Influence of Fibrinogen/Albumin Ratio and Fibrinogen/Pre-Albumin Ratio on Cardiac Autonomic Neuropathy in Type 2 Diabetes.

Purpose: Subclinical inflammation may be involved in the pathogenesis of diabetic cardiac autonomic neuropathy (DCAN). The purpose of the study is to explore the relationship between novel inflammation biomarkers fibrinogen-albumin ratio (FAR), fibrinogen-prealbumin ratio (FPR), and DCAN in type 2 diabetes mellitus (T2DM). Patients and Methods: A total of 715 T2DM patients were enrolled in this retrospective study, divided into non-DCAN (n=565) and DCAN (n=150) groups by Ewing's test. Serum fibrinogen, albumin, prealbumin, routine inflammatory and other biochemical markers were measured. Results: Patients with versus without DCAN had higher FAR (10.29 ± 4.83 vs 7.22 ± 2.56 g/g, P < 0.001) and FPR (2.19 ± 1.85 vs 1.43 ± 0.93 g/mg, P < 0.001). As FAR and FPR quartiles increased, the incidence of DCAN increased (Quartile 1 vs Quartile 4: 8.4 vs 42.7%, 9.6 vs 39.2%, respectively, P < 0.001), heart rate variability parameters decreased (P < 0.001); the incidence of diabetic nephropathy, retinopathy and peripheral neuropathy tended to be higher and inflammation factors were more active (P < 0.01). FAR (OR, 95% CI: 1.16, 1.08-1.25, P < 0.001) and FPR (OR, 95% CI: 1.22, 1.03-1.44, P = 0.021) were independent determinants of DCAN; the risk of DCAN increased by approximately 65% and 27% with each increase in the standard deviation (SD) of FAR (OR per SD, 95% CI: 1.65, 1.29-2.11, P < 0.001) and FPR (OR per SD, 95% CI: 1.27, 1.04-1.56, P = 0.021). Conclusion: FAR and FPR are independent risk factors and may influence DCAN development through inflammation.

Loaded delta-hemolysin shapes the properties of Staphylococcus aureus membrane vesicles.

Background: Membrane vesicles (MVs) are nanoscale vesicular structures produced by bacteria during their growth in vitro and in vivo. Some bacterial components can be loaded in bacterial MVs, but the roles of the loaded MV molecules are unclear. Methods: MVs of Staphylococcus aureus RN4220 and its derivatives were prepared. Dynamic light scattering analysis was used to evaluate the size distribution, and 4D-label-free liquid chromatography-tandem mass spectrometry analysis was performed to detect protein composition in the MVs. The site-mutation S. aureus RN4220-Δhld and agrA deletion mutant RN4220-ΔagrA were generated via allelic replacement strategies. A hemolysis assay was performed with rabbit red blood cells. CCK-8 and lactate dehydrogenase release assays were used to determine the cytotoxicity of S. aureus MVs against RAW264.7 macrophages. The serum levels of inflammatory factors such as IL-6, IL-1ß, and TNFα in mice treated with S. aureus MVs were detected with an enzyme-linked immunosorbent assay kit. Results: Delta-hemolysin (Hld) was identified as a major loaded factor in S. aureus MVs. Further study showed that Hld could promote the production of staphylococcal MVs with smaller sizes. Loaded Hld affected the diversity of loaded proteins in MVs of S. aureus RN4220. Hld resulted in decreased protein diversity in MVs of S. aureus. Site-mutation (RN4220-Δhld) and agrA deletion (RN4220-ΔagrA) mutants produced MVs (ΔhldMVs and ΔagrAMVs) with a greater number of bacterial proteins than those derived from wild-type RN4220 (wtMVs). Moreover, Hld contributed to the hemolytic activity of wtMVs. Hld-loaded wtMVs were cytotoxic to macrophage RAW264.7 cells and could stimulate the production of inflammatory factor IL-6 in vivo. Conclusion: This study presented that Hld was a major loaded factor in S. aureus MVs, and the loaded Hld played vital roles in the MV-property modification.

