Nanoparticles for the treatment of spinal cord injury.

Spinal cord injuries lead to significant loss of motor, sensory, and autonomic functions, presenting major challenges in neural regeneration. Achieving effective therapeutic concentrations at injury sites has been a slow process, partly due to the difficulty of delivering drugs effectively. Nanoparticles, with their targeted delivery capabilities, biocompatibility, and enhanced bioavailability over conventional drugs, are garnering attention for spinal cord injury treatment. This review explores the current mechanisms and shortcomings of existing treatments, highlighting the benefits and progress of nanoparticle-based approaches. We detail nanoparticle delivery methods for spinal cord injury, including local and intravenous injections, oral delivery, and biomaterial-assisted implantation, alongside strategies such as drug loading and surface modification. The discussion extends to how nanoparticles aid in reducing oxidative stress, dampening inflammation, fostering neural regeneration, and promoting angiogenesis. We summarize the use of various types of nanoparticles for treating spinal cord injuries, including metallic, polymeric, protein-based, inorganic non-metallic, and lipid nanoparticles. We also discuss the challenges faced, such as biosafety, effectiveness in humans, precise dosage control, standardization of production and characterization, immune responses, and targeted delivery in vivo. Additionally, we explore future directions, such as improving biosafety, standardizing manufacturing and characterization processes, and advancing human trials. Nanoparticles have shown considerable progress in targeted delivery and enhancing treatment efficacy for spinal cord injuries, presenting significant potential for clinical use and drug development.

Prognostic factors for lacrimal gland adenoid cystic carcinoma: a retrospective study in Chinese patients.

AIM: To explore the prognostic factors for lacrimal gland adenoid cystic carcinoma (LGACC) in Chinese patients. METHODS: Clinical and histopathological data were reviewed in patients with pathologically confirmed LGACC. Local recurrence, metastasis, and disease-specific death were the main outcome measures. Univariate and multivariate analyses were performed by the Kaplan-Meier method and a Cox proportional hazard model. RESULTS: This retrospective cohort study included 45 patients with pathologically confirmed LGACC between January 2008 and June 2022. Tumor (T) classification (P=0.005), nodal metastasis (N) classification (P=0.018) and positive margin (P=0.008) were independent risk factors of recurrence; T (P=0.013) and N (P=0.003) classification and the basaloid tumor type (P=0.032) were independent risk factors for metastasis; T classification (P<0.001) was an independent factor of death of disease. In the further analysis, the durations from first surgery to radiotherapy is correlated with metastatic risk in LGACC patients with basaloid component (P=0.022). CONCLUSION: Histological subtype should be emphasized when evaluating prognosis and guiding treatment. Timely radiotherapy may reduce the risk of metastasis in patients with basaloid component.

Blocking CX3CR1+ Tumor-associated Macrophages Enhances the Efficacy of Anti-PD-1 Therapy in Hepatocellular Carcinoma.

The efficacy of immune checkpoint inhibitors (ICI) in the treatment of hepatocellular carcinoma (HCC) remains limited, highlighting the need for further investigation into the underlying mechanisms. Accumulating evidence indicates that tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) are implicated in immune evasion and treatment resistance. This study aimed to explore the contribution of TAMs in the HCC TME. Our findings reveal the critical involvement of CX3C motif chemokine receptor 1 (CX3CR1)-positive TAMs in inducing T cell exhaustion through interleukin-27 (IL-27) secretion, providing valuable insights into the mechanisms underlying the suboptimal efficacy of anti-PD-1 therapy in HCC. Moreover, we identified prostaglandin E2 (PGE2), released by immune-attacked tumor cells, as a key regulator of CX3CR1+ TAM phenotype transition. To augment the therapeutic response to current anti-PD-1 therapy, we propose an innovative treatment strategy that incorporates targeting CX3CR1+ TAMs in addition to anti-PD-1 therapy. In conclusion, our study contributes to the understanding of TAMs' role in cancer immunotherapy and highlights potential clinical implications for HCC treatment. The combination of targeting CX3CR1+ TAMs with anti-PD-1 therapy holds promise for enhancing the efficacy of immunotherapeutic interventions in HCC patients.

