Context Obstructive sleep apnea (OSA) is highly prevalent in patients with obesity and contributes to metabolic dysfunction and cardiovascular burden. However, its association with cardiopulmonary fitness in metabolic bariatric surgery candidates remains less well characterized. Objective To examine the association between OSA severity and preoperative cardiopulmonary fitness in patients undergoing sleeve gastrectomy (SG). Methods A retrospective cohort study including 104 patients who underwent SG with preoperative sleep evaluations and Cardiopulmonary exercise testing (CPET). Data from clinical characteristics, portable sleep monitoring studies, cardiopulmonary fitness, and metabolic measurements were collected. Setting A university-affiliated hospital. Results Higher OSA severity was associated with lower oxygen uptake (VO2) at anaerobic threshold (AT), reduced power output, blunted heart rate (HR) responses, and decreased oxygen uptake efficiency slope (OUES). After adjustment, higher OSA severity remained significantly associated with lower PowerAT, HRAT, and OUES, among other CPET indices. This effect was observed in both male and female subgroups. Conclusions Higher severity of OSA was associated with reduced preoperative cardiopulmonary fitness in patients undergoing SG. These results may underscore the potential importance of screening for OSA as part of the comprehensive preoperative evaluation in this population.

The influence of preoperative psychological profiles on weight loss following sleeve gastrectomy (SG) has not been thoroughly examined, particularly with respect to sex differences. To analyze the preoperative psychological profiles of individuals with obesity and explore whether sex differences exist in the associations between preoperative psychological factors and weight loss after SG. This prospective cohort study involved participants scheduled for SG at an affiliated hospital between November 2020 and September 2022, with a follow-up period of 1-year post-surgery. Preoperative psychological profiles were assessed using validated scales, covering anxiety, depression, self-esteem, internalized weight bias, eating behaviors, sleep quality, and quality of life. Independent t-tests and Pearson correlation analyses were used to assess sex differences and associations between psychological factors and

INTRODUCTION: Inadequate weight loss (IWL) after sleeve gastrectomy may lead to persistent obesity-related comorbidities and adversely affect long-term health outcomes. Evidence suggests that preoperative metabolic status and body fat distribution are closely associated with postoperative weight loss outcomes. This study aimed to identify preoperative predictors of IWL 1 year after laparoscopic sleeve gastrectomy (LSG) and to develop a clinically applicable nomogram for risk stratification. METHODS: A total of 1,111 patients were initially included. Due to unavailable follow-up data, 989 patients were included in the final analysis. Patients were randomly allocated into training (70%) and validation (30%) sets. Predictor selection used least absolute shrinkage and selection operator (LASSO) regression, followed by multivariable logistic regression. The nomogram was evaluated via discrimination (area under the receiver operating characteristic (AUC) curve) and calibration plots. RESULTS: Four independent predictors of IWL were identified: fasting plasma glucose (FPG) [odds ratio (OR) = 1.09, P = 0.02], visceral fat area (VFA) (OR = 1.01, P < 0.001), fatty liver index (FLI) (OR = 1.02, P < 0.001), and body roundness index (BRI) (OR = 1.28, P = 0.04). The nomogram demonstrated moderate discriminative ability, with an AUC of 0.79 in the training set and 0.77 in the validation set and calibration was excellent (Hosmer-Lemeshow test P > 0.05). CONCLUSION: FPG, VFA, FLI, and BRI were identified as key predictors of IWL after LSG. The developed nomogram may serve as a preliminary tool for preoperative risk stratification of patients with obesity at risk for IWL, although further external validation is required before clinical implementation, enabling personalized intervention strategies.

