Assessment of the CYP3A4 Induction Potential by Carbamazepine: Insights from Two Clinical DDI Studies and PBPK Modeling.

In the past, rifampicin was well-established as strong index CYP3A inducer in clinical drug-drug interaction (DDI) studies. However, due to identified potentially genotoxic nitrosamine impurities, it should not any longer be used in healthy volunteer studies. Available clinical data suggest carbamazepine as an alternative to rifampicin as strong index CYP3A4 inducer in clinical DDI studies. Further, physiologically-based pharmacokinetic (PBPK) modeling is a tool with increasing importance to support the DDI risk assessment of drugs during drug development. CYP3A4 induction properties and the safety profile of carbamazepine were investigated in two open-label, fixed sequence, crossover clinical pharmacology studies in healthy volunteers using midazolam as a sensitive index CYP3A4 substrate. Carbamazepine was up-titrated from 100 mg twice daily (b.i.d.) to 200 mg b.i.d., and to a final dose of 300 mg b.i.d. for 10 consecutive days. Mean area under plasma concentration-time curve from zero to infinity (AUC(0-∞)) of midazolam consistently decreased by 71.8% (ratio: 0.282, 90% confidence interval (CI): 0.235-0.340) and 67.7% (ratio: 0.323, 90% CI: 0.256-0.407) in study 1 and study 2, respectively. The effect was adequately described by an internally developed PBPK model for carbamazepine which has been made freely available to the scientific community. Further, carbamazepine was safe and well-tolerated in the investigated dosing regimen in healthy participants. The results demonstrated that the presented design is appropriate for the use of carbamazepine as alternative inducer to rifampicin in DDI studies acknowledging its CYP3A4 inductive potency and safety profile.

Effectiveness of a breastfeeding promotion intervention model based on Society ecosystems Theory for maternal women: a study protocol of randomized controlled trial.

BACKGROUND: Breastfeeding is recognized internationally as the most scientific and effective way to feed infants and young children. According to the World Health Organization in 2022, the exclusive breastfeeding rate within 6 months is 34.1% in China, which is still far from the goal of "more than 60% exclusive breastfeeding rate of infants within 6 months" by 2030 required by China's State Council. It is necessary to promote breastfeeding and provide maternal breastfeeding guidance to increase exclusive breastfeeding. Factors influencing breastfeeding can be explained by the society ecosystems theory, distributed in macro, mezzo and micro systems. The interventions focused on breastfeeding promotion are mainly carried out in the health systems and services, home and family environment, community environment, work environment, policy environment or a combination of these facilities. But there is sparse research on integrating resources in the macro, mezzo and micro systems of maternal breastfeeding processes to promote breastfeeding behavior. A randomized controlled trial will test the effect of a breastfeeding promotion intervention model based on the society ecosystems theory versus usual prenatal and postnatal care on maternal and infant health and the exclusive breastfeeding rate at 6 months. METHODS/DESIGN: The study is a single-blind, parallel design, randomized controlled trial with an intervention group (n = 109) and a control group (n = 109) that compares the effect of a breastfeeding promotion intervention model based on the society ecosystems theory with usual prenatal and postnatal care. The intervention covers macro- (policy, culture), mezzo- (family-hospital-community) and micro- (biological, psychological and social) systems of the maternal breastfeeding process. Infant feeding patterns, neonatal morbidity and physical and mental health of antenatal and postpartum women will be collected at baseline (28 to 35 weeks of gestation), 1-, 4-, and 6-month postpartum. DISCUSSION: This is a multifaceted, multifactorial, and multi-environmental breastfeeding promotion strategy to help mothers and their families learn breastfeeding knowledge and skills. The study provides a new modality for adding breastfeeding interventions to prenatal and postnatal care for healthcare providers in the hospital and the community. TRIAL REGISTRATION: Chinese Clinical Trial Registry at www.chictr.org.cn , ChiCTR2300075795.

