Clinical and Molecular Characteristics of Patients with Bloodstream Infections Caused by KPC and NDM Co-Producing Carbapenem-Resistant Klebsiella pneumoniae.

Purpose: Klebsiella pneumoniae carbapenemase (KPC) and New Delhi metallo-ß-lactamase (NDM) co-producing carbapenem-resistant Klebsiella pneumoniae (KPC-NDM-CRKP) isolates have been increasingly reported worldwide but have not yet been systematically studied. Thus, we have conducted a study to compare the risk factors, molecular characteristics, and mortality involved in clinical bloodstream infections (BSIs) caused by KPC-NDM-CRKP and KPC-CRKP strains. Methods: A retrospective study was conducted on 231 patients with BSIs caused by CRKP at Jinling Hospital in China from January 2020 to December 2022. Antimicrobial susceptibility testing, carbapenemase genes detection and whole-genome sequencing were performed subsequently. Results: Overall, 231 patients were included in this study: 25 patients with KPC-NDM-CRKP BSIs and 206 patients with KPC-CRKP BSIs. Multivariate analysis implicated ICU-acquired BSI, surgery within 30 days, and longer stay of hospitalization prior to CRKP isolation as independent risk factors for KPC-NDM-CRKP BSIs. The 30-day mortality rate of the KPC-NDM-CRKP BSIs group was 56% (14/25) compared with 32.5% (67/206) in the KPC-CRKP BSIs control group (P = 0.02). The ICU-acquired BSIs, APACHE II score at BSI onset, and BSIs caused by KPC-NDM-CRKP were independent predictors for 30-day mortality in patients with CRKP bacteremia. The most prevalent ST in KPC-NDM-CRKP isolates was ST11 (23/25, 92%), followed by ST15 (2/25, 8%). Conclusion: In patients with CRKP BSIs, KPC-NDM-CRKP was associated with an excess of mortality. The likelihood that KPC-NDM-CRKP will become the next "superbug" highlights the significance of epidemiologic surveillance and clinical awareness of this pathogen.

Polyaspartic acid increases potassium content and reduces the ratio of total sugar to nicotine in tobacco leaves.

Tobacco is an important cash crop in China, but the low potassium (K) content and high ratio of total sugar to nicotine in tobacco leaves have seriously affected the quality of tobacco leaves. As a fertilizer synergist, polyaspartic acid (PASP) can improve the K content in tobacco leaves, but it is unknown how it affects the K content in different parts of tobacco leaves, and how PASP affects the ratio of total sugar to nicotine in tobacco leaves has not been reported. Therefore, "Zhongyan 100" was selected for pot experiments with 5 different PASP addition levels: CK (0.0 %), P1 (0.1 %), P2 (0.2 %), P3 (0.4 %) and P4 (0.6 %), to reveal the effects of PASP on tobacco growth, K content, sugar content, nicotine content and the ratio of total sugar to nicotine in different tobacco parts, and determine the optimal PASP dosage for regulating the K content and the ratio of total sugar to nicotine in tobacco. The results showed that P1 (0.1 %) and P2 (0.2 %) only had slighter effects on tobacco growth and quality, while P3 (0.4 %) and P4 (0.6 %)treatments significantly promoted dry matter accumulation, increased K and nicotine content in leaves, decreased reducing sugar and total soluble sugar content in leaves, thereby reducing the ratio of total sugar to nicotine in tobacco leaves, especially in upper leaves. Considering the economic cost savings, 0.4% PASP was determined as the best application level to improve the growth and quality of tobacco. Thus, proper application of PASP is beneficial to improve tobacco leaf quality and reduce chemical K fertilizer application, thereby decreasing agricultural environmental risks of chemical fertilizer and alleviating the rapid depletion of potash in the world.

Amino acid application inhibits root-to-shoot cadmium translocation in Chinese cabbage by modulating pectin methyl-esterification.

