Fascia forms a continuous connective tissue network throughout the body and is persistently subjected to complex mechanical loading, including stretching, compression, shear and torsion during daily activity. Growing evidence suggests that fascia is not merely a passive mechanical linkage for force transmission but may also participate in diverse physiological processes, implying its functional versatility. Such multifunctionality is likely governed by the coupling of multiple factors, yet the underlying biophysical properties remain incompletely understood. Here, we performed a systematic investigation of dried ex vivo fascial tissues from multiple anatomical regions of rats in two age groups (1-2-month and 12-month) using Piezoresponse Force Microscopy. We demonstrate that fascia exhibits measurable electromechanical coupling and that the effective piezoelectric coefficient is significantly higher in the 12-month group than in the 1-2-month group, whereas differences among anatomical regions within the same age group are comparatively small. Integrating the experimental observations with theoretical analysis suggests that the stronger effective electromechanical response may be associated with the presence of thicker collagen fiber bundles, and that the inclination angle of collagen bundles may also contribute to the overall effective electromechanical response. Together, these findings confirm the electromechanical coupling of fascia and link its magnitude to collagen morphology, providing a biophysical basis for understanding the multifaceted roles of fascia in physiological function and for addressing clinically relevant conditions associated with fascial morphological alterations.

Osteochondral defects present substantial clinical challenges due to the complex, multilayered structure and distinct physiological properties of cartilage and subchondral bone. Here, we report a three-dimensional (3D)-printed osteochondral scaffold featuring a dual biomimetic design that integrates vertically oriented microchannels with bioinspired nano-mineral precursors. Specifically, a multifunctional hierarchical construct was developed by incorporating ultrasmall (∼1 nm) polymer-induced liquid precursor-modified amorphous calcium phosphate (nCaP) into a GelMA-based matrix. Using digital light processing-based 3D printing, a biphasic scaffold with spatially defined architectures was fabricated, consisting of a pure GelMA upper layer featuring combined lotus-like and radial pore distributions to emulate the cartilage microenvironment, and a nCaP/GelMA lower layer with lotus-like pore architecture to support subchondral bone regeneration. Notably, in contrast to conventional inorganic fillers such as nanohydroxyapatite (nHAp), the incorporation of ultrasmall nCaP nanoclusters did not adversely affect photopolymerization behavior or printing fidelity, thereby enabling high-resolution fabrication. Beyond structural advantages, nCaP incorporation markedly enhanced the bioactivity of the scaffold. Compared with nHAp, nCaP significantly promoted the recruitment and osteogenic differentiation of endogenous bone marrow-derived mesenchymal stem cells, while also facilitating extracellular matrix deposition, mineralization, and angiogenesis. Transcriptomic analysis further indicated that these effects were associated with the upregulation of angiogenic factor EGFL6, suppression of inflammation-related TNFSF14/NF-κB signaling, and activation of the PI3K-Akt pathway. Collectively, bothin vitroandin vivoevaluations demonstrated that the nCaP/GelMA scaffold achieved improved tissue integration, restoration of hierarchical architecture, and enhanced mechanical performance compared with control groups. These findings underscore the potential of dual biomimetic scaffold design as an effective strategy for osteochondral regeneration.

Osteoarthritis (OA) is a progressive degenerative joint disease characterized by dynamic pathological evolution. Existing therapies are largely confined to single-phase interventions and therefore fail to address the distinct biological requirements that arise during disease progression. Here, we report an intelligent responsive multifunctional nanoplatform that enables spatiotemporally programmed, stage-specific intervention of osteoarthritis through precisely controlled near-infrared (NIR) irradiation. During the initial phase, high-intensity NIR irradiation (1.5 W/cm2) preferentially eliminates pathological fibroblast-like synoviocytes through activation of an Rn7sk-associated apoptotic signaling pathway, thereby attenuating oxidative stress and inflammation-associated matrix degradation. Following microenvironmental remodeling, repeated low-intensity NIR irradiation (0.5 W/cm2) activates endogenous mesenchymal stem cells, enhances chondrogenic differentiation, and promotes extracellular matrix reconstruction, accompanied by increased expression of COL2A1, ELN, COL9A2, and COL11A2, ultimately restoring cartilage structure and function. Rather than relying on a static therapeutic modality, this programmable photothermal strategy synchronizes pathological suppression with regenerative activation according to the evolving biological requirements of osteoarthritis. Collectively, this work establishes a stage-matched therapeutic framework for precise microenvironmental regulation and provides a conceptual strategy for treating chronic degenerative diseases characterized by dynamically evolving pathological processes.

