Marital status impacts survival of stage I non-small-cell lung cancer: a propensity-score matching analysis.

Aim: This population-based analysis aimed to explore the associations among marital status, prognosis and treatment of stage I non-small-cell lung cancer. Materials & methods: The propensity score matching (PSM), logistic regression and Cox proportional hazards model were used in this study. Results: A total of 13,937 patients were included. After PSM, 10579 patients were co-insured. The married were more likely to receive surgical treatment compared with the unmarried patients (OR: 1.841, p < 0.001), and patients who underwent surgery also tended to have better survival (HR: 0.293, p < 0.001). Conclusion: Compared with unmarried patients, a married group with stage I NSCLC had timely treatment and more satisfactory survival. This study highlights the importance of prompt help and care for unmarried patients.

Examining the association between delay discounting, delay aversion and physical activity in Chinese adults with type-2 diabetes mellitus.

BACKGROUND: The role of physical activity in diabetes is critical, influencing this disease's development, man-agement, and overall outcomes. In China, 22.3% of adults do not meet the minimum level of physical activity recommended by the World Health Organization. Therefore, it is imperative to identify the factors that contributing to lack of physical activity must be identified. AIM: To investigate the relationship among delay discounting, delay aversion, glycated hemoglobin (HbA1c), and various levels of physical activity in Chinese adults diagnosed with type 2 diabetes mellitus (T2DM). METHODS: In 2023, 400 adults with T2DM were recruited from the People's Hospital of Linxia Hui Autonomous Prefecture of Gansu Province. A face-to-face questionnaire was used to gather demographic data and details on physical activity, delay discounting, and delay aversion. In addition, HbA1c levels were measured in all 400 participants. The primary independent variables considered were delay discounting and delay aversion. The outcome variables included HbA1c levels and different intensity levels of physical activity, including walking, moderate physical activity, and vigorous physical activity. Multiple linear regression models were utilized to assess the relationship between delay discounting, delay aversion, and HbA1c levels, along with the intensity of different physical activity measured in met-hours per week. RESULTS: After controlling for the sample characteristics, delay discounting was negatively associated with moderate physical activity (ß = -2.386, 95%CI: -4.370 to -0.401). Meanwhile, delay aversion was negatively associated with the level of moderate physical activity (ß = -3.527, 95% CI: -5.578 to -1.476) in the multiple linear regression model, with statistically significant differences. CONCLUSION: Elevated delay discounting and increased delay aversion correlated with reduced levels of moderate physical activity. Result suggests that delay discounting and aversion may influence engagement in moderate physical activity. This study recommends that health administration and government consider delay discounting and delay aversion when formulating behavioral intervention strategies and treatment guidelines involving physical activity for patients with T2DM, which may increase participation in physical activity. This study contributes a novel perspective to the research on physical activity in adults with T2DM by examining the significance of future health considerations and the role of emotional responses to delays.

Impact of preoperative anemia on patients undergoing total joint replacement of lower extremity: a systematic review and meta-analysis.

PURPOSE: Preoperative anemia increases postoperative morbidity, mortality, and the risk of allogeneic transfusion. However, the incidence of preoperative anemia in patients undergoing total hip arthroplasty and total knee arthroplasty (TKA) and its relationship to postoperative outcomes has not been previously reported. METHODS: We conducted a comprehensive literature search through PubMed, Cochrane Library, Web of Sincien, and Embase from inception to July 2023 to investigate the prevalence of preoperative anemia in patients undergoing Total Joint Arthroplasty, comorbidities between anemic and non-anemicpatients before surgery, and postoperative outcomes. postoperative outcomes were analyzed. Overall prevalence was calculated using a random-effects model, and heterogeneity between studies was examined by Cochran's Q test and quantified by the I2 statistic. Subgroup analyses and meta-regression analyses were performed to identify sources of heterogeneity. Publication bias was assessed by funnel plots and validated by Egger's test. RESULTS: A total of 21 studies with 369,101 samples were included, all of which were retrospective cohort studies. 3 studies were of high quality and 18 studies were of moderate quality. The results showed that the prevalence of preoperative anemia was 22% in patients awaiting arthroplasty; subgroup analyses revealed that the prevalence of preoperative anemia was highest in patients awaiting revision of total knee arthroplasty; the highest prevalence of preoperative anemia was found in the Americas; preoperative anemia was more prevalent in the female than in the male population; and preoperative anemia with a history of preoperative anemia was more common in the female than in the male population. patients with a history of preoperative anemia; patients with joint replacement who had a history of preoperative anemia had an increased risk of infection, postoperative blood transfusion rate, postoperative blood transfusion, Deep vein thrombosis of the lower limbs, days in hospital, readmission within three months, and mortality compared with patients who did not have preoperative anemia. CONCLUSION: The prevalence of preoperative anemia in patients awaiting total joint arthroplasty is 22%, and is higher in TKA and female patients undergoing revision, while preoperative anemia is detrimental to the patient's postoperative recovery and will increase the risk of postoperative complications, transfusion rates, days in the hospital, readmission rates, and mortality.

