Post-amputation pain causes great suffering to amputees, but still no effective drugs are available due to its elusive mechanisms. Our previous clinical studies found that surgical removal or radiofrequency treatment of the neuroma at the axotomized nerve stump effectively relieves the phantom pain afflicting patients after amputation. This indicated an essential role of the residual nerve stump in the formation of chronic post-amputation pain (CPAP). However, the molecular mechanism by which the residual nerve stump or neuroma is involved and regulates CPAP is still a mystery. In this study, we found that nociceptors expressed the mechanosensitive ion channel TMEM63A and macrophages infiltrated into the dorsal root ganglion (DRG) neurons worked synergistically to promote CPAP. Histology and qRT-PCR showed that TMEM63A was mainly expressed in mechanical pain-producing non-peptidergic nociceptors in the DRG, and the expression of TMEM63A increased significantly both in the neuroma from amputated patients and the DRG in a mouse model of tibial nerve transfer (TNT). Behavioral tests showed that the mechanical, heat, and cold sensitivity were not affected in the Tmem63a^-/- mice in the naïve state, suggesting the basal pain was not affected. In the inflammatory and post-amputation state, the mechanical allodynia but not the heat hyperalgesia or cold allodynia was significantly decreased in Tmem63a^-/- mice. Further study showed that there was severe neuronal injury and macrophage infiltration in the DRG, tibial nerve, residual stump, and the neuroma-like structure of the TNT mouse model, Consistent with this, expression of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β all increased dramatically in the DRG. Interestingly, the deletion of Tmem63a significantly reduced the macrophage infiltration in the DRG but not in the tibial nerve stump. Furthermore, the ablation of macrophages significantly reduced both the expression of Tmem63a and the mechanical allodynia in the TNT mouse model, indicating an interaction between nociceptors and macrophages, and that these two factors gang up together to regulate the formation of CPAP. This provides a new insight into the mechanisms underlying CPAP and potential drug targets its treatment.
Animals ; Mice ; Amputation, Surgical ; Chronic Pain/pathology* ; Disease Models, Animal ; Ganglia, Spinal/pathology* ; Hyperalgesia/etiology* ; Ion Channels/metabolism* ; Macrophages ; Neuroma/pathology*

Abstract: Objective To analyze the epidemiological characteristics of pulmonary tuberculosis (PTB) in Ankang City from 2011 to 2021, so as to provide a scientific basis for the formulation of PTB prevention and control strategy. Methods Descriptive statistics were used to analyze the epidemiological characteristics of PTB in Ankang City from 2011 to 2021, and a time series model was established to quantitatively predict the incidence of pulmonary tuberculosis in 2023. Results The incidence rate in Ankang City showed a significant upward trend from 2011 to 2017, and a more obvious downward trend in 2017-2021 (P<0.05), and the decrease rate in 2021 was 40.36% compared with that in 2017. The proportion of etiological positivity increased from 12.5% in 2014 to over 50.00% after 2019. The incidence season was mainly concentrated in the first quarter, accounting for 28.39% of the annual incidence. High incidence areas were concentrated in the south of Ankang: Langao County, Ziyang County and Zhenping County, with 128.32/100 000, 117.07/100 000 and 110.44/100 000, respectively. Low incidence areas were located in the north of Ankang: Ningshan County, with 60.62/100 000. Farmers and students were the high incidence groups, accounting for 81.80% and 4.97% of the total cases respectively. The incidence of young children was relatively low, but cases were reported every year. The incidence rate of male was 2.39 times that of female. The age of onset increased significantly from 15 years old, and the peak incidence was in the age group of 60-<80 years old, followed by the age group of 45-<60 years old, the average annual incidence was 136.44/100 000 and 104.47/100 000, respectively. The model ARIMA(0,1,1)(0,1,1)12 predicted that the incidence of the disease generally increased from October 2022 to March 2023, then steadily decreased, and increased again in December. Conclusions The incidence of tuberculosis varies in different areas of Ankang City, and males, farmers, students and the elderly are all factors of high incidence of tuberculosis. Therefore, different prevention and control strategies should be adopted according to the characteristics of population in different areas. The number of cases in Ankang City in 2023 showed an overall downward trend, which can provide a reference for the prevention and control of PTB.