H3K9me3 loss and ERV activation as hallmarks for osteoarthritis progression and knee joint aging.

OBJECTIVE: This study aims to link aberrant endogenous retroviruses (ERV) activation and osteoarthritis (OA) progression by comparing the chromatin accessibility and transcriptomic landscapes of diseased or intact joint tissues of OA patients. METHOD: We performed ERV-centric analysis on published ATAC-seq and RNA-seq data from OA patients' cartilage tissues. Here, we compared the outer region of the lateral tibial plateau, representing intact cartilage, to the inner region of the medial tibial plateau, representing damaged cartilage. In addition, cartilage tissue sections from OA patients and post-traumatic OA mouse models were assayed for global H3K9me3 abundance through immunohistochemistry staining. RESULTS: Chromatin accessibility and transcription of ERVs, particularly from evolutionarily "intermediate age" ERV families (ERV1 and ERVL), were enriched and elevated in OA cartilage. This integrative analysis suggests that H3K9me3-related heterochromatin loss might be mechanistically connected to ERV activation in OA tissue. We further verified that global H3K9me3 levels were reduced in diseased cartilage relative to intact tissue in OA patients and injury-induced OA mice. CONCLUSION: The findings suggest a compelling hypothesis that the loss of H3K9me3, either due to aging or cellular stressors, may lead to ERV reactivation that contributes to tissue inflammation and OA progression. This study unveils the intricate relationship between epigenetic alterations, ERV activation, and OA, paving the way for potential therapeutic interventions targeting these pathogenic mechanisms.

Synthesis of ß-Carbonyl α-Iminoamides by Double Insertion of Isocyanides into Aldehydes.

An unprecedented trimethylsilyl trifluoromethanesulfonate (TMSOTf)-promoted selective double insertion of isocyanides into aldehydes was developed, providing an efficient protocol for synthetically challenging ß-carbonyl α-iminoamides. The given approach is applicable for a diverse selection of readily accessible aldehydes, along with isocyanides serving as essential precursors for "amide" and "imine" scaffolds. The versatile transformations of the given products were demonstrated, and the pivotal intermediates for the plausible mechanism were identified.

Differences and implications of strontium distribution coefficient on various granite compositional materials.

The distribution coefficient (Kd) of radionuclides is a crucial parameter in assessing the safety of high-level radioactive waste (HLW) geological repository. It is determined in the laboratory through batch and column experiments. However, differences in obtained Kd values from distinct experiments have not been thoroughly assessed and compared. This study evaluated strontium (Sr) sorption on different granite materials using static batch and dynamic experiments (column and core-flooding experiments). The results from batch sorption experiments showed higher Sr sorption on granite under acidic and strongly alkaline conditions, low solid-liquid ratios, and low ionic strength. In column experiments, a two-site sorption model was used to simulate Sr transport in crushed granite and mixed pure minerals. The sorption of Sr on crushed granite exhibited a higher affinity than that of mixed pure minerals. The dual-porosity transport model was employed to investigate Sr transport behavior in fractured granite in the core-flooding experiment. Kd obtained from batch sorption experiments are four to twenty times higher than those from column experiments, and two to three orders of magnitude higher than that from a core-flooding experiment. The results of this study provide valuable insights into safety assessment for the HLW geological repository.

Structural insight into the functional regulation of Elongation factor Tu by reactive oxygen species in Synechococcus elongatus PCC 7942.

In cyanobacteria, Elongation factor Tu (EF-Tu) plays a crucial role in the repair of photosystem II (PSII), which is highly susceptible to oxidative stress induced by light exposure and regulated by reactive oxygen species (ROS). However, the specific molecular mechanism governing the functional regulation of EF-Tu by ROS remains unclear. Previous research has shown that a mutated EF-Tu, where C82 is substituted with a Ser residue, can alleviate photoinhibition, highlighting the important role of C82 in EF-Tu photosensitivity. In this study, we elucidated how ROS deactivate EF-Tu by examining the crystal structures of EF-Tu in both wild-type and mutated form (C82S) individually at resolutions of 1.7 Šand 2.0 Šin Synechococcus elongatus PCC 7942 complexed with GDP. Specifically, the GDP-bound form of EF-Tu adopts an open conformation with C82 located internally, making it resistant to oxidation. Coordinated conformational changes in switches I and II create a tunnel that positions C82 for ROS interaction, revealing the vulnerability of the closed conformation of EF-Tu to oxidation. An analysis of these two structures reveals that the precise spatial arrangement of C82 plays a crucial role in modulating EF-Tu's response to ROS, serving as a regulatory element that governs photosynthetic biosynthesis.

