Fragility fracture is one of the most serious consequences of female aging, which can increase the risk of death. Therefore, paying attention to the pathogenesis of postmenopausal osteoporosis (PMOP) is very important for elderly women.Forty 12-week-old female rats were divided into two groups including the ovariectomy (OVX) group and the control group. Four rats in each group were selected at 1, 4, 8, 12 and 16 weeks after operation. Vertebral bones and femurs were dissected completely for micro-Computed Tomography (micro-CT) scanning, biological modulus detection and histomorphological observation.P < 0.05). The elastic modulus of femur in OVX group was lower than that in control group, but there was no significant difference between them (P > 0.05). Over time, the tartrate resistant acid phosphatase (TRAP), osteocalcin (BGP), type I procollagen amino terminal propeptide (PINP) and type I collagen carboxy terminal peptide (CTX-I) in OVX group increased significantly (P < 0.05). The micrographs of the OVX group showed sparse loss of the trabecular interconnectivity and widening intertrabecular spaces with time.In OVX group, bone volume/total volume (BV/TV), bone trabecular connection density (Conn.D) and trabecular bone number (Tb.N) decreased significantly with time (The bone loss patterns of vertebral body and femur were different in the early stage of estrogen deficiency. The bone turnover rate of OVX rats increased, however the changes of biomechanical properties weren’t obvious. Mature bone requires continuous bone remodeling, which is the key mechanism to maintain normal bone mineral density (BMD). Therefore, bone formation is closely related to bone resorption and they are in a relatively balanced state in healthy individuals . PostmenIn addition to BMD, changes in bone microstructure and bone strength should also be considered when predicting the risk of fragility fracture. Micro-Computed Tomography (micro-CT) can clearly describe the three-dimensional distribution and structural characteristics of bone. It also can measure accurately and monitor the changes of bone volume and bone microstructure –6. BesidAt present, many scholars have discussed the characteristics of PMOP from the perspective of bone mass, bone microstructure or bone metabolic indexes. However, there are few reports on the changes of bone microstructure, bone strength and blood biochemistry with time, especially in the early stage. In this study, the ovariectomized rat model was used to simulate the postmenopausal state of women. We aimed to explore the early manifestations of estrogen deficiency in rats’ axial bone and peripheral bone by micro-CT combined with BTMs and mechanical properties.A total of 40 female Sprague–Dawley (SD) rats  were purchased from the Beijing weitonglihua Experimental Animal Technology Co., Ltd. Then divided them into two groups with 20 rats per group. One group of rats underwent abdominal incision and bilateral ovariectomy (OVX). Subsequently, sutured the incision. The other group was the control group which is only performed abdominal incision without ovariectomy. Then the incision was sutured. The animals received ad libitum access to standard chow pellets and water throughout the experimental period.At each time period of 1 week, 4 weeks, 8 weeks, 12 weeks and 16 weeks post-OVX surgery, four rats of each group weighted under anesthesia . After that, they were killed by over anesthesia to get the L4 and L5 vertebral bones and bilateral femurs completely. Then stored them in 70% ethanol solution respectively. Animal usage and all procedures were in strict compliance with the guidelines of the National Institutes of Health and approved by the Shandong First Medical University Institutional Animal Care and Use Committee. This study is reported in accordance with ARRIVE guidelines.3), trabecular bone number , trabecular bone thickness  and trabecular bone separation  were evaluated based on the micro-CT scan results.Micro-CT of the harvested left femoral and L5 vertebral bones were acquired at 55 kVp, 145 μA for 221 ms, using Scanco μCT80 scanner . All trabecular bone of the left femoral shaft and L5 vertebral bones were analyzed as the region of interest (ROI). See Fig. The attached tissues of the right femur and L4 vertebral bones specimens of rats were removed. Then cut the vertebral facet joints, upper and lower endplates with serrated surgical scissors to obtain lumbar vertebra samples similar to a cylinder. The compressive stress modulus was tested by Instron testing machine. For right femur, the samples were placed on the center of the lower pressing plate with the patella facing upward. As for L4 vertebral bone, axially placed on the center of the lower pressing plate. The compression test was performed until the pressure load drops by 40% and then recorded the elastic modulus .Five milliliter whole blood  was collected from the heart in terminal anesthesia through cardiac puncture. Centrifuged for 10 min at 3000 r.p.m. for serum separation. The tartrate resistant acid phosphatase (TRAP), type I collagen carboxy terminal peptide (CTX-I), osteocalcin (BGP), type I procollagen amino terminal propeptide (PINP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were determined by ELISA kits, using an autoanalyzer.The harvested bones including lumbar vertebra (L5) and left-femur were dissected to get free from soft tissues. Fixed them in 10% neutral buffered formalin solution. Then decalcified, dehydrated and embedded in paraffin. Subsequently, 5 μm thick sections were prepared and then stained with hematoxylin and eosin (HE). The histological sections used a microscope (20X) equipped with a camera to observe the morphological structure of trabecular bone.All statistical analyses were performed by SPSS software, Version 22.0. One-way ANOVA with subsequent LSD post-hoc test, independent t-test or rank sum test were used to compare the quantitative data between the groups and intra groups.Over the entire study period, there was no significant difference and abnormality in the appearance of rats in OVX group and control group, including hair, paw, tail, etc.P < 0.05). At 4–16 weeks post-OVX surgery, the weight of rats in OVX group was significantly higher than that in control group (P < 0.05). The results are shown in Table The body weight of rats in both groups increased significantly with time (P < 0.05). Besides, Tb.Th of vertebral bone and femur in OVX group and all indexes of vertebral bone and femur in control group did not show significant intra-group differences (P > 0.05). Specifically, BV/TV and Tb.Th differences of vertebral bone between the OVX group and control group occurred at the 4th week, while Conn. D, Tb.N and Tb.Sp occurred at the 12th week (P < 0.05). Moreover, BV/TV, Conn.D and Tb.N of femur were significantly lower than that in the control group, whereas Tb.Sp was significantly higher than that in the control group at 4–16 weeks post-OVX surgery (P < 0.05). Interestingly, Tb.Th of femur did not show significant inter-group differences at each time point (P > 0.05). The results are shown in Tables In OVX group, BV/TV, Conn.D and Tb.N of vertebral bone and femur showed a time-course decreasing trend, whereas Tb.Sp demonstrated an increasing trend (P > 0.05), however, the elastic modulus of femur increased significantly (P < 0.05). Compared to control group, the femur of OVX group showed inferior elastic modulus, whereas there was no significant difference between the two groups (P > 0.05). The results are shown in Table In the temporal analysis for OVX rats, the elastic modulus of vertebral bone did not show significant intra-group differences (P < 0.05). No statistically significant differences in the level of IL-6 and TNF-αin OVX group, although they were also increased with time (P > 0.05). Moreover, the level of TNF- α in the OVX group was significantly higher than the control group at 16 weeks after operation (P < 0.05). The results are shown in Table Over time, the levels of TRAP, CTX-I, BGP and PINP increased significantly in OVX group P < 0.0. No statAll HE-stained sections from two groups at different time were comparatively evaluated histologically Fig. . Normal With the prolongation of life span, the incidence rate of PMOP and fragility fracture is increasing year by year. According to the recent report showed that fragility fractures are related to up 50% of the disability rate and 20% of the mortality rate . The medIn this study, the finding showed that the weight of OVX rats increased by 38% at 4 weeks after operation, and this result was consistent with the findings in other studies conducted on OVX rats . PreviouBone is a composite biomaterial composed of 35–45% mineral crystals, 40% organic matrix and 15–25% water . After 1Tb.N, Tb.Th and Tb.Sp are main index to evaluate the spatial morphological structure of trabecular bone , 7. It iIn addition to bone microstructure, bone cortex plays a decisive role in bone biomechanical ability and fracture risk , 21. In Some limitations of this study need to be mentioned. Firstly, CTX-I is the product of type I collagen decomposition, which has a strong circadian rhythm and needs to be collected in the morning . HoweverIn conclusion, the bone loss patterns of vertebral body and femur were different in the early stage of estrogen deficiency. The bone turnover rate of OVX rats increased, however the changes of biomechanical properties weren’t obvious.


