Predictive markers of safety and immunogenicity of adjuvanted vaccines

Vaccination represents one of the greatest public health triumphs; in part due to the effect of adjuvants that have been included in vaccine preparations to boost the immune responses through different mechanisms. Although a variety of novel adjuvants have been under development, only a limited number have been approved by regulatory authorities for human vaccines. This report reflects the conclusions of a group of scientists from academia, regulatory agencies and industry who attended a conference on the current state of the art in the adjuvant field. Held at the U.S. Pharmacopeial Convention (USP) in Rockville, Maryland, USA, from 18 to 19 April 2013 and organized by the International Association for Biologicals (IABS), the conference focused particularly on the future development of effective adjuvants and adjuvanted vaccines and on overcoming major hurdles, such as safety and immunogenicity assessment, as well as regulatory scrutiny. More information on the conference output can be found on the IABS website, http://www.iabs.org/.     

Superiority of total white blood cell count over other leukocyte differentials for predicting long-term outcomes in patients with non-ST elevation acute coronary syndrome

Abstract

Context: Leukocytes have been found to be the predictor of outcome following acute coronary syndrome (ACS).

Objective: We sought to determine the relationship between leukocyte differentials and developing major adverse cardiac events (MACE) in patients with non-ST elevation ACS (NSTE-ACS).

Materials and methods: A total of 490 consecutive patients were enrolled, and MACE incidence was evaluated at long-term follow-up period.

Results: Total white blood cell (WBC) was higher in subjects occurring MACE. Moreover, elevated total WBC, ≥7.5?×?10³/µL, independently predicted MACE.

Discussion and conclusion: Elevated admission total WBC can predict long-term MACE in NSTE-ACS patients better than other differentials.     

Acclimation responses to temperature vary with vertical stratification: implications for vulnerability of soil‐dwelling species to extreme temperature events

The occurrence of summer heat waves is predicted to increase in amplitude and frequency in the near future, but the consequences of such extreme events are largely unknown, especially for belowground organisms. Soil organisms usually exhibit strong vertical stratification, resulting in more frequent exposure to extreme temperatures for surface‐dwelling species than for soil‐dwelling species. Therefore soil‐dwelling species are expected to have poor acclimation responses to cope with temperature changes. We used five species of surface‐dwelling and four species of soil‐dwelling Collembola that habituate different depths in the soil. We tested for differences in tolerance to extreme temperatures after acclimation to warm and cold conditions. We also tested for differences in acclimation of the underlying physiology by looking at changes in membrane lipid composition. Chill coma recovery time, heat knockdown time and fatty acid profiles were determined after 1 week of acclimation to either 5 or 20 °C. Our results showed that surface‐dwelling Collembola better maintained increased heat tolerance across acclimation temperatures, but no such response was found for cold tolerance. Concordantly, four of the five surface‐dwelling Collembola showed up to fourfold changes in relative abundance of fatty acids after 1 week of acclimation, whereas none of the soil‐dwelling species showed a significant adjustment in fatty acid composition. Strong physiological responses to temperature fluctuations may have become redundant in soil‐dwelling species due to the relative thermal stability of their subterranean habitat. Based on the results of the four species studied, we expect that unless soil‐dwelling species can temporarily retreat to avoid extreme temperatures, the predicted increase in heat waves under climatic change renders these soil‐dwelling species more vulnerable to extinction than species with better physiological capabilities. Being able to act under a larger thermal range is probably costly and could reduce maximum performance at the optimal temperature.     

Persistent versus transient tree encroachment of temperate peat bogs: effects of climate warming and drought events

Peatlands store approximately 30% of global soil carbon, most in moss‐dominated bogs. Future climatic changes, such as changes in precipitation patterns and warming, are expected to affect peat bog vegetation composition and thereby its long‐term carbon sequestration capacity. Theoretical work suggests that an episode of rapid environmental change is more likely to trigger transitions to alternative ecosystem states than a gradual, but equally large, change in conditions. We used a dynamic vegetation model to explore the impacts of drought events and increased temperature on vegetation composition of temperate peat bogs. We analyzed the consequences of six patterns of summer drought events combined with five temperature scenarios to test whether an open peat bog dominated by moss (Sphagnum) could shift to a tree‐dominated state. Unexpectedly, neither a gradual decrease in the amount of summer precipitation nor the occurrence of a number of extremely dry summers in a row could shift the moss‐dominated peat bog permanently into a tree‐dominated peat bog. The increase in tree biomass during drought events was unable to trigger positive feedbacks that keep the ecosystem in a tree‐dominated state after a return to previous ‘normal’ rainfall conditions. In contrast, temperature increases from 1 °C onward already shifted peat bogs into tree‐dominated ecosystems. In our simulations, drought events facilitated tree establishment, but temperature determined how much tree biomass could develop. Our results suggest that under current climatic conditions, peat bog vegetation is rather resilient to drought events, but very sensitive to temperature increases, indicating that future warming is likely to trigger persistent vegetation shifts.     

Evidence for interplay between genes and maternal stress in utero: monoamine oxidase A polymorphism moderates effects of life events during pregnancy on infant negative emotionality at 5 weeks

The low activity variant of the monoamine oxidase A (MAOA) functional promoter polymorphism, MAOA‐LPR, in interaction with adverse environments (G × E) is associated with child and adult antisocial behaviour disorders. MAOA is expressed during foetal development so in utero G × E may influence early neurodevelopment. We tested the hypothesis that MAOA G × E during pregnancy predicts infant negative emotionality soon after birth. In an epidemiological longitudinal study starting in pregnancy, using a two stage stratified design, we ascertained MAOA‐LPR status (low vs. high activity variants) from the saliva of 209 infants (104 boys and 105 girls), and examined predictions to observed infant negative emotionality at 5 weeks post‐partum from life events during pregnancy. In analyses weighted to provide estimates for the general population, and including possible confounders for life events, there was an MAOA status by life events interaction (P = 0.017). There was also an interaction between MAOA status and neighbourhood deprivation (P = 0.028). Both interactions arose from a greater effect of increasing life events on negative emotionality in the MAOA‐LPR low activity, compared with MAOA‐LPR high activity infants. The study provides the first evidence of moderation by MAOA‐LPR of the effect of the social environment in pregnancy on negative emotionality in infancy, an early risk for the development of child and adult antisocial behaviour disorders .     

PCI术后是否抗凝治疗的临床疗效比较

目的：研究PCI术后是否应用依诺肝素抗凝治疗对患者临床疗效的影响。方法：于2011年5月至2012年1月间,连续入选在我院行冠状动脉造影并置入了支架的患者158例,将符合标准的患者随机分为非抗凝组或抗凝组两组各79名。非抗凝组术后常规应用阿司匹林和氯吡格雷。抗凝组术后加用依诺肝素。对入选患者进行院内随访记录其主要心脏不良事件及出血事件。结果：支架植入成功率100%。术后抗凝组113处病变共置入支架135枚;非抗凝组109处病变置入支架115枚。院内随访：主要心脏不良事件和严重出血差异无统计学意义。小出血事件抗凝组多于非抗凝组（P=0.007）。结论：冠状动脉支架置入术后非抗凝治疗组缺血不良事件发生率较抗凝组无明显增加,小出血并发症明显减少。该研究结果表明,对PCI术无特殊并发症的患者术后无需常规抗凝治疗。     

心源性猝死心电预测和综合防治研究进展

随着社会老龄化的进一步加剧,冠心痛、高血压、心肌病、恶性心律失常的发病率也成为导致人群中猝死率上升的重要诱发因素.对猝死发病机制的研究中,室性心动过速和室颤往往是导致病人发生猝死的最主要的终末事件.在这篇文章中我们通过12导联心电图(ECG)的心电学预测因子的研究,揭示心电学预测因子在预防心源性猝死中的临床应用价值.另一方面,如何能提高预防猝死的预测因子的敏感性和特异性,发现新的更有临床应用价值的心电学预测因子,更好的防治猝死对社会人群的危害,成为临床研究中不断探寻的答案.最后,我们将近年来对心源性猝死的防治措施及未来的发展方向做一简要的综述.     

Validation of discrete time-to-event prediction models in the presence of competing risks

Clinical prediction models play a key role in risk stratification, therapy assignment and many other fields of medical decision making. Before they can enter clinical practice, their usefulness has to be demonstrated using systematic validation. Methods to assess their predictive performance have been proposed for continuous, binary, and time-to-event outcomes, but the literature on validation methods for discrete time-to-event models with competing risks is sparse. The present paper tries to fill this gap and proposes new methodology to quantify discrimination, calibration, and prediction error (PE) for discrete time-to-event outcomes in the presence of competing risks. In our case study, the goal was to predict the risk of ventilator-associated pneumonia (VAP) attributed to Pseudomonas aeruginosa in intensive care units (ICUs). Competing events are extubation, death, and VAP due to other bacteria. The aim of this application is to validate complex prediction models developed in previous work on more recently available validation data.     

Comparison of random-effects meta-analysis models for the relative risk in the case of rare events: A simulation study

Pooling the relative risk (RR) across studies investigating rare events, for example, adverse events, via meta-analytical methods still presents a challenge to researchers. The main reason for this is the high probability of observing no events in treatment or control group or both, resulting in an undefined log RR (the basis of standard meta-analysis). Other technical challenges ensue, for example, the violation of normality assumptions, or bias due to exclusion of studies and application of continuity corrections, leading to poor performance of standard approaches. In the present simulation study, we compared three recently proposed alternative models (random-effects [RE] Poisson regression, RE zero-inflated Poisson [ZIP] regression, binomial regression) to the standard methods in conjunction with different continuity corrections and to different versions of beta-binomial regression. Based on our investigation of the models' performance in 162 different simulation settings informed by meta-analyses from the Cochrane database and distinguished by different underlying true effects, degrees of between-study heterogeneity, numbers of primary studies, group size ratios, and baseline risks, we recommend the use of the RE Poisson regression model. The beta-binomial model recommended by Kuss (2015) also performed well. Decent performance was also exhibited by the ZIP models, but they also had considerable convergence issues. We stress that these recommendations are only valid for meta-analyses with larger numbers of primary studies. All models are applied to data from two Cochrane reviews to illustrate differences between and issues of the models. Limitations as well as practical implications and recommendations are discussed; a flowchart summarizing recommendations is provided.     

Penalized survival models for the analysis of alternating recurrent event data

Recurrent event data are widely encountered in clinical and observational studies. Most methods for recurrent events treat the outcome as a point process and, as such, neglect any associated event duration. This generally leads to a less informative and potentially biased analysis. We propose a joint model for the recurrent event rate (of incidence) and duration. The two processes are linked through a bivariate normal frailty. For example, when the event is hospitalization, we can treat the time to admission and length-of-stay as two alternating recurrent events. In our method, the regression parameters are estimated through a penalized partial likelihood, and the variance-covariance matrix of the frailty is estimated through a recursive estimating formula. Moreover, we develop a likelihood ratio test to assess the dependence between the incidence and duration processes. Simulation results demonstrate that our method provides accurate parameter estimation, with a relatively fast computation time. We illustrate the methods through an analysis of hospitalizations among end-stage renal disease patients.