patients.In summary, As shown in Fifty male SD rats of SPF grade were used in the experiment, with a weight of (260 ± 10) g, and the animal license number was SCXK (Chuan) 2020–2030, as provided by Chengdu Dashuo Biotechnology Co., Ltd. . The animals were housed at Southwest Jiaotong University at a temperature of 24–26°C, a relative humidity of 40–60%, and a 12 h light/dark cycle, with free access to food and water. The animals were acclimated for one week prior to the experiment. All operations in this experiment complied with the requirements of the Southwest Jiaotong University Experimental Animal Ethics Committee, with approval number SWJTU-2020-0824-05.The reagents used in the experiment were aloe-emodin , fluoxetine hydrochloride , SDS-PAGE gel preparation kit , PVDF membrane , Allergic ECL Chemiluminescence substrate , Beta Actin-Ab , goat anti-rabbit secondary antibody -HRP , GAPDH antibodies , AQP3 antibodies , AQP4 antibodies , AQP5 antibodies , BDNF antibodies .Male SD rats weighing between 280–300 g were selected for the study. The MCAO model was constructed using the suture method . After aAt 7 days after the MCAO modeling, CUMS was administered for 21 days : the ratAs shown in Neurological function damage was evaluated using the Zea-Longa 5-point scale . NeurobeOn the first day, two bottles of 1% sucrose solution were given to each cage of rats. On the second day, food and water were withheld. On the third day, one bottle of regular water and one bottle of 1% sucrose solution were given to each cage of rats. The positions of the two water bottles were exchanged every hour, and the consumption of each bottle was recorded after 3 h. The experimental data were collected on the first, seventh, fourteenth, and twenty-first day after the PSD modeling .SucroseThe rats were placed in a 70 cm × 70 cm cardboard box in a dark environment. The box was divided into 25 areas using a marker pen, and the number of areas crossed and the number of times the rats stood up were recorded for 1 h. The experimental data were collected on the first, seventh, fourteenth, and twenty-first day after the PSD modeling .The rats were placed in a bucket with a diameter of 50 cm and a water depth of 25 cm. After a 1 min adaptation period in the water, the immobility time of the rats was recorded for the following 6 min. The experimental data were collected on the twenty-first day after the PSD modeling .The brain tissue was collected and frozen at −20 ℃, and then cut into 5 slices. After staining with a TTC solution in the dark, the tissue was fixed with 4% paraformaldehyde. The red area represents the normal brain tissue, and the white area represents the area of cerebral infarction.The fresh brain tissue of the rats was washed, wiped clean, and weighed (wet weight), and then the brain tissue was dried in an oven at 37 ℃ to a constant weight and weighed again (dry weight).The rat brain was fixed, dehydrated, cleaned with xylene, embedded in paraffin, and sliced. Hematoxylin and eosin (H&E) staining was performed, followed by 1% hydrochloric acid differentiation, ammonia water bluing, eosin counterstaining, water washing, gradient dehydration, drying, and slide sealing. The samples were then observed under a microscope.Similar to The rats’ brain tissue was paraffin-sectioned, dewaxed, antigen-retrieved, and incubated at room temperature. The tissue sections were then incubated overnight with antibodies against AQP3, AQP4, AQP5, BDNF, GFAP, TRPV4, and NTF3. After incubation with secondary antibodies, DAB staining was performed, followed by counterstaining with hematoxylin, dehydration, transparency, and slide sealing.The brain tissue was taken and homogenized. The expression levels of AQP3, AQP4, AQP5, and AQP11 were determined by following the instructions of an ELISA kit.The brain tissue was homogenized in a protein lysis buffer and centrifuged; the protein was then extracted and its concentration was determined. Electrophoresis was performed by transferring the samples to a membrane, blocking with skim milk for 1 h, then adding antibodies against AQP3, AQP4, AQP5, BDNF, GFAP, TRPV4, and NTF3, and finally incubating overnight at 4 ℃. After incubation with the corresponding antibodies at room temperature, the signal intensity of the bands was measured using chemiluminescence, and the grayscale values were analyzed using ImageJ software.p < 0.05, p < 0.01, and p < 0.001 were considered statistically significant. The GraphPad Prism 8.0.1 software was used for statistical analysis. The data were expressed as AE can significantly improve behavioral function, reduce depression levels, improve brain tissue damage and lesions, increase the number of brain tissue neurons, decrease the contents of AQP3, AQP4, AQP5, GFAP, and TRPV4 in the brain and brain tissue, and increase the protein expressions of BDNF and NTF3 in PSD rats. AE may have a significant therapeutic effect on PSD rats.