Moreover, the expression levels of COX15 were higher in CKD patients with aortic arch calcification (AAC) than those without AAC, and the AAC scores were correlated with the expression level of COX15. Suppressing COX sufficiently attenuated vascular calcification. Our findings verify the relationship between OXPHOS and calcification, and may provide potential therapeutic approaches for vascular calcification in CKD.Metabolism has been reported to associate with the progression of vascular diseases. However, how vascular calcification in chronic kidney disease (CKD) is regulated by metabolic status remains poorly understood. Using a model of 5/6 nephrectomy, we demonstrated that the aortic tissues of CKD mice had a preference for using oxidative phosphorylation (OXPHOS). Both high phosphate and human uremic serum-stimulated vascular smooth muscle cells (VSMCs) had enhanced mitochondrial respiration capacity, while the glycolysis level was not significantly different. Besides, 2-deoxy-d-glucose (2-DG) exacerbated vascular calcification by upregulating OXPHOS. The activity of cytochrome  Chronic kidney disease (CKD) is a rising health problem worldwide, and the prevalence of CKD was 9.2% in the world . CKD patVascular smooth muscle cells (VSMCs), the dominating components of the artery’s media, are known to be the major cells regulating the progress of medial calcification , 7. In cd-glucose (2-DG), which is considered a better option than other glycolysis inhibitors as it inhibits the first crucial step in glycolysis [Glucose has been implicated as the main energy source for VSMCs . Recentlycolysis , signifiycolysis . To our In addition to glycolysis, mitochondria fuel metabolic processes through their generation of ATP. Mitochondrial respiratory complexes are essential to OXPHOS, where electron transfer to oxygen is combined with ATP production . A previIn this study, we investigated the glucose requirement for VSMCs calcification under the uremic condition both in vivo and in vitro. We tested the role of OXPHOS in vascular calcification, and explored that whether interfering with OXPHOS helps alleviate calcification.As shown in Supplementary Fig. In order to induce CKD, 5/6 nephrectomy was performed in mice and high phosphate diet was fed Fig. . The levTo explore the key signaling pathways involved in metabolic pathways, GSEA enrichment was performed. The results showed that OXPHOS was significantly enriched Fig. . ClusterMitochondrial biogenesis is the basis for cellular energy metabolism under stress, and reactive oxygen species (ROS) are the byproduct of OXPHOS metabolism in cells . Thus, wTo identify the effect of uremic serum, VSMCs were treated with serum from healthy participants (control serum) and uremic patients (uremic serum). As shown in Fig. 2-DG is an inhibitor of the predominantly glycolytic protein, hexokinase 2 . A previTo further investigate the molecular mechanisms that control the metabolic status of the calcifying VSMCs, we investigated several clusters that were upregulated in calcified VSMCs. GSEA enrichment revealed that COX, also known as mitochondrial complex IV, which is the final and rate-limiting step of the OXPHOS , was sigTo assess the COX function in calcification, we assessed whether pharmacological inhibition of COX could attenuate the calcification of vascular tissue ex vivo. Therefore, aortic rings were isolated from the thoracic aortas of mice and incubated with high phosphate in the presence or absence of ADDA 5 hydrochloride, a non-competitive specific inhibitor of COX . ApplicaTo investigate the role of COX15 in CKD patients, we conducted an immunohistochemical study in cases from our center. The intensity of COX15 expression was notably higher in the CKD group compared to the control group Fig. . ConsistP = 0.035). Moreover, we compared the intensity of COX15 staining between CKD patients with and without AAC. As shown in Fig. In our cohort, all cases were positive for COX15 protein in different degrees, 20 of 34 (58.8%) cases showed strong positive staining for COX15 protein, and 14 cases showed weak positive staining. According to the intensity of the expression of COX15, we further divided CKD patients into two groups. The relationship between COX15 staining levels and clinicopathological factors are summarized in Table In this study, we uncovered a previously unrecognized role of OXPHOS in vascular calcification in CKD and acquired some interesting findings. First, this is the first study to directly measure the contribution of OXPHOS to VSMCs treated with serum from uremic patients, which showed that OXPHOS plays a pivotal role in the progression of calcification in CKD. Second, the data presented herein document that COX, a key component of the mitochondrial respiratory chain, expressed higher in arteries from CKD patients and mice than those from the control group. Moreover, the artery of CKD patients with AAC expressed higher level of COX15, and the AAC scores were correlated with the level of COX15 staining. Finally, we found that inhibition of COX15 attenuated high phosphate-induced calcium deposition both ex vivo and in vitro, which provided potential therapeutic strategies for vascular calcification. Together, our data underline the importance of OXPHOS for vascular calcification.Increasing evidence has shown that abnormal metabolic signaling participates in the progression of calcification. In this study, we applied three inhibitors affecting the major pathways of energy production, and found that glucose is the main energy substrate for VSMCs. Glucose metabolism makes key functions in vascular reactivity . As the It has been known that the major source of intracellular ATP is mitochondrial OXPHOS. Mitochondria are crucial in the regulation of cellular metabolism and growth , it has c to molecular oxygen [COX is the terminal complex of the mitochondrial respiratory chain, which catalyzes the transfer of electrons from cytochrome r oxygen . Studiesr oxygen , 27. Besr oxygen . In our r oxygen . Numerour oxygen –32. TherThis study has several limitations. First, our cohort is a retrospective study, a prospective study is required to further confirm the association of expression level of COX15 and cardiovascular or all-cause mortality in CKD patients. Second, we have shown that suppression of COX had a significant inhibitory effect on vascular calcification ex vivo, further in vivo studies might be necessary.In summary, our study unravels a novel metabolic feature of calcified VSMCs, which revealed a preference for OXPHOS in glucose metabolism. The expression level of COX15 was positively related to AAC in CKD, and suppressing COX could significantly reduce vascular calcification. Our findings thus provide novel potential therapeutic strategies for treating vascular calcification in CKD.c oxidase activity kit (BC0940) were from Solarbio . The antibody of COX15 (A14665) and β-actin (AC038) was obtained from Abclonal .Fasentin (HY-101849), etomoxir (HY-50202A), BPTES (HY-12683), ADDA 5 hydrochloride (HY-U00448), 2-DG (HY-13966), and cetylpyridinium chloride monohydrate (HY-B1289) were purchased from MedChemExpress . The trizol reagent was purchased from Takara (Japan), and the reverse transcription system kit and SYBR Green PCR master mix kit were obtained from Vazyme . ATP assay kit (S0026), ROS assay kit (S0033S), and Mito-Tracker Green (C1048) were from Beyotime . Calcium assay kit (C004-2-1), lactate assay kit (A019-2-1), and glucose assay kit (A154-1-1) were purchased from Nanjing Jiancheng . Cytochrome n = 5) underwent amputation surgery due to arm trauma with no medical history of diabetes or CKD were also acquired, CKD was defined as eGFR less than 60 mL/min per 1.73 m2, or markers of kidney damage , or both, of at least 3 months duration [A cohort of 34 patients (61.8% men) with end-stage renal diseases undergoing arteriovenous fistula creation or arteriovenous graft placement was enrolled at Tongji Hospital from July 2020 to August 2021. The exclusion criteria were age <18 years old, diabetes, HIV, and malignant tumors. Informed written consent was obtained from all patients. The artery samples of the 34 patients were acquired during the arteriovenous fistula creation or arteriovenous graft placement. Radial artery samples of control patients  for 14 days. The medium was replaced every 3 days.Aortic tissues were removed from male C57BL/6 mice in a sterile manner. After the adventitia and adipose tissues were removed, the aortas were cut into 2–3-mm rings and cultured in Dulbecco’s Modified Eagle’s Medium (DMEM) containing 15% fetal bovine serum (FBS) at 37 °C in 5% COMouse vascular smooth muscle cells (MOVAS) cell line and HASMCs were cultured in DMEM supplemented with 10% FBS. For calcification experiments, cells were treated with 3.0 mmol/L Pi for 24 h (RT-qPCR) or 3 days , or 7 days . For ATP concentration, ROS, Mito-Tracker Green, and lactic acid concentration experiments, cells were treated with 3.0 mmol/L Pi for 24 h. Fresh media with agents were replaced every 2–3 days. For human serum study, HASMCs were treated with 2.5% uremic serum or control serum.The quantification of VSMCs calcification was performed by incubation of the VSMCs overnight at 4 °C in 0.6 M HCL. Calcium content was measured with calcium assay kit and the results were normalized to protein concentration. Alizarin red staining was performed in aortas and VSMCs. Paraformaldehyde-fixed thoracic aortic tissues were stained with 2% alizarin red solution after deparaffinization and rehydration. For VSMCs experiments, cells were fixed and then stained with 2% alizarin red solution. To quantify Alizarin red staining, we added hexadecylpyridinium chloride solution (100 mM) to each well and measured the optical density at 560 nm.2O2 for 15 min and blocked with goat serum for 1 h at room temperature, and then incubated overnight at 4 °C with primary antibodies against COX15 (1:100). Vascular sections were washed with PBST and then stained with horseradish peroxidase (HRP)-labeled secondary antibodies. Then, color was developed in all samples at the same time with 3,3-diaminobenzidine (DAB), and sections were counterstained with hematoxylin and visualized.Vascular tissues were fixed in paraformaldehyde and embedded in paraffin. After deparaffinization and rehydration, antigen retrieval was performed by citrate buffer (pH 6.0). Then, aortic sections were blocked with HTotal protein from artery tissues and VSMCs were extracted in RIPA buffer supplemented with protease and phosphatase inhibitors. Proteins were separated by 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to 0.45-μm polyvinylidene fluoride (PVDF) membranes. The membranes were blocked with 5% milk and then incubated with the following antibodies overnight at 4 °C: COX15 (1:1000) and β-actin (1:4000). Then, the membranes were washed by TBST and incubated with HRP-conjugated second antibodies (1:4000) for 1.5 h at room temperature, and the bound proteins were visualized by the enhanced chemiluminescence (ECL) method. The relative protein levels were calculated by normalizing to the loading control by using Image J.c oxidase 1 (mt-Co1) and normalized to β-2 macroglobulin (B2M) [Total RNA was extracted from the aortas or VSMCs using Trizol reagent, and then reverse-transcribed into complementary DNA by the reverse transcription system kit. Each expression level was detected by the SYBR master mix. The mRNA expression level was normalized to GAPDH, which were measured as an internal control. For analysis of mtDNA levels, total DNA from HASMCs was amplified using primers specific for mitochondrially encoded cytochrome in (B2M) . The desThe ATP contents were detected by ATP determination kit. In brief, samples (aortas or VSMCs) were lysed and centrifuged, then, the supernatants were collected and incubated with ATP detection working solution. The luminescence was measured and normalized to total protein content.c at 550 nm and normalized to protein concentration.The activity of COX was measured according to the manufacturer’s instructions, by