Prediction model for low bone mass mineral density in type 2 diabetes: an observational cross-sectional study.

PURPOSE: Considering the prevalence of type 2 diabetes (T2D), osteoporosis should be considered a serious complication. However, an effective tool for the assessment of low bone mass mineral density (BMD) in T2D patients is not currently available. Therefore, the aim of our study was to establish a simple-to-use risk assessment tool by exploring risk factors for low BMD in T2D patients. METHODS: This study included 436 patients with a low BMD and 381 patients with a normal BMD. Multiple logistic regression analysis was performed to evaluate risk factors for low BMD in T2D patients. A nomogram was then developed from these results. A receiver operating characteristic (ROC) curve, calibration plot, and goodness-of-fit test were used to validate the nomogram. The clinical utility of the nomogram was also assessed. RESULTS: Multivariate logistic regression indicated that age, sex, education, body mass index (BMI), fasting C-peptide, high-density cholesterol (HDL), alkaline phosphatase (ALP), estimated glomerular filtration rate (eGFR), and type I collagen carboxy terminal peptide (S-CTX) were independent predictors for low BMD in T2D patients. The nomogram was developed from these variables using both the unadjusted area under the curve (AUC) and the bootstrap-corrected AUC (0.828). Calibration plots and the goodness-of-fit test demonstrated that the nomogram was well calibrated. CONCLUSIONS: The nomogram-illustrated model can be used by clinicians to easily predict the risk of low BMD in T2D patients. Our study also revealed that common factors are independent predictors of low BMD risk. Our results provide a new strategy for the prediction, investigation, and facilitation of low BMD in T2D patients.

Metabolic surgery results in greater metabolic benefits in patients who achieve healthy weight.

BACKGROUND: A percentage of total weight loss (%TWL) >20% as the expected weight loss target after metabolic surgery might be insufficient to produce adequate metabolic benefits. OBJECTIVES: This study identified the optimal weight loss target to achieve substantial benefits from metabolic surgery. SETTING: University-affiliated tertiary care center. METHODS: In this retrospective study, participants were categorized into healthy weight (18.5 kg/m2 ≤ body mass index [BMI] < 24 kg/m2), overweight (24 kg/m2 ≤ BMI < 28 kg/m2), and obesity groups (BMI ≥28 kg/m2) according to their BMI 1 year after metabolic surgery. The weight loss and remission of obesity-related comorbidities were evaluated. Ordinal logistic regression analysis was used to identify predictors for achieving healthy weight 1 year postoperatively. RESULTS: Overall, 125 patients (112 sleeve gastrectomies, 13 Roux-en-Y gastric bypasses) were recruited in this study. Forty-two participants achieved healthy weight, 38 were overweight, and 45 had obesity. Type 2 diabetes mellitus and obstructive sleep apnea were relieved in all groups. Individuals who achieved healthy weight showed more improvements in nonalcoholic fatty liver disease, hypertension, and hyperuricemia than those who did not. Preoperative BMI was an independent predictor for the BMI achieved postoperatively, and the optimal cut-off point for achieving healthy weight was 34.9 kg/m2. CONCLUSIONS: Healthy weight was a more stringent target for patients who underwent metabolic surgery than the %TWL. Populations with a preoperative BMI of <34.9 kg/m2 were prone to realize the goal. Additional weight loss interventions could be considered for those with higher preoperative BMIs and enforced within 1 year postoperatively.

Metabolic regulator LKB1 controls adipose tissue ILC2 PD-1 expression and mitochondrial homeostasis to prevent insulin resistance.

Adipose tissue group 2 innate lymphoid cells (ILC2s) help maintain metabolic homeostasis by sustaining type 2 immunity and promoting adipose beiging. Although impairment of the ILC2 compartment contributes to obesity-associated insulin resistance, the underlying mechanisms have not been elucidated. Here, we found that ILC2s in obese mice and humans exhibited impaired liver kinase B1 (LKB1) activation. Genetic ablation of LKB1 disrupted ILC2 mitochondrial metabolism and suppressed ILC2 responses, resulting in exacerbated insulin resistance. Mechanistically, LKB1 deficiency induced aberrant PD-1 expression through activation of NFAT, which in turn enhanced mitophagy by suppressing Bcl-xL expression. Blockade of PD-1 restored the normal functions of ILC2s and reversed obesity-induced insulin resistance in mice. Collectively, these data present the LKB1-PD-1 axis as a promising therapeutic target for the treatment of metabolic disease.