One month after applying anti-adhesive materials, postoperative intrauterine adhesions were evaluated using second-look hysteroscopy; the incidence rate of postoperative intrauterine adhesions examined through second-look hysteroscopy showed no significant differences between the groups. There were no statistical differences between the frequency and mean scores of the type and intensity of adhesions in both groups. Finally, no significant differences in adverse events, serious adverse events, adverse device effects, and serious adverse device effects were noted between the two groups; type 1 collagen gel can be effectively and safely used in intrauterine surgery to minimize postoperative adhesions, thereby eventually decreasing the prevalence of infertility, secondary amenorrhea, and recurrent pregnancy loss in reproductive women.We evaluated the clinical outcomes of using type 1 collagen gel after therapeutic resectoscopy; overall, 150 women aged > 20 who planned to undergo therapeutic resectoscopy were enrolled. The patients were randomly assigned to either of the anti-adhesive treatment groups: the type 1 collagen gel (Collabarrier Adhesion is the tendency of different cellular surfaces to cling to one another after various insults or physiological changes, such as surgery, inflammation, injury, or infection. Among these causes, surgical wounds seem to be the most concerning cause of adhesion . During As postoperative adhesions induce various complications, several trials have been conducted to minimize these adhesions through minimal tissue manipulation during surgery. The development of surgical techniques has decreased the occurrence of postoperative adhesion by minimizing trauma, exposure to foreign materials, and dryness of tissues. However, there are fundamental limitations to preventing postoperative adhesion using surgical methods. This has prompted the development of other methods, including using anti-inflammatory agents, preventing fibroblast formation by activating tissue plasminogen activators, and using physical barriers . Anti-adCommercially, there are several types of anti-adhesion barriers, each with specific strengths and weaknesses. Anti-adhesion barriers formulated as solutions or gels are easy to apply and have high viscosities. However, they slide down due to gravity, and present difficulty in determining functionality as a barrier . On the ® with type 1 collagen , a hydrophilic, biocompatible, and biodegradable material in the form of a gel, was created. Type I collagen is an extracellular matrix protein which is found in tissues such as skin, tendon, bone, and blood vessels [To compensate for these drawbacks, the Collabarrier vessels . Type I  vessels . They haThe primary objective was to compare the incidence rate of postoperative intrauterine adhesions with type 1 collagen gel to that of control anti-adhesives. This was based on the hypothesis that type 1 collagen gels are not inferior compared to other anti-adhesives. The secondary objective was to further compare the type and intensity of the postoperative intrauterine adhesions between the two groups to affirm the efficacy of type 1 collagen gel. Finally, as the safety assessment was also an important objective, we examined any adverse events that may occur concerning the procedure or the materials.The study was assigned the clinical trial registration number Korea Clinical Trial Registry 0002946 (or KCTR0002946). The Clinical Research Information Service approved it on 22 June 2018.Between November 2017 and February 2020, 213 patients were consecutively screened, of whom 48 patients were excluded because 27 were screened before the government’s approval and 21 patients declined to participate. A total of 165 patients were randomly assigned to two groups. Some 7 and 8 patients were lost to follow-up in the study and control groups, respectively. Therefore, 150 patients were included in the analysis . WrittenThe inclusion criteria included females older than 20 years old, suspected of having gynecological issues, who planned to undergo therapeutic resectoscopy, and who provided informed consent. The gynecological issues to be treated included submucosal myoma, endometrial polyps, uterine septa, endometrial hyperplasia, intrauterine adhesion, and abnormal uterine bleeding. Patients who planned to insert a hormone-secreting intrauterine device and had been treated with an agonist for gonadotropin-releasing hormone within 3 months of the study were excluded, as were those who required postoperative hormonal therapy.