monitoring the absorbance of reduced cytochrome A glucose assay kit was used to detect glucose uptake according to the manufacturer’s protocol. Lactate generation was determined using the lactate assay kit, for measurement of aortas, the results were normalized to the total protein concentration.The measurement Mito-Tracker Green was determined using the assay kit according to the manufacturer’s protocol. In brief, cells were washed with PBS three times and incubated with 200 nM Mito-Tracker Green working solution for 40 min at 37 °C in the dark. After incubation, cells were washed with cell culture medium and the fluorescence intensity was measured. The intracellular ROS level was determined with the ROS assay kit. Cells were washed with PBS three times and incubated with 10 μM DCFH-DA for 20 min at 37 °C in the dark. After incubation, cells were washed with serum-free DMEM and the fluorescence intensity was measured.Q value with a rigorous threshold  by Bonferroni.RNA samples were isolated from normal cultured or high phosphate-treated MOVAS. Sequencing was performed on the DNBSEQ platform. Then, the sequencing reads were processed with the determination of quality using the SOAPnuke tool. The clean reads were mapped to the reference genome using HISAT2 (v2.0.4). The heatmap was drawn by pheatmap (v1.0.8) according to the gene expression in different samples. Essentially, differential expression analysis was performed. To take insight to the change of phenotype, gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and gene set enrichment analysis (GSEA) of annotated differently expressed genes were performed. The significant levels of terms and pathways were corrected by HASMCs were treated with phosphate or human serum for 12 h for analysis of extracellular flux. An XF-24 Extracellular Flux Analyzer  was used for real-time analyses of OCR of HASMCs according to the manufacturer’s instruction. OCR was measured under basal conditions followed by the injection of oligomycin (1 μM), FCCP (1 μM), and rotenone (0.5 μM) plus antimycin (0.5 μM). The results were measured and normalized to total protein content.t test, or Mann–Whitney U test were used for continuous data as appropriate. Chi-square tests or Fisher’s exact tests were used for categorical variables. The number of samples for each data (n) is mentioned in figure legends. The statistical significance is expressed as follows: *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001; and n.s., not significant.Statistical analysis was conducted using SPSS 22.0 software  and GraphPad Prism version 6 software . Continuous variables were displayed as mean ± standard error of mean or median with interquartile range. Categorical variables were expressed as frequencies and percentages. One-way ANOVA test, unpaired Table S1supplementary figure legendFigure S1Figure S2Figure S3checklistchange of authorship request form


The association between visceral adiposity index (VAI) and diabetic complications has been reported in cross-sectional studies, while the effect of VAI on complication development remains unclear. This study aims to evaluate the longitudinal association of VAI and Chinese VAI (CVAI) with the incidence of diabetic nephropathy and retinopathy using a Chinese cohort.A total of 8 948 participants with type 2 diabetes from Beijing Health Management Cohort were enrolled during 2013–2014, and followed until December 31, 2019. Nephropathy was confirmed by urine albumin/creatinine ratio and estimated glomerular filtration rate; retinopathy was diagnosed using fundus photograph.The mean (SD) age was 53.35 (14.66) years, and 6 154 (68.8%) were men. During a median follow-up of 4.82 years, 467 participants developed nephropathy and 90 participants developed retinopathy. One-SD increase in VAI and CVAI levels were significantly associated with an increased risk of nephropathy, and the adjusted hazard ratios (HR) were 1.127 (95% CI 1.050–1.210) and 1.165 (95% CI 1.003–1.353), respectively. On contrary, VAI and CVAI level were not associated with retinopathy after adjusting confounding factors.VAI and CVAI are independently associated with the development of nephropathy, but not retinopathy in Chinese adults with diabetes.The online version contains supplementary material available at 10.1186/s12933-022-01464-1. Type 2 diabetes accounts for around 90% of diabetes, becoming a serious public health issue worldwide. It is estimated that 366 million people are expected to have diabetes by 2030, and the vascular complications have become the leading cause of death in type 2 diabetes , 2. The Abdominal obesity is recognized as one of the important risk factors of cardiometabolic diseases , diabeteTherefore, this study aims to investigate the longitudinal association of VAI and CVAI with the incidence of diabetic nephropathy and retinopathy using a population-based cohort.The Beijing health management cohort (BHMC) is an open cohort study conducted in Beijing Xiaotangshan Hospital and Beijing Physical Examination Center in Beijing, China. Briefly, the BHMC study is designed to investigate the risk factors and biomarkers for cardiometabolic diseases, such as metabolic syndrome and type 2 diabetes. The details of the study design have been described in previous studies , 15.From 2013 to 2014, a total of 47,543 participants aged 20 years or above underwent a comprehensive health examination, and 10,948 were confirmed to have type 2 diabetes. To minimize the possible influence of reverse causality, 220 participants with a history of retinopathy and 478 participants with nephropathy at baseline were excluded. In addition, we excluded 65 participants with type 1 diabetes and 1027 participants lacking anthropometric measurement data at baseline. Finally, 8948 participants with complete data were annually followed under same identical conditions for the development of nephropathy and retinopathy until December 31, 2019, and the incident cases in each follow-up year were shown in Fig. Baseline data on demographic variables and health information, including age, sex, education level, physical activity, smoking status, drinking status, diagnosis history of diseases and medication use were collected via a standard questionnaire by our trained staff. Educational level was categorized as illiteracy or primary school, middle school, high school or above. Smoking status was defined as ‘current smoker’, ‘former smoker’ and ‘never smoked’. Drinking status was defined as ‘current drinking’ and ‘no current drinking’. Physical activity was defined as having moderate or intense exercise ‘ ≥ 20 min per time and ≥ 4 times per week’. Self-reported health conditions included the physician-diagnosed history of diabetes, hypertension and dyslipidemia. The uses of antidiabetic, antihypertensive and lipid lowering medication were defined as a positive response to the following question: ‘Do you take antidiabetic, antihypertensive or lipid lowering medication regularly following the physician's prescription?’.2 (in metres squared). Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were calculated as the average of two measurements on the right arm using a sphygmomanometer after resting for at least 10 min. The overnight fasting venous blood samples were obtained from all participants, and measured in the central laboratory of Beijing Xiaotangshan Examination Center or Beijing Physical Examination Center. The data of fasting blood glucose, glycated haemoglobin (HbA1c), serum total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, serum creatinine, urinary albumin/creatinine ratio (ACR) were collected in this current study. The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration serum creatinine equation −16.32*HDL cholesterol (mmol/l).Women:VAI = WC/(36.58 + 1.89*BMI)*(triglycerides/0.813)*(1.52/HDL cholesterol).CVAI = − 187.32 + 1.71*age (years) + 4.32*BMI (kg/m2) + 1.12*WC (cm) + 39.76*lg(triglycerides (mmol/l))−11.66*HDL cholesterol (mmol/l).The VAI and CVAI showed significant correlations with visceral adipose tissue volume as described previously , 20.2 according to the organization Kidney Disease Improving Global Outcomes (KDIGO)  of baseline VAI and CVAI were 1.46  and 112.60 . During a median follow-up of 4.82 years, 467 participants developed nephropathy and 90 participants developed retinopathy. Table In the fully adjusted model, one-SD increase in VAI and CVAI levels were significantly associated with an increased risk of nephropathy, and the HR values were 1.127 (95% CI 1.050–1.210) and 1.165 (95% CI 1.003–1.353), respectively. On contrary, VAI and CVAI levels were not significantly associated with retinopathy after adjusting confounding factors, and the HR values were 1.071 (95% CI 0.950–1.207) and 0.878 (95% CI 0.615–1.252), as shown in Table In addition, we observed no significant interaction effect of age, sex, obesity, smoking with VAI and CVAI for incident nephropathy . After excluding participants using antidiabetic medication, we found that VAI, not CVAI was significantly associated with incident nephropathy . The results remained almost consistent when HbA1c level was further adjusted, and VAI was independently associated with nephropathy development , as shown in Fig. This study evaluated the longitudinal association of visceral adiposity index with the development of nephropathy and retinopathy in a diabetic population. In the current analysis, we found that One-SD increase of VAI and CVAI levels were significantly associated with an increased risk of nephropathy, but not retinopathy in Chinese adults with diabetes after adjusting confounding factors. In the multiple sensitivity analyses, we found that VAI was more independently associated with incident nephropathy than CVAI.Previous studies found that excess visceral fat, but not general adiposity, is strongly correlated with incident prediabetes and type 2 diabetes in obese adults , 26. SomAlthough the underlying mechanisms of VAI with diabetic nephropathy have not been fully illustrated, there are several possible explanations accounting for the observed associations. First, VAI is a representative marker to assess visceral adiposity which is strongly related with insulin resistance , and insWan et al.  found thIn this study, we did not find a positive association of VAI and CVAI with incident diabetic retinopathy, which is different from some other studies. Moh et al.  reportedOur study is based on a population cohort of people with type 2 diabetes, which could explain the longitudinal associations of VAI and CVAI with the development of diabetic complications. In addition, the data were obtained from the central medical system or using the standardized questionnaire, which allow us to adjust for the potential confounding factors. However, several limitations in our study should be acknowledged. First, the visceral adiposity was not directly measured by MRI method, and we failed to examine the consistence between actual visceral fat mass and VAI in Chinese population. Second, the exact duration of diabetes in this cohort was unavailable, and the duration is an important risk factor of diabetic complication, which could bias the relationship between VAI and diabetic nephropathy. Third, information about the neurological complication is unavailable in this current cohort. We failed to assess the longitudinal association between VAI and the neuropathy development in diabetic population.Our findings suggest that elevated levels of VAI and CVAI at baseline are significantly associated with increased risk of incident nephropathy, but not retinopathy in diabetic population.Additional file 1: Table S1. Baseline characteristics according to tertiles groups of VAI. Table S2: Baseline characteristics according to tertiles groups of CVAI. Table S3: Full regression results of VAI and CVAI with diabetic nephropathy and retinopathy. Table S4: Interaction effect test of age, sex, obesity and smoking with incident nephropathy.Additional file 2: Figure S1. Time-dependent ROC curves of VAI and CVAI for predicting diabetic retinopathy development.


