Prusogliptin (DBPR108) monotherapy in treatment-naïve patients with type 2 diabetes: A randomized, double-blind, active and placebo-controlled, phase 3 study.

AIM: This study aimed to assess the efficacy and safety of prusogliptin (DBPR108), a novel and highly selective dipeptidyl peptidase-4 inhibitor, in individuals with type 2 diabetes who had not been using glucose-lowering agents regularly for the 8 weeks before the screening period. MATERIALS AND METHODS: In this multicentre, randomized, double-blind, phase 3 study, adult patients with type 2 diabetes were randomly assigned to receive either DBPR108 100 mg, sitagliptin 100 mg, or placebo once daily during the initial 24-week double-blind treatment period, followed by a 28-week open-label extension period during which all patients received DBPR108 100 mg once daily. The primary endpoint was the mean change in glycated haemoglobin (HbA1c) levels from baseline to week 24. RESULTS: In total, 766 patients were enrolled and received DBPR108 100 mg (n = 462), sitagliptin 100 mg (n = 152), or placebo (n = 152). The mean age of all patients was 54.3 ± 10.5 years, with 58% being men. The median duration of type 2 diabetes was 0.38 (0.02, 2.65) years, and the mean HbA1c (SD) at baseline was 7.94% (0.62), 7.88% (0.61) and 7.83% (0.59) for DBPR108, sitagliptin and placebo groups, respectively. At week 24, the least square mean (SE) changes from baseline in HbA1c were -0.63% (0.04%) for DBPR108, -0.60% (0.07%) for sitagliptin and -0.02% (0.07%) for placebo. The mean treatment difference between DBPR108 and placebo was -0.61% (95% CI -0.77% to -0.44%), and between DBPR108 and sitagliptin was -0.03% (95% CI -0.19% to 0.13%). These results indicate that DBPR108 was superior to placebo and non-inferior to sitagliptin. DBPR108 also significantly reduced fasting and postprandial plasma glucose levels and had little effect on body weight. The mean (SD) changes in HbA1c from baseline to week 52 were -0.50% (0.97%) for the DBPR108 group, -0.46% (0.96%) for the sitagliptin group and -0.41% (0.95%) for the placebo group. The incidence of adverse events was comparable across all three groups. CONCLUSIONS: DBPR108 showed superiority to placebo and non-inferiority to sitagliptin in terms of glycaemic control over the initial 24 weeks in treatment-naïve patients with type 2 diabetes. Furthermore, its efficacy was sustained for up to 52 weeks.

Divergent adaptation strategies of abundant and rare bacteria to salinity stress and metal stress in polluted Jinzhou Bay.

Understanding how abundant (AT) and rare (RT) taxa adapt to diverse environmental stresses is vital for assessing ecological processes, yet remains understudied. We collected sediment samples from Liaoning Province, China, representing rivers (upstream of wastewater outlet), estuaries (wastewater outlets), and Jinzhou Bay (downstream of wastewater outlets), to comprehensively evaluate AT and RT adaptation strategies to both natural stressors (salinity stress) and anthropogenic stressors (metal stress). Generally, RT displayed higher α- and ß-diversities and taxonomic groups compared to AT. Metal and salinity stresses induced distinct α-diversity responses in AT and RT, while ß-diversity remained consistent. Both subcommunities were dominated by Woeseia genus. Metal stress emerged as the primary driver of diversity and compositional discrepancies in AT and RT. Notably, AT responded more sensitively to salinity stress than RT. Stress increased topological parameters in the biotic network of AT subcommunities while decreasing values in RT subcommunities, concurrently loosening interactions of AT with other taxa and strengthening interactions of RT with others in biotic networks. RT generally exhibited greater diversity of metal resistance genes compared to AT. Greater numbers of genes related to salinity tolerance was observed for the RT than for AT. Compared to AT, RT demonstrated higher diversity of metal resistance genes and a greater abundance of genes associated with salinity tolerance. Additionally, deterministic processes governed AT community assembly, reinforced by salinity stress. However, the opposite trend was observed in the RT, where the importance of stochastic process gradually increased with metal stresses. The study is centered on exploring the adaptation strategies of both AT and RT to environmental stress. It underscores the importance of future research incorporating diverse ecosystems and a range of environmental stressors to draw broader and more reliable conclusions. This comprehensive approach is essential for gaining a thorough understanding of the adaptive mechanisms employed by these microorganisms.