The exogenous application of amino acids (AAs) generally alleviates cadmium (Cd) toxicity in plants by altering their subcellular distribution. However, the physiological mechanisms underlying AA-mediated cell wall (CW) sequestration of Cd in Chinese cabbage remain unclear. Using two genotypes of Chinses cabbage, Jingcui 60 (Cd-tolerant) and 16-7 (Cd-sensitive), we characterized the root structure, subcellular distribution of Cd, CW component, and related gene expression under the Cd stress. Cysteine (Cys) supplementation led to a reduction in the Cd concentration in the shoots of Jingcui 60 and 16-7 by 65.09 % and 64.03 %, respectively. Addition of Cys alleviated leaf chlorosis in both cultivars by increasing Cd chelation in the root CW and reducing its distribution in the cytoplasm and organelles. We further demonstrated that Cys supplementation mediated the downregulation of PMEI1 expression and improving the activity of pectin methyl-esterase (PME) by 17.98 % and 25.52 % in both cultivars, respectively, compared to the Cd treatment, resulting in an approximate 12.00 %-14.70 % increase in Cd retention in pectin. In contrast, threonine (Thr) application did not significantly alter Cd distribution in the shoots of either cultivar. Taken together, our results suggest that Cys application reduces Cd root-to-shoot translocation by increasing Cd sequestration in the root CW through the downregulation of pectin methyl-esterification.

Advancements in hydrogel-based drug delivery systems for the treatment of inflammatory bowel disease: a review.

Inflammatory bowel disease (IBD) is a chronic disorder that affects millions of individuals worldwide. However, current drug therapies for IBD are plagued by significant side effects, low efficacy, and poor patient compliance. Consequently, there is an urgent need for novel therapeutic approaches to alleviate IBD. Hydrogels, three-dimensional networks of hydrophilic polymers with the ability to swell and retain water, have emerged as promising materials for drug delivery in the treatment of IBD due to their biocompatibility, tunability, and responsiveness to various stimuli. In this review, we summarize recent advancements in hydrogel-based drug delivery systems for the treatment of IBD. We first identify three pathophysiological alterations that need to be addressed in the current treatment of IBD: damage to the intestinal mucosal barrier, dysbiosis of intestinal flora, and activation of inflammatory signaling pathways leading to disequilibrium within the intestines. Subsequently, we discuss in depth the processes required to prepare hydrogel drug delivery systems, from the selection of hydrogel materials, types of drugs to be loaded, methods of drug loading and drug release mechanisms to key points in the preparation of hydrogel drug delivery systems. Additionally, we highlight the progress and impact of the hydrogel-based drug delivery system in IBD treatment through regulation of physical barrier immune responses, promotion of mucosal repair, and improvement of gut microbiota. In conclusion, we analyze the challenges of hydrogel-based drug delivery systems in clinical applications for IBD treatment, and propose potential solutions from our perspective.

Prediction models of surgical site infection after gastrointestinal surgery: a nationwide prospective cohort study.

OBJECTIVE: This study aimed to construct and validate a clinical prediction model for surgical site infection (SSI) risk 30 days after gastrointestinal surgery. MATERIALS AND METHODS: This multicentre study involving 57 units conducted a 30-day postoperative follow-up of 17 353 patients who underwent gastrointestinal surgery at the unit from 1 March 2021 to 28 February 2022. The authors collected a series of hospitalisation data, including demographic data, preoperative preparation, intraoperative procedures and postoperative care. The main outcome variable was SSI, defined according to the Centres for Disease Control and Prevention guidelines. This study used the least absolute shrinkage and selection operator (LASSO) algorithm to screen predictive variables and construct a prediction model. The receiver operating characteristic curve, calibration and clinical decision curves were used to evaluate the prediction performance of the prediction model. RESULTS: Overall, 17 353 patients were included in this study, and the incidence of SSI was 1.6%. The univariate analysis combined with LASSO analysis showed that 20 variables, namely, chronic liver disease, chronic kidney disease, steroid use, smoking history, C-reactive protein, blood urea nitrogen, creatinine, albumin, blood glucose, bowel preparation, surgical antibiotic prophylaxis, appendix surgery, colon surgery, approach, incision type, colostomy/ileostomy at the start of the surgery, colostomy/ileostomy at the end of the surgery, length of incision, surgical duration and blood loss were identified as predictors of SSI occurrence ( P <0.05). The area under the curve values of the model in the train and test groups were 0.7778 and 0.7868, respectively. The calibration curve and Hosmer-Lemeshow test results demonstrated that the model-predicted and actual risks were in good agreement, and the model forecast accuracy was high. CONCLUSIONS: The risk assessment system constructed in this study has good differentiation, calibration and clinical benefits and can be used as a reference tool for predicting SSI risk in patients.