Despite the rapid scale-up of antiretroviral therapy, virologic failure has become global public health concern and challenge, especially in developing countries. Viral load monitoring is an important approach to identify treatment failure and develop public health interventions in children receiving antiretroviral therapy. Thus, this study aims to assess the magnitude and associated factors of virological failure among children on antiretroviral therapy.p-values < 0.25 were fitted into the multivariable analysis. Finally, variables with p-values <0.05 were considered as statistically significant factors.A facility-based cross-sectional study was conducted among 399 HIV-positive children on antiretroviral therapy from 2016 to 2019 in Bahir Dar Town public health facilities. Data were extracted from children’s charts using a standardized data extraction tool, adapted from ART intake and follow-up forms. Data were entered using Epi-Data Version 3.1, and analyzed using SPSS Version 25. Bivariable and multivariable binary logistic regression models were done to identify factors associated with virological failure. Variables with The period prevalence of virological failure was found to be 14.8% (95% CI: 11.5–19.3%). Opportunistic infections , history of treatment interruption and restart , younger age , poor/fair ART adherence , and advanced baseline WHO clinical staging  were found to be factors significantly associated with virological failure.The magnitude of virological failure among HIV-infected children remained high. Children with poor/fair ART adherence, history of treatment interruption, advanced baseline WHO clinical staging, younger age, and opportunistic infections were significantly associated with virologic failure. Thus, special attention should be given to children who had poor/fair ART adherence and presenting with opportunistic infections. Globally, human immunodeficiency virus (HIV) is a major public health problem and associated with a range of short-and long-term consequences. Approximately 1.8 million children (age < 15 years) were living with HIV globally in 2018 .The goal of antiretroviral therapy (ART) is to suppress viral replication and reduce HIV associated mortality among infected children. Thus, monitoring people on ART is important to ensure treatment success, identify adherence problems, and determine whether ART regimens should be switched in case of treatment failure (TF). Treatment failure can be assessed in three ways: clinically, immunologically, and virologically, which offers early and accurate indication of treatment failure .The World Health Organization (WHO) recommends routine annual viral load monitoring for all patients on ART, as the most accurate and preferred method to measure treatment response , 5. In 2In Ethiopia, few studies have been conducted on TF by considering previous guidelines . However- infected children, the magnitude and associated factors of VF among children on ART has not yet been well investigated in Ethiopia. Current and up-to-date information regarding virological failure (VF) in HIV-positive children using routine viral load testing to measure treatment failure is essential for policy makers to take appropriate actions. Therefore, the findings of this study will highlight the prevalence and associated factors of VF with implications to improve health workers’ interventions, to ensure treatment cost-effectiveness, and to accelerate the reduction of HIV related morbidity and mortality of children.Though, different studies have been conducted on survival, ART adherence, and other aspects of HIVA health facility-based cross-sectional study was carried out from February to March 2020 among HIV-infected children on ART between September 2016 and December 2019. In Ethiopia, chronic HIV/AIDS care and treatment services are provided at hospital and health center settings throughout the country. This study was conducted in Bahir Dar town public health facilities, which is 565 km away from Addis Ababa. The study was conducted in four selected public health facilities .All HIV-infected children (aged < 15 years) taking ART in Bahir Dar Town public health facility were the target population. All HIV-infected children who took ART at least for 9 months with documented viral load test results were included. Conversely, children with incomplete medical records  were excluded.The minimum required sample size was determined using a single population proportion formula. To compute the sample size, the following statistical assumptions were considered: - prevalence of VF =50% because there was no published study done on this topic in Ethiopia, margin of error = 5% and the value of Zα/2 = 1.96, which is the corresponding Z score of 95% confidence interval (CI).Where, n = the required sample size, Zα/2 = Standard normal variation for type 1 error, p = prevalence (0.5) & d = Margin of sampling error tolerated (0.05).The calculated sample size was 385. By considering a 10% contingency rate for incomplete charts, the final minimum required sample size of this study was 424 medical records.).This study was conducted in three randomly selected health centers, and one purposively (because it has high patient flow and case-team composite) selected comprehensive specialized hospital. First, a sampling frame was prepared based on the patient’s medical registration number (MRN) from each health facility’s recorded documents. The total sample sizes were then allocated for each healthy facility proportionally to the number of population size. Finally, medical charts of HIV-infected children taking ART at the selected public health facilities were sorted and selected using a simple random sampling technique Fig. .Fig. 1SAvailable information from patient’s chart was extracted using structured checklist, prepared in English. The data extraction checklist was adapted from the Ethiopian Federal Ministry of Health ART clinic intake and follow-up forms and included socio-demographic, clinical, laboratory, and treatment-related characteristics. Data were extracted by trained health professionals through document review. Five ART trained nurses were recruited as data collector. Orientation about the objectives of the study, contents of the tool, and data extraction procedures was given for data collectors and supervisors for 1 day. The assigned supervisors and principal investigator closely monitored the whole data collection process. Besides, the consistency between collected data and medical records was checked using randomly selected reviews of previously extracted charts.Was diagnosed when the viral load above or equal to 1000 copies/ml under ART based on two consecutive VL results 3 months apart, with adherence support following the first viral load test after at least 6 months of ART .Was defined as “good”, “fair” or “poor” if the patient took ≥95% (missing one from 30 doses or two out of 60 doses), 85–94% (missing 2–4 doses out of 30 doses or 4–9 from 60 doses) or <85% (missing ≥5 doses from 30 doses or > 10 from 60 doses), respectively of monthly doses [Was diagnosed when HIV-positive child has one of the following forms of malnutrition: Height/Age < − 2, or Weight/Age < − 2, or Weight/Height < − 2 standard deviation based on the WHO curve .Was defined as a treatment interruption for at least 1 week during the previous 6 months., frequencies, percentages, proportions, and summary statistics  were used to summarize the study population characteristics. Variables with p-values < 0.25 in the bivariable analysis were entered into the multivariable analysis to control the effects of confounders. Goodness of fit of the model was checked using Hosemer-Lemeshow goodness of fit test. In the multivariable analysis, variables with p-values less than 0.05 were considered as statistically significant factors. Lastly, odds ratios with their correspondence 95% CIs were used to assess the strength and the direction of association.Data were entered into Epi Data Version 3.1 and exported to Statistics Package for Social Science (SPSS) Version 25 for further analysis. Tables were used to present descriptive results. AdditionallyAfter reviewing 424 HIV-infected children’s charts, 399 charts were included and 25 charts were excluded  in the final analysis. The medical record retrieval rate was 94.1%. More than half (62.4%) of the study participants were recruited from Felege Hiwot Comprehensive Specialized Hospital. The mean age of children at ART initiation was 6.66 years (SD: ±3.49). Majority (82%) of the children were from Bahir Dar Town. Nearly half of the respondents (48.6%) were females . Majority (83%) of the participants had good level of ART adherence. Regarding nutritional status, only 7% of the children were malnourished. Of these 25% were severely malnourished. More than half (61.7%) of the children had CD4 counts ≥350 cells/mm3, with a median of 453 (IQR: 288–735) cells/mm3. More than half (52.1%) of the children were taking nevirapine-based ART drugs. Additionally, about 14.5% of the children were anemic (Hgb < 10 mg/dl). Nearly, 16.5% of the participants restarted ART after treatment interruption. Furthermore, almost 81% of the participants had history of regimen change due to different reasons. Lastly, most (82.5%) of the participants were classified as WHO clinical stage I/II at ART initiation . Most (90%) of the VF occurred after 25 months of ART initiation.In the multivariable logistic regression analysis, poor ART drug adherence level, treatment restart after the interruption, younger age at ART initiation, history of opportunistic infections, and advanced baseline WHO clinical staging (stage III and IV) were factors significantly associated with the occurrence of virologic failure. Accordingly, the odds of virological failure among children classified as WHO clinical stage III and IV was 2.3 times more likely  compared to their WHO clinical stage I and II counterparts. Moreover, the odds of virological failure among children who had opportunistic infections during follow-up was two times higher as compared to those who did not have OIs . Similarly, the odds of virological failure among younger age (age ≤ 5 years) was 2.4 times higher odds  compared to older age children (age 10–15 years). The odds of virological failure was 2.2 times higher  among children who had history of treatment interruption compared with those who did not have history of treatment interruption. Finally, the odds of virological failure among participants who had poor/fair ART adherence level was 2.2 times higher  compared to those who had good ART adherence level . This finding is in line with the magnitude of virological failure reported from Ghana 15.7%%) .5–19.3%., and Mal.7%% .5–1We found that different factors were significantly associated with the occurrence of virological failure. In this regard, younger ages (age ≤ 5 years) were more prone to develop virologic failure. This finding is in agreement with other previous studies done in Swaziland , AfricanHowever, this finding contradicts with researches done in Cameroon , and TanThis study also revealed opportunistic infections during follow-up were strongly associated with the occurrence of virological failure. This result is concordant with other reports from Tanzania  and KenyHistory of ART treatment interruption/discontinuation was also significantly associated with the occurrence of virological failure. This is because ART suppresses the viral replication resulting in boosting the patient’s immunity, decreasing the incidence of OIs, and reducing the viral load . MoreoveThis study also found that children classified as advanced WHO clinical staging (stage III and IV) were more likely to develop virological failure. This finding is in agreement with studies reported from Uganda  and SwazFinally, children who had fair/poor ART adherence level were also positively associated with virological failure. This finding is supported by studies conducted in Uganda , TanzaniThis study has some limitations that must be considered before interpreting results. Since the study was based on secondary data, some important variables  were missed. Thus, there might be information bias because of underreporting/missing data elements. There could also be selection bias during data collection as individuals with incomplete medical records were excluded. As the study used cross-sectional study design, it did not establish the possible cause and effect relationship between dependent and independent variables.This study demonstrated that, there was a high magnitude of virological failure among HIV positive children compared to the current Ethiopian ART guidelines target (not more than 10%). Children with poor/fair ART adherence level, history of ART treatment interruption, advanced baseline WHO clinical staging (stage III and IV), younger age, and opportunistic infections were found to be factors significantly associated with the occurrence of virological failure.


