Temporal patterns of organ dysfunction in COVID-19 patients hospitalized in the intensive care unit: A group-based multitrajectory modeling analysis.

BACKGROUND: The course of organ dysfunction (OD) in Corona Virus Disease 2019 (COVID-19) patients is unknown. Herein, we analyze the temporal patterns of OD in intensive care unit-admitted COVID-19 patients. METHODS: Sequential organ failure assessment scores were evaluated daily within 2 weeks of admission to determine the temporal trajectory of OD using group-based multitrajectory modeling (GBMTM). RESULTS: A total of 392 patients were enrolled with a 28-day mortality rate of 53.6%. GBMTM identified four distinct trajectories. Group 1 (mild OD, n = 64), with a median APACHE II score of 13 (IQR 9-21), had an early resolution of OD and a low mortality rate. Group 2 (moderate OD, n = 140), with a median APACHE II score of 18 (IQR 13-22), had a 28-day mortality rate of 30.0%. Group 3 (severe OD, n = 117), with a median APACHR II score of 20 (IQR 13-27), had a deterioration trend of respiratory dysfunction and a 28-day mortality rate of 69.2%. Group 4 (extremely severe OD, n = 71), with a median APACHE II score of 20 (IQR 17-27), had a significant and sustained OD affecting all organ systems and a 28-day mortality rate of 97.2%. CONCLUSIONS: Four distinct trajectories of OD were identified, and respiratory dysfunction trajectory could predict nonpulmonary OD trajectories and patient prognosis.

Robust Gradient Hydrogel-Loaded Nanofiber Fleshy Artificial Skin Via A Coupled Microfluidic Electrospinning-Reactive Coating Strategy.

Skin regeneration attracts tremendous interest due to the important role of skin for human protection and beauty. Thus, methods allowing artificial skin to be carried out in a controllable fashion are potentially important for wound healing, which involves an intersection of materials, medicine, biology, and other disciplines. Herein, aiming at a new general methodology for fleshy materials, a new hydrogel-loaded hydrophobic-hydrophilic nanofiber fleshy artificial skin is designed and fabricated. The gradient hydrogel-loaded nanofiber artificial skin integrates both advantages of nanofiber and hydrogel, exhibiting fleshy feature (comparability to real skin in terms of appearance, texture, and function), excellent air permeability, compatibility, and good mechanical and antibacterial property. Interestingly, the efficient transport channels are formed throughout the hydrogel-loaded nanofiber structure, which is beneficial for water absorption and transfer. These advantages enable the establishment of a moist and favorable microenvironment; thus, greatly accelerating wound healing process. This work couples microfluidic electrospinning with reactive coating technique, which is in favor of material design and fabrication with controllable and uniform structures. The hydrogel-loaded nanofiber fleshy artificial skin shows comparability to real skin in terms of beauty, texture, and function, which would definitely provide new opportunities for the further optimization and upgrading of artificial skin.

Carboxymethyl chitosan-based hydrogel-Janus nanofiber scaffolds with unidirectional storage-drainage of biofluid for accelerating full-thickness wound healing.

Self-pumping wound scaffolds designed for directional biofluid transport are extensively investigated. They efficiently extract excessive biofluids from wounds, while maintaining an optimally humid wound environment, thus facilitating rapid wound healing. However, the existing designed scaffolds are insufficiently focused on stimulating the hydrophobic layer at the wound site, thereby exacerbating inflammation and impeding the wound healing process. Herein, we engineered and fabricated a hydrophilic-hydrophobic-hydrophilic sandwich-structured hydrogel-Janus nanofiber scaffold (NFS) employing a Layer-by-Layer (LbL) method. This scaffold comprises a hydrophilic carboxymethyl chitosan/silver (CMCS-Ag) hydrogel component in conjunction with a poly(caprolactone)/poly(caprolactone)-poly(citric acid)-co-ε-polylysine (PCL/PCL-PCE) Janus NFS. It is noteworthy that the hydrogel-Janus nanofiber scaffold not only demonstrates outstanding water absorption (202.2 %) and unidirectional biofluid transport capability but also possesses high breathability (308.663 m3/m2 h kPa), appropriate pore size (6.7-7.5 µm), excellent tensile performance (270 ± 10 %), and superior mechanical strength (26.36 ± 1.77 MPa). Moreover, in vitro experimentation has convincingly demonstrated the impeccable biocompatibility of hydrogel-Janus NFS. The inherent dual-antibacterial properties in CMCS-Ag and PCE significantly augment fibroblast proliferation and migration. In vivo studies further underscore its capability to expedite wound healing by absorption and expulsion of wound exudates, thereby fostering collagen deposition and vascularization. As such, this work potentially provides fresh insights into the design and fabrication of multifunctional biomimetic scaffolds, holding immense potential in the medical field for efficient wound healing.