Detection of Glutamate Decarboxylase Antibodies and Simultaneous Multi-Molecular Translocation Exploration by Glass Nanopores.

Glutamic acid decarboxylase antibody (GADAb) has emerged as a significant biomarker for clinical diagnosis and prognosis in type 1 diabetes (T1D). In this study, we investigated the potential utilization of glass capillary solid-state nanopores as a cost-effective and easily preparable platform for the detection of individual antigens, antibodies, and antigen-antibody complexes without necessitating any modifications to the nanopores. Our findings revealed notable characteristic variations in the translocation events of glutamic acid decarboxylase (GAD65) through nanopores under different voltage conditions, discovered that anomalous phenomenon of protein translocation events increasing with voltage may potentially be caused by the crowding of multiple proteins in the nanopores, and demonstrated that there are multiple components in the polyclonal antibodies (GADAb-poly). Furthermore, we achieved successful differentiation between GAD65, GADAb, and GADAb-GAD65 complexes. These results offer promising prospects for the development of a rapid and reliable GADAb detection method, which holds the potential to be applied in patient serum samples, thereby facilitating a label-free, cost-effective, and early diagnosis of type I diabetes.

Clostridioides Difficile: A Concise Review of Best Practices and Updates.

Clostridioides difficile infection (CDI) is one of the most common and severe nosocomial infections worldwide. It can also affect healthy individuals in the community. The incidence of CDI has been on the rise globally for the past decade, necessitating a proactive approach to combat its spread; new strategies are being developed to enhance diagnostic accuracy and optimize treatment outcomes. Implementing the 2-step testing has increased diagnostic specificity, reducing the usage of CD-specific antibiotics with no concomitant increase in surgical complication rates. In 2021, the Infectious Diseases Society of America/Society for Healthcare Epidemiology of America (IDSA/SHEA) shifted its preference for initial treatment to fidaxomicin over vancomycin and metronidazole due to its lower recurrence rate. It also prioritized fidaxomicin for the treatment of recurrent CDI. There are new developments on the frontiers of fecal microbiota therapies, with RBX2660 and SER-109 approved recently by the FDA for prevention, with other microbiome-based therapies in various development and clinical trials. This review offers providers an updated and practical guide for CDI management.

The combined effects of ultrasound and plasma-activated water on silkworm pupae:Physicochemical properties, microbiological diversity and ultrastructure.

A novel technique was proposed for processing silkworm pupae by combining plasma- activated water (PAW) with ultrasound (US). The microbial diversity and quality characteristics of the silkworm pupae were also evaluated. The results of the microbial diversity analysis indicated that PAW combined with US treatment significantly reduced the relative abundance of Streptococcaceae, Leuconostocaceae, and Acetobacteraceae from 32%, 18% and 16% to 27%, 11% and 11%, respectively. Microstructural analysis demonstrated that the collapse of the internal structure of chitin in silkworm pupae facilitated the release of nutrients and flavour compounds including fatty acids, water-soluble proteins (WSP), amino acids, phenolics, and volatile compounds. Furthermore, the increase in antioxidant capacity and the decrease in catalase activity and malondialdehyde content confirmed the mechanism of quality change. These findings provide new insights into the possible mechanism of PAW combined with US to improve the quality of edible insects.

Temporal Trends in Body Composition and Metabolic Markers Prior to Diagnosis of Pancreatic Ductal Adenocarcinoma.

BACKGROUND & AIMS: Changes in body composition and metabolic factors may serve as biomarkers for the early detection of pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to capture the longitudinal changes in body composition and metabolic factors before diagnosis of PDAC. METHODS: We performed a retrospective cohort study in which all patients (≥18 years) diagnosed with PDAC from 2002 to 2021 were identified. We collected all abdominal computed tomography scans and 10 different blood-based biomarkers up to 36 months before diagnosis. We applied a fully automated abdominal segmentation algorithm previously developed by our group for 3-dimensional quantification of body composition on computed tomography scans. Longitudinal trends of body composition and blood-based biomarkers before PDAC diagnosis were estimated using linear mixed models, compared across different time windows, and visualized using spline regression. RESULTS: We included 1690 patients in body composition analysis, of whom 516 (30.5%) had ≥2 prediagnostic computed tomography scans. For analysis of longitudinal trends of blood-based biomarkers, 3332 individuals were included. As an early manifestation of PDAC, we observed a significant decrease in visceral and subcutaneous adipose tissue (ß = -1.94 [95% confidence interval (CI), -2.39 to -1.48] and ß = -2.59 [95% CI, -3.17 to -2.02]) in area (cm2)/height (m2) per 6 months closer to diagnosis, accompanied by a decrease in serum lipids (eg, low-density lipoprotein [ß = -2.83; 95% CI, -3.31 to -2.34], total cholesterol [ß = -2.69; 95% CI, -3.18 to -2.20], and triglycerides [ß = -1.86; 95% CI, -2.61 to -1.11]), and an increase in blood glucose levels. Loss of muscle tissue and bone volume was predominantly observed in the last 6 months before diagnosis. CONCLUSIONS: This study identified significant alterations in a variety of soft tissue and metabolic markers that occur in the development of PDAC. Early recognition of these metabolic changes may provide an opportunity for early detection.