Human-multimodal deep learning collaboration in 'precise' diagnosis of lupus erythematosus subtypes and similar skin diseases.

BACKGROUND: Lupus erythematosus (LE) is a spectrum of autoimmune diseases. Due to the complexity of cutaneous LE (CLE), clinical skin image-based artificial intelligence is still experiencing difficulties in distinguishing subtypes of LE. OBJECTIVES: We aim to develop a multimodal deep learning system (MMDLS) for human-AI collaboration in diagnosis of LE subtypes. METHODS: This is a multi-centre study based on 25 institutions across China to assist in diagnosis of LE subtypes, other eight similar skin diseases and healthy subjects. In total, 446 cases with 800 clinical skin images, 3786 multicolor-immunohistochemistry (multi-IHC) images and clinical data were collected, and EfficientNet-B3 and ResNet-18 were utilized in this study. RESULTS: In the multi-classification task, the overall performance of MMDLS on 13 skin conditions is much higher than single or dual modals (Sen = 0.8288, Spe = 0.9852, Pre = 0.8518, AUC = 0.9844). Further, the MMDLS-based diagnostic-support help improves the accuracy of dermatologists from 66.88% ± 6.94% to 81.25% ± 4.23% (p = 0.0004). CONCLUSIONS: These results highlight the benefit of human-MMDLS collaborated framework in telemedicine by assisting dermatologists and rheumatologists in the differential diagnosis of LE subtypes and similar skin diseases.

Skin mottling score assesses peripheral tissue hypoperfusion in critically ill patients following cardiac surgery.

BACKGROUND: Skin mottling is a common manifestation of peripheral tissue hypoperfusion, and its severity can be described using the skin mottling score (SMS). This study aims to evaluate the value of the SMS in detecting peripheral tissue hypoperfusion in critically ill patients following cardiac surgery. METHODS: Critically ill patients following cardiac surgery with risk factors for tissue hypoperfusion were enrolled (n = 373). Among these overall patients, we further defined a hypotension population (n = 178) and a shock population (n = 51). Hemodynamic and perfusion parameters were recorded. The primary outcome was peripheral hypoperfusion, defined as significant prolonged capillary refill time (CRT, > 3.0 s). The characteristics and hospital mortality of patients with and without skin mottling were compared. The area under receiver operating characteristic curves (AUROC) were used to assess the accuracy of SMS in detecting peripheral hypoperfusion. Besides, the relationships between SMS and conventional hemodynamic and perfusion parameters were investigated, and the factors most associated with the presence of skin mottling were identified. RESULTS: Of the 373-case overall population, 13 (3.5%) patients exhibited skin mottling, with SMS ranging from 1 to 5 (5, 1, 2, 2, and 3 cases, respectively). Patients with mottling had lower mean arterial pressure, higher vasopressor dose, less urine output (UO), higher CRT, lactate levels and hospital mortality (84.6% vs. 12.2%, p < 0.001). The occurrences of skin mottling were higher in hypotension population and shock population, reaching 5.6% and 15.7%, respectively. The AUROC for SMS to identify peripheral hypoperfusion was 0.64, 0.68, and 0.81 in the overall, hypotension, and shock populations, respectively. The optimal SMS threshold was 1, which corresponded to specificities of 98, 97 and 91 and sensitivities of 29, 38 and 67 in the three populations (overall, hypotension and shock). The correlation of UO, lactate, CRT and vasopressor dose with SMS was significant, among them, UO and CRT were identified as two major factors associated with the presence of skin mottling. CONCLUSION: In critically ill patients following cardiac surgery, SMS is a very specific yet less sensitive parameter for detecting peripheral tissue hypoperfusion.

Pancreas-directed AAV8-hSPINK1 gene therapy safely and effectively protects against pancreatitis in mice.