Current approaches for bone repair predominantly target localized delivery of growth factors that are aimed at the coupling of angiogenesis and osteogenesis. However, delayed revascularization and regeneration of critical-sized bone defects are still challenging. In this study, we engineer an ossification center-like organoid (OCO) that consist of an inner-core bone morphogenetic and neurotrophic spheroid generated via MSCs-loaded 3D printing, alongside the interstitially distributed outer-shell proangiogenic neurotrophic phase. Our results demonstrate that collective implantation of OCOs achieves rapid bone bridging with successive OC-like bone ossicles formation across the bone defect in a "divide-and-conquer" way. Single-cell RNA sequencing analysis unveils a developmentally mimicking stem cell community that dominated with Krt8+ skeletal stem cells (SSCs) is uniquely recruited by the pro-regenerative in-situ organoid fusion and maturation. Particularly noteworthy is the specific expansion of Krt8+ SSCs concomitant with the simultaneous reduction of Has1+ migratory fibroblasts (MFs) post-OCO implantation. Furthermore, cross-species comparisons employing machine learning reveal high resemblance of the relative Krt8+ SSCs/Has1+ MFs composition in bone regeneration with that in public data from developmental bone tissues. Our findings advocate an approach akin to "divide-and-conquer" utilizing engineered OC-like organoids for prompt regeneration of large-sized bone defects.

The cancer genomic instability drives the generation of neoantigens, making them ideal targets for immunotherapy. Neoantigen-specific tumor-infiltrating lymphocytes achieve precise tumor cell killing by recognizing neoantigens on the tumor surface, but their efficacy is limited by complex physical barriers within the tumor microenvironment. These barriers not only directly impede TIL migration and infiltration but also synergize with immunosuppressive signals to weaken antitumor immune responses. The tumor extracellular matrix forms a dense fibrous network due to enhanced collagen crosslinking, pathological hyaluronic acid deposition, and increased stiffness, hindering TIL mobility. Aberrant tumor vasculature, characterized by hyperpermeability and elevated interstitial fluid pressure, collaborates with pro-fibrotic factors, such as VEGF, TGF-β secreted by cancer-associated fibroblasts and regulatory T cells to create mechanical compression barriers. This review systematically explores the composition, molecular mechanisms, and therapeutic strategies targeting these physical barriers, providing novel insights for neoantigen-based therapies. Future efforts should integrate biomechanical interventions with immunotherapy, elucidate the interplay between mechanical signaling and immunometabolism, and optimize multi-target combinatorial approaches to enhance the clinical translation potential of neoantigen therapies.

Infection with carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP) is life-threatening because of its pronounced virulence and antibiotic resistance. Recent studies revealed that iron and ROS enhance the ability of macrophages to eliminate intracellular pathogenic bacteria. However, whether and how iron-related oxygen stress responses in macrophages elicit a protective role against CR-hvKP infection remains largely unknown. In a mouse model of CR-hvKP pulmonary infection, the production of the Solute Carrier Family 7 member 11 (SLC7A11) was increased. Treatment with the ferroptosis agonist Erastin or Sorafenib decreased the SLC7A11 expression and the bacterial load in infected lung tissues, alleviating CR-hvKP-induced acute lung injury, increasing the content of TLR4, ROS and LPO. In vitro experiments showed that CR-hvKP infection resulted in a remarkable time-dependent changes in the expression of SLC7A11, GSH, ferrous iron, ROS and LPO in MH-S cells. Mechanically, blocking the expression of SLC7A11 in CR-hvKP-infected MH-S cells increased iron and ROS, improving the ability of macrophages to clear CR-hvKP in an LPO-dependent manner. Taken together, our study reveals that improving iron-related oxygen stress via blocking the SLC7A11/GSH pathway promoting the macrophages to phagocytose and eliminate CR-hvKP, which provides a new promising strategy against CR-hvKP infection.

