Prophylactic-dose direct oral anticoagulants for non-hospitalised people with COVID-19: A meta-analysis of randomised controlled trials.

Background: Several reviews have been conducted on thromboprophylaxis in non-hospitalised patients with coronavirus disease 2019 (COVID-19). In this systematic review and meta-analysis, we sought to investigate the impact of prophylactic-dose direct oral anticoagulants (DOACs) in this population. Methods: We searched PubMed, Web of Science, EMBASE and Cochrane Library for randomised controlled trials (RCTs) comparing prophylactic-dose DOACs with placebo or no treatment in non-hospitalised patients with COVID-19 until September 2023. The primary efficacy outcome was a composite of all-cause mortality and thromboembolic events, while major bleeding events were the primary safety outcome. We expressed continuous outcome data as mean differences (MDs) with 95% confidence intervals (CIs) and dichotomous outcome data as risk ratios (RRs) with 95% CIs. Results: We included six RCTs involving 4307 patients. Prophylactic-dose DOAC therapy compared with placebo or no treatment was associated with significantly decreased risks of the composite outcome of all-cause mortality and thromboembolic events (1.43% vs 2.67% (RR = 0.53; 95% CI = 0.34-0.82, P = 0.004, I2 = 3%)). Major bleeding events were infrequent, and we detected no significant differences between patients assigned to prophylactic-dose DOACs vs placebo or no treatment (0.19% vs 0.05% (RR = 2.50; 95% CI = 0.49-12.87, P = 0.27, I2 = 0%)). The use of prophylactic-dose DOACs was also associated with a reduction in venous thromboembolism, with no difference in all-cause mortality, arterial thromboembolism, hospitalisations, and clinically relevant nonmajor bleeding between two groups. Sensitivity analyses with the leave-one-out method for the primary efficacy and safety outcome did not change the effect estimate substantially. Conclusions: We found that prophylaxis-dose DOACs could significantly improve clinical outcomes and reduce venous thrombotic events without increasing the risk of major bleeding events compared with placebo or no treatment in non-hospitalised patients with COVID-19. Registration: PROSPERO: CRD42023466889.

Early elevations of RAS protein level and activity are critical for the development of PDAC in the context of inflammation.

The KRASG12D mutation was believed to be locked in a GTP-bound form, rendering it fully active. However, recent studies have indicated that the presence of mutant KRAS alone is insufficient; it requires additional activation through inflammatory stimuli to effectively drive the development of pancreatic ductal adenocarcinoma (PDAC). It remains unclear to what extent RAS activation occurs during the development of PDAC in the context of inflammation. Here, in a mouse model with the concurrent expression of KrasG12D/+ and inflammation mediator IKK2 in pancreatic acinar cells, we showed that, compared to KRASG12D alone, the cooperative interaction between KRASG12D and IKK2 rapidly elevated both the protein level and activity of KRASG12D and NRAS in a short term. This high level was sustained throughout the rest phase of PDAC development. These results suggest that inflammation not only rapidly augments the activity but also the protein abundance, leading to an enhanced total amount of GTP-bound RAS (KRASG12D and NRAS) in the early stage. Notably, while KRASG12D could be further activated by IKK2, not all KRASG12D proteins were in the GTP-bound state. Overall, our findings suggest that although KRASG12D is not fully active in the context of inflammation, concurrent increases in both the protein level and activity of KRASG12D as well as NRAS at the early stage by inflammation contribute to the rise in total GTP-bound RAS.

Synthetic Membraneless Droplets for Synaptic-Like Clustering of Lipid Vesicles.

In eukaryotic cells, the membraneless organelles (MLOs) formed via liquid-liquid phase separation (LLPS) are found to interact intimately with membranous organelles (MOs). One major mode is the clustering of MOs by MLOs, such as the formation of clusters of synaptic vesicles at nerve terminals mediated by the synapsin-rich MLOs. Aqueous droplets, including complex coacervates and aqueous two-phase systems, have been plausible MLO-mimics to emulate or elucidate biological processes. However, neither of them can cluster lipid vesicles (LVs) like MLOs. In this work, we develop a synthetic droplet assembled from a combination of two different interactions underlying the formation of these two droplets, namely, associative and segregative interactions, which we call segregative-associative (SA) droplets. The SA droplets cluster and disperse LVs recapitulating the key functional features of synapsin condensates, which can be attributed to the weak electrostatic interaction environment provided by SA droplets. This work suggests LLPS with combined segregative and associative interactions as a possible route for synaptic clustering of lipid vesicles and highlights SA droplets as plausible MLO-mimics and models for studying and mimicking related cellular dynamics.

