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The current therapies to treat hepatitis B virus (HBV) infection are limited. Recently, clustered regularly interspaced short palindromic repeat (CRISPR) systems, originally identified in bacteria and archaea, have been found to consist of an RNA-based adaptive immune system that degrades complimentary sequences of invading plasmids and viruses. Here, we studied the effects of the CRISPR/CRISPR-associated Cas9 system that was targeted to the surface antigen (HBsAg)-encoding region of HBV, both in a cell culture system and in vivo . The HBsAg levels in the media of the cells and in the sera of mice were analyzed by a quantitative enzyme-linked immunosorbent assay. The HBV DNA levels were assessed by quantitative PCR and HBsAg expression in mouse livers was assessed by an immunohistochemical assay. The amount of HBsAg secreted in the cell culture and mouse serum was reduced by CRISPR/Cas9 treatment. Immunohistochemistry analyses showed almost no HBsAg-positive cells in the liver tissue of CRISPR/Cas9-S1+X3-treated mice. The CRISPR/Cas9 system efficiently produced mutations in HBV DNA. Thus, CRISPR/Cas9 inhibits HBV replication and expression in vitro and in vivo and may constitute a new therapeutic strategy for HBV infection.

Preoperative sedation is critical to alleviate anxiety in children undergoing neurosurgery, but the role of remimazolam is still uncertain such as its unestablished dosing and safety. This study was aimed to determine the 90% effective dose (ED90) of remimazolam for moderate sedation in this pediatric population. This dose-finding study enrolled children aged 3 months to 6 years scheduled for neurosurgery. The up-and-down method (k-in-a-row, k= 6) was employed to investigate the ED90 of remimazolam for moderate sedation. According to the k-in-a-row rule, one patient received a predefined dose of remimazolam and the dosing assignment of the next patient depended on whether the former patient reached moderate sedation or not. Moderate sedation was assessed using the modified Observer's Assessment of Alertness/Sedation (MOAA/S). Remimazolam doses ranged from 0.05mg/kg to 0.35mg/kg with a step gradient of 0.05mg/kg. The ED90 and 95% confidence interval (CI) were calculated by centered isotonic regression. Secondary outcomes included drug-related adverse events, the incidence of emergence delirium (ED), and changes in brain network connectivity which were monitored by functional near-infrared spectroscopy (fNIRS). Forty-eight children were enrolled with a median age of 20.5 (9.0, 35.0) months. The ED90 of remimazolam for moderate sedation was 0.28 (95% CI 0.24-0.42) mg/kg. The incidence of drug-related adverse events was about 12.5%, including respiratory depression and hiccup. The incidence of ED was 62.2%. fNIRS showed increased connectivity in right frontal lobe-right occipital lobe, right frontal lobe-left occipital lobe, and right frontal lobe-left parietal lobe (all P values < 0.05 after correction by false discovery rate). This study reported the ED90 of remimazolam for moderate sedation in neurosurgical children. These results provided important information for the use of remimazolam in children with neurologic disease.

To evaluate the pharmacokinetics (PK), safety, and bioequivalence of two formulations of apixaban in healthy Chinese subjects under fasting and fed conditions. A single-center, randomized, open, single-dose, two-period crossover PK study was carried out under fasting and fed conditions in 64 healthy subjects enrolled in either the fasting (36 subjects) or the fed (28 subjects) arms of the study. Subjects received a single oral dose of 2.5 mg apixaban tablets as test (T) or reference (R) formulation. The primary PK parameters determined were the area under the plasma concentration-time curve from zero to t and ∞ (AUC and AUC ) and the maximal plasma concentration (C ). Safety was assessed mainly from the occurrence of adverse events (AEs). A single drop-out in the fed arm of the trial was excluded from the statistical evaluation. The 90% confidence intervals (CIs) for the geometric mean ratio (GMR) for T/R using AUC were 95.4 - 100.9% and 97.8 - 103.8%, and for AUC were 95.3 - 100.6% and 98.3 - 104.3% under fasting (36 subjects) and fed (27 subjects) conditions, respectively. Similarly, the 90% CIs for C were 94.6 - 103.1% and 88.8 - 102.0% under fasting (36 subjects) and the fed (27 subjects) conditions, respectively. Therefore, the 90% CIs for the T/R AUC and C ratios were within the standard range for bioequivalence (80.0 - 125.0%). There were no serious adverse events (SAEs). The test and reference 2.5 mg apixaban tablets were bioequivalent and both showed good tolerability and safety.