Maternal education and support during breastfeeding can increase maternal breastfeeding self-efficacy, promote breastfeeding behaviors, and improve maternal and infant health outcomes. The interventions focused on breastfeeding promotion are mainly carried out in the health systems and services, home and family environment, community environment, work environment, policy environment or a combination of any of these facilities. But there is sparse research on integrating in multifaceted, multifactorial, and multi-environmental resources of maternal breastfeeding processes to help pregnant women and their families learn breastfeeding knowledge and skills. The current study optimizes the existing breastfeeding promotion intervention program and construct a breastfeeding promotion intervention program to correct the public's perception of breastfeeding, increase breastfeeding self-efficacy and improve breastfeeding behavior, thus increasing the breastfeeding duration and improving maternal and infant outcomes. The program includes presenting breastfeeding-related policies and support facilities; prenatal educational sessions combined with theories and skills on breastfeeding, development of lactation, infants feeding and cares for maternal families; postnatal hands-on instruction and WeChat group peer support from hospital; home visits, group counseling and experience sharing from community and one-on-one personalized counseling throughout the intervention. The present study will be conducted to evaluate the effect of breastfeeding promotion intervention including prenatal and postnatal care on the breastfeeding duration, breastfeeding attitudes, knowledge, and self-efficacy, maternal and infant health.

Enterprise marketing strategy using big data mining technology combined with XGBoost model in the new economic era.

The technological development in the new economic era has brought challenges to enterprises. Enterprises need to use massive and effective consumption information to provide customers with high-quality customized services. Big data technology has strong mining ability. The relevant theories of computer data mining technology are summarized to optimize the marketing strategy of enterprises. The application of data mining in precision marketing services is analyzed. Extreme Gradient Boosting (XGBoost) has shown strong advantages in machine learning algorithms. In order to help enterprises to analyze customer data quickly and accurately, the characteristics of XGBoost feedback are used to reverse the main factors that can affect customer activation cards, and effective analysis is carried out for these factors. The data obtained from the analysis points out the direction of effective marketing for potential customers to be activated. Finally, the performance of XGBoost is compared with the other three methods. The characteristics that affect the top 7 prediction results are tested for differences. The results show that: (1) the accuracy and recall rate of the proposed model are higher than other algorithms, and the performance is the best. (2) The significance p values of the features included in the test are all less than 0.001. The data shows that there is a very significant difference between the proposed features and the results of activation or not. The contributions of this paper are mainly reflected in two aspects. 1. Four precision marketing strategies based on big data mining are designed to provide scientific support for enterprise decision-making. 2. The improvement of the connection rate and stickiness between enterprises and customers has played a huge driving role in overall customer marketing.

A mixed-methods study to evaluate the effectiveness and cost-effectiveness of aerobic exercise for primary dysmenorrhea: A study protocol.

BACKGROUND AND PURPOSE: Several studies have evaluated the effects of high-intensity aerobic training (HIAT) on pain severity and quality of life (QoL) among women with primary dysmenorrhea. However, to date, no studies have evaluated the effectiveness of HIAT on academic performance or absenteeism or examined the cost-effectiveness of HIAT relative to other treatments in women with primary dysmenorrhea. Furthermore, the mechanisms underlying aerobic exercise-induced analgesia in primary dysmenorrhea remain unclear. The objectives of this study are to: (1) evaluate the effects of HIAT on absenteeism and academic performance among university students, (2) identify the underlying mechanisms associated with aerobic exercise-induced analgesia in primary dysmenorrhea, and (3) determine the cost-effectiveness of HIAT compared with a wait-list control (WLC) group receiving usual care. METHODS: A sequential, embedded, mixed-methods study design, including a crossover, randomised controlled trial (RCT) and semi-structured focus groups, will be conducted alongside an economic evaluation. A total of 130 women aged 18-24 years will be randomised into either HIAT (n = 65) or wait-list control (n = 65) groups. Primary outcomes will include average pain intensity, absenteeism from university, and academic performance. Primary mediators will include salivary progesterone and prostaglandin F2α levels. Outcome and meditator variables will be assessed at baseline and post-treatment, at 12 and 28 weeks. An economic analysis will be conducted from the societal and healthcare perspective of Hong Kong. Semi-structured focus groups will be conducted at 32 weeks. Of the 130 participants included in the RCT, 70 will be included in the focus groups. STATISTICAL ANALYSIS: All statistical analyses will be performed on an intention-to-treat basis, using SPSS (version 24). Preliminary analysis using an independent samples t-test and a two-sided, unpaired Student's t-test will be performed to exclude carryover effects and identify within-participant differences in outcome variables between the study periods, respectively. Treatment effects will be evaluated using analysis of variance via a mixed-effects model with fixed effects for intervention, period, and sequence. In all models, random effects will include the participants nested within the sequence as a sampling cluster. The mediation effects will be assessed using the Sobel test. The EQ-5D responses will be converted into utility scores to estimate the gain or loss of quality-adjusted life-years. Seemingly unrelated regression analyses will be used to estimate the total cost differences and effect differences. Qualitative data will be analysed using the process of thematic analysis.