Enantioselective Synthesis of Diarylmethylamines through the Aza-Friedel-Crafts Reaction of 1,3,5-Trialkoxy Benzenes and N-Sulfonyl Aldimines Catalyzed by BINOL-Derived Disulfonimides.

A 1,1'-bi-2-naphthol (BINOL)-derived disulfonimide (DSI)-catalyzed enantioselective aza-Friedel-Crafts reaction between 1,3,5-trialkoxy benzenes and N-sulfonyl aldimines gives direct access to a series of chiral diarylmethylamines in good yields and good to excellent enantioselectivities (up to 97% ee). This reaction provides a useful protocol for the direct synthesis of diarylmethylamine derivatives.

Targeting unfolded protein response using albumin-encapsulated nanoparticles attenuates temozolomide resistance in glioblastoma.

BACKGROUND: Chemoresistant cancer cells frequently exhibit a state of chronically activated endoplasmic reticulum (ER) stress. Engaged with ER stress, the unfolded protein response (UPR) is an adaptive reaction initiated by the accumulation of misfolded proteins. Protein disulfide isomerase (PDI) is a molecular chaperone known to be highly expressed in glioblastomas with acquired resistance to temozolomide (TMZ). We investigate whether therapeutic targeting of PDI provides a rationale to overcome chemoresistance. METHODS: The activity of PDI was suppressed in glioblastoma cells using a small molecule inhibitor CCF642. Either single or combination treatment with TMZ was used. We prepared nanoformulation of CCF642 loaded in albumin as a drug carrier for orthotopic tumour model. RESULTS: Inhibition of PDI significantly enhances the cytotoxic effect of TMZ on glioblastoma cells. More importantly, inhibition of PDI is able to sensitise glioblastoma cells that are initially resistant to TMZ treatment. Nanoformulation of CCF642 is well-tolerated and effective in suppressing tumour growth. It activates cell death-triggering UPR beyond repair and induces ER perturbations through the downregulation of PERK signalling. Combination treatment of TMZ with CCF642 significantly reduces tumour growth compared with either modality alone. CONCLUSION: Our study demonstrates modulation of ER stress by targeting PDI as a promising therapeutic rationale to overcome chemoresistance.

Celastrol-loaded lactosylated albumin nanoparticles attenuate hepatic steatosis in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disease with several liver-associated pathologic characteristics such as aberrant lipid accumulation, persistent chronic inflammation and hyperactive endoplasmic reticulum (ER) stress. Plant-derived celastrol (CEL) appeared to be a promising anti-inflammatory and anti-obesity drug but the clinical application was delayed by low oral bioavailability. The present study was designed for developing biodegradable albumin-based nanoparticles to deliver CEL to the liver for treating NAFLD. CEL was entrapped into lactosylated bovine serum albumin (Lac-BSA) by high pressure homogenization to generate CEL-loaded Lac-BSA nanoparticles (CEL-Lac-BSA). CEL-Lac-BSA displayed spherical morphology, narrow size distribution at 158.6 ± 3.4 nm and reasonable drug-loading efficiency at 13.62 ± 0.13%. CEL-Lac-BSA not only showed better hepatocyte uptake and hepatic deposition than free CEL, but also outperformed in reducing lipid deposition, ameliorating liver function and enhancing insulin sensitivity in a mouse model of diet-induced NAFLD. Mechanistic studies indicated that CEL-Lac-BSA more effectively downregulated the mRNA levels of genes for lipogenesis and lipid transporter while upregulated the mRNA levels of lipolysis mediators. Western blot analysis confirmed the outperformance of CEL-Lac-BSA in enhancing the activation of AMP-activated protein kinase (AMPK) and silent information regulation 2 homolog (SIRT1) and the protein levels of fatty acid synthase (FASN) and sterol regulatory element-binding protein-1c (SREBP1c) in NAFLD mice. Taken together, CEL-Lac-BSA showed better potential in the treatment of diet-induced NAFLD. Lactose-coating of albumin-based nanoparticles effectively facilitated the liver-targeting release of hydrophobic drug CEL for ameliorating hepatic steatosis. Therefore, CEL-Lac-BSA may be translated into a potential clinical therapy against obesity and NAFLD.

Biodegradable celastrol-loaded albumin nanoparticles ameliorate inflammation and lipid accumulation in diet-induced obese mice.

