The Impact of Postoperative Complications on Short- and Long-Term Health-Related Quality of Life After Total Mesorectal Excision for Rectal Cancer

BackgroundSurvival for rectal cancer patients has improved over the past decades. In parallel, long-term health-related quality of life (HRQoL) is gaining interest. This study focuses on the effect of complications following rectal cancer surgery on HRQoL and survival.MethodsThe TME-trial (1996-1999) randomized patients with operable rectal cancer between surgery with preoperative short-course radiotherapy and surgery. Questionnaires including the Rotterdam Symptom Checklist were sent at 6 time points within the first 24 months and after 14 years the EORTC QLQ-C30 and EORTC QLQ-CR29 questionnaires. Differences in HRQoL and survival between patients with and without complications were analyzed.ResultsA total of 1207 patients were included, of which 482 (39.9%) patients experienced complications, surgical complications occurred in 177 (14.6%) patients, non-surgical complications in 197 (16.3%) and 108 patients (8.9%) had a combination of both types of complications. Three months after surgery, patients with a combination of surgical- and non-surgical complications, especially patients with anastomotic leakage, had the worst HRQoL. Twelve months postoperative HRQoL returned to a similar level as before surgery, regardless of complications. In patients who survived 14 years, no significant differences in HRQoL were seen between patients with and without complications. However, patients with complications did have lower overall survival.ConclusionThis study shows that survival and short-term HRQoL are negatively affected by complications. Twelve months after surgery HRQoL had returned to the preoperative level regardless, of complications. Also, in patients that survived 14 years, there was no effect of complications on HRQoL detected.     

Pan-cancer proteomic map of 949 human cell lines

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Contributions of the NICHD neonatal research network's generic database to documenting and advancing the outcomes of extremely preterm infants

The Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) maintains a database of extremely preterm infants known as the Generic Database (GDB). Begun in 1987, this database now includes more than 91,000 infants, most of whom are extremely preterm (<29 weeks gestation). The GDB has been the backbone of the NRN, providing high quality, prospectively collected data to study the changing epidemiology of extreme prematurity and its outcomes over time. In addition, GDB data have been used to generate hypotheses for prospective studies and to develop new clinical trials by providing information about the numbers and characteristics of available subjects and the expected event rates for conditions and complications to be studied. Since its inception, the GDB has been the basis of more than 200 publications in peer-reviewed journals, many of which have had a significant impact on the field of neonatology.     

ECFS standards of care on CFTR-related disorders: Updated diagnostic criteria

This paper is the first in a series providing updated guidance on the definition, evaluation and management of people with a Cystic Fibrosis Transmembrane conductance Regulator (CFTR)-Related Disorder (CFTR-RD). The need for this update relates to more precise characterisation of CFTR gene variants and improved assessment of CFTR protein dysfunction. The exercise is co-ordinated by the European CF Society Standards of Care Committee and Diagnostic Network Working Group and involves stakeholder engagement. This first paper was produced by a core group using an extensive literature review and papers graded for their quality. Subsequent wider stakeholder agreement was achieved.The definition of a CFTR-RD remains “a clinical condition with evidence of CFTR protein dysfunction that does not fulfil the diagnostic criteria for CF”. Clearer guidance on CFTR dysfunction and relevant CFTR variants will be provided. Thresholds for clinical presentations are presented and the paradigm that pathobiological processes may be evident in more than one organ is agreed. In this paper we reflect on the early patient journey, highlighting that CF specialists as well as other relevant specialists should be involved in the care of people with a CFTR-RD.     

