Causal effects of genetically vitamins and sepsis risk: a two-sample Mendelian randomization study.

BACKGROUND: In recent years, observational studies have been conducted to investigate the potential impact of vitamins on sepsis. However, many of these studies have produced inconsistent results. Our Mendelian randomization (MR) study aims to evaluate the causality between vitamins and sepsis from a genetic perspective. METHODS: Our MR study was designed following the STROBE-MR guidelines. Genetic instrumental variables for vitamins including folate, vitamin B12, B6, A (Retinol), C, D, and K were obtained from previous genome-wide association studies (GWAS) and MR studies. Five different sepsis severity levels were included in the analysis. The genetic instrumental variables were screened for potential confounders using PhenoScanner V2. MR analysis was performed using MR-egger, inverse-variance weighted multiplicative random effects (IVW-RE), inverse-variance weighted multiplicative fixed-effects (IVW-FE), and wald ratio methods to assess the relationship between vitamins and sepsis. Sensitivity analysis was performed using the MR-egger_intercept method, and the MR-PRESSO package and Cochran's Q test were used to evaluate the heterogeneity of the instrumental variables. RESULTS: Our MR study found no statistically significant association between vitamins and sepsis risk, regardless of the type of vitamin (P-value > 0.05). The odds ratios (ORs) for folate, vitamin B6, vitamin B12, vitamin A, vitamin D, vitamin K, and vitamin C were 1.164 (95% CI: 0.895-1.514), 0.987 (95% CI: 0.969-1.005), 0.975 (95% CI: 0.914-1.041), 0.993 (95% CI: 0.797-1.238), 0.861 (95% CI: 0.522-1.42), 0.955 (95% CI: 0.86-1.059), and 1.049 (95% CI: 0.911-1.208), respectively. Similar results were observed in subgroups of different sepsis severity levels. CONCLUSIONS: Our MR study found no evidence of a causal association between vitamins and sepsis risk from a genetic perspective. Further randomized controlled trials are necessary to confirm these results.

Polydopamine functionalized polyurethane shape memory sponge with controllable expansion performance triggered by near-infrared light for incompressible hemorrhage control.

Uncontrolled expansion of shape memory sponges face a significant challenge in the treatment of lethal incompressible hemorrhage, which can lead to blood overflow or damage to the surrounding tissue. Herein, we developed a polydopamine functionalized polyurethane shape memory sponge (PDA-TPI-PU) with a controllable degree of expansion by near-infrared (NIR) light-triggered stimulation for the treatment of incompressible hemorrhage. The sponge has excellent liquid absorption performance and robust mechanical strength as well as good photothermal conversion ability. Under NIR light of 0.32 W/cm2, the maximum recovery rate of the fixed-shape compression sponge was 91% within 25 s in air and 80% within 25 s in blood. In the SD rat liver penetrating injury model, compared with commercial medical gelatin sponge and PVA sponge, the PDA-TPI-PU sponge could effectively control the bleeding under the NIR light irradiation and did not cause excessive compression of the wound. The sponge with these characteristics shows potential application prospects as a hemostatic material.

Genetic association of lipids and lipid-lowering drugs with sepsis: a Mendelian randomization and mediation analysis.

Background: The impact of lipid-lowering medications on sepsis is still not well defined. A Mendelian randomization (MR) study was carried out to probe the causal connections between genetically determined lipids, lipid-reducing drugs, and the risk of sepsis. Materials and methods: Data on total serum cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A-I (ApoA-I), apolipoprotein B (ApoB), and triglycerides (TG) were retrieved from the MR-Base platform and the Global Lipids Genetics Consortium in 2021 (GLGC2021). Our study categorized sepsis into two groups: total sepsis and 28-day mortality of sepsis patients (sepsis28). The inverse-variance weighted (IVW) method was the primary method used in MR analysis. Cochran's Q test and the MR-Egger intercept method were used to assess the heterogeneity and pleiotropy. Results: In the MR analysis, we found that ApoA-I played a suggestively positive role in protecting against both total sepsis (OR, 0.863 per SD increase in ApoA-I; 95% CI, 0.780-0.955; P = 0.004) and sepsis28 (OR, 0.759; 95% CI, 0.598-0.963; P = 0.023). HDL-C levels were also found to suggestively reduce the incidence of total sepsis (OR, 0.891 per SD increase in HDL-C; 95% CI, 0.802-0.990; P = 0.031). Reverse-MR showed that sepsis28 led to a decrease in HDL-C level and an increase in TG level. In drug-target MR, we found that HMGCR inhibitors positively protected against total sepsis (1OR, 0.719 per SD reduction in LDL-C; 95% CI, 0.540-0.958; P = 0.024). LDL-C and HDL-C proxied CETP inhibitors were found to have a protective effect on total sepsis, with only LDL-C proxied CETP inhibitors showing a suggestively protective effect on sepsis28. In Mediated-MR, BMI exhibited a negative indirect effect in HMGCR inhibitors curing sepsis. The indirect impact of ApoA-I explained over 50% of the curative effects of CETP inhibitors in sepsis. Conclusions: Our MR study suggested that ApoA-I and HDL-C protected against sepsis, while HMGCR and CETP inhibitors showed therapeutic potential beyond lipid-lowering effects. ApoA-I explained the effects of CETP inhibitors. Our study illuminates how lipids affect sepsis patients and the effectiveness of new drugs, opening new avenues for sepsis treatment.

