寻找HLA匹配无关供者概率曲线的计算及其应用

目的　建立在骨髓库中寻找到HLA匹配供者概率曲线P的回归方程式 ,并用于评估骨髓库的最适大小。方法　在哈迪 -温伯格群体中的HLA单体型频率可以从供者表型资料求得。寻找到一个HLA匹配供者的概率可以表示成供者数和HLA单体型频率的函数。使用对数曲线拟合方法推导出该概率曲线的回归方程。结果　笔者推导出在中国人骨髓库中寻找到至少一例HLA -A ,B ,DR抗原全配合供者概率的回归方程式为P =- 0 .6 7+0 .2 5lgN(N为骨髓库中的供者数 ,介于 5万到 1 0 0万 )。在骨髓库供者数达到 75万人时 ,大约 80 %的患者可以找到HLA配合供者。结论　找到HLA配合供者概率取决于骨髓库供者人数的多寡以及HLA单体型频率。HLA群体遗传学资料有助于决定骨髓库的最适大小及其供者成员的组成。     

Usefulness of β-lactam and macrolide combination therapy for treating community-acquired pneumonia patients hospitalized in the intensive care unit: Propensity score analysis of a prospective cohort study

IntroductionWhether β-lactam and macrolide combination therapy reduces mortality in severe community-acquired pneumonia (SCAP) patients hospitalized in the intensive care unit (ICU) is controversial. The aim of the present study was to evaluate the usefulness of β-lactam and macrolide combination therapy for SCAP patients hospitalized in the ICU.MethodsA prospective, observational, cohort study of hospitalized pneumonia patients was performed. Hospitalized SCAP patients admitted to the ICU within 24 h between October 2010 and October 2017 were included for analysis. The primary outcome was 30-day mortality, and secondary outcomes were 14-day mortality and ICU mortality. Inverse probability of treatment weighting (IPTW) analysis as a propensity score analysis was used to reduce biases, including six covariates: age, sex, C-reactive protein, albumin, Pneumonia Severity Index score, and APACHE II score.ResultsA total of 78 patients were included, with 48 patients in the non-macrolide-containing β-lactam therapy group and 30 patients in the macrolide combination therapy group. β-lactam and macrolide combination therapy significantly decreased 30-day mortality (16.7% vs. 43.8%; P = 0.015) and 14-day mortality (6.7% vs. 31.3%; P = 0.020), but not ICU mortality (10% vs 27.1%, P = 0.08) compared with non-macrolide-containing β-lactam therapy. After adjusting by IPTW, macrolide combination therapy also decreased 30-day mortality (odds ratio, 0.29; 95%CI, 0.09–0.96; P = 0.04) and 14-day mortality (odds ratio, 0.19; 95%CI, 0.04–0.92; P = 0.04), but not ICU mortality (odds ratio, 0.34; 95%CI, 0.08–1.36; P = 0.13).ConclusionsCombination therapy with β-lactam and macrolides significantly improved the prognosis of SCAP patients hospitalized in the ICU compared with a non-macrolide-containing β-lactam regimen.     

Comparative Evaluation of Specific Phytochemical Indicatives in Cirivilvādi Ka?āya Prepared Freshly and at Commercial Scale

Kaṣāya or decoction is an Ayurvedic dosage form, prescribed based on the stage of the disease according to the principles of Ayurveda. This dosage form is traditionally prepared fresh and consumed on the same day but for the sake of convenience; the process of preparation has been modified so that it can be stored with longer shelf life, easy availability and produced in large quantities. There is a need to understand the implications of this modification in terms of chemical changes. This work attempted to check the phytochemical profile of both freshly prepared decoction and commercially available decoction with reference to some analytical parameters like pH, total soluble solids, phenols, alkaloids, potassium and to assess the changes in the thin layer chromatography profiling of the decoction. The results showed that phenols and potassium are found to be two fold higher in freshly prepared decoction, compared to commercially available decoction diluted to dosage in practice (1:4 ratio). However, the total alkaloid content was found to be approximately ten fold higher in commercially available decoction. It was observed that the thin layer chromatography profile of decoctions was extracted into petroleum ether and chloroform was similar and consistent with different batches though the bands in commercially available decoction were slightly more intense compared to freshly prepared decoction. The total soluble solids in commercially available decoction were four times higher than freshly prepared decoction. The study reveals that there are differences in the phytochemical profiles of the freshly prepared decoction and commercially available decoction of the same formulation. However, the significance of these differences can be determined only by further clinical studies. On the other hand, the study lends support to the practice of diluting the commercially available decoction to make it equivalent to freshly prepared decoction.     

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。     

Fitting the Balding–Nichols model to forensic databases

Large forensic databases provide an opportunity to compare observed empirical rates of genotype matching with those expected under forensic genetic models. A number of researchers have taken advantage of this opportunity to validate some forensic genetic approaches, particularly to ensure that estimated rates of genotype matching between unrelated individuals are indeed slight overestimates of those observed. However, these studies have also revealed systematic error trends in genotype probability estimates. In this analysis, we investigate these error trends and show how they result from inappropriate implementation of the Balding–Nichols model in the context of database-wide matching. Specifically, we show that in addition to accounting for increased allelic matching between individuals with recent shared ancestry, studies must account for relatively decreased allelic matching between individuals with more ancient shared ancestry.     