Research on On-Line Monitoring of Grinding Wheel Wear Based on Multi-Sensor Fusion.

The state of a grinding wheel directly affects the surface quality of the workpiece. The monitoring of grinding wheel wear state can allow one to efficiently identify grinding wheel wear information and to timely and effectively trim the grinding wheel. At present, on-line monitoring technology using specific sensor signals can detect abnormal grinding wheel wear in a timely manner. However, due to the non-linearity and complexity of the grinding wheel wear process, as well as the interference and noise of the sensor signal, the accuracy and reliability of on-line monitoring technology still need to be improved. In this paper, an intelligent monitoring system based on multi-sensor fusion is established, and this system can be used for precise grinding wheel wear monitoring. The proposed system focuses on titanium alloy, a typical difficult-to-process aerospace material, and addresses the issue of low on-line monitoring accuracy found in traditional single-sensor systems. Additionally, a multi-eigenvalue fusion algorithm based on an improved support vector machine (SVM) is proposed. In this study, the mean square value of the wavelet packet decomposition coefficient of the acoustic emission signal, the grinding force ratio of the force signal, and the effective value of the vibration signal were taken as inputs for the improved support vector machine, and the recognition strategy was adjusted using the entropy weight evaluation method. A high-precision grinding machine was used to carry out multiple sets of grinding wheel wear experiments. After being processed by the multi-sensor integrated precision grinding wheel wear intelligent monitoring system, the collected signals can accurately reflect the grinding wheel wear state, and the monitoring accuracy can reach more than 92%.

Dammann gratings-based truly parallel optical matrix multiplication accelerator.

Matrix multiplication (MM) is a fundamental operation in various scientific and engineering computations, as well as in artificial intelligence algorithms. Efficient implementation of MM is crucial for speeding up numerous applications. Photonics presents an opportunity for efficient acceleration of dense matrix computation, owing to its intrinsic advantages, such as huge parallelism, low latency, and low power consumption. However, most optical matrix computing architectures have been limited to realizing single-channel vector-matrix multiplication or using complex configurations to expand the number of channels, which does not fully exploit the parallelism of optics. In this study, we propose a novel, to the best of our knowledge, scheme for the implementation of large-scale two-dimensional optical MM with truly massive parallelism based on a specially designed Dammann grating. We demonstrate a sequence of MMs of 50 pairs of randomly generated 4 × 8 and 8 × 4 matrices in our proof-of-principle experiment. The results indicate that the mean relative error is approximately 0.048, thereby demonstrating optical robustness and high accuracy.

Rational targeting of autophagy in colorectal cancer therapy: From molecular interactions to pharmacological compounds.

The abnormal progression of tumors has been a problem for treatment of cancer and therapeutic should be directed towards targeting main mechanisms involved in tumorigenesis in tumors. The genomic mutations can result in changes in biological mechanisms in human cancers. Colorectal cancer is one of the most malignant tumors of gastrointestinal tract and its treatment has been faced some difficulties due to development of resistance in tumor cells and also, their malignant behavior. Hence, new therapeutic modalities for colorectal cancer are being investigated. Autophagy is a "self-digestion" mechanism that is responsible for homeostasis preserving in cells and its aberrant activation/inhibition can lead to tumorigenesis. The current review focuses on the role of autophagy mechanism in colorectal cancer. Autophagy may be associated with increase/decrease in progression of colorectal cancer due to mutual function of this molecular mechanism. Pro-survival autophagy inhibits apoptosis to increase proliferation and survival rate of colorectal tumor cells and it is also involved in cancer metastasis maybe due to EMT induction. In contrast, pro-death autophagy decreases growth and invasion of colorectal tumor cells. The status of autophagy (upregulation and down-regulation) is a determining factor for therapy response in colorectal tumor cells. Therefore, targeting autophagy can increase sensitivity of colorectal tumor cells to chemotherapy and radiotherapy. Interestingly, nanoparticles can be employed for targeting autophagy in cancer therapy and they can both induce/suppress autophagy in tumor cells. Furthermore, autophagy modulators can be embedded in nanostructures in improving tumor suppression and providing cancer immunotherapy.

Factors associated with the mental health of back-to-Wuhan university students based on quantile regression model during the COVID-19 period.

