Shanghai Ninth People's Hospital

Lower extremity nerve decompression (LEND) for painful diabetic peripheral neuropathy (PDPN) remains controversial, and evidence regarding its long-term effectiveness in real-world clinical practice is limited. This retrospective real-world cohort study included patients with PDPN treated with LEND or medical therapy alone between 2008 and 2011. Ultra-long-term outcomes were assessed after > 10 years of follow-up. Pain intensity was evaluated using the visual analogue scale (VAS). Composite pain burden and functional impact were assessed with the Brief Pain Inventory for Diabetic Peripheral Neuropathy (BPI-DPN). Psychological symptoms were measured using the Hospital Anxiety and Depression Scale (HADS), and analgesic medication burden was quantified by the Medication Quantification Scale III (MQS-III). Exploratory prognostic factor and subgroup analyses based on pain distribution were performed. Seventy-six patients in the LEND group and 31 patients in the medical group were available for ultra-long-term analysis. Compared with medical management, LEND was associated with greater long-term pain relief (mean VAS change - 5.63 ± 2.16 vs - 1.03 ± 1.92; p < 0.001) and higher responder rates (≥ 50% pain reduction: 65.8% vs 9.7%; p < 0.001). Significant long-term improvements were also observed in BPI-DPN pain severity and pain interference (both p < 0.001), anxiety and depression symptoms (both p < 0.001), and medication burden (MQS-III p < 0.001). Within the LEND cohort, younger age at surgery and lower body mass index were independently associated with greater long-term pain improvement. Both focal and diffuse pain subgroups demonstrated significant improvements in pain and functional outcomes after surgery, with no meaningful differences at ultra-long-term follow-up. Diabetic foot ulcer events occurred less frequently after LEND (0% vs 32.3%; p < 0.001). LEND demonstrated long-term efficacy in alleviating pain and concurrently improving the pain-related interference and psychological status of patients with PDPN. A Graphical Abstract is available for this article. This study was retrospectively registrated in Chinese Clinical Trial Registry chictr.org. cn (ChiCTR2500099348), https://www.chictr.org.cn/bin/project/edit?pid=266042 .

Skeletal aging is characterized by increased fragility, reduced bone mass, and deterioration of bone microstructure. Although aging-related immune dysfunction of macrophages, namely immunosenescence, is known to contribute to this process, the underlying mechanism remains poorly understood. Here, we find that the senescence of macrophages leads to a decrease in the expression of Sirtuin3 (Sirt3), which in turn leads to increased basal and lipopolysaccharides (LPS)-induced protein expression of NLRP3 and facilitates the assembly of NLRP3 inflammasome in macrophages that mediates aging-related osteoporosis. Given the phagocytic property of macrophages, we develop a genetically engineered apoptotic body-based platform for targeted delivery of Sirt3 to macrophages and verify that Sirt3-enriched apoptotic bodies (ABs-Sirt3) delay skeletal aging by promoting ubiquitination and degradation of NLRP3. Our work reveals that Sirt3 plays a key role in regulating aggravated inflammatory responses that accelerate skeletal aging during macrophage senescence and illustrates a novel nanotechnology-based therapeutic approach targeting immune senescence-induced acceleration of skeletal aging, which may provide potential therapeutic value for human patients with age-related osteoporosis.

A major challenge in precision medicine is the development of advanced biomaterials for targeted intervention in precancerous states. Here, we introduce an interfacial bioengineering strategy to construct a dynamic network for programmed intervention in epithelial precancerous lesions. Our dual-bioinspired hydrogel, MSA@PGel (macrophage membrane-coated and salvianolic acid B [SAB] /5-aminolevulinic acid co-loaded liposomes embedded in a polydopamine-based gel), leverages both the powerful wet adhesion of mussels and the immune-targeting capabilities of macrophages. The material's core innovation lies in its dynamic catecholato-Fe3+ coordination bonds, which form a robust network with a storage modulus (G') exceeding 8.8kPa higher than that of the base hydrogel (G' > 2.2kPa), thereby demonstrating superior mechanical properties and exceptional mucosal adhesion. This system achieves unprecedented lesion-specific delivery by functionalizing the network with macrophage membranes to exploit VCAM-1 overexpression in dysplastic epithelium, thereby overcoming the "mucosal delivery barrier" and ensuring prolonged retention (>3h). The programmed intervention specifically targets HIF-1α, a metabolic regulator of malignant transformation. Through SAB-mediated HIF-1α sequestration, our dynamic network not only effectively disrupts hypoxia adaptation to enhance phototherapy but also triggers a significant apoptotic cascade. In vivo studies confirm significant histological normalization, a significant increase in ROS generation, and excellent biosafety. This work establishes a versatile interfacial bioengineering platform, pioneering a new paradigm for the programmed management of epithelial precancerous states through the synergistic integration of biomaterial design and disease-specific targeting.

A 20-year-old woman had, since age 8 years, a lesion on the left side of her face that had slowly progressed over 12 years, causing facial asymmetry. Examination revealed an ill-defined soft tissue mask, and imaging showed bone involvement. What is your diagnosis?

The association between nonalcoholic fatty liver disease (NAFLD) and atrial fibrillation (AF) remains controversial. This study aimed to investigate the potential relationship between NAFLD and AF risk, utilizing data from the UK Biobank. In this large-scale population-based cohort study, participants without a history of AF were captured from the UK Biobank from 2006 to 2010. NAFLD was identified using a fatty liver index threshold of ≥60. Cox regression models with progressive covariate adjustment were employed. Propensity score matching and competing risk models were utilized in sensitivity analysis. Subgroup analyses were performed to explore potential heterogeneity in the association. Overall, 92 581 participants (47.6% male, median [interquartile range] age, 53.00 [47.00-58.00] years, 30 972 [33.5%] NAFLD, 61 609 [65.5%] non-NAFLD) were included at baseline. During a median follow-up of 12.88 years, 1633 new-onset AF were diagnosed in NAFLD (5.27%), while 1583 new-onset AF were diagnosed in non-NAFLD (2.57%). Incidence curves showed that the incidence of new-onset AF was consistently higher in NAFLD participants throughout the observation period. However, in the fully-adjusted multivariable Cox regression model, this association was markedly attenuated and no longer significant (hazard ratio, 0.93; 95% confidence interval, 0.84-1.02; P = 0.12). Sensitivity and subgroup analyses yielded results largely consistent with the primary findings. In this large cohort study from the UK Biobank, NAFLD was not an independent risk factor for AF. This implies that the increased incidence of AF observed in participants with NAFLD may be more closely related to cardiometabolic risk factors contributing to the development of NAFLD rather than the condition itself.