Objective: To analyze and compare therapy responses, outcomes, and incidence of severe hematologic adverse events of flumatinib and imatinib in patients newly diagnosed with chronic phase chronic myeloid leukemia (CML) . Methods: Data of patients with chronic phase CML diagnosed between January 2006 and November 2022 from 76 centers, aged ≥18 years, and received initial flumatinib or imatinib therapy within 6 months after diagnosis in China were retrospectively interrogated. Propensity score matching (PSM) analysis was performed to reduce the bias of the initial TKI selection, and the therapy responses and outcomes of patients receiving initial flumatinib or imatinib therapy were compared. Results: A total of 4 833 adult patients with CML receiving initial imatinib (n=4 380) or flumatinib (n=453) therapy were included in the study. In the imatinib cohort, the median follow-up time was 54 [interquartile range (IQR), 31-85] months, and the 7-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.2%, 88.4%, 78.3%, and 63.0%, respectively. The 7-year FFS, PFS, and OS rates were 71.8%, 93.0%, and 96.9%, respectively. With the median follow-up of 18 (IQR, 13-25) months in the flumatinib cohort, the 2-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.4%, 86.5%, 58.4%, and 46.6%, respectively. The 2-year FFS, PFS, and OS rates were 80.1%, 95.0%, and 99.5%, respectively. The PSM analysis indicated that patients receiving initial flumatinib therapy had significantly higher cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) and higher probabilities of FFS than those receiving the initial imatinib therapy (all P<0.001), whereas the PFS (P=0.230) and OS (P=0.268) were comparable between the two cohorts. The incidence of severe hematologic adverse events (grade≥Ⅲ) was comparable in the two cohorts. Conclusion: Patients receiving initial flumatinib therapy had higher cumulative incidences of therapy responses and higher probability of FFS than those receiving initial imatinib therapy, whereas the incidence of severe hematologic adverse events was comparable between the two cohorts.
Adult ; Humans ; Adolescent ; Imatinib Mesylate/adverse effects* ; Incidence ; Antineoplastic Agents/adverse effects* ; Retrospective Studies ; Pyrimidines/adverse effects* ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Treatment Outcome ; Benzamides/adverse effects* ; Leukemia, Myeloid, Chronic-Phase/drug therapy* ; Aminopyridines/therapeutic use* ; Protein Kinase Inhibitors/therapeutic use*

Objectives: To investigated the safety and efficacy of treating patients with acute non-ST-segment elevation myocardial infarction (NSTEMI) and elevated levels of N-terminal pro-hormone B-type natriuretic peptide (NT-proBNP) with levosimendan within 24 hours of first medical contact (FMC). Methods: This multicenter, open-label, block-randomized controlled trial (NCT03189901) investigated the safety and efficacy of levosimendan as an early management strategy of acute heart failure (EMS-AHF) for patients with NSTEMI and high NT-proBNP levels. This study included 255 patients with NSTEMI and elevated NT-proBNP levels, including 142 males and 113 females with a median age of 65 (58-70) years, and were admitted in the emergency or outpatient departments at 14 medical centers in China between October 2017 and October 2021. The patients were randomly divided into a levosimendan group (n=129) and a control group (n=126). The primary outcome measure was NT-proBNP levels on day 3 of treatment and changes in the NT-proBNP levels from baseline on day 5 after randomization. The secondary outcome measures included the proportion of patients with more than 30% reduction in NT-proBNP levels from baseline, major adverse cardiovascular events (MACE) during hospitalization and at 6 months after hospitalization, safety during the treatment, and health economics indices. The measurement data parameters between groups were compared using the t-test or the non-parametric test. The count data parameters were compared between groups using the χ² test. Results: On day 3, the NT-proBNP levels in the levosimendan group were lower than the control group but were statistically insignificant [866 (455, 1 960) vs. 1 118 (459, 2 417) ng/L, Z=-1.25,P=0.21]. However, on day 5, changes in the NT-proBNP levels from baseline in the levosimendan group were significantly higher than the control group [67.6% (33.8%,82.5%)vs.54.8% (7.3%,77.9%), Z=-2.14, P=0.03]. There were no significant differences in the proportion of patients with more than 30% reduction in the NT-proBNP levels on day 5 between the levosimendan and the control groups [77.5% (100/129) vs. 69.0% (87/126), χ²=2.34, P=0.13]. Furthermore, incidences of MACE did not show any significant differences between the two groups during hospitalization [4.7% (6/129) vs. 7.1% (9/126), χ²=0.72, P=0.40] and at 6 months [14.7% (19/129) vs. 12.7% (16/126), χ²=0.22, P=0.64]. Four cardiac deaths were reported in the control group during hospitalization [0 (0/129) vs. 3.2% (4/126), P=0.06]. However, 6-month survival rates were comparable between the two groups (log-rank test, P=0.18). Moreover, adverse events or serious adverse events such as shock, ventricular fibrillation, and ventricular tachycardia were not reported in both the groups during levosimendan treatment (days 0-1). The total cost of hospitalization [34 591.00(15 527.46,59 324.80) vs. 37 144.65(16 066.90,63 919.00)yuan, Z=-0.26, P=0.80] and the total length of hospitalization [9 (8, 12) vs. 10 (7, 13) days, Z=0.72, P=0.72] were lower for patients in the levosimendan group compared to those in the control group, but did not show statistically significant differences. Conclusions: Early administration of levosimendan reduced NT-proBNP levels in NSTEMI patients with elevated NT-proBNP and did not increase the total cost and length of hospitalization, but did not significantly improve MACE during hospitalization or at 6 months.
Male ; Female ; Humans ; Aged ; Natriuretic Peptide, Brain ; Simendan/therapeutic use* ; Non-ST Elevated Myocardial Infarction ; Heart Failure/drug therapy* ; Peptide Fragments ; Arrhythmias, Cardiac ; Biomarkers ; Prognosis