Uniform, Fully Connected, High-Quality Monocrystalline Freestanding Perovskite Oxide Films Fabricated from Recyclable Substrates.

Releasing epitaxial perovskite oxide films from their native oxide substrates produces high quality, 2D-material-like monocrystalline freestanding oxide membranes, as potential key components for the next-generation electronic devices. Two major obstacles still limit their practical applications: macroscopic material defects (mainly cracks) that lowers uniformity and yield, and the high cost of the consumed oxide substrates. Here, a two-step film transfer method and a substrate recycling method enable repetitive fabrication of millimeter-scale, fully-connected freestanding oxide films of various chemical compositions from the same substrates; arrays of capacitor and resistor devices based on these oxides transferred on silicon indicate high uniformity, low sample-to-sample variation, and satisfactory electrical connectivity. The two-step transfer suppresses crack formation by avoiding buckling-delamination-type relaxation of epitaxial strain, and the key point to achieve substrate reuse is to remove the residual Al species bonded to the substrate surfaces. The mitigation of such long-lasting issues in freestanding oxide fabrication techniques may eventually pave roads toward future industrial-grade devices, as well as enabling many research opportunities in fundamental physics.

WTAP/YTHDF1-mediated m6A modification amplifies IFN-γ-induced immunosuppressive properties of human MSCs.

INTRODUCTION: The immunosuppressive capacity of mesenchymal stem cells (MSCs) is dependent on the "license" of several pro-inflammatory factors to express immunosuppressive molecular profiles, which determines the therapeutic efficacy of MSCs in immune-mediated inflammatory diseases. Of those, interferon-γ (IFN-γ) is a key inducer for the expression of immunosuppressive molecular profiles; however, the mechanism underlying this effect is unknown. OBJECTIVES: To elucidate the regulation mechanism and biological functions of N6-methyladenosine (m6A) modification in the immunosuppressive functions by the IFN-γ-licensing MSCs. METHODS: Epitranscriptomic microarray analysis and MeRIP-qPCR assay were performed to identify the regulatory effect of WTAP in the IFN-γ-licensing MSCs. RIP-qPCR, western blot, qRT-PCR and RNA stability assays were used to determine the regulation of WTAP/m6A/YTHDF1 signaling axis in the expression of immunosuppressive molecules. Further, functional capacity of T cells was tested using flow cytometry, and both DSS-induced colitis mice and CIA mice were constructed to clarify the effect of WTAP and YTHDF1 in MSC-mediated immunosuppression. RESULTS: We identified that IFN-γ increased the m6A methylation levels of immunosuppressive molecules, while WTAP deficiency abolished the IFN-γ-induced promotion of m6A modification. IFN-γ activated ERK signaling, which induced WTAP phosphorylation. Additionally, the stabilization of WTAP post-transcriptionally increased the mRNA expression of immunosuppressive molecules (IDO1, PD-L1, ICAM1, and VCAM1) in an m6A-YTHDF1-dependent manner; this effect further impacted the immunosuppressive capacity of IFN-γ licensing MSCs on activated T cells. Notably, WTAP/YTHDF1 overexpression enhanced the therapeutic efficacy of IFN-γ licensing MSCs and restructures the ecology of inflammation in both colitis and arthritis models. CONCLUSION: Our results showed that m6A modification of IDO1, PD-L1, ICAM1, and VCAM1 mRNA mediated by WTAP-YTHDF1 is involved in the regulation of IFN-γ licensing MSCs immunosuppressive abilities, and shed a light to enhance the clinical therapeutic potential of IFN-γ-licensing MSCs.

Model for end-stage liver disease-dependent prognostic capacity of platelet-to-lymphocyte ratio following liver transplantation for hepatocellular carcinoma.

