Finite Element Analysis of Extrinsic Parameters on the Onset of Tensile Strength in Powders

Most food, pharmaceutical, and chemical industries rely heavily on the supply of free-flowing powders that finds their application in raw materials, additives, and manufactured products. Improper storage conditions combined with environmental factors affect the free-flowing ability of powders. An undesirable transformation of these free-flowing powders into a coherent mass that resists flow is called caking. An important metric that can be used to measure the caking propensity of a material is the tensile strength, which is essentially the resistant stress needed to separate two layers of materials using an isostatic tensile strain. Even though several models have quantified the propensity of caking, the complex nature of interactions between the powder and its micro-environment makes the prediction of caking a challenging task. In the present work, the onset of tensile strength in isomalt with changes in temperature, relative humidity, and consolidation pressures using a shear cell was modeled using a finite element approach. The study found that at a consolidation pressure of 3 kPa and relative humidity of 85±0.1%, an increase in temperature by 5˚C increased the tensile strength of isomalt by a factor of 2. On the other hand, at a constant temperature of 25˚C, an increase in relative humidity from 85±0.1% to 86±0.1% registered an increase in tensile strength by 42.7%. This study also found that an increase in consolidation pressure from 3 kPa to 6 and 9 kPa increased the tensile strength by a factor of 1.79 and 2.54, respectively. The model had good agreement with the measurements and had an overall MAPE of 12.13%. This model can be applied to study the influence of extrinsic parameters on the propensity of caking during storage of bulk solids.     

ArgD of Mycobacterium tuberculosis is a functional N-acetylornithine aminotransferase with moonlighting function as an effective immune modulator

Mycobacterium tuberculosis (M. tuberculosis) encodes an essential enzyme acetyl ornithine aminotransferase ArgD (Rv1655) of arginine biosynthetic pathway which plays crucial role in M. tuberculosis growth and survival. ArgD catalyzes the reversible conversion of N-acetylornithine and 2 oxoglutarate into glutamate-5-semialdehyde and L-glutamate. It also possesses succinyl diaminopimelate aminotransferase activity and can thus carry out the corresponding step in lysine biosynthesis. These essential roles played by ArgD in amino acid biosynthetic pathways highlight it as an important metabolic chokepoint thus an important drug target. We showed that M. tuberculosis ArgD rescues the growth of ΔargD E. coli grown in minimal media validating its functional importance. Phylogenetic analysis of M. tuberculosis ArgD showed homology with proteins in gram positive bacteria, pathogenic and non-pathogenic mycobacteria suggesting the essentiality of this protein. ArgD is a secretory protein that could be utilized by M. tuberculosis to modulate host innate immunity as its moonlighting function. In-silico analysis predicted it to be a highly antigenic protein. The recombinant ArgD protein when exposed to macrophage cells induced enhanced production of pro-inflammatory cytokines TNF, IL6 and IL12 in a dose dependent manner. ArgD also induced the increased production of innate immune effector molecule NOS2 and NO in macrophages. We also demonstrated ArgD mediated activation of the canonical NFkB pathway. Notably, we also show that ArgD is a specific TLR4 agonist involved in the activation of pro-inflammatory signaling for sustained production of effector cytokines. Intriguingly, ArgD protein treatment activated macrophages to acquire the M1 phenotype through the increased surface expression of MHCII and costimulatory molecules CD80 and CD86. ArgD induced robust B-cell response in immunized mice, validating its antigenicity potential as predicted by the in-silico analysis. These properties of M. tuberculosis ArgD signify its functional plasticity that could be exploited as a possible drug target to combat tuberculosis.     

Effect of Tartrazine as Photoabsorber for Improved Printing Resolution of 3D Printed “Ghost Tablets”: Non-Erodible Inert Matrices