®, Dalim Center Co., Ltd.)  or the HA and CMC gel group . An individual randomly assigned patients to the two treatment protocols with a 1:1 ratio. Random allocations were made based on the “PROC-PLAN” command in SAS, version 9.4 , using the permuted block randomization method to prevent selection bias. The demographic parameters that were recorded included age, body mass index (BMI), body temperature, blood pressure, pulse rate, physical examination, pregnancy test, and laboratory examination, including red blood cell count, white blood cell count, segment neutrophil count, lymphocyte count, monocyte count, eosinophil count, basophil count, platelet count; hemoglobin, hematocrit, glucose, blood urea nitrogen, creatinine, total protein, albumin, total bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase (γ-GT), total cholesterol, sodium, potassium, chloride, and calcium levels; prothrombin and activated partial thromboplastin times; and urine analysis. Personal medical, smoking, and alcohol histories were also recorded.When a patient was screened and deemed suitable for the study, they were assigned to a treatment group after randomization. During the study, 150 women were randomized to one of two groups: the type 1 collagen gel group  as the distension medium, under anesthesia. Intrauterine cavities were inspected with hysteroscopy by surgeons, and surgeries were performed according to their decision. After resectoscopy, the antiadhesive materials were randomly allocated, and they were inserted using a thin, long, patent catheter into upper one third area of the uterine cavity.One-week post-surgery, the patients were followed up to evaluate any adverse events due to the surgery. Adverse events (AEs) were defined as any unfavorable and unintended signs, symptoms, or diseases that were temporally associated with product use but did not necessarily have a causal relationship with the product. On the other hand, adverse device effects (ADEs) were defined as any serious adverse effects on health or safety or any life-threatening problem or death caused by or associated with the product. After applying the anti-adhesive materials, a second-look hysteroscopy was performed 4 weeks after the primary surgery to evaluate postoperative intrauterine adhesion. The intrauterine cavity was photographed during the second-look hysteroscopy. In addition, the presence and severity of intrauterine adhesions were assessed by an independent assessor.The types of adhesion were scored based on the Classification of Intrauterine Adhesions as follows: No adhesion , Filmy , Filmy and Dense , Dense .An independent assessor evaluated the severity and scores of the intrauterine adhesions from the cavity pictures of the second-look hysteroscopy after the information for each patient was blinded. Adhesion was diagnosed when the score was ≥1. The incidence rate of intrauterine adhesion was calculated as the ratio of patients with postoperative intrauterine adhesion to the total number of enrolled patients.The mean scores of the intrauterine adhesion severities and the mean adhesion extent in the uterine cavity from the second-look hysteroscopy were assessed by one independent assessor. The extent of cavity involvement was scored based on the Classification of Intrauterine Adhesions as follows: 0 intensity , less than 1/3 intensity , between 1/3 and 2/3 intensity , greater than 2/3 intensity .t-test or Wilcoxon rank sum test was used for continuous variables’ baseline characteristics. In contrast, the chi-square or Fisher’s exact test was used for categorical variables. To calculate the percentages of intrauterine adhesions after 4 weeks of resectoscopy, we presented the percentages of cases with postoperative intrauterine adhesions according to each group. Moreover, sub-groups were made according to the presence of intrauterine adhesions for further analysis, and statistical significance within each group was tested using the Cochran–Mantel–Haenszel test or Fisher’s exact test. One independent assessor evaluated the types and extent of postoperative intrauterine adhesions 4 weeks after the intrauterine surgery. The number of patients, mean values, standard deviations, median values, and minimum and maximum values were shown as descriptive statistics. Statistical significance between the groups was tested using an independent two-sample t-test or Wilcoxon rank sum test. Statistical analysis was performed using SPSS Statistics for Windows, version 22.0 . Statistical significance was set at a p-value of < 0.05.An independent two-sample ®). Women with adhesion scores >1 point were included when calculating the rate of intrauterine adhesion. Based on the results inferred by the independent assessor, the postoperative intrauterine adhesion incidence rates were 18.67% (14/75) and 13.33% (10/75) in the study and control groups, respectively  had preoperative intrauterine adhesions, whereas 16.67% (12/72) only developed the adhesions postoperatively. In the control group, postoperative intrauterine adhesions were seen in 0.00% (0/4) of patients preoperatively, and these developed only post-surgery in 14.08% (10/71) of patients. Therefore, the subgroup analysis based on the preoperative presence of intrauterine adhesion did not show any statistical significance . There wWe evaluated the secondary objective by comparing the type of adhesion formed in the uterine cavity a month after the intrauterine surgery. The results of the analysis of the postoperative intrauterine adhesions performed by an independent assessor were classified as scored in the methods. No adhesions were seen in 81.33% (61/75) of patients in the study group versus 86.67% (65/75) of patients in the control group. Filmy adhesions were observed in 14.67% (11/75) of patients in the study group versus 13.33% (10/75) of patients in the control group. Filmy and dense adhesions were seen in 4.00% (3/75) of patients in the