Background Cloperastine is a pivotal antibechic widely prescribed to treat cough caused by respiratory diseases. The present trial evaluated the pharmacokinetics (PK), bioequivalence (BE) and safety effects of the generic test (T) tablet of cloperastine after single-dose administration of cloperastine, compared with the original reference (R) tablet of cloperastine. Objective The purpose of this trial was to compare the PK, BE and safety of a test 10 mg versus the reference 10 mg formulation of cloperastine under fasting and postprandial conditions in healthy Chinese volunteers. Methods A single-centre, randomised, open, double-cycle, self-crossover, single oral administration Phase I trial was performed in healthy Chinese volunteers. A total of 60 subjects were enrolled in either the fasting (28 subjects) or the postprandial condition (32 subjects). Subjects randomly received a single dose of the T or R preparation (10 mg dose). Plasma concentrations of cloperastine were analysed by a validated LC-MS/MS method. The primary endpoints of the PK parameters were the area under the plasma concentration-time curve from zero to 72 h (AUC 0–72h ), under the plasma concentration-time curve from zero to infinity (AUC 0–∞ ) and the maximal plasma concentration ( C max ). The equivalence standard range (80.0–125.0%) was used to evaluate the BE of the two preparations. The safety parameter as secondary endpoint was mainly evaluated by the occurrence of adverse events (AEs). Results A total of 25 and 30 subjects in the fasting and postprandial conditions completed this clinical trial, respectively. The geometric mean ratio (GMR) of the T/R for the C max , AUC 0–72h and AUC 0–∞ were 102.1%, 103.8% and 104.0% in the fasting condition, respectively. In the postprandial condition, the GMR of the T/R for the C max , AUC 0–72h and AUC 0–∞ were 94.2%, 98.8% and 99.0%, respectively. All the values fell within the range (80.0–125.0%). The C max and AUC 0–72h values of the T and R preparations in fasting and postprandial conditions were not statistically significant ( P > 0.05). Furthermore, no serious adverse events (SAEs) occurred during the whole trial. Conclusions The T and R preparations were bioequivalent under both conditions. Food has no significant effect on the absorption of cloperastine. Moreover, T and R preparations were well tolerated. The trial registration number (TRN) and date of registrations were CTR20212515, 13 October 2021.

Aim To investigate whether single-nucleotide polymorphisms (SNPs) in the P450 oxidoreductase (POR) gene were correlated with interindividual variations in cytochrome P450 (CYP) 2B6 activity. Methods Thirty-six healthy volunteers who tested CYP2B6 and POR polymorphisms were enrolled in the study. CYP2B6 activity was measured by bupropion hydroxylation with LC/MS/MS. The ratio of hydroxybupropion versus bupropion (AUC_hyd/AUC_bup) in terms of area under the time-concentration curve (AUC) was used to represent the CYP2B6 activity. Results The volunteers carrying CYP2B6*1/*1 showed a significantly higher mean AUC_hyd/ AUC_bup than those CYP2B6*1/*6 and CYP2B6*6/*6 variants (15.66 ± 1.65 vs. 9.25 ± 1.92, P  = 0.008 and 15.66 ± 1.65 vs. 8.21 ± 1.74, P  = 0.006, respectively). POR rs2868177 (6593 A > G) AA homozygotes showed a significantly lower mean AUC_hyd/ AUC_bup than that of POR rs2868177 AG heterozygotes or GG homozygotes (8.13 ± 1.37 vs. 12.15 ± 2.97, P  = 0.005 and 8.13 ± 1.37 vs. 17.59 ± 3.25, P  = 0.001, respectively). Moreover, POR rs2868177 AG heterozygotes and GG homozygotes showed a significantly increased mean AUC_hyd/AUC_bup than AA homozygotes in the CYP2B6*1/*1 and CYP2B6*6 carriers (16.40 ± 2.01 vs. 12.40 ± 1.45, P  = 0.006 and 10.65 ± 1.47 vs. 6.54 ± 1.25, P  = 0.004, respectively). Meanwhile, a strong correlation between the genetic variations ( POR rs2868177 and CYP2B6*6 ) and AUC_hyd/ AUC_bup was found ( P  = 0.009 and P  = 0.001, respectively). There was no significant difference in the mean AUC_hyd/AUC_bup among different POR *28 genotypes ( P  > 0.05) . Conclusion POR rs2868177 and CYP2B6*6 variants contribute to the interindividual variability in human CYP2B6 activity, which may affect the disposition and interaction of other CYP2B6 substrate drugs.