Flexible Accelerated-Wound-Healing Antibacterial Hydrogel-Nanofiber Scaffold for Intelligent Wearable Health Monitoring.

Flexible epidermal sensors hold significant potential in personalized healthcare and multifunctional electronic skins. Nonetheless, achieving both robust sensing performance and efficient antibacterial protection, especially in medical paradigms involving electrophysiological signals for wound healing and intelligent health monitoring, remains a substantial challenge. Herein, we introduce a novel flexible accelerated-wound-healing biomaterial based on a hydrogel-nanofiber scaffold (HNFS) via electrostatic spinning and gel cross-linking. We effectively engineer a multifunctional tissue nanoengineered skin scaffold for wound treatment and health monitoring. Key features of HNFS include high tensile strength (24.06 MPa) and elasticity (214.67%), flexibility, biodegradability, and antibacterial properties, enabling assembly into versatile sensors for monitoring human motion and electrophysiological signals. Moreover, in vitro and in vivo experiments demonstrate that HNFS significantly enhances cell proliferation and skin wound healing, provide a comprehensive therapeutic strategy for smart sensing and tissue repair, and guide the development of high-performance "wound healing-health monitoring" bioelectronic skin scaffolds. Therefore, this study provides insights into crafting flexible and repairable skin sensors, holding potential for multifunctional health diagnostics and intelligent medical applications in intelligent wearable health monitoring and next-generation artificial skin fields.

Green Synthesis of Carbon Dots and Their Integration into Nylon-11 Nanofibers for Enhanced Mechanical Strength and Biocompatibility.

Carbon dots (CDs) have been extensively explored to show good optical features, low toxicity, and good biocompatibility. Herein, we report the new synthesis of forsythia-derived CDs (F-CDs) and their incorporation into Nylon-11 nanofibers for improved mechanical properties and biocompatibility. F-CDs are prepared from a Chinese herb forsythia via a magnetic hyperthermia method in 90 s without the use of any organic solvents. The as-prepared F-CDs with rich surface functional groups can be well embedded into Nylon-11 nanofibers via electrospinning, providing Nylon-11/F-CD nanofiber mats with remarkably enhanced mechanical properties. With the incorporation of F-CDs at 10 wt% into the Nylon-11 nanofiber mats, the tensile strength increases from 7.5 to 16.6 MPa, and the elongation ratio at break increases from 39% to 125%. Moreover, the Nylon-11/F-CD nanofiber mats exhibit excellent cytocompatibility towards L929 fibroblast cells with cell viability of 96%. These findings may guide the development of various CD-embedded nanofiber mats with good mechanical properties and biocompatibility potentially useful for biomedical applications, such as tissue engineering scaffolds or wound dressing.

Stable and large-scale organic-inorganic halide perovskite nanocrystal/polymer nanofiber films prepared via a green in situ fiber spinning chemistry method.

Organic-inorganic halide perovskite nanocrystals (PNCs) have shown great advantages in recent years due to their tunable emission wavelengths, narrow full-width at half-maximum (FWHM) and high photoluminescence quantum yield (PLQY). However, PNCs still face the challenges of poor stability, difficulty in processing and generation of heavy metal wastes; therefore, it is necessary to develop a green synthetic method to prepare PNCs. Here, we present for the first time a facile fiber spinning chemistry (FSC) method for the rapid preparation of organic-inorganic halide PAN/MAPbX3 (MA = CH3NH3, X = Cl, Br and I) nanofiber films at room temperature. The FSC process utilizes spinning fibers as the reactor, and polymer solidification and the in situ generation of PNCs occur simultaneously with solvent evaporation during the spinning process. This method not only achieves a continuous large-scale preparation of PNC/polymer nanofiber films but also avoids the generation of heavy metal waste. The organic-inorganic halide PAN/MAPbX3 nanofiber films fabricated by FSC demonstrated tunable emission in the range of 464-612 nm and PLQY of up to 58%, and the fluorescence intensity remained essentially unchanged after 90 days of storage in the atmospheric environment. Interestingly, we successfully prepared high-efficiency white light-emitting diodes (WLEDs) and wide color gamut liquid crystal displays (LCDs) with a color gamut of 116.1% using PAN/MAPbBr3 nanofiber films as fluorescence conversion materials. This study provides a novel way to construct high-performance PNC/polymer fiber composites on a large scale.

