Treatment of Uterine Fibroid Symptoms with Relugolix Combination Therapy.

BACKGROUND: Uterine fibroids are a common cause of heavy menstrual bleeding and pain. Treatment with the combination of relugolix (an oral gonadotropin-releasing hormone-receptor antagonist), estradiol, and norethindrone acetate, administered once daily, may have efficacy in women with uterine fibroids and heavy bleeding while avoiding hypoestrogenic effects. METHODS: We conducted two replicate international, double-blind, 24-week, phase 3 trials involving women with fibroid-associated heavy menstrual bleeding. Participants were randomly assigned in a 1:1:1 ratio to receive once-daily placebo, relugolix combination therapy (40 mg of relugolix, 1 mg of estradiol, and 0.5 mg of norethindrone acetate), or delayed relugolix combination therapy (40 mg of relugolix monotherapy, followed by relugolix combination therapy, each for 12 weeks). The primary efficacy end point in each trial was the percentage of participants with a response (volume of menstrual blood loss <80 ml and a ≥50% reduction in volume from baseline) in the relugolix combination therapy group, as compared with the placebo group. Key secondary end points were amenorrhea, volume of menstrual blood loss, distress from bleeding and pelvic discomfort, anemia, pain, fibroid volume, and uterine volume. Safety and bone mineral density were assessed. RESULTS: A total of 388 women in trial L1 and 382 in trial L2 underwent randomization. A total of 73% of the participants in the relugolix combination therapy group in trial L1 and 71% of those in trial L2 had a response (primary end point), as compared with 19% and 15%, respectively, of those in the placebo groups (P<0.001 for both comparisons). Both relugolix combination therapy groups had significant improvements, as compared with the placebo groups, in six of seven key secondary end points, including measures of menstrual blood loss (including amenorrhea), pain, distress from bleeding and pelvic discomfort, anemia, and uterine volume, but not fibroid volume. The incidence of adverse events was similar with relugolix combination therapy and placebo. Bone mineral density was similar with relugolix combination therapy and placebo but decreased with relugolix monotherapy. CONCLUSIONS: Once-daily relugolix combination therapy resulted in a significant reduction in menstrual bleeding, as compared with placebo, and preserved bone mineral density in women with uterine fibroids. (Funded by Myovant Sciences; LIBERTY 1 [L1] and LIBERTY 2 [L2] ClinicalTrials.gov numbers, NCT03049735 and NCT03103087, respectively.).

Effects of Total Intravenous Anesthesia on Circadian Rhythms in Patients Undergoing Cardiac Transcatheter Closure.

Objective To evaluate the effects of total intravenous anesthesia on the circadian rhythms in the patients undergoing cardiac transcatheter closure. Methods Thirty patients undergoing cardiac transcatheter closure under elective intravenous anesthesia were included in this study.Paired t-tests were performed to compare the mRNA levels of the genes encoding circadian locomotor output cycles kaput(CLOCK),brain and muscle ARNT-1 like protein-1(BMAL1),cryptochrome 1(CRY1),and period circadian clock 2(PER2),the Munich Chronotype Questionnaire(MCTQ)score,and the Pittsburgh Sleep Quality Index(PSQI)score before and after anesthesia.Multiple stepwise regression analysis was performed to screen the factors influencing sleep chronotype and PSQI total score one week after surgery. Results The postoperative mRNA level of CLOCK was higher [1.38±1.23 vs.1.90±1.47;MD(95%CI):0.52(0.20-0.84),t=3.327,P=0.002] and the postoperative mRNA levels of CRY1 [1.56±1.50 vs.1.13±0.98;MD(95%CI):-0.43(-0.81--0.05),t=-2.319,P=0.028] and PER2 [0.82±0.63 vs.0.50±0.31;MD(95%CI):-0.33(-0.53--0.12),t=-3.202,P=0.003] were lower than the preoperative levels.One week after surgery,the patients presented advanced sleep chronotype [3∶03±0∶59 vs.2∶42±0∶37;MD(95%CI):-21(-40--1),t=-2.172,P=0.038],shortened sleep latency [(67±64)min vs.(37±21)min;MD(95%CI):-30.33(-55.28--5.39),t=-2.487,P=0.019],lengthened sleep duration [(436±83)min vs.(499±83)min;MD(95%CI):62.80(26.93-98.67),t=3.581,P=0.001],increased sleep efficiency [(87.59±10.35)% vs.(92.98±4.27)%;MD(95%CI):5.39(1.21-9.58),t=2.636,P=0.013],decreased sleep quality score [1.13±0.78 vs.0.80±0.71;MD(95%CI):-0.33(-0.62--0.05),t=-2.408,P=0.023],and declined PSQI total score [6.60±3.17 vs.4.03±2.58;MD(95%CI):-2.57(-3.87--1.27),t=-4.039,P<0.001].Body mass index(BMI)(B=-227.460,SE=95.475,t=-2.382,P=0.025),anesthesia duration(B=-47.079,SE=18.506,t=-2.544,P=0.017),and mRNA level of PER2(B=2815.804,SE=1080.183,t=2.607,P=0.015)collectively influenced the sleep chronotype,and the amount of anesthesia medicine(B=0.067,SE=0.028,t=2.385,P=0.024)independently influenced the PSQI one week after surgery. Conclusions Total intravenous anesthesia can improve sleep habits by advancing sleep chronotype.BMI,anesthesia duration,and mRNA level of PER2 collectively influence sleep chronotype one week after surgery.The amount of anesthesia medicine independently influences the PSQI total score one week after surgery.

