ObjectiveTo investigate the incidence rate of primary liver cancer （PLC） and the progression of liver fibrosis in chronic hepatitis B （CHB） patients with low-level viremia （LLV） （HBV DNA<2 000 IU/mL but ≥20 IU/mL） after treatment adjustment， and to provide more robust evidence for clinical practice. MethodsA retrospective analysis was performed for the clinical data of LLV patients who initially received nucleos（t）ide analogue （NAs） for at least 48 weeks at the Fifth Medical Center of PLA General Hospital from August 2007 to April 2017 and subsequently underwent NAs adjustment due to LLV， and according to the virologic response after 48 weeks of treatment adjustment， the patients were divided into LLV group and complete virological response （CVR） group （HBV DNA<20 IU/mL）. The patients were followed up once every 3‍ ‍—‍ ‍6 months till the primary endpoint event of PLC or October 2024. The incidence rate of PLC and the progression of liver fibrosis were observed， and the progression of liver fibrosis was defined as an increase of ≥1 grade in fibrosis-4 （FIB-4） index. The independent-samples t test was used for comparison of normally distributed continuous data between two groups， and the Mann-Whitney U test was used for comparison of continuous data with skewed distribution between two groups； the chi-square test was used for comparison of categorical data between groups. The Kaplan-Meier method was used to calculate the cumulative incidence rate of PLC， and the Log-rank test was used for comparison between groups； the Cox regression analysis was used to investigate the risk factors for PLC， and the Logistic regression analysis was used to investigate the influencing factors for the progression of liver fibrosis. ResultsA total of 307 patients were enrolled， with a mean age of 50.0 years， and the male patients accounted for 80.5%. After 48 weeks of treatment with the adjusted NAs regimen， 254 patients （82.7%） achieved CVR， and 53 patients （17.3%） still had LLV. For the LLV group， the incidence rate of PLC was 30.2% and the rate of liver fibrosis progression was 22.6%， while for the CVR group， the incidence rate of PLC was only 13.4%， and the rate of liver fibrosis progression was 7.5%. The multivariate regression analyses showed that LLV was an independent risk factor for the onset of PLC （hazard ratio=2.623， 95% confidence interval ［CI］： 1.315‍ ‍—‍ ‍5.234， P=0.006） and the progression of liver fibrosis （odds ratio=3.213， 95%CI： 1.385‍ ‍—‍ ‍7.455， P=0.007）. ConclusionActive adjustment of treatment is needed immediately after the diagnosis of LLV to improve CVR， and if LLV persists after treatment adjustment， it is necessary to enhance the monitoring of liver fibrosis progression and PLC， so as to facilitate early diagnosis and treatment.

Objective To investigate the sputum metabolic profiles of patients with occupational coal workers' pneumoconiosis (CWP) by an untargeted metabolomics method, and to identify relevant differential metabolic pathways and potential biomarkers. Methods A total of 12 male patients with stage Ⅰ CWP were selected as the CWP group, and 16 healthy male individuals were selected as the control group, using a judgmental sampling method. Sputum metabolites of individuals in both groups were detected to perform non-targeted metabolomic analysis using the ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Differential metabolites (DMs) and their pathways were screened using principal component analysis, partial least squares discriminant analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Potential biomarkers were analyzed and identified via the receiver operating characteristic curve (ROC). Results There were apparent metabolic alterations observed in sputum of CWP patients compared with healthy controls. In the positive ion mode, a total of 42 DMs were identified in sputum from CWP patients, including 19 downregulated and 23 upregulated metabolites. In the negative ion mode, a total of 25 DMs were identified in sputum from CWP patients, including 16 downregulated and 9 upregulated metabolites. KEGG enrichment analysis of sputum from CWP patients showed that seven DMs pathways were enriched in ABC transporters, histidine metabolism, phenylalanine metabolism, arachidonic acid metabolism, linoleic acid metabolism, purine metabolism, and oxidative phosphorylation, involving 26 DMs. ROC analysis indicated that 16(R)-hydroxyarachidonic acid, pyrophosphate, and 2-hydroxyphenylacetate of these 26 DMs may serve as potential biomarkers for CWP. Conclusion Sputum metabolomic profiles were altered in CWP patients compared with healthy controls. The potential biomarkers of CWP prevention and treatment are 16(R)-hydroxyarachidonic acid, pyrophosphate, and 2-hydroxyphenylacetate.