Panacis Quinquefolii Radix is the dry root of Panax quinquefolium, which is a perennial plant of Araliaceae. The plant has a long growth cycle and serious growth barrier problem, which leads to the use of pesticides. As a result, the pesticide residues in Panacis Quinquefolii Radix are arousing great concern. This paper reviews the research findings on the investigation, detection methods, content analysis and risk assessment of pesticide residues in Panacis Quinquefolii Radix since 1993, and compares the pesticide residue limit standards of different countries and regions. The pesticide residues in Panacis Quinquefolii Radix have been changing from organochlorines with high toxicity to triazines and triazoles with low toxicity. The pesticide residues are generally low, while the pollution of pentachloronitrobenzene and other pesticides still exist. The detection method has evolved from chromatography to chromatography-mass spectrometry. There are no reports of health risks caused by pesticide residues of Panacis Quinquefolii Radix. Pesticide residue is a major factor restricting the sound development of Panacis Quinquefolii Radix industry in China. Therefore, we suggest to improve the registration of pesticides applied to the plant, popularize mature ecological planting mode and supporting technology, and strengthen the research on the risk assessment and limit standard of pesticide residue in Panacis Quinquefolii Radix.
Drugs, Chinese Herbal/chemistry* ; Ginsenosides/analysis* ; Mass Spectrometry ; Panax/chemistry* ; Pesticide Residues/analysis*

Objective: To analyze HIV transmission hotspots and characteristics of cross-regional transmission in Guangxi Zhuang autonomous region (Guangxi) based on the molecular network analysis, and provide evidence for optimization of precise AIDS prevention and control strategies. Methods: A total of 5 996 HIV pol sequences sampled from Guangxi between 1997 and 2020 were analyzed together with 165 534 published HIV pol sequences sampled from other regions. HIV-TRACE was used to construct molecular network in a pairwise genetic distance threshold of 0.5%. Results: The proportion of HIV sequences entering the molecular network of HIV transmission hotspots in Guangxi was 31.5% (1 886/5 996). In the molecular network of HIV cross-regional transmission, the links within Guangxi accounted for 51.6% (2 613/5 062), the links between Guangxi and other provinces in China accounted for 48.0% (2 430/5 062), and the links between Guangxi and other countries accounted for 0.4% (19/5 062). The main regions which had cross-regional linked with Guangxi were Guangdong (49.5%, 1 212/2 449), Beijing (17.5%, 430/2 449), Shanghai (6.9%, 168/2 449), Sichuan (5.7%, 140/2 449), Yunnan (4.2%, 102/2 449), Shaanxi (3.8%, 93/2 449), Zhejiang (2.8%, 69/2 449), Hainan (2.0%, 49/2 449), Anhui (1.5%, 37/2 449), Jiangsu (1.3%, 33/2 449), and other regions (each one <1.0%), respectively. The risk factors of entering the molecular network of HIV transmission hotspots in Guangxi included being aged ≥50 years (compared with being aged 25-49 years, aOR=1.68,95%CI:1.46-1.95), males (compared with females, aOR=1.21,95%CI:1.05-1.40), being single (compared with being married, aOR=1.18,95%CI:1.00-1.39), having education level of high school or above (compared with having education level of junior high school or below, aOR=1.21,95%CI:1.04-1.42), acquired HIV through homosexual intercourse (compared with acquired with HIV through heterosexual intercourse, aOR=1.77, 95%CI:1.48-2.12). The risk factors of cross-regional transmission included males (compared with females, aOR=1.74,95%CI:1.13-2.75), having education level of high school or above (compared with having education level of junior high school or below, aOR=1.96,95%CI:1.43-2.69), being freelancer/unemployed/retired (compared with being farmers, aOR=1.50,95%CI:1.07-2.11), acquired HIV through homosexual intercourse (compared with acquired with HIV through heterosexual intercourse, aOR=3.28,95%CI:2.30-4.72). Conclusion: There are HIV transmission hotspots in Guangxi. Guangxi and other provinces in China form a complex cross-regional transmission network. Future studies should carry out social network surveys in high-risk populations inferred from the molecular network analysis for the timely identification of hidden transmission chains and reduction of the second-generation transmission of HIV.
Acquired Immunodeficiency Syndrome ; China/epidemiology* ; Disease Hotspot ; Female ; HIV Infections/epidemiology* ; Heterosexuality ; Humans ; Male