Once daily oral relugolix combination therapy versus placebo in patients with endometriosis-associated pain: two replicate phase 3, randomised, double-blind, studies (SPIRIT 1 and 2).

BACKGROUND: Endometriosis is a common cause of pelvic pain in women, for which current treatment options are suboptimal. Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, combined with estradiol and a progestin, was evaluated for treatment of endometriosis-associated pain. METHODS: In these two replicate, phase 3, multicentre, randomised, double-blind, placebo-controlled trials at 219 community and hospital research centres in Africa, Australasia, Europe, North America, and South America, we randomly assigned women aged 18-50 years with surgically or directly visualised endometriosis with or without histological confirmation, or with histological diagnosis alone. Participants were eligible if they had moderate to severe endometriosis-associated pain and, during the 35-day run-in period, a dysmenorrhoea Numerical Rating Scale (NRS) score of 4·0 or higher on two or more days and a mean non-menstrual pelvic pain NRS score of 2·5 or higher, or a mean score of 1·25 or higher that included a score of 5 or more on 4 or more days. Women received (1:1:1) once-daily oral placebo, relugolix combination therapy (relugolix 40 mg, estradiol 1 mg, norethisterone acetate 0·5 mg), or delayed relugolix combination therapy (relugolix 40 mg monotherapy followed by relugolix combination therapy, each for 12 weeks) for 24 weeks. During the double-blind randomised treatment and follow-up period, all patients, investigators, and sponsor staff or representatives involved in the conduct of the study were masked to treatment assignment. The co-primary endpoints were responder rates at week 24 for dysmenorrhoea and non-menstrual pelvic pain, both based on NRS scores and analgesic use. Efficacy and safety were analysed in the modified intent-to-treat population (randomised patients who received ≥1 study drug dose). The studies are registered at ClinicalTrials.gov (SPIRIT 1 [NCT03204318] and SPIRIT 2 [NCT03204331]) and EudraCT (SPIRIT 1 [2017-001588-19] and SPIRIT 2 [2017-001632-19]). Eligible patients who completed the SPIRIT studies could enrol in a currently ongoing 80-week open-label extension study (SPIRIT EXTENSION [NCT03654274, EudraCT 2017-004066-10]). Database lock for the on-treatment duration has occurred, and post-treatment follow-up for safety, specificially for bone mineral density and menses recovery, is ongoing at the time of publication. FINDINGS: 638 patients were enrolled into SPIRIT 1 and randomly assigned between Dec 7, 2017, and Dec 4, 2019, to receive relugolix combination therapy (212 [33%]), placebo (213 [33%]), or relugolix delayed combination therapy (213 [33%]). 623 patients were enrolled into SPIRIT 2 and were randomly assigned between Nov 1, 2017 and Oct 4, 2019, to receive relugolix combination therapy (208 [33%]), placebo (208 [33%]), or relugolix delayed combination therapy (207 [33%]). 98 (15%) patients terminated study participation early in SPIRIT 1 and 115 (18%) in SPIRIT 2. In SPIRIT 1, 158 (75%) of 212 patients in the relugolix combination therapy group met the dysmenorrhoea responder criteria compared with 57 (27%) of 212 patients in the placebo group (treatment difference 47·6% [95% CI 39·3-56·0]; p<0·0001). In SPIRIT 2, 155 (75%) of 206 patients in the relugolix combination therapy group were dysmenorrhoea responders compared with 62 (30%) of 204 patients in the placebo group (treatment difference 44·9% [95% CI 36·2-53·5]; p<0·0001). In SPIRIT 1, 124 (58%) of 212 patients in the relugolix combination therapy group met the non-menstrual pelvic pain responder criteria versus 84 (40%) patients in the placebo group (treatment difference 18·9% [9·5-28·2]; p<0·0001). In SPIRIT 2, 136 (66%) of 206 patients were non-menstrual pelvic pain responders in the relugolix combination therapy group compared with 87 (43%) of 204 patients in the placebo group (treatment difference 23·4% [95% CI 13·9-32·8]; p<0·0001). The most common adverse events were headache, nasopharyngitis, and hot flushes. There were nine reports of suicidal ideation across both studies (two in the placebo run-in, two in the placebo group, two in the relugolix combination therapy group, and three in the delayed relugolix combination therapy group). No deaths were reported. Least squares mean percentage change in lumbar spine bone mineral density in the relugolix combination therapy versus placebo groups was -0·70% versus 0·21% in SPIRIT 1 and -0·78% versus 0·02% in SPIRIT 2, and in the delayed relugolix combination group was -2·0% in SPIRIT 1 and -1·9% in SPIRIT 2. Decreases in opioid use were seen in treated patients as compared with placebo. INTERPRETATION: Once-daily relugolix combination therapy significantly improved endometriosis-associated pain and was well tolerated. This oral therapy has the potential to address the unmet clinical need for long-term medical treatment for endometriosis, reducing the need for opioid use or repeated surgical treatment. FUNDING: Myovant Sciences.

LIBERTY randomized withdrawal study: relugolix combination therapy for heavy menstrual bleeding associated with uterine fibroids.