In situ bioprinting of double network anti-digestive xanthan gum derived hydrogel scaffolds for the treatment of enterocutaneous fistulas.

The clinical treatment of enterocutaneous fistula is challenging and causes significant patient discomfort. Fibrin gel can be used to seal tubular enterocutaneous fistulas, but it has low strength and poor digestion resistance. Based on in situ bioprinting and the anti-digestive properties of xanthan gum (XG), we used carboxymethyl chitosan (CMC) and xanthan gum modified by grafted glycidyl methacrylate (GMA) and aldehyde (GCX) as the ink to print a double network hydrogel that exhibited high strength and an excellent anti-digestive performance. In addition, in vitro studies confirmed the biocompatibility, degradability, and self-healing of hydrogels. In our rabbit tubular enterocutaneous fistula model, the in situ printed hydrogel resisted corrosion due to the intestinal fluid and acted as a scaffold for intestinal mucosal cells to proliferate on its surface. To summarize, in situ bioprinting GCX/CMC double network hydrogel can effectively block tubular enterocutaneous fistulas and provide a stable scaffold for intestinal mucosal regeneration.

Establishment and evaluation of an improved rat model of open abdomen.

INTRODUCTION: This study aimed to establish an animal model of open abdomen (OA) through temporary abdominal closure via different techniques. METHODS: Adult male Sprague-Dawley rats were randomly divided into three groups: group A (OA with polypropylene mesh alone); group B (OA with polypropylene mesh combined with a patch); and group C (OA with polypropylene mesh and a sutured patch). Vital signs, pathophysiological changes, and survival rates were closely monitored in the rats for 7 days after surgery. Abdominal X-rays and histopathological examinations were performed to assess abdominal organ changes and wound healing. RESULTS: The results showed no significant difference in mortality rates among the three groups (p > 0.05). However, rats in group B exhibited superior overall condition, cleaner wounds, and a higher rate of wound healing compared to the other groups (p < 0.05). Abdominal X-rays indicated that varying degrees of distal intestinal obstruction in all groups. Histopathological examinations revealed fibrous hyperplasia, inflammatory cell infiltration, neovascularization, and collagen deposition in all groups. Group B demonstrated enhanced granulation tissue generation, neovascularization, and collagen deposition compared to the other groups (p < 0.05). CONCLUSIONS: Polypropylene mesh combined with patches is the most suitable method for establishing an animal model of OA. This model successfully replicated the pathological and physiological changes in postoperative patients with OA, specifically the progress of abdominal skin wound healing. It provides a practical and reliable animal model for OA research.

A click chemistry-mediated all-peptide cell printing hydrogel platform for diabetic wound healing.