OBJECTIVE: Currently, there is no cure for chronic pancreatitis (CP). Germline loss-of-function variants in SPINK1 (encoding trypsin inhibitor) are common in patients with CP and are associated with acute attacks and progression of the disease. This preclinical study was conducted to explore the potential of adeno-associated virus type 8 (AAV8)-mediated overexpression of human SPINK1 (hSPINK1) for pancreatitis therapy in mice. DESIGN: A capsid-optimised AAV8-mediated hSPINK1 expression vector (AAV8-hSPINK1) to target the pancreas was constructed. Mice were treated with AAV8-hSPINK1 by intraperitoneal injection. Pancreatic transduction efficiency and safety of AAV8-hSPINK1 were dynamically evaluated in infected mice. The effectiveness of AAV8-hSPINK1 on pancreatitis prevention and treatment was studied in three mouse models (caerulein-induced pancreatitis, pancreatic duct ligation and Spink1 c.194+2T>C mouse models). RESULTS: The constructed AAV8-hSPINK1 vector specifically and safely targeted the pancreas, had low organ tropism for the heart, lungs, spleen, liver and kidneys and had a high transduction efficiency (the optimal expression dose was 2×1011 vg/animal). The expression and efficacy of hSPINK1 peaked at 4 weeks after injection and remained at significant level for up to at least 8 weeks. In all three mouse models, a single dose of AAV8-hSPINK1 before disease onset significantly alleviated the severity of pancreatitis, reduced the progression of fibrosis, decreased the levels of apoptosis and autophagy in the pancreas and accelerated the pancreatitis recovery process. CONCLUSION: One-time injection of AAV8-hSPINK1 safely targets the pancreas with high transduction efficiency and effectively ameliorates pancreatitis phenotypes in mice. This approach is promising for the prevention and treatment of CP.

Exploring the enigmatic association between PNLIP variants and risk of chronic pancreatitis in a large Chinese cohort.

BACKGROUND & AIMS: Protease-sensitive PNLIP variants were recently associated with chronic pancreatitis (CP) in European populations. The pathological mechanism yet remains elusive. Herein, we performed a comprehensive genetic and functional analysis of PNLIP variants found in a large Chinese cohort, aiming to further unravel the enigmatic association of PNLIP variants with CP. METHODS: All coding and flanking intronic regions of the PNLIP gene were analyzed for rare variants by targeted next-generation sequencing in 1082 Chinese CP patients and 1196 controls. All novel missense variants were subject to analysis of secretion, lipase activity, and proteolytic degradation. One variant was further analyzed for its potential to misfold and induce endoplasmic reticulum (ER) stress. p.F300L, the most common PNLIP variant associated with CP, was used as a control. RESULTS: We identified 12 rare heterozygous PNLIP variants, with 10 being novel. The variant carrier frequency did not differ between the groups. Of them, only the variant p.A433T found in a single patient was considered pathologically relevant. p.A433T exhibited increased susceptibility to proteolytic degradation, which was much milder than p.F300L. Interestingly, both variants exhibited an increased tendency to misfold, leading to intracellular retention as insoluble aggregates, reduced secretion, and elevated ER stress. CONCLUSIONS: Our genetic and functional analysis of PNLIP variants identified in a Chinese CP cohort suggests that the p.A433T variant and the previously identified p.F300L variant are not only protease-sensitive but also may be potentially proteotoxic. Mouse studies of the PNLIP p.F300L and p.A433T variants are needed to clarify their role in CP.

The molecular characteristics could supplement the staging system of pT2/T3N0M0 esophageal squamous cell carcinoma: a translational study based on a cohort with over 20 years of follow-up.

OBJECTIVE: This study aimed to construct a model based on 23 enrolled molecules to evaluate prognoses of pT2/3N0M0 esophageal squamous cell carcinoma (ESCC) patients with up to 20 years of follow-up. METHODS: The lasso-Cox model was used to identify the candidate molecule. A nomogram was conducted to develop the survival model (molecular score, MS) based on the molecular features. Cox regression and Kaplan-Meier analysis were used in this study. The concordance index (C-index) was measured to compare the predicted ability between different models. The primary endpoint was overall survival (OS). RESULTS: A total of 226 patients and 23 proteins were enrolled in this study. Patients were classified into high-risk (MS-H) and low-risk (MS-L) groups based on the MS score of 227. The survival curves showed that the MS-L cohort had better 5-year and 10-year survival rates than the MS-H group (5-year OS: 51.0% vs. 8.0%; 10-year OS: 45.0% vs. 5.0%, all p < 0.001). Furthermore, multivariable analysis confirmed MS as an independent prognostic factor after eliminating the confounding factors (Hazard ratio 3.220, p < 0.001). The pT classification was confirmed to differentiate ESCC patients' prognosis (Log-rank: p = 0.029). However, the combination of pT and MS could classify survival curves evidently (overall p < 0.001), which showed that the prognostic prediction efficiency was improved significantly by the combination of the pT and MS than by the classical pT classification (C-index: 0.656 vs. 0.539, p < 0.001). CONCLUSIONS: Our study suggested an MS for significant clinical stratification of T2/3N0M0 ESCC patients to screen out subgroups with poor prognoses. Besides, the combination of pT staging and MS could predict survival more accurately for this cohort than the pT staging system alone.