Photo-controllable burst generation of peroxynitrite based on synergistic interactions of polymeric nitric oxide donors and IR780 for enhancing broad-spectrum antibacterial therapy.

The newly attractive peroxynitrite (ONOO-) therapy can prominently enhance antibacterial therapeutic efficacy. However, it is a great challenge but urgently needed to generate ONOO- with adjustable release rate and dosage in order to satisfy personalized treatments for different disease types and severities. Herein, PSNO@IR780 nanoparticles are fabricated via co-assembly of an amphiphilic PEG-b-PAASNO block copolymer grafted with abundant nitric oxide (NO) donor units and IR780 as a photothermal and photodynamic agent. Photo-controllable burst generation of ONOO- from PSNO@IR780 nanoparticles could be realized based on synergistic reactions of rapid NO release induced by increased local temperature and efficiently produced superoxide anion radical (O2•-) from IR780. The maximum ONOO- release dosage is up to 6.73 ± 0.07 µM and release rate is up to 98.1 ± 1.38 nM/s. Furthermore, the ONOO- release behavior can be precisely manipulated by varying sample concentrations, irradiated durations, output power densities, and laser switches, respectively. Ultra-efficiently generated ONOO- from biocompatible PSNO@IR780 nanoparticles significantly elevated broad spectrum antibacterial efficiency through damaging bacterial membranes. Thus, PSNO@IR780 nanoparticles may present a new insight into preparation of burst and controllable generating ONOO- materials, and provide new opportunities for antibacterial therapy. STATEMENT OF SIGNIFICANCE: 1. Polymeric NO donor (PEG-b-PAASNO) grafted with abundant NO donor units was synthesized. 2. PSNO@IR780 nanoparticles were prepared by co-assembly of IR780 and amphiphilic PEG-b-PAASNOpolymer. 3. The maximum ONOO- release dosage from PSNO@IR780 nanoparticles was 6.73 ± 0.08 µM. 4. The fastest ONOO- release rate from PSNO@IR780 nanoparticles was 98.1 ± 1.4 nM/s. 5. Ultra-efficiently generated ONOO- significantly elevated antibacterial efficiency via damaging bac-terial membranes.

Polyvinyl alcohol/sodium alginate composite sponge with 3D ordered/disordered porous structure for rapidly controlling noncompressible hemorrhage.

It is still a challenge to develop a sponge that can efficiently control noncompressible bleeding to meet the emergency treatment and clinical demand. Herein, we combined the 3D printing sacrificial template method and freeze-drying technology to prepare polyvinyl alcohol/sodium alginate (PVA/SA) composite sponges with ordered microchannels and disordered porous structure. Compared with conventional sponges, the prepared sponge showed ultra-rapid water/blood absorption capacity and satisfactory mechanical properties. Furthermore, when the sponge was stuffed into a noncompressible wound and contacted with blood, it could accurately guide and quickly absorb a large amount of blood through the microchannels. Moreover, the platelets, red blood cells and coagulation factors would be enriched in the microchannels and microporous structure. In the SD rat liver noncompressible hemorrhage and femoral artery puncture injury model, PVA-SA composite sponge with 3D ordered/disordered porous structure showed enhanced hemostatic performance compared with commercial MPVA sponges. Depend on the special ordered/disordered porous structure, PVA-SA composite sponge could accelerate the blood convergence and promote coagulation. This design of special porous structure opened up a new avenue to develop hemostatic sponges for rapidly controlling noncompressible hemorrhage.

Thrombin Embedded in eMPs@Thr/Sponge with Enhanced Procoagulant Ability for Uncompressible and Massive Hemorrhage Control.

Uncontrollable hemorrhage, especially uncompressible and massive hemorrhage, is life threatening. To develop a kind of hemostatic material that is biocompatible and has effective hemostatic performance, a starch-polyethylene glycol sponge (St-PEG sponge) incorporated with electrospraying microspheres made from carboxymethyl chitosan and sodium alginate (CMC/SA eMPs) is employed to fabricate the topical hemostatic agent for application. To load thrombin safely and effectively, CMC/SA eMPs encapsulating thrombin compounds (eMPs@Thr) are further incorporated with St-PEG sponge to obtain eMPs@Thr/sponge. The results show that eMPs@Thr/sponge could obviously reduce blood loss and shorten the hemostatis time compared with commercial hemostatic products Kuai Kang. The construction of the eMPs@Thr/sponge could not only maintain the expandable properties of the St-PEG sponge but also strengthen the procoagulant activity. Therefore, this work provides a facile approach for loading thrombin given the fact that thrombin suffers from instability and risk of thrombus. It is predicted that eMPs@Thr/sponge might hold great potential in uncompressible and massive hemorrhage control.