BACKGROUND: The COVID-19 pandemic had brought the increased levels of depression and anxiety on people. Our study investigated the levels of mental health and influencing factors among back-to-Wuhan university students. METHODS: A cross-sectional questionnaire survey was conducted from 31 August 2020, to 14 September 2020 by convenience sampling on the back-to-Wuhan university students, which included the Generalized Anxiety Disorder Scale (GAD-7), Patient Health Questionnaire-9 (PHQ-9), the Insomnia Severity Index-7 (ISI-7), the revised Impact of Event Scale (IES-R) scales, and the basic demographic characteristics. Moreover, quantile regression analysis was used to identify the key factors related to the mental health variables of the back-to-Wuhan university students during the COVID-19 period. RESULTS: The results from 1017 participants suggested that the prevalence rates of the anxiety, depression, insomnia, and distress were 44%, 47.5%, 37.7%, 57.7%, respectively. Quantile regression showed that mental health scores were negatively associated to age, years from graduation, being discriminated against owing to the experience in Wuhan, and the attitude on the future of COVID-19, while was positively related to the education level (P < 0.05). Especially, the education level was highly related with anxiety (25th = 1.64, 50th = 2.54). CONCLUSION: The finding showed that the respondents who were near graduation, discriminated owing to the experience in Wuhan, and worried about the future trend of COVID-19 had a higher risk of negative psychologic status, especially in the bottom and median quantile, and might require more psycho-social interventions or support.

An IL-1ß homologue induced inflammation and antibacterial immune defense in Siberian sturgeon (Acipenser baeri).

Interleukin-1ß is a key pro-inflammatory cytokine functioning in initiation of inflammatory responses against bacterial- and viral-infections. In the present study, a putative IL-1ß counterpart was identified from Siberian sturgeon (Acipenser baeri) and designated as AbIL-1ß. The Abil-1ß cDNA sequence consists of 1130 bp with an open reading frame (ORF) of 585 bp, which encodes a 194 amino acid (aa) protein. Multiple amino acid sequence alignment revealed that a possible mature peptide could start at Leu18, although no cut site for ICE (IL-1ß converting enzyme) enzyme was present in Siberian sturgeon IL-1ß. Even if AbIL-1ß shares a relative low identity (33.6%) with another sturgeon type II IL-1ß gene from Acipenser dabryanus, they still clustered together in phylogenetic tree. Endogenous Abil-1ß was highly expressed in brain, blood, head kidney and spleen of healthy Siberian sturgeon, and remarkably up regulated in head kidney, spleen, and liver upon Aeromonas hydrophila (A.h) challenge. Consistently, in vitro stimulation test using heat-killed A.h and LPS significantly increased Abil-1ß transcripts of primary spleen cells. To investigate the bactericidal capability of AbIL-1ß, recombinant AbIL-1ß (rAbIL-1ß) was generated by prokaryotes. Pre-injection of rAbIL-1ß reduced the bacterial load in sturgeon spleen after A.h infection. Further, rAbIL-1ß was served as feed additive and demonstrated to enhance hybrid sturgeon's defense against A.h infection by increased expressional levels of immune-related genes (IL-1ß, IL-6, IL-8, IgM and MHCIIß), elevated activities of serum lysosome, ACH50, and MPO, as well as higher percent survival. In summary, the current results suggested that AbIL-1ß functions in immune regulation and could improve sturgeon's resistance to bacterial infection.

Interleukin-6 in Siberian sturgeon (Acipenser baeri): Molecular characterization and immune functional activity.

Interleukin-6 (IL-6) is a pleiotropic cytokine with crucial immunoregulatory functions in both innate and adaptive immune responses. However, the IL-6 sequence and function remain unknown in sturgeon, one chondrostean fish. In the present study, we identified an interleukin-6 homolog from Siberian sturgeon (Acipenser baeri), named AbIL-6. Its open reading frame (ORF) was 657 nucleotides in length, encoding a polypeptide of 218 amino acids, which contains a signal peptide and the IL-6 family domain. Phylogenetic analysis showed that sturgeon IL-6 had close relationship with both teleost and chondrichthyes IL-6s. Abil-6 mRNA was highly expressed in spleen, brain and liver tissues of healthy sturgeon, and significantly up-regulated in the spleen, head kidney and liver by A.hydrophila (A.h) challenge. Heat-killed A.h and LPS effectively stimulated Abil-6 transcripts in primary spleen cells in vitro. In order to understand the bioactivity and influence of AbIL-6 on immune responses, recombinant AbIL-6 (rAbIL-6) was synthesized by prokaryotes and demonstrated to promote the proliferation of spleen cells and head kidney cells in vitro. Additionally, intraperitoneal injection of rAbIL-6 induced significantly higher expression of four immuno-related genes including il-1ß, cxcl10, mhcIIß and igm. rAbIL-6 improved the survival rate and reduced the tissue bacterial load after A.h infection. Taken together, these results suggest that AbIL-6 plays an important role in inflammatory responses and immune defense against bacterial infection of sturgeon.