study group compared with 0.00% (0/75) of patients in the control group. Finally, dense adhesions were not observed in either group. The mean score of the adhesion types in the study group was 1.19 compared with 1.14 in the control group. Therefore, there were no statistical inter-group differences in the percentages of adhesion types and the mean scores for both groups .An independent assessor also evaluated the extent of the cavity involved (or intensity) of intrauterine adhesions a month after the initial surgery, as described in the methods. The percentages of each group based on the intensity of the adhesions were as follows: 0 intensity adhesions were seen in 81.33% (61/75) of patients in the study group versus 86.67% (65/75) of patients in the control group. Adhesions with <1/3 intensity were seen in 13.33% (10/75) of patients in the study group and 13.33% (10/75) of patients in the control group. Adhesions between 1/3 and 2/3 intensity were observed in 5.33% (4/75 patients) of the study group and 0.00% (0/75 patients) of the control group. Finally, adhesions with an intensity >2/3 were not observed in either group.Furthermore, the mean score of the extent of the intrauterine adhesions was 1.20 in the study group and 1.14 in the control group. Finally, no statistical inter-group differences were observed in the adhesion intensity scores. .Overall, 102 patients (58.29%) had a medical history that included details of prior illnesses and surgeries. These were evaluated to observe the outcomes according to the presence of a previous medical history, but the difference found was not statistically significant. Medical histories were classified based on the System Organ Classes (SOC) of the Medical Dictionary for Regulatory Activities (MedDRA); the most frequently observed category was “reproductive system” (40 patients with 45 incidences) and “breast disorders” (20 patients with 22 incidences). The personal history, which includes information on allergies and ailments, was recorded in 84 patients with 136 incidences. The two groups did not show any statistically significant different prevalence. When the present personal history was classified based on the SOC of MedDRA, the most frequently ranked category was “reproductive system and breast disorders,” noted in 33 patients with 38 incidences. However, it did not have a significant impact on the outcome. There were no significant changes from visit 1 to visit 4 in the laboratory, evaluations except in one case, where the γ-GT level at visit 4 was clinically significant.No statistically significant differences were noted between the two groups in the AEs and serious AEs . MoreoveOverall, 39 patients were reported to have 53 AEs, of which 22 (29.33%) and 17 (22.67%) patients from the study and control groups had 32 and 21 AEs, respectively. Seven patients experienced seven serious AEs . PatientADEs were recorded in four events in four patients (2.67%), of which three patients (4.00%) were from the study group, and one patient (1.33%) was from the control group. All ADEs were judged as “mild,” which did not require intervention, and the patients recovered completely. The study group included one case of procedural hemorrhage, one of procedural pain, and one of vaginal discharge. In contrast, the control group showed one case of vaginal hemorrhage that spontaneously regressed. There were no serious ADEs . WithoutIn addition to the analysis of the ADEs, laboratory tests were performed to monitor safety. Analyzing changes in the laboratory parameters before and after applying the materials into uterine cavity did not reveal any differences between the groups. The healthy levels or non-clinically significant parameters before the procedure did not become clinically significant.Therefore, in evaluating the safety of type 1 collagen gel, there were no statistical differences between the study and control groups. Notably, a few cases of AEs were reported as “few associations”; however, most AEs were reported as irrelevant to the medical device. All adverse device events were categorized into mild cases with no requirement of a specific intervention, and they were reported to be “recovered” or “in the process of recovery.” There were no serious medical device-related AEs. Therefore, type 1 collagen gel proved safe as an anti-adhesive after intrauterine surgery.® and the control groups. The frequency and mean scores of the type and intensity of adhesions and AEs, serious AEs, adverse device effects, and serious adverse device effects were not significantly different between the two groups. These results demonstrate the beneficial effects of Collabarrier® in terms of effectiveness and safety.The incidence rate of postoperative intrauterine adhesions did not show any significance between the CollabarrierSince postoperative adhesions induce various complications such as infertility, amenorrhea, and recurrent pregnancy loss; several trials have been conducted to minimize postoperative adhesions through minimal tissue manipulation during surgery through the use of anti-inflammatory agents, the activation of tissue plasminogen activators to prevent fibroblast formation, and the use of physical barriers . The ant® was made with type 1 collagen