Liver fibrosis is a vital cause of morbidity in patients with liver diseases and developing novel anti-fibrotic drugs is imperative. Isovalerylspiramycin I (ISP I) as a major component of carrimycin applied to upper respiratory infections, was first found to possess anti-fibrotic potential. The present study aims to evaluate the functions and mechanisms of ISP I in protecting against liver fibrosis. According to our results, ISP I not only reduced the expressions of fibrogenic markers in LX-2 cells but also appeared great protective effects on liver injury and liver fibrosis in bile duct ligation (BDL) rats and carbon tetrachloride (CCl₄) mice. We proved that nucleotide-binding protein 2 (NUBP2) was the direct target of ISP I. ISP I through targeting NUBP2, increased the amount of vascular non-inflammatory molecule-1 (VNN1) on the cell membrane, which will inhibit oxidative stress and fibrosis. Simultaneously, the original carrimycin's protective effect on liver damage and fibrosis was verified. Therefore, our study provides potential agents for patients with liver fibrosis-related diseases, and the clear mechanism supports wide application in the clinic.

[This corrects the article DOI: 10.1016/j.jpha.2023.08.006.].

To effectively exploit the tumor microenvironment (TME), TME-responsive nanocarriers based on cascade reactions have received much attention. In this study, we designed a novel nanoparticle PB@SiO₂@MnO₂@P-Arg (PMP) to construct a cascade reaction nanoplatform. While using biosafety Prussian blue (PB) for photothermal therapy (PTT), this nanoplatform uses silica (SiO₂) as an intermediate layer to assemble Prussian blue and manganese dioxide (MnO₂) into a core-shell structure, which effectively enhances the response of the nanoplatform to TME and promotes the effect of chemodynamic therapy (CDT) resulting from glutathione (GSH) depletion and Fenton-like reaction. The released Mn²⁺ can also be used for magnetic resonance imaging (MRI). Through the cascade reaction, poly-l-arginine (P-Arg) coated on the surface of the nanoparticles can react with hydroxyl radical (•OH) obtained from the Fenton-like reaction to release nitric oxide (NO), which further reacts with O₂•^- to produce the more toxic peroxynitrite anion (ONOO^-). The photothermal effect of PB further enhances the effect of the cascade reaction while reducing the amount of heat required for treatment. In vitro and in vivo studies confirmed the antitumor effects of cascade reaction-based nanoplatforms in combined photothermal/chemodynamic/gas cancer therapies, providing new strategies for the design and fabrication of multifunctional nanoplatforms that integrate diagnostic and therapeutic functions, as well as the application of cascade reactions in multimodal synergistic therapy.