Regulation of 14-3-3ß/α gene expression in response to salinity, thermal, and bacterial stresses in Siberian sturgeon (Acipenser baeri).

The 14-3-3 proteins are a family of widely expressed acidic proteins, which are involved in the regulation of many biological processes of animals. However, no research regarding 14-3-3 has been described in sturgeon to date, one of the most primitive Actinopterygii species. Here, we identified the first 14-3-3 gene from Siberian sturgeon (Acipenser baeri), named Ab14-3-3ß/α (GenBank Accession No. KY094076.1). The cDNA of Ab14-3-3ß/α is 1212 bp in length, containing a 5'-untranslated region (UTR) of 82 bp, a 3'UTR of 392 bp, and an open reading frame (ORF) of 738 bp, encoding a polypeptide of 245 amino acids which contains a 14-3-3 homologs domain (PF00244). Phylogenetic analysis showed that the 14-3-3 gene product from Acipenser baeri is a counterpart of vertebrate 14-3-3ß/α. The deduced Ab14-3-3ß/α protein shares high identities of 46.5-95.5% with the homologs of other species. Ab14-3-3ß/α mRNA was constitutively expressed in all examined tissues, with high expression levels in the blood and gill. Furthermore, the expression level of Ab14-3-3ß/α mRNA increased significantly in the gill at 1 h under acute salinity shock by transfer of Siberian sturgeons from fresh water (FW) to 15 ppt. In fish subjected to a high temperature (31 °C), Ab14-3-3ß/α showed a significant upregulation in the liver at 3 h compared with the control group (24 °C). A 4.85-fold increase of Ab14-3-3ß/α expression in the spleen of Siberian sturgeon was observed at 24 h following Aeromonas hydrophila challenge. Collectively, these results indicated that Ab14-3-3ß/α might play a certain role in sturgeon in response to some environmental stresses and bacterial challenge.

Molecular characterization and biological functioning of interleukin-8 in Siberian sturgeon (Acipenser baeri).

Interleukin-8, otherwise known as CXCL8, is a CXC chemokine that plays a pivotal regulatory role in immune and inflammation responses of animals. Here, we identified an interleukin-8 homologue from Siberian sturgeon (Acipenser baeri), named AbIL-8, which belongs to the lineage 1 group of teleost fish IL-8s. The cDNA of Abil-8 is 1130 bp in length, containing a 5'- untranslated region (UTR) of 50 bp, a 3'- UTR of 783 bp, and an open reading frame (ORF) of 297 bp that encodes a protein consisting of 98 amino acids. The deduced AbIL-8 contained five cysteines, four of which are highly conserved, and an ELR motif typical of known mammalian CXC chemokines was also found preceding the CXC motif. Our phylogenetic analysis showed that AbIL-8 clustered with the CXCL8_L1 sequences from other teleosts, being clearly distinct from those of either birds or mammals. Abil-8 mRNA was constitutively expressed in all tested tissues and significantly up-regulated in the liver and spleen tissues by the bacteria Aernomas hydrophila. The in vitro experiment using primary spleen cells stimulated with heat-killed Aernomas hydrophila or lipopolysaccharide (LPS) revealed a similar expression pattern to that found in vivo, whereas stimulation on spleen cells with ß-glucan or polyI:C elicited negligible changes in levels of Abil-8 mRNA. Purified recombinant AbIL-8 not only exhibited chemotactic activity for lymphocytes and monocytes in peripheral blood leukocytes (PBLs) and, to a lesser extent, spleen cells, but also stimulated the proliferation of spleen cells at 10 ng/mLor above. Furthermore, intraperitoneal injection of rAbIL-8 also up-regulated the expression of immuno-related genes (IL-6, IgM and MHCIIß) at 24 h. Collectively, these results enhance our understanding of how IL-8 functions in the regulation of the immune responses in sturgeon.

Proinflammatory follicular helper T cells promote immunoglobulin G secretion, suppress regulatory B cell development, and correlate with worse clinical outcomes in gastric cancer.

