Integration of preclinical and clinical data with pharmacokinetic modeling and simulations to characterize the disposition of orally-active antiparasitic prodrugs and metabolites: prediction of the dose-exposure relationship in humans

Prediction of the disposition and selection of the appropriate dosage regimen of drug candidates prior to clinical studies presents a major challenge in drug development. In this dissertation project, a multiexperimental approach, including Caco-2 cells, rat isolated perfused livers (IPLs), rat and human sandwich-cultured hepatocytes (SCH), a plasma/tissue binding assay, and pharmacokinetic modeling was employed to 1) examine mechanisms underlying differences in systemic exposure of two active metabolites (furamidine and CPD-0801) of respective antiparasitic prodrugs (pafuramidine and CPD-0868), and 2) quantitatively integrate preclinical and clinical data to elucidate the dose-plasma/exposure relationship in humans using pafuramidine/furamidine as a model prodrug/active metabolite pair. Pafuramidine and CPD-0868 exhibited similar permeability properties in Caco-2 monolayers when the basolateral compartment was supplemented with 4% bovine serum albumin, suggesting that the difference in systemic exposure of active metabolites was not due to the difference in intestinal permeabilities between the prodrugs. Hepatic accumulation of both active metabolites was extensive (>95% of total formed) in rat IPLs and SCH. Compared to furamidine, the extent of formation and perfusate/medium exposure of CPD-0801 was greater, by ≤ 2.5- and ≥ 7-fold, respectively. The unbound fraction of both active metabolites in rat liver (fu,L) was lower than that in plasma and perfusate by ≥ 24-fold; fu,L of CPD-0801 was 5-fold higher than that of furamidine (1.6 versus 0.3%). These observations suggested that intrahepatic binding influences the disposition of these active metabolites. A higher fu,L) mostly explained the enhanced perfusate exposure of CPD-0801 compared to furamidine in rat IPLs. A strong concordance between rat IPL and SCH data substantiated SCH as a useful tool to study the hepatobiliary disposition of these compounds. Pafuramidine/furamidine preclinical and clinical data were used as a training set to develop whole-body semi-physiologically-based pharmacokinetic (PBPK) models for rats and humans. The PBPK models suggested that the intestine may contribute to pre-systemic furamidine formation. Based on the prodrug dose-plasma/exposure relationship predicted by the human model, a dosage regimen of pafuramidine, 40 mg/day, was proposed. This dissertation project, through integration of preclinical and clinical data with pharmacokinetic modeling and simulations, provided a framework to guide dose-ranging studies in humans for next-in-class antiparasitic compounds

Psychometric evaluation of the Chinese version of the fear of pregnancy scale: a translation and validation study

IntroductionMany women experience fear toward pregnancy, which can impact their desire to have children and the national birth rate. Thus, assessing women’s fear of pregnancy is of great importance. However, there is currently no specialized tool for assessing women’s fear of pregnancy in China. The purpose of this study is to translate the Fear of Pregnancy Scale into Chinese and test its reliability and validity among women of childbearing age.MethodsUsing convenience sampling combined with a snowballing method, a cross-sectional survey was conducted on 886 women of childbearing age in two cities in China. The translation was strictly carried out according to the Brislin model. Item analysis, validity analysis, and reliability analysis were employed for psychometric assessment.ResultsThe Chinese version of the Fear of Pregnancy Scale comprises 28 items. Exploratory factor analysis extracted four factors with a cumulative variance contribution rate of 72.578%. Confirmatory factor analysis showed: NFI = 0.956, CFI = 0.986, GFI = 0.927, IFI = 0.986, TLI = 0.985, RMSEA = 0.032, and χ2/df = 1.444. The scale’s Cronbach’s α coefficient is 0.957, split-half reliability is 0.840, and test–retest reliability is 0.932.ConclusionThe Chinese version of the Fear of Pregnancy Scale possesses robust psychometric properties and can assess the degree of pregnancy fear among Chinese women of childbearing age. It provides a reference for formulating relevant policies in the prenatal care service system and implementing targeted intervention measures

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

RIGID-FLEXIBLE COUPLING DYNAMIC STRESS AND FATIGUE ANALYSIS OF DRIVING WHEELS UNDER TYPICAL WORKING CONDITIONS (MT)

In order to solve the problem that the driving wheel teeth are easy to break in the harsh working environment, this paper used RecurDyn software to establish the virtual prototype model of the driving wheel crawler mechanism with different number of teeth, and used the finite element software WorkBench to make the driving wheel teeth flexible, and established the rigid-flexible coupling model with the driving wheel teeth as the flexible body. Under the typical working conditions of the Spreader, the driving wheel was simulated, and the contact load between the driving wheel and the crawler shoe and the stress nephogram of the driving wheel teeth with different number of teeth are obtained. On this basis, the fatigue life of the nine tooth driving wheel teeth was analyzed. The results show that: with the increase of the number of driving wheel teeth, the maximum stress in the root area of the driving wheel teeth will decrease; the root area of the driving wheel teeth is the weakest position of the teeth, and the fatigue life is the shortest under the steering condition. The research results provide the basis for the design optimization of the driving wheel

