Long-acting beta-agonists reduce mortality of patients with severe and very severe chronic obstructive pulmonary disease: a propensity score matching study

Background

Long-acting beta-agonists were one of the first-choice bronchodilator agents for stable chronic obstructive pulmonary disease. But the impact of long-acting beta-agonists on mortality was not well investigated.

Methods

National Emphysema Treatment Trial provided the data. Severe and very severe stable chronic obstructive pulmonary disease patients who were eligible for volume reduction surgery were recruited at 17 clinical centers in United States during 1988–2002. We used the 6–10 year follow-up data of patients randomized to non-surgery treatment. Hazard ratios for death by long-acting beta-agonists were estimated by three models using Cox proportional hazard analysis and propensity score matching were measured.

Results

The pre-matching cohort was comprised of 591 patients (50.6% were administered long-acting beta-agonists. Age: 66.6 ± 5.3 year old. Female: 35.4%. Forced expiratory volume in one second (%predicted): 26.7 ± 7.1%. Mortality during follow-up: 70.2%). Hazard ratio using a multivariate Cox model in the pre-matching cohort was 0.77 (P = 0.010). Propensity score matching was conducted (C-statics: 0.62. No parameter differed between cohorts). The propensity-matched cohort was comprised of 492 patients (50.0% were administered long-acting beta-agonists. Age: 66.8 ± 5.1 year old. Female: 34.8%. Forced expiratory volume in one second (%predicted) 26.5 ± 6.8%. Mortality during follow-up: 69.1%). Hazard ratio using a univariate Cox model in the propensity-matched cohort was 0.77 (P = 0.017). Hazard ratio using a multivariate Cox model in the propensity-matched cohort was 0.76 (P = 0.011).

Conclusions

Long-acting beta-agonists reduce mortality of severe and very severe chronic obstructive pulmonary disease patients.     

基于InVEST与倾向评分匹配模型评估秦岭国家级自然保护区水源涵养服务保护成效

自然保护区在保障水源涵养等生态系统服务方面发挥了重要作用, 对区域水资源的可持续利用具有重要意义。然而, 自然保护区水源涵养服务保护成效的主要影响因素仍然不清, 不利于自然保护区的有效管理和区域可持续发展目标的实现。本文拟探讨: (1)秦岭区域水源涵养服务的总体情况; (2)自然保护区对水源涵养服务的保护成效; (3)自然保护区水源涵养服务保护成效的主要影响因素是什么。本文采用InVEST模型计算秦岭区域19个国家级自然保护区2010-2015年的水源涵养量, 基于倾向评分配比法研究了自然保护区水源涵养服务保护成效, 并通过随机森林回归判断自然保护区水源涵养服务保护成效的主要影响因素。研究结果表明, 虽然在2010-2015年秦岭区域水源涵养服务整体降低, 但与自然保护区外的配对样本相比, 大多数自然保护区(63.16%)水源涵养服务保护成效显著(N = 12, P < 0.05); 少数保护区(26.32%)在减缓水源涵养服务降低的作用不如自然保护区外(N = 5, P < 0.05); 也有个别自然保护区(10.52%)对水源涵养服务保护成效不明显(N = 2, P > 0.05)。从主要影响因素来看, 自然保护区水源涵养服务保护成效主要受降水量变化和自然保护区资金投入的影响。结果显示: (1) 2010-2015年间秦岭区域水源涵养量减少较为明显, 但总体来看自然保护区在减缓水源涵养服务降低方面取得了积极成效。(2)降水量变化对水源涵养服务保护成效起到主导作用; (3)管理因素也对保护区水源涵养服务保护成效有一定影响, 在管理因素中资金投入的大小对水源涵养服务保护效果影响最大。因此, 建议进一步增加资金投入, 以提升自然保护区水源涵养服务的保护成效。     

High preoperative albumin-bilirubin score predicts poor survival in patients with newly diagnosed high-grade gliomas