Gastric cancer is one of the most common and aggressive malignancies. Both bacterial virulence factors and host chronic inflammation are thought to promote gastric cancer development. In this study, we investigated the potential involvement of follicular helper T cells in gastric cancer. Functions of follicular helper T subsets were examined in Helicobacter pylori-infected gastric cancer patients and H. pylori-infected but asymptomatic individuals. We found that the follicular helper T cells in gastric cancer individuals were skewed toward the Th1 and Th17 subsets compared to those in H. pylori-infected but asymptomatic individuals. In a naive B cell-follicular helper T cell coculture, the Th1-follicular helper T cells by themselves were ineffective at stimulating a robust antibody response, unlike the Th2-follicular helper T and Th17-follicular helper T cells. However, Th1-follicular helper T cells significantly promoted the immunoglobulin G response in collaboration with other follicular helper T subsets, through the secretion of interferon gamma. We also found that Th1-follicular helper T cells suppressed the development of interleukin-10+ regulatory B cells, a cell type previously thought to protect H. pylori-infected individuals from tissue damage. In addition, the frequency of Th1-follicular helper T cells in gastric cancer patients was negatively correlated with the disease-free survival of gastric cancer patients after tumor resection. These results suggested that dysregulation of follicular helper T subsets in gastric cancer patients, characterized by increased Th1-follicular helper T cells, contributed to inflammation and tumor development.

The forecasting of surface displacement for tunnel slopes utilizing the WD-IPSO-GRU model.

To quickly assess slope stability based on field displacement monitoring data, this paper constructs a hybrid optimization model that predicts surface displacement during tunnel excavation in base-overburden slopes. The model combines Wavelet Decomposition (WD) with a Gated Recurrent Unit (GRU), and the GRU's hyperparameters are optimized using an Improved Particle Swarm Optimization algorithm (IPSO). The specific steps are as follows: First, the Wavelet Decomposition (WD) technique is applied to decompose the raw displacement data, extracting features at different time-frequency scales. Next, the Dropout technique is incorporated into the GRU model to prevent overfitting. Additionally, nonlinear inertia weight ω improved cognitive factor c1, and social factor c2 are introduced. The PSO algorithm is improved by integrating crossover and mutation concepts from genetic algorithms. Finally, the IPSO is used to optimize the number of neural units hN, HN, LN and dropout rates D1 and D2 in the GRU network architecture. After constructing the WD-IPSO-GRU model, a comprehensive comparison is made with various swarm intelligence algorithms and state-of-the-art models. The experimental results demonstrate that the WD-IPSO-GRU model significantly improves the prediction accuracy of surface displacement in slopes during tunnel excavation. Compared to directly using raw data for prediction, the introduction of the WD preprocessing technique improved the prediction accuracy at measurement points 01 and 02 by 28% and 45.9%, respectively. Additionally, with the model optimized by IPSO, the prediction accuracy at measurement points 01 and 02 increased by 76% and 56.7%, respectively. The WD-IPSO-GRU model effectively addresses the challenges of extracting features from univariate displacement time-series data and determining the parameters of the GRU network. It improves the prediction accuracy of surface displacement in base-overburden type slopes and demonstrates excellent generalization ability and reliability. The research results validate the potential application of the model in geotechnical engineering and provide strong support for assessing slope stability during tunnel excavation.

Omental fibroma combined with right indirect inguinal hernia masquerades as a scrotal tumor: A case report.

BACKGROUND: The most common causes of scrotal enlargement in patients include primary tumor of the scrotum, inflammation, hydrocele of the tunica vaginalis, and indirect inguinal hernia; scrotal enlargement caused by external tumors of the scrotum is rare. The patient had both a greater omentum tumor and an inguinal hernia, and the tumor protruded into the scrotum through the hernia sac, which is even rarer. Moreover, omental tumors are mostly metastatic, and primary omental fibroma is rare. CASE SUMMARY: Here, we report a rare case of a 25-year-old young man with scrotal enlargement and pain for 3 months. Preoperative examination and multidisciplinary discussions considered intra-abdominal tumor displacement and inguinal hernia, and intraoperative exploration confirmed that the greater omentum tumor protruded into the scrotum. Therefore, tumor resection and tension-free inguinal hernia repair were performed. The final diagnosis was benign fibroma of the greater omentum accompanied by an indirect inguinal hernia. CONCLUSION: This unusual presentation of a common inguinal hernia disease illustrates the necessity of performing detailed history taking, physical examination, and imaging before surgery.