Osteochondral defect regeneration is challenging due to the mismatch between cartilage and subchondral bone. We developed a functionalized scaffold replicating the natural architecture, biochemical and biomechanical environment of both tissues to promote concurrent regeneration. Our bilayered, zone-specific scaffold combines tailored materials for each tissue type: gelatin methacryloyl (GelMA), modified hyaluronic acid, and umbilical cord-derived extracellular matrix (ECM) for the cartilage layer; GelMA, placenta-derived ECM, and nano amorphous calcium phosphate for the osseous layer. Using 3D digital light-processing printing, we constructed the scaffold with spatially distributed biochemical and biomechanical signaling. This approach created dual chondro-/osteogenic microenvironments facilitating bone marrow mesenchymal stem cell differentiation. In vivo studies demonstrated concurrent regeneration of cartilage and subchondral bone tissues with robust integration. This 3D-printed biomimetic scaffold, featuring dual-lineage inductive properties, shows promising potential for efficient osteochondral regeneration and addresses complex tissue engineering requirements.

UBE2M, an essential neddylation E2 enzyme, has been implicated in the pathogenesis of various diseases, including cancers, viral infections, and obesity. However, whether UBE2M is involved in the pathogenesis of bacterial sepsis remains unclear. In an Escherichia coli (E. coli)-induced sepsis mouse model, increased UBE2M expression in macrophages in liver and lung tissues postinfection was observed. To further clarify the role of UBE2M in macrophages, mice with macrophage-specific deletion of UBE2M (Lysm+Ube2mf/f) were constructed. Compared with control mice, these mice presented decreased levels of proinflammatory cytokines, such as IL-1b, IL-6, and TNF-a; reduced sepsis-induced organ injury; and improved survival. Notably, macrophage-specific deletion of UBE2M did not impair E. coli clearance. In vitro experiments also revealed that UBE2M-deficient macrophages produced fewer proinflammatory cytokines after E. coli infection without hindering E. coli clearance. RNA-sequencing analysis revealed that UBE2M deletion in macrophages after lipopolysaccharide stimulation notably suppressed transcriptional activation within the JAK-STAT and Toll-like receptor signaling pathways, which was further confirmed by gene set enrichment analysis. Additionally, Western blotting results confirmed that UBE2M deletion inhibited the activation of the NF-kB, ERK, and JAK-STAT signaling pathways. In conclusion, our findings indicate that specific deletion of UBE2M in macrophages protects against E. coli-induced sepsis by downregulating the excessive inflammatory response, potentially providing a novel strategy against sepsis by targeting UBE2M.

Copper, an essential trace element, is integral to numerous metabolic pathways across biological systems. In recent years, copper-based biomaterials have garnered significant interest due to their superior biocompatibility and multifaceted functionalities, particularly in the treatment of malignancies such as sarcomas and cancers. On the one hand, these copper-based materials serve as efficient carriers for a range of therapeutic agents, including chemotherapeutic drugs, small molecule inhibitors, and antibodies, allowing them for precise delivery and controlled release triggered by specific modifications and stimuli. On the other hand, they can induce cell death through mechanisms such as ferroptosis, cuproptosis, apoptosis, and pyroptosis, or inhibit the proliferation and invasion of cancer cells via their outstanding properties. Furthermore, advanced design approaches enable these materials to support tumor imaging and immune activation. Despite this progress, the full scope of their functional capabilities remains to be fully elucidated. This review provides an overview of the anti-tumor functions, underlying mechanisms, and design strategies of copper-based biomaterials, along with their advantages and limitations. The aim is to provide insights into the design, study, and development of novel multifunctional biomaterials, with the ultimate goal of accelerating the clinical application of copper-based nanomaterials in cancer therapy. STATEMENT OF SIGNIFICANCE: This study explores the groundbreaking potential of copper-based biomaterials in cancer therapy, uniquely combining biocompatibility with diverse therapeutic mechanisms such as targeted drug delivery and inhibition of cancer cells through specific cell death pathways. By enhancing tumor imaging and immune activation, copper-based nanomaterials have opened new avenues for cancer treatment. This review examines these multifunctional biomaterials, highlighting their advantages and current limitations while addressing gaps in existing research. The findings aim to accelerate clinical applications of these materials in the field of oncology, providing valuable insights for the design of next-generation copper-based therapies. Therefore, this work is highly relevant to researchers and practitioners focused on innovative cancer treatments.