Lower Limb Arterial Ischemia: An Independent Risk Factor of Sudomotor Dysfunction in Type 2 Diabetes.

Background: As an early manifestation of diabetic peripheral neuropathy (DPN), sudomotor dysfunction significantly increases the risk of diabetic foot ulcer. The pathogenesis of sudomotor dysfunction is still unclear. Lower limb ischemia may be related to sudomotor dysfunction, but few studies have explored it. The purpose of this study is to explore the relationship between sudomotor function and comprehensive lower limb arterial ischemia including large arteries, small arteries and microvascular in type 2 diabetes mellitus (T2DM). Patients and Methods: 511 T2DM patients were enrolled in this cross-sectional study. Sudomotor function was assessed qualitatively and quantitatively by Neuropad. Lower limb arterial ischemia was defined as any abnormality of the ankle brachial index (ABI), toe brachial index (TBI) or transcutaneous oxygen tension (TcPO2). Results: In this study, 75.1% of patients had sudomotor dysfunction. Compared with normal sudomotor function, patients with sudomotor dysfunction had a higher incidence of lower limb arterial ischemia (51.2% vs 36.2%, p = 0.004). Similarly, compared with the non-arterial ischemia group, the proportion of sudomotor disorders was higher in the arterial ischemia group (p = 0.004). Low TBI and low TcPO2 groups also had a higher proportion of sudomotor disorders (all p < 0.05).Compare with normal groups, low ABI, low TBI, and low TcPO2 groups had lower Slop4 which quantitatively reflecting Neuropad discoloration. Arterial ischemia was an independent risk factor for sudomotor dysfunction [OR = 1.754, p = 0.024]. Low TcPO2 also independently increased the risk of sudomotor disorders [OR = 2.231, p = 0.026]. Conclusion: Lower limb arterial ischemia is an independent risk factor of sudomotor dysfunction. Especially below the ankle (BTA) small arteries and microvascular ischemia may also be involved in the occurrence of sudomotor disorders.

GLP-1 receptor agonist-associated tumor adverse events: A real-world study from 2004 to 2021 based on FAERS.

Background: GLP-1 receptor agonists (GLP-1RA) have demonstrated cardiovascular benefits, but the relationship between GLP-1RA and tumors is controversial. Recently, clinical trials reported higher rates of malignancy with semaglutide than control group. As real-world evidence of GLP-1RA-associated tumor risk is very limited, we explored the association of GLP-1RA and all types of neoplasms by mining the FDA Adverse Event Reporting System (FAERS) database. Methods: The FAERS data from the first quarter (Q1) of 2004 to the second quarter (Q2) of 2020 in the AERSMine were extracted to conduct disproportionality analysis, which was used by the proportional reporting ratio (PRR) to assess the relationship between GLP-1RA and all types of neoplasms. Then, the details of disproportionate GLP-1RA-associated tumor cases from Q1 2004 to Q2 2021 in the FAERS Public Dashboard were collected to analyze demographic characteristics. Results: A total of 8718 GLP-1RA-associated tumors were reported. Excluding cases with pre-existing tumors, other glucose-lowering drugs, and other GLP-1RA-related adverse events, diabetes cases with GLP-1RA as the main suspected drug were selected. GLP-1RA did not cause a disproportionate increase in all tumor cases (PRR 0.83) at the SOC level, and there was also no increase in most types of tumors associated with GLP-1RA at the HLGT/HLT levels. Significant signals were detected between GLP-1RA and certain tumors, including thyroid cancers [medullary thyroid cancer (PRR 27.43) and papillary thyroid cancer (PRR 8.68)], pancreatic neoplasms malignant (PRR 9.86), and islet cell neoplasms and APUDoma NEC (PRR 2.86). The combination of GLP-1RA with dipeptidyl-peptidase IV inhibitors (DPP4i) perhaps caused the increased reporting rate in some tumors. Conclusion: Our study provided new real-world evidence for oncology safety information of GLP-1RA. Given the wide use of GLP-1RA, clinicians should be well informed about important potential adverse events. Our pharmacovigilance analysis also prompted clinicians to raise concerns about potential tumor-related adverse effects when combining GLP-1RA with DPP4i.