Lidocaine effects on neutrophil extracellular trapping and angiogenesis biomarkers in postoperative breast cancer patients with different anesthesia methods: a prospective, randomized trial

Abstract Background Anesthesia techniques and drug selection may influence tumor recurrence and metastasis. Neutrophil extracellular trapping (NETosis), an immunological process, has been linked to an increased susceptibility to metastasis in individuals with tumors. Furthermore, recurrence may be associated with vascular endothelial growth factor A (VEGF-A), a mediator of angiogenesis. This study investigates the impact of lidocaine (combined with sevoflurane or propofol anesthesia ) during breast cancer surgery inhibits the expression of biomarkers associated with metastasis and recurrence (specifically H3Cit, NE, MPO, MMP-9 and VEGF-A). Methods We randomly assigned 120 women undergoing primary or invasive breast tumor resection to receive one of four anesthetics: sevoflurane (S), sevoflurane plus i.v. lidocaine (SL), propofol (P), and propofol plus i.v. lidocaine (PL). Blood samples were collected before induction and 3 h after the operation. Biomarkers associated with NETosis (citrullinated histone H3 [H3Cit], myeloperoxidase [MPO], and neutrophil elastase [NE]) and angiogenesis were quantified using enzyme-linked immunosorbent assays. Results Patient and breast tumor characteristics, along with perioperative management, did not differ between study groups. In intra-group comparisons, S and P groups demonstrated a statistically significant increase in post-operative MPO (S group: 10.39[6.89–17.22] vs. 14.31[8.55–20.87] ng ml-1, P = 0.032; P group: 9.45[6.73–17.37] vs. 14.34[9.87–19.75] ng ml-1, P = 0.035)and NE(S group: 182.70[85.66-285.85] vs. 226.20[91.85-391.65] ng ml-1, P = 0.045; P group: 154.22[97.31–325.30] vs. 308.66[132.36-483.57] ng ml-1, P = 0.037) concentrations compared to pre-operative measurements, whereas SL and PL groups did not display a similar increase. H3Cit, MMP-9, and VEGF-A concentrations were not significantly influenced by the anesthesia techniques and drugs. Conclusions Regardless of the specific technique employed for general anesthesia, there was no increase in the postoperative serum concentrations of MPO and NE after perioperative lidocaine infusion compared to preoperative serum concentrations. This supports the hypothesis that intravenous lidocaine during cancer surgery aimed at achieving a cure may potentially decrease the likelihood of recurrence. Further interpretation and discussion of clinical implications are warranted, emphasizing the significance of these findings in the context of cancer surgery and recurrence prevention. Clinical trial registration ChiCTR2300068563

Antenatal Depressive Symptoms and the Risk of Preeclampsia or Operative Deliveries: A Meta-Analysis

<div><p>Background</p><p>The purpose of the study was to investigate the association between depression and/or depressive symptoms during pregnancy and the risk of an operative delivery or preeclampsia, and to quantify the strength of the association.</p><p>Methods</p><p>A search of the PubMed, SCI/SSCI, Proquest PsycARTICLES and CINAHL databases was supplemented by manual searches of bibliographies of key retrieved articles and review articles. We aimed to include case control or cohort studies that reported data on antenatal depression and /or depressive symptoms and the risk of an operative delivery and/or preeclampsia.</p><p>Results</p><p>Twelve studies with self-reported screening instruments were eligible for inclusion with a total of 8400 participants. Seven articles that contained 4421 total participants reported the risk for an operative delivery, and five articles that contained 3979 total participants reported the risk for preeclampsia. The pooled analyses showed that both operative delivery and preeclampsia had a statistically significant association with antenatal depressive symptoms (RR = 1.24; 95% CI, 1.14 to 1.35, and OR = 1.63, 95% CI, 1.32 to 2.02, respectively). When the pre-pregnancy body mass indices were controlled in their initial design, the risk for preeclampsia still existed (OR = 1.48, 95% CI, 1.04 to 2.01), while the risk for an operative delivery became uncertain (RR = 1.01, 95% CI, 0.85 to 1.22).</p><p>Conclusions</p><p>Antenatal depressive symptoms are associated with a moderately increased risk of an operative delivery and preeclampsia. An abnormal pre-pregnancy body mass index may modify this association.</p></div

Quality Assessment of the Nine Included Studies.

<p>*1 indicates case definition or ascertainment of exposure; 2, representativeness of the cases or exposed cohort; 3, selection of controls or non-exposed cohort; 4, description of the control source or demonstration of outcome of interest in cohort; 5A, based on the most important factor to select and study controls; 5B, based on a second crucial factor to select and study controls; 6, assessment of exposure or outcome by blinded interview or record; 7, same method of ascertainment used for cases and controls or adequate follow-up period; 8, evenly distributed non-response rate or adequacy of follow-up of cohorts</p><p>Quality Assessment of the Nine Included Studies.</p