BACKGROUND: To improve liver organ allocation, the model for end-stage liver disease (MELD) score was adopted in candidates reflecting the severity of liver disease and the physical condition of patients. Inflammatory markers are prognostic factors for various cancers and play prognostic roles in patients after liver transplantation (LT) for hepatocellular carcinoma (HCC). Researchers focused more on pre-LT inflammatory markers, while the role of dynamic change of these inflammatory markers is still unknown. The purpose of this study was to estimate the prognostic value of pre-LT and post-LT inflammatory markers. MATERIAL AND METHODS: We collected the pre-LT complete blood count and the post-LT result with highest count of white blood cells within 48 h. Platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio and systemic immune-inflammation index were calculated, and their prognostic roles were analyzed for their MELD scores. RESULTS: This retrospective two-center cohort study enrolled 290 patients after LT for HCC. Multivariate analysis identified pre-LT PLR as independent risk factor for recurrence-free survival (RFS) [HR (95%CI): 1.002 (1.000-1.003), p = 0.023]. A high pre-LT PLR or post-LT PLR were associated with poorer RFS (p < 0.001 and p = 0.004, respectively). Based on the MELD scores, the pre-LT PLR value was able to predict the RFS in high MELD group (p < 0.001) but had no predictive power in low MELD group (p = 0.076). On the contrary, the post-LT PLR value was better to predict the overall RFS value in low MELD group (p = 0.007) but could not predict the overall RFS value in high MELD group (p = 0.136). CONCLUSIONS: Both pre-LT PLR and post-LT PLR demonstrated prognostic value in patients following LT for HCC. Monitoring PLR values based on the MELD score can improve the predictive prognosis and more effectively guide the individual decisions for the postoperative intervention.

Rapidly damping hydrogels engineered through molecular friction.

Hydrogels capable of swift mechanical energy dissipation hold promise for a range of applications including impact protection, shock absorption, and enhanced damage resistance. Traditional energy absorption in such materials typically relies on viscoelastic mechanisms, involving sacrificial bond breakage, yet often suffers from prolonged recovery times. Here, we introduce a hydrogel designed for friction-based damping. This hydrogel features an internal structure that facilitates the motion of a chain walker within its network, effectively dissipating mechanical stress. The hydrogel network architecture allows for rapid restoration of its damping capacity, often within seconds, ensuring swift material recovery post-deformation. We further demonstrate that this hydrogel can significantly shield encapsulated cells from mechanical trauma under repetitive compression, owing to its proficient energy damping and rapid rebound characteristics. Therefore, this hydrogel has potential for dynamic load applications like artificial muscles and synthetic cartilage, expanding the use of hydrogel dampers in biomechanics and related areas.

The role of immune cell signatures in the pathogenesis of ovarian-related diseases: a causal inference based on mendelian randomization.

BACKGROUND: Immune cells play a pivotal role in maintaining ovarian function. However, the specific contributions of different immune cell phenotypes to the pathogenesis of specific ovarian-related diseases remain poorly understood. We aim to investigate the correlation between 731 immunophenotypes and ovarian-related diseases. MATERIALS AND METHODS: Utilizing publicly available genetic data, we undertook a series of quality control measures to identify instrumental variables (IVs) associated with exposure. Subsequently, we conducted two-sample Mendelian randomization (MR) using inverse variance weighting to explore the causal relationships between 731 immune cell features and six ovarian-related diseases: ovarian cysts, ovarian dysfunction, premature ovarian failure (POF), polycystic ovary syndrome (PCOS), benign neoplasm of ovary, and malignant neoplasm of ovary at the genetic level. Sensitivity analyses, including leave-one-out and other MR analysis models, were performed. Finally, Bayesian colocalization (COLOC) analysis was employed to identify specific co-localized genes, thereby validating the MR results. RESULTS: At the significance level corrected by Bonferroni, four immune phenotypes, including CD25 on IgD- CD38- B cells, were associated with ovarian cysts; four immune phenotypes, including CD39+ CD4+ T cell Absolute Count, were associated with ovarian dysfunction; eight immune phenotypes, including SSC-A on HLA DR+ CD8+ T cells, were associated with POF; five immune phenotypes, including CD20- CD38- B cell Absolute Count, were associated with PCOS; five immune phenotypes, including CD4+ CD8dim T cell Absolute Count, were associated with benign ovarian tumors; and three immune phenotypes, including BAFF-R on IgD- CD38+ B cells, were associated with malignant ovarian tumors. Sensitivity analysis indicated robust results. COLOC analysis identified four immune cell co-localized variants (rs150386792, rs117936291, rs75926368, rs575687159) with ovarian diseases. CONCLUSION: Our study elucidates the close genetic associations between immune cells and six ovarian-related diseases, thereby providing valuable insights for future research endeavors and clinical applications.