The role of allogeneic platelet-rich plasma in patients with diabetic foot ulcer: Current perspectives and future challenges.

The frequency of chronic cutaneous wounds are sharply increasing in aging populations. Patients with age-related diseases, such as diabetes, tumors, renal failure and stroke are prone to soft tissue and skin injury, compounded by slowed healing in aging. Imbalance of wound inflammation, loss of growth factor secretion, and impairment of tissue repair abilities are all possible reasons for failed healing. Therefore, it is vital to explore novel approaches to accelerate wound healing. Platelet-rich plasma (PRP) as a cell therapy has been widely applied for tissue repair and regeneration. PRP promotes wound healing by releasing antimicrobial peptides, growth factors and micro-RNAs. Medical evidence indicates that autologous platelet-rich plasma (au-PRP) can promote wound healing effectively, safely and rapidly. However, its clinical application is usually restricted to patients with chronic cutaneous wounds, generally because of other severe complications and poor clinical comorbidities. Allogeneic platelet-rich plasma (al-PRP), with abundant sources, has demonstrated its superiority in the field of chronic wound treatment. Al-PRP could overcome the limitations of au-PRP and has promising prospects in clinical applications. The aim of this review is to summarize the current status and future challenges of al-PRP in chronic cutaneous wound management. We also summarized clinical cases to further describe the application of al-PRP for chronic wounds in clinical practice.

Association of the gallbladder or biliary diseases with dipeptidyl peptidase 4 inhibitors in patients with type 2 diabetes: a meta-analysis of randomized controlled trials.

BACKGROUND: Previous studies have shown inconsistent conclusions regarding the association between incretin-based therapies and the risk of developing gallbladder or biliary diseases. We conducted a meta-analysis to evaluate the risk of gallbladder or biliary diseases associated with dipeptidyl peptidase 4 inhibitors (DPP4i) in patients with type 2 diabetes. METHODS: The PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were searched (from inception up to March 14, 2022) for published randomized controlled trials (RCTs) that compared DPP4i with placebo or other glucose-lowering drugs in patients with type 2 diabetes. The outcomes of interest were cholecystitis, cholangitis, cholelithiasis, bile duct stones, and biliary colic. Relative risks (RRs) and 95% confidence intervals (CI) were pooled using a random-effects model. Subgroup analyses were performed according to patient age, trial duration, and types of DPP4i. RESULTS: In total, 97,150 participants from 75 eligible RCTs were included in the meta-analysis. DPP4i were associated with an increased risk of composite of gallbladder or biliary diseases (RR 1.20 [95% CI 1.01-1.42]) and cholecystitis (RR 1.38 [95% CI 1.08-1.75]). Among all included trials, DPP4i showed no association with the following manifestations of gallbladder or biliary diseases: cholelithiasis (RR 1.00 [95% CI 0.76-1.32]), cholangitis (RR 0.81 [95% CI 0.39-1.66]), bile duct stones (RR 1.08 [95% CI 0.57-2.05]), and biliary colic (RR 0.72 [95% CI 0.23-2.25]). Subgroup analyses showed that DPP4i were associated with a higher risk of cholecystitis in older patients (RR 1.37 [95% CI 1.03-1.83]) compared with younger patients (RR 1.08 [95% CI 0.89-2.18]) and in those with a longer duration of drug use (RR 1.43 [95% CI 1.08-1.89]) compared with shorter use (RR 1.23 [95% CI 0.74-2.03]). CONCLUSIONS: This systematic review and meta-analysis of RCTs found that the use of DPP4i was associated with an increased risk of cholecystitis, especially in patients of advanced age or in those who were exposed to the drugs for a long period of time.

Graphene-Based Moisture Actuator with Oriented Microstructures Prepared by One-Step Laser Reduction for Accurately Controllable Responsive Direction and Position.