Correlation between thyroid hormone sensitivity and the risk of polycystic ovary syndrome.

OBJECTIVE: There has been some confusion in earlier research on the connection between thyroid function and polycystic ovary syndrome (PCOS). This research is aimed to probe into the correlation between thyroid condition and the risk of PCOS from a new standpoint of thyroid hormone sensitivity. METHODS: This research comprised 415 females with PCOS from Drum Tower Hospital Affiliated with the Medical School of Nanjing University, and 137 non-PCOS individuals were selected as the normal control. Based on free thyroxine (FT4), free triiodothyronine (FT3), and thyroid-stimulating hormone (TSH), we calculated the thyroid hormone sensitivity indices, which consist of Thyroid Feedback Quantile-based Index (TFQI), Thyroid-stimulating Hormone Index (TSHI), Thyrotroph Thyroxine Resistance Index (TT4RI) and Free Triiodothyronine /Free thyroxine (FT3/FT4). The binary logistic regression model was adopted to investigate the correlation between thyroid hormone sensitivity indices with the risk of PCOS. Pearson or Spearman correlation analysis was employed to explore the association among thyroid-related measures with metabolic parameters in PCOS. RESULTS: Results of this research showed that females with PCOS had rising TFQI, TSHI, TT4RI, and FT3/FT4 levels compared with the control group. After adjustment for the impact of various covariates, there was no significant correlation between FT3/FT4 and the risk of PCOS; However, the odds ratio of the third and fourth vs. the first quartile of TFQI were 3.57(95% confidence interval [CI]:1.08,11.87) and 4.90(95% CI:1.38,17.38) respectively; The odds ratio of the fourth vs. the first quartile of TSHI was 5.35(95% CI:1.48,19.37); The odds ratio of the second vs. the first quartile of TT4RI was 0.27(95%CI 0.09,0.82). In addition, no significant correlation was observed between thyroid-related measures and metabolic measures in females with PCOS. CONCLUSIONS: A reduction in the sensitivity of central thyroid hormone is closely correlated with a higher risk of PCOS. Further research is necessary to corroborate our findings and the supporting mechanisms.

Posterior capsular radial sign: a novel method to confirm anterior vitreous cortex resection in phacovitrectomy.

BACKGROUND: The main purpose of this paper is to introduce a method that can accurately locate the posterior capsule of the lens to facilitate a relatively complete resection of the anterior vitreous body. METHODS: A total of 51 patients in the experimental group and control group were enrolled in this study. Phacoemulsification combined with vitrectomy was performed in all cases. After the cataract procedure was completed in the control group, the surgeon performed a conventional anterior vitrectomy with the operative eye. In the experimental group, anterior vitrectomy was performed according to the threadiness corrugation of the posterior capsule of the lens. During the operation, with the help of triamcinolone, two surgeons confirmed the resection of the anterior vitreous cortex; the best corrected visual acuity and intraocular pressure of all patients were recorded at 1 week, 1 month and 3 months after surgery. RESULTS: Fifty patients underwent phacoemulsification combined with vitrectomy, except one patient in the experimental group who was lost to follow-up. After surgery, no significant complications were observed in all patients except two patients in the control group with temporary increases in intraocular pressure. There was no significant difference in preoperative visual acuity between the two groups (t = 0.83, P = 0.25). Both groups had varying degrees of improvement in best corrected visual acuity at 1 week, 1 month and 3 months after surgery. Moreover, there was no significant difference in BCVA between the two groups at the three follow-up time points (t=-1.15, -1.65, -1.09, P = 0.53, 0.21, 0.23). After surgery, no significant complications were observed in all patients except two patients in the control group with temporary increases in intraocular pressure. Incomplete resection of the anterior vitreous cortex was observed in 2 patients in each group, but there was no significant difference (χ2 = 7.81, P > 0.05). CONCLUSION: In the process of cataract surgery combined with vitrectomy, thready corrugation appears in the posterior capsule of the lens and is an important sign of its localization. Anterior vitrectomy can be accomplished safely and effectively with the help of thread-like corrugation, and the surgical effect is almost the same as that of traditional surgery. Especially suitable for beginners in vitreous surgery.

