This research study focuses on addressing the limitations of current neuropathic pain(NP)treatments by developing a novel dual-target modulator,E0199,targeting both Nav1.7,Nay1.8,and Nay1.9 and Kv7 channels,a crucial regulator in controlling NP symptoms.The objective of the study was to synthesize a compound capable of modulating these channels to alleviate NP.Through an experimental design involving both in vitro and in vivo methods,E0199 was tested for its efficacy on ion channels and its therapeutic potential in a chronic constriction injury(CCI)mouse model.The results demonstrated that E0199 significantly inhibited Nav1.7,Nav1.8,and Nav1.9 channels with a particularly low half maximal inhibitory concentration(ICs0)for Nay1.9 by promoting sodium channel inactivation,and also effectively increased Kv7.2/73,Kv7.2,and Kv7.5 channels,excluding Kv7.1 by promoting potassium channel acti-vation.This dual action significantly reduced the excitability of dorsal root ganglion neurons and alle-viated pain hypersensitivity in mice at low doses,indicating a potent analgesic effect without affecting heart and skeletal muscle ion channels critically.The safety of E0199 was supported by neurobehavioral evaluations.Conclusively,E0199 represents a ground-breaking approach in NP treatment,showcasing the potential of dual-target small-molecule compounds in providing a more effective and safe thera-peutic option for NP.This study introduces a promising direction for the future development of NP therapeutics.

In recent years,the problem of population aging in China has been continuously intensifying.The mechanism of aging and its prevention and treatment have gradually become research hotspots.The successful establishment of aging animal models is an important part of aging-related research,and behavioral experiments can effectively evaluate these models.This article reviews the methods of constructing aging animal models from different aspects,analyzes the advantages and disadvantages of various behavioral evaluation experiments and their comparisons,with the aim of providing theoretical references for aging-related research.

Objective To evaluate the efficacy and safety of amoxicillin-clavulanate(10∶1)for injection in the treatment of community-acquired pneumonia(CAP)in adult patients.Methods Eligible patients were randomized to receive amoxicillin-clavulanate(10∶1)2.2 g or ampicillin-sulbactam(2∶1)3.0 g via intravenous infusion q12h or q8h for 7 to 14 days.The primary endpoint was to the clinical efficacy 7-14 days after discontinuation of treatment.The secondary endpoints included microbiological efficacy and safety.Results All enrolled patients(n=324)were included in the full analysis set(FAS),specifically 165 patients receiving amoxicillin sodium-clavulanate potassium(10∶1)and 159 patients receiving ampicillin sodium-sulbactam sodium(2∶1).The clinical cure rate was 78.8％(130/165)for amoxicillin-clavulanate(10∶1)and 77.4％(123/159)for ampicillin-sulbactam 7-14 days after end of treatment(P＞0.05).The clinical cure rate was 87.5％(126/144)for amoxicillin-clavulanate(10∶1)and 87.4％(111/127)for ampicillin-sulbactam(2∶1)in per protocol set(P＞0.05).Therefore,amoxicillin-clavulanate(10∶1)was non-inferior to ampicillin-sulbactam in the primary endpoint in the treatment of CAP in adult patients.The overall bacterial eradication rate was 94.4％(34/36)for amoxicillin-clavulanate(10∶1)and 89.3％(25/28)for ampicillin-sulbactam(P＞0.05).The common study drug-related clinical adverse event were abnormalities of hepatic function in both the amoxicillin-clavulanate(10∶1)group(4.8％,8/165)and ampicillin-sulbactam group(3.1％,5/159)(P＞0.05).Conclusions Amoxicillin-clavulanate(10∶1)2.2 g Ⅳ infusion q12h or q8h for 7-14 days was noninferior to ampicillin-sulbactam in terms of clinical and microbiological efficacy in the treatment of CAP in adult patients.The safety of the two dosing regimens was comparable.