Anomaly of cornea and ocular adnexa in spinster homolog 2 (Spns2) knockout mice

Spinster 2 (Spns2) is a transporter that pumps sphingosine-1-phosphate (S1P), a bioactive lipid mediator synthesized in the cytoplasm, out of cells into the inter cellular space. S1P is a signal that modulates cellular behavior during embryonic development, inflammation and tissue repair, etc. A Spns2-null (KO) mouse is born with failure of eyelid closure (eyelid-open-at birth; EOB) and develop corneal fibrosis in adulthood. It remains elusive whether corneal lesion is caused by exposure to keratitis (lagophthalmos) of EOB phenotype or the loss of Spns2 directly perturbs the corneal tissue morphogenesis and intra-eyelid structures. Therefore, we investigated differences between the cornea and ocular adnexa morphogenesis in KO and wild-type (WT) embryos and adults as well.The loss of Spns2 perturbs cornea morphogenesis during embryonic development as early as E16.5 besides EOB phenotype. Histology showed that the corneal stroma was thinner with less extracellular matrix accumulation, e.g., collagen and keratocan in the KO mouse. Epithelial stratification, expression of keratin 12 and formation of desmosomes and hemidesmosomes were also perturbed in these KO corneas. Lacking Spns2 impaired morphogenesis of the Meibomian glands and of orbicularis oculi muscles. KO glands were labeled for ELOVL4 and PPARγ and were Oil-Red O-positive, suggesting KO acinar cells possessed functionality as the glands.This is the first report on the roles of Spns2 in corneal and Meibomian gland morphogenesis. Corneal tissue destruction in an adult KO mouse might be due to not only lagophthalmos but also to an impaired morphogenesis of cornea, Meibomian glands, and orbicularis oculi muscle.     

橙皮苷在低压低氧所致大鼠视网膜抗氧化能力和炎症介质调控改变中的作用

目的　探讨橙皮苷（HSD）在低压低氧所致大鼠视网膜抗氧化应激能力及炎性介质调控改变中的干预作用。方法　取健康雄性清洁级成年SD大鼠72只（144眼），随机分为对照组、低压低氧组及HSD干预组，每组24只（48眼）。对照组大鼠饲养于常氧环境，低压低氧组及HSD干预组大鼠放置于模拟海拔5000 m高度的低压氧舱内喂养。HSD干预组大鼠给予HSD灌胃，对照组和低压低氧组大鼠给予生理盐水，各组大鼠每天等量灌胃一次，连续7 d。通过HE染色光镜下观察大鼠视网膜组织形态变化；采用酶联免疫吸附(ELISA)法检测大鼠视网膜谷胱甘肽(GSH)和半胱氨酸(Cys)蛋白浓度、丙二醛（MDA）含量以及肿瘤坏死因子-α（TNF-α）活性；Western-blot检测大鼠视网膜核因子-κB p65（NF-κB p65）和细胞色素C（Cyto-C)蛋白表达水平。结果　光镜下观察可见，与对照组相比，低压低氧组大鼠出现视网膜水肿，HSD干预组较低压低氧组大鼠视网膜水肿程度减轻。与对照组相比，低压低氧组大鼠视网膜中GSH蛋白浓度和Cys蛋白浓度降低，MDA含量升高，差异均有统计学意义（均为P<0.001）；与低压低氧组相比，HSD干预组提高了GSH蛋白浓度和Cys蛋白浓度，降低了MDA含量，GSH蛋白浓度和MDA含量两组相比差异均有统计学意义（均为P<0.001），Cys蛋白浓度两组相比差异无统计学意义（P>0.05）。与对照组相比，低压低氧组大鼠视网膜中NF-κB p65蛋白表达水平和TNF-α活性升高，差异均有统计学意义（P<0.01、 P<0.001）；与低压低氧组相比，HSD干预组大鼠视网膜中NF-κB p65蛋白表达水平和TNF-α活性降低，差异均有统计学意义（P<0.05、P<0.001）。与对照组相比，低压低氧组大鼠视网膜Cyto-C蛋白表达水平明显升高，差异有统计学意义（P<0.01）；与低压低氧组相比，HSD干预组大鼠视网膜中Cyto-C蛋白表达水平降低，差异有统计学意义（P<0.05）。结论　HSD能够通过提高大鼠视网膜抗氧化应激能力、抑制炎症介质释放以及减少线粒体损伤而发挥保护视网膜功能的作用。     