Low Concentration of Wenyang Tonglin Decoction Promotes Conjugation and Transfer of Drug-Resistant Plasmids among Heterologous Strains.

OBJECTIVE: To investigate the effect of low concentration of Wenyang Tonglin Decoction (WTD) on the binding conditions of R45 plasmid conjugative transfer under liquid phase conjugation and its mechanism. METHODS: Escherichia coli CP9 (R45) and Staphylococcus aureus RN450RF were cultured in medium containing WTD, and their minimum inhibitory concentration (MIC) values were obtained. Using promoter fusion technology, E. coli CP9 (R45) containing a promoter fusion was obtained. ß-Galactosidase activity of TrfAp and TrbBp was tested, and the mRNA expression of regulatory factors (TrbA, KorA, and KorB) was detected by real-time fluorescent quantitative polymerase chain reaction. RESULTS: The MIC of E. coli CP9 (R45) was 400 g/L and that of S. aureus RN450RF was 200 g/L. When the drug concentration in the culture medium was 200 g/L, the highest number of conjugants was (3.47 ±0.20) × 107 CFU/mL At 90 h of conjugation, the maximum number of conjugants was (1.15 ±0.06) × 108 CFU/mL When the initial bacterial concentration was 108 CFU/mL, the maximum number of conjugants was (3.47 ± 0.20) × 107 CFU/mL. When the drug concentration was 200 g/L, the ß-galactosidase activity of TrfAp and TrbBp significantly increased; the relative quantification of TrbA, KorA and KorB were significantly inhibited. CONCLUSION: Low concentration of WTD promoted the development of bacterial resistance by affecting promoters and inhibiting the expression of regulatory factors.

OsATL32 ubiquitinates the reactive oxygen species-producing OsRac5-OsRbohB module to suppress rice immunity.

Ubiquitination-mediated protein degradation is integral to plant immunity, with E3 ubiquitin ligases acting as key factors in this process. Here, we report the functions of OsATL32, a plasma membrane-localized Arabidopsis Tóxicos En Levadura (ATL)-type E3 ubiquitin ligase, in rice (Oryza sativa) immunity and its associated regulatory network. We found that the expression of OsATL32 is downregulated in both compatible and incompatible interactions between rice and the rice blast fungus Magnaporthe oryzae. The OsATL32 protein level declines in response to infection by a compatible M. oryzae strain or to chitin treatment. OsATL32 negatively regulates rice resistance to blast and bacterial leaf blight diseases, as well as chitin-triggered immunity. Biochemical and genetic studies revealed that OsATL32 suppresses pathogen-induced reactive oxygen species (ROS) accumulation by mediating ubiquitination and degradation of the ROS-producing OsRac5-OsRbohB module, which enhances rice immunity against M. oryzae. The protein phosphatase PHOSPHATASE AND TENSIN HOMOLOG enhances rice blast resistance by dephosphorylating OsATL32 and promoting its degradation, preventing its negative effect on rice immunity. This study provides insights into the molecular mechanism by which the E3 ligase OsATL32 targets a ROS-producing module to undermine rice immunity.

3-Methyl-4-nitrophenol Exposure Deteriorates Oocyte Maturation by Inducing Spindle Instability and Mitochondrial Dysfunction.