in gels with hydrophilic, biocompatible, and biodegradable characteristics, to act as a deep wound-covering material. It has been shown to have anti-adhesive properties and to be safe in previous clinical trials. It has already been approved as a surgical wound-covering material in thyroid surgery to prevent adhesions [To compensate for these drawbacks, Collabarrierdhesions . Moreove®) was not inferior to the HA and CMC gels in preventing postoperative intrauterine adhesions. Moreover, the secondary assessment of the type and intensity of the postoperative intrauterine adhesion showed no statistically significant differences between the two groups, thereby demonstrating the type 1 collagen gel to be an effective anti-adhesive. In evaluating the safety of type 1 collagen gel, there were no statistical differences in the adverse device events between the two groups. Moreover, all the events were in various stages of recovery by the end of the trial. Therefore, in evaluating the safety of type 1 collagen gel, there were no statistical differences between the study and control groups.This study’s primary objective was to examine the postoperative adhesion rate between the two groups. The lack of difference in this rate showed that the type 1 collagen gel (CollabarrierA few cases of AEs were reported as “few associations”; however, most AEs were reported as irrelevant to the medical materials used. All adverse events were categorized into mild cases with no requirement of a specific intervention, and they were reported to be “recovered” or “in the process of recovery”. There were no serious medical device-related AEs.This study had some limitations. First, this study was multi-centered; however, it was exclusively focused on Korean women. Secondly, during the postoperative assessment, we asked the operators conducting the second-look hysteroscopies to take pictures of the intrauterine cavity, especially focusing on postoperative adhesions if there were any. Therefore, the independent assessors who evaluated the postoperative intrauterine adhesions had to make judgments with only these few pictures from the second-look hysteroscopies. Therefore, we could not say that full inspections of the intrauterine cavity were properly carried out. Third, we should have not performed the second look hysteroscopy on five patients who were pathologically diagnosed with uterine malignancy. The use of hysteroscopy in already confirmed endometrial cancer is still controversial. Some studies have reported that spillages of washing fluids into the pelvic cavity may impact negatively on the prognosis of the disease, whereas others report that hysteroscopy does not result in cancer cell spreading into the peritoneal cavity .Through this trial, we demonstrate that type 1 collagen gel can be used effectively and safely in intrauterine surgery to minimize postoperative adhesions, eventually decreasing the prevalence of infertility, secondary amenorrhea, and recurrent pregnancy loss in reproductive women.


This association was independent from other foods whose consumption is associated with the high legume intake. Conclusions: In people with T2D and hypertension, three servings of legumes per week are associated with significantly better BP control. This gives further support to current dietary guidelines in recommending the frequent consumption of legumes, as a “ready-to-use” dietary strategy to achieve optimal BP control.Background: Our aims were to evaluate the relationship of habitual legume consumption with blood pressure (BP) control in a large cohort of people with T2D and hypertension, and to investigate whether specific nutritional components of legumes or other foods may contribute to regulate BP levels. Methods: We studied 1897 participants with T2D and hypertension. Dietary habits were assessed through a validated food frequency questionnaire. Sex-specific quartiles of legume consumption were created. Results: Higher legume consumption was associated with a lower intake of energy, carbohydrates, glycaemic load, alcohol, and sodium, and a significantly greater intake of proteins, fat, monounsaturated, polyunsaturated, fibre, potassium, and polyphenols. Significantly lower systolic and diastolic BP values were observed in the highest vs. lowest quartile of legume consumption (132.9 ± 6.7 vs. 137.3 ± 7.0 mmHg,  Hypertension is a major risk factor for coronary artery disease, stroke, heart failure, peripheral vascular disease, and chronic kidney disease . To dateData from observational studies show that high blood pressure levels cause a significant increase in the risk of vascular complications in individuals with diabetes and predispose to a higher incidence of chronic kidney disease, ischemic cerebrovascular disease, retinopathy, and cardiovascular mortality ,6,7,8. TPharmacological treatment is required in the management of most patients, but lifestyle modification, including a better quality of diet, and weight management, are key components to control both blood glucose and blood pressure. Previous studies have shown that the consumption of specific foods, such as fruit and vegetables, dairy products, and whole grains, or the adherence to specific dietary patterns, such as the Mediterranean