Obesity predisposes individuals to hypercoagulation, a key factor in life-threatening complications like stroke and cardiovascular disease. While clotting factors are primarily secreted by the liver, the mechanisms linking obesity to hypercoagulation remain unclear. In this study, we established an obesity cohort and conducted genetic analyses, single-nucleus and bulk RNA sequencing of human liver tissues, and in vitro experiments to elucidate the underlying mechanisms. Genetic analysis identified a causal relationship between body mass index (BMI) and coagulation parameters, specifically elevated fibrinogen levels. Clinical cohort data demonstrated a significant association between BMI and plasma fibrinogen levels and fibrinogen function. Hepatic transcriptomic data revealed a significant link between BMI and hepatic fibrinogen expression. snRNA-seq data and deconvolution analysis of bulk RNA-seq uncovered a specific hepatocyte subpopulation (Hep5) that was significantly increased and responsible for aberrant coagulation factor secretion in obesity. Pseudotime trajectory analysis indicated that increased interleukin 6 (IL6) signaling in obese patients contributed to the activation of the hepatocyte identity-related transcription factor CEBPB, promoting the differentiation of other hepatocyte subpopulations into Hep5. Further analysis in an independent obesity cohort confirmed serum IL6 as a critical mediator of the BMI-fibrinogen relationship, supporting the potential value of IL6 antibodies, which are currently in Phase 2b trials, for improving coagulation abnormalities. In vitro experiments demonstrated that the CEBPB inhibitor helenalin acetate reversed the aberrant expression of hepatocyte differentiation-related genes induced by IL6. This study defines the hepatic transcriptomic landscape in obesity, elucidates mechanisms of fibrinogen elevation, and highlights therapeutic targets for managing hypercoagulation in obesity.

Background and Aims Obesity is a global health challenge significantly increasing cardiovascular disease (CVD) burden. Effective prevention and treatment necessitate targeting early pathological changes, particularly obesity-induced endothelial dysfunction (ED). This study aimed to characterize ED heterogeneity in non-hypertensive obese (NHO) individuals, investigate the association of serum metabolites with obesity-induced ED, and identify potentially predictive and therapeutic metabolites.Methods Utilizing wire myograph, this study assessed ED of ex vivo arterioles from omental adipose tissue of 213 NHO patients, categorized into metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO). Targeted metabolomic profiling identified associations between serum metabolites and ED.Results Obesity-induced ED in NHO patients lacked correlations with many traditional cardiovascular risk factors. The MHO and MUO individuals exhibited similar ED and metabolomic profile characteristics. Serum metabolomics identified bile acids (BAs), particularly chenodeoxycholic acid (CDCA), as negatively correlated with ED in NHO patients. Taurochenodeoxycholic acid (TCDCA), a taurine-conjugated derivative of CDCA, protected against obesity-induced ED and hypertension. Mechanistically, endothelial Farnesoid X receptor (FXR) deletion aggravated obesity-induced ED and hypertension, negating the beneficial effects of bariatric surgery or TCDCA treatment. The TCDCA-FXR activation in endothelial cells upregulated ATF4 transcription, which was suppressed by PHB1, thereby enhancing serine and one-carbon metabolism.Conclusions This study suggests CDCA as a promising biomarker for identification of obesity-induced ED. Taurochenodeoxycholic acid demonstrates significant therapeutic potential for alleviating various forms of obesity-induced ED. This effect is mediated by the endothelial TCDCA-FXR-PHB1-ATF4 axis, which upregulates serine and one-carbon metabolism, thereby offering a novel strategy to delay the onset of hypertension and other CVDs.

Obstructive sleep apnea (OSA) and metabolic dysfunction-associated steatotic liver disease (MASLD) are frequently encountered in patients with obesity. The interplay of OSA, MASLD and obesity is unknown. We aimed to elucidate the role of OSA in the relationship between the severity of obesity and MASLD. We enrolled 552 patients intending to undergo sleeve gastrectomy (SG) from January 2020 to August 2023. Biochemical parameters were detected, and sleep breathing conditions were measured before SG. Liver biopsy was performed during SG. Multiple linear regressions and logistic regressions were performed to determine the effect of OSA on MASLD. Multiple mediation analyses were conducted to elucidate the mediating role of OSA in the obesity-MASLD association. OSA severity was independently associated with liver histology, including steatosis score [odds ratio (OR) = 1.424, 95