[Current Status and Prospect of PD-1/PD-L1 Immune Checkpoint Inhibitor Therapy 
in Elderly Patients with Advanced NSCLC].

The incidence of cancer is closely correlated with age, as 75% of non-small cell lung cancer (NSCLC) patients are aged at least 65 years. The availability of immune checkpoint inhibitors (ICIs) has altered the available NSCLC therapeutic pattern. Limited studies on elderly patients have demonstrated that ICIs as monotherapy provide substantial benefits for patients aged 65-75 years, showing no significant difference compared to younger patients. This benefit is also observed in combination with immune-combined chemotherapy or radiotherapy. For individuals older than 75 years, the survival effect was not evident, though. Immune-related adverse events (irAEs) with ICIs alone were similar in incidence across age categories. Immune-combination chemotherapy resulted in a higher incidence of irAEs than chemotherapy alone, and patients ≥75 years of age were more likely to experience higher-grade irAEs. Besides the fact that immunosenescence in older patients influences the immune milieu in a multifaceted manner, which in turn impacts the effectiveness of immunotherapy, the prognosis is also influenced by the Eastern Cooperative Oncology Group performance status (ECOG PS) score, among other factors. For certain individuals aged ≥75 years or in poor physical health, immunotherapy combined with low-intensity chemotherapy has emerged as a viable treatment option. However, there are fewer related studies, so there should be a conscious effort to increase the number of elderly patients enrolled in the trial and a comprehensive assessment to explore individualized treatment options. To provide additional references and guidance for immunotherapy in elderly NSCLC patients and to propose new therapeutic perspectives in combination with their characteristics, this review aims to summarize and analyze the pertinent studies on the application of programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors in these patients.
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Activity-Dependent Remodeling of Corticostriatal Axonal Boutons During Motor Learning.

Motor skill learning induces long-lasting synaptic plasticity at not only the inputs, such as dendritic spines1-4, but also at the outputs to the striatum of motor cortical neurons5,6. However, very little is known about the activity and structural plasticity of corticostriatal axons during learning in the adult brain. Here, we used longitudinal in vivo two-photon imaging to monitor the activity and structure of thousands of corticostriatal axonal boutons in the dorsolateral striatum in awake mice. We found that learning a new motor skill induces dynamic regulation of axonal boutons. The activities of motor corticostriatal axonal boutons exhibited selectivity for rewarded movements (RM) and un-rewarded movements (UM). Strikingly, boutons on the same axonal branches showed diverse responses during behavior. Motor learning significantly increased the fraction of RM boutons and reduced the heterogeneity of bouton activities. Moreover, motor learning-induced profound structural dynamism in boutons. By combining structural and functional imaging, we identified that newly formed axonal boutons are more likely to exhibit selectivity for RM and are stabilized during motor learning, while UM boutons are selectively eliminated. Our results highlight a novel form of plasticity at corticostriatal axons induced by motor learning, indicating that motor corticostriatal axonal boutons undergo dynamic reorganization that facilitates the acquisition and execution of motor skills.

A novel nanobody broadly neutralizes SARS-CoV-2 via induction of spike trimer dimers conformation.