Actuators with fast and precise controllable responses are highly in demand for implementing agilely accurate mechanical movements in smart robots, intelligent sensors, biomimetic devices, and so on. Here, we report a graphene-based moisture actuator with accurately controllable direction and position responses achieved by a fast, controlled, and even programmable one-step laser reduction method. The laser reduction-induced oriented microstructures help to precisely guide the direction and location of the moisture response in graphene-based Janus films. The excellent moisture-mechanical response behaviors in these novel moisture actuators originate from the Janus structures and the periodic microstructures of a line-scanned layer. Our customized complex intelligent devices such as drums, bands, and three-dimensional wave humidity drives can highly match and verify the finite element simulations, which will inspire the creation of further smart robot designs for accurate deformation.

The association between GLP-1 receptor agonist and diabetic ketoacidosis in the FDA adverse event reporting system.

BACKGROUND AND AIMS: In 2019, the Medicines and Healthcare products Regulatory Agency (MHRA) of the United Kingdom (UK) and food and drug administration (FDA) of the United States of America (US) suggested that the relationship between glucagon-like peptide-1 receptor agonists (GLP-1RA) and diabetic ketoacidosis (DKA) deserved attention. This study is aiming to assess the association between GLP-1RA and DKA/ketosis in the FDA Adverse Event Reporting System (FAERS) database. METHODS AND RESULTS: Using FAERS database, we firstly extract the number of DKA reports from the first quarter (Q1) of 2004 to the fourth quarter (Q4) of 2019 and calculate proportional reporting ratios (PRRs). We then mined each FAERS file from 2004 Q1 to 2020 Q4 and obtained detailed information on DKA reports. From the first quarter (Q1) of 2004 to the fourth quarter (Q4) of 2019, there are 1382 DKA cases (1491 ketosis cases) associated with GLP-1RA in the FAERS database. There was a slight disproportionate reporting of DKA associated with overall GLP-1RA (PRR 1.49, 95%CI 1.24-1.79, p < 0.001) after excluding the impact of SGLT2i, T1D and insulin. Any disproportionality disappeared after selecting the GLP-1RA combined with insulin for comparison. CONCLUSIONS: When GLP-1RA not combined with insulin, the disproportionality of DKA reports associated with GLP-1RA was observed. Our analysis mined the FAERS database to provide evidence and highlight the potential association between DKA adverse events and GLP-1RA therapy that clinicians tend to overlook.

Bio-Inspired High Sensitivity of Moisture-Mechanical GO Films with Period-Gradient Structures.

Moisture actuators can accomplish humidity-triggered energy-conversion process, through material screening and structural design. Inspired by natural caterpillars and the hydrophilic properties of graphene oxide (GO), this work proposes a geometrical design of period-gradient structures in GO films for fabricating moisture actuators. These novel period-gradient-structured GO films exhibit excellent dynamic performance that they could deform at 1000° with a small radius in several seconds at a high relative humidity (RH ≈ 80%). The properties of fast actuating speed and high response to deformation are achieved through the structural designing of the sole GO film by a one-step formation process. A mechanics-based theoretical model combined with the finite element simulation is presented to demonstrate the actuating mechanism in geometry, moisture, and mechanics, which lays the foundation for potential applications of GO films in remote control, environmental monitoring, and man-machine interactions.

Multi-functional stretchable sensors based on a 3D-rGO wrinkled microarchitecture.

The structural design of sensing active layers plays a critical role in the development of electromechanical sensors. In this study, we established an innovative concept for constructing sensors, pre-straining & laser reduction (PS&LR), based on a laser-induced wrinkle effect. This method combines and highlights the advantages of a wrinkled structure in the flexibility of sensors and the advantages of laser in the efficient reduction of GO; thus, it can efficiently introduce tunable, stretchable 3D-rGO expansion bulges in wrinkled GO films. Particularly, the sensors based on this special structure (1.5 cm × 3 cm) demonstrated a multi-functional and distinguished sensing ability in the cases of bending, stretching and touching modes. Moreover, the 3D-rGO architecture endowed the sensors with great sensitivity and design flexibility, i.e., a high sensing factor of 122, relative current value change of 60 times at the bending angle of 60°, decreased relative resistance-strain curve and diverse bending strategies for various detection purposes. Thus, the established design and preparation strategy provides large design flexibility for various promising applications.