3-methyl-4-nitrophenol (PNMC), a well-known constituent of diesel exhaust particles and degradation products of insecticide fenitrothion, is a widely distributed environmental contaminant. PNMC is toxic to the female reproductive system; however, how it affects meiosis progression in oocytes is unknown. In this study, in vitro maturation of mouse oocytes was applied to investigate the deleterious effects of PNMC. We found that exposure to PNMC significantly compromised oocyte maturation. PNMC disturbed the spindle stability; specifically, it decreased the spindle density and increased the spindle length. The weakened spindle pole location of microtubule-severing enzyme Fignl1 may result in a defective spindle apparatus in PNMC-exposed oocytes. PNMC exposure induced significant mitochondrial dysfunction, including mitochondria distribution, ATP production, mitochondrial membrane potential, and ROS accumulation. The mRNA levels of the mitochondria-related genes were also significantly impaired. Finally, the above-mentioned alterations triggered early apoptosis in the oocytes. In conclusion, PNMC exposure affected oocyte maturation and quality through the regulation of spindle stability and mitochondrial function.

Glucose regulation of adipose tissue browning by CBP/p300- and HDAC3-mediated reversible acetylation of CREBZF.

Glucose is required for generating heat during cold-induced nonshivering thermogenesis in adipose tissue, but the regulatory mechanism is largely unknown. CREBZF has emerged as a critical mechanism for metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD). We investigated the roles of CREBZF in the control of thermogenesis and energy metabolism. Glucose induces CREBZF in human white adipose tissue (WAT) and inguinal WAT (iWAT) in mice. Lys208 acetylation modulated by transacetylase CREB-binding protein/p300 and deacetylase HDAC3 is required for glucose-induced reduction of proteasomal degradation and augmentation of protein stability of CREBZF. Glucose induces rectal temperature and thermogenesis in white adipose of control mice, which is further potentiated in adipose-specific CREBZF knockout (CREBZF FKO) mice. During cold exposure, CREBZF FKO mice display enhanced thermogenic gene expression, browning of iWAT, and adaptive thermogenesis. CREBZF associates with PGC-1α to repress thermogenic gene expression. Expression levels of CREBZF are negatively correlated with UCP1 in human adipose tissues and increased in WAT of obese ob/ob mice, which may underscore the potential role of CREBZF in the development of compromised thermogenic capability under hyperglycemic conditions. Our results reveal an important mechanism of glucose sensing and thermogenic inactivation through reversible acetylation.

Echocardiographic measures of the left heart and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact adults: The CABLE study.

INTRODUCTION: This study delineated the interrelationships between subclinical alterations in the left heart, cerebrospinal fluid (CSF), Alzheimer's disease (AD) biomarkers, and cognition. METHODS: Multiple linear regressions were conducted in 1244 cognitively normal participants (mean age = 65.5; 43% female) who underwent echocardiography (left atrial [LA] and left ventricular [LV] morphologic or functional parameters) and CSF AD biomarkers measurements. Mediating effects of AD pathologies were examined. Differences in cardiac parameters across ATN categories were tested using analysis of variance (ANOVA) and logistic regressions. RESULTS: LA or LV enlargement (characterized by increased diameters and volumes) and LV hypertrophy (increased interventricular septal or posterior wall thickness and ventricular mass) were associated with higher CSF phosphorylated (p)-tau and total (t)-tau levels, and poorer cognition. Tau pathologies mediated the heart-cognition relationships. Cardiac parameters were higher in stage 2 and suspected non-Alzheimer's pathology groups than controls. DISCUSSION: These findings suggested close associations of subclinical cardiac changes with tau pathologies and cognition. HIGHLIGHTS: Various subclinical alterations in the left heart related to poorer cognition. Subclinical cardiac changes related to tau pathologies in cognitively normal adults. Tau pathologies mediated the heart-cognition relationships. Subclinical cardiac changes related to the AD continuum, especially to stage 2. The accumulation of cardiac alterations magnified their damage to the brain.

The identification of a novel shared therapeutic target and drug across all insulin-sensitive tissues under insulin resistance.