PA was classified as moderate- to high-intensity PA (High PA) and low-intensity PA (Low PA). SD was classified as Short SD (<6.1 h) and Long SD (≥6.1 h). Conditional logistic regression was used to calculate the odds ratios (ORs) with 95%-confidence intervals (CIs) of the combined PA and SD groups for the occurrence of each osteoporotic fracture. Compared to ‘Low PA + Short SD’, the adjusted ORs (95% CIs) for vertebral fracture in ‘High PA + Short SD’ and ‘High PA + Long SD’ were 0.83 (0.76–0.91) and 0.84 (0.77–0.92), respectively. Hip/distal radius fractures were not associated with the combined PA and SD group. We suggest that a higher intensity of PA is inversely associated with the risk of vertebral fracture.This study examined the associations between the occurrence of osteoporotic fractures in detailed sites and combined physical activity (PA) and sunshine duration (SD). Data from the Korean National Health Insurance Service—National Health Screening Cohort for 7-year periods and from the Korea Meteorological Administration were used. Osteoporotic fractures ( Physical inactivity is one of the major health problems worldwide. For the COVID-19 pandemic, physical activity (PA) is recommended not only for severe COVID-19 infection itself . HoweverOutdoor PA could increase sun exposure, which improves vitamin D status in the body. Both PA and sun exposure are effective in improving musculoskeletal conditions, especially increasing bone mineral density (BMD) .Osteoporotic fractures caused by decreased BMD with falls could lead to death in elderly individuals. Because aging is ongoing worldwide, fracture is considered one of the major health problems . The incIncreasing evidence with large data from population studies demonstrated that PA could reduce the risk of osteoporotic fractures, especially hip fractures ,10. HoweOur previous study, which used the same national cohort data and meteorological data as our present study, found that a long sunshine duration (SD) and higher intensity PA were associated with a lower occurrence of osteoporosis . A studyBased on previous studies, we hypothesized that a higher intensity of PA with a long SD might be associated with a lower occurrence of each osteoporotic fracture. The purpose of our current study was to identify the association between osteoporotic fractures in specific sites  and combined PA and SD using national cohort data.This study was approved by the ethics committee of Hallym University (HALLYM 2019-08-029) following the guidelines of the Institutional Review Board (IRB).The Korean National Health Insurance Service—National Health Screening Cohort (NHIS—HEALS) was used in this study. The details of the Korean NHIS—HEALS have been described elsewhere .n = 33,337 in the osteoporotic fractures group; n = 57,788 in the control group). In the osteoporotic fractures group, participants who did not undergo the BMD test before the first fracture diagnosis (index date) were excluded . The matching method that was previously used in our studies was conducted [Among 514,866 participants, 56,333 were included in the osteoporotic fracture group according to the definition of each fracture in our study, and 458,533 were included in the control group. Because the PA information was different from 2002 to 2008, those participants and participants without PA records were removed (lsewhere ). In theOsteoporotic fractures were vertebral fractures, hip fractures, and distal radius fractures. All fractures were defined using the codes of International Classification of Diseases 10th Edition (ICD-10). Vertebral fracture was defined if the participants were diagnosed with S220 (fracture of thoracic vertebra) or S320 (fracture of lumbar vertebra). Hip fracture was defined if the participants were diagnosed with S720 (fracture of neck of femur), S721 (pertrochanteric fracture), or S722 (subtrochanteric fracture). Distal radius fracture was defined if the participants were diagnosed with S525 (fracture of lower end of radius).PA information was collected using a modified International Physical Activity Questionnaire (IPAQ) . We usedSD data were collected by the Korea Meteorological Administration (KMA), which takes measurements hourly using an automated synoptic observing system (ASOS) plus manual measurement at 94 locations . We linkPA and SD were combined into 4 groups as follows: ‘Low PA + Short SD’, ‘Low PA + Long SD’, ‘High PA + Short SD’, and ‘High PA + Long SD’.Age, sex, income, and region of residence were used as covariates in analyses and performed as described in our previous study ,23. Age p-value for the interaction for each fracture between each variable and the combined PA and SD groups. For the subgroup analyses, we regrouped participants by combined age group (<60 years old and ≥60 years old) and sex and analyzed them using a conditional logistic regression model. Additionally, subgroup analyses according to osteoporosis history (nonosteoporosis vs. osteoporosis) was assessed using unconditional logistic regression.The general characteristics were compared between each type of fracture and matched control groups using the absolute standardized difference (sd) . ConditiOther subgroup analyses were performed according to covariates .p-value < 0.05. Since we used three types of fractures as dependent variables, Bonferroni correction was used to avoid type 1 error when calculating the p-value (α = 0.05/3). We used SAS version 9.4  for statistical analyses.Two-tailed analyses were performed, and significance was indicated by a The rate of high PA was relatively lower in the vertebral fracture group (37.1% (2547/6858) vs. 41.4% ; sd = 0.09) and in the hip fracture group (35.2% (386/1096) vs. 39.7% (870/2192); sd = 0.09) but not in the distal radius fracture group compared to each matched control group. The rate of long SD was relatively lower in the vertebral fracture group (48.8% (3344/6858) vs. 49.6% ; sd = 0.02) and in the distal radius fracture group (50.0% (2075/4149) vs. 50.3% (4175/8298); sd = 0.01) and higher in the hip fracture group (53.4% (585/1096) vs. 51.1% (1119/2192); sd = 0.05) than in each matched control group .p = 0.519), 0.83 , and 0.84 , respectively  for vertebral fracture in ‘Low PA + Long SD’, ‘High PA + Short SD’, and ‘High PA + Long SD’ were 0.98  [2 (4.5%) larger vertebral cross-sectional area than the reference group [n < 2000) [Previous studies regarding the association between PA and osteoporotic fractures have been controversial depending on the specific site of fracture . Accordi= 0.031) . One cohce group . However < 2000) .p ≤ 0.001). Moreover, the greater UV radiation exposure, the lower the risk of hip fracture in all age- and sex-specific groups  [Several studies have investigated the association between sunlight exposure and vitamin D and fractures. One study from Sweden reported the correlation between latitude in Sweden and the risk of hip fracture, and the correlation between UV radiation and hip fracture. According to the study findings, the higher the latitude, the higher the risk of hip fracture in all age- and sex-specific groups  . Another≤ 0.029) . Few stuAlthough we combined two variables as one, our finding that the association of low occurrence of vertebral fracture in ‘High PA + Short SD’ and ‘High PA + Long SD’ was consistent with the findings from previous studies ,13,16. AOn the other hand, only the <60-year-old subgroup had a low occurrence of vertebral fracture in ‘Low PA + Long SD’ in our study. In one previous case report, a 33-year-old man was reported to have bilateral femoral neck (hip) fracture with low T-scores in the lumbar spine and femoral neck. The authors discussed that the fracture and low T-score occurred because the man had not been exposed to sunlight for 3 years . In othen = 6858) was higher than that of other fractures . An association between hip/distal radius fracture and combined PA and SD might not have been found due to the smaller number of participants. Moreover, because SD is a broad indicator of vitamin D, the association might not be evident. In fact, PA was associated with a low occurrence of hip fracture in each normal weight subgroup, the less-than-once-a-week alcohol consumption subgroup, and the nonosteoporosis subgroup, which was consistent with previous studies , dietary vitamin D or calcium intake, or supplementation with vitamin D or calcium—factors which may modify the risk of fractures or affect the onset of BMD. PA groups were classified into only ‘Low PA’ and ‘High PA’ because the calculation of METs was limited. In addition, the type of PA was not specified because of limited information. The SD variable is another limitation in that it provides limited information regarding individuals’ actual sunlight exposure. In addition, although we used large cohort data from health insurance holders in Korea, the study findings should be carefully applied because the data do not represent the Korean population. Finally, due to this being an observational study, the determination of causality is not evident between combined PA and SD and osteoporotic fractures.We suggest that ‘High PA’ is associated with a decreased risk of vertebral fracture regardless of SD. ‘Long SD’ could reduce the risk of vertebral fracture only in younger age as well as with ‘High PA’. Nonosteoporotic individuals are recommended to have a ‘High PA’ with ‘Long SD’, whereas osteoporotic individuals are recommended to have a ‘High PA’ with ‘Short SD’.