High glucose-induced vascular endothelial injury is a major pathological factor involved in non-healing diabetic wounds. To interrupt this pathological process, we design an all-peptide printable hydrogel platform based on highly efficient and precise one-step click chemistry of thiolated γ-polyglutamic acid, glycidyl methacrylate-conjugated γ-polyglutamic acid, and thiolated arginine-glycine-aspartate sequences. Vascular endothelial growth factor 165-overexpressed human umbilical vein endothelial cells are printed using this platform, hence fabricating a living material with high cell viability and precise cell spatial distribution control. This cell-laden hydrogel platform accelerates the diabetic wound healing of rats based on the unabated vascular endothelial growth factor 165 release, which promotes angiogenesis and alleviates damages on vascular endothelial mitochondria, thereby reducing tissue hypoxia, downregulating inflammation, and facilitating extracellular matrix remodeling. Together, this study offers a promising strategy for fabricating tissue-friendly, high-efficient, and accurate 3D printed all-peptide hydrogel platform for cell delivery and self-renewable growth factor therapy.

Phenethylferulate as a natural inhibitor of inflammation in LPS-stimulated RAW 264.7 macrophages: focus on NF-κB, Akt and MAPK signaling pathways.

BACKGROUND: Notopterygii Rhizoma et Radix (NRR) is commonly used for the treatment of inflammation-linked diseases. Phenethylferulate (PF) is high content in NRR crude, but its anti-inflammatory effect remains unclear. Therefore, we aimed to investigate the anti-inflammatory properties of PF and its underlying molecular mechanisms in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. METHODS: The effect of PF on cell viability was measured by MTT assay. The anti-inflammatory properties of PF were studied by detecting the levels of inflammatory mediators and cytokines using enzyme-linked immunosorbent assay (ELISA). Furthermore, the anti-inflammatory mechanisms of PF were determined by Western blot analysis. RESULTS: PF was not cytotoxic to RAW 264.7 macrophages at the concentrations of below 48 µM. ELISA showed that PF conspicuously inhibited overproduction of prostaglandin E2 (PGE2), tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß) and interleukin 6 (IL-6). Western blot analysis showed that PF remarkably suppressed overproduction of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2), the phosphorylation of inhibitor of NF-κB kinase α (IκB-α), protein kinase B (Akt), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinases (JNK) and p38, as well as the degradation and subsequent nuclear translocation of p65. CONCLUSIONS: PF is a potent inhibitor of inflammation acting on nuclear factor kappa-B (NF-κB), Akt and mitogen-activated protein kinase (MAPK) signaling pathways in LPS-stimulated RAW 264.7 macrophages. This work provides evidence for the suitability of PF as a therapeutic candidate for the management of inflammatory-mediated immune disorders.

Precise Orchestration of Gasdermins' Pore-Forming Function by Posttranslational Modifications in Health and Disease.

Gasdermins (GSDMs) serve as pivotal executors of pyroptosis and play crucial roles in host defence, cytokine secretion, innate immunity, and cancer. However, excessive or inappropriate GSDMs activation is invariably accompanied by exaggerated inflammation and results in tissue damage. In contrast, deficient or impaired activation of GSDMs often fails to promptly eliminate pathogens, leading to the increasing severity of infections. The activity of GSDMs requires meticulous regulation. The dynamic modulation of GSDMs involves many aspects, including autoinhibitory structures, proteolytic cleavage, lipid binding and membrane translocation (oligomerization and pre-pore formation), oligomerization (pore formation) and pore removal for membrane repair. As the most comprehensive and efficient regulatory pathway, posttranslational modifications (PTMs) are widely implicated in the regulation of these aspects. In this comprehensive review, we delve into the complex mechanisms through which a variety of proteases cleave GSDMs to enhance or hinder their function. Moreover, we summarize the intricate regulatory mechanisms of PTMs that govern GSDMs-induced pyroptosis.

Itaconate inhibits SYK through alkylation and suppresses inflammation against hvKP induced intestinal dysbiosis.