Untreated osteochondral defects will develop into osteoarthritis, affecting patients' quality of life. Since articular cartilage and subchondral bone exhibit distinct biological characteristics, repairing osteochondral defects remains a major challenge. Previous studies have tried to fabricate multilayer scaffolds with traditional methods or 3D printing technology. However, the efficacy is unsatisfactory because of poor control over internal structures or a lack of integrity between adjacent layers, severely compromising repair outcomes. Therefore, there is a need for a biomimetic scaffold that can simultaneously boost osteochondral defect regeneration in both structure and function. Herein, an integrated bilayer scaffold with precisely controlled structures is successfully 3D-printed in one step via digital light processing (DLP) technology. The upper layer has both 'lotus- and radial-' distribution pores, and the bottom layer has 'lotus-' pores to guide and facilitate the migration of chondrocytes and bone marrow mesenchymal stem cells, respectively, to the defect area. Tuning pore sizes could modulate the mechanical properties of scaffolds easily. Results show that 3D-printed porous structures allow significantly more cells to infiltrate into the area of 'lotus- and radial-' distribution pores during cell migration assay, subcutaneous implantation, andin situtransplantation, which are essential for osteochondral repair. Transplantation of this 3D-printed bilayer scaffold exhibits a promising osteochondral repair effect in rabbits. Incorporation of Kartogenin into the upper layer of scaffolds further induces better cartilage formation. Combining small molecules/drugs and precisely size-controlled and layer-specific porous structure via DLP technology, this 3D-printed bilayer scaffold is expected to be a potential strategy for osteochondral regeneration.

OBJECTIVE:Cartilage injury is a common clinical condition, and treatment approaches have evolved over time from traditional conservative and surgical methods to regenerative repair. In this context, hydrogels, as widely used biomaterials in the field of cartilage repair, have garnered significant attention. Particularly, responsive hydrogels (also known as "smart hydrogels") have shown immense potential due to their ability to respond to various physicochemical properties and environmental changes. This paper aims to review the latest research developments of hydrogels in cartilage repair, utilizing a more systematic and comprehensive meta-analysis approach to evaluate the research status and application value of responsive hydrogels. The goal is to determine whether these materials demonstrate favorable therapeutic effects for subsequent clinical applications, thereby offering improved treatment methods for patients with cartilage injuries.METHOD:This study employed a systematic literature search method to summarize the research progress of responsive hydrogels by retrieving literature on the subject and review studies. The search terms included "hydrogel" and "cartilage," covering data from database inception up to October 2023. The quality of the literature was independently evaluated using Review Manager v5.4 software. Quantifiable data was statistically analyzed using the R language.RESULTS:A total of 7 articles were retrieved for further meta-analysis. In the quality assessment, the studies demonstrated reliability and accuracy. The results of the meta-analysis indicated that responsive hydrogels exhibit unique advantages and effective therapeutic outcomes in the field of cartilage repair. Subgroup analysis revealed potential influences of factors such as different types of hydrogels and animal models on treatment effects.CONCLUSION:Responsive hydrogels show significant therapeutic effects and substantial application potential in the field of cartilage repair. This study provides strong scientific evidence for their further clinical applications and research, with the hope of promoting advancements in the treatment of cartilage injuries.

AbstractAcute lung injury/acute respiratory distress syndrome (ALI/ARDS) is characterised by an uncontrolled inflammatory response, and current treatment strategies have limited efficacy. Although the protective effect of M2‐like macrophages (M2φ) and their extracellular vesicles (EVs) has been well‐documented in other inflammatory diseases, the role of M2φ‐derived EVs (M2φ‐EVs) in the pathogenesis of ALI/ARDS remains poorly understood. The present study utilised a mouse model of lipopolysaccharide‐induced ALI to first demonstrate a decrease in endogenous M2‐like alveolar macrophage‐derived EVs. And then, intratracheal instillation of exogenous M2φ‐EVs from the mouse alveolar macrophage cell line (MH‐S) primarily led to a take up by alveolar macrophages, resulting in reduced lung inflammation and injury. Mechanistically, the M2φ‐EVs effectively suppressed the pyroptosis of alveolar macrophages and inhibited the release of excessive cytokines such as IL‐6, TNF‐α and IL‐1β both in vivo and in vitro, which were closely related to NF‐κB/NLRP3 signalling pathway inhibition. Of note, the protective effect of M2φ‐EVs was partly mediated by miR‐709, as evidenced by the inhibition of miR‐709 expression in M2φ‐EVs mitigated their protective effect against lipopolysaccharide‐induced ALI in mice. In addition, we found that the expression of miR‐709 in EVs derived from bronchoalveolar lavage fluid was correlated negatively with disease severity in ARDS patients, indicating its potential as a marker for ARDS severity. Altogether, our study revealed that M2φ‐EVs played a protective role in the pathogenesis of ALI/ARDS, partly mediated by miR‐709, offering a potential strategy for assessing disease severity and treating ALI/ARDS.