Micro-Gel Ensembles for Accelerated Healing of Chronic Wound via pH Regulation.

The pH value in the wound milieu plays a key role in cellular processes and cell cycle processes involved in the process of wound healing. Here, a microfluidic assembly technique is employed to fabricate micro-gel ensembles that can precisely tune the pH value of wound surface and accelerate wound healing. The micro-gel ensembles consist of poly (hydroxypropyl acrylate-co-acrylic acid)-magnesium ions (poly-(HPA-co-AA)-Mg2+ ) gel and carboxymethyl chitosan (CMCS) gel, which can release and absorb hydrogen ion (H+ ) separately at different stages of healing in response to the evolution of wound microenvironment. By regulating the wound pH to affect the proliferation and migration of cell on the wound and the activity of various biological factors in the wound, the physiological processes are greatly facilitated which results in much accelerated healing of chronic wound. This work presents an effective strategy in designing wound healing materials with vast potentials for chronic wound management.

Microfluidic spinning-induced heterotypic bead-on-string fibers for dual-cargo release and wound healing.

The preparation of dual-release pharmaceutical microfibers provides an ideal material for new biomedical applications. We describe a microfluidic spinning method for engineering heterotypic bead-on-string fibers with the ability to carry dual cargos and to deliver on demand. The core of our technology is to combine microfluidic spinning with biomaterial preparation, in which hydrophobic and hydrophilic cargos can be integrated into a bead-on-string microfiber structure. We demonstrate the loading of bovine serum albumin (BSA) in the sodium alginate phase and ibuprofen in the polylactic acid (PLA) phase, respectively. The heterotypic bead-on-string fibers are biocompatible and show hemostatic ability in vivo. These heterotypic bead-on-string fibers are then woven as a skin scaffold and shown to promote wound healing by loading antibacterial and anti-inflammatory cargos.

CCL4-mediated targeting of spleen tyrosine kinase (Syk) inhibitor using nanoparticles alleviates inflammatory bowel disease.

Inflammatory bowel disease (IBD) has emerged a global disease and the ascending incidence and prevalence is accompanied by elevated morbidity, mortality, and substantial healthcare system costs. However, the current typical one-size-fits-all therapeutic approach is suboptimal for a substantial proportion of patients due to the variability in the course of IBD and a considerable number of patients do not have positive response to the clinically approved drugs, so there is still a great, unmet demand for novel alternative therapeutic approaches. Spleen tyrosine kinase (Syk), a cytoplasmic nonreceptor protein tyrosine kinase, plays crucial roles in signal transduction and there are emerging data implicating that Syk participates in pathogenesis of several gut disorders, such as IBD. In this study, we observed the Syk expression in IBD patients and explored the effects of therapeutic Syk inhibition using small-molecule Syk inhibitor piceatannol in bone marrow-derived macrophages (BMDMs). In addition, due to the poor bioavailability and pharmacokinetics of small-molecule tyrosine kinase inhibitors and superiority of targeting nanoparticles-based drug delivery system, we herein prepared piceatannol-encapsulated poly(lactic-co-glycolic acid) nanoparticles that conjugated with chemokine C-C motif ligand 4 (P-NPs-C) and studied its therapeutic effects in vitro in BMDMs and in vivo in experimental colitis model. Our results indicated that in addition to alleviating colitis, oral administration of P-NPs-C promoted the restoration of intestinal barrier function and improved intestinal microflora dysbiosis, which represents a promising treatment for IBD.

Large-Scale Fabrication of Robust Artificial Skins from a Biodegradable Sealant-Loaded Nanofiber Scaffold to Skin Tissue via Microfluidic Blow-Spinning.

Given that many people suffer from large-area skin damage, skin regeneration is a matter of high concern. Here, an available method is developed for the formation of large-area robust skins through three stages: fabrication of a biodegradable sealant-loaded nanofiber scaffold (SNS), skin tissue reconstruction, and skin regeneration. First, a microfluidic blow-spinning strategy is proposed to fabricate a large-scale nanofiber scaffold with an area of 140 cm × 40 cm, composed of fibrinogen-loaded polycaprolactone/silk fibroin (PCL/SF) ultrafine core-shell nanofibers with mean diameter of 65 nm. Then, the SNS forms, where the gelling reaction of fibrin sealant occurs in situ between thrombin and fibrinogen on PCL/SF nanofiber surface, to promote the migration and proliferation of fibroblasts, accelerating skin regeneration. Through an in vivo study, it is shown that the SNS can rapidly repair acute tissue damage such as vascular bleeding and hepatic hemorrhage, and also promote angiogenesis, large-area abdominal wall defect repair, and wound tissue regeneration for medical problems in the world. Besides, it avoids the risk of immune rejection and secondary surgery in clinical applications. This strategy offers a facile route to regenerate large-scale robust skin, which shows great potential in abdominal wall defect repair.

