A Bias Correction Method in Meta-analysis of Randomized Clinical Trials with no Adjustments for Zero-inflated Outcomes

Many clinical endpoint measures, such as the number of standard drinks consumed per week or the number of days that patients stayed in the hospital, are count data with excessive zeros. However, the zero-inflated nature of such outcomes is often ignored in analyses, which leads to biased estimates and, consequently, a biased estimate of the overall intervention effect in a meta-analysis. The current study proposes a novel statistical approach, the Zero-inflation Bias Correction (ZIBC) method, that can account for the bias introduced when using the Poisson regression model despite a high rate of zeros in the outcome distribution for randomized clinical trials. This correction method utilizes summary information from individual studies to correct intervention effect estimates as if they were appropriately estimated in zero-inflated Poisson regression models. Simulation studies and real data analyses show that the ZIBC method has good performance in correcting zero-inflation bias in many situations. This method provides a methodological solution in improving the accuracy of meta-analysis results, which is important to evidence-based medicine

A Simulation Study of the Performance of Statistical Models for Count Outcomes with Excessive