BACKGROUND: In the pivotal LIBERTY 1 and 2 trials and long-term extension study, once-daily relugolix combination therapy (40 mg relugolix, 1 mg estradiol, 0.5 mg norethindrone acetate) reduced menstrual blood loss volume and pain among women with uterine fibroids. Relugolix combination therapy was well tolerated with preservation of bone mineral density through 52 weeks. OBJECTIVE: This study aimed to report the 2-year relugolix combination therapy efficacy and safety results of the phase 3 LIBERTY randomized withdrawal study. STUDY DESIGN: Women with uterine fibroid-associated heavy menstrual bleeding who completed the 24-week LIBERTY 1 or 2 trials, followed by the 28-week long-term extension study (up to 52 weeks total treatment), and who met the responder criteria (menstrual blood loss volume <80 mL and ≥50% reduction from pivotal study baseline at week 48 [week 24 of long-term extension]) were randomized in a 1:1 ratio to either blinded treatment with relugolix combination therapy or placebo for 52 weeks (total treatment period, 104 weeks). For women who had a relapse of heavy menstrual bleeding during the study (menstrual blood loss volume ≥80 mL), open-label relugolix combination therapy was offered. The primary endpoint was the proportion of women who maintained menstrual blood loss volume <80 mL through week 76 (week 24 of randomized withdrawal study). Secondary endpoints included time to menstrual blood loss volume ≥80 mL, proportion of women who maintained a menstrual blood loss volume of <80 mL through week 104 (over the 52-week randomized treatment period), the proportion of women who achieved or maintained amenorrhea at week 76 at the end of treatment, and the change in Uterine Fibroid Symptom-Quality of Life Bleeding and Pelvic Discomfort Scale and symptom severity scores. Analyses were performed for the modified intent-to-treat population, including all randomized women who received ≥1 dose of the study drug. RESULTS: Of the 229 randomized women (relugolix combination therapy, n=115; placebo, n=114), 228 received the study drug and 175 (76.7%) completed the randomized withdrawal study. Through week 76, 78.4% of women on relugolix combination therapy maintained menstrual blood loss volume <80 mL vs 15.1% in the placebo group (difference, 63.4%; 95% confidence interval, 52.9%-73.9%; P<.0001). At week 104, 69.8% of women on relugolix combination therapy maintained menstrual blood loss volume <80 mL vs 11.8% in the placebo group (difference, 58.0%; 95% confidence interval, 47.0%-69.1%; P<.0001). Through week 104, 88.3% of women on placebo relapsed with heavy menstrual bleeding (median time to relapse, 5.9 weeks). Among the 89 women in the placebo group who relapsed and received open-label rescue treatment, 87 women responded to relugolix combination therapy with a menstrual blood loss volume <80 mL. The proportion of women who achieved or maintained amenorrhea were 57.4% vs 13.3% at week 76 (difference, 44.1%; 95% confidence interval, 33.10%-55.1%; P<.0001) and 58.3% vs 10.6% at week 104 (difference, 47.6%; 95% confidence interval, 37.0%-58.3%; nominal P<.0001) for relugolix combination therapy and the placebo group, respectively. Relugolix combination therapy was generally well tolerated; no new safety signals were identified, and the adverse event profile over the second year was consistent with that reported through the first year of treatment. Bone mineral density remained stable in women who received relugolix combination therapy from week 52 to week 104. In women continuously treated with relugolix combination therapy up to 2 years, bone mineral density was generally preserved. CONCLUSION: After 2 years of treatment with relugolix combination therapy, there was evidence of durability of the effect in maintaining low menstrual blood loss volume in women with symptomatic uterine fibroids. Most women had return of heavy menstrual bleeding and associated symptoms after treatment cessation, which improved upon retreatment with relugolix combination therapy. Relugolix combination therapy was well tolerated, the adverse event profile remained consistent, and the mean bone mineral density was generally preserved through 2 years of treatment.

Quality of life with relugolix combination therapy for uterine fibroids: LIBERTY randomized trials.

BACKGROUND: Symptomatic uterine fibroids are burdensome to live with; they are associated with symptom-related distress, affect daily activities, and reduce health-related quality of life. The LIBERTY randomized clinical trials showed that oral relugolix combination therapy (40 mg relugolix, 1 mg estradiol, and 0.5 mg norethindrone acetate once daily) markedly improved fibroid-associated symptoms and conditions, including heavy menstrual bleeding, pain, and anemia, and was well-tolerated. OBJECTIVE: This study aimed to evaluate the effect of relugolix combination therapy on the symptom burden and health-related quality of life among women with uterine fibroids. STUDY DESIGN: Two replicate, multinational, double-blind, 24-week, randomized, placebo-controlled, phase 3 studies, LIBERTY 1 and LIBERTY 2, were conducted in premenopausal women with uterine fibroid-associated heavy menstrual bleeding (≥80 mL per cycle for 2 cycles or ≥160 mL during 1 cycle). The symptom burden and health-related quality of life were secondary endpoints and were assessed using the validated Uterine Fibroid Symptom and Quality of Life questionnaire, which the participants completed at baseline and at week 12 and 24 of treatment. For this secondary analysis, the pooled LIBERTY 1 and LIBERTY 2 data set was used. The Uterine Fibroid Symptom and Quality of Life questionnaire is made up of a Symptom Severity scale and a Health-Related Quality of Life scale, the latter of which includes 6 subscales focusing on the following aspects of daily life: concern, activities, energy or mood, control, self-consciousness, and sexual function. The Revised Activities subscale of the Health-Related Quality of Life scale addresses the impact of uterine fibroids on physical and social activities. Symptom burden was also assessed via the Bleeding and Pelvic Discomfort subscale, a patient-reported outcome measure derived from the Uterine Fibroid Symptom Severity scale that focuses on distress from key uterine fibroid symptoms, which was a key secondary endpoint. Least squares mean changes from baseline to week 24 in the Symptom Severity scale, Bleeding and Pelvic Discomfort subscale, overall Health-Related Quality of Life scale, and the respective subscales were compared between the relugolix combination therapy and placebo groups. Responder analyses of the proportion of women who experienced a clinically meaningful change from baseline to week 24 were conducted for the Bleeding and Pelvic Discomfort and the activity subscales. A stratified Cochran-Mantel-Haenszel test, adjusted for stratification factors (region [North America vs rest of world] and baseline menstrual blood loss volume), was used for treatment comparisons. RESULTS: Across both trials, 509 women were randomized to the relugolix combination therapy or placebo groups (April 2017-December 2018). Participants on relugolix combination therapy showed a statistically significant reduction in symptom severity (-33.5 vs -12.1; nominal P<.0001) and the Bleeding and Pelvic Discomfort subscale from baseline to week 24 when compared with those on placebo treatment (-48.4 vs -17.4; nominal P<.0001). Overall, the total Health-Related Quality of Life scores improved significantly from baseline to week 24 in the relugolix combination therapy group when compared with the placebo (+37.6 vs +13.1; nominal P<.0001). Responder analyses demonstrated that more women treated with relugolix combination therapy reported a clinically meaningful reduction in the Bleeding and Pelvic Discomfort subscale and an improvement in physical and social activities when compared with those treated with the placebo (nominal P<.0001). CONCLUSION: After 24 weeks of treatment with relugolix combination therapy, women with symptomatic uterine fibroids experienced substantial improvements in health-related quality of life with all subscales showing improvement, including emotional well-being, physical and social activities, and sexual function. In addition, women reported substantial reductions in the overall symptom burden and distress caused by key fibroid-associated symptoms.