diet, or the low glycaemic index diet, can improve blood pressure control in diabetes patients ,11,12. TAmong plant-based foods, legumes contain various components linked to lower blood pressure, including dietary fibre, bioactive peptides, and flavonoid polyphenols ,17, but Therefore, the aims of the present study were to evaluate the association between habitual legume consumption and systolic and diastolic blood pressure control in a large cohort of people with type 2 diabetes and hypertension, and to investigate whether specific nutritional components of legumes, or other foods associated with a legume rich dietary pattern, may contribute to modulate blood pressure levels in real life conditions.clinicaltrials.gov (accessed on 31 May 2023) NCT00700856), a randomized clinical trial designed to assess the cardiovascular effects of two different hypoglycaemic drugs. The TOSCA.IT study complied with the Declaration of Helsinki and was granted the approval of the Ethics Committee of the coordinating centre and of each participating centre; written informed consent was obtained from all participants. Details on the study protocol, inclusion and exclusion criteria have been published elsewhere [We analysed the baseline data from the TOSCA.IT trial  was calculated as kg/mFasting blood sample were analysed in a central laboratory. High-performance liquid chromatography (HPLC) was used to measure HbA1c. Lipid profile  were measured by standard methods. The LDL-cholesterol was calculated by the Friedewald equation for people with triglycerides values < 400 mg/dL . The stuDietary habits during the past 12 months were assessed by the validated EPIC food frequency questionnaire (FFQ)  for a toThrough the use of a specifically designed software developed ad hoc by the Epidemiology and Prevention Unit, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan , questioData are given as numbers and percentages, or mean values (M) and standard deviation (SD) for continuous variables, as appropriate.To correct for the different energy intake between subjects, the intake of legumes was expressed as g/1000 kcal/day. The sex specific quartiles of legume consumption were created to assess the relation of legume consumption with blood pressure, anthropometric variables, glucose control, and plasma lipids.2 test was used to compare proportions. To compare variables across the quartiles, the analysis of variance with a test for a linear trend was used for the continuous variables, and the χMultivariate linear regression analysis was used to estimate the separate and combined association of legumes and other dietary factors with the variables of interest  and results were expressed as regression coefficients (β). The explored dietary factors were cereals, wholegrains, potatoes, vegetables, fruits, nuts, fish, meat, eggs, dairy products, milk and yogurt, olive oil, animal fat, alcoholic beverages, sweeteners beverages, coffee and tea, and cakes and pastries. Multivariate linear regression analyses were performed to explore the impact of nutrients or bioactive compounds of legumes  on systolic and diastolic blood pressure.p values of less than 0.05 were considered to indicate statistical significance.The statistical analyses were performed with IBM version 28.0. Statistical tests were two-sided, and 2. Most participants were taking anti-hypertensive medications (95.6%) and 22% of total population had micro-albuminuria (The study population consisted of 1079 men (56.9%) and 818 women (43.1%) with a history of type 2 diabetes 8.7 years (±5.7 years) and hypertension of about 7.2 years (±6.4 years). The mean age was 62.8 years (±6.4 years), and BMI 30.8 ± 4.5 Kg/muminuria .p < 0.001; 78.9 ± 4.1 vs. 81.0 ± 4.2 mmHg, p = 0.002; respectively). Accordingly, the percentage of people on target for systolic and diastolic blood pressure significantly increased across the quartiles of legumes intake   and diastolic (<80 mmHg) blood pressure across the sex-specific quartiles of legume consumption are reported in  < 0.01) .No significant differences were observed across quartiles regarding age, diabetes duration, BMI, waist circumference, HbA1c, total cholesterol, LDL- and HDL-cholesterol, triglycerides, C-reactive protein, and percentage of people with micro-albuminuria . The samp < 0.05), and a lower intake of refined cereals, animal fat , alcoholic beverages, and cake and pastries (p < 0.05). No significant differences were detected for potatoes, nuts, meat, dairy products, milk and yogurt, sweetened beverages, and coffee and tea consumption (The specific food pattern associated with legume consumption is shown in sumption .p < 0.001) (p < 0.05). The intake of saturated fat, cholesterol and added sugar, and the glycaemic index of the diet did not change across the quartiles (As compared to subjects with lower legume intakes (Q1), participants reporting higher legume consumption (Q4) had significantly lower intake of energy, total carbohydrates and starch, glycaemic load, alcohol, and sodium (< 0.001) . Signifiuartiles .p < 0.001; β = −0.061, p = 0.014, respectively) independently of any other dietary item; none of the other foods consumed by the study participants was associated with blood pressure . This