Genetic Factors Associated With Adverse Pregnancy Outcomes in Chronic Pancreatitis.

INTRODUCTION: The effects of genetic factors on pregnancy outcomes in chronic pancreatitis (CP) patients remain unclear. We evaluated the impacts of clinical features and mutations in main CP-susceptibility genes ( SPINK1 , PRSS1 , CTRC , and CFTR ) on pregnancy outcomes in Chinese CP patients. METHODS: This was a prospective cohort study with 14-year follow-up. The sample comprised female CP patients with documented pregnancy and known genetic backgrounds. Adverse pregnancy outcomes were compared between patients with and without gene mutations. Univariate and multivariate analyses were performed to determine the impact factors for adverse pregnancy outcomes. RESULTS: Totally, 160 female CP patients with a pregnancy history were enrolled; 59.4% of patients carried pathogenic mutations in CP-susceptibility genes. Adverse pregnancy outcomes occurred in 38 patients (23.8%); the prevalence of adverse outcomes was significantly higher in those harboring gene mutations than those without (30.5% vs 13.8%, P = 0.015). Notably, the rates of preterm delivery (12.6% vs 3.1%, P = 0.036) and abortion (17.9% vs 4.6%, P = 0.013) were remarkably higher in patients with gene mutations (especially SPINK1 mutations) than those without. In multivariate analyses, both CP-susceptibility gene mutations (odds ratio, 2.52; P = 0.033) and SPINK1 mutations (odds ratio, 2.60; P = 0.037) significantly increased the risk of adverse pregnancy outcomes. Acute pain attack during pregnancy was another risk factor for adverse pregnancy outcomes. DISCUSSION: Pathogenic mutations in CP-susceptibility genes, especially SPINK1 , were independently related to adverse pregnancy outcomes in CP patients. Significant attention should be paid to pregnant females harboring CP-susceptibility gene mutations (ClinicalTrials.gov: NCT06055595).

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.

Serological Comparison of Native Antigen ELISAs with Rapid ICT Test Kits for the Diagnosis of Human Alveolar and Cystic Echinococcosis in China.

BACKGROUND: The aim of this study was to compare the diagnostic performance of native antigen ELISAs and ADAMU-AE/CE commercial ICT test kits in subjects either exposed to Echinococcus infection or with clinically diagnosed alveolar (AE) or cystic (CE) echinococcosis. METHODS: A total of 370 subjects with a previous clinical confirmation of CE or AE from northwestern China were recruited. Serum samples were also obtained from 3923 children/teenagers during a community survey. All sera were tested using native antigen ELISAs. The ADAMU-AE/CE test kits were subsequently used for the serology of the 370 clinically confirmed individuals and of 251 children/teenagers that were ELISA antibody-positive for both Echinococcus species but ultrasound-negative during baseline survey. An analysis of the association between the serological tests and ultrasound classification was carried out amongst 89 AE and 164 CE cases. A Kappa consistency analysis was undertaken to compare the diagnostic performance of the native antigen ELISAs and the ADAMU kits and the ultrasound imaging results. The χ² test was also used for a comparison of the different seropositivity rates between the groups. FINDINGS: There was poor consistency (Kappa = 0.26 and 0.28 for AE and CE respectively) between the native antigen ELISAs and the ADAMU kits for the diagnosis of AE and CE among the cases and the surveyed children/teenagers, but a relatively good consistency (Kappa = 0.63) between the ADAMU-AE kit and ultrasound observations for the AE cases. Additionally, of the 251 teenagers co-positive for both AE and CE antibodies by the native antigen ELISAs, only one was found positive by the ADAMU-AE kit, verified as a new AE case on subsequent ultrasound follow-up. The remainder (N = 250) were negative by serology using the ADAMU-AE/CE kits and by ultrasound examination. The two native antigen ELISAs did not discriminate well between cases of clinically diagnosed AE and CE. In contrast, ADAMU-AE and ADAMU-CE commercial ICT test kits readily differentiated cases of AE from CE with specificities of 99% for AE and 100% for CE. CONCLUSIONS: The ADAMU-AE/CE kits proved reliable, accurate, and amenable diagnostic tools in the clinical setting for confirmation of suspected AE/CE cases. The native antigen ELISAs tests can provide useful information on the level of human exposure to Echinococcus infection.

