验前概率联合冠脉CT造影对于稳定型冠心病的诊断价值

目的：比较升级的Diamond-Forrester法(updated Diamond-Forrester method,UDFM)和Duke临床评分(Duke clinical score,DCS)对于冠心病的评估准确性,并进一步分析验前概率与冠脉CT造影(computed tomographic coronary angiography, CTCA)联合应用的诊断准确性。方法纳入2012年1月-2013年12月因稳定型心绞痛在解放军总医院心内科先后行CTCA和传统冠状动脉造影(conventional coronary angiography,CCA)的患者523例,分别用UDFM和DCS估算每例患者患冠心病的验前概率。以CCA结果为金标准,分析验前概率、CTCA及两者联合应用对冠心病的诊断准确性。理论验后概率根据贝叶斯公式进行计算。结果523例患者中有385例(74%)CCA结果为阳性。与UDFM相比,DCS将更多的CCA结果阳性患者分入高验前概率组(46%vs 23%,P＜0.0001)。DCS的ROC曲线下面积明显大于UDFM[0.77(0.73,0.82)vs 0.71(0.66,0.77),P=0.0009]。根据DCS估算结果划分的低、中和高3个验前概率亚组中,CTCA的敏感性、特异性、阳性预测值及阴性预测值分别是94%、98%和97%,94%、87%和55%,91%、94%和93%及96%、96%和77%。中验前概率亚组的理论验后概率十分接近实际验后概率(阳性：94.7%vs 93.6%,阴性：3.7%vs 4.0%)。结论对于稳定型心绞痛患者,DCS比UDFM更适用于冠心病验前概率的估算。将按DCS估算的验前概率与CTCA联合应用,能够有效提高CTCA的诊断准确性,并避免过度检查。     

Impacts of Recombinant Human Erythropoietin Treatment During Predialysis Periods on the Progression of Chronic Kidney Disease in a Large‐Scale Cohort Study (Co‐JET study)

The effect of recombinant human erythropoietin (rHuEPO) treatment on the progression of chronic kidney disease (CKD) has not been fully evaluated in Japan. We therefore retrospectively evaluated this in a sub‐cohort of a prospective multicenter study to investigate optimal hemoglobin (Hb) level of CKD patients on hemodialysis (HD) treated with rHuEPO; Japan Erythropoietin Treatment Study for Target Hb and Survival (JET study). Effect of rHuEPO treatment during predialysis period to delay initiation of HD was retrospectively assessed in 2434 patients from the JET study comparing groups with and without rHuEPO treatment. The assessment was done by Cox proportional hazards regression analysis and inverse probability‐weighted (IPW) analysis to adjust for time‐dependent confounders. The weights used in the IPW analysis were calculated using a logistic model that included baseline confounders and time‐dependent variables. During the predialysis period, 71.7% (1746 patients) were treated with rHuEPO (mean Hb level of 8.7 g/dL at initiation of rHuEPO treatment). Covariates significantly associated with initiation of rHuEPO treatment were Hb level, serum creatinine level, age, diabetes, cardiac insufficiency, and hypertension. The adjusted hazard ratio for time until HD initiation under rHuEPO treatment was 0.272 (95% CI, 0.223–0.331; P < 0.001) in the Cox analysis and 0.63 (95% CI, 0.53–0.76; P < 0.0001) in the IPW analysis. This retrospective study suggests that rHuEPO treatment during the predialysis period has preventive effects on the progression of CKD although further prospective investigation on the efficacy is needed.     

Lateral mobility of individual integrin nanoclusters orchestrates the onset for leukocyte adhesion

Integrins are cell membrane adhesion receptors involved in morphogenesis, immunity, tissue healing, and metastasis. A central, yet unresolved question regarding the function of integrins is how these receptors regulate both their conformation and dynamic nanoscale organization on the membrane to generate adhesion-competent microclusters upon ligand binding. Here we exploit the high spatial (nanometer) accuracy and temporal resolution of single-dye tracking to dissect the relationship between conformational state, lateral mobility, and microclustering of the integrin receptor lymphocyte function-associated antigen 1 (LFA-1) expressed on immune cells. We recently showed that in quiescent monocytes, LFA-1 preorganizes in nanoclusters proximal to nanoscale raft components. We now show that these nanoclusters are primarily mobile on the cell surface with a small (ca. 5%) subset of conformational-active LFA-1 nanoclusters preanchored to the cytoskeleton. Lateral mobility resulted crucial for the formation of microclusters upon ligand binding and for stable adhesion under shear flow. Activation of high-affinity LFA-1 by extracellular Ca(2+) resulted in an eightfold increase on the percentage of immobile nanoclusters and cytoskeleton anchorage. Although having the ability to bind to their ligands, these active nanoclusters failed to support firm adhesion in static and low shear-flow conditions because mobility and clustering capacity were highly compromised. Altogether, our work demonstrates an intricate coupling between conformation and lateral diffusion of LFA-1 and further underscores the crucial role of mobility for the onset of LFA-1 mediated leukocyte adhesion.     

