Effective annotation of in vivo drug metabolites using liquid chromatography-mass spectrometry (LC-MS) remains a formidable challenge. Herein, a metabolic reaction-based molecular networking (MRMN) strategy is introduced, which enables the "one-pot" discovery of prototype drugs and their metabolites. MRMN constructs networks by matching metabolic reactions and evaluating MS² spectral similarity, incorporating innovations and improvements in feature degradation of MS² spectra, exclusion of endogenous interference, and recognition of redundant nodes. A minimum 75% correlation between structural similarity and MS² similarity of neighboring metabolites was ensured, mitigating false negatives due to spectral feature degradation. At least 79% of nodes, 49% of edges, and 97% of subnetworks were reduced by an exclusion strategy of endogenous ions compared to the Global Natural Products Social Molecular Networking (GNPS) platform. Furthermore, an approach of redundant ions identification was refined, achieving a 10%-40% recognition rate across different samples. The effectiveness of MRMN was validated through a single compound, plant extract, and mixtures of multiple plant extracts. Notably, MRMN is freely accessible online at https://yaolab.network, broadening its applications.

Five novel nor-eremophilane-type sesquiterpenoids, peniroqueforins E-H and J (1-4 and 7), two new eremophilane-type sesquiterpenoids, peniroqueforins I and K (5 and 8), and a new eudesmane-type sesquiterpenoid, peniroqueforin L (9), along with four known compounds (6 and 10-12), were isolated and characterized from fungus Penicillium roqueforti (P. roqueforti). The structures and absolute configurations of these compounds were determined through comprehensive spectroscopic analyses, electronic circular dichroism (ECD) data analyses, and single-crystal X-ray diffraction methods. The anti-multi-drug resistance (MDR) cancer activity of these compounds was evaluated using SW620/Ad300 cells. Notably, the half maximal inhibitory concentration (IC₅₀) value of paclitaxel (PTX) combined with 1 in SW620/Ad300 cells was 50.36 nmol·L^-1, which was 65-fold more potent than PTX alone (IC₅₀ 3.26 μmol·L^-1). Subsequent molecular docking studies revealed an affinity between compound 1 and P-glycoprotein (P-gp), suggesting that this nor-eremophilane-type sesquiterpenoid (1) could serve as a potential lead for MDR reversal in cancer cells through P-gp inhibition.
Penicillium/chemistry* ; Humans ; Sesquiterpenes/isolation & purification* ; Cell Line, Tumor ; Molecular Structure ; Drug Resistance, Neoplasm/drug effects* ; Antineoplastic Agents/pharmacology* ; Drug Resistance, Multiple/drug effects* ; Molecular Docking Simulation