Bacterial community in the metal(loid)-contaminated marine vertical sediments of Jinzhou Bay: Impacts and adaptations.

Metal(loid) discharge has led to severe coastal contamination; however, there remains a significant knowledge gap regarding its impact on sediment profiles and depth-resolved bacterial communities. In this study, geochemical measurements (pH, nutrient elements, total and bioavailable metal(loid) content) consistently revealed decreasing nitrogen, phosphorus, and metal(loid) levels with sediment depth, accompanied by reduced alpha diversity. Principal coordinate analysis indicated distinct community compositions with varying sediment depths, suggesting a geochemical influence on diversity. Ecological niche width expanded with depth, favoring specialists over generalists, but both groups decreased in abundance. Taxonomic shifts emerged, particularly in phyla and families, correlated with sediment depth. Microbe-microbe interactions displayed intricate dynamics, with keystone taxa varying by sediment layer. Zinc and arsenic emerged as key factors impacting community diversity and composition using random forest, network analysis, and Mantel tests. Functional predictions revealed shifts in potential phenotypes related to mobile elements, biofilm formation, pathogenicity, N/P/S cycles, and metal(loid) resistance along sediment profiles. Neutral and null models demonstrated a transition from deterministic to stochastic processes with sediment layers. This study provides insights into the interplay between sediment geochemistry and bacterial communities across sediment depths, illuminating the factors shaping these ecosystems.

Efficacy and safety of insulin degludec biosimilar B01411 versus originator insulin degludec in Chinese patients with type 2 diabetes inadequately controlled on oral antidiabetic drugs: a multicenter, randomized, open-label, phase 3 study.

OBJECTIVE: To compare the efficacy and safety of insulin degludec biosimilar B01411 (HS-IDeg) with originator insulin degludec-Tresiba (NN-IDeg) in Chinese patients with type 2 diabetes mellitus (T2DM) who were inadequately controlled on oral antidiabetic drugs (OADs) for at least 3 months. METHODS: This multicenter, randomized, open-label, parallel-group, active-controlled, phase 3 study enrolled 362 participants with T2DM. Participants were stratified according to whether the insulin secretagogue (sulfonylurea or glinide) had been used before the screening and then randomized 1:1 to receive once-daily subcutaneous injections of HS-IDeg (n = 180) or NN-IDeg (n = 182) for 18 weeks. The primary endpoint was the change from baseline in glycated hemoglobin (HbA1c) to week 18. RESULTS: At week 18, the least squares (LS) mean change in HbA1c from baseline was -1.34% (95% CI -1.47 to -1.21) and -1.25% (95% CI -1.38 to -1.12) with HS-IDeg and NN-IDeg, respectively. The LS mean difference (HS-IDeg minus NN-IDeg) in HbA1c at week 18 was -0.09% (95% CI -0.28 to 0.10), demonstrating non-inferiority of HS-IDeg to NN-IDeg. Participants achieving HbA1c <7.0% at week 18 were 34.5% and 29.5% with HS-IDeg and NN-IDeg, respectively. Mean decreases in fasting plasma glucose and standard deviation of blood glucose were similar between both groups. Safety and tolerability, including hypoglycemia, adverse events, and weight change were similar between both groups. No severe hypoglycemia and no death occurred in the study. CONCLUSIONS: HS-IDeg and NN-IDeg demonstrated similar efficacy and safety over 18 weeks of treatment in Chinese patients with T2DM who had inadequate responses to OADs for at least 3 months.

Efficacy and safety of GLP-1 analog ecnoglutide in adults with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 2 trial.

Glucagon-like peptide-1 (GLP-1) analogs are important therapeutics for type 2 diabetes and obesity. Ecnoglutide (XW003) is a novel, long-acting GLP-1 analog. We conducted a Phase 2, randomized, double-blind, placebo-controlled study enrolling 145 adults with T2DM. Participants were randomized to 0.4, 0.8, or 1.2 mg ecnoglutide or placebo as once-weekly injections for 20 weeks. The primary objective was to evaluate the efficacy of ecnoglutide, as measured by HbA1c change from baseline at Week 20. Secondary endpoints included body weight, glucose and lipid parameters, as well as safety. We show that, at end of treatment, the 0.4, 0.8, and 1.2 mg groups had statistically significant HbA1c reductions from baseline of -1.81%, -1.90%, and -2.39%, respectively, compared to -0.55% for placebo (P < 0.0001). At end of treatment, 71.9% of the 1.2 mg group had HbA1c ≤ 6.5% versus 9.1% on placebo, and 33.3% had body weight reductions ≥5% versus 3.0% for placebo. Ecnoglutide was generally safe and well tolerated. China Drug Trials Registry CTR20211014.