Analysis of the potential biological value of pyruvate dehydrogenase E1 subunit ß in human cancer.

BACKGROUND: The pyruvate dehydrogenase E1 subunit ß (PDHB) gene which regulates energy metabolism is located in mitochondria. However, few studies have elucidated the role and mechanism of PDHB in different cancers. AIM: To comprehensive pan-cancer analysis of PDHB was performed based on bioinformatics approaches to explore its tumor diagnostic and prognostic value and tumor immune relevance in cancer. In vitro experiments were performed to examine the biological regulation of PDHB in liver cancer. METHODS: Pan-cancer data related to PDHB were obtained from the Cancer Genome Atlas (TCGA) database. Analysis of the gene expression profiles of PDHB was based on TCGA and Genotype Tissue Expression Dataset databases. Cox regression analysis and Kaplan-Meier methods were used to assess the correlation between PDHB expression and survival prognosis in cancer patients. The correlation between PDHB and receiver operating characteristic diagnostic curve, clinicopathological staging, somatic mutation, tumor mutation burden (TMB), microsatellite instability (MSI), DNA methylation, and drug susceptibility in pan-cancer was also analyzed. Various algorithms were used to analyze the correlation between PDHB and immune cell infiltration and tumor chemotaxis environment, as well as the co-expression analysis of PDHB and immune checkpoint (ICP) genes. The expression and functional phenotype of PDHB in single tumor cells were studied by single-cell sequencing, and the functional enrichment analysis of PDHB-related genes was performed. The study also validated the level of mRNA or protein expression of PDHB in several cancers. Finally, in vitro experiments verified the regulatory effect of PDHB on the proliferation, migration, and invasion of liver cancer. RESULTS: PDHB was significantly and differently expressed in most cancers. PDHB was significantly associated with prognosis in patients with a wide range of cancers, including kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, breast invasive carcinoma, and brain lower grade glioma. In some cancers, PDHB expression was clearly associated with gene mutations, clinicopathological stages, and expression of TMB, MSI, and ICP genes. The expression of PDHB was closely related to the infiltration of multiple immune cells in the immune microenvironment and the regulation of tumor chemotaxis environment. In addition, single-cell sequencing results showed that PDHB correlated with different biological phenotypes of multiple cancer single cells. This study further demonstrated that down-regulation of PDHB expression inhibited the proliferation, migration, and invasion functions of hepatoma cells. CONCLUSION: As a member of pan-cancer, PDHB may be a novel cancer marker with potential value in diagnosing cancer, predicting prognosis, and in targeted therapy.

Prevalence and adverse perinatal outcomes of anaemia in the third trimester of pregnancy in Hebei Province, China.

BACKGROUND: Anaemia in pregnancy is one of the most frequent complications related to pregnancy and is a public health concern. This article examines the prevalence of anaemia in the third trimester of pregnancy and the associations between anaemia and adverse perinatal outcomes in Hebei Province, China. METHODS: We used SPSS software to describe the incidence of anaemia in the third trimester of pregnancy in Hebei Province and analysed the clinical characteristics in anaemic patients and the relationship between anaemia and adverse pregnancy outcomes. RESULTS: The overall prevalence of anaemia in the third trimester of pregnancy was 35.0% in Hebei Province. The prevalence of anaemia in the population with a high education level was lower than that in the population with a low education level. The incidence rate in rural areas was higher than that in urban areas. After adjustment for confounding factors, anaemia in the third trimester of pregnancy is an independent risk factor in terms of placenta previa, placental abruption, uterine atony, pre-eclampsia, gestational diabetes mellitus, heart disease, postpartum haemorrhage, premature birth, laceration of birth canal, puerperal infection, caesarean section and large for gestational age. CONCLUSIONS: The prevalence of anaemia in the third trimester of pregnancy is associated with an increased risk of adverse perinatal outcomes. A comprehensive approach to prevent anaemia is needed to improve maternal and child health outcomes.