In the present paper, the influence of α-Al2O3 seeds and sintering methods on elongated grain growth and fracture toughness is investigated. The preparation of alumina ceramics started with commercial aluminum hydroxide. Abrasives were introduced to the starting materials by wet-grinding of high-purity alumina milling balls. Abrasives, playing the role of seeds, lowered the transformation temperature of aluminum hydroxide to alumina. Microstructures with elongated grains were developed by hot-pressing for the above calcined powders containing α-Al2O3 seeds, and alumina grain shapes changed with the amount of seeds introduced. However, only equiaxed grains were observed for the samples pressureless sintered. Fracture toughness of the alumina ceramics was dramatically improved by elongated grains. For the sample hot-pressed at 1600°C for 2 h under 40 MPa pressure, fracture toughness reached 7.1 MPa·m1/2, which is much higher than that of normal alumina ceramics without elongated grains. In addition, high flexural strength of 630 MPa for the hot-pressed samples was also obtained.

In this paper, an oscillated model, which results from the shortage action in market economy with elastic replacement of goods, is obtained. And some natural relations between the model and a typically oscillatory model are established. The results can interpret some market phenomena and provide the theoretical tools for the economic program.

Background Guselkumab is a selective interleukin (IL)-23 inhibitor targeting the IL-23p19 subunit. In the phase 3b COSMOS trial, guselkumab demonstrated efficacy in treating participants with active psoriatic arthritis (PsA) and inadequate response (IR; lack of efficacy or intolerance) to tumor necrosis factor inhibitors (TNFi). Methods Adults with active PsA (≥ 3 swollen joints,  ≥ 3 tender joints) and IR to one or two TNFi (TNFi-IR) were randomized 2:1 to guselkumab at Weeks 0, 4, then every 8 weeks (Q8W) or placebo➔guselkumab Q8W at Week 24 with possible early escape at Week 16. Levels of serum cytokines, including interferon γ (IFNγ), IL-10, and tumor necrosis factor α (TNFα); T helper 17 (Th17) effector cytokines IL-17A, IL-17F, and IL-22; and acute phase proteins C-reactive protein (CRP), IL-6, and serum amyloid A (SAA), were assessed and compared with demographically matched healthy controls; guselkumab pharmacodynamics through Week 24 were also assessed. Associations between baseline biomarker levels and 1) baseline disease activity (28-joint disease activity score using CRP [DAS28-CRP], psoriasis area and severity index [PASI], and % body surface area [BSA] affected by psoriasis) and 2) clinical response (including  ≥ 20% improvement in American College of Rheumatology criteria [ACR20] response) at Week 24 were assessed. Results Baseline serum levels of IL-6, IL-10, IL-17A, IL-17F, IL-22, TNFα, and IFNγ were significantly higher in COSMOS TNFi-IR participants than in healthy controls. Baseline IL-6, CRP, and SAA levels were associated with baseline DAS28-CRP. IL-17A and IL-17F levels were associated with baseline PASI score and psoriasis BSA. Baseline swollen or tender joint counts did not associate with baseline biomarker levels. At Week 24, significant decreases from baseline in CRP, SAA, IL-17A, IL-17F, and IL-22 levels were seen in guselkumab-, but not placebo-, treated participants. IL-17F and IL-22 levels at Week 24 in guselkumab-treated participants did not significantly differ from those of healthy controls. Guselkumab-treated participants achieving ACR20 response at Week 24 exhibited higher baseline IL-22 and IFNγ levels versus nonresponders. Conclusions Results from COSMOS participants with active, TNFi-IR PsA suggest guselkumab reduces levels of effector cytokines associated with the IL-23/IL-17 pathway, including those associated with baseline arthritis and skin disease activity. Trial registration ClinicalTrials.gov: NCT03796858.