Hypervirulent Klebsiella pneumoniae (hvKP) is a highly lethal opportunistic pathogen that elicits more severe inflammatory responses compared to classical Klebsiella pneumoniae (cKP). In this study, we investigated the interaction between hvKP infection and the anti-inflammatory immune response gene 1 (IRG1)-itaconate axis. Firstly, we demonstrated the activation of the IRG1-itaconate axis induced by hvKP, with a dependency on SYK signaling rather than STING. Importantly, we discovered that exogenous supplementation of itaconate effectively inhibited excessive inflammation by directly inhibiting SYK kinase at the 593 site through alkylation. Furthermore, our study revealed that itaconate effectively suppressed the classical activation phenotype (M1 phenotype) and macrophage cell death induced by hvKP. In vivo experiments demonstrated that itaconate administration mitigated hvKP-induced disturbances in intestinal immunopathology and homeostasis, including the restoration of intestinal barrier integrity and alleviation of dysbiosis in the gut microbiota, ultimately preventing fatal injury. Overall, our study expands the current understanding of the IRG1-itaconate axis in hvKP infection, providing a promising foundation for the development of innovative therapeutic strategies utilizing itaconate for the treatment of hvKP infections.

NPs-Ca promotes Cd accumulation and enhances Cd tolerance of rapeseed shoots by affecting Cd transfer and Cd fixation in pectin.

The use of rapeseed (Brassica napus) as a hyperaccumulator plant has shown great promise for the remediation of cadmium (Cd) contaminated soils. Nanosized materials (NPs) have been shown to mitigate heavy metal toxicity in plants, but it is unknown how l-aspartate nano-calcium (NPs-Ca) affects Cd uptake, transport, and tolerance in rapeseed. A soil pot experiment was conducted with two treatments: a control treatment (CK) with 2.16 g CaCl2 and NPs-Ca treatment with 6.00 g NPs-Ca, to evaluate the effects and mechanisms of NPs-Ca on Cd tolerance in rapeseed. Compared to CaCl2, NPs-Ca promoted Cd transportation from roots to shoots by up-regulating the expression of Cd transport genes (ABCC12, HMA8, NRAM6, ZIP6, CAX4, PCR2, and HIP6). Therefore, NPs-Ca increased Cd accumulation in rapeseed shoots by 39.4%. Interestingly, NPs-Ca also enhanced Cd tolerance in the shoots, resulting in lower hydrogen peroxide (H2O2) accumulation and proline content, as well as higher antioxidant enzyme activities (POD, CAT). Moreover, NPs-Ca reduced the activity of pectin-degrading enzymes (polygalacturonase: PG, ß-galactosidase: ß-GAL), promoted the activity of pectin methyl esterase (PME), and changed transcription levels of related genes (PME, PMEI, PG, PGIP, and ß-GAL). NPs-Ca treatment also significantly increased the Cd content in cell walls by 59.8%, that is, more Cd was immobilized in cell walls, and less Cd entered organelles in shoots of NPs-Ca treatment due to increased pectin content and degree of pectin demethylation. Overall, NPs-Ca increased Cd accumulation in rapeseed shoots by promoting Cd transport from roots to shoots. And meantime, NPs-Ca enhanced Cd tolerance of shoots by inhibiting pectin degradation, promoting pectin demethylation and increasing Cd fixation in pectin. These findings suggest that NPs-Ca can improve the potential of rapeseed as a hyperaccumulator for the remediation of Cd-contaminated soil and the protection of the environment. Furthermore, the study provides a theoretical basis for the application of NPs-Ca in the phytoremediation of Cd-contaminated soils with hyperaccumulating plants.

An artificial intelligence-based pipeline for automated detection and localisation of epileptic sources from magnetoencephalography.