Evaluation and comparison of efficacy and safety of tirzepatide and semaglutide in patients with type 2 diabetes mellitus: A Bayesian network meta-analysis.

BACKGROUND: As new antidiabetic drugs, tirzepatide (Tir) and semaglutide (Sem) are progressively applied in clinical practice. However, their efficacy and safety profiles have not been comprehensively assessed. Therefore, a Bayesian network meta-analysis was used to evaluate and compare the efficacy and safety of Tir and Sem in treating type 2 diabetes mellitus (T2DM). METHODS: PubMed, EMBASE, Web of Science, Cochrane Library and ClinicalTrials.gov were systematically searched from inception to April 3rd, 2023. Randomized clinical trials (RCTs) comparing the efficacy and safety of Tir and Sem with placebo or the other antidiabetic drugs in treating T2DM were included. The efficacy outcomes included changes in glycated hemoglobin (HbA1c), body weight (BW), body mass index (BMI), and the proportion of participants with HbA1c< 7 %. The safety outcome was the proportion of participants experiencing gastrointestinal adverse events (GIAEs). RESULTS: A total of 38 studies involving 34,166 participants were included. Compared to 1 mg of subcutaneous Sem (Sem SC), 5 mg, 10 mg and 15 mg of Tir demonstrated superior efficacy in reducing HbA1c (mean difference (MD), [95 % CI], -0.22 [-0.40, -0.03] %, -0.42 [-0.60, -0.24] % and -0.53 [-0.71, -0.35] %, respectively) and BW (MD [95 % CI], -1.48 [-2.53, -0.43] kg, -4.00 [-5.05, -2.95] kg and -5.71 [-6.73, -4.68] kg, respectively). Conversely, 7 mg and 14 mg of oral Sem (Sem PO) displayed inferior efficacy in reducing HbA1c (MD [95 % CI], 0.47 [0.26, 0.68] % and 0.35 [0.16, 0.54] %, respectively) and BW (MD [95 % CI], 2.36 [1.24, 3.48] kg and 1.11 [0.10, 2.13] kg). However, 20 mg and 40 mg of Sem PO were non-inferior in reducing HbA1c (MD [95 % CI], 0.13 [-0.29, 0.55] % and 0.01 [-0.38, 0.40] %, respectively) and BW (MD [95 % CI], -0.41 [-2.71, 1.90] kg and -1.32 [-3.58, 0.92] kg). In terms of safety, compared to 1 mg of Sem SC, 5 mg, 10 mg and 15 mg of Tir did not significantly increase the incidence of GIAEs (odd ratio (OR) [95 % CI], 0.70 [0.42, 1.10], 0.87 [0.52, 1.36] and 0.99 [0.60, 1.54], respectively), while 7 mg of Sem PO showed a lower incidence of GIAEs (OR [95 % CI], 0.48 [0.25, 0.83]). Compared to insulin, 0.5 mg of Sem SC, 1 mg of Sem SC, 5 mg of Tir, 10 mg of Tir and 15 mg of Tir displayed better efficacy in lowering HbA1c (MD [95 % CI], -0.40 [-0.63, -0.18] %, -0.69 [-0.90, -0.48] %, -0.91 [-1.10, -0.72] %, -1.11 [-1.30, -0.92] % and -1.22 [-1.41, -1.03] %, respectively) and BW (MD [95 % CI], -5.34[-6.60, -4.09] kg, -6.70 [-7.90,-5.51] kg, -8.18 [-9.27, -7.10] kg, -10.70 [-11.79, -9.61] kg and -12.41 [-13.49,-11.33] kg, respectively). According to the surface under the cumulative ranking curve (SUCRA) value, among all the included interventions, 15 mg of Tir exhibited the most potent effect in reducing HbA1c (99.81 %) and BW (99.98 %), followed by 10 mg of Tir (96.83 % and 95.72 %), 5 mg of Tir (92.88 % and 86.04 %), 1 mg of Sem SC (85.85 % and 74.97 %), 40 mg of Sem PO (83.66 % and 84.31 %), 20 mg of Sem PO (76.98 % and 77.12 %), 300 mg of Can (49.93 % and 60.89 %), insulin (36.38 % and 0.22 %) and 100 mg of Sit (12.28 % and 18.51 %) respectively. Meanwhile, 5 mg, 10 mg, and 15 mg of Tir (48.32 %, 30.96 %, and 21.07 %, respectively), 0.5 mg and 1 mg of Sem SC (33.54 % and 24.77 %, respectively) significantly increased the incidence of GIAEs. CONCLUSION: Both Tir and Sem demonstrated favorable antidiabetic effects and were particularly suitable for T2DM patients who were obese or overweight. Despite a high incidence of GIAEs, their safety profile was deemed acceptable. Tir was the best option among all the included interventions.