Efficacy and safety of janagliflozin monotherapy in Chinese patients with type 2 diabetes mellitus inadequately controlled on diet and exercise: A multicentre, randomized, double-blind, placebo-controlled, Phase 3 trial.

AIMS: To evaluate the efficacy and safety of janagliflozin, a selective renal sodium-glucose cotransporter-2 inhibitor, as monotherapy in drug-naive Chinese patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: This Phase 3 trial included a 24-week, multicentre, randomized, double-blind, placebo-controlled period, followed by a 28-week extension period. A total of 432 patients with glycated haemoglobin (HbA1c) levels ≥7.0% (53 mmol/mol) and ≤10.5% (91 mmol/mol) were randomized (1:1:1) to receive once-daily placebo, 25 mg or 50 mg janagliflozin. After 24 weeks, patients on placebo were switched and re-randomized (1:1) to 25 mg or 50 mg janagliflozin, whereas patients on janagliflozin maintained the initial therapy. The primary endpoint was change from baseline in HbA1c after 24 weeks. RESULTS: At Week 24, the placebo-adjusted least squares mean changes in HbA1c were -0.80% (95% confidence interval [CI] -0.98% to -0.62%)/-8.7 mmol/mol (95% CI -10.7 mmol/mol to -6.8 mmol/mol) and -0.88% (95% CI -1.06% to -0.70%)/-9.6 mmol/mol (95% CI -11.6 mmol/mol to -7.7 mmol/mol), respectively (P < 0.001 for both). A higher proportion of patients achieved HbA1c <7.0% (53 mmol/mol) with janagliflozin 25 mg and janagliflozin 50 mg compared with placebo (47.2%, 49.3%, and 23.5%, respectively). Both janagliflozin doses significantly decreased fasting plasma glucose, 2-hour postprandial glucose, body weight and systolic blood pressure, as well as increased high-density lipoprotein (HDL) cholesterol and insulin sensitivity compared with placebo (P < 0.05 for all). The trends in improvement of these variables were sustained during the 28-week extension period. Overall incidences of adverse events were 67.8%, 71.5% and 60.7% with janagliflozin 25 mg, janagliflozin 50 mg and placebo, respectively. The incidence of urinary tract infections and genital fungal infections was low. No severe hypoglycaemia or ketoacidosis occurred. CONCLUSIONS: Janagliflozin 25 mg and 50 mg monotherapy once-daily effectively improved glycaemic control, reduced body weight and blood pressure, improved HDL cholesterol and insulin sensitivity, and was generally well tolerated.

Semi-Supervised Semantic Segmentation of Remote Sensing Images Based on Dual Cross-Entropy Consistency.

Semantic segmentation is a growing topic in high-resolution remote sensing image processing. The information in remote sensing images is complex, and the effectiveness of most remote sensing image semantic segmentation methods depends on the number of labels; however, labeling images requires significant time and labor costs. To solve these problems, we propose a semi-supervised semantic segmentation method based on dual cross-entropy consistency and a teacher-student structure. First, we add a channel attention mechanism to the encoding network of the teacher model to reduce the predictive entropy of the pseudo label. Secondly, the two student networks share a common coding network to ensure consistent input information entropy, and a sharpening function is used to reduce the information entropy of unsupervised predictions for both student networks. Finally, we complete the alternate training of the models via two entropy-consistent tasks: (1) semi-supervising student prediction results via pseudo-labels generated from the teacher model, (2) cross-supervision between student models. Experimental results on publicly available datasets indicate that the suggested model can fully understand the hidden information in unlabeled images and reduce the information entropy in prediction, as well as reduce the number of required labeled images with guaranteed accuracy. This allows the new method to outperform the related semi-supervised semantic segmentation algorithm at half the proportion of labeled images.

[Inhibitory Effects and Mechanisms of Three Benzodiazepines on Helicobacter pylori].