Cognitive behavioral therapy (CBT) is now included in the treatment of patients with inflammatory bowel disease (IBD) in many settings. However, different clinical trials report different outcomes without consensus. This study aims to evaluate the impact of CBT on the mental state, quality of life and disease activity of patients with IBD.Systematic review.This systematic review searched eligible studies from 1946 to December 8, 2019, in MEDLINE, EMBASE, CINAHL, Cochrane library, ClinicalTrials.gov, PsycINFO, Web of Science for eligible randomized controlled trials (RCT).Among the initial identified 1807 references, 11 studies met inclusion criteria. CBT was shown to improve patient's quality of life and reduce the level of depression and anxiety post-intervention but was not sustained. Evidence is not enough for the effect of CBT on disease activity, or C-reactive protein level.CBT has shown short-term positive psychological effects on IBD patients, but there is insufficient evidence for sustained physical and psychological improvements of IBD patients.PROSPERO registration: CRD42019152330.The online version contains supplementary material available at 10.1186/s12876-021-02003-0. The results indicated short-term improvements in depressive symptoms, quality of life measures, after the CBT intervention, though the effect was not sustained.Evidence for the efficacy of CBT for disease activity and CRP level in IBD patients is insufficient.This study did not investigate the effects of CBT on patients with UC and CD separately, which is consistent with the included studies.Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by chronic inflammation of the gastrointestinal (GI) tract . Recent Living with these symptoms has negative impacts on both psychological well-being and health-related life quality. Some studies have found a significant proportion of individuals with IBD suffer from anxiety or depression, including children –10. But The activation of the brain-gut axis includes the release of catecholamines mediated by the autonomic nervous system and stress hormones by the hypothalamus–pituitary–adrenal axis to activate the gastrointestinal response –15. StudAmong IBD patients, the prevalence of anxiety and depressive symptoms have reached 35% and 22% . With deWe designed and report this systematic review according to the Preferred Reporting Items for Systematic Reviews for systematic review protocols (PRISMA-P) 2015 . The IntRandomized controlled trials (RCT) with a follow-up of at least 3 months were included with no language limitation, including studies analysed at different times on the same population.Interventions that were not randomized controlled trials, with incomplete data, or without the full text and secondary studies  were excluded.Studies that referred to population with inflammatory bowel disease diagnosed using any well-established criteria are included.Studies not using standard diagnostic criteria were excluded.Any broadly defined form and type of CBT (such as Acceptance and Commitment Therapy (ACT) and mindfulness therapy, online and offline) were included. The control groups all received IBD treatment as usual (TUA) without any psychotherapy.Studies using non-CBT psychotherapy were excluded.Studies using precise and validated screening scales to evaluate psychological indicators where the data provided is complete.Primary outcomesLevel of depression and anxiety .Index of disease activity in Crohn's disease and ulcerative colitis (such as Crohn’s Disease Activity Index (CDAI) and Simple Clinical Colitis Activity Index (SSCAI)).Secondary outcomesLevel of stress.Levels of Health-Related Quality of Life (HRQoL) (e.g. Inflammatory Bowel Disease Questionnaire (IBDQ).Level of C-reactive protein (to reflect the severity of inflammation).Studies that did not report the indicators of interest and used non-validated scales are excluded.We searched MEDLINE (PubMed), EMBASE, CINAHL, Cochrane library, ClinicalTrials.gov, PsycINFO, Web of Science and references of all papers for eligible studies from 1946 to December 8 2019. There were no restrictions on language. The full search strategy is in Additional file The title/abstract and full text were screened by two reviewers (XJC and YHS) according to predetermined eligibility criteria and based on pre-prepared extraction sheets , intervention  control group , follow-up and data for each outcome indicator). The data was verified by the third reviewer (JC).Quality assessment of the included randomized controlled trials (RCT) was conducted using the Cochrane Collaboration tool . The assNo patient involved.This study is exempt from ethics approval because it was conducted based on the published articles.Initial screening identified 1807 references  and online CBT group . Two stuFor the control group, all but two studies used standard or usual medical treatment without any psychological treatment for IBD. Three studies used treatment as usual (TAU) , 44, 51,The results of the included studies are listed in Additional file The exclusion studies and reasons can be found in Additional file There is a risk of selection bias. Except for one study , other sFour studies (339 participants) reported the level of depression of participants immediately after the intervention. Different psychological scales were used: two studies used the Hospital Anxiety and Depression Scale (HADS) , 51 and P = 0.01 [P < 0.01 [P < 0.01) [. Mikocka-Walus et al. found that the CBT group has a significant improvement in HADS Depression over 12 months (P = 0.02) [P = 0.01) at 3 months, but there was no significance at 9 or 12 months [Five studies (355 participants) reported on the level of depression at follow-up. Two studies claimed that the depression level of participants in the intervention group during follow-up was significantly reduced  while nP < 0.01 , 46. Dep < 0.01) . Mikocka2 months .P < 0.05 [P < 0.01 [P < 0.05) [P = 0.04) [Three studies (264 participants) reported the level of anxiety of participants post-intervention , 48, 49.P < 0.05 ; P < 0.0 < 0.05) . Another < 0.05) , 49, 51. = 0.04) .P = 0.04) [P = 0.34) [P = 0.04 [P < 0.01 [P = 0.01) [Two studies  reported participants' stress levels after the intervention, one reported effectiveness ( = 0.04) , the oth = 0.34) . Four st = 0.34) , 51, andP < 0.01 ). Howeve = 0.01) .P < 0.01; IBDQ: P < 0.05) [P = 0.01) [P = 0.04) while no significance was shown at 8 and 12 months [P = 0.01) [Three studies (287 participants) reported on the quality of life of participants after the intervention , 48, 50. = 0.01) . Berrill = 0.01) .P = 0.67) [P < 0.01) post-intervention using the Harvey-Bradshaw Index (HBI) [Since the CBT concerned are mainly aimed at psychological symptoms, the studies included few reports on physiological outcomes. These studies reported the degree of Crohn's disease activity of participants after CBT. Wynne’s study reported no effect post-intervention using Crohn's Disease Activity Index (CDAI) . Mikocka = 0.67) . On the ex (HBI) .P = 0.51) [P = 0.51 [P = 0.55 [Only one study reported the weak effect of ACT on disease activity of ulcerative colitis after the intervention ( = 0.51) . Two stuP = 0.51 ; P = 0.5P = 0.55 ).P = 0.66) [C-reactive protein (CRP) is an indicator of disease activity or severity of inflammation. The level of CRP will increase during disease activity. Only Wynne et al. reported the CPR level after the intervention ( = 0.66) , and two = 0.66) , 49.This systematic review aimed to determine whether CBT can improve psychological or physical outcomes in IBD patients. Though two previous papers have mentioned the effect of psychological therapy/cognitive-behavioural therapy for IBD, studies published after 2017 have never been covered in any reviews , 53. In The results indicated short-term improvements in depressive symptoms and quality of life measures after the CBT intervention, though the effect was not sustained. We also found that CBT does not have significant effects on other indicators such as stress, anxiety, and disease activity. It may relate to the following reasons: (1) when recruiting participants, researchers have not selected according to baseline mental status; participants whose psychological state is relatively normal, are less likely to experience a change in mental health status , 57. (2)At the physiological level, we analysed disease activity and CRP level. The results of the systematic review showed that there is insufficient evidence that CBT can improve physical symptoms of IBD patients with whether CD or UC. But other studies have shown that for some other chronic gastrointestinal diseases such as intestinal stress syndrome (ISS), functional dyspepsia and non-cardiac chest pain, and psychotherapy including CBT has been proven to aid in the treatment . The patThe results of Wynne's research are quite different from most of other studies included. Wynne's study specifically designed for the stress response of IBD patients, it focused on increasing mental flexibility related to stress improvement as other studies had done , 59. ParP = 0.01; SF-12 mental: P = 0.03) [A single study used online CBT, and the single positive result reported was that the patient's quality of life could be improved within a 4-week follow-up (IBDQ:  = 0.03) . A syste = 0.03) . These c = 0.03) , 46. shoAlthough the included studies inevitably have different attrition rates, they all report methods for managing missing data, which reduces the risk of attrition bias. But the observation that the control group had a higher drop-out rate than the experimental group may skew the results in favor of positive outcomes. In addition, the drop-out rate of CBT is significantly higher than that of other psychotherapy . HoweverExisting studies on the use of cognitive behavioral therapy in the treatment of IBD have varied in their interventions and there is no standard criteria or framework. Besides, the scales measuring outcomes like mental states or quality of life are also at an uneven level, making it difficult to evaluate the effect of CBT among IBD patients. Further research is needed for a standardized CBT research and application paradigm.Limitations of this study are listed as follows: almost no study specifically reported disease activity outcomes classified into CD and UC, therefore, we failed to investigate the effects of CBT on patients with UC and CD respectively and could only discuss the outcome indicators of the total IBD patients. In addition, we didn't set a specific target population, neither concerning the active degree nor the age of the patient. So, we can't get a specific conclusion aiming at the sub-group of IBD patients. However, the purpose of the study was to summarize the results of CBT treatments, as it acts as a foundation for future researches. Thirdly, heterogeneity in terms of different interventions designs and lack of uniform outcomes measures is another limitation. Besides, due to the small number of included studies, we didn’t report publication bias as well.Our results show that CBT has short-term improvement effects on depression level and quality of life of patients, but it is not sustained. CBT has no significant impact on physical outcomes. Future studies should pay more attention to the different types of CBT and the long-term effectiveness physiologically and psychologically, for patients with different levels of severity of IBD in different age groups.Additional file 1. Detailed information of included and excluded studies, as well as the searching queries in databases.