Cognitive Deficits and Alzheimer's Disease-Like Pathologies in the Aged Chinese Tree Shrew.

Alzheimer's disease (AD) is the most common chronic progressive neurodegenerative disease in the elderly. It has an increasing prevalence and a growing health burden. One of the limitations in studying AD is the lack of animal models that show features of Alzheimer's pathogenesis. The tree shrew has a much closer genetic affinity to primates than to rodents and has great potential to be used for research into aging and AD. In this study, we aimed to investigate whether tree shrews naturally develop cognitive impairment and major AD-like pathologies with increasing age. Pole-board and novel object recognition tests were used to assess the cognitive performance of adult (about 1 year old) and aged (6 years old or older) tree shrews. The main AD-like pathologies were assessed by Western blotting, immunohistochemical staining, immunofluorescence staining, and Nissl staining. Our results showed that the aged tree shrews developed an impaired cognitive performance compared to the adult tree shrews. Moreover, the aged tree shrews exhibited several age-related phenotypes that are associated with AD, including increased levels of amyloid-ß (Aß) accumulation and phosphorylated tau protein, synaptic and neuronal loss, and reactive gliosis in the cortex and the hippocampal tissues. Our study provides further evidence that the tree shrew is a promising model for the study of aging and AD.

Furosemide Responsiveness Predicts Acute Kidney Injury Progression After Cardiac Surgery.

BACKGROUND: As patients with acute kidney injury (AKI) progress to a higher stage, the risk for poor outcomes dramatically rises. Early identification of patients at high risk for AKI progression remains a major challenge. This study aimed to evaluate the value of furosemide responsiveness (FR) for predicting AKI progression in patients with initial mild and moderate AKI after cardiac surgery. METHODS: We performed 2 separate exploratory analyses. The Zhongshan cohort was a single-center, prospective, observational cohort, whereas the Beth Israel Deaconess Medical Center cohort was a single-center, retrospective cohort. We calculated 2 FR parameters for each patient, namely the FR index and modified FR index, defined as 2-hour urine output divided by furosemide dose (FR index, mL/mg/2 h) and by furosemide dose and body weight (modified FR index, mL/[mg·kg]/2 h), respectively. The primary outcome was AKI progression within 7 days. RESULTS: AKI progression occurred in 80 (16.0%) and 359 (11.3%) patients in the Zhongshan and Beth Israel Deaconess Medical Center cohorts, respectively. All FR parameters (considered continuously or in quartiles) were inversely associated with risk of AKI progression in both cohorts (all adjusted P < .01). The addition of FR parameters significantly improved prediction for AKI progression based on baseline clinical models involving C-index, net reclassification improvement, and integrated discrimination improvement index in both cohorts (all P < .01). CONCLUSIONS: FR parameters were inversely associated with risk of AKI progression in patients with mild and moderate AKI after cardiac surgery. The addition of FR parameters significantly improved prediction for AKI progression based on baseline clinical models.

Rheumatoid arthritis is a protective factor against Alzheimer's disease: a bidirectional two-sample Mendelian randomization study.

BACKGROUND: Epidemiological evidence suggests that there is an association between rheumatoid arthritis (RA) and Alzheimer's disease (AD). However, the causal relationship between RA and AD remains unclear. Therefore, this study aimed to investigate the causal relationship between RA and AD. METHODS: Using publicly available genome-wide association study datasets, bidirectional two-sample Mendelian randomization (TSMR) was performed using the inverse-variance weighted (IVW), weighted median, MR‒Egger regression, simple mode, and weighted mode methods. RESULTS: The results of MR for the causal effect of RA on AD (IVW, odds ratio [OR] = 0.959, 95% confidence interval [CI]: 0.941-0.978, P = 2.752E-05; weighted median, OR = 0.960, 95% CI: 0.937-0.984, P = 0.001) revealed a causal association between genetic susceptibility to RA and an increased risk of AD. The results of MR for the causal effect of AD on RA (IVW, OR = 0.978, 95% CI: 0.906-1.056, P = 0.576; weighted median, OR = 0.966, 95% CI: 0.894-1.043, P = 0.382) indicated that there was no causal association between genetic susceptibility to AD and an increased risk of RA. CONCLUSIONS: The results of this two-way two-sample Mendelian randomization analysis revealed a causal association between genetic susceptibility to RA and a reduced risk of AD but did not reveal a causal association between genetic susceptibility to AD and an increased or reduced risk of RA.

