Process development of a New Haemophilus influenzae type b conjugate vaccine and the use of mathematical modeling to identify process optimization possibilities

Vaccination is one of the most successful public health interventions being a cost‐effective tool in preventing deaths among young children. The earliest vaccines were developed following empirical methods, creating vaccines by trial and error. New process development tools, for example mathematical modeling, as well as new regulatory initiatives requiring better understanding of both the product and the process are being applied to well‐characterized biopharmaceuticals (for example recombinant proteins). The vaccine industry is still running behind in comparison to these industries. A production process for a new Haemophilus influenzae type b (Hib) conjugate vaccine, including related quality control (QC) tests, was developed and transferred to a number of emerging vaccine manufacturers. This contributed to a sustainable global supply of affordable Hib conjugate vaccines, as illustrated by the market launch of the first Hib vaccine based on this technology in 2007 and concomitant price reduction of Hib vaccines. This paper describes the development approach followed for this Hib conjugate vaccine as well as the mathematical modeling tool applied recently in order to indicate options for further improvements of the initial Hib process. The strategy followed during the process development of this Hib conjugate vaccine was a targeted and integrated approach based on prior knowledge and experience with similar products using multi‐disciplinary expertise. Mathematical modeling was used to develop a predictive model for the initial Hib process (the ‘baseline’ model) as well as an ‘optimized’ model, by proposing a number of process changes which could lead to further reduction in price. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:568–580, 2016     

Testing plasmid stability of Escherichia coli using the Continuously Operated Shaken BIOreactor System

Plasmids are common vectors to genetically manipulate Escherichia coli or other microorganisms. They are easy to use and considerable experience has accumulated on their application in heterologous protein production. However, plasmids can be lost during cell growth, if no selection pressure like, e.g., antibiotics is used, hampering the production of the desired protein and endangering the economic success of a biotechnological production process. Thus, in this study the Continuously Operated Shaken BIOreactor System (COSBIOS) is applied as a tool for fast parallel testing of strain stability and operation conditions and to evaluate measures to counter such plasmid loss. In specific, by applying various ampicillin concentrations, the lowest effective ampicillin dosage is investigated to secure plasmid stability while lowering adverse ecological effects. A significant difference was found in the growth rates of plasmid‐bearing and plasmid‐free cells. The undesired plasmid‐free cells grew 30% faster than the desired plasmid‐bearing cells. During the testing of plasmid stability without antibiotics, the population fraction of plasmid‐bearing cells rapidly decreased in continuous culture to zero within the first 48 h. An initial single dosage of ampicillin did not prevent plasmid loss. By contrast, a continuous application of a low dosage of 10 µg/mL ampicillin in the feed medium maintained plasmid stability in the culture. Consequently, the COSBIOS is an apt reactor system for measuring plasmid stability and evaluating methods to enhance this stability. Hence, decreased production of heterologous protein can be prevented. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1418–1425, 2016     

浅谈二尖瓣交界分离术中监护和输液与复苏的关系

本文通过116例二尖瓣决窄分离术中监护和输液,从中体会到术中监护是心脏手术成功必不可少的条件。只有做好术中监护,才能及时了解病情发展,正确指导复苏和输液,提高手术的安全系数。     

外科手术增加人的血清抗黑变激素浓度

本工作测定了8个20—39岁男病人在外科手术前、手术中和手术后血清抗黑变激素(meLatonin)的浓度,样本均在日间(11—18时)静脉血中抽取,由甲烷抽提后,用放射免疫法来鉴定和测定浓度。实验结果表明在手术前和手术过程中抗黑变激素浓度高于手术后的浓度(P<0.05)。上述结果提示,增加抗黑变激素的分泌,其作用也许在于平衡应激状态下过量的反应。     