ObjectiveTo analyze the reported incidence rate of pulmonary tuberculosis and diagnosis and treatment of pulmonary tuberculosis patients in Jing’an District, Shanghai from 2018 to 2023, and to provide a reference basis for the prevention and treatment of pulmonary tuberculosis. MethodsMedical records, including demographic information, diagnosis and treatment information, laboratory testing results, treatment outcomes, patient prognoses, and etc., of all the patients registered for first-time management, with the disease type of pulmonary tuberculosis in Jing’an District from January 1, 2018 to December 31, 2023 were extracted from the Tuberculosis Management Information System of China’s Disease Control and Prevention Information System.The reported incidence rate of pulmonary tuberculosis from 2018 to 2023 was analyzed. Additionally, the delay rate for medical consultation, diagnostic delay rate, prevalence of pulmonary cavity, rate of sputum smear-positive, sputum conversion rate of smear-positive patients after 2 months, proportion of deaths attributable to pulmonary tuberculosis or other causes, and the proportion of patients with treatment duration >1 year in 2018‒2019, 2020‒2022, and 2023 were compared, respectively. ResultsA total of 1 378 pulmonary tuberculosis patients were registered for management in Jing’an District in 2018‒2023, with a reported incidence rate of 25.97/100 000, 25.72/100 000, 23.93/100 000, 22.36/100 000, 18.18/100 000, and 22.32/100 000, respectively. Meanwhile, the overall reported incidence rates in 2018‒2019, 2020‒2022, and 2023 were 25.84/100 000, 21.53/100 000, and 22.32/100 000, respectively. The median age of the patients was 56 (33, 67) years, with a male-to-female ratio of 1.94∶1. The patients with a household registration of Shanghai accounted for 70.75%, among whom those aged between 61‒<71 years were the majority. Whereas, those aged between 31‒<41 years accounted for a higher proportion in the long-term resident population. The median delay times of patient’s medical consultation, diagnosis, and case-finding were 25 (19, 33) days, 29 (21, 43) days, and 41 (32, 66) days, respectively. The delay rate for medical consultation was higher in 2020‒2022 (47.99%) and 2023 (46.89%), but lower in 2018‒2019 (31.02%). In 2018‒2019, 2020‒2022, and 2023, the diagnostic delay rate was 12.41% (68/548), 13.53% (84/621), and 16.75% (35/209), respectively. Besides, during the same time the delay rate in case-finding was 19.53%, 27.05% and 34.45%, respectively, all exhibited an increasing trend. Furthermore, the rate of patients with pulmonary cavity was 16.06%, 14.98%, and 11.00%, respectively, showing a decreasing trend. Furthermore, the rate of sputum smear-positive was 27.19%, 33.33% and 32.54%, while the sputum conversion rate of smear-positive patients after 2 months was 81.21%, 85.02% and 89.71%. The mortality rates due to tuberculosis and other causes were 3.10%, 5.64%, and 3.83%, respectively. The proportion of patients with a treatment duration of ≥365 days was 44.27% in 2018‒2019, 39.93% in 2020‒2022 and 26.60% in 2023. ConclusionThe overall reported incidence rate of pulmonary tuberculosis in Jing’an District showed a decline trend from 2018‒2022, with a slight rebound in 2023. Targeted interventions should be prioritized for the elderly with local household registration and young permanent residents without Shanghai household registration.

Objective:In chronic hepatitis B (CHB) patients with previous 96-week treatment with tenofovir amibufenamide (TMF) or tenofovir disoproxil fumarate (TDF), we investigated the efficacy of sequential TMF treatment from 96 to 144 weeks.Methods:Enrolled subjects who were previously assigned (2:1) to receive either 25 mg TMF or 300 mg TDF with matching placebo for 96 weeks received extended or switched TMF treatment for 48 weeks. Efficacy was evaluated based on virological, serological, biological parameters, and fibrosis staging. Statistical analysis was performed using the McNemar test, t-test, or Log-Rank test according to the data. Results:593 subjects from the initial TMF group and 287 subjects from the TDF group were included at week 144, with the proportions of HBV DNA<20 IU/ml at week 144 being 86.2% and 83.3%, respectively, and 78.1% and 73.8% in patients with baseline HBV DNA levels ≥8 log10 IU/ml. Resistance to tenofovir was not detected in both groups. For HBeAg loss and seroconversion rates, both groups showed a further increase from week 96 to 144 and the 3-year cumulative rates of HBeAg loss were about 35% in each group. However, HBsAg levels were less affected during 96 to 144 weeks. For patients switched from TDF to TMF, a substantial further increase in the alanine aminotransferase (ALT) normalization rate was observed (11.4%), along with improved FIB-4 scores.Conclusion:After 144 weeks of TMF treatment, CHB patients achieved high rates of virological, serological, and biochemical responses, as well as improved liver fibrosis outcomes. Also, switching to TMF resulted in significant benefits in ALT normalization rates (NCT03903796).