Stereolithography (SLA) 3D printing of pharmaceuticals suffers from the problem of light scattering, which leads to over-curing, resulting in the printing of objects that are non-compliant with design dimensions and the overloading of drugs. To minimize this problem, photoabsorbers such as tartrazine (food grade) can be used to absorb the stray light produced by scattering, leading to unintended photopolymerization. Ghost tablets (i.e., non-erodible inert matrices) were additively manufactured using SLA with varying ratios of polyethylene glycol diacrylate (PEGDA): polyethylene glycol (PEG) 300, along with tartrazine concentrations. The 3D printed ghost tablets containing maximum (0.03%) tartrazine were extremely precise in size and adhered to the nominal value of the metformin hydrochloride content. Resolution analysis reinstated the influence of tartrazine in achieving highly precise objects of even 0.07 mm² area. Furthermore, 3D printed ghost tablets were characterized using analytical means, and swelling studies. Additionally, ghost tablets were tested for their mechanical robustness using dynamic mechanical and texture analysis, and were able to withstand strains of up to 5.0% without structural failure. The printed ghost tablets displayed a fast metformin hydrochloride release profile, with 93.14% release after 12 h when the PEG 300 ratio was at its maximum. Ghost tablets were also subjected to in vivo X-ray imaging, and the tablets remained intact even after four hours of administration and were eventually excreted in an intact form through fecal excretion.     

广泛期小细胞肺癌一线化疗肿瘤缓解深度与生存期的相关性

目的:分析广泛期小细胞肺癌一线化疗后肿瘤缓解深度与患者生存期的相关性。方法:回顾性分析符合入组条件的50例初治广泛期小细胞肺癌患者的临床资料。通过Spearman秩相关检验评价广泛期小细胞肺癌化疗后肿瘤缓解深度与生存期的相关性，应用Log-rank检验比较不同肿瘤缓解深度对生存期的影响，应用COX比例回归模型进行多因素分析。结果:Spearman秩相关分析显示肿瘤缓解深度与PFS及OS均呈中等程度相关。不同缓解深度患者的生存期存在统计学差异。体重减少（P＜0.000 1）、缓解深度（P＜0.001）为无进展生存期的独立影响因素；体重减少（P＜0.000 1）、体力状态（P=0.001 2）、缓解深度（P＜0.001）、化疗周期（P=0.000 2）、二线治疗（P=0.006 7）为总生存期的独立预后因素。结论:广泛期小细胞肺癌一线化疗后肿瘤缓解深度对患者生存期有一定的预测价值。     

补骨脂酚通过MAPK途径诱导人肝癌HepG2细胞凋亡的研究

目的:研究补骨脂酚对人肝癌细胞凋亡的影响及其作用机制。方法:应用噻唑蓝法（MTT法）和倒置显微镜技术考察补骨脂酚对HepG2细胞生长的影响；采用荧光显微镜观察补骨脂酚处理后细胞凋亡；利用蛋白免疫印迹法检测补骨脂酚对HepG2细胞中凋亡相关蛋白及MAPK家族蛋白表达的影响；引入MAPK家族蛋白抑制剂考察生长抑制率和凋亡相关蛋白表达的变化。结果:补骨脂酚可以剂量依赖性地抑制人肝癌HepG2细胞增殖，其生长抑制作用明显强于临床上常用的抗肿瘤药5-氟尿嘧啶，并且补骨脂酚对人正常肝L02细胞具有较低的毒性。进一步研究发现，补骨脂酚可以诱导HepG2细胞发生凋亡。此外，MAPK家族参与到补骨脂酚诱导的HepG2细胞凋亡过程中，补骨脂酚可以剂量依赖性激活JNK的表达发挥促凋亡的作用，同时抑制了ERK促存活通路，然而对p38无明显影响。结论:本研究首次阐明了补骨脂酚诱导人肝癌HepG2细胞生长抑制作用机制，为进一步的临床应用提供了理论依据。     

Colitis following the use of immune checkpoint inhibitors: A real-world analysis of spontaneous reports submitted to the FDA adverse event reporting system