OBJECTIVES:The correlation between fatty pancreas (FP) and metabolic-associated steatotic liver disease (MASLD), diabetes and other metabolic diseases is still controversial, and it is crucial to recognize the risk factors of FP to prevent its clinical complications. METHODS:Retrospective collection of clinical, pathologic, and imaging data of people with obesity attending Qilu Hospital of Shandong University from January 1, 2020 to October 1, 2022. FP was diagnosed by non-enhanced computed tomography with the ratio of pancreas/spleen <0.7. Using binary logistics regression analysis to construct an FP prediction nomogram model, bootstrap repeated sampling internal validation and temporal external validation were used to test the predictive performance of the model. RESULTS:In this cohort, the average age of the participants was 32.2 years, and the average BMI was 41.3 Kg/m2. The prevalence of FP 23.3% (144/617). People with obesity with or without comorbid FP have partial differences in blood glucose, lipid. Independent factors for FP were body mass index (BMI) (OR = 1.97, 95% CI 1.29-3.01; P = 0.002), diastolic blood pressure (DBP) (OR = 1.55, 95% CI 1.03-2.33; P = 0.035), high-density lipoprotein (HDL) (OR = 1.67, 95% CI 1.11-2.52; P = 0.014), HbA1C (OR = 1.99, 95% CI 1.19-3.34; P = 0.009). This study constructed a nomogram containing these four indicators for FP, and receiver operating characteristic curve analysis indicated that the nomogram has moderate predictive performance. CONCLUSIONS:This study identified key risk factors and developed a validated prediction nomogram for FP in adults with obesity. This model may facilitate early identification of FP and the prevention of related metabolic disorders.

Bariatric surgery has emerged as a promising intervention for obese women with polycystic ovary syndrome (PCOS), a condition strongly associated with obesity and anovulatory infertility. While weight management is a key therapeutic strategy, the optimal approach remains uncertain. A recent randomized controlled trial evaluated the impact of bariatric surgery on ovulation rates in obese women with PCOS. However, methodological limitations, including baseline body mass index discrepancies and minimal weight loss in the medical management group, necessitate cautious interpretation of the findings. To further investigate this issue, we conducted a prospective cohort study involving 192 women with PCOS who had undergone bariatric surgery. We assessed 30 reproductive and metabolic parameters at baseline and at 3, 6, and 12 months postoperatively. Most metabolic parameters improved significantly by 3 months postsurgery but plateaued thereafter, with only triglycerides and high-density lipoprotein cholesterol showing continued improvement. Reproductive outcomes demonstrated sustained improvements in ovulatory dysfunction, coinciding with a reduction in luteinizing hormone levels. However, testosterone levels and polycystic ovarian morphology showed limited improvement, while anti-Müllerian hormone levels remained unchanged. Despite the total weight loss exceeding 30%, further weight reduction did not proportionally enhance outcomes. These findings suggest that while bariatric surgery effectively improves metabolic health and ovulation in PCOS, its long-term hormonal and ovarian effects remain unclear and require further investigation. Head-to-head comparisons with emerging therapies are also urgently needed to refine weight management strategies for this high-risk population.

AIMS:Obesity, as a worldwide healthcare problem, has become more prevalent. ZFP36 is a well-known RNA-binding protein and involved in the posttranscriptional regulation of many physiological processes. Whether the adipose ZFP36 plays a role in obesity and insulin resistance remains unclear. METHODS:The expression levels of ZFP36 were analyzed in adipose tissues of obese patients, diet-induced obese mice, ob/ob mice and db/db mice. To determine whether adipose ZFP36 protects against the diet-induced obesity, we generated adipose-specific ZFP36 knockout (ZFP36AKO) mice, which were subjected to high-fat-diet (HFD) for 16 weeks. To explore the specific molecular mechanisms of ZFP36 regulating metabolic disorders, we used gene array assay of control and ZFP36-deficient adipose tissue, and assessed the pathways in vitro and vivo. RESULTS:Western blotting and RT-PCR were performed to determine the downregulating level of ZFP36 in adipose tissues of obese patients, diet-induced obese mice, ob/ob mice and db/db mice. Relative to control mice, ZFP36AKO mice were more susceptible to HFD-induced obesity, along with insulin resistance, glucose tolerance, and increased metabolic disorders. The obesity of ZFP36AKO mice was attributed to hypertrophy of adipocytes in white adipose tissue via decreased expression of Perilipin1 (PLIN1), adipose triglyceride lipase (ATGL), and hormone-sensitive lipase (HSL). We discovered that ZFP36 oppositely regulated RNF128 expression by repressing the mRNA stability and translation of RNF128, a negative regulator of Sirt1 expression. CONCLUSIONS:This study suggests that ZFP36 in adipose tissue plays an important role in diet-induced obesity, and identifies a novel molecular signaling pathway of ZFP36/RNF128/Sirt1 involved in obesity.