Objective To explore the inhibitory effects and mechanisms of benzodiazepines on Helicobacter pylori (Hp).Methods The Hp international standard strain ATCC43504 was treated with benzodiazepines diazepam,midazolam,and remimazolam,respectively.The treatments with amoxicillin and clarithromycin were taken as the positive controls,and that with water for injection as the negative control.The inhibition zone of each drug was measured by the disk diffusion method.The minimum inhibitory concentration(MIC)and minimum bactericidal concentration(MBC)of each drug against Hp were determined.Hp suspension was configured and treated with diazepam and midazolam,respectively.The bacterial suspension without drug added was used as the control group.The concentration of K+ in each bacterial suspension was measured by an automatic biochemical analyzer before drug intervention(T0)and 1(T1),2(T2),3(T3),4(T4),5(T5),6(T6),and 7 h(T7)after intervention.Hp urease was extracted and treated with 1/2 MIC diazepam,1 MIC diazepam,2 MIC diazepam,1/2 MIC midazolam,1 MIC midazolam,2 MIC midazolam,1 mg/ml acetohydroxamic acid,and water for injection,respectively.The time required for the rise from pH 6.8 to pH 7.7 in each group was determined by the phenol red coloring method.Results The inhibition zones of diazepam,midazolam,remimazolam,amoxicillin,clarithromycin,and water for injection against Hp were 52.3,42.7,6.0,72.3,60.8,and 6.0 mm,respectively.Diazepam and midazolam showed the MIC of 12.5 µg/ml and 25.0 µg/ml and the MBC of 25 µg/ml and 50 µg/ml,respectively,to Hp.The concentrations of K+ in the diazepam,midazolam,and control groups increased during T1-T7 compared with those at T0(all P<0.01).The concentration of K+ in diazepam and midazolam groups during T1-T4 was higher than that in the control group(all P<0.01).The time of inhibiting urease activity in the 1/2 MIC diazepam,1 MIC diazepam,2 MIC diazepam,1/2 MIC midazolam,1 MIC midazolam,and 2 MIC midazolam groups was(39.86±5.11),(36.52±6.65),(38.58±4.83),(39.25±6.19),(36.36±4.61),and(35.81±6.18)min,respectively,which were shorter than that in the acetohydroxamic acid group(all P<0.01)and had no significance differences from that in the water for injection group(all P>0.05).Conclusion Diazepam and midazolam exerted inhibitory effects on Hp,which may be related to the cleavage of Hp cells rather than inhibiting urease.

[Excess Oxygen Supply for Different Time Periods Affect Energy Metabolism in Rat Alveolar Epithelial Type â ¡ Cells].

Objective To observe the effect of excess oxygen supply for different time periods on the mitochondrial energy metabolism in alveolar epithelial type Ⅱ cells. Methods Rat RLE-6TN cells were assigned into a control group (21% O2 for 4 h) and excess oxygen supply groups (95% O2 for 1,2,3,and 4 h,res-pectively).The content of adenosine triphosphate (ATP),the activity of mitochondrial respiratory chain complex V,and the mitochondrial membrane potential were determined by luciferase assay,micro-assay,and fluorescent probe JC-1,respectively.Real-time fluorescence quantitative PCR was employed to determine the mRNA levels of NADH dehydrogenase subunit 1 (ND1),cytochrome b (Cytb),cytochrome C oxidase subunit I (COXI),and adenosine triphosphatase 6 (ATPase6) in the core subunits of mitochondrial respiratory chain complexes Ⅰ,Ⅲ,Ⅳ,and Ⅴ,respectively. Results Compared with the control group,excess oxygen supply for 1,2,3,and 4 h down-regulated the mRNA levels of ND1 (q=24.800,P<0.001;q=13.650,P<0.001;q=9.869,P<0.001;q=20.700,P<0.001),COXI (q=16.750,P<0.001;q=10.120,P<0.001;q=8.476,P<0.001;q=14.060,P<0.001),and ATPase6 (q=22.770,P<0.001;q=15.540,P<0.001;q=12.870,P<0.001;q=18.160,P<0.001).Moreover,excess oxygen supply for 1 h and 4 h decreased the ATPase activity (q=9.435,P<0.001;q=11.230,P<0.001) and ATP content (q=5.615,P=0.007;q=5.029,P=0.005).The excess oxygen supply for 2 h and 3 h did not cause significant changes in ATPase activity (q=0.156,P=0.914;q=3.197,P=0.116) and ATP content (q=0.859,P=0.557;q=1.273,P=0.652).There was no significant difference in mitochondrial membrane potential among the groups (F=0.303,P=0.869). Conclusion Short-term excess oxygen supply down-regulates the expression of the core subunits of mitochondrial respiratory chain complexes and reduces the activity of ATPase,leading to the energy metabolism disorder of alveolar epithelial type Ⅱ cells.

Capture Instead of Release: Defect-Modulated Radionuclide Leaching Kinetics in Metal-Organic Frameworks.

Comparison of defect-controlled leaching-kinetics modulation of metal-organic frameworks (MOFs) and porous functionalized silica-based materials was performed on the example of a radionuclide and radionuclide surrogate for the first time, revealing an unprecedented readsorption phenomenon. On a series of zirconium-based MOFs as model systems, we demonstrated the ability to capture and retain >99% of the transuranic 241Am radionuclide after 1 week of storage. We report the possibility of tailoring radionuclide release kinetics in MOFs through framework defects as a function of postsynthetically installed organic ligands including cation-chelating crown ether-based linkers. Based on comprehensive analysis using spectroscopy (EXAFS, UV-vis, FTIR, and NMR), X-ray crystallography (single crystal and powder), and theoretical calculations (nine kinetics models and structure simulations), we demonstrated the synergy of radionuclide integration methods, topological restrictions, postsynthetic scaffold modification, and defect engineering. This combination is inaccessible in any other material and highlights the advantages of using well-defined frameworks for gaining fundamental knowledge necessary for the advancement of actinide-based material development, providing a pathway for addressing upcoming challenges in the nuclear waste administration sector.