ObjectiveTo determine the prognostic value of the preoperative Albumin-bilirubin (ALBI) score in high-grade glioma (HGG) patients.MethodsA retrospective study of 194 HGG patients was conducted. ROC analysis was used to determine the optimal cut-off value of ALBI score. Univariate and multivariate analysis was performed to identify prognostic factors associated with progression free survival (PFS) and overall survival (OS). The resulting prognostic models were externally validated by a demographic-matched cohort of 130 HGG patients.ResultsOptimal cutoff value of ALBI score was -2.941. In training set, ALBI was correlated with age (P = 0.001), tumor location (P = 0.012) and adjuvant therapy (P = 0.016). Both PFS (8.27 vs. 18.40 months, P<0.001) and OS (13.93 vs. 27.57 months, P<0.001) were significantly worse in the ALBI-high group. Strikingly, patients in ALBI-low group had 56% decrease in the risk of tumor progression and 57% decrease in the risk of death relative to high ALBI. Multivariate analysis further identified ALBI score as an independent predictor for both PFS (HR=0.47, 95% CI 0.34, 0.66) and OS (HR=0.45, 95% CI 0.32, 0.63). The ALBI score remained independent prognostic value in the validation set for both PFS (P = 0.01) and OS (P = 0.007). Patients with low ALBI score had better PFS and OS in all subgroups by tumor grade and treatment modalities.ConclusionsThe preoperative ALBI score is a noninvasive and valuable prognostic marker for HGG patients.     

Effects of Hydration on Steric and Electric Charge-Induced Interstitial Volume Exclusion—a Model

The presence of collagen and charged macromolecules like glycosaminoglycans (GAGs) in the interstitial space limits the space available for plasma proteins and other macromolecules. This phenomenon, known as interstitial exclusion, is of importance for interstitial fluid volume regulation. Physical/mathematical models are presented for calculating the exclusion of electrically charged and neutral macromolecules that equilibrate in the interstitium under various degrees of hydration. Here, a central hypothesis is that the swelling of highly electrically charged GAGs with increased hydration shields parts of the neutral collagen of the interstitial matrix from interacting with electrically charged macromolecules, such that exclusion of charged macromolecules exhibits change due to steric and charge effects. GAGs are also thought to allow relatively small neutral, but also charged macromolecules neutralized by a very high ionic strength, diffuse into the interior of GAGs, whereas larger macromolecules may not. Thus, in the model, relatively small electrically charged macromolecules, such as human serum albumin, and larger neutral macromolecules such as IgG, will have quite similar total volume exclusion properties in the interstitium. Our results are in agreement with ex vivo and in vivo experiments, and suggest that the charge of GAGs or macromolecular drugs may be targeted to increase the tissue uptake of macromolecular therapeutic agents.     

Spotlight: Assembly of protein complexes by integrating graph clustering methods

As is generally assumed, clusters in protein–protein interaction (PPI) networks perform specific, crucial functions in biological systems. Various network community detection methods have been developed to exploit PPI networks in order to identify protein complexes and functional modules. Due to the potential role of various regulatory modes in biological networks, a single method may just apply a single graph property and neglect communities highlighted by other network properties.     

Association of Worse Prognosis With an Aberrant Diurnal Cortisol Rhythm in Patients With Advanced Lung Cancer

A flatter diurnal rhythm of cortisol has been reported to be associated with early mortality in patients with metastatic breast cancer. The clinical stage of disease at the time of diagnosis and the patient's performance status (PS) are known to be important prognostic factors for lung cancer (LC) survival. The authors examined the relationship between diurnal cortisol rhythms and these prognostic factors in patients with advanced LC. Cortisol concentrations were measured in saliva samples collected from 52 patients (37 males/15 females) with advanced LC and from 56 healthy subjects (32 males/24 females) to characterize the diurnal cortisol rhythm, specifically the cortisol awakening response (CAR) and diurnal cortisol decline (DCD). Variations of CAR and DCD in the patients were analyzed according to their clinical disease stage and PS score, and the differences in CAR and DCD between patients and healthy controls were compared. The patient group showed significantly reduced diurnal cortisol secretory activity and rhythmicity, compared with healthy controls. When the patients were subgrouped according to their clinical disease stage, patients with stage 4 disease showed significantly reduced CAR and flatter DCD compared with the healthy controls. However, the CAR and DCD in patients with stage 3a and 3b disease were comparable to those of healthy controls. Neither the CAR nor the DCD showed stepwise changes as the disease stage worsened. When patients were subgrouped according to their Eastern Cooperative Oncology Group (ECOG) PS score, there was stepwise reduction in the CAR and flattening of the DCD as the PS score increased. Both an abolished CAR and a flattened DCD were common in patients with ECOG PS scores of 3 and 4. These results indicate that alteration of the diurnal cortisol rhythm in patients with advanced LC is more closely associated with their PS score than with their clinical disease stage. Gradual alteration of the CAR and DCD, indicative of loss of 24-h cortisol rhythm, in concert with increase in PS score implies that endogenous circadian rhythms may also be disintegrating as the PS score worsens in these patients. (Author correspondence: ryunsup@yahoo.co.kr)     

Informative cluster sizes for subcluster-level covariates and weighted generalized estimating equations