The ongoing mutations of the SARS-CoV-2 pose serious challenges to the efficacy of the available antiviral drugs, and new drugs with fantastic efficacy are always deserved investigation. Here, a nanobody called IBT-CoV144 is reported, which exhibits broad neutralizing activity against SARS-CoV-2 by inducing the conformation of spike trimer dimers. IBT-CoV144 was isolated from an immunized alpaca using the RBD of wild-type SARS-CoV-2, and it showed strong cross-reactive binding and neutralizing potency against diverse SARS-CoV-2 variants, including Omicron subvariants. Moreover, the prophylactically and therapeutically intranasal administration of IBT-CoV144 confers fantastic protective efficacy against the challenge of Omicron BA.1 variant in BALB/c mice model. The structure analysis of the complex between spike (S) protein, conducted using Cryo-EM, revealed a special conformation known as the trimer dimers. This conformation is formed by two trimers, with six RBDs in the "up" state and bound by six VHHs. IBT-CoV144 binds to the lateral region of the RBD on the S protein, facilitating the aggregation of S proteins. This aggregation results in steric hindrance, which disrupts the recognition of the virus by ACE2 on host cells. The discovery of IBT-CoV144 will provide valuable insights for the development of advanced therapeutics and the design of next-generation vaccines.

Interface Engineering via Manipulating Solvation Chemistry for Liquid Lithium-Ion Batteries Operated≥100 °C.

High-performance and temperature-resistant lithium-ion batteries (LIBs), which are able to operate at elevated temperatures (i.e., >60 °C) are highly demanded in various fields, especially in military or aerospace exploration. However, their applications were largely impeded by the poor electrochemical performance and unsatisfying safety issues, which were induced by the severe side reactions between electrolytes and electrodes at high temperatures. Herein, with the synergetic effects of solvation chemistry and functional additive in the elaborately designed weakly solvating electrolyte, a unique robust organic/inorganic hetero-interphase, composed of gradient F, B-rich inorganic components and homogeneously distributed Si-rich organic components, was successfully constructed on both cathodes and anodes, which would effectively inhibit the constant decomposition of electrolytes and dissolution of transition metal ions, thus highly enhancing the high-temperature electrochemical performance. As a result, both cathodes and anodes, without compromising their low-temperature performance, can operate at temperatures ≥100 °C, with excellent capacity retentions of 96.1 % after 500 cycles and 93.5 % after ≥200 cycles, respectively, at 80 °C. Ah-level LiCoO2||graphite full cells with a cut-off voltage of 4.3 V also exhibited superior temperature-resistance with a capacity retention of 89.9 % at temperature as high as 120 °C. Moreover, the fully charged pouch cells exhibited highly enhanced safety, demonstrating their potentials in practical applications at ultrahigh temperatures.

Annual trends in pain management modalities in patients with newly diagnosed autoimmune rheumatic diseases in the USA from 2007 to 2021: an administrative claims-based study.

BACKGROUND: Autoimmune rheumatic diseases have distinct pathogenic mechanisms and are causes of disability and increased mortality worldwide. In this study, we aimed to examine annual trends in pain management modalities among patients with autoimmune rheumatic diseases. METHODS: We identified newly diagnosed patients with ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, Sjögren's syndrome, systemic sclerosis, or systemic lupus erythematosus (SLE) in the Merative Marketscan Research Databases from 2007 to 2021. The database includes deidentified inpatient and outpatient health encounters with employment-sponsored health insurance claims in the USA. We found minimal occurrences of multiple overlapping conditions and included only the initial recorded diagnosis for each patient. We determined the annual incidence of patients treated with opioids, anticonvulsants, antidepressants, skeletal muscle relaxants, non-steroidal anti-inflammatory drugs (NSAIDs), topical analgesics, and physical therapy in the year following diagnosis. Logistic regression was used to estimate the association between calendar year and outcomes, adjusted for age, sex, and region. FINDINGS: We included 141 962 patients: 10 927 with ankylosing spondylitis, 21 438 with psoriatic arthritis, 71 393 with rheumatoid arthritis, 16 718 with Sjögren's syndrome, 18 018 with SLE, and 3468 with systemic sclerosis. 107 475 (75·7%) were women and 34 487 (24·3%) were men. Overall, the incidence of opioid use increased annually until 2014 by 4% (adjusted odds ratio [aOR] 1·04 [95% CI 1·03-1·04]) and decreased annually by 15% after 2014 (0·85 [0·84-0·86]). The incidence of physical therapy use increased annually by 5% until 2014 (aOR 1·05 [95% CI 1·04-1·06]), with a slight decrease annually by 1% after 2014 (0·99 [0·98-1·00]). The incidence of anticonvulsant use increased annually by 7% until 2014 (aOR 1·07 [95% CI 1·07-1·08]) and did not significantly change after 2014 (1·00 [0·99-1·00]). Before 2014, the incidence of NSAIDs use increased by 2% annually (aOR 1·02 [95% CI 1·02-1·03]); however, after 2014, the incidence decreased annually by 5% (0·95 [0·95-0·96]). These trends did not differ by sex except for NSAID use before 2014 (pinteraction=0·02) and topical analgesic use after 2014 (pinteraction=0·0100). INTERPRETATION: Since 2014, the use of non-opioid pain management modalities has increased or stabilised, whereas opioid and NSAID use has declined. Future studies are needed to evaluate the effectiveness of these changes, and the effects they have had on outcomes such as quality of life, disability, and function. FUNDING: National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Bone transport induces the release of factors with multi-tissue regenerative potential for diabetic wound healing in rats and patients.