Development of the Bleeding and Pelvic Discomfort Scale for Use in Women With Heavy Menstrual Bleeding Associated With Uterine Fibroids.

OBJECTIVES: This study aimed to define a cardinal symptom burden measure based on items from the Uterine Fibroid Symptom and Quality of Life questionnaire for use as a clinical trial endpoint. METHODS: Exploratory factor analysis was computed to assess the Uterine Fibroid Symptom and Quality of Life symptom severity scale factor structure, using phase 2 data. Pooled blinded data from phase 3 studies were used for the confirmatory factor analysis and the psychometric evaluation of the new measure. Exit interviews in 30 patients from phase 3 studies provided additional qualitative evidence. A meaningful change threshold was determined using anchor-based analyses supported by patient feedback in the exit interviews. RESULTS: Three factors emerged from the exploratory factor analysis. Factor 1, called the bleeding and pelvic discomfort (BPD) scale, consists of cardinal symptoms, measuring menstrual distress owing to heavy bleeding, passing blood clots, and feeling tightness or pressure in pelvic area. Patients generally understood the items in the scale and the recall period as intended. The BPD scale had good item performance and internal consistency reliability, strong item-to-total correlations, good item discrimination, known-groups validity, and ability to detect change. A 20-point change on the BPD scale was determined as the clinically meaningful change threshold. CONCLUSIONS: The BPD scale assesses symptom burden owing to bleeding, passing blood clots, and pelvic pressure. The subscale is based on a subset of items selected to measure the cardinal symptoms of uterine fibroids in a clinical trial setting. The responder threshold evaluates whether patients experience a meaningful treatment benefit over the on-treatment period.

Carotid artery corrected flow time and respiratory variations of peak blood flow velocity for prediction of hypotension after induction of general anesthesia in elderly patients.

BACKGROUND: Postinduction hypotension is closely related to postoperative complications. Elderly patients with compromised cardiovascular compensatory reserve are more susceptible to hypotension after induction of general anesthesia. This study investigated whether the carotid artery corrected flow time (FTc) and respiratory variation of peak blood flow velocity in the common carotid artery (ΔVpeak) could predict postinduction hypotension in elderly patients. METHODS: This prospective observational study included elderly patients aged 65 to 75 who were scheduled for elective surgery under general anesthesia with ASA physical status class of I-II, without cardiovascular disease, hypertension, diabetes, or obesity. Anesthesia was induced by midazolam, sufentanil, and etomidate and was maintained by sevoflurane. The carotid artery FTc and ΔVpeak were measured by ultrasound before induction of anesthesia. Hemodynamic data were recorded before induction and then during the first 10 min after induction. RESULTS: Ninety-nine patients were included in the final analysis, of whom 63 developed postinduction hypotension. The area under the receiver operating characteristic curves was 0.87 (0.78 to 0.93) for carotid artery FTc and 0.67 (0.56 to 0.76) for ΔVpeak, respectively. The optimal cutoff value for predicting postinduction hypotension was 379.1 ms for carotid artery FTc, with sensitivity and specificity of 72.2 and 93.7%, respectively. The best cutoff value was 7.5% for ΔVpeak, with sensitivity and specificity of 55.6 and 75.0%, respectively. CONCLUSIONS: The carotid artery FTc is a reliable predictor of postinduction hypotension in elderly patients with ASA status of I or II, without cardiovascular disease, hypertension, diabetes, or obesity. Elderly patients with a carotid artery FTc less than 379.1 ms before anesthesia have a higher risk of postinduction hypotension. TRIAL REGISTRATION: Clinical Trial Registry on August 2nd, 2020 ( www.chictr.org.cn ; ChiCTR2000035190).

Comparison of different sedatives in children before general anaesthesia for selective surgery: A network meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: It is estimated that 60% of children undergoing anaesthesia develop severe preoperative anxiety. The anxiety is associated with adverse reactions. Sedatives such as dexmedetomidine, midazolam, clonidine, ketamine, and melatonin can be used as premedication against preoperative anxiety. However, no consensus has been reached on the choice of pre-anaesthetic sedatives in children before selective surgery. Therefore, the current network meta-analysis (NMA) was carried out to evaluate different sedatives in children aged between 1 and 7 before general anaesthesia for selective surgery. METHODS: Randomized clinical trials (RCTs) were retrieved from Pubmed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science databases from inception to October 22, 2021. Primary outcomes showed satisfactory sedation at parent separation and also at induction or mask acceptance. Secondary outcomes were those related to added benefits and side effects. The present NMA was conducted using the R software. Results of the study were reported as Relative Risk (RR) or Mean Difference (MD) at a 95% credible intervals (CrIs). RESULTS AND DISCUSSION: A total of 48 trials were included in the present study. It was found that the effectiveness of dexmedetomidine, midazolam, clonidine, and ketamine were superior to that of placebo in satisfactory sedation at parent separation and induction or mask acceptance. There was no significant difference between melatonin and placebo in satisfactory sedation at induction or mask acceptance. Dexmedetomidine, ketamine, clonidine, and melatonin were superior to placebo in reducing emergence delirium (ED). In addition, midazolam prolonged the length of stay in the post anaesthesia care unit (PACU) as compared with placebo. Dexmedetomidine caused a significant reduction in systolic blood pressure (SBP) and heart rate (HR). Nevertheless, it was noted that the hemodynamic changes were roughly within safety limits. WHAT IS NEW AND CONCLUSION: It was evident that the studied drugs can provide effective sedation with exception of melatonin and placebo. However, it was found that midazolam, ketamine, and clonidine lead to several side effects. The findings of the present study supported that dexmedetomidine, especially intranasal administration, has potential in the optimal selection of the sedatives for premedication in children. This is because the drug has effective sedation, reduced incidence of ED, side effects, and onset time.