Summary Williamson, Datta, and Satten's (2003, Biometrics 59 , 36–42) cluster‐weighted generalized estimating equations (CWGEEs) are effective in adjusting for bias due to informative cluster sizes for cluster‐level covariates. We show that CWGEE may not perform well, however, for covariates that can take different values within a cluster if the numbers of observations at each covariate level are informative. On the other hand, inverse probability of treatment weighting accounts for informative treatment propensity but not for informative cluster size. Motivated by evaluating the effect of a binary exposure in presence of such types of informativeness, we propose several weighted GEE estimators, with weights related to the size of a cluster as well as the distribution of the binary exposure within the cluster. Choice of the weights depends on the population of interest and the nature of the exposure. Through simulation studies, we demonstrate the superior performance of the new estimators compared to existing estimators such as from GEE, CWGEE, and inverse probability of treatment‐weighted GEE. We demonstrate the use of our method using an example examining covariate effects on the risk of dental caries among small children.     

Corrections for measurement error due to delayed onset of illness for case-crossover designs

Epidemiologic studies of the short-term effects of ambient particulate matter (PM) on the risk of acute cardiovascular or cerebrovascular events often use data from administrative databases in which only the date of hospitalization is known. A common study design for analyzing such data is the case-crossover design, in which exposure at a time when a patient experiences an event is compared to exposure at times when the patient did not experience an event within a case-control paradigm. However, the time of true event onset may precede hospitalization by hours or days, which can yield attenuated effect estimates. In this article, we consider a marginal likelihood estimator, a regression calibration estimator, and a conditional score estimator, as well as parametric bootstrap versions of each, to correct for this bias. All considered approaches require validation data on the distribution of the delay times. We compare the performance of the approaches in realistic scenarios via simulation, and apply the methods to analyze data from a Boston-area study of the association between ambient air pollution and acute stroke onset. Based on both simulation and the case study, we conclude that a two-stage regression calibration estimator with a parametric bootstrap bias correction is an effective method for correcting bias in health effect estimates arising from delayed onset in a case-crossover study.     

Ancient genes can be served as pan‐cancer diagnostic and prognostic biomarkers

One important challenge for cancer is efficient biomarkers monitoring its formation and developments remain greatly limited. Although the accumulated big omics data provide great opportunities to the above purpose, the biomarkers identified by the data‐driven strategy often do not work well in new datasets, which is one of the main bottlenecks limiting their utilities. Given that atavistic phenotype is generally observed in cancer cells, we have been suggested that the activity of progenitor genes in tumour could serve as an efficient cancer biomarker. For doing so, we first curated 77 progenitor genes and then proposed a quantitative score to evaluate cancer progenitorness. After applying progenitorness score to ~ 22 000 samples, 33 types of cancers from 81 datasets, this method generally performs well in the diagnosis, prognosis and therapy monitoring of cancers. This study proposed a potential pan‐cancer biomarker and revealed a significant role of atavism in the formation and development of cancers.     

Genetic risk for Alzheimer disease in children: Evidence from early‐life IQ and brain white‐matter microstructure

It remains unclear whether the genetic risk for late‐onset Alzheimer disease (AD) is linked to premorbid individual differences in general cognitive ability and brain structure. The objective of the present study was to determine whether the genetic risk of late‐onset AD is related to premorbid individual differences in intelligence quotient (IQ) and characteristics of the cerebral white‐matter in children. The study sample included children of the Generation R Study from Rotterdam, The Netherlands. IQ was measured using a well‐validated Dutch nonverbal IQ test (n = 1908) at ages 5 to 9 years. White‐matter microstructure was assessed by measuring fractional anisotropy (FA) of white‐matter tracts using diffusion tensor imaging (DTI) (n = 919) at ages 9 to 12 years. Genetic risk was quantified using three biologically defined genetic risk scores (GRSs) hypothesized to be related to the pathophysiology of late‐onset AD: immune response, cholesterol/lipid metabolism and endocytosis. Higher genetic risk for late‐onset AD that included genes associated with immune responsivity had a negative influence on cognition and cerebral white‐matter microstructure. For each unit increase in the immune response GRS, IQ decreased by 0.259 SD (95% CI [?0.500, ?0.017]). For each unit increase in the immune response GRS, global FA decreased by 0.373 SD (95% CI [?0.721, ?0.026]). Neither cholesterol/lipid metabolism nor endocytosis GRSs were associated with IQ or cerebral white‐matter microstructure. Our findings suggest that elevated genetic risk for late‐onset AD may in part be manifest during childhood neurodevelopment through alterations in immune responsivity.