Implications and measurement of herd protection (indirect effects) for enteric vaccine development

Diarrhea remains one of the top five causes of disease and death among young children in developing nations. Fortunately, scientists are making progress developing vaccines against enterotoxigenic E. coli (ETEC) and Shigella, two of the leading diarrhea pathogens. As vaccine developers start to consider field efficacy trials of these vaccines, they should be aware of the importance of evaluating not only vaccine direct effects on the immunized, but also the herd effects that vaccination can afford to the unimmunized in a community. In a workshop held at the conference titled “Vaccines against Shigella and ETEC (VASE)”, we described to participants what herd effects are and we presented on methods used in cholera and rotavirus studies that could be useful for future ETEC and Shigella vaccine trials conducted in low and middle-income nations. We also presented evidence on the effects of vaccine herd effects for estimates of vaccine cost-effectiveness.     

The role of immune correlates of protection on the pathway to licensure,policy decision and use of group B Streptococcus vaccines for maternal immunization: considerations from World Health Organization consultations

The development of a group B Streptococcus (GBS) vaccine for maternal immunization constitutes a global public health priority, to prevent GBS-associated early life invasive disease, stillbirth, premature birth, maternal sepsis, adverse neurodevelopmental consequences, and to reduce perinatal antibiotic use. Sample size requirements for the conduct of a randomized placebo-controlled trial to assess vaccine efficacy against the most relevant clinical endpoints, under conditions of appropriate ethical standards of care, constitute a significant obstacle on the pathway to vaccine availability. Alternatively, indirect evidence of protection based on immunologic data from vaccine and sero-epidemiological studies, complemented by data from opsonophagocytic in vitro assays and animal models, could be considered as pivotal data for licensure, with subsequent confirmation of effectiveness against disease outcomes in post-licensure evaluations. Based on discussions initiated by the World Health Organization we present key considerations about the potential role of correlates of protection towards an accelerated pathway for GBS vaccine licensure and wide scale use. Priority activities to support progress to regulatory and policy decision are outlined.     

Sample size re-estimation for clinical trials with longitudinal negative binomial counts including time trends

In some diseases, such as multiple sclerosis, lesion counts obtained from magnetic resonance imaging (MRI) are used as markers of disease progression. This leads to longitudinal, and typically overdispersed, count data outcomes in clinical trials. Models for such data invariably include a number of nuisance parameters, which can be difficult to specify at the planning stage, leading to considerable uncertainty in sample size specification. Consequently, blinded sample size re-estimation procedures are used, allowing for an adjustment of the sample size within an ongoing trial by estimating relevant nuisance parameters at an interim point, without compromising trial integrity. To date, the methods available for re-estimation have required an assumption that the mean count is time-constant within patients. We propose a new modeling approach that maintains the advantages of established procedures but allows for general underlying and treatment-specific time trends in the mean response. A simulation study is conducted to assess the effectiveness of blinded sample size re-estimation methods over fixed designs. Sample sizes attained through blinded sample size re-estimation procedures are shown to maintain the desired study power without inflating the Type I error rate and the procedure is demonstrated on MRI data from a recent study in multiple sclerosis.     

Measuring catastrophic medical expenditures: Reflections on three issues

In the “basic” approach, medical expenses are catastrophic if they exceed a prespecified percentage of consumption or income; the approach tells us if expenses cause a large percentage reduction in living standards. The ability‐to‐pay (ATP) approach defines expenses as catastrophic if they exceed a prespecified percentage of consumption less expenses on nonmedical necessities or an allowance for them. The paper argues that the ATP approach does not tell us whether expenses are large enough to undermine a household's ability to purchase nonmedical necessities. The paper compares the income‐based and consumption‐based variants of the basic approach, and shows that if the individual is a borrower after a health shock, the income‐based ratio will exceed the consumption‐based ratio, and both will exceed the more theoretically correct Flores et al. ratio; whereas if the individual continues to be a saver after a health shock, the ordering is reversed and the income‐based ratio may not overestimate Flores et al.'s ratio. Last, the paper proposes a lifetime money metric utility (LMMU) approach defining medical expenses as catastrophic in terms of their lifetime consequences. Under certain assumptions, the LMMU and Flores et al. approaches are identical, and neither requires data on how households finance their medical expenses.     