Background: To identify key and shared insulin resistance (IR) molecular signatures across all insulin-sensitive tissues (ISTs), and their potential targeted drugs. Methods: Three datasets from Gene Expression Omnibus (GEO) were acquired, in which the ISTs (fat, muscle, and liver) were from the same individual with obese mice. Integrated bioinformatics analysis was performed to obtain the differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA) was carried out to determine the "most significant trait-related genes" (MSTRGs). Enrichment analysis and PPI network were performed to find common features and novel hub genes in ISTs. The shared genes of DEGs and genes between DEGs and MSTRGs across four ISTs were identified as key IR therapeutic target. The Attie Lab diabetes database and obese rats were used to verify candidate genes. A medical drug-gene interaction network was conducted by using the Comparative Toxicogenomics Database (CTD) to find potential targeted drugs. The candidate drug was validated in Hepa1-6 cells. Results: Lipid metabolic process, mitochondrion, and oxidoreductase activity as common features were enriched from ISTs under an obese context. Thirteen shared genes (Ubd, Lbp, Hp, Arntl, Cfd, Npas2, Thrsp., Tpx2, Pkp1, Sftpd, Mthfd2, Tnfaip2, and Vnn3) of DEGs across ISTs were obtained and confirmed. Among them, Ubd was the only shared gene between DEGs and MSTRGs across four ISTs. The expression of Ubd was significantly upregulated across four ISTs in obese rats, especially in the liver. The IR Hepa1-6 cell models treated with dexamethasone (Dex), palmitic acid (PA), and 2-deoxy-D-ribose (dRib) had elevated expression of Ubd. Knockdown of Ubd increased the level of p-Akt. A lowing Ubd expression drug, promethazine (PMZ) from CTD analysis rescued the decreased p-Akt level in IR Hepa1-6 cells. Conclusion: This study revealed Ubd, a novel and shared IR molecular signature across four ISTs, as an effective biomarker and provided new insight into the mechanisms of IR. PMZ was a candidate drug for IR which increased p-Akt level and thus improved IR by targeting Ubd and downregulation of Ubd expression. Both Ubd and PMZ merit further clinical translational investigation to improve IR.

Utilization and Outcomes of Multigene Panel Testing in Patients With Pancreatic Ductal Adenocarcinoma.

PURPOSE: Guidelines recommend germline genetic testing (GT) for patients with pancreatic ductal adenocarcinoma (PDAC). This study aims to evaluate the utilization and outcomes of multigene panel GT in patients with PDAC. METHODS: This retrospective, multisite study included patients with PDAC diagnosed between May 2018 and August 2020 at Mayo Clinic Arizona, Florida, and Minnesota. Discussion, uptake, and outcomes of GT were compared before (May 1, 2018-May 1, 2019) and after (August 1, 2019-August 1, 2020) the guideline update, accounting for a transition period. RESULTS: The study identified 533 patients with PDAC, with 321 (60.2%) preguideline and 212 (39.8%) postguideline. Patient characteristics did not differ between the preguideline and postguideline periods. GT was discussed in 34.3% (110 of 321) of preguideline and 39.6% (84 of 212) of postguideline patients (odds ratio [OR], 1.26 [95% CI, 0.88 to 1.80]) and subsequently performed in 80.9% (89 of 110) of preguideline and 75.0% (63 of 84) of postguideline patients (OR, 1.10 [95% CI, 0.75 to 1.61]). Of 152 tested patients, 26 (17.1%) had a pathogenic variant (PV), of whom 17 (11.2%; 17 of 152) were PDAC-associated. Over the entire study period, GT was more likely in younger patients (65 v 70 years; P < .001), those seen by a medical oncologist (82.9% v 69.0%; P < .001), and those surviving more than 12 months from diagnosis (70.4% v 43.4%; P < .001). Demographics and personal/family cancer history were comparable between patients with and without a PDAC PV. CONCLUSION: GT remains underutilized despite National Comprehensive Cancer Network guideline recommendations. Given the poor prognosis of PDAC and potential implications of GT, efforts to increase utilization are needed to provide surveillance and support to both patients with PDAC and at-risk family members.

The Pancreatic Cancer Early Detection (PRECEDE) Study is a Global Effort to Drive Early Detection: Baseline Imaging Findings in High-Risk Individuals.