Although natural polymers have been widely used in constructing bone scaffolds, it still remains challenging to fabricate natural polymer-derived bone scaffolds with biomimetic mechanical properties as well as outstanding osteogenic properties for large-size and weight-bearing bone defects regeneration. Herein, an “organic-inorganic assembly” strategy is developed to construct silk fibroin (SF)-based bone scaffolds with the aforementioned merits. After secondary structure reshuffling, the 3.3-fold increment of β-sheet structures in SF hydrogel resulted in a 100-fold improvement of mineral-assembly efficacy via influencing the ion adsorption process and providing templates for mineral growth. Notably, abundant minerals were deposited within the hydrogel and also on the surface, which indicated entire mineral-assembly, which ensured the biomimetic mechanical properties of the digital light processing 3D printed SF hydrogel scaffolds with haversian-mimicking structure. In vitro experiments proved that the assembly between the mineral and SF results in rapid adhesion and enhanced osteogenic differentiation of human bone marrow-derived mesenchymal stem cells. In vivo experiments further proved that the mineral-assembled SF hydrogel scaffold could significantly enhance integration and bone regeneration at the weight-bearing site within one month. This SF-based “organic-inorganic assembly” strategy sheds light on constructing cell-free, growth factor-free and natural polymer-derived bone scaffolds with biomimetic 3D structure, mechanical properties and excellent osteogenic properties.

Stem cell therapy holds promise for treating various diseases, but low engraftment efficacy remains a significant hurdle. Most stem cells are unable to rapidly anchor in the pathological microenvironment, and these dissociated cells undergo anoikis. In this study, we engineer a tissue adhesive coat wearing adipose-derived stem cells (TAC-ADSCs) using a biotin-streptavidin-amplified o-nitrobenzene (NB). TAC-ADSCs can rapidly anchor at the target site. TAC-ADSCs exhibit prolonged retention time in the joint cavity, even on cartilage surfaces that are difficult for cells to adhere to, without affecting their viability and differentiation capacity. In a rabbit cartilage defect model and a mouse osteoarthritis (OA) model, we find that TAC-ADSCs exhibit better therapeutic effects than unmodified ADSCs, demonstrating the potential of this modification method for improving cell engraftment efficiency. This safe, facile, and efficient method for achieving rapid cell adhesion capability on tissue has important implications for enhancing the therapeutic effectiveness of stem cell therapy.

Osteoarthritis (OA) is one of the most prevalent age-related degenerative diseases. With an increasingly aging global population, greater numbers of OA patients are providing clear economic and societal burdens. Surgical and pharmacological treatments are the most common and conventional therapeutic strategies for OA, but often fall considerably short of desired or optimal outcomes. With the development of stimulus-responsive nanoplatforms has come the potential for improved therapeutic strategies for OA. Enhanced control, longer retention time, higher loading rates, and increased sensitivity are among the potential benefits. This review summarizes the advanced application of stimulus-responsive drug delivery nanoplatforms for OA, categorized by either those that depend on endogenous stimulus (reactive oxygen species, pH, enzyme, and temperature), or those that depend on exogenous stimulus (near-infrared ray, ultrasound, magnetic fields). The opportunities, restrictions, and limitations related to these various drug delivery systems, or their combinations, are discussed in areas such as multi-functionality, image guidance, and multi-stimulus response. The remaining constraints and potential solutions that are represented by the clinical application of stimulus-responsive drug delivery nanoplatforms are finally summarized.