BACKGROUND AND AIMS:At-risk metabolic dysfunction-associated steatohepatitis (MASH) elevates risks of liver-related and all-cause morbidity and mortality. We developed and validated a noninvasive score using routine clinical indicators to identify at-risk MASH in obesity. APPROACH AND RESULTS:Using data from 1961 individuals across 5 independent bariatric cohorts with liver biopsy, we developed the predictive score in 1 derivation cohort (n=1095), performed internal validation (bootstrapping), and conducted external validation using the remaining 4 biopsy-confirmed cohorts (n=866). The score was also validated in the international overweight/obese cohorts from the UK Biobank (n=15,745) and NHANES database (n=1573). Predictive value for severe liver-related outcomes (SLROs, including cirrhosis, hepatocellular carcinoma, etc) was assessed in a UK Biobank subcohort (n=1955; median 13.7-year follow-up). Head-to-head comparisons with existing indices were performed. The predictive model, designated as FMO (Fibrotic/at-risk MASH in Obesity), incorporated aspartate aminotransferase, alanine aminotransferase, triglyceride, and high-density lipoprotein cholesterol. The FMO model demonstrated robust discrimination in derivation (AUROC=0.874, 95% CI 0.844-0.905) and nationwide external validation cohorts (AUROCs=0.803-0.874), and in global validation in both NHANES and UK Biobank (AUROCs=0.866 and 0.753, respectively). Longitudinal analysis confirmed SLRO's prediction (the Harrell C-index=0.703). In the derivation cohort, the FMO model demonstrated optimal rule-out [cutoff 0.05, sensitivity ≥0.90, negative predictive value (NPV) 0.976] and rule-in [cutoff 0.22, specificity ≥0.90, positive predictive value (PPV) 0.481] performance. External validation showed NPVs of 0.907-1.00 and PPVs of 0.333-0.630. Comparative analyses revealed superior diagnostic performance of the FMO model versus some existing models. CONCLUSIONS:The FMO is an accurate and cost-effective noninvasive score for at-risk MASH identification in populations with obesity.

BackgroundNo sex-specific guidelines for surgical anti-obesity strategies have been proposed, partially due to the controversy regarding sex-related differences in weight loss after bariatric metabolic surgery.ObjectivesTo explore sex dimorphism in the effect and predictors of weight loss after sleeve gastrectomy (SG), thereby providing clinical evidence for the sex-specific surgical treatment strategy.MethodsIn a prospective cohort design, participants scheduled for SG at an affiliated hospital between November 2020 and January 2022 were assessed for eligibility and allocated to the Male or Female group with a 1-year follow-up after surgery. The primary outcome was the sex difference in the weight-loss effect after SG indicated by both percentage of total weight loss (TWL%) and excess weight loss (EWL%). The secondary outcome was the analysis of sex-specific preoperative predictors of weight loss after SG based on univariate and multivariate analyses. Independent predictors were obtained to construct a nomogram model. The discrimination, calibration, and clinical utility of the nomogram were based on receiver operating characteristic curve, concordance index, calibration curve, and decision curve analysis, respectively.ResultsNinety-five male and 226 female patients were initially included. After propensity score matching by baseline body mass index (BMI), 85 male and 143 female patients achieved comparable TWL% and EWL% for 1 year after SG. For male patients, baseline BMI, area under the curve for insulin during oral glucose tolerance test, and progesterone were independent predictors of weight loss after SG. Baseline BMI, age, thyroid stimulating hormone, and Self-Rating Anxiety Scale score were independent predictors for female patients.ConclusionNo obvious sex difference is detected in the weight-loss effect after SG. Sex dimorphism exists in the predictors of weight loss after SG. Further research with long-term and a multicenter design is needed to confirm the predictive model.