Objective To evaluate the efficacy and safety of polyethylene glycol electrolyte powder(PEG)combined with linaclotide(Lin)for bowel preparation in elderly constipated patients before colonoscopy.Methods In this prospective,randomized controlled trial,90 elderly patients with constipation undergoing colonoscopy were recruited at our hospital from June 2022 to December 2023.Participants were randomly assigned to three groups(n=30 each):PEG-3L alone,PEG-3L+Lin,and PEG-2L+Lin.Primary outcome was Boston Bowel Preparation Scale(BBPS)score and secondary outcomes included adverse event rates,colonoscopy completion rate,withdrawal time,and polyp detection rate.Statistical analysis was performed using independent t-tests and chi-square tests.Results The PEG-3L+Lin group achieved significantly higher BBPS scores than both PEG-3L alone and PEG-2L+Lin groups did(both P<0.001).The PEG-2L+Lin group also outperformed the PEG-3L alone group in cleansing efficacy(90.0%vs.76.7%,P=0.008).The PEG-2L+Lin group demonstrated the best tolerability and lowest adverse event rate,the PEG-3L group had the longest withdrawal time(P<0.05),but the three groups showed no significant difference in polyp detection rates.Conclusion PEG combined with linaclotide significantly improves bowel cleansing in elderly constipated patients.PEG-2L+Lin regimen provides optimal balance between efficacy,safety,and tolerability,making it a preferable choice for this population.

This research study focuses on addressing the limitations of current neuropathic pain (NP) treatments by developing a novel dual-target modulator, E0199, targeting both Na_V1.7, Na_V1.8, and Na_V1.9 and K_V7 channels, a crucial regulator in controlling NP symptoms. The objective of the study was to synthesize a compound capable of modulating these channels to alleviate NP. Through an experimental design involving both in vitro and in vivo methods, E0199 was tested for its efficacy on ion channels and its therapeutic potential in a chronic constriction injury (CCI) mouse model. The results demonstrated that E0199 significantly inhibited Na_V1.7, Na_V1.8, and Na_V1.9 channels with a particularly low half maximal inhibitory concentration (IC₅₀) for Na_V1.9 by promoting sodium channel inactivation, and also effectively increased K_V7.2/7.3, K_V7.2, and K_V7.5 channels, excluding K_V7.1 by promoting potassium channel activation. This dual action significantly reduced the excitability of dorsal root ganglion neurons and alleviated pain hypersensitivity in mice at low doses, indicating a potent analgesic effect without affecting heart and skeletal muscle ion channels critically. The safety of E0199 was supported by neurobehavioral evaluations. Conclusively, E0199 represents a ground-breaking approach in NP treatment, showcasing the potential of dual-target small-molecule compounds in providing a more effective and safe therapeutic option for NP. This study introduces a promising direction for the future development of NP therapeutics.

Given that ovarian stimulation is vital for assisted reproductive technology (ART) and results in elevated serum estrogen levels, exploring the impact of elevated estrogen exposure on oocytes and embryos is necessary. We investigated the effects of various ovarian stimulation treatments on oocyte and embryo morphology and gene expression using a mouse model and estrogen-treated mouse embryonic stem cells (mESCs). Female C57BL/6J mice were subjected to two types of conventional ovarian stimulation and ovarian hyperstimulation; mice treated with only normal saline served as controls. Hyperstimulation resulted in high serum estrogen levels, enlarged ovaries, an increased number of aberrant oocytes, and decreased embryo formation. The messenger RNA (mRNA)‍-sequencing of oocytes revealed the dysregulated expression of lysine-specific demethylase 6b (Kdm6b), which may be a key factor indicating hyperstimulation-induced aberrant oocytes and embryos. In vitro, Kdm6b expression was downregulated in mESCs treated with high-dose estrogen; treatment with an estrogen receptor antagonist could reverse this downregulated expression level. Furthermore, treatment with high-dose estrogen resulted in the upregulated expression of histone H3 lysine 27 trimethylation (H3K27me3) and phosphorylated H2A histone family member X (γ-H2AX). Notably, knockdown of Kdm6b and high estrogen levels hindered the formation of embryoid bodies, with a concomitant increase in the expression of H3K27me3 and γ-H2AX. Collectively, our findings revealed that hyperstimulation-induced high-dose estrogen could impair the demethylation of H3K27me3 by reducing Kdm6b expression. Accordingly, Kdm6b could be a promising marker for clinically predicting ART outcomes in patients with ovarian hyperstimulation syndrome.
Female ; Mice ; Demethylation/drug effects* ; Embryonic Stem Cells ; Estrogens/administration & dosage* ; Gene Expression/drug effects* ; Histones/metabolism* ; Jumonji Domain-Containing Histone Demethylases/metabolism* ; Mice, Inbred C57BL ; Oocytes ; Ovary/drug effects* ; Reproductive Techniques, Assisted ; Animals