唤醒状态联合中央沟定位切除脑运动区胶质瘤对患者运动功能保护作用探讨

目的 探究唤醒状态联合中央沟定位对脑运动区胶质瘤切除术患者运动功能的保护作用。方法 选取本院2016年12月—2017年10月期间收治的脑运动区胶质瘤患者70例。所有患者均行唤醒状态联合中央沟定位运动区胶质瘤切除术。观察患者术后复发情况及术后第6、12个月的Kamofsky评分,并记录并发症发生情况。结果 所有患者均成功完成手术,未出现术中大出血、死亡等严重并发症。70例患者中,有40例全切除,26例次全切除,4例大部分切除。术后,感觉减退者有6例,肌力下降者有5例,肌力下降伴感觉减退者有2例,并发症发生率为18.57%(13/70)。6个月后,应用增强MRI显示有4例患者肿瘤灶周围明显强化,进一步使用正电子发射断层显像发现有1例患者肿瘤复发。术前及术后第6、12个月的Kamofsky评分分别为(89.62±11.88)及(80.73±9.91)、(65.82±12.36)。结论 唤醒状态联合中央沟定位能最大限度切除脑运动区胶质瘤,提高患者预后效果。     

The need for new control strategies for particulate matter in parenterals

An undesirable characteristic in lyophilized parenteral products is the potential presence of particulate matter in the final product, which may affect patient safety. In this study, quality risk management tools described in the International Conference on Harmonization Guideline Q9 were used to estimate the risks for a pharmaceutical manufacturing line, based on three critical quality attributes: (1) visible particulate matter; (2) lyo-cake collapse traces; and (3) lyo-cake melt-back traces. Together with a Process Failure Mode Effect Analysis (PFMEA), an input-output analysis of the individual unit operations identified seven major material classes of extrinsic particulate matter. In addition to the process assessment, an experimental investigation of the location of impurities in lyophilized products was performed. To that end, intentionally contaminated vials were examined to locate the particulate matter and its possible migration. The results emphasize the importance of a full transmission mode release testing since the particles may enter the interior of the lyo-cake. A theoretical explanation of the observed impurity locations is provided.     

Treatment sequence network meta-analysis in Crohn’s disease: a methodological case study

Objective: Several biologic therapies are available for the treatment of mild-to-moderate Crohn’s disease (CD). This network meta-analysis (NMA) aimed to assess the comparative efficacy of ustekinumab, adalimumab, vedolizumab and infliximab in the maintenance of clinical response and remission after 1?year of treatment.

Methods: A systematic literature search was performed to identify relevant randomized controlled trials (RCTs). Key outcomes of interest were clinical response (CD activity index [CDAI] reduction of 100 points; CDAI-100) and remission (CDAI score under 150 points; CDAI < 150). A treatment sequence Bayesian NMA was conducted to account for the re-randomization of patients based on different clinical definitions, the lack of similarity of the common comparator for each trial and the full treatment pathway from the induction phase onwards.

Results: Thirteen RCTs were identified. Ustekinumab 90?mg q8w was associated with statistically significant improvement in clinical response relative to placebo and vedolizumab 300?mg. For clinical remission, ustekinumab 90?mg q8w was associated with statistically significant improvement relative to placebo and vedolizumab 300?mg q8w. Findings from sub-population analyses had similar results but were not statistically significant.

Conclusions: The NMA suggest that ustekinumab is associated with the highest likelihood of reaching response or remission at 1?year compared with placebo, adalimumab and vedolizumab. Results should be interpreted with caution because this is a novel methodology; however, the treatment sequence analysis may be the most methodologically sound analysis to derive estimates of comparative efficacy in CD in the absence of head-to-head evidence.     

医院临床技能培训中心在应对疫情专项技能培训中的作用——以南通大学第五附属医院临床技能培训中心为例

2019 年底新型冠状病毒肺炎（以下简称新冠肺炎）疫情发生后，为抗击疫情和保障医护人员自身安全，开展了传染病防护技能专项培训。在本医院的临床技能培训中心，按“三区两通道”设置模拟隔离病区、开发传染病防控专项培训课程，对全体医护人员（特别是一线医护人员）进行传染病防护技能、进出隔离病区等项目实景培训及实战练习。以期迅速有效地提升医护人员传染病防护技能和防护下临床操作的熟练度、精准度，在更好地治疗患者的同时，实现了医护人员“零感染”的目标。同时也说明在医院临床技能培训中心设置模拟隔离病区、开设传染病防护技能课程，并纳入常态化培训考核的必要性和重要性。