腹腔镜袖状胃切除术和胃旁路术治疗肥胖合并2型糖尿病近期疗效的对比研究

摘要 目的：对比腹腔镜袖状胃切除术（LSG）和胃旁路术（LRYGB）治疗肥胖合并2型糖尿病（T2DM）的近期疗效。方法：回顾性分析我院于2016年2月至 2019年1月期间收治的63例肥胖合并T2DM患者的临床资料，根据患者手术方式，将患者分为LRYGB组34例、LSG组29例。对比两组术中、术后临床指标，对比两组术前、术后6个月的体质量指数（BMI）、腰臀比（WHR）、糖脂代谢指标，记录两组治疗期间并发症发生情况。结果：两组术后胃肠功能恢复时间、下床活动时间、术中出血量组间对比无统计学差异（P>0.05），LSG组手术时间、住院时间短于LRYGB组（P<0.05）。两组术后6个月BMI、WHR均较术前下降（P<0.05）。两组术后6个月总胆固醇（TC）、糖化血红蛋白（HbAlc）、甘油三酯（TG）、低密度脂蛋白（LDL-C）、空腹血糖（FBG）、餐后2 h 血糖 （2hPG）均较术前下降（P<0.05），高密度脂蛋白（HDL-C）较术前升高（P<0.05）。两组并发症发生率对比无统计学差异（P>0.05）。结论：LSG、LRYGB治疗肥胖合并T2DM患者，均可有效控制患者体重，调节血糖血脂，两者近期疗效相当，但是LSG的手术操作相对更简单，可视患者具体病情选择合适的术式。     

Genetic analysis of the wing vein pattern of Drosophila

Summary Of the many mutations known to affect the wing vein pattern we have selected the most extreme in 29 genes for study. Their phenotype can be classified in two major classes: lack-of-veins and excess-of-veins, and in several internally coherent groups. The study of multiple mutant combinations, within groups and between groups, reveals several genetic operations at work in the generation of the vein pattern. The finding that some of these mutations also affect cell proliferation in characteristic ways has prompted a generative model of wing morphogenetic and pattern formation based on cell behaviour properties defined by the corresponding wild-type genes.     

乳癌术后方对乳腺癌术后患者生活质量、肿瘤标志物和外周血T细胞亚群的影响

摘要 目的：观察乳癌术后方对乳腺癌术后患者生活质量、肿瘤标志物和外周血T细胞亚群的影响。方法：选择2017年6月~2018年6月期间我院收治的乳腺癌术后长期门诊随访患者100例,根据双色球法将患者分为对照组（50例）和实验组（50例）,对照组接受西医常规标准化治疗,实验组在此基础上于术后接受乳癌术后方治疗,治疗1年后对比两组疗效、生活质量、肿瘤标志物、外周血T细胞亚群和3年无病生存率。结果：实验组的临床总有效率为84.00%（42/50）,效果优于对照组的56.00%（28/50）,组间比较有统计学差异（P<0.05）。治疗后,实验组症状领域评分较对照组低,总体健康状况、功能领域评分高于对照组（P<0.05）。治疗后,实验组血清糖类抗原125（CA125）、癌胚抗原（CEA）、恶性肿瘤特异性生长因子（TSGF）水平低于对照组（P<0.05）。与对照组比较,治疗后实验组CD3⁺、CD4⁺、CD4⁺/CD8⁺较高,CD8⁺较低（P<0.05）。实验组的3年无病生存率高于对照组（P<0.05）。结论：乳腺癌术后患者在西医常规标准化治疗基础上添加乳癌术后方,效果较好,可有效控制癌症,提高机体免疫功能,促进生活质量改善,提高3年无病生存率。     