ObjectiveTo investigate the features of liver histopathological damage in patients with indeterminate phase of chronic HBV infection， as well as the timing for initiating antiviral therapy in such patients. MethodsA retrospective screening was performed for the patients with chronic HBV infection who were hospitalized in The Fifth Medical Center of Chinese PLA General Hospital and underwent liver biopsy from March 2018 to April 2022， among whom the patients who met the criteria for indeterminate phase defined in Chinese guidelines for chronic hepatitis B prevention and treatment （2022 edition） were enrolled， and their clinical data were collected. Liver histopathological stage was determined using the Scheuer scoring system， with stages 0 — 4 for inflammation grade （G） and stages 0 — 4 for fibrosis degree （S）， and the patients were divided into groups based on the presence of significant necroinflammation （≥G2） and significant liver fibrosis （≥S2）. The independent samples t-test was used for comparison of normally distributed continuous data between two groups， and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups； the chi-square test or the Fisher’s exact test was used for comparison of categorical data between two groups. A Spearman’s rank correlation analysis was used to investigate the correlation between liver histopathology and clinical factors， and the Logistic regression model was used to identify the independent influencing factors for significant necroinflammation and liver fibrosis. ResultsA total of 271 patients with indeterminate phase of chronic HBV infection were enrolled， among whom 61 （22.5%） had significant necroinflammation （≥G2） and 124 （45.8%） had significant liver fibrosis （≥S2）. The Logistic regression analysis showed that alanine aminotransferase ≥30 U/L （for male patients） or ≥19 U/L （for female patients） （odds ratio ［OR］=2.69， 95% confidence interval ［CI］： 1.39 — 5.21， P=0.003）， HBV DNA ≥2 000 IU/mL （OR=2.75， 95%CI： 1.38 — 5.48， P=0.004）， and liver stiffness measurement （LSM） ≥6.0 kPa （OR=4.57， 95%CI： 2.17 — 9.62， P<0.001） were independent risk factors for significant inflammation. HBV DNA ≥2 000 IU/mL （OR=1.82， 95%CI： 1.01 — 3.32， P=0.049） and LSM ≥6.0 kPa （OR=2.06， 95%CI： 1.23 — 3.43， P=0.006） were independent influencing factors for significant liver fibrosis. ConclusionAmong the patients with indeterminate phase of chronic HBV infection， a substantial proportion of patients have significant liver histopathological damage. Antiviral therapy should be initiated in a timely manner for patients with high-risk factors.

Objective: To explore the treatment options for congenitally missing teeth in patients with ectodermal dysplasia and provide a clinical reference. Methods: A patient with ectodermal dysplasia with a concave midface, anterior protrusion of the chin, and underdevelopment of the lower third of the face presented with congenital loss of multiple maxillary teeth, malocclusion of the remaining teeth, congenital loss of mandibular dentition, small dental arches, and upper and lower alveolar bone hypoplasia. The patient was treated by means of a removable partial maxillary prosthesis, implants in the anterior region of the lower mandible designed with the assistance of digital guides, and bar-clamped implant-overlay prostheses. A literature review of the protocol for the treatment of this condition was also conducted. Results: In addition to good retention and stability after denture wear, an excellent occlusal relationship, improvement of the patient's facial appearance, including upper and lower lip fullness, more equal balancing of the lower and middle 1/3 of the face, and improved masticatory function were achieved. The results of the literature review showed that patients with ectodermal dysplasia who are congenitally edentulous usually have a complex intraoral situation that makes restoration difficult, and common restorative modalities for these patients include fixed bridges, removable partial dentures, complete dentures, overdentures, and implant prostheses, which need to be selected according to the actual intraoral situation of each patient. Currently, there is no consensus on the treatment of congenitally missing teeth in patients with ectodermal dysplasia, and some scholars have suggested that fixed restorations be recommended for patients with fewer missing teeth, while the option of removable or implant-covered denture restorations should be given to patients with more missing teeth, with removeable prostheses for underage patients that are replaced with permanent fixed prostheses when the jaws have stabilized. Conclusion In patients with ectodermal dysplasia with congenital tooth loss, all factors should be taken into account, and an individualized restorative plan should be developed.

Objective:The study retrospectively analyzed the etiology, clinical manifestations, emergency treatment and etiological treatment of a large sample of cases with hypercalcemic crisis.Methods:The clincial data of patients with hypercalcaemia cirisis who were administered in First Medical Center of Chinese PLA General Hospital from January 2009 to July 2022 were analyzed, inculding the general data, clinical manifestations, etiology, photographic examination, emergency treatment, etiological treatment, serological examination before and after treatment, pathological immunohistochemical findings and prognosis.Results:A total of 143 hypercalcaemia crisis patients(84 males and 59 females) with a mean age of 53.51±16.60 were enrolled. The most common disease was hyperparathyroidism(62/143), followed by solid malignancy(57/143) and multiple myeloma(12/143). Patients presented with digestive system symptoms at 76.91%, followed by neurological symptoms at 63.60%, urinary system symptoms at 58.76%, musculoskeletal symptoms at 55.23%, and cardiovascular system symptoms at 32.91%. After emergency calcium-lowering treatment, the remission rate of hypercalcemic crisis in 143 patients was 100%(143/143), and after etiological treatment, the remission rate of hypercalcemia was 85.31%(122/143).Conclusion:Early identification, emergency treatment and etiology treatment of hypercalcaemia crisis are essential. Effective treament with comprehensive calcium reduction can quickly relieve clinical symptoms and create opportunities for treatment for the cause. Targeted etiological interventions can lead to the correction or long-term remission of hypercalcemia.