Terahertz elastic waves travelling in piezoelectric semiconductors (PSs) with the deformation-polarization-carrier coupling have a huge potential application in elastic wave-based devices. To reveal wave propagation characteristics of terahertz elastic waves in rod-like PS structures, we present three typical rod models based on the Hamilton principle and the linearization of the nonlinear current, which are extensions of the classical, Love, and Mindlin-Herrmann rod models for elastic media to those for PS materials. Using the derived equations, the analytical dispersion relations of the elastic longitudinal waves propagating in an n-type PS rod are obtained, which can be reduced to those for piezoelectric and elastic rods by sequentially dropping the corresponding electron- and piezoelectricity-related terms. The Mindlin-Herrmann rod model is more accurate for analysis of terahertz elastic longitudinal wave in rod-like PS structures. The effects of the interaction between the piezoelectricity and semiconducting properties on the dispersion behaviors of terahertz elastic longitudinal waves are investigated in detail. Numerical results show that both phase and group velocities have a 50%-60% reduction in the terahertz range in comparison with those in the low frequency range, and the effective tuning range of the initial electron concentration is different for longitudinal waves with different frequencies. It lays the theoretical foundations for the design of terahertz elastic wave-based devices.

To the Editor: Despite major advances in medical care, the incidence and mortality of bloodstream infection (BSI) remain high, which is still a global public health challenge. BSI can be caused by various microorganisms, and the most common organisms are Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus (S. aureus), according to the China Antimicrobial Surveillance Network (CHINET).[1]S. aureus is the third most common cause of BSI, which is associated with short-term mortality rates of 15–30%, long-term excess mortality, and increased healthcare costs. At present, there are many studies on Gram-negative bacteremia but relatively few on S. aureus bloodstream infection (SA-BSI), especially in China. With the occurrence of new treatments and clinical conditions, such as aging and extensive antibiotic resistance, it is necessary to reanalyze the clinical characteristics and prognosis of SA-BSI. This single-center retrospective cohort study was conducted in the Second Affiliated Hospital, Zhejiang University School of Medicine. The Ethics Committee of our hospital granted ethics approval (No. 2019-194) for the present study. The requirement for signed informed consent was exempted because of the retrospective nature of the study. Furthermore, a statement of permission from patients for submission was not needed, as no personal information was included. During the six-year study period (2013–2018), a total of 1174 blood culture specimens positive for S. aureus were initially included. Four patients aged <18 years, 54 patients with nonpathogenic bacteria, 45 patients with incomplete or missing data, and nine patients lost to follow-up were excluded. Finally, 349 patients were included. The patients were followed for at least 28 days after the onset of BSI. According to 28-day mortality, the patients were divided into nonsurvival (61 cases) and survival groups (288 cases) [Figure 1A].Figure 1: (A) Flowchart of study participant enrollment with blood culture specimens positive for Staphylococcus aureus. (B) Age and sex distributions of patients with SA-BSI. (C) Distribution proportions of MRSA and MSSA from 2013 to 2018. (D) Forest plot of the results of the univariate and multivariate logistic regression analyses for prognostic factors for death in patients with SA-BSI. APACHE: Acute Physiology and Chronic Health Evaluation; COPD: Chronic obstructive pulmonary disorder; CVC: Central venous catheter; ICU: Intensive care unit; MRSA: Methicillin-resistant Staphylococcus aureus; MSSA: Methicillin-sensitive Staphylococcus aureus; SA-BSI: Staphylococcus aureus bloodstream infections; SOFA: Sequential Organ Failure Assessment.Using a self-created Excel sheet, the clinical data of cases were collected through the hospital identification of blood culture-positive specimens for S. aureus provided by the microbiology laboratory. We recorded demographic and microbiological data, sensitivity to antibiotics, and clinical treatment and evaluation data (the Sequential Organ Failure Assessment [SOFA] score, the Acute Physiology and Chronic Health Evaluation [APACHE] II score in the first 24 h following the onset of BSI) by reviewing electronic medical records. To ensure data quality, a homogeneous data collection form was carefully prepared before data collection. Additionally, two days of training were provided to data collectors and supervisors. Furthermore, the