[Overwork Affects Extracellular Matrix of Arterial Vessel Wall in Rats].

Objective To explore the effect of overwork (OW) on extracellular matrix of arterial vessel wall in rats. Methods Random number grouping method was employed to assign 18 Sprague-Dawley rats into three groups(n=6):the control group(no special treatment),group OW(forced swimming twice a day for 15 days),and sleep deficiency(SD)+OW group(in addition to forced swimming twice a day,the rats were put on the platforms in water to limit sleep for 15 days).On the 16th day,the abdominal aorta and common carotid artery were collected after blood sampling from heart under deep anesthesia.A part of the abdominal aorta sample was taken for Masson staining of collagen fiber,and Verhoeff-Van Gieson staining was carried out for the elastic fiber of common carotid artery.Image J was employed for the quantitative analysis of collagen fiber and elastic fiber content.The expression of collagen 1(Col-1) protein was quantified by immunohistochemistry and the ultrastructure of vascular matrix was examined by transmission electron microscopy.The other part of the abdominal aorta sample was used to determine the mRNA levels of matrix metalloproteinase(MMP)-1,MMP-2,MMP-9,tissue inhibitor of metalloproteinases-1(TIMP-1),and Col-1 by quantitative real-time polymerase chain reaction. Results Compared with that in control group,the content of collagen fiber in groups OW and SD+OW had no significant change(all P>0.05);the content of elastic fiber in groups OW and SD+OW decreased(all P<0.001) and had no significant difference between each other(P>0.05).The vascular vessel wall of group OW showed slight fiber breakage,while that of group SD+OW presented wormhole-like or spongy fiber fragmentation.The mRNA levels of MMP-1 and MMP-2 in groups OW and SD+OW had no significant difference between each other(P>0.05) but were higher than that in control group(all P<0.001).The mRNA levels of MMP-9 and TIMP-1 had no significant difference among the three groups(all P>0.05).Groups OW and SD+OW had lower mRNA level(all P<0.001) and protein level(all P<0.001) of Col-1 than control group,while the mRNA and protein levels of Col-1 had no significant difference between groups OW and SD+OW(P>0.05). Conclusion OW can reduce the content of Col-1 and elastic fibers in the extracellular matrix of arterial vessels,destroy the elastic lamina of vascular wall,up-regulate the expression of MMP-1 and MMP-2,thereby injuring arterial vessels.

IL-37bΔ1-45 suppresses the migration and invasion of endometrial cancer cells by targeting the Rac1/NF-κB/MMP2 signal pathway.

Endometrial carcinoma is one of the most common malignancies in the female reproductive system. Interleukin-37 (IL-37) is a newly discovered anti-inflammatory factor belonging to the IL-1 family. IL-37 has five different isoforms, and IL-37b is the most biologically functional subtype. In recent years, the protective roles of IL-37 in different cancers, including lung and liver cancers, have been successively reported. IL-37 also plays an important role in some gynecological diseases such as endometriosis, adenomyosis, and cervical cancer. However, the role and mechanism of IL-37b, especially the mature form of IL-37b, in endometrial carcinoma have not been elucidated. The present study demonstrated that IL-37 protein was downregulated in endometrial carcinoma cells compared with the control endometrium. IL-37b did not affect the proliferation and colony-forming ability of endometrial cancer cells. A mature form of IL-37b (IL-37bΔ1-45) effectively suppressed the migration and invasion of endometrial cancer cells by decreasing the expression of matrix metalloproteinase 2 (MMP2) via Rac1/NF-κB signal pathway. However, it did not affect epithelial-mesenchymal transition (EMT) or filamentous actin (F-actin) depolymerization of endometrial cancer cells. IL-37bΔ1-45 attenuated tumor metastasis in a peritoneal metastatic xenograft model of endometrial cancer. To sum up, these results suggested IL-37b could be involved in the pathogenesis of endometrial carcinoma and provide a novel target for the diagnosis and treatment of endometrial carcinoma.

Higenamine mitigates interleukin-1ß-induced human nucleus pulposus cell apoptosis by ROS-mediated PI3K/Akt signaling.

Intervertebral disc degeneration (IDD) is a natural problem linked to the inflammation. Higenamine exerts multiple pharmacological properties in inflammation-related disorders. Our study aimed to explore the function of higenamine on interleukin (IL)-1ß-caused apoptosis of human nucleus pulposus cells (HNPCs). Cell apoptosis was investigated by TUNEL and flow cytometry. Apoptosis-related biomarkers were determined by qRT-PCR or Western blotting. The protein in the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling was measured by Western blotting. We found that higenamine showed little effect on cell apoptosis, but mitigated IL-1ß-caused apoptosis in a dose-dependent pattern. Higenamine attenuated IL-1ß-induced decrease of Bcl-2 and increase of Bax and cleaved caspase-3. Higenamine did not affect the reactive oxygen species (ROS) level and the PI3K/Akt signaling, but attenuated IL-1ß-induced ROS production and inhibition of the PI3K/Akt signaling. IL-1ß repressed the activation of the PI3K/Akt pathway, but ROS inhibition using N-acetylcysteine (NAC) rescued this pathway. The PI3K/Akt signaling suppression using LY294002 reversed the inhibitive effect of higenamine on IL-1ß-caused apoptosis, and this effect was weakened by ROS inhibition. In conclusion, higenamine attenuates IL-1ß-caused apoptosis of HNPCs via ROS-mediated PI3K/Akt pathway.