Obesity is hallmarked by endoplasmic reticulum (ER) stress, chronic inflammation and metabolic dysfunctions. The control of obesity is the key to preventing the onset of non-alcoholic fatty liver disease, diabetes, cerebro-cardiovascular diseases and cancers. As a promising anti-obesity drug, plant-derived celastrol is challenged by poor water solubility and low oral bioavailability in clinical applications. The present study was designed to develop a biocompatible albumin-based nanoparticle carrier system for the controlled release of celastrol in diet-induced obese mice. Celastrol was loaded into bovine serum albumin (BSA) nanoparticles to yield celastrol-BSA-NPs by high pressure homogenization. Celastrol-BSA-NPs exhibited spherical morphology, narrow size distribution with a diameter of 125.6 ± 2.2 nm, satisfactory drug-loading efficiency at 13.88 ± 0.12% and a sustained-release profile over a period of 168 h. Compared with free celastrol, celastrol-BSA-NPs effectively improved cellular uptake, intestinal absorption and hepatic deposition. In animal experiments, celastrol-BSA-NPs outperformed free celastrol in lowering lipid accumulation, improving insulin sensitivity, and reducing inflammation in diet-induced obesity. Collectively, celastrol-BSA-NPs exhibited better bioavailability and in vivo efficacy in the treatment of diet-induced obesity. Importantly, such albumin-based nanoparticles may be a general biocompatible drug carrier system for the controlled release of hydrophobic compounds (e.g., celastrol) for the treatment of obesity and non-alcoholic fatty liver disease.

Effects of particle size on the electrocoalescence dynamics and arrested morphology of liquid marbles.

HYPOTHESIS: The coalescence of bare droplets when surface tension dominates always results in one larger spherical droplet. In contrast, droplets coated with particles may be stabilized into non-spherical structures after arrested coalescence, which can be achieved by different approaches, such as changing the particle surface coverage. The size of particles coating the initial liquid marbles can be used to control the coalescence dynamics and the resulting morphology of arrested droplets. EXPERIMENT: We characterized the electrocoalescence of liquid marbles coated with particles ranging from hundred nanometers to hundred micrometers. The electrocoalescence was recorded using high-speed imaging. FINDINGS: When the electrocoalescence initiates, particles jam and halt the relaxation of the marbles at different stages, resulting in four possible final morphologies that are characterized using the Gaussian curvature at the neck region. The four regimes are total coalescence, arrested puddle coalescence, arrested saddle coalescence, and non-coalescence. The coalescence is initiated at the center of the contact zone, independent of the particle size. Small particles show little resistance to the coalescence, while marbles coated by large particles demonstrate a viscous-like behavior, indicated by the growth of the liquid bridge and the damping. The present study provides guidelines for applications that involve the formulation of liquid marbles with complex morphologies.

Controlled Formation of All-Aqueous Janus Droplets by Liquid-Liquid Phase Separation of an Aqueous Three-Phase System.

Janus droplets have been demonstrated in a wide range of applications, ranging from drug delivery, to biomedical imaging, to bacterial detection. However, existing fabrication strategies often involve nonaqueous solvents, such as organic solvent or oil, which largely limits their use in fields that require a high degree of biocompatibility. Here, we present a method to achieve all-aqueous Janus droplets by liquid-liquid phase separation of an aqueous three-phase system (A3PS). An aqueous droplet containing two initially miscible polymers is first injected into an aqueous solution of another concentrated polymer, and then it spontaneously phase-separates into a Janus droplet due to the diffusive mass exchange between the drop and bulk phases during equilibration. To achieve continuous generation of the Janus droplets, the A3PS is further integrated with microfluidics and electrospray. The size and shape of the phase-separated Janus droplets can be easily controlled by tuning the operation parameters, such as the flow rate and/or the initial composition of the drop phases. Dumbbell-shaped and snowman-shaped Janus droplets with average sizes between 100 and 400 µm can be generated by both coflow microfluidics and electrospray. In particular, the phase-separated Janus droplets can simultaneously load two different liposomes into each compartment, which are promising carriers for combination drugs. The obtained Janus droplets are superior templates for biocompatible materials, which can serve as building blocks such as high-order droplet patterns for constructing advanced biomaterials.

Early forest-fire detection using scanning polarization lidar.