supervisor and principal investigators supervised the data collectors throughout the entire data collection period. After data collection was completed, the supervisor organized and carefully cleaned the data and then entered the data into Statistical Package for Social Sciences (SPSS, 26.0, IBM Corp., Armonk, NY, USA) for statistical analysis. Variables with P <0.05 in the univariate analysis were entered into the multivariable model. Continuous variables were treated as dichotomous variables based on Youden index. Multivariate analysis was performed with logistic regression to identify independent prognostic factors for death in patients with SA-BSI. A two-tailed P <0.05 was considered statistically significant. The demographics showed that the median age was 59.0 (45.5–68.0) years, and 69.6% (243/349) were male [Supplementary Table 1, https://links.lww.com/CM9/B557]. The age distribution was left-skewed, with a peak incidence in the group of 60–69 years. In addition, the proportion of men was significantly higher than that of women in all age groups except for those >90 years old [Figure 1B]. Patients in the nonsurvivor group were significantly older than survivor group (median, 65.0 vs. 58.0 years, P = 0.005). In terms of comorbidities, significantly higher percentages of chronic obstructive pulmonary disease (COPD) and severe asthma were observed in the nonsurvivor group than in the survivor group (6.6% [4/61] vs. 1.0% [3/288], P = 0.005). In comparison with survivors, nonsurvivors had a more severe condition, evidenced by a higher APACHE II score (median, 24 vs. 11, P <0.001), a higher SOFA score (median, 12 vs. 3, P <0.001), and had a higher rate of intensive care unit (ICU) admission (85.2% [52/61] vs. 27.4% [79/288], P <0.001), indwelling central venous catheter placement (73.8% [45/61] vs. 42.4% [122/288], P <0.001), and invasive mechanical ventilation (82.0% [50/61] vs. 34.4% [99/288], P <0.001). Compared with those in survivors, the proportions of polymicrobial SA-BSI (26.2% [16/61] vs. 13.2% [38/288], P = 0.011), methicillin-resistant S. aureus (MRSA) (82.0% [50/61] vs. 57.3% [165/288], P <0.001), and septic shock (50.8% [31/61] vs. 1.4% [4/288], P <0.001) in nonsurvivors were higher. In comparison with survivors, nonsurvivors had a lower hematocrit (median [%], 26.8 vs. 29.1, P = 0.009), a lower platelet count (median [109/L], 85 vs. 187, P <0.001), a lower albumin level (mean [g/L], 27.73 vs. 29.95, P =0.005), and worse liver and kidney function. In addition, the absolute neutrophil count (ANC) and procalcitonin (PCT) level were significantly higher in nonsurvivors than in survivors [Supplementary Table 2, https://links.lww.com/CM9/B557]. In comparison with those in survivors, the ratios of resistance of S. aureus to ciprofloxacin, levofloxacin, and moxifloxacin were significantly higher in nonsurvivors [Supplementary Table 3, https://links.lww.com/CM9/B557]. Of note, MRSA occurred significantly more frequently in nonsurvivors than in survivors (82% [50/61] vs. 57.3% [165/288], P <0.001). The proportion of MRSA had a significant downwards trend from 70.8% (46/65) in 2014 to 43.6% (24/55) in 2018 [Figure 1C]. The main source of SA-BSI was pneumonia (26.6%, 93/349), followed by skin/soft tissue infection (24.4%, 85/349). Compared with survivors, nonsurvivors had higher rates of pneumonia (37.7% [23/61] vs. 24.3% [70/288], P =0.032) and intra-abdominal infection (27.9% [17/61] vs. 8.7% [25/288], P <0.001) [Supplementary Table 4, https://links.lww.com/CM9/B557]. In terms of infection control, there was no significant difference in the rates of drainage of the infection source and removal of contaminated sutures between the two groups. We also did not observe any differences in mortality between the survivors and nonsurvivors based on antibiotic exposure (P >0.05). For targeted treatment, 189 (54.2%) patients received glycopeptides (vancomycin or teicoplanin), 25 (7.2%) patients received piperacillin/tazobactam, 58 (16.6%) patients received linezolid, 26 (7.4%) patients received tigecycline, and 43 (12.3%) patients received fluoroquinolone (levofloxacin or moxifloxacin), but there was no statistical significance between the two groups. In addition, a total of 8.3% (29/349) of patients did not receive appropriate therapy within 24 h after the release of antibiotic susceptibility results, but there was no difference between the two groups (6.6% [4/61] vs. 8.7% [25/288], P =0.585) [Supplementary Table 4, https://links.lww.com/CM9/B557]. The multivariate logistic regression model showed that the independent prognostic factors for 28-day mortality were age >67 years (adjusted odds ratio [aOR], 4.46; 95% confidence interval [CI], 1.18–16.88), an APACHE II score >17 (aOR, 42.47; 95% CI, 8.11–222.48), a SOFA score >7 (aOR, 8.01; 95% CI, 2.06–31.12), septic shock (aOR, 9.86; 95% CI, 1.18–82.37), and albumin <30 g/L (aOR, 5.14; 