Physiologically Based Pharmacokinetic Models Are Effective Support for Pediatric Drug Development.

Pediatric drug development faces many difficulties. Traditionally, pediatric drug doses are simply calculated linearly based on the body weight, age, and body surface area of adults. Due to the ontogeny of children, this simple linear scaling may lead to drug overdose in pediatric patients. The physiologically based pharmacokinetic (PBPK) model, as a mathematical model, contributes to the research and development of pediatric drugs. An example of a PBPK model guiding drug dose selection in pediatrics has emerged and has been approved by the relevant regulatory agencies. In this review, we discuss the principle of the PBPK model, emphasize the necessity of establishing a pediatric PBPK model, introduce the absorption, distribution, metabolism, and excretion of the pediatric PBPK model, and understand the various applications and related prospects of the pediatric PBPK model.

Lung injury induced by short-term mechanical ventilation with hyperoxia and its mitigation by deferoxamine in rats.

BACKGROUND: Long-term mechanical ventilation with hyperoxia can induce lung injury. General anesthesia is associated with a very high incidence of hyperoxaemia, despite it usually lasts for a relatively short period of time. It remains unclear whether short-term mechanical ventilation with hyperoxia has an adverse impact on or cause injury to the lungs. The present study aimed to assess whether short-term mechanical ventilation with hyperoxia may cause lung injury in rats and whether deferoxamine (DFO), a ferrous ion chelator, could mitigate such injury to the lungs and explore the possible mechanism. METHODS: Twenty-four SD rats were randomly divided into 3 groups (n = 8/group): mechanical ventilated with normoxia group (MV group, FiO2 = 21%), with hyperoxia group (HMV group, FiO2 = 90%), or with hyperoxia + DFO group (HMV + DFO group, FiO2 = 90%). Mechanical ventilation under different oxygen concentrations was given for 4 h, and ECG was monitored. The HMV + DFO group received continuous intravenous infusion of DFO at 50 mg•kg- 1•h- 1, while the MV and HMV groups received an equal volume of normal saline. Carotid artery cannulation was carried out to monitor the blood gas parameters under mechanical ventilation for 2 and 4 h, respectively, and the PaO2/FiO2 ratio was calculated. After 4 h ventilation, the right anterior lobe of the lung and bronchoalveolar lavage fluid from the right lung was sampled for pathological and biochemical assays. RESULTS: PaO2 in the HMV and HMV + DFO groups were significantly higher, but the PaO2/FiO2 ratio were significantly lower than those of the MV group (all p < 0.01), while PaO2 and PaO2/FiO2 ratio between HMV + DFO and HMV groups did not differ significantly. The lung pathological scores and the wet-to-dry weight ratio (W/D) in the HMV and HMV + DFO groups were significantly higher than those of the MV group, but the lung pathological score and the W/D ratio were reduced by DFO (p < 0.05, HMV + DFO vs. HMV). Biochemically, HMV resulted in significant reductions in Surfactant protein C (SP-C), Surfactant protein D (SP-D), and Glutathion reductase (GR) levels and elevation of xanthine oxidase (XOD) in both the Bronchoalveolar lavage fluid and the lung tissue homogenate, and all these changes were prevented or significantly reverted by DFO. CONCLUSIONS: Mechanical ventilation with hyperoxia for 4 h induced oxidative injury of the lungs, accompanied by a dramatic reduction in the concentrations of SP-C and SP-D. DFO could mitigate such injury by lowering XOD activity and elevating GR activity.

Sample size allocation in multiregional equivalence studies.

With the increasing globalization of drug development, the multiregional clinical trial (MRCT) has gained extensive use. The data from MRCTs could be accepted by regulatory authorities across regions and countries as the primary sources of evidence to support global marketing drug approval simultaneously. The MRCT can speed up patient enrollment and drug approval, and it makes the effective therapies available to patients all over the world simultaneously. However, there are many challenges both operationally and scientifically in conducting a drug development globally. One of many important questions to answer for the design of a multiregional study is how to partition sample size into each individual region. In this paper, two systematic approaches are proposed for the sample size allocation in a multiregional equivalence trial. A numerical evaluation and a biosimilar trial are used to illustrate the characteristics of the proposed approaches.

Rhodium (II) complex with 2-benzoylpyridine, a novel potential chemotherapeutic drug, induces cell cycle arrest and apoptosis in HepG2 cells.

Rhodium (II) complex with 2-benzoylpyridine (Rh(L)2Cl2) is a new, synthetic, active metal-complex, which is produced by the reaction of 2-benzoylpyridine (L) with rhodium chloride hydrate (RhCl3·nH2O). The crystal structure was determined by X-ray diffraction which is mono-nuclear. In order to explore the biological properties of the novel complex, a series of studies were performed. The results showed that Rh(L)2Cl2 had the anti-tumor activity in HepG2 and other cell lines and has been shown to induce G1 cell cycle arrest and apoptosis in HepG2 cells. The anti-cancer effect of Rh(L)2Cl2 is regulated by increased expression of caspase-3 and PARP via the mitochondrial and the death receptor pathways. Bcl-2 family proteins might play an important role in the Rh(L)2Cl2-induced changes in these two pathways. Further studies indicated that Rh(L)2Cl2 increased the level of reactive oxygen species (ROS), but that Rh(L)2Cl2-induced apoptosis was ROS-independent. In conclusion, Rh(L)2Cl2 is a potential new anti-tumor drug, which induces HepG2 cell death via the mitochondrial and death receptor pathways and has no obvious toxicity to normal liver cell.