Objective.Magnetoencephalography (MEG) is a powerful non-invasive diagnostic modality for presurgical epilepsy evaluation. However, the clinical utility of MEG mapping for localising epileptic foci is limited by its low efficiency, high labour requirements, and considerable interoperator variability. To address these obstacles, we proposed a novel artificial intelligence-based automated magnetic source imaging (AMSI) pipeline for automated detection and localisation of epileptic sources from MEG data.Approach.To expedite the analysis of clinical MEG data from patients with epilepsy and reduce human bias, we developed an autolabelling method, a deep-learning model based on convolutional neural networks and a hierarchical clustering method based on a perceptual hash algorithm, to enable the coregistration of MEG and magnetic resonance imaging, the detection and clustering of epileptic activity, and the localisation of epileptic sources in a highly automated manner. We tested the capability of the AMSI pipeline by assessing MEG data from 48 epilepsy patients.Main results.The AMSI pipeline was able to rapidly detect interictal epileptiform discharges with 93.31% ± 3.87% precision based on a 35-patient dataset (with sevenfold patientwise cross-validation) and robustly rendered accurate localisation of epileptic activity with a lobar concordance of 87.18% against interictal and ictal stereo-electroencephalography findings in a 13-patient dataset. We also showed that the AMSI pipeline accomplishes the necessary processes and delivers objective results within a much shorter time frame (∼12 min) than traditional manual processes (∼4 h).Significance.The AMSI pipeline promises to facilitate increased utilisation of MEG data in the clinical analysis of patients with epilepsy.

Microfluidic intestinal organoid-on-a-chip uncovers therapeutic targets by recapitulating oxygen dynamics of intestinal IR injury.

Increasing evidence demonstrates that mammals have different reactions to hypoxia with varied oxygen dynamic patterns. It takes ∼24 h for tri-gas incubator to achieve steady cell hypoxia, which fails to recapitulate ultrafast oxygen dynamics of intestinal ischemia/reperfusion (IR) injury. Inspired from the structure of native intestinal villi, we engineered an intestinal organoid chip embedded with engineered artificial microvessels based on co-axial microfluidic technology by using pH-responsive ZIF-8/sodium alginate scaffold. The chip was featured on: (i) eight times the oxygen exchange efficiency compared with the conventional device, tri-gas incubator, (ii) implantation of intestinal organoid reproducing all types of intestinal epithelial cells, and (iii) bio-responsiveness to hypoxia and reoxygenation (HR) by presenting metabolism disorder, inflammatory reaction, and cell apoptosis. Strikingly, it was found for the first time that Olfactomedin 4 (Olfm4) was the most significantly down-regulated gene under a rapid HR condition by sequencing the RNA from the organoids. Mechanistically, OLFM4 played protective functions on HR-induced cell inflammation and tissue damage by inhibiting the NF-kappa B signaling activation, thus it could be used as a therapeutic target. Altogether, this study overcomes the issue of mismatched oxygen dynamics between in vitro and in vivo, and sets an example of next-generation multisystem-interactive organoid chip for finding precise therapeutic targets of IR injury.

Smart implants: 4D-printed shape-morphing scaffolds for medical implantation.

Biomedical implants have recently shown excellent application potential in tissue repair and replacement. Applying three-dimensional (3D) printing to implant scaffold fabrication can help to address individual needs more precisely. Fourdimensional (4D) printing emerges rapidly based on the development of shape-responsive materials and design methods, which makes the production of dynamic functional implants possible. Smart implants can be pre-designed to respond to endogenous or exogenous stimuli and perform seamless integration with regular/ irregular tissue defects, defect-luminal organs, or curved structures via programmed shape morphing. At the same time, they offer great advantages in minimally invasive surgery due to the small-to-large volume transition. In addition, 4D-printed cellular scaffolds can generate extracellular matrix (ECM)-mimetic structures that interact with the contacting cells, expanding the possible sources of tissue/organ grafts and substitutes. This review summarizes the typical technologies and materials of 4D-printed scaffolds, and the programming designs and applications of these scaffolds are further highlighted. Finally, we propose the prospects and outlook of 4D-printed shape-morphing implants.

RIPK3-MLKL necroptotic signalling amplifies STING pathway and exacerbates lethal sepsis.