Receptor-binding domain recombinant protein on alum-CpG induces broad protection against SARS-CoV-2 variants of concern

We conducted preclinical studies in mice using a yeast-produced SARS-CoV-2 RBD subunit vaccine candidate formulated with aluminum hydroxide (alum) and CpG deoxynucleotides. This formulation is equivalent to the Corbevax^TM vaccine that recently received emergency use authorization by the Drugs Controller General of India. We compared the immune response of mice vaccinated with RBD/alum to mice vaccinated with RBD/alum + CpG. We also evaluated mice immunized with RBD/alum + CpG and boosted with RBD/alum. Mice were immunized twice intramuscularly at a 21-day interval. Compared to two doses of the /alum formulation, the RBD/alum + CpG vaccine induced a stronger and more balanced Th1/Th2 cellular immune response, with high levels of neutralizing antibodies against the original Wuhan isolate of SARS-CoV-2 as well as the B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 and (Delta) variants. Neutralizing antibody titers against the B.1.1.529 (BA.1, Omicron) variant exceeded those in human convalescent plasma after Wuhan infection but were lower than against the other variants. Interestingly, the second dose did not benefit from the addition of CpG, possibly allowing dose-sparing of the adjuvant in the future. The data reported here reinforces that the RBD/alum + CpG vaccine formulation is suitable for inducing broadly neutralizing antibodies against SARS-CoV-2, including variants of concern.     

2型糖尿病患者扫描式葡萄糖监测系统指标与尿白蛋白/肌酐比值的相关性研究

背景 随着血糖监测技术的发展，近些年来人们开始使用扫描式葡萄糖监测系统（FGMS）"全景式"地观察2型糖尿病（T2DM）患者的血糖水平，明确FGMS指标与T2DM并发症之间的关系有助于提高其临床应用价值，但目前相关研究较少。 目的 探究佩戴FGMS的T2DM患者葡萄糖在目标范围内时间（TIR）等指标与尿白蛋白/肌酐比值（UACR）的相关性。 方法 选取2019年1月至2021年10月于北京大学人民医院老年科就诊并佩戴FGMS的T2DM患者79例，以尿液检查中UACR是否<30 mg/g将患者分为无白蛋白尿组（n=50）和白蛋白尿组（n=29）。比较两组患者的临床特征、实验室检查指标及FGMS指标等。采用Pearson相关、Spearman秩相关分析探讨TIR、高血糖时间（TAR）与糖化血红蛋白（HbA1c）的相关性。分别采用Pearson相关、Spearman秩相关、偏相关分析探讨FGMS指标与lnUACR的相关性。使用多因素Logistic回归分析探究T2DM患者发生白蛋白尿的影响因素，采用受试者工作特征（ROC）曲线评估TIR对白蛋白尿的预测价值。 结果 白蛋白尿组T2DM病程长于无白蛋白尿组，三酰甘油（TG）、HbA1c、平均血糖（MBG）、TAR、平均血糖标准差（SDBG）、最大葡萄糖波动幅度（LAGE）、平均葡萄糖波动幅度（MAGE）、连续每隔2 h血糖净作用（CONGA2）高于无白蛋白尿组，TIR低于无白蛋白尿组（P<0.05）。Pearson相关、Spearman秩相关分析结果显示，TIR与HbA1c呈负相关（P<0.001），TAR与HbA1c呈正相关（P<0.001）。Pearson相关、Spearman秩相关、偏相关分析结果均表明，TIR与lnUACR呈负相关（P<0.001），MBG、TAR、SDBG、LAGE、MAGE、CONGA2与lnUACR呈正相关（P<0.001）。多因素Logistic回归分析结果显示，TIR>70%〔OR=0.038，95%CI（0.003，0.467）〕是T2DM患者出现白蛋白尿的保护因素（P<0.05），TAR升高〔OR=1.046，95%CI（1.000，1.094）〕是T2DM患者出现白蛋白尿的危险因素（P<0.05）。TIR预测T2DM患者出现白蛋白尿的ROC曲线下面积（AUC）为0.784〔95%CI（0.674，0.894）〕（P=0.003），灵敏度为78%，特异度为83%，最佳切点为69.71%。 结论 在FGMS指标中，TIR>70%是T2DM患者出现白蛋白尿的保护因素，TAR升高是T2DM患者出现白蛋白尿的危险因素。同时，SDBG、LAGE、MAGE、CONGA2等多种反映血糖波动的指标也与UACR密切相关。对TIR水平较低及TAR、SDBG、LAGE、MAGE、CONGA2水平较高的T2DM患者进行FGMS筛查有助于早期识别及预防白蛋白尿的发生、发展。     