Prediction of pediatric dose of tirzepatide from the reference adult dose using physiologically based pharmacokinetic modelling.

Tirzepatide is an emerging hypoglycemic agent that has been increasing used in adults, yet its pharmacokinetic (PK) behavior and dosing regimen in pediatric population remain unclear. This study aimed to employ the physiologically based pharmacokinetic (PBPK) model to predict changes of tirzepatide exposure in pediatric population and to provide recommendations for its dose adjustments. A PBPK model of tirzepatide in adults was developed and verified by comparing the simulated plasma exposure with the observed data using PK-Sim&MoBi software. This model was then extrapolated to three specific age subgroups, i.e., children (10-12 years), early adolescents (12-15 years), and adolescents (15-18 years). Each subgroup included healthy and obese population, respectively. All known age-related physiological changes were incorporated into the pediatric model. To identify an appropriate dosing regimen that yielded PK parameters which were comparable to those in adults, the PK parameters for each aforementioned subgroup were predicted at pediatric doses corresponding to 87.5%, 75%, 62.5%, and 50% of the adult reference dose. According to the results of simulation, dose adjustments of tirzepatide are necessary for the individuals aged 10-12 years, as well as those aged 12-15 years with healthy body weights. In conclusion, the adult PBPK model of tirzepatide was successfully developed and validated for the first time, and the extrapolated pediatric model could be used to predict pediatric dosing regimen of tirzepatide, which will provide invaluable references for the design of future clinical trials and its rational use in the pediatric population.

Cardiovascular benefits and safety of sotagliflozin in type 2 diabetes mellitus patients with heart failure or cardiovascular risk factors: a bayesian network meta-analysis.

Background: As an antidiabetic agent, sotagliflozin was recently approved for heart failure (HF). However, its cardiovascular benefits in type 2 diabetic mellitus (T2DM) patients with HF or cardiovascular (CV) risk factors have not been systematically evaluated. The aim of this study is to evaluate the cardiovascular benefits and safety of sotagliflozin in T2DM patients with HF or CV risk factors using Bayesian network meta-analysis. Methods: Data were retrieved from PubMed, Embase, Web of Science, ClinicalTrials.gov, and Cochrane Library from their inception to 16 August 2023. Randomized controlled trials (RCTs) comparing sotagliflozin with a placebo, dapagliflozin, and empagliflozin in adult T2DM patients with HF or CV risks for at least 12 weeks were included in the study. Data analysis was conducted using R 4.2.3 and Stata 17.0. Cardiovascular efficacy outcomes included HF events (hospitalization or urgent visits for HF), MACE (deaths from CV causes, hospitalizations for HF, nonfatal myocardial infarctions, and strokes), cardiovascular death, the decrease in SBP, and weight loss. Safety outcomes are urinary tract infection, diarrhea, and diabetic ketoacidosis. Results: Eleven studies with 30,952 patients were included. Compared to dapagliflozin and empagliflozin, 200 mg of sotagliflozin showed the best effect in reducing HF events [OR (95% CI), 0.79 (0.66, 0.94) and 0.90 (0.63, 1.27)]. Compared to dapagliflozin, 200 mg of sotagliflozin [OR (95% CI), 0.76 (0.66, 0.87)] was superior in preventing MACE. Compared to empagliflozin, 200 mg of sotagliflozin [OR (95% CI), 1.46 (1.04, 2.05)] was inferior in preventing CV death. Sotagliflozin showed a poorer SBP decreasing effect than empagliflozin and dapagliflozin [MD (95% CI), 1.30 (0.03, 2.56) and 2.25 (0.35, 4.14), respectively]. There was no significant difference between sotagliflozin and other interventions in weight loss. Sotagliflozin exhibited no increased risk for diabetic ketoacidosis or urinary tract infection among all interventions, however, it showed a mild risk for diarrhea than placebo [OR (95% CI), 1.47 (1.28, 1.69)]. Conclusion: Sotagliflozin displayed moderate CV benefits and acceptable safety. Sotagliflozin can be one of the recommended options for T2DM patients with HF or CV risk factors, which will be important for evidence-based use of sotagliflozin as well as decision-making of T2DM medication.