BACKGROUNDS: The stimulator of interferon genes (STING) is an important driver in various inflammatory diseases. METHODS AND RESULTS: Here, we have demonstrated that inhibition of RIPK3 and MLKL dampens STING signaling, indicating that necroptosis may be involved in sustaining STING signaling. Furthermore, RIPK3 knockout in HT-29 cells significantly suppressed STING signaling. Mechanistically, RIPK3 inhibits autophagic flux during STING activation. RIPK3 knockout inhibits STING signaling by intensifying STING autophagy. In contrast, MLKL regulates the STING pathway bidirectionally. MLKL deficiency enhances STING signaling, whereas suppression of MLKL-mediated pore formation restricts STING signaling. Mechanistically, upon abrogating the pro-necroptotic activity of MLKL, MLKL bound to activated STING is secreted to the extracellular space, where it restricts TBK1 and IRF3 recruitment. Targeting necroptotic signaling ameliorates STING activation during DMXAA-induced intestinal injury and sepsis. CONCLUSIONS: These findings elucidate molecular mechanisms linking necroptosis to the STING pathway, and suggest a potential benefit of therapeutic targeting of necroptosis in STING-driven inflammatory diseases.

Identification of Risk Factors and Phenotypes of Surgical Site Infection in Patients After Abdominal Surgery.

OBJECTIVES: We aimed to determine the current incidence rate and risk factors for surgical site infection (SSI) after abdominal surgery in China and to further demonstrate the clinical features of patients with SSI. BACKGROUND: Contemporary epidemiology and clinical features of SSI after abdominal surgery remain poorly characterized. METHODS: A prospective multicenter cohort study was conducted from March 2021 to February 2022; the study included patients who underwent abdominal surgery at 42 hospitals in China. Multivariable logistic regression analysis was performed to identify risk factors for SSI. Latent class analysis (LCA) was used to explore the population characteristics of SSI. RESULTS: In total, 23,982 patients were included in the study, of whom 1.8% developed SSI. There was a higher SSI incidence in open surgery (5.0%) than in laparoscopic or robotic surgeries (0.9%). Multivariable logistic regression indicated that the independent risk factors for SSI after abdominal surgery were older age, chronic liver disease, mechanical bowel preparation, oral antibiotic bowel preparation, colon or pancreas surgery, contaminated or dirty wounds, open surgery, and colostomy/ileostomy. LCA revealed 4 subphenotypes in patients undergoing abdominal surgery. Types α and ß were mild subclasses with a lower SSI incidence; whereas types γ and δ were the critical subgroups with a higher SSI incidence, but their clinical features were different. CONCLUSIONS: LCA identified 4 subphenotypes in patients who underwent abdominal surgery. Types γ and δ were critical subgroups with a higher SSI incidence. This phenotype classification can be used to predict SSI after abdominal surgery.

Melt electrowriting-printed peritoneal scaffold prevents peritoneal adhesion and facilitates peritoneal repair.

Peritoneal adhesion is a critical issue after abdominal surgery. Cell-based methods for preventing peritoneal adhesion have not yet been fully investigated. Here, we constructed a highly biomimetic peritoneal scaffold by seeding mesothelial cells, the natural physiological barrier of the peritoneum, onto a melt electrowriting-printed scaffold. The scaffolds with the microfibers crossed at different angles (30°, 60°, and 90°) were screened based on mesothelial cell proliferation and orientation. Thirty degrees were more suitable for improving proliferation of mesothelial cells and cell growth in a single direction; therefore, the 30° peritoneal scaffold could better mimic the physiological structure of native peritoneum. Mechanistically, such a peritoneal scaffold was able to act as a barrier to prevent peritoneal resident macrophages from migrating to the site of the peritoneal lesion. In vivo mesothelial cell tracking using lentivirus technology confirmed that the peritoneal scaffold, compared to the scaffold without mesothelial cells, could prevent peritoneal adhesion and was directly involved in the repair of injured peritoneum. This study suggests that the peritoneal scaffolds can potentially prevent peritoneal adhesion, offering a new approach for clinical treatment.