Previous studies observed have reported that electroacupuncture (EA) is effective in relieving diabetic bladder dysfunction (DBD); however, little is known about the mechanism. Therefore, we explored the effects and mechanisms of EA on DBD in streptozotocin–high-fat diet- (STZ–HFD-) induced diabetic rats. The Sprague-Dawley male rats were divided randomly into four groups: normal group, diabetes mellitus group (DM group), DM with EA treatment group (EA group), and DM with sham EA treatment group (sham EA group). After 8 weeks of EA treatment, the body weight, serum glucose, bladder weight, and cystometrogram were evaluated. The bladder wall thickness was examined by abdominal ultrasound imaging. After the transabdominal ultrasound measurements, hematoxylin-eosin (HE) staining was used to observe the bladder mucosa layer. The bladder detrusor smooth muscle cells (SMCs) and fibroblasts were observed under transmission electron microscopy (TEM). The phospho-myosin light chain (p-MLC), phospho-myosin light chain kinase (p-MLCK), and phospho-myosin phosphatase target subunit 1 (p-MYPT1) levels in the bladder were examined using Western blot. The bladder weight, serum glucose, bladder wall thickness, volume threshold for micturition, and postvoid residual (PVR) volume in the diabetic rats were significantly higher than those in the control animals. EA treatment significantly reduced the bladder weight, bladder wall thickness, volume threshold for micturition, and PVR volume in diabetic rats. EA caused a significant increase in the MLC dephosphorylation and MLCK phosphorylation levels in the group compared to the sham EA and model groups. EA reduced the infiltration of inflammatory cells in the bladder mucosa layer of diabetic rats. In addition, EA repaired the damaged bladder detrusor muscle of diabetic rats by reducing mitochondrial damage of the SMCs and fibroblasts. Therefore, EA could reduce the bladder hypertrophy to ameliorate DBD by reversing the impairment in the mucosa layer and detrusor SMCs, which might be mainly mediated by the regulation of p-MLC and p-MLCK levels. Diabetes mellitus (DM) as a metabolic disease has reached epidemic proportions worldwide and is associated with various complications, including retinopathy, neuropathy, and nephropathy . The glo2+-calmodulin- (CAM-) dependent MLCK and dephosphorylation catalyzed by MLCP help regulate the contraction and relaxation of smooth muscle [2+ sensitization. When the Ca2+ concentration continuously decreases, the smooth muscle contraction can be maintained by inhibiting the activity of MLCP [The level of myosin light chain (MLC) phosphorylation is an important determinant of smooth muscle contraction. The phosphorylation of MLC primarily regulates the force production and maintenance in the smooth muscle . Myosin h muscle , 9. The h muscle . It is g of MLCP . The myo of MLCP . The und of MLCP . Multipl of MLCP . These rAcupuncture has been used to treat DM for thousands of years, and its curative effect has been confirmed by many clinical pieces of evidence and animal studies . It is rA total of 50 male Sprague-Dawley rats, aged 13–15 weeks and weighing 180–220 g, were obtained from the Chengdu Dossy Experimental Animals Company (China). The rats were kept under standard conditions .n = 10) and a model group (n = 40). The model rats were fed with HFD for 4 weeks to induce insulin resistance. After 24 h of fasting, the diabetic model rats were induced by a single intraperitoneal injection of STZ (60 mg/kg) diluted in 0.1 mol/L citrate buffer solution [n = 10), (2) DM with EA treatment group , and (3) DM with sham EA treatment group . After 8 weeks of intervention, the body weight, serum glucose, and bladder weight of the rats were tested. All rats underwent cystometry and transabdominal ultrasound to examine the bladder function at week 12. HE staining was used to observe the state of bladder mucosa layer. The morphological features of the bladder detrusor smooth muscle cells (SMCs) and fibroblasts were evaluated under TEM. The expressions of p-MLC, p-MLCK, and p-MYPT1 were measured using Western blot.After one week of adaptive feeding, the rats were randomly divided into a control group . The study has also been approved by the Hospital of Chengdu University of Traditional Chinese Medicine .E Stimulator, a Hua Tuo Acupoint Nerve instrument , was connected to the acupuncture needles at all acupoints. EA stimulation parameters were as follows. Continuous wave frequency was 2 Hz. The intensity was set to 0.1 mA and increased to 10 mA, resulting in mild limb trembling, which was tolerated by the rats. The treatment was performed once a day for 8 consecutive weeks, and each session lasted 20 minutes.Rats in the EA group were treated with EA for 8 weeks. Acupuncture points were located according to “the map of acupuncture points for rats” in Experimental Acupuncture Science. SP6 is located 10 mm above the tip of the medial malleolus in rats. Since rats have only three pairs of posterior sacral foramina, we located the BL33 point at the second posterior sacral foramen , 26. DisAccording to our previous animal experimental protocol  and relan = 8 per group) were anesthetized with sodium pentobarbital . A polyethylene tube  was inserted into the bladder through the urethra and connected to a pressure transducer  and a microinjection pump  via a 3-way stopcock, to record the bladder pressure and infuse the bladder with normal saline. The micturition volume was recorded by a liquid collector . Saline was infused into the bladder at a rate of 0.6 ml/min. The urodynamic parameters of each group, such as volume threshold for eliciting micturition, maximum intravesical pressure , BC, voided volume, postvoid residual (PVR) volume, and V% (100 × PVR/BC), were calculated and compared. Measurements in each rat represented the average of five micturition cycles after an initial 45 min stabilization period.After 8 weeks of intervention, the rats  and a clinically compatible linear array ultrasound transducer were used. Changes in bladder volume and bladder imaging, such as shape, size, bladder wall status, and abnormal echo, were detected.n = 8, per group) were anesthetized with sodium pentobarbital  and decapitated. The whole bladder was weighed. A portion of the bladder was fixed in a 10% neutral formaldehyde solution for 24 h and then embedded in paraffin. The bladder tissue sections were stained with HE stain. The gross appearance was observed in high-power (×100) fields by examining each section, and specific pathological changes were then observed in higher power (×400) fields. The rest of the bladder tissue was frozen in liquid nitrogen and stored at −80°C.After the transabdominal ultrasound measurements, the rats  for 60 min and infiltrated overnight in a mixture of acetone and embedding agent. A pure embedding medium was poured into the embedding board, which formed a solid matrix by thermal polymerization. An ultrathin microtome was used to cut the bladder samples into 50 nm sections. The samples were stained with uranium acetate (15 min) and lead citrate (2 min) at room temperature. Finally, TEM  was used to perform image analysis.μg) were fractionated by electrophoresis through a 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis and then transferred onto polyvinylidene difluoride membranes . Membranes were blocked with TBST  for 1 h and then incubated with primary antibodies overnight at 4°C. The concentrations of primary antibodies were as follows: p-MLC , p-MLCK , p-MYPT1 , and β-actin . After overnight incubation, the membranes were washed three times with TBST for 5 min each and then incubated with horseradish peroxidase-conjugated secondary antibodies for 3 h at room temperature, followed by three more washes with TBST for 10 min each. Finally, protein bands were detected with the enhanced chemiluminescence kit . Chemiluminescent signals were detected and analyzed by the ChemiDoc XRS imaging system .The bladder tissue proteins were prepared using the Total Protein Extraction Kit , and the protein concentration was determined using a Pierce® BCA Protein Assay Kit . Membrane proteins . The bladder weight of rats in the DM group (368 ± 29.5 mg), EA group (216 ± 18.6 mg), and sham EA group (331 ± 25.6 mg) was significantly (P < 0.05) greater than that of the control group rats (120 ± 19.7 mg). However, the bladder weight of diabetic rats in the EA group significantly decreased compared to the sham EA group (P < 0.05). There was no significant difference between the sham EA group and the DM group. EA and sham EA treatment did not have any effect on the body weight and serum glucose levels throughout the experiment , EA group , and sham EA group  compared to those in the control group  higher than those in the control group. EA treatment significantly (P < 0.05) decreased the volume threshold for micturition, PVR volume, and V% in the DM group compared to those of the sham EA group. Furthermore, there was no significant difference in Pv, max among the four groups . There was no significant difference between the DM and sham EA group. After 8 weeks of treatment, the bladder wall thickness was significantly decreased in the EA group compared to the sham EA group , and the nuclear membrane was clear and complete. Organelles such as mitochondria (Mi), rough endoplasmic reticulum (RER), and ribosomes were observed in the cytoplasm and between muscle fibers, with complete and clear structures. Occasionally, the RER expanded into a cystic shape .In the DM group, most of the Mi in SMCs were swollen; cristae were broken, dissolved, or even disappeared; and a small amount of autophagy was observed. In the fibroblasts, swelling of a few Mi was observed, the cristae were broken, dissolved, or even disappeared, and a few RER appeared cystic .In the EA group, some Mi were swollen and the cristae were broken, dissolved, or even disappeared in SMCs. Mild swelling of some Mi was observed in the fibroblasts .In the sham EA group, mild swelling of a small number of Mi was observed in SMCs. In the fibroblasts, most of the Mi were swollen; the cristae were broken, dissolved, or even disappeared; and some RER showed slight expansion .P < 0.05). It was reduced after EA treatment as compared to the sham EA group (P < 0.05). The expression of p-MLCK protein was significantly lower (P < 0.01) in the DM group than in the control group. The p-MLCK protein level was significantly increased in the EA group compared to the sham EA group (P < 0.05). No differences were found in p-MYPT1 comparisons among all the groups  at 1 week after STZ administration and a decompensated state (underactive bladder) at 4 months [Previous studies have found that DBD symptoms can appear 2-3 months after STZ administration . It is s4 months . Their r4 months , 41. TheV% were significantly decreased compared with the sham EA group, suggesting that EA treatment could restore the micturition reflex. In order to further evaluate the lesions of the bladder, we used transabdominal ultrasound measurements to detect the thickness of the bladder wall. We observed that the bladder wall of the DM group was significantly thicker than that of the control group. This is mainly due to bladder detrusor smooth muscle layer hypertrophy [EA has been widely accepted as an alternative therapy for various diseases . The effertrophy . Further2+- and ATP-dependent process. The MLC phosphorylation process decomposes enough ATP, converts chemical energy into mechanical energy, and causes smooth muscle contraction through the myosin-affecting actin [2+, which in turn causes the relaxation of rabbit detrusor muscles to alleviate the symptoms of interstitial cystitis [2+, and the balance between MLCK and MLCP regulates the relationship between intracellular Ca2+ contractility [2+ binds with CAM to form Ca2+-CAM complex, which then binds with downstream MLCK and activates serine 19 of MLC 20. The p-MLC 20 myosin combines with actin to form a transmembrane bridge. ATPase in the head of myosin decomposes ATP to produce energy, which causes a cross-bridge swing and finally triggers myofilament contraction [Currently, it is generally believed that the contraction of bladder detrusor smooth muscle is a Cang actin , 50. Thecystitis . The Wesactility . Intracetraction . The contraction . Our resThe internal wall of the bladder detrusor smooth muscle is covered by mucosa, which also provides a sensory function to monitor the degree of bladder filling and composition of urine . There iMicturition is a complex process, which mainly involves the activation and contraction of detrusor smooth muscle receptors , 56. ThePrevious studies have found that the phosphorylation level of MLC in diabetic animals is significantly higher . Our resCystometrogram is commonly used to assess bladder dysfunction. It is used to detect the effects of interventions on the three urodynamic parameters: Pv, max; emptying volume; and PVR volume , 58. FurEA may alleviate bladder dysfunction in STZ–HFD-induced diabetic rats, reduce the bladder hypertrophy, and reverse the impairment in the mucosa layer and detrusor SMCs by regulating MLC and MLCK phosphorylation in the bladder detrusor.


