Effect of deuteration on the single dose pharmacokinetic properties and postoperative analgesic activity of methadone

Although methadone is effective in the management of acute pain, the complexity of its absorption-distribution-metabolism-excretion profile limits its use as an opioid of choice for perioperative analgesia. Because deuteration is known to improve the pharmacokinetic, pharmacodynamic and toxicological properties of some drugs, here we characterized the single dose pharmacokinetic properties and post-operative analgesic efficacy of d₉-methadone.The pharmacokinetic profiles of d₉-methadone and methadone administered intravenously to CD-1 male mice revealed that deuteration leads to a 5.7- and 4.4-fold increase in the area under the time-concentration curve and maximum concentration in plasma, respectively, as well as reduction in clearance (0.9 ± 0.3 L/h/kg vs 4.7 ± 0.8 L/h/kg). The lower brain-to-plasma ratio of d₉-methadone compared to that of methadone (0.35 ± 0.12 vs 2.05 ± 0.62) suggested that deuteration decreases the transfer of the drug across the blood-brain barrier. The estimated LD₅₀ value for a single intravenous dose of d₉-methadone was 2.1-fold higher than that for methadone. Moreover, d₉-methadone outperformed methadone in the efficacy against postoperative pain by primarily activating peripheral opioid receptors. Collectively, these data suggest that the replacement of three hydrogen atoms in three methyl groups of methadone altered its pharmacokinetic properties, improved safety, and enhanced its analgesic efficacy.     

Risk factors and a simple scoring system for predicting bowel resection in infants with NEC

Background and aimsWe intended to investigate the predictors for bowel resection in infants with necrotizing enterocolitis (NEC). We further developed a scoring system for better predicting bowel resection.MethodsA total of 207 infants who underwent surgical management at Children's Hospital, Chongqing Medical University between April 2008 and December 2020 were identified for the following investigation. Bowel resection was reviewed among the infants who underwent the procedure. Potential parameters related to bowel resection were explored using a multiple logistic regression method, and then a scoring system was developed.ResultsAmong the 207 patients who underwent operative intervention that were reviewed, 109 infants underwent bowel resection. Multivariate logistic regression analysis showed that birth weight, hypotension, neutropenia, pneumoperitoneum, acidosis, and intestinal wall thickness were predictors related to the occurrence of bowel resection. A 6-point scoring system was further developed based on the obtained total coefficient, and the infants could be divided into low-, moderate- and high-risk groups according to cut values of 7 and 13.ConclusionThe results of this study demonstrated that severe NEC features and low birth weight were associated with bowel resection. The risk scoring system could accurately separate infants that were suspected to have bowel loss during surgery.     

TOPSIS法和秩和比法模糊联合在基本公共卫生服务质量综合评价中的应用研究

背景国家基本公共卫生服务项目的开展是我国新医改的重要举措，自2009年国家基本公共卫生服务项目开展后，其服务经费与服务项目不断扩增，由于涉及指标较多，覆盖面较广，探寻科学、客观、全面的基本公共卫生服务综合评价方法十分必要。目的探索适宜的基本公共卫生服务质量综合评价方法，通过质量评价为调整相关政策和提高服务质量提供依据。方法2019年2—4月，采用多阶段立意抽样方式从Z省南部、中部和北部地区共选取24家社区卫生服务中心（乡镇卫生院）作为评价对象，记为机构A~X。采用逼近理想解排序法（TOPSIS法）、秩和比法及二者模糊联合的方法对24家社区卫生服务中心（乡镇卫生院）2018年基层医疗卫生机构基本公共卫生服务质量进行综合评价（参考2018年国家基本公共卫生服务项目选取12项评价指标）。结果在TOPSIS法评价中，Ci值排名前三名的为A（0.917 4）、C（0.875 9）和G（0.787 9），Ci值排名后三名的为I（0.414 2）、W（0.413 7）和N（0.407 7）。在秩和比法评价中，RSR值排名前三名的为A（0.890 6）、G（0.765 6）和C（0.711 8），RSR值排名后三名的为V（0.381 9）、W（0.362 8）和K（0.357 6）。根据模糊集理论，将W1Ci+W2RSR值进行排序，依据"择多原则"，排名前三名的分别为A、C和G，排名后三名的分别为I、K和W，这与TOPSIS法和秩和比法的评价结果基本一致。结论TOPSIS法和秩和比法模糊联合得到的评价结果及影响因素与其他研究结果相一致，并且两者联用能克服单一使用TOPSIS法或秩和比法的局限性，适宜在基本公共卫生服务质量评价中推广应用。     

Cervical cancer in Morocco: A systematic review

BackgroundThis systematic review aims to determine the epidemiological profile, etiology and risk factors, prevention, diagnosis, treatment, cost-effectiveness, survival, and quality of life related to cervical cancer in Morocco.MethodsThis study was conducted according to the recommendations of the "preferred reporting items for systematic reviews and meta-analysis." The PubMed, ScienceDirect, Springer, Web of Science data bases were used, as was Google Scholar for the grey literature. The review protocol was registered in the PROSPERO register (CRD42021235241).ResultsFifty studies were selected. The mean age was 49.31 ±6.3 years. HPV infection prevalence ranged from 13.30% to 76%, with a peak in HIV-positive women. Acceptability of the HPV vaccine was higher among parents (35% and 82%) than among adolescents (16.9% to 46.6%). Knowledge of the vaccine and its price are two key factors related to vaccine acceptability among parents. This systematic review highlights that the fact that few eligible women (not more than 11%) were participating in the cervical cancer screening program. Moroccan women's level of knowledge and awareness regarding cervical cancer screening was low, negatively impacting their use of such screening tools, as illustrated by the high percentage (mean 76.32% ± 17.21) of women who had never been screened for cervical cancer. Treatment was the most significant component of the global care budget (95.87%), with an annual cost of $13,027,609. Five-year overall survival ranged from 41.3% to 73.6%, with higher survival rates for patients diagnosed at an earlier stage (77.3–85% for stage I). Lastly, low quality of life was observed in women with tumors at an advanced stage who had received brachytherapy and lacked social support.ConclusionsSubjects that require further investigation include Moroccan women's knowledge, attitudes, and awareness, especially among those at high risk of developing cervical cancer, and its impact on their quality of life and survival.     

Inhibition of autophagy enhances apoptosis induced by bortezomib in AML cells

Bortezomib is a novel proteasome inhibitor, which has been successfully used to treat mantle cell lymphoma and multiple myeloma. However, the direct effects of bortezomib on acute promyelocytic leukaemia (APL) have not been fully investigated. In the present study, the WST-8 assay, western blotting, flow cytometry, monodansylcadaverine staining and transmission electron microscopy were performed. It was demonstrated that bortezomib treatment induced a time- and dose-dependent decrease in the viability of NB4 cells. Bortezomib treatment induced cell apoptosis in NB4 cells, as assessed by Annexin V/propidium iodide analysis, and the detection of cleaved caspase-3, cleaved poly(ADP-ribose) polymerase, Bax and Bcl-2 expression. Furthermore, bortezomib treatment induced autophagy in NB4 cells, as indicated by autophagosome formation, p62 degradation, LC3-I to LC3-II conversion and formation of acidic autophagic vacuoles. Notably, autophagy induced by bortezomib was initiated prior to apoptosis. Inhibition of autophagy by knocking down Beclin-1 expression increased bortezomib-induced apoptosis in NB4 cells. Therefore, the present study revealed that the combination of bortezomib and autophagy inhibition may be a potential treatment strategy for APL.