Background: Performing bariatric surgery on patients with a BMI of over 50 kg/m 2 is challenging. This study aimed to explore the status and challenges related to the perioperative management of such patients in China. Materials and methods: A prospective survey was designed to investigate the perioperative management of patients with a BMI of greater than or equal to 50 kg/m 2 undergoing bariatric surgery in China. The questionnaire of our survey included general information, preoperative management measures, surgical procedures performed, technical details regarding anaesthesia, and postoperative management measures. A response from only one attending physician per bariatric centre was accepted. Results: Physicians from a total of 101 hospitals responded to the questionnaire, and the questionnaire data from 98 hospitals were complete. These centres had completed a total of 44 702 bariatric surgeries since the launch of such surgery to December 2021. A total of 3280 patients had a BMI exceeding 50 kg/m 2 . The preferred surgical procedures for patients with super obesity were sleeve gastrectomy by 62 centres, Roux-en-Y gastric bypass by 11 centres, sleeve gastrectomy plus jejunojejunal bypass by 19 centres, one anastomosis gastric bypass by 1 centre, and duodenal switch by 1 centre. The most worrying issues were cardiopulmonary failure and difficulty in extubation. 91 centres believed that preoperative weight loss was beneficial. A low-calorie diet was the specific measure mainly implemented, only three centres considered using intragastric balloon placement. Postoperative management measures varied greatly. Conclusion: Bariatric surgery has seen rapid development. Chinese physicians show significant differences regarding the perioperative management for patients with a BMI of over 50 kg/m 2 . The perioperative risks of these patients remain relatively high, making further development of clinical pathways is necessary.

Improved β-cell function seems to be essential for better glucose homeostasis after Roux-en-Y gastric bypass but is less studied after sleeve gastrectomy (SG). We evaluated the effects of SG on β-cell function in obese patients with diabetes (DM group) and without (Control group) in response to both oral and intravenous glucose stimulation. The DM group demonstrated impaired insulin sensitivity and insulin response to glucose before surgery. The insulin sensitivity index of both groups significantly improved after SG. In addition, the insulin response to glucose (early insulinogenic index in OGTT and AIRglu in IVGTT) increased in the DM group but decreased in the Control group. As a result, β-cell function improved significantly in both groups after SG since the disposition index (DI) increased in both. However, the DI of DM group still can’t restore to the level of Control group up to 1 year after SG. Our results support that both obese patients with and without diabetes could benefit from SG in β-cell function. For obese patients at risk of or have been diagnosed with diabetes, interventions should be recommended early to preserve or restore β-cell function, and SG could be an effective choice. Further studies are needed for long-term effects.

BackgroundPeriodontitis is a chronic inflammatory disease potentially associated with obesity and type 2 diabetes (T2D). Sleeve gastrectomy (SG) has shown substantial effect on weight loss and treatment of T2D. However, there is no direct evidence comparing the impact of SG on the periodontal status of patients with and without T2D.ObjectivesTo determine the impact of SG on the periodontal status of patients with and without T2D in a real-world setting.MethodsIn a prospective and two-armed cohort design, participants who were scheduled for SG at an affiliated hospital between April 2022 and December 2022 were approached for eligibility. After a clinical evaluation and oral examination, those with periodontitis were included and further divided into the DM group (diabetic) and the Control group (non-diabetic) with a 1-year follow-up after surgery. The primary outcome was the periodontal status of patients at 12 months after SG. The secondary outcomes included weight loss, diabetes remission, and alterations in inflammatory markers for up to 1 year after SG.ResultsFifty-seven and 49 patients were included in the DM and the Control group, respectively. Before surgery, patients in the DM group had further worsened periodontal condition compared with those in the Control group. Accompanied by weight loss and glucose reduction, patients in both groups demonstrated significant decreases in plaque index (PLI) and bleeding index (BI) with no alterations in probing depth or clinical attachment loss for up to 1 year after SG. Even patients in the DM group achieved less TWL% (32.79 ± 6.20% vs. 37.95 ± 8.34, P<0.01), their periodontal condition had more substantial improvement with no significant difference in PLI and BI between groups at 1 year after SG. We also observed a significant reduction in the levels of high sensitive C-reactive protein and interleukin-6 in both groups at 1 year after SG.ConclusionBoth patients with and without T2D demonstrated improved periodontal status for up to 1 year after SG. Patients with T2D achieved less weight loss but a more substantial improvement in periodontal condition. The significant reduction in inflammatory biomarkers contributed to the improvement of periodontal status after SG.

IntroductionPolycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting reproductive-aged women. Some retrospective studies with small sample sizes have reported that bariatric metabolic surgery is effective in remission of irregular menstruation in patients with PCOS and obesity. However, the correlation between preoperative body mass index (BMI), postoperative weight loss, and remission of irregular menstruation in patients with obesity and PCOS after sleeve gastrectomy (SG) is lack of consensus.MethodsWe enrolled 229 participants with obesity and PCOS who underwent SG. All patients were followed up for one year after surgery. Remission of irregular menstruation was defined as a spontaneous consecutive six-month menstrual cycle in one year. Subgroup analysis was conducted using tertiles of preoperative BMI and postoperative total weight loss (TWL)% to determine their correlation with the remission of irregular menstruation after SG.Results79.03% (181/229) patients achieved remission of irregular menstruation one year after SG with a TWL% of 33.25 ± 0.46%. No significant difference was detected in the remission rate among the subgroups with different BMI (P=0.908). TWL% was correlated with the remission of irregular menstruation (OR 1.78, 95% CI 1.18-2.69, P<0.05).ConclusionsSG had a significant effect on the remission of irregular menstruation in patients with obesity and PCOS. Preoperative BMI did not emerge as a decisive factor correlated with remission; instead, TWL% showed potential as a key factor.

STUDY QUESTION:Does the concurrent type 2 diabetes mellitus (T2DM) aggravate the features and prognosis of PCOS in patients undergoing sleeve gastrectomy (SG)? SUMMARY ANSWER:For patients undergoing SG with obesity, concurrent T2DM is associated with aggravated metabolic but milder reproductive features of PCOS and did not attenuate the resumption of regular menstruation for up to 1 year after surgery. WHAT IS KNOWN ALREADY:Women with T2DM have an increased risk of PCOS. However, whether concurrent T2DM further increases the disease burden and treatment difficulty of PCOS in patients with obesity requires further investigation. STUDY DESIGN, SIZE, DURATION:This was a single-center, two-arm, prospective, cohort study enrolling a total of 329 women with PCOS and scheduled for SG because of obesity at an university-affiliated hospital between January 2020 and August 2023, with a 1-year follow-up after surgery. PARTICIPANTS/MATERIALS, SETTING, METHODS:Comparisons were made between patients with T2DM (PCOS+T2DM) and without (PCOS) to examine the impact of T2DM on the metabolic, reproductive, and psychological features of PCOS. The follow-up data of weight loss and menstruation were analyzed to determine the impact of T2DM on PCOS prognosis for up to 1 year after SG. MAIN RESULTS AND THE ROLE OF CHANCE:After controlling for confounders, patients in the PCOS+T2DM group (n = 98) showed more severe insulin resistance, glucose intolerance, dyslipidemia, and non-alcoholic fatty liver disease (NAFLD) (NAFLD activity score 4.31 ± 1.15 versus 3.52 ± 1.42, P < 0.001) than those in the PCOS group (n = 149). In addition, the PCOS+T2DM group had a lower level of total testosterone (1.63 ± 0.69 versus 1.82 ± 0.76, P = 0.045), a lower ratio between luteinizing hormone and follicle-stimulating hormone (median 1.48 versus 1.68, P = 0.030), and a lower proportion of patients with polycystic ovarian morphology (88% versus 96%, P = 0.022) than the PCOS group. As a result, the two groups differed significantly in terms of the Rotterdam classification of PCOS (P = 0.009). No significant difference was detected by group in the psychological features of PCOS except a lower degree of emotional eating in the PCOS+T2DM group (P = 0.001). Although the PCOS+T2DM group took longer to resume regular menstruation after SG (P = 0.037), the two groups had similar proportions of patients with regular menstruation (85% versus 87%, P = 0.758) 1 year after SG, which was further confirmed by subgroup analyses by body mass index. LIMITATIONS, REASONS FOR CAUTION:The prognosis of PCOS after SG mainly focused on the results of menstruation rather than a complete evaluation of the remission of the disease. WIDER IMPLICATIONS OF THE FINDINGS:Our study showed that, for patients with obesity, concurrent T2DM is associated with aggravated metabolic but milder reproductive features of PCOS and did not attenuate the resumption of regular menstruation for up to 1 year after surgery. Our study also highlights the need for high-quality studies with a more comprehensive evaluation of the impact of T2DM on the prognosis of patients with PCOS after SG. STUDY FUNDING/COMPETING INTEREST(S):This study was funded by the National Natural Science Foundation of China Grants (82100853), the Natural Science Foundation of Shandong Province of China (ZR2021QH028), and the Clinical Research Project of Shandong University (2020SDUCRCC024). The authors have no conflicts of interest. TRIAL REGISTRATION:Chinese Clinical Trial Registry with No. ChiCTR1900026845.