Postoperative delayed hyponatremia is a complication associated with transsphenoidal pituitary surgery. Due to a wide spectrum of symptoms, the reported incidence and predictors of postoperative delayed hyponatremia vary among studies, and this deserves to be reviewed systematically.  PubMed, EMBASE, and CENTRAL databases were searched until September 1, 2020. Studies were included when (1) the event number of delayed hyponatremia after transsphenoidal pituitary surgery was reported, or (2) the associated factors of such complication were evaluated. P = 0.006).  A total of 27 studies were included for meta-analysis. The pooled incidence of overall and symptomatic delayed hyponatremia was 10.5%  = 7.4–14.7%) and 5.0% (95% CI = 3.6–6.9%), respectively. No overt variations of the pooled estimates were observed upon subgroups stratified by endoscopic and microscopic procedure, publication year, and patients' age. In addition, 44.3% (95% CI = 29.6–60.2%) of unplanned hospital readmissions within 30 days were caused by delayed hyponatremia. Among the predictors evaluated, older age was the only significant factor associated with increased delayed hyponatremia (odds ratio = 1.16, 95% CI = 1.04–1.29,  This meta-analysis and systematic review evaluated the incidence of postoperative delayed hyponatremia and found it as a major cause of unplanned readmissions after transsphenoidal pituitary surgery. Older patients are more prone to such complications and should be carefully followed. The retrospective nature and heterogeneity among the included studies and the small number of studies used for risk factor evaluation might weaken the corresponding results. Future prospective clinical studies are required to compensate for these limitations. Postoperative delayed hyponatremia, defined as serum sodium <130–135 mmol/L, can occur in 1.8–35% of patients who underwent transsphenoidal pituitary tumour surgery, with the peak incidence reported on day 7-8 following surgery , patientSeveral pathophysiological mechanisms of posttranssphenoidal pituitary surgery delayed hyponatremia have been proposed, with the syndrome of inappropriate antidiuretic hormone (SIADH) and cerebral salt wasting (CSW) syndrome as the main stream models –3. PartiThe aims of this systematic review and meta-analysis are to address (1) the incidence of postoperative delayed hyponatremia following transsphenoidal pituitary surgery and its role on unplanned readmission and (2) the potential predictors of such complication by reviewing the published literature.A literature search through the major public databases  was conducted using “transsphenoidal,” “pituitary neoplasms,” “pituitary adenoma,” “surgery,” and “hyponatremia” as keywords combined with Boolean operators and using Medical Subject-Headings (MeSH) terms where appropriate for studies published prior to September 1, 2020. As an example, the search string used for PubMed was AND hyponatremia [MeSH].The inclusion criteria were studies that either reported (1) event number and/or incidence of delayed hyponatremia during the postoperative follow-up of either endoscopic or microscopic transsphenoidal surgery for pituitary tumours or (2) the associated factors of such delayed hyponatremia. In contrast, studies where (1) early or delayed onset hyponatremias cannot be clearly distinguished, (2) paediatric patients were enrolled only, (3) no quantitative outcomes of interest were available, and (4) language other than English was adopted were excluded from the present review. Regarding publication type, only cohort studies performed prospectively or retrospectively were eligible for inclusion, while letters, commentaries, editorials, proceedings, case reports, and personal communications were not considered. In addition, the reference lists of included studies were hand-searched to identify other potentially relevant studies. This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines .The incidence of postoperative delayed hyponatremia, defined as serum sodium concentration <130–135 mmol/L occurring on a postoperative day (POD) three and onwardsThe incidence of symptomatic delayed hyponatremia, defined as delayed hyponatremia with patient-reported symptomsThe rate of postoperative delayed hyponatremia in unplanned hospital readmission within 30 days after surgeryThe demographic and/or clinical factors associated with the occurrence of delayed hyponatremiasThe eligibility of studies identified via the above search and selection strategy was confirmed by two independent reviewers (CCL and YCH), and a third reviewer (CCC) was consulted where there was uncertainty regarding eligibility. From these eligible studies and when available, the following information was extracted: the name of the first author, year of publication, study design, study country, the total number of patients, type of surgery, patients' mean age, sex, tumour characteristics , aetiology of hyponatremia, and main outcomes of interest. Due to the nature of the present review, raw patient data and private information were neither required nor used, and thus informed consent from study subjects or approval from the institutional review board was waived.We assessed the quality of included studies using the Newcastle-Ottawa scale (NOS) for cohort studies as recommended by the Cochrane Nonrandomized Studies Methods Working Group . This scEvent rates of the outcomes of interest with 95% confidence interval (CI) were extracted or calculated from each individual study, and then the summary effect with 95% CI was estimated. Planned subgroup analyses of overall postoperative delayed hyponatremia incidence were performed based on the type of surgery, publication year, and patients' mean age. For the associated factors, the OR with 95% CI was extracted from the included studies, and pooled estimates were generated.χ2-based test of homogeneity was performed to determine the inconsistency index (I2) and Q statistics. If the I2 statistic was >50%, the random-effects model was utilized to calculate pooled effects, and a fixed-effect model was employed when otherwise. A 2-sided P value of <0.05 was considered to indicate the statistical significance of the pooled estimate. Sensitivity analysis for the endpoints was addressed by the leave-one-out approach. Potential publication bias was assessed by Egger's test  [P > 0.05. All analyses were performed using the Comprehensive Meta-Analysis statistical software, version 2.0 .An was >10) , respectThe electronic search and study selection process is shown in Specifically, 10 of the 27 studies were published before 2011 , 34, 37,In general, the definition used for postoperative delayed hyponatremia was comparable among studies, with serum sodium of <130–135 mmol/L as the cut-off and onset on or beyond postoperative day 3 . The incQ statistic = 764.5, I2 = 96.5%, P < 0.001); therefore, the random-effects model was used. Consequently, the pooled overall incidence of postoperative delayed hyponatremia was 10.5% (95% CI = 7.4–14.7%)  . Twenty –14.7% . I2 > 75%). The pooled incidence of delayed hyponatremia following endoscopic transsphenoidal surgery was 11.3% (95% CI = 7.5–16.8%) and 9.2% (95% CI = 3.6–21.8%) in microscopic transsphenoidal surgery. The pooled postoperative delayed hyponatremia incidence of studies published before 2011 and after 2011 was 12.1% (95% CI = 5.6–24.1%) and 9.7% (95% CI = 6.8–13.5%), respectively. The pooled postoperative delayed hyponatremia incidence of studies with a patient cohort aged below 50 years in average and that of studies ≥50 years were similar . The pooled postoperative delayed hyponatremia incidence of studies using the definition for hyponatremia of <135 mmol/L and others was similar to that of the studies using other definitions .Q statistic = 25.2, I2 = 78.4%, P < 0.001, Among the 6 studies that reported the rate of delayed hyponatremia as a cause of unplanned readmission within 30 days following transsphenoidal pituitary surgery , 30, 36,t = 1.106, P = 0.140, t = 0.153, P = 0.440, Sensitivity analyses were performed using the leave-one-out approach in which meta-analysis was performed with each study removed in turn . The sumP = 0.006), whereas no significant associations were found with respect to sex, tumour type, or size  have systematically reviewed the incidence and predictors of delayed hyponatremia after transsphenoidal pituitary surgery based on 10 studies with a total of 2,947 patients  which weAmong the studies evaluating predictors of delayed hyponatremia after transsphenoidal pituitary surgery, most studies found that older age was associated with the occurrence of delayed hyponatremia , 26–28. SIADH, which commonly results from iatrogenic injury of the neurohypophysis during surgical exploration and leads to degeneration of magnocellular neurons and excessive release of antidiuretic hormone, is proposed as an aetiology of postoperative delayed hyponatremia , 2. AnotTo date, there are only limited studies that directly compared the potential impact of endoscopic versus microscopic transsphenoidal pituitary surgery on the occurrence of delayed hyponatremia. It may be intuitive to speculate that less iatrogenic injury in the neurohypophysis is associated with endoscopic than microscopic procedures due to improved visualization. However, a prior systematic review compared postoperative complications between these two surgical approaches and only found 3 published articles reporting relevant data , with noDue to the increased awareness of postoperative delayed hyponatremia and the evidence showing such complication as the main cause of unplanned readmissions after transsphenoidal pituitary surgery, clinicians have devoted to constructing and implementing outpatient care algorithm in preventing delayed hyponatremia-associated rehospitalizations –14. In bAs with previously published studies of similar nature, the interpretation of the results of the present meta-analysis is limited by the heterogeneity across the eligible studies, although they were selected based on stringent criteria and a thorough literature search. To address this issue, we have adopted the random-effects model, study stratification, and sensitivity analysis. Nonetheless, no specific source of heterogeneity could be indicated. Additionally, the retrospective nature of most included studies presents as a potential source of selection bias overall, whereas the small number of studies used for risk factor evaluation may weaken the corresponding results. In the present study, all functional adenomas were pooled together, and we were not able to look at Cushing's disease and acromegaly separately because most of the included studies did not separately report the outcomes by tumour pathologies. Only a rough categorization of age as a risk factor (above 50 vs. below 50) was done in the present analysis due to the nature of data extracted. More research efforts and prospective clinical studies in the field are required to compensate for the limitations discussed herein, especially with an in-depth investigation on the risk factor age.Taking together, this systematic review and meta-analysis demonstrated an incidence of hyponatremia which is unignorable following transsphenoidal pituitary surgery. Furthermore, delayed hyponatremia is a major cause of 30-day readmissions in these patients. Among the potential risk factors, only old age is associated with this complication. Despite several limitations, the present findings may enhance the surgeons' awareness of the patient profile with an increased risk of delayed hyponatremia. Based on such understanding, clinicians may be motivated to develop preventive or interventive measures to reduce the possibility and impact of postoperative delayed hyponatremias.