95% CI, 1.34–19.71) [Figure 1D]. There is still some controversy about the relationship between polymicrobial BSI and mortality in ICU patients. A study by Park et al[2] showed that polymicrobial SA-BSI was an independent prognostic factor for bacteremia-related mortality, which is not consistent with our current study. In their study, patients with polymicrobial SA-BSI were significantly less likely to receive appropriate empirical antibiotics than those with monomicrobial SA-BSI; 25% were infected with S. aureus plus a Gram-positive pathogen; and evidence did not shown that coinfection with Gram-positive pathogens resulted in death faster than coinfection with Gram-negative organisms. In our study, appropriate antibiotic therapy did not differ between the two groups, and the proportion of Gram-positive coinfections (36.1% [22/61]) with S. aureus was significantly higher than that in the study by Park et al[2] (25%). Therefore, we speculate that fatal polymicrobial SA-BSI is associated with a more severe condition and is not a direct independent prognostic factor of death for patients with SA-BSI. The incidence of SA-BSI has generally been reported to be higher in males than in females, while some studies have reported increased mortality in females.[3] We found that most of the proportions of infections in males in the different age groups were generally higher than those in females [Figure 1B], and the mortality rates of SA-BSI in men and women were 19.3% [47/243] and 13.2% [14/106], respectively. We did not detect any sex difference in outcomes. We found that the age distribution was left-skewed, with a peak incidence in the 60–69 years group [Figure 1B], and age >67 years was an independent prognostic factor for death in patients with SA-BSI. This might be related to more comorbidities in older patients. As described in many studies,[3] age was the strongest independent predictor of mortality, and the mortality rate increased from 6% in young individuals (<15 years old) to 57% in adults >85 years of age according to Lamagni et al.[4] Therefore, clinicians should pay more attention to the age of patients with SA-BSI than to their sex. In our current study, the proportion of MRSA had a significant downwards trend from 70.8% (46/65) in 2014 to 43.6% (24/55) in 2018, which is in line with the MRSA trend reported by CHINET,[3] probably as a result of a greater understanding of SA-BSI management. Although MRSA was associated with mortality, it was not an independent prognostic factor for death in patients with SA-BSI. This might be related to a decrease in the pathogenicity of MRSA in recent years, which is indirectly refected by the decrease in the detection rate of MRSA in our hospital in recent years. In addition, we found that septic shock was an independent prognostic factor for death in patients with SA-BSI. In conclusion, SA-BSI was characterized by a peak incidence in 60–69 years old, and pneumonia and skin/soft tissue infection as the main infection sources. There were several independent prognostic factors for 28-day mortality of SA-BSI patients, including age >67 years, an APACHE II score >17, a SOFA score >7, septic shock, and albumin <30 g/L. By contrast, MRSA and polymicrobial BSI were associated with 28-day mortality, but not independent prognostic factors. To properly manage SA-BSI, clinicians should be aware of patients with one or more of the abovementioned independent prognostic factors. Funding This work was supported in part by grants from the National Natural Science Foundation of China (No. 81901941), Natural Science Foundation of Zhejiang Province (No. LY19H150007; No. LY20H150008), Medical and Health Research Program of Zhejiang Province (No. 2019RC038; No. 2018KY427; No. 2022KY1396, No. 2022KY1398). Conflicts of interest None.

Nonuniform microstretching (NUMS) naturally occurs in real bone tissues in vivo, but its profound effects have not been identified yet. In order to explore the biological effects of NUMS and static stretch (uniform stretch [US]) on cells, a new "musical dish" device was developed. Musical signal was used to provide NUMS to cells. More stress fibers, arranging along the long axis of cells, were formed throughout the cells under NUMS, compared with US and untreated control group, although cell morphology did not show any alteration. Whole transcriptome sequencing revealed enhanced osteogenic differentiation of cells after NUMS treatment. Cells in the NUMS group showed a higher expression of bone-related genes, while genes related to stemness and other lineages were down-regulated. Our results give insights into the biological effects of NUMS and US on stem cell osteogenic differentiation, suggesting beneficial effects of micromechanical stimulus for osteogenesis. The newly developed device provides a basis for the development of NUMS derived rehabilitation technology to promote bone healing.