Quantitative assessment of carotid artery atherosclerosis by three-dimensional magnetic resonance and two-dimensional ultrasound imaging: a comparison study.

BACKGROUND: It has been proven that magnetic resonance (MR) and ultrasound imaging are useful tools in the quantification of carotid atherosclerotic plaques. However, there are only a few pieces of evidence to illustrate the links of quantitative measurements of carotid plaques between MR and ultrasound imaging. This study looked to compare the quantitative measurements of carotid plaques and investigate their relationship between three-dimensional (3D) MR vessel wall imaging and two-dimensional (2D) ultrasound imaging. METHODS: Seventy-five asymptomatic elderly subjects (mean age: 73.3±5.7 years; 45 males) with carotid atherosclerotic plaques diagnosed by both ultrasound and MR imaging were included in this study. The plaque size, including the maximum wall thickness (Max WT), plaque length, and plaque area, was measured by 3D MR and ultrasound imaging on longitudinal and cross-sectional views. The quantitative assessments of carotid plaque size were compared and correlated between 3D MR and 2D ultrasound imaging. RESULTS: In total, the quantitative measurements of 101 plaques on longitudinal views or 44 plaques on cross-sectional views of both MR and ultrasound imaging were compared. The Max WT of the plaques (longitudinal: 2.9±0.8 vs. 2.4±0.9 mm; cross-sectional: 3.2±1.1 vs. 2.6±0.7 mm) and plaque areas (longitudinal: 24.3±13.4 vs. 17.0±12.7 mm2; cross-sectional: 24.9±24.6 vs. 16.8±13.3 mm2) measured by MR imaging were found to be significantly higher than those measured by ultrasound imaging (all P<0.001). Moderate to strong correlations were found in Max WT, plaque area, plaque length between 3D MR and ultrasound imaging. CONCLUSIONS: The quantitative measurements of carotid plaques using 3D MR and 2D ultrasound are significantly correlated. The plaque area and Max WT measured by 3D MR imaging are more significant than these parameters measured by 2D ultrasound imaging, which might be explained by the resolution of MR imaging and the workflow of measurements.

Assessment of longitudinal distribution of subclinical atherosclerosis in femoral arteries by three-dimensional cardiovascular magnetic resonance vessel wall imaging.

BACKGROUND: Lower extremity peripheral artery disease has become a significant health burden worldwide. Since the treatment strategies can be different if atherosclerotic disease involves different femoral artery segments, it is important to assess plaque distribution among different segments of femoral arteries. We sought to investigate the longitudinal distribution of subclinical femoral artery atherosclerosis in asymptomatic elderly adults using cardiovascular magnetic resonance (CMR) vessel wall imaging. METHODS: Asymptomatic elderly subjects underwent three-dimensional (3D) CMR vessel wall imaging for femoral arteries. The 3D motion sensitized-driven equilibrium prepared rapid gradient-echo (3D-MERGE) sequence was acquired from the common femoral artery to the popliteal artery. The femoral artery was divided into 4 segments: common femoral artery (CFA), proximal superficial femoral artery (pSFA), adductor canal (AC) segment of femoral artery, and popliteal artery (PA). The morphological characteristics including lumen area, wall area, maximum and minimum wall thickness, normalized wall index (NWI = wall area / [lumen area + wall area] × 100%), and eccentricity index ([maximum wall thickness - minimum wall thickness] / maximum wall thickness), luminal stenosis, and presence of atherosclerotic plaque were evaluated and compared between bilateral sides and among different femoral artery segments in each side of femoral artery. The associations between ankle-brachial index (ABI) and cardiovascular risk factors and femoral artery plaque characteristics were also determined. RESULTS: Of 107 recruited subjects (71.9 ± 5.6 years; 48 males), 70 (65.4%) were found to have femoral artery plaques. The atherosclerotic plaques were most frequently found in PA (41.1%) and CFA (40.2%) segments, followed by pSFA (31.8%) and AC (23.4%) segments (p = 0.002). Similarly, PA and CFA segments showed significantly greater maximum wall thickness and eccentricity index compared with pSFA and AC segments (all p < 0.001). Significant differences can be found in NWI among four segments of femoral arteries (p < 0.001) and PA showed the highest NWI (54.8%), followed by AC (54.3%), pSFA (52.4%) and CFA (45.9%) segments. Compared with right femoral artery, left femoral artery had significant smaller lumen area and greater NWI in most of segments (p < 0.002). There were no significant differences in ABI between subjects with and without atherosclerotic plaques (p = 0.161). The presence of subclinical atherosclerotic plaque in femoral arteries was significantly associated with cardiovascular risk factors including age (odds ratio [OR], 1.133; 95% confidence interval [CI], 1.048-1.224, p = 0.002), male gender (OR, 3.914; 95% CI, 1.612-9.501, p = 0.003), and hypertension (OR, 4.000; 95% CI, 1.700-9.411, p = 0.001), respectively. CONCLUSIONS: Subclinical femoral artery atherosclerosis is prevalent in the elderly population, particularly in the left femoral artery and segments of CFA and PA, and is associated with age, male gender and hypertension. Our findings suggest that, for screening subclinical atherosclerosis, more attention needs to be paid to the specific side and segments of femoral arteries, particularly older individuals and those with these cardiovascular disease risk factors.