Efficacy and Safety of Mazdutide in Chinese Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial.

OBJECTIVE: We conducted a randomized, double-blind, placebo-controlled phase 2 trial to evaluate the efficacy and safety of mazdutide, a once-weekly glucagon-like peptide 1 and glucagon receptor dual agonist, in Chinese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Adults with type 2 diabetes inadequately controlled with diet and exercise alone or with stable metformin (glycated hemoglobin A1c [HbA1c] 7.0-10.5% [53-91 mmol/mol]) were randomly assigned to receive 3 mg mazdutide (n = 51), 4.5 mg mazdutide (n = 49), 6 mg mazdutide (n = 49), 1.5 mg open-label dulaglutide (n = 50), or placebo (n = 51) subcutaneously for 20 weeks. The primary outcome was change in HbA1c from baseline to week 20. RESULTS: Mean changes in HbA1c from baseline to week 20 ranged from -1.41% to -1.67% with mazdutide (-1.35% with dulaglutide and 0.03% with placebo; all P < 0.0001 vs. placebo). Mean percent changes in body weight from baseline to week 20 were dose dependent and up to -7.1% with mazdutide (-2.7% with dulaglutide and -1.4% with placebo). At week 20, participants receiving mazdutide were more likely to achieve HbA1c targets of <7.0% (53 mmol/mol) and ≤6.5% (48 mmol/mol) and body weight loss from baseline of ≥5% and ≥10% compared with placebo-treated participants. The most common adverse events with mazdutide included diarrhea (36%), decreased appetite (29%), nausea (23%), vomiting (14%), and hypoglycemia (10% [8% with placebo]). CONCLUSIONS: In Chinese patients with type 2 diabetes, mazdutide dosed up to 6 mg was generally safe and demonstrated clinically meaningful HbA1c and body weight reductions.

Pulse pressure and its association with body composition among Chinese men and women without diagnosed hypertension: the China Kadoorie Biobank.

BACKGROUND: Wide brachial pulse pressure (PP) has been associated with cardiovascular events, while its population distribution and association with body composition were poorly characterized in large populations. METHODS: We evaluated the age and sex distributions of PP and its associations with body composition using baseline data from the China Kadoorie Biobank. A total of 434 200 participants without diagnosed hypertension were included in the analysis. Wide PP was defined as PP above 65 mmHg. Body composition variables, including BMI, waist circumference, waist-to-hip ratio (WHR), fat mass index (FMI), fat-free mass index (FFMI), and body fat percentage (BF%), were obtained from bioelectrical impedance analysis. RESULTS: Overall, 14.3% of the participants had wide PP. Older age was consistently associated with wider PP in women but only after the andropause stage in men. The independent associations of BMI with wide PP were stronger than other body composition measures. The adjusted differences (men/women, mmHg) in PP per standard deviation (SD) increase in BMI (1.55/1.47) were higher than other body composition (BF%: 0.32/0.64, waist circumference: 0.33/0.39; WHR: 0.49/0.42). In addition, sex differences were observed. In men, the per SD difference in PP was higher for FFMI than for FMI (0.91 vs. 0.67, P  < 0.05), whereas in women, it was higher for FMI than for FFMI (1.01 vs. 0.72, P  < 0.05). CONCLUSION: Our nationwide population-based study presented the sex-specific distribution of PP over age and identified differential associations of PP with fat and fat-free mass in men and women.

Differential Gut Microbiota, Dietary Intakes in Constipation Patients with or without Hypertension.