Hold your pauses: external globus pallidus neurons respond to behavioural events by decreasing pause activity

Awareness of its rich structural pathways has earned the external segment of the globus pallidus (GPe) recognition as a central figure within the basal ganglia circuitry. Interestingly, GPe neurons are uniquely identified by the presence of prominent pauses interspersed among a high‐frequency discharge rate of 50–80 spikes/s. These pauses have an average pause duration of 620 ms with a frequency of 13/min, yielding an average pause activity (probability of a GPe neuron being in a pause) of (620 × 13)/(60 × 1000) = 0.13. Spontaneous pause activity has been found to be inversely related to arousal state. The relationship of pause activity with behavioural events remains to be elucidated. In the present study, we analysed the electrophysiological activity of 200 well‐isolated GPe pauser cells recorded from four non‐human primates (Macaque fascicularis) while they were engaged in similar classical conditioning tasks. The isolation quality of the recorded activity and the pauses were determined with objective automatic methods. The results showed that the pause probability decreased by 9.09 and 10.0%, and the discharge rate increased by 2.96 and 1.95%, around cue and outcome presentation, respectively. Analysis of the linear relationship between the changes in pause activity and discharge rate showed r² = 0.46 and r² = 0.66 upon cue onset and outcome presentation, respectively. Thus, pause activity is a pertinent element in short‐term encoding of relevant behavioural events, and has a significant, but not exclusive, role in the modulation of GPe discharge rate around these events.     

Is the noun ending a cue to grammatical gender processing? An ERP study on sentences in Italian

Gender‐to‐ending consistency has been shown to influence grammatical gender retrieval in isolated word presentation. Notwithstanding the wealth of evidence, the exact role and the time course of processing of this distributional information remain unclear. This ERP study investigated if and when the brain detects gender‐to‐ending consistency in sentences containing Italian determiner‐noun pairs. Determiners either agreed or disagreed in gender with the nouns whose endings were reliable or misleading cues to gender (transparent and irregular nouns). Transparent nouns elicited an increased frontal negativity and a late posterior positivity compared to irregular nouns (350–950 ms), suggesting that the system is sensitive to gender‐to‐ending consistency from relatively early stages of processing. Gender agreement violations evoked a similar LAN‐P600 pattern for both types of nouns. The present findings provide evidence for an early detection of reliable gender‐related endings during sentence reading.     

One- and Two-Stage Arrhenius Models for Pharmaceutical Shelf Life Prediction

One of the most challenging aspects of the pharmaceutical development is the demonstration and estimation of chemical stability. It is imperative that pharmaceutical products be stable for two or more years. Long-term stability studies are required to support such shelf life claim at registration. However, during drug development to facilitate formulation and dosage form selection, an accelerated stability study with stressed storage condition is preferred to quickly obtain a good prediction of shelf life under ambient storage conditions. Such a prediction typically uses Arrhenius equation that describes relationship between degradation rate and temperature (and humidity). Existing methods usually rely on the assumption of normality of the errors. In addition, shelf life projection is usually based on confidence band of a regression line. However, the coverage probability of a method is often overlooked or under-reported. In this paper, we introduce two nonparametric bootstrap procedures for shelf life estimation based on accelerated stability testing, and compare them with a one-stage nonlinear Arrhenius prediction model. Our simulation results demonstrate that one-stage nonlinear Arrhenius method has significant lower coverage than nominal levels. Our bootstrap method gave better coverage and led to a shelf life prediction closer to that based on long-term stability data.     

Adolescent Intermittent Ethanol Exposure Is Associated with Increased Risky Choice and Decreased Dopaminergic and Cholinergic Neuron Markers in Adult Rats

Background:

Binge drinking is prevalent during adolescence and may have effects on the adult brain and behavior. The present study investigated whether adolescent intermittent ethanol exposure alters adult risky choice and prefrontal dopaminergic and forebrain cholinergic neuronal marker levels in male Wistar rats.

Methods:

Adolescent (postnatal day 28–53) rats were administered 5g/kg of 25% (vol/vol) ethanol 3 times/d in a 2-days–on/2-days–off exposure pattern. In adulthood, risky choice was assessed in the probability discounting task with descending and ascending series of large reward probabilities and after acute ethanol challenge. Immunohistochemical analyses assessed tyrosine hydroxylase, a marker of dopamine and norepinephrine in the prelimbic and infralimbic cortices, and choline acetyltransferase, a marker of cholinergic neurons, in the basal forebrain.

Results:

All of the rats preferred the large reward when it was delivered with high probability. When the large reward became unlikely, control rats preferred the smaller, safe reward, whereas adolescent intermittent ethanol-exposed rats continued to prefer the risky alternative. Acute ethanol had no effect on risky choice in either group of rats. Tyrosine hydroxylase (prelimbic cortex only) and choline acetyltransferase immunoreactivity levels were decreased in adolescent intermittent ethanol-exposed rats compared with controls. Risky choice was negatively correlated with choline acetyltransferase, implicating decreased forebrain cholinergic activity in risky choice.

Conclusions:

The decreases in tyrosine hydroxylase and choline acetyltransferase immunoreactivity suggest that adolescent intermittent ethanol exposure has enduring neural effects that may lead to altered adult behaviors, such as increased risky decision making. In humans, increased risky decision making could lead to maladaptive, potentially harmful consequences.