Subphenotyping heterogeneous patients with chronic critical illness to guide individualised fluid balance treatment using machine learning: a retrospective cohort study.

Background: The great heterogeneity of patients with chronic critical illness (CCI) leads to difficulty for intensive care unit (ICU) management. Identifying subphenotypes could assist in individualized care, which has not yet been explored. In this study, we aim to identify the subphenotypes of patients with CCI and reveal the heterogeneous treatment effect of fluid balance for them. Methods: In this retrospective study, we defined CCI as an ICU length of stay over 14 days and coexists with persistent organ dysfunction (cardiovascular Sequential Organ Failure Assessment (SOFA) score ≥1 or score in any other organ system ≥2) at Day 14. Data from five electronic healthcare record datasets covering geographically distinct populations (the US, Europe, and China) were studied. These five datasets include (1) subset of Derivation (MIMIC-IV v1.0, US) cohort (2008-2019); (2) subset Derivation (MIMIC-III v1.4 'CareVue', US) cohort (2001-2008); (3) Validation I (eICU-CRD, US) cohort (2014-2015); (4) Validation II (AmsterdamUMCdb/AUMC, Euro) cohort (2003-2016); (5) Validation III (Jinling, CN) cohort (2017-2021). Patients who meet the criteria of CCI in their first ICU admission period were included in this study. Patients with age over 89 or under 18 years old were excluded. Three unsupervised clustering algorithms were employed independently for phenotypes derivation and validation. Extreme Gradient Boosting (XGBoost) was used for phenotype classifier construction. A parametric G-formula model was applied to estimate the cumulative risk under different daily fluid management strategies in different subphenotypes of ICU mortality. Findings: We identified four subphenotypes as Phenotype A, B, C, and D in a total of 8145 patients from three countries. Phenotype A is the mildest and youngest subgroup; Phenotype B is the most common group, of whom patients showed the oldest age, significant acid-base abnormality, and low white blood cell count; Patients with Phenotype C have hypernatremia, hyperchloremia, and hypercatabolic status; and in Phenotype D, patients accompany with the most severe multiple organ failure. An easy-to-use classifier showed good effectiveness. Phenotype characteristics showed robustness across all cohorts. The beneficial fluid balance threshold intervals of subphenotypes were different. Interpretation: We identified four novel phenotypes that revealed the different patterns and significant heterogeneous treatment effects of fluid therapy within patients with CCI. A prospective study is needed to validate our findings, which could inform clinical practice and guide future research on individualized care. Funding: This study was funded by 333 High Level Talents Training Project of Jiangsu Province (BRA2019011), General Program of Medical Research from the Jiangsu Commission of Health (M2020052), and Key Research and Development Program of Jiangsu Province (BE2022823).

Whole Model Path Planning-Guided Multi-Axis and Multi-Material Printing of High-Performance Intestinal Implantable Stent.

The problems of step effects, supporting material waste, and conflict between flexibility and toughness for 3D printed intestinal fistula stents are not yet resolved. Herein, the fabrication of a support-free segmental stent with two types of thermoplastic polyurethane (TPU) using a homemade multi-axis and multi-material conformal printer guided with advanced whole model path planning is demonstrated. One type of TPU segment is soft to increase elasticity, and the other is used to achieve toughness. Owing to advancements in stent design and printing, the obtained stents present three unprecedented properties compared to previous three-axis printed stents: i) Overcoming step effects; ii) Presenting comparable axial flexibility to a stent made of a single soft TPU 87A material, thus increasing the feasibility of implantation; and iii) Showing equivalent radial toughness to a stent made of a single hard TPU 95A material. Hence, the stent can resist the intestinal contractive force and maintain intestinal continuity and patency. Through implanting such stents to the rabbit intestinal fistula models, therapeutic mechanisms of reducing fistula output and improving nutritional states and intestinal flora abundance are revealed. Overall, this study develops a creative and versatile method to improve the poor quality and mechanical properties of medical stents.