A major impedance to neuronal regeneration after peripheral nerve injury(PNI)is the activation of various programmed cell death mechanisms in the dorsal root ganglion.Ferroptosis is a form of pro-grammed cell death distinguished by imbalance in iron and thiol metabolism,leading to lethal lipid peroxidation.However,the molecular mechanisms of ferroptosis in the context of PNI and nerve regeneration remain unclear.Ferroportin(Fpn),the only known mammalian nonheme iron export protein,plays a pivotal part in inhibiting ferroptosis by maintaining intracellular iron homeostasis.Here,we explored in vitro and in vivo the involvement of Fpn in neuronal ferroptosis.We first delineated that reactive oxygen species at the injury site induces neuronal ferroptosis by increasing intracellular iron via accelerated UBA52-driven ubiquitination and degradation of Fpn,and stimulation of lipid peroxidation.Early administration of the potent arterial vasodilator,hydralazine(HYD),decreases the ubiquitination of Fpn after PNI by binding to UBA52,leading to suppression of neuronal cell death and significant ac-celeration of axon regeneration and motor function recovery.HYD targeting of ferroptosis is a promising strategy for clinical management of PNI.

Objective:To study positive rates and typing of oligoclonal bands (OCB) in patients with neurological disorders, and to reveal the clinical significance and applicational value of OCB test.Methods:A retrospective analysis was performed on the detection results of 3 217 patients with neurological disorders who undertook both serum and cerebrospinal fluid OCBs in the First Hospital of Peking University from January 2012 to August 2022. According to the final diagnosis, the patients were divided into 13 groups including multiple sclerosis (479 cases), neuromyelitis optica spectrum disorders (935 cases), autoimmune encephalitis (192 cases), viral encephalitis (94 cases), nervous system complication after HSCT (232 cases), Guillain-Barré syndrome (644 cases), chronic inflammatory demyelinating polyneuropathy (157 cases), etc. Cerebrospinal fluid and serum OCBs were detected using isoelectric focusing electrophoresis combining immunofixation, then classified into Ⅰ-Ⅴ types according to the morphology. Consequently, positive rates and types were analyzed for each group. χ2 test was used for comparison between groups. Results:The positive rates of cerebrospinal fluid OCB in multiple sclerosis, nervous system complication after hematopoietic stem cell transplantation (HSCT), autoimmune encephalitis, viral encephalitis, neuromyelitis optica spectrum disorders, Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy were respectively 66.8% (320/479), 48.7% (113/232), 46.4%(89/192), 19.1% (18/94), 17.6% (165/935), 9.9% (64/644), 5.1% (8/157). For patients with multiple sclerosis, neuromyelitis optica spectrum disorders, viral encephalitis, and autoimmune encephalitis, Type Ⅱ bands took the majority of cerebrospinal fluid OCB-positive cases with the rates of 94.1% (301/320), 78.7% (70/89), 77.8% (14/18), and 77.6% (128/165) respectively, indicating intrathecal IgG synthesis; for patients with nervous system complication after HSCT, Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy, type Ⅳ bands took the majority of cerebrospinal fluid OCB-positive cases with the rates of 94.7% (107/113), 82.8% (53/64) and 100% (8/8), indicating no obvious intrathecal IgG synthesis. The positive rates of cerebrospinal fluid oligoclonal bands were significantly different among all groups (χ 2=1 268.31, P<0.001). Conclusion:The positive rates of cerebrospinal fluid oligoclonal bands are different among different neurological disorders, in which the positive rate of cerebrospinal fluid OCB is higher with type Ⅱ bands as the majority type in multiple sclerosis, which indicates that the detection and typing of cerebrospinal fluid OCB are helpful for the diagnosis of various neurological diseases, especially for multiple sclerosis.