association disappeared when legumes were included in the model and was replaced by a significant inverse association between systolic and diastolic blood pressure values with legume consumption, thus suggesting that dietary fibre plays a significant role in modulating the relationship between legume consumption and blood pressure control.In addition, in order to evaluate which nutrients linked legume consumption to systolic and diastolic blood pressure values, separate linear regression models were used. As reported in This study investigated, for the first time, the association between legume consumption and blood pressure in a large cohort of people with type 2 diabetes, in the context of real-life conditions, where the amount of legumes intake was that habitually consumed by the study population and substantially lower than in the intervention trials conducted so far ,19,30. NLegume consumption in relation to blood pressure has been studied in people with or without type 2 diabetes in intervention studies exploring the beneficial effects of high legume intakes. Jenkins et al.  reportedA feature shared by all these studies is the high amounts of legumes used within dietary interventions which is unfeasible for the long term in real life conditions. Yet, our study confirms the association of legumes with lower systolic and diastolic blood pressure for a lesser amount of consumption (70 g three times a week), which is more feasible and in line with that recommended for the general population and suggested by the dietary guidelines for people with type 2 diabetes.Prior population studies in non-diabetic people have also reported that an increased legume intake is associated with a reduced risk of developing hypertension. A meta-analysis of five observational studies reported a ~5% risk reduction to develop hypertension for about 70 g/day of legume consumption . A subseAll these previous observational studies were performed in people without diabetes; conversely, we performed our study in a large cohort of individuals with type 2 diabetes; it is of interest that our population was almost entirely under anti-hypertensive pharmacological treatment. This means that legume consumption can represent an additional tool—besides medications—to lower blood pressure, allowing a larger proportion of people with type 2 diabetes to reach the target. Among several legume components potentially involved in the beneficial relationship observed with blood pressure in people with type 2 diabetes, like proteins, fibre, sodium, potassium, and polyphenols, only fibre showed a significant association with lower levels of systolic and diastolic blood pressure according to our results. This can be due, at least in part, to the demonstrated role of fibre in reducing inflammation ,38 and iHowever, the possible contribution of other macro- and micro-nutrients present in legumes in explaining the association between consumption of this food group with a better blood pressure control should also be considered. In this respect, the vasodilatory effect of arginine in legume proteins via converting into nitric oxide has been demonstrated in animal and in vitro models and proposed as a potential mechanism driving the relationship observed ,41. OtheThe health benefits of polyphenols from legumes in relation to blood pressure control were summarized in a recent comprehensive review by Ganesan et al.  demonstrThere are several strengths of this study. This is the first large cohort of people with type 2 diabetes in which the links between legume intake and blood pressure were investigated in real-life conditions. Furthermore, the study was able to control for medications, metabolic parameters, and dietary components, which can play a significant modulating effect on blood pressure. Finally, the use of a central laboratory for biochemical analyses ensures good quality standards for the measurements. Our study also has limitations, the most relevant being the cross-sectional study design which does not enable the establishing of a cause–effect relationship. Residual confounding cannot be ruled out, even though our findings are independent of (1) other dietary items and their components, such as mono- and poly-unsaturated fatty acids, glycaemic load, sodium, and alcohol intake; and (2) the main potential confounders, such as age, BMI, and smoking habit, were controlled. Furthermore, we did not analyse the role of different types of legumes consumed, as legume intake was aggregated into total amount. In this regard, we cannot exclude that different types of legumes may have different effects due to their distinct nutritional characteristics. Finally, we cannot exclude that individuals eating a healthier diet and consuming less alcohol may be more adherent to their medication.Our findings in people with type 2 diabetes showed that the association of legume consumption with lower systolic and diastolic blood pressure values is already present for an intake of approximately three servings per week, which is feasible and in line with the current dietary recommendations for people with diabetes. This gives further support to current dietary guidelines in recommending the use of legumes  for people with type 2 diabetes.