Tibial cortex transverse distraction is a surgical method for treating severe diabetic foot ulcers (DFUs), but the underlying mechanism is unclear. We show that antioxidant proteins and small extracellular vesicles (sEVs) with multiple-tissue regenerative potential are released during bone transport (BT) in humans and rats. These vesicles accumulate in diabetic wounds and are enriched with microRNAs (miRNAs) (e.g., miR-494-3p) that have high regenerative activities that improve the circulation of ischemic lower limbs while also promoting neovascularization, fibroblast migration, and nerve fiber regeneration. Deletion of miR-494-3p in rats reduces the beneficial effects of BT on diabetic wounds, while hydrogels containing miR-494-3p and reduced glutathione (GSH) effectively repair them. Importantly, the ginsenoside Rg1 can upregulate miR-494-3p, and a randomized controlled trial verifies that the regimen of oral Rg1 and GSH accelerates wound healing in refractory DFU patients. These findings identify potential functional factors for tissue regeneration and suggest a potential therapy for DFUs.

A disease warranting attention from neurosurgeons: primary central nervous system post-transplant lymphoproliferative disorder.

Background: Primary central nervous system post-transplant lymphoproliferative disorder (PCNS-PTLD) is a rare condition, posing diagnostic and treatment challenges, with histological biopsy essential for diagnosis. Standardized treatment protocols are lacking. This disease requires urgent attention due to the increasing number of organ transplant surgeries and the use of immunosuppressive agents. Methods: From 2020 to 2023, our center diagnosed five patients with PCNS-PTLD. We reviewed their clinical records and conducted a comprehensive analysis of 22 literatures on PCNS-PTLD cases following renal transplantation or allogeneic hematopoietic stem cell transplantation (HSCT). Results: Four patients had previously received a kidney transplant, one had undergone allogeneic HSCT. The median time from the last transplant surgery to the diagnosis of PCNS-PTLD differs between kidney transplant (21.5 years) and allogeneic HSCT (9 months). Common symptoms included motor weakness (n = 4), headache (n = 2), confusion (n = 2), and nausea (n = 2), with ring-enhancing (n = 5), typically solitary (n = 3) and supratentorial (n = 3) lesions on imaging. Diagnosis involved robot-assisted stereotactic brain biopsy (n = 4) or craniotomy (n = 1), all showing Epstein-Barr virus and CD20 positivity. Most cases (n = 4) were monomorphic diffuse large B-cell lymphoma. Treatment included rituximab (n = 3), surgical resection (n = 2), zanubrutinib (n = 1), whole-brain radiation (n = 1), and methotrexate (n = 1). At the last follow-up, the median duration of follow-up for all patients was 19 months. During this time, 3 patients had died and 2 patients were still alive. Conclusion: In patients with a history of kidney transplantation or allogeneic HSCT who are on long-term immunosuppressive therapy, any neurological symptoms, particularly the presence of supratentorial ring-enhancing masses in the brain on imaging, whether solitary or multiple, should raise high suspicion for this disease, warranting a timely brain biopsy. Additionally, we found that besides reducing immunosuppressants, zanubrutinib may be a potential, safe, and effective treatment for this condition. Moreover, post-surgical administration of rituximab in conjunction with whole-brain radiotherapy also appears to be a potentially safe and effective approach.