As forest terrain is complex, containing leaves and other obstacles, it is difficult to distinguish the signal of forest-fire smoke when using single-channel lidar. To address this difficulty, a scanning micropulse polarization lidar system is developed, and a new method to detect forest fires is proposed in this study. Based on the characteristics of the depolarization ratio of in-scene obstacles, a matrix is constructed to remove obstacle signals, which in turn reduces the misidentification rate. Artificial forest-fire tests are carried out to verify the correctness of the proposed method and the feasibility of early forest-fire detection using the scanning polarization lidar system. In the working mode, the developed polarizing lidar system can locate a forest fire within three minutes with the proposed method. The experimental results show that forest fires can be accurately detected in real time when using scanning polarization lidar.

Comparative assessment of in vitro/in vivo performances of orodispersible electrospun and casting films containing rizatriptan benzoate.

The electrospinning process is a promising approach to produce various drug-loaded orodispersible films (ODFs) with a rapid onset of their actions. However, there is only limited number of studies comparing the pharmacological performances of electrospun ODFs (eODFs) with traditional casting films (CFs). In this study, rizatriptan benzoate (RB), a pain relieving agent was formulated with PVP and PVA into ODFs using electrospinning and casting methods. The ODFs were subsequently characterized with respect to their morphology, solid state properties and mechanical characteristics. The uniformity of the dosage units, disintegration behavior and dissolution patterns of the ODFs were also evaluated prior to the pharmacokinetic study. The obtained CFs and eODFs were semitransparent and white in appearance, respectively. The scanning electron microscopy revealed that the eODFs contained nanoporous structure, while the CFs showed no observable pores. RB was amorphously dispersed in both these films without drug-polymer interactions. The uniformity of dosage units for both eODFs and CFs was complied with European Pharmacopeia. As compared to the CFs, the eODFs were more flexible and lesser rigid in nature and showed faster disintegration and dissolution rates. In addition, the eODFs exhibited a higher bioavailability with a shorter Tmax relative to the CFs and commercial RB tablets. This study demonstrated that eODFs were superior to CFs with respect to in vivo pharmacological effects, which could be attributed to the submicron structure of eODFs obtained through the electrospinning process.

Anti-solvent Precipitation Method Coupled Electrospinning Process to Produce Poorly Water-Soluble Drug-Loaded Orodispersible Films.

Orodispersible films (ODFs) are more convenient for paediatric and geriatric patients to take as compared to conventional tablets and capsules. Electrospinning has recently been attempted to produce ODFs. This study investigated the feasibility of formulating poorly water-soluble drug into ODFs using electrospinning technology coupled with the anti-solvent precipitation method. Piroxicam (PX), a poorly water-soluble drug, was chosen as a model drug. Polyvinyl alcohol and polyvinylpyrrolidone were used as film forming polymers. PX microcrystals were prepared using poloxamer as the stabilizer with the anti-solvent precipitation method, and then loaded in ODFs through the electrospinning process. The obtained ODFs were characterized using a scanning electron microscope, X-ray powder diffraction and Fourier transform infrared spectroscopy with respect to the morphology, solid state and potential molecular interaction between the model drug and polymers. The mechanical property, disintegration and dissolution rate of the obtained ODF were evaluated using dynamic mechanical analysis, a customized method and USP2 apparatus. The results showed that PX microcrystals suspended in polymeric solutions could be readily electrospun into fibrous films, where the microcrystals scattered between the fibers. The electrospun fibrous film-based ODFs exhibited satisfactory mechanical behaviour, and fast disintegration upon the polymer selection. In the dissolution tests, almost 90% of PX was dissolved within 6 min from the ODFs, whereas 40% of PX dissolved from physical mixtures in 60 min. This study demonstrated that poorly water-soluble drugs could be formulated into ODFs with satisfactory quality attributes by combining micronization and the electrospinning process.

Novel Lidar algorithm for horizontal visibility measurement and sea fog monitoring.

Traditionally, Klett and Fernald inversion estimates an initial value using the slope method for horizontal visibility, which causes inversion uncertainty. We proposed an algorithm to retrieve the extinction coefficient and visibility distribution information from scanning Lidar to overcome instability due to initial atmospheric extinction coefficient choice and assuming the Lidar ratio. Numerical simulations showed that extinction coefficient maximum relative was much larger for inhomogeneous atmosphere using the Klett method, reaching 0.31. In contrast, it is only 0.049 using the proposed algorithm. Experimental showed that the proposed algorithm and scanning Lidar system provide very high stability and accuracy, can work in different weather conditions and monitor sea fog evolution over real time, and is suitable for various situations with different visibility.