BackgroundAlthough colitis has been reported in patients treated with immune checkpoint inhibitors (ICIs), associations between colitis and ICIs had not been thoroughly assessed in real-world studies. Here, we identified and characterized significant colitis-associated with ICIs.MethodsBased on the Food and Drug Administration Adverse Event Reporting System (FAERS) from January 2004 to December 2019, the disproportionality analysis and Bayesian analysis, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN) and the multi-item gamma Poisson shrinker (MGPS) algorithms were adopted to data mining of the suspected adverse events of colitis after ICIs administrating. Clinical characteristics of patients with ICIs-associated colitis and the time to onset of colitis following different ICI regimens were collected.ResultsA total of 3786 reports of colitis adverse events were identified with ICIs. Seven ICI monotherapies were associated with the reporting of colitis. Statistically significant ROR, PRR, information component (IC), and empirical Bayesian geometric mean (EBGM) emerged for all ICI monotherapies and combination therapies. ICIs-associated colitis affected mostly male (53.51%), with a wide mean age range (60.65 to 72 years). Colitis adverse events were commonly reported in patients with melanoma and lung cancer. Adverse outcomes of colitis concerning ICI were mainly outcomes of hospitalization-initiated or prolonged and other serious. Among colitis cases, 17.43% cases of colitis concerning ICI lead to death. The adverse event of colitis occurred earliest in ipilimumab monotherapy with a median time to onset of 64.21 days (IQR: 27–69 days) among all monotherapies.ConclusionsICI may lead to severe and disabling ICIs-associated colitis during therapy. Analysis of FAERS data identified signals for adverse events of colitis with ICI regimens. Practitioners should consider the factors that may increase the likelihood of colitis. The findings support a continued surveillance and risk factor identification studies.     

药物临床试验伦理审查质量风险的管理研究

目的:为提高我国药物临床试验伦理审查质量、保障受试者权益提供参考。方法:以风险管理理论为指导,运用文献研究法、专家意见法和层次分析法对药物临床试验伦理审查流程进行梳理,提取并确定影响伦理审查质量的风险因素及其权重,并对我国药物临床试验伦理审查工作提出改进建议。结果与结论:构建的药物临床试验伦理审查风险指标体系包括5个方面共31个影响因素,其中影响药物临床试验伦理审查质量的5个方面的重要性(权重)排序依次为医学伦理委员会的自身建设(0.2635)、审查会议的管理(0.2514)、跟踪审查(0.1945)、审查申请的受理与处理(0.1892)、文件档案的管理(0.1014);权重较高的影响因素包括"讨论投票过程利益冲突人员回避(0.0787)""对方案修改、知情同意修改、严重不良事件等情形及时审查或召开会议讨论(0.0705)""明确伦理审查工作流程及时间并对外公示(0.0598)""统一、规范的审查标准与批准标准(0.0521)"等。建议可通过讨论投票环节利益冲突人员予以回避,对方案修改、知情同意修改、严重不良事件等情形及时审查或召开伦理会议讨论,明确伦理审查工作流程及时间,建立统一、规范的审查标准和批准标准等方式提高药物临床试验伦理审查的质量。     

Low-molecular-weight heparin followed by rivaroxaban for acute occlusive portomesenteric vein thrombosis in a cirrhotic patient treated with multiple endoscopic variceal procedures

Acute portomesenteric vein thrombosis is potentially lethal. In the present paper, a cirrhotic patient with a previous history of esophageal variceal bleeding presented with acute occlusive portomesenteric vein thrombosis, but achieved complete recanalization by low-molecular-weight heparin followed by rivaroxaban. Notably, no bleeding episode occurred during anticoagulation therapy. This case supported early initiation of anticoagulation in such patients.     

Microbiology and clinical characteristics of industrial oil burns

IntroductionInfections complicating burns generally transition from Gram-positive to Gram-negatives over the first couple weeks, but this depends on multiple factors. The microbiology of infections complicating crude oil (CO) and hydraulic fracturing (FRAC) burns is unknown.MethodsWe performed a retrospective study of patients with industrial thermal burns hospitalized >2 days with ≥1 day in the ICU between 4/2011–11/2016. Burns were oil-related (ORB; CO or FRAC) or non-oil related (NORB). Epidemiology and microbiology during the first 15 hospital days was compared.Results149 patients were included, with 11 FRAC and 24 CO. CO burns were more severely burned than those with FRAC and NORB (p < 0.05). Mortality was 17% and 18% for CO and FRAC burns compared to 3% in NORB (p < 0.01). More cultures were obtained from ORB than NORB (p < 0.05). ORB were associated with Stenotrophomonas maltophilia and FRAC associated with Serratia marcescens and Candida glabrata. Patients with FRAC, CO and NORB had a median of 13, 3.5, and 4 days to first positive culture respectively (p = 0.03).ConclusionORB were associated with more severe burns and unique microbiology. FRAC burns had longer to initial positive culture, potentially suggesting our current methodology is inadequate to diagnose infections associated with FRAC.