In recent years,the problem of population aging in China has been continuously intensifying.The mechanism of aging and its prevention and treatment have gradually become research hotspots.The successful establishment of aging animal models is an important part of aging-related research,and behavioral experiments can effectively evaluate these models.This article reviews the methods of constructing aging animal models from different aspects,analyzes the advantages and disadvantages of various behavioral evaluation experiments and their comparisons,with the aim of providing theoretical references for aging-related research.

Objective To evaluate the efficacy and safety of amoxicillin-clavulanate(10∶1)for injection in the treatment of community-acquired pneumonia(CAP)in adult patients.Methods Eligible patients were randomized to receive amoxicillin-clavulanate(10∶1)2.2 g or ampicillin-sulbactam(2∶1)3.0 g via intravenous infusion q12h or q8h for 7 to 14 days.The primary endpoint was to the clinical efficacy 7-14 days after discontinuation of treatment.The secondary endpoints included microbiological efficacy and safety.Results All enrolled patients(n=324)were included in the full analysis set(FAS),specifically 165 patients receiving amoxicillin sodium-clavulanate potassium(10∶1)and 159 patients receiving ampicillin sodium-sulbactam sodium(2∶1).The clinical cure rate was 78.8％(130/165)for amoxicillin-clavulanate(10∶1)and 77.4％(123/159)for ampicillin-sulbactam 7-14 days after end of treatment(P＞0.05).The clinical cure rate was 87.5％(126/144)for amoxicillin-clavulanate(10∶1)and 87.4％(111/127)for ampicillin-sulbactam(2∶1)in per protocol set(P＞0.05).Therefore,amoxicillin-clavulanate(10∶1)was non-inferior to ampicillin-sulbactam in the primary endpoint in the treatment of CAP in adult patients.The overall bacterial eradication rate was 94.4％(34/36)for amoxicillin-clavulanate(10∶1)and 89.3％(25/28)for ampicillin-sulbactam(P＞0.05).The common study drug-related clinical adverse event were abnormalities of hepatic function in both the amoxicillin-clavulanate(10∶1)group(4.8％,8/165)and ampicillin-sulbactam group(3.1％,5/159)(P＞0.05).Conclusions Amoxicillin-clavulanate(10∶1)2.2 g Ⅳ infusion q12h or q8h for 7-14 days was noninferior to ampicillin-sulbactam in terms of clinical and microbiological efficacy in the treatment of CAP in adult patients.The safety of the two dosing regimens was comparable.

Objective To evaluate the efficacy and safety of polyethylene glycol electrolyte powder(PEG)combined with linaclotide(Lin)for bowel preparation in elderly constipated patients before colonoscopy.Methods In this prospective,randomized controlled trial,90 elderly patients with constipation undergoing colonoscopy were recruited at our hospital from June 2022 to December 2023.Participants were randomly assigned to three groups(n=30 each):PEG-3L alone,PEG-3L+Lin,and PEG-2L+Lin.Primary outcome was Boston Bowel Preparation Scale(BBPS)score and secondary outcomes included adverse event rates,colonoscopy completion rate,withdrawal time,and polyp detection rate.Statistical analysis was performed using independent t-tests and chi-square tests.Results The PEG-3L+Lin group achieved significantly higher BBPS scores than both PEG-3L alone and PEG-2L+Lin groups did(both P<0.001).The PEG-2L+Lin group also outperformed the PEG-3L alone group in cleansing efficacy(90.0%vs.76.7%,P=0.008).The PEG-2L+Lin group demonstrated the best tolerability and lowest adverse event rate,the PEG-3L group had the longest withdrawal time(P<0.05),but the three groups showed no significant difference in polyp detection rates.Conclusion PEG combined with linaclotide significantly improves bowel cleansing in elderly constipated patients.PEG-2L+Lin regimen provides optimal balance between efficacy,safety,and tolerability,making it a preferable choice for this population.