SCOPE: Diet and gut microbiota are involved in blood pressure regulations, but few studies have focused on the constipation patients. The study seeks to identify differences in gut microbiota between hypertensive and normotensive subjects in constipation patients, analyzes the relationship between dietary patterns and blood pressure, and explores mediation effects of gut microbiota. METHODS AND RESULTS: Gut microbial genera and dietary information of 186 functional constipation participants are characterized by 16S rRNA sequencing and a food frequency questionnaire. The hypertensive subjects shows lower α-diversity and ß-diversity of gut microbiota than normotensive (p < 0.05) and 17 differential microbial genera. The dried-beans intake frequency inversely correlated with systolic and diastolic blood pressure after multivariate adjustment (r = -0.273, p-FDR < 0.01; r = -0.251, p-FDR = 0.026, respectively). Logistic regression indicates that the individuals often consumed dried-beans have a lower hypertension risk than those never consumed [OR = 0.137, 95% CI: (0.022, 0.689), p = 0.022]. A marginal mediating effect of the genus Monoglobus is observed for the association between high-fiber dietary pattern and hypertension. CONCLUSION: In patients with functional constipation, hypertension-related gut microbial differences are identified. Dried-beans intake is inversely associated with blood pressure, and a genus may potentially mediate the association between high-fiber dietary pattern and hypertension.

Effects of dietary fibers or probiotics on functional constipation symptoms and roles of gut microbiota: a double-blinded randomized placebo trial.

Dietary fibers/probiotics may relieve constipation via optimizing gut microbiome, yet with limited trial-based evidences. We aimed to evaluate the effects of formulas with dietary fibers or probiotics on functional constipation symptoms, and to identify modulations of gut microbiota of relevance. We conducted a 4-week double-blinded randomized placebo-controlled trial in 250 adults with functional constipation. Intervention: A: polydextrose; B: psyllium husk; C: wheat bran + psyllium husk; D: Bifidobacterium animalis subsp. lactis HN019 + Lacticaseibacillus rhamnosus HN001; Placebo: maltodextrin. Oligosaccharides were also included in group A to D. 16S rRNA sequencing was used to assess the gut microbiota at weeks 0, 2, and 4. A total of 242 participants completed the study. No time-by-group effect was observed for bowel movement frequency (BMF), Bristol stool scale score (BSS), and degree of defecation straining (DDS), while BSS showed mean increases of 0.95-1.05 in group A to D (all P < 0.05), but not significantly changed in placebo (P = 0.170), and 4-week change of BSS showed similarly superior effects of the interventions as compared placebo. Group D showed a marginal reduction in plasma 5-hydroxytryptamine. Group A resulted in a higher Bifidobacterium abundance than placebo at week 2 and 4. Fourteen genera showed intervention-specific increasing or decreasing trends continuously, among which Anaerostipes showed increasing trends in groups B and C, associated with BMF increase. Random forest models identified specific baseline microbial genera panels predicting intervention responders. In conclusion, we found that the dietary fibers or probiotics may relieve hard stool, with intervention-specific changes in gut microbiota relevant to constipation relief. Baseline gut microbiota may predispose the intervention responsiveness. ClincialTrials.gov number, NCT04667884.

What is the context?Supplementation of dietary fibers, such as psyllium husk or wheat bran (10 ~ 15 g/day) may relieve constipation symptoms, but bloating and flatulence are major concerns on a high fiber intake.Functional constipation patients had alternated gut microbiota profiles, while meta-analysis suggested that multispecies probiotics may increase bowel movement frequency and relieve hard stool in functional constipation.Dietary fibers or probiotics may lead to before-after changes of gut microbiota in patients with functional constipation, but time-series continued changes of gut microbiota during the intervention are unknown.Elevation of 5-hydroxytryptamine synthesis in enterochromaffin cells may affect bowel movement. And the elevated plasma 5-hydroxytryptamine was observed in functional constipation patients.What is new? Daily supplement of three prebiotic formulas with dietary fibers (polydextrose, psyllium husk, wheat bran, together with oligosaccharides), or a probiotic formula with Bifidobacterium animalis subsp. lactis HN019 + Lacticaseibacillus rhamnosus HN001 effectively relieved hard stool in functional constipation patients after 4 weeks intervention.We identified continued increasing or decreasing gut microbial genera over the intervention. Dietary fiber ­ gut microbiota (Anaerostipes)­constipation relieve (bowel movement frequency) evidence axis was identified in this human trial.Probiotic supplementation marginally reduced plasma 5-hydroxytryptamine, possibly associated with changes in BMF-related gut microbial genera.Intervention-specific baseline gut microbiota well predicted the responsiveness of constipation symptom relief.What is the impact? We provided references for the dosage and duration of dietary fiber/probiotics recommendations for adults with functional constipation, and advanced the microbial genera evidences of the fibers/probiotics-microbiota-laxation theory in humans.