Hybrid material for open abdomen: saving the wound from intestinal fistula.

Treatment of an open abdomen (OA) wound combined with an intestinal fistula is a challenge in the clinic. Here, inspired by the antibacterial activity of graphene (G) and its derivatives, we present a hybrid patch based on the ability of graphene and polycaprolactone (PCL) to kill bacteria and save the cells in a wound. Benefiting from the antibacterial ability of graphene oxide (GO), cells could survive in the presence of bacteria. With the increased ability to protect cells, this patch accelerated wound healing in an OA and intestinal fistula wound model. Additionally, the sub-acute toxicity score showed no extra damage to organs. In conclusion, the employment of the hybrid material for an OA and an intestinal fistula wound healing is encouraging. A hybrid patch based on graphene oxide and polycaprolactone electrospun was generated for open abdomen and fistula wound. The application of the hybrid patch could save the cells from bacteria which contribute to accelerating wound healing.

RpoS regulates a novel type of plasmid DNA transfer in Escherichia coli.

Spontaneous plasmid transformation of Escherichia coli is independent of the DNA uptake machinery for single-stranded DNA (ssDNA) entry. The one-hit kinetic pattern of plasmid transformation indicates that double-stranded DNA (dsDNA) enters E. coli cells on agar plates. However, DNA uptake and transformation regulation remain unclear in this new type of plasmid transformation. In this study, we developed our previous plasmid transformation system and induced competence at early stationary phase. Despite of inoculum size, the development of competence was determined by optical cell density. DNase I interruption experiment showed that DNA was taken up exponentially within the initial 2 minutes and most transforming DNA entered E. coli cells within 10 minutes on LB-agar plates. A half-order kinetics between recipient cells and transformants was identified when cell density was high on plates. To determine whether the stationary phase master regulator RpoS plays roles in plasmid transformation, we investigated the effects of inactivating and over-expressing its encoding gene rpoS on plasmid transformation. The inactivation of rpoS systematically reduced transformation frequency, while over-expressing rpoS increased plasmid transformation. Normally, RpoS recognizes promoters by its lysine 173 (K173). We found that the K173E mutation caused RpoS unable to promote plasmid transformation, further confirming a role of RpoS in regulating plasmid transformation. In classical transformation, DNA was transferred across membranes by DNA uptake proteins and integrated by DNA processing proteins. At stationary growth phase, RpoS regulates some genes encoding membrane/periplasmic proteins and DNA processing proteins. We quantified transcription of 22 of them and found that transcription of only 4 genes (osmC, yqjC, ygiW and ugpC) encoding membrane/periplasmic proteins showed significant differential expression when wildtype RpoS and RpoS(K173E) mutant were expressed. Further investigation showed that inactivation of any one of these genes did not significantly reduce transformation, suggesting that RpoS may regulate plasmid transformation through other/multiple target genes.

Reduced expression of vps11 causes less pigmentation in medaka, Oryzias latipes.

In this article, we describe the medaka mutant pale gray eyes (pge) that shows reduction of black, white, and silver pigmentation and lethality approximately a week after hatching. The pge mutation was mapped to the tip of linkage group 14 and no recombinations were observed between the mutation and medaka vps11 in 900 meioses. Vps 11 is one of the evolutionarily conserved class C vacuolar protein sorting genes (c-vps: vps11, vps16, vps18, and vps33), whose products physically associate to form the c-vps protein complex required for vesicle docking and fusion in the budding yeast. Mutations in vps16, vps18, and vps33 are known to result in decreased pigmentation in organisms such as Drosophila. We cloned the full-length medaka vps11 cDNA by rapid amplification of cDNA ends (RACE) and found no RACE products from the pge mutants. Similarly, no vps11 transcripts were detected from the pge mutants by Northern analysis. The injection of an antisense morpholino against vps11 phenocopied the pge mutant. Taken together, the results suggest that reduced expression of medaka vps11 causes pge and that medaka vps11 is indispensable for survival and normal pigmentation.