Objective:To analyze the efficacy, safety and learning curve of Thulium laser enucleation of the prostate by laser controller(LC-THuLEP) anchored at six o'clock position of the bladder neck in the treatment of benign prostatic hyperplasia(BPH) with large gland.Methods:The clinical data of the 1st to 45th BPH cases with large gland(prostate volume> 80 ml) treated by a doctor with LC-THuLEP anchored at six o'clock position of bladder neck in Shanghai East Hospital from January to October 2022 were retrospectively analyzed. The patients were divided into groups A, B and C according to the order of operation time, with 15 cases in each group. There were no significant differences among the three groups( P>0.05) in age[(71.8±9.4)years old vs. (73.5±8.2) years old vs.(71.4±5.5)years old], prostate volume[88.3(84.8, 100.6)ml vs.91.5(86.1, 118.4)ml vs. 94.5(84.7, 101.8)ml], prostate specific antigen(PSA)[4.8(2.9, 8.5)ng/ml vs. 7.2(3.2, 11.2)ng/ml vs. 7.8(4.5, 12.7)ng/ml], postvoid residual volume[44.0(34.0, 67.0)ml vs. 60.0(40.0, 76.0)ml vs. 39.0(0, 59.0)ml], maximum urine flow rate(Q max)[8.4(7.6, 11.1)ml/s vs. 8.6(6.5, 10.6)ml/s vs. 10.4(7.8, 13.2)ml/s], international prostate symptom score(IPSS)[20(18, 21) vs. 20(20, 22) vs. 20(20, 25)]and quality of life(QOL)[4(4, 5) vs. 4(4, 4) vs. 4(3, 5)].The doctor had more than 100 cases of TURP surgery experience. LC-THuLEP anchored at six o'clock position of bladder neck was described as follows. The bladder neck at six o'clock position is reserved 0.5-1.0 cm as an "anchor" to fix the prostatic bladder neck when the gland was pushed directly by the laser controller, preventing the detached prostate gland from turning. Finally the bladder neck was cut off at six o'clock position, and the prostate was en-bloc removed. The effect of surgery and postoperative complications were compared. The enucleation efficiency was equal to the weight of prostate tissue removed divided by the time of enucleation. Results:The differences among the three groups in operation time [100.0(90.0, 110.0)min vs. 80.0(70.0, 90.0)min vs. 75.0(70.0, 90.0)min], enucleation time[89.0(72.0, 97.0)min vs. 67.0(64.0, 77.0)min vs. 64.0(60.0, 77.0)min] and the efficiency of enucleation [0.65(0.62, 0.68)g/min vs. 0.84(0.83, 0.94)g/min vs. 0.93(0.82, 1.00)g/min] were statistically significant( P<0.05). The operation time and enucleation time in groups B and C were significantly lower than those in group A, and the enucleation efficiency was significantly higher than that in group A( P<0.05), while there was no significant difference between group B and C. However, the difference of three groups in hemoglobin decrease [8.0(5.0, 11.0)g/L vs. 7.0(2.0, 10.0)g/L vs. 11.0(4.0, 16.0)g/L] and catheter indwelling duration[4.0(2.0, 6.0)d vs. 6.0(3.0, 7.0)d vs. 4.0(3.0, 6.0)d] were not statistically different( P>0.05). All patients were followed up for 6 months after surgery. In three groups, postoperative Q max were 23.2(21.0, 25.1)ml/s, 22.7(21.1, 26.1)ml/s and 22.9(21.5, 25.7)ml/s, IPSS were 6(5, 8), 7(6, 8) and 7(7, 8), QOL were 2(1, 2), 2(1, 2) and 2(1, 2), postvoid residual volume were 20.0(10.0, 25.0)ml, 22.0(15.0, 25.0)ml and 5.0(0, 25.0)ml, respectively, which were all significantly different from that of pre-operation( P<0.05).However, there were no statistically significant differences in the postoperative indicators among the three groups ( P>0.05). No statistical difference was found in postoperative complications among the three groups[26.7%(4/15) vs. 20.0%(3/15) vs. 20.0%(3/15), P>0.05]. Conclusions:LC-THuLEP anchored at six o'clock position of bladder neck was an effective operation in the treatment of BPH with large gland, and the learning curve could be reached after 15 cases.