BACKGROUND: Pancreatic adenocarcinoma (PC) is a highly lethal malignancy with a survival rate of only 12%. Surveillance is recommended for high-risk individuals (HRIs), but it is not widely adopted. To address this unmet clinical need and drive early diagnosis research, we established the Pancreatic Cancer Early Detection (PRECEDE) Consortium. METHODS: PRECEDE is a multi-institutional international collaboration that has undertaken an observational prospective cohort study. Individuals (aged 18-90 years) are enrolled into 1 of 7 cohorts based on family history and pathogenic germline variant (PGV) status. From April 1, 2020, to November 21, 2022, a total of 3,402 participants were enrolled in 1 of 7 study cohorts, with 1,759 (51.7%) meeting criteria for the highest-risk cohort (Cohort 1). Cohort 1 HRIs underwent germline testing and pancreas imaging by MRI/MR-cholangiopancreatography or endoscopic ultrasound. RESULTS: A total of 1,400 participants in Cohort 1 (79.6%) had completed baseline imaging and were subclassified into 3 groups based on familial PC (FPC; n=670), a PGV and FPC (PGV+/FPC+; n=115), and a PGV with a pedigree that does not meet FPC criteria (PGV+/FPC-; n=615). One HRI was diagnosed with stage IIB PC on study entry, and 35.1% of HRIs harbored pancreatic cysts. Increasing age (odds ratio, 1.05; P<.001) and FPC group assignment (odds ratio, 1.57; P<.001; relative to PGV+/FPC-) were independent predictors of harboring a pancreatic cyst. CONCLUSIONS: PRECEDE provides infrastructure support to increase access to clinical surveillance for HRIs worldwide, while aiming to drive early PC detection advancements through longitudinal standardized clinical data, imaging, and biospecimen captures. Increased cyst prevalence in HRIs with FPC suggests that FPC may infer distinct biological processes. To enable the development of PC surveillance approaches better tailored to risk category, we recommend adoption of subclassification of HRIs into FPC, PGV+/FPC+, and PGV+/FPC- risk groups by surveillance protocols.

Toll-like receptor signaling pathway involved in pathogenesis of thromboangiitis obliterans through activating of NF-κB.

OBJECTIVES: The pathogenic mechanisms of Thromboangiitis Obliterans (TAO) are not entirely known and autoimmune inflammation plays a vital role in the initiation and continuance of TAO activity. The authors investigated in this study the role of the TLR signaling pathway in the pathogenesis of TAO. METHODS: First, the authors detected the expressions of MyD88, TRIF and NF-κB in vascular walls of 46 patients with TAO and 32 patients with trauma and osteosarcoma by western blot assay. Second, the authors detected the cellular localization of MyD88, TRIF and NF-κB in vascular walls of patients with TAO by immunofluorescent assay. RESULTS: The protein expressions of MyD88, TRIF and NF-κB were much higher in vascular walls of TAO patients (p < 0.05). Higher expressions of MyD88 and NF-κB were detected both on vascular endothelial and vascular smooth muscle cells of TAO patients. However, higher expression of TRIF was just detected on vascular smooth muscle cells of TAO patients. CONCLUSIONS: These dates suggest that the TLR signaling pathway might play an important role in the pathogenesis of TAO, it might induce vasospasm, vasculitis and thrombogenesis to lead to the pathogenesis and progression of TAO.

Combination of retagliptin and henagliflozin as add-on therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin: A multicentre, randomized, double-blind, active-controlled, phase 3 trial.

AIM: This study assessed the efficacy and safety of co-administering retagliptin and henagliflozin versus individual agents at corresponding doses in patients with type 2 diabetes mellitus who were inadequately controlled with metformin. METHODS: This multicentre, phase 3 trial consisted of a 24-week, randomized, double-blind, active-controlled period. Patients with glycated haemoglobin (HbA1c) levels between 7.5% and 10.5% were randomized to receive once-daily retagliptin 100 mg (R100; n = 155), henagliflozin 5 mg (H5; n = 156), henagliflozin 10 mg (H10; n = 156), co-administered R100/H5 (n = 155), or R100/H10 (n = 156). The primary endpoint was the change in HbA1c from baseline to week 24. RESULTS: Based on the primary estimand, the least squares mean reductions in HbA1c at week 24 were significantly greater in the R100/H5 (-1.51%) and R100/H10 (-1.54%) groups compared with those receiving the corresponding doses of individual agents (-0.98% for R100, -0.86% for H5 and -0.95% for H10, respectively; p < .0001 for all pairwise comparisons). Achievement of HbA1c <7.0% at week 24 was observed in 27.1% of patients in the R100 group, 21.2% in the H5 group, 24.4% in the H10 group, 57.4% in the R100/H5 group and 56.4% in the R100/H10 group. Reductions in fasting plasma glucose and 2-h postprandial glucose were also more pronounced in the co-administration groups compared with the individual agents at corresponding doses. Decreases in body weight and systolic blood pressure were greater in the groups containing henagliflozin than in the R100 group. The incidence rates of adverse events were similar across all treatment groups, with no reported episodes of severe hypoglycaemia. CONCLUSIONS: For patients with type 2 diabetes mellitus inadequately controlled by metformin monotherapy, the co-administration of retagliptin and henagliflozin yielded more effective glycaemic control through 24 weeks compared with the individual agents at their corresponding doses.