Background The objective of this post-hoc analysis was to assess the efficacy and safety of upadacitinib in psoriatic arthritis (PsA) patients with axial involvement. Methods Post-hoc analysis of SELECT-PsA 1 and SELECT-PsA 2 in patients randomized to upadacitinib 15 mg (UPA15), placebo (switched to UPA15 at week 24), or adalimumab 40 mg (ADA; SELECT-PsA 1 only). Axial involvement was determined by investigator judgement (yes or no; based on the totality of available clinical information, such as duration and characteristics of back pain, age of onset, and previous lab investigations and imaging, if available) alone, or investigator judgement and patient-reported outcome (PRO)-based criteria (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] ≥ 4 and BASDAI Q2 ≥ 4). Efficacy outcomes that describe axial disease activity, including BASDAI endpoints, such as change from baseline in the overall BASDAI score or proportion of patients achieving BASDAI50 (≥ 50% improvement from baseline), as well as Ankylosing Spondylitis Disease Activity Score (ASDAS) endpoints, such as mean change from baseline in overall ASDAS or proportion of patients achieving ASDAS inactive disease or low disease activity, were evaluated at weeks 12, 24, and 56, with nominal P -values shown. Treatment-emergent adverse events (TEAEs) are summarized through week 56. Results 30.9% of patients in SELECT-PsA 1 and 35.7% in SELECT-PsA 2 had axial involvement by investigator judgement alone; 22.6% (SELECT-PsA 1) and 28.6% (SELECT-PsA 2) had axial involvement by investigator judgement and PRO-based criteria. Greater proportions of patients achieved BASDAI50 with UPA15 versus placebo using either criterion, and versus ADA using investigator judgement alone, at week 24 in SELECT-PsA 1 (investigator alone: UPA15, 59.0%, placebo, 26.9%, P  < 0.0001, ADA, 44.1%, P  = 0.015; investigator and PRO-based: UPA15, 60.4%, placebo, 29.3%, P  < 0.0001, ADA, 47.1%, P  = 0.074), with comparable findings in SELECT-PsA 2. Similar results were observed with UPA15 for additional BASDAI and ASDAS endpoints at weeks 12 and 24, with improvements maintained at week 56. Rates of TEAEs were generally similar across sub-groups irrespective of axial involvement status. Conclusions PsA patients with axial involvement determined by predefined criteria showed greater BASDAI and ASDAS responses with UPA15 versus placebo, and numerically similar/greater responses versus ADA. Safety results were generally comparable between patients with or without axial involvement. Trial registration ClinicalTrials.gov: SELECT-PsA 1, NCT03104400; SELECT-PsA 2, NCT0310437.

Colles fracture, a common wrist injury, often requires surgical intervention. After surgery, patients may experience persistent pain and reduced wrist function, potentially resulting in long-term disability. In clinical practice, traditional Chinese medicine practitioners frequently use Ru-Yi-Jin-Huang-Saan (RYJHS) to treat such patients in Taiwan. RYJHS is a traditional Chinese herbal formula with a history spanning centuries, primarily used topically for the treatment of bone fractures and the promotion of healing. However, there is currently a lack of substantial clinical evidence supporting its efficacy in the management of postsurgical Colles fractures. To the best of our knowledge, there are no studies evaluating the clinical effectiveness of RYJHS. This study aims to investigate the therapeutic potential of RYJHS in postsurgical Colles fracture cases. An additional objective is to provide an alternative treatment option for postoperative patients unable to take anti-inflammatory and pain relief medications. This is a protocol for a randomized, double-blind, placebo-controlled trial. A total of 100 postoperative patients with Colles fracture, aged 20-80 years, will be recruited for this study. They will be randomly assigned to either the experimental or control group in a 1:1 allocation ratio. Both groups will receive standard postoperative Colles fracture treatment. The primary outcome measure will assess wrist functional recovery using the Patient-Rated Wrist Evaluation score. Secondary outcomes will include C-reactive protein levels and ultrasound measurements of wrist swelling. All of these examinations will be assessed at baseline, 3 days after surgery, and 6 days after surgery. In addition, the Dyshidrotic Eczema Area and Severity Index will be used to monitor for adverse skin reactions. This protocol was registered at ClinicalTrials.gov on December 6, 2022. It was performed in accordance with the approved guidelines and regulations of the participating institutions. Recruitment began in May 2023, with data collection expected to conclude in May 2025. Study completion is expected in December 2025. This is the first protocol discussing the assessment of the therapeutic efficacy and safety of topical traditional Chinese medicine in patients after fracture surgery. The protocol will establish an integrated care model combining both traditional Chinese medicine and Western medicine for postsurgical fracture cases. ClinicalTrials.gov NCT05638360; https://clinicaltrials.gov/ct2/show/NCT05638360. DERR1-10.2196/56849.