达芬奇机器人与腹腔镜手术治疗胰腺癌的近期疗效比较及对血清CRP、PCT及肿瘤标志物的影响

摘要 目的：探讨达芬奇机器人与腹腔镜手术治疗胰腺癌的近期疗效比较及对血清C-反应蛋白（CRP）、降钙素原（PCT）及肿瘤标志物的影响。方法：选择2019年1月至2020年1月在我院接受治疗的61例胰腺癌患者,根据手术方法分为机器人组（n=26）和腹腔镜组（n=35）。腹腔镜组给予腹腔镜手术治疗,机器人组给予达芬奇机器人辅助治疗。比较两组围术期情况、CRP 、PCT、糖类抗原19-9（CA19-9）、糖类抗原125（CA125）、术后恢复情况及并发症发生情况。结果：机器人组禁食时间及排气时间显著低于腹腔镜组,差异显著（P<0.05）;治疗前,两组血清CA19-9、CA125水平无明显差异;治疗后,两组血清CA19-9、CA125水平治疗后较治疗前均显著下降差异显著（P<0.05）;两组治疗后血清CA19-9、CA125水平比较无显著差异（P>0.05）;治疗前,两组CRP、PCT水平无明显差异;治疗后,两组CRP、PCT明显升高,且机器人组低于腹腔镜组差异显著（P<0.05）;机器人组和腹腔镜组术后下床活动时间、拔尿管时间、术后住院时间比较无显著差异;机器人组术后重症监护时间显著低于腹腔镜组,差异显著（P<0.05）;两组患者治疗期间并发症总发生率分别为4.44%、6.67%,无显著差异（P>0.05）。结论：达芬奇机器人辅助能够显著提高胰腺癌手术质量,且对血清CRP 、PCT的影响较小,且对肿瘤标志物的影响与腹腔镜手术较为接近,为患者提供机器人微创治疗是未来临床的必然发展趋势。     

显微外科与腹腔镜手术治疗精索静脉曲张疗效比较的回顾性研究

摘要 目的：对比显微外科与腹腔镜手术治疗索静脉曲张（VC）的临床效果。方法：回顾性分析2018年8月~2020年8月期间在我院接受精索静脉结扎术治疗的75例VC患者,其中接受腹腔镜手术的34例纳为A组,接受显微外科手术的41例纳为B组。观察两组手术及住院指标情况,对比两组手术前后精液质量变化,观察两组术后并发症发生率和复发率。结果：两组住院天数、住院费用组间对比差异无统计学意义（P>0.05）。B组手术时间长于A组,排气时间短于A组,组间对比差异有统计学意义（P<0.05）。手术后6个月,两组患者的精液量均增加,精子密度均增大,精子活率、活动精子总数均升高,精液液化时间均下降,且B组的变化程度大于A组（P<0.05）。B组的并发症发生率小于A组（P<0.05）。A组有2例患者随访期间复发,B组未见有患者复发,两组复发率组间对比差异无统计学意义（P>0.05）。结论：与腹腔镜手术治疗VC相比,显微外科手术能更有效地改善精液质量、缩短排气时间、降低并发症发生率,虽然手术时间稍长,仍属于较为可靠的术式。     

右美托咪定联合七氟醚对老年腹腔镜胃肠肿瘤切除术患者应激反应和脑氧代谢的影响

摘要 目的：观察老年腹腔镜胃肠肿瘤切除术患者使用七氟醚联合右美托咪定复合麻醉后,机体应激反应和脑氧代谢的变化情况。方法：将我院2020年1月至2020年12月期间收治的100例老年腹腔镜胃肠肿瘤切除术患者根据随机数字表法分为对照组（n=50,七氟醚麻醉）和研究组（n=50,右美托咪定联合七氟醚麻醉）。观察两组血流动力学、应激反应、脑氧代谢、认知功能和不良反应。结果：两组手术60 min（T1）~手术后30 min（T3）时间点较麻醉诱导前（T0）时间点心率（HR）先下降后升高,平均动脉压（MAP）先升高后下降（P<0.05）。研究组T1~T3时间点HR及MAP低于对照组（P<0.05）。两组术后3 d多巴胺（DA）、肾上腺素（AD）、去甲肾上腺素（NE）水平升高,但研究组低于对照组（P<0.05）。两组术后3 d血氧含量差（DajvO₂）和脑氧摄取率（CERO₂）下降,且研究组低于对照组（P<0.05）。研究组术后6 h、术后1 d、术后3 d简易精神状态检查量表（MMSE）评分高于对照组（P<0.05）。两组不良反应发生率,对比无显著性差异（P>0.05）。结论：七氟醚联合右美托咪定应用于老年腹腔镜胃肠肿瘤切除术患者,可有效减轻机体应激反应,减轻机体认知功能损伤,维持血流动力学稳定和脑氧代谢。