Remitting seronegative symmetrical synovitis with pitting edema(RS3PE),the inflammatory arthritis attacking mainly elderly males,is characterized by symmetrical synovitis with pitting edema of the dorsum of hands and feet and the absence of rheumatoid factor.RS3PE commonly accompanies malignant tumor,infections and other diseases.Here we report a case of RS3PE associated with lung malignancy and review other six cases to summarize the clinical features,treatment and prognosis.
Aged ; Edema/etiology* ; Humans ; Lung Neoplasms/complications* ; Male ; Syndrome ; Synovitis/drug therapy*

Objective: To investigate the effect of insertion technique and electrode array type on the insertion force of electrode array, and to provide a basis for further optimizing electrode design and facilitating mini-invasive electrode insertion. Methods: Three types of electrode array from Nurotron (Standard Electrode, Slim-medium Electrode, Slim-long Electrode) were studied. from July 2019 to December 2019. These electrode arrays were inserted into the phantom models of the cochlea, manually or robot-assisted(medium speed and low speed). The real-time force during electrode array insertion was recorded by ATI Nano 17 Ti sensors and was analyzed by accessory software. Origin 2020b software was used for statistical processing. Results: The insertion force of all electrode arrays progressively increased with the insertion depth. With the manual technique, the peak force of slim-medium electrode insertion was significantly smaller than that of the standard electrode insertion((71.0±16.6) mN vs (140.9±52.7) mN, Z=3.683, P<0.01), and the peak force of the slim-long electrode insertion was between the peak force of standard electrode and slim-medium electrode(P>0.05). No difference was found in the force variation of insertion among the three electrodes(P>0.05). With medium-speed and low-speed robotic assistance, the peak force characteristics of three electrodes were similar to those with the manual technique, but the force variation of standard electrode insertion ((83.9±9.7) mN/s) at medium speed was significantly larger than that of the slim-long electrode insertion ((69.2±4.0)mN/s), and the force variation of the standard electrode insertion at low speed was significantly greater than the other two electrodes. For the same electrode, robot-assisted insertion presented significantly lower peak force and force variation than manual insertion for each type of electrode array. But there was no difference in the peak force and force variation between two-speed levels of robot assistance (P>0.05). Conclusions: The insertion force of the electrode array will be lower when a slim electrode array or robot technique is applied. Long electrode array might make manual insertion difficult or less precise. Robot assistance has advantage on force control during electrode array insertion.
Cochlea/surgery* ; Cochlear Implantation ; Cochlear Implants ; Electrodes, Implanted ; Humans ; Robotics

The TEA domain (TEAD) family proteins (TEAD1‒4) are essential transcription factors that control cell differentiation and organ size in the Hippo pathway. Although the sequences and structures of TEAD family proteins are highly conserved, each TEAD isoform has unique physiological and pathological functions. Therefore, the development and discovery of subtype selective inhibitors for TEAD protein will provide important chemical probes for the TEAD-related function studies in development and diseases. Here, we identified a novel TEAD1/3 covalent inhibitor (DC-TEADin1072) with biochemical IC