Adherence to and persistence with antidiabetic medications and associations with clinical and economic outcomes in people with type 2 diabetes mellitus: A systematic literature review

We designed a systematic literature review to identify available evidence on adherence to and persistence with antidiabetic medication in people with type 2 diabetes (T2D). Electronic screening and congress searches identified real-world noninterventional studies (published between 2010 and October 2020) reporting estimates of adherence to and persistence with antidiabetic medication in adults with T2D, and associations with glycaemic control, microvascular and/or macrovascular complications, hospitalizations and healthcare costs. Ninety-two relevant studies were identified, the majority of which were retrospective and reported US data. The proportions of patients considered adherent (median [range] 51.2% [9.4%-84.3%]) or persistent (median [range] 47.7% [16.9%-94.0%]) varied widely across studies. Multiple studies reported an association between greater adherence/persistence and greater reductions in glycated haemoglobin levels. Better adherence/persistence was associated with fewer microvascular and/or macrovascular outcomes, although there was little consistency across studies in terms of which outcomes were improved. More adherent and more persistent patients were typically less likely to be hospitalized or to have emergency department visits/admissions and spent fewer days in hospital annually than less adherent/persistent patients. Greater adherence and persistence were generally associated with lower hospitalization costs, higher pharmacy costs and lower or budget-neutral total healthcare costs compared with lower adherence/persistence. In conclusion, better adherence and persistence in people with T2D is associated with lower rates of microvascular and/or macrovascular outcomes and inpatient hospitalization, and lower or budget-neutral total healthcare expenditure. Education and treatment strategies to address suboptimal adherence and persistence are needed to improve clinical and economic outcomes.     

Carboxylesterase-2 plays a critical role in dabigatran etexilate active metabolite formation

Dabigatran etexilate (DABE), an oral anticoagulant prodrug, is nearly completely metabolized to the dabigatran (DAB) active metabolite by carboxylesterase-1 (CES1) and carboxylesterase-2 (CES2). The high interpatient variation in DAB plasma concentrations, coupled with its low therapeutic index, emphasizes the need to understand how CES1 and CES2 impact active metabolite formation. Previous work focused on CES1 enzyme activity but the contributions of CES2 remain unclear. The purpose of this study was to determine how CES2 activity influences DAB active metabolite formation. We compared the efficiency of DAB formation from DABE when exposed sequentially to human intestinal and then human hepatic microsomes (mimicking the normal metabolic sequence) with the reverse metabolic sequence in which DABE is exposed to hepatic and then intestinal microsomes. The poor efficiency of DAB formation with reverse sequential hydrolysis indicates that CES2 activity is crucial for active metabolite formation. Thus, the decrease in DAB formation with normal sequential hydrolysis was more sensitive to CES2 inhibition by verapamil (CES2 IC50 = 3.4 μM) than CES1 inhibition by diltiazem (CES2 IC50 = 9.1 μM). These results show CES2 activity plays a crucial role in DAB formation and that variability in its activity is an important determinant of therapeutic response.