Scan-rescan reproducibility of quantitative assessment of inflammatory carotid atherosclerotic plaque using dynamic contrast-enhanced 3T CMR in a multi-center study.

BACKGROUND: The aim of this study is to investigate the inter-scan reproducibility of kinetic parameters in atherosclerotic plaque using dynamic contrast-enhanced (DCE) cardiovascular magnetic resonance (CMR) in a multi-center setting at 3T. METHODS: Carotid arteries of 51 subjects from 15 sites were scanned twice within two weeks on 3T scanners using a previously described DCE-CMR protocol. Imaging data with protocol compliance and sufficient image quality were analyzed to generate kinetic parameters of vessel wall, expressed as transfer constant (K trans ) and plasma volume (v p ). The inter-scan reproducibility was evaluated using intra-class correlation coefficient (ICC) and coefficient of variation (CV). Power analysis was carried out to provide sample size estimations for future prospective study. RESULTS: Ten (19.6%) subjects were found to suffer from protocol violation, and another 6 (11.8%) had poor image quality (n=6) in at least one scan. In the 35 (68.6%) subjects with complete data, the ICCs of K trans and v p were 0.65 and 0.28, respectively. The CVs were 25% and 62%, respectively. The ICC and CV for v p improved to 0.73 and 28% in larger lesions with analyzed area larger than 25 mm2. Power analysis based on the measured CV showed that 50 subjects per arm are sufficient to detect a 20% difference in change of K trans over time between treatment arms with 80% power without consideration of the dropout rate. CONCLUSION: The result of this study indicates that quantitative measurement from DCE-CMR is feasible to detect changes with a relatively modest sample size in a prospective multi-center study despite the limitations. The relative high dropout rate suggested the critical needs for intensive operator training, optimized imaging protocol, and strict quality control in future studies.

Progression of experimental lesions of atherosclerosis: assessment by kinetic modeling of black-blood dynamic contrast-enhanced MRI.

Pharmacokinetic modeling of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) is used to noninvasively characterize neovasculature and inflammation in atherosclerotic vessels by estimating perfusion characteristics, such as fractional plasma volume vp and transfer constant Ktrans. DCE-MRI has potential to study the evolution of nascent lesions involving early pathological changes. However, currently used bright-blood DCE-MRI approaches are difficult to apply to small lesions because of the difficulty in separating the signal in the thin vessel wall from the adjacent lumen. By suppressing the lumen signal, black-blood DCE-MRI techniques potentially provide a better tool for early atherosclerotic lesion assessment. However, whether black-blood DCE-MRI can detect temporal changes in physiological kinetic parameters has not been investigated for atherosclerosis. This study of balloon-injured New Zealand White rabbits used a reference-region-based pharmacokinetic model of black-blood DCE-MRI to evaluate temporal changes in early experimental atherosclerotic lesions of the abdominal aorta. Six rabbits were imaged at 3 and 6 months after injury. Ktrans was found to increase from 0.10±0.03 min(-1) to 0.14±0.05 min(-1) (P=0.01). In histological analysis of all twelve rabbits, Ktrans showed a significant correlation with macrophage content (R=0.70, P=0.01). These results suggest black-blood DCE-MRI and a reference-region kinetic model could be used to study plaque development and therapeutic response in vivo.