Objective:In chronic hepatitis B (CHB) patients with previous 96-week treatment with tenofovir amibufenamide (TMF) or tenofovir disoproxil fumarate (TDF), we investigated the safety profile of sequential TMF treatment from 96 to 144 weeks.Methods:Enrolled subjects that previously assigned (2:1) to receive either 25 mg TMF or 300 mg TDF with matching placebo for 96 weeks received extending or switching TMF treatment for 48 weeks. Safety profiles of kidney, bone, metabolism, body weight, and others were evaluated.Results:666 subjects from the initial TMF group and 336 subjects from TDF group with at least one dose of assigned treatment were included at week 144. The overall safety profile was favorable in each group and generally similar between extended or switched TMF treatments from week 96 to 144. In subjects switching from TDF to TMF, the non-indexed estimated glomerular filtration rate (by non-indexed CKD-EPI formula) and creatinine clearance (by Cockcroft-Gault formula) were both increased, which were (2.31±8.33) ml/min and (4.24±13.94) ml/min, respectively. These changes were also higher than those in subjects with extending TMF treatment [(0.91±8.06) ml/min and (1.30±13.94) ml/min]. Meanwhile, switching to TMF also led to an increase of the bone mineral density (BMD) by 0.75% in hip and 1.41% in spine. On the other side, a slight change in TC/HDL ratio by 0.16 (IQR: 0.00, 0.43) and an increase in body mass index (BMI) by (0.54±0.98) kg/m 2 were oberved with patients switched to TMF, which were significantly higher than that in TMF group. Conclusion:CHB patients receiving 144 weeks of TMF treatment showed favorable safety profile. After switching to TMF, the bone and renal safety was significantly improved in TDF group, though experienceing change in metabolic parameters and weight gain (NCT03903796).

The STAR tool was used to evaluate and analyze the science, transparency, and applicability of Chinese pathology guidelines and consensus published in medical journals in 2022. There were a total of 18 pathology guidelines and consensuses published in 2022, including 1 guideline and 17 consensuses. The results showed that the guideline score was 21.83 points, lower than the overall guideline average (43.4 points). Consensus ratings scored an average of 27.87 points, on par with the overall consensus level (28.3 points). Areas that scored above the overall level were "conflict of interest" and "working groups", while areas that scored below the overall level were "proposals", "funding", "evidence", "consensus approaches" and "accessibility". To sum up, the formulation of pathology guidelines and consensuses in 2022 is not standardized, and the evidence retrieval process, evidence evaluation methods and grading criteria for recommendations on clinical issues are not provided in the formulation process; the process and method for reaching consensus are not provided, the plan is lacking, and registration is not carried out. It is therefore suggested that guidelines/consensus makers in the field of pathology should attach importance to evidence-based medical evidence, strictly follow guideline formulation methods and processes, further improve the scientific, applicable and transparent guidelines/consensuses in the field, and better provide support for clinicians and patients.

Objective:To explore the clinical and genetic characteristics of a child with mental retardation, language and motor developmental delay and epilepsy.Methods:A Child who was admitted to the First Affiliated Hospital of Zhengzhou University in March 2020 for intermittent seizures for over two months was Selected as the study subject. Clinical data of the child was collected. Peripheral blood samples of the child and his parents were collected and subjected to high throughput sequencing. Candidate variants were verified by Sanger sequencing and bioinformatic analysis.Results:The clinical manifestations of the child have included mental retardation, language and motor developmental delay, and seizures. High-throughput sequencing revealed that he has harbored a hemizygous splice site variant (NM_032591.3: c.1030-1G>C) of the SLC9A7 gene, which was inherited from his mother and unreported previously. Conclusion:The hemizygous splice site variant (NM_032591.3: c. 1030-1G>C) of the SLC9A7 gene probably underlay the disease in this child. Above finding has provided a basis for clinical diagnosis and genetic counseling.

Induced sputum testing is a non-invasive test that reflects the nature and extent of airway inflammation and plays an important role in the diagnosis, treatment and prognosis of chronic airway diseases. This article outlines the development history of induced sputum technology, introduces the principle and operation of induced sputum technology, evaluates its safety, summarizes the three main test components, elaborates the role of this technology in various chronic airway diseases, such as reflecting the type of airway inflammation, predicting the efficacy of medication, and combining it with transcriptomics to study disease mechanisms, and briefly summarizes its innovations and makes a vision for the future.

Induced sputum testing is a non-inva-sive test that reflects the nature and extent of air-way inflammation and plays an important role in the diagnosis,treatment and prognosis of chronic airway diseases.This article outlines the develop-ment history of induced sputum technology,intro-duces the principle and operation of induced spu-tum technology,evaluates its safety,summarizes the three main test components,elaborates the role of this technology in various chronic airway diseases,such as reflecting the type of airway in-flammation,predicting the efficacy of medication,and combining it with transcriptomics to study dis-ease mechanisms,and briefly summarizes its inno-vations and makes a vision for the future.