Do phonological neighbourhood density and phonotactic probability influence speech output accuracy in acquired speech impairment?

Background: Among the many factors that may affect speech production, phonological neighbourhood density (ND) and phonotactic probability (PROB) have displayed effects on speech and language performance in healthy speakers. It is not clear if they show an effect in impaired speech output after stroke and if they do whether this is facilitatory or inhibitory.

Aims: To determine whether ND and/or PROB play a role in speech production accuracy in acquired output impairment after stroke.

Methods & Procedures: A total of 20 English native speakers with acquired spoken output impairment after stroke repeated 906 single-word stimuli. They included real and nonsense words varying in syllable structure, length, and complexity, as well as syllable and word frequency, ND, and PROB. Responses were transcribed phonetically and scored as either correct or incorrect. Logistic regression analyses were completed for each speaker separately to determine the effects of ND and PROB on repetition accuracy in relation to controlled variables.

Outcomes & Results: A total of 14 speakers showed a positive effect of PROB on repetition accuracy. Only two individuals displayed a positive effect of ND. No double dissociations regarding the effect of ND and PROB were noted.

Conclusions: ND does not appear to have a significant independent effect on repetition accuracy in speakers with acquired output impairment after stroke. By contrast PROB has a positive effect on repetition accuracy in impaired speakers, but does not appear to be a major determinant of output accuracy. Results are discussed in relation to study design and future work to further examine issues around ND and PROB and their possible role in clinical differential diagnosis of output disorders.     

合理进行多重Logistic回归分析——结合平均处理效应分析

本文目的是介绍如何结合平均处理效应分析,合理地进行多重Logistic回归分析的方法。第一,介绍了与平均处理效应分析有关的4个基本概念。第二,介绍了平均处理效应分析中的核心内容,即6种估算方法。第三,通过一个假设的药物临床试验实例,介绍了如何用SAS软件进行分析的全过程,内容如下：①采用传统的多重Logistic回归分析;②采用倾向性评分模型计算逆概率权重;③分别采用6种估算方法估计潜在结果均值和平均处理效应。     

The effect of stimulus probability on the somatosensory mismatch field

We investigated the effect of deviant stimulus probability on the somatosensory magnetic mismatch negativity (MMNm) using an electrical two-point stimulation. First, we determined the discrimination threshold (DT) of the two-point distance. We applied standard stimuli at a distance that subjects felt as one point and deviant stimuli at a distance that subjects definitely felt as two points. We used three deviant stimulus probabilities, 10, 30, and 50%. The components peaking around 30–70 ms (first component) and 150–250 ms (fourth component) following deviant stimuli were significantly larger than those following standard stimuli in 10% condition, but not in 30 or 50% condition. The equivalent current dipole (ECD) was located in the contralateral primary somatosensory cortex (cSI) for the first component, and in the cSI and in the contralateral secondary somatosensory cortex (cSII) for the fourth component. The peak amplitude of the MMNm decreased as the probability of the deviant stimulus increased. The Somatosensory MMNm was affected by deviant stimulus probability similar to an auditory mismatch negativity (MMN).     

Using previous trial results to inform hypothesis testing of new interventions

Results of industry-sponsored Phase III trials registered at clinicaltrials.gov include a rich amount of information on the efficacy of medical interventions. We propose that these results can be used to inform hypothesis testing of a new intervention through the Bayes principle. The posterior probability of positive efficacy offers an accessible interpretation of the uncertainty of efficacy and a convenient metric for global false-positive control.     

On evaluation of consistency in multi-regional clinical trials

In recent years, multi-regional clinical trials (MRCT) that conduct clinical trials simultaneously in Asian Pacific region, Europe, and the United States have become very popular for global pharmaceutical development. The main purpose of multi-regional clinical trials is to shorten the time for pharmaceutical development and regulatory submission, and approval around the world. In practice, however, clinical results observed from some regions (sub-population) may not be consistent with the results from other regions and/or all regions combined (entire population). The inconsistency observed may be due to ethnic differences in different regions, differences in medical practice, time points of assessment, or by random chance due to small sample size for the region. Some regional regulatory agencies require consistency evaluation between local country results and overall results. However, the challenge is there is no detailed guidance on the definition of ‘consistency’ and methodology to evaluate it. Therefore, the questions are: how to evaluate consistency and what statistical methods are appropriate to be used for consistency evaluation? In this article, several statistical tests for consistency (similarity) between clinical results observed from a specific sub-population and the entire population are proposed. These methods are compared through extensive simulation. As most published articles discussed consistency evaluation for superiority situations, we have discussed consistency evaluation for non-inferiority situation in this article through a simulated example concerning consistency in some countries. Recommendations of the statistical methods to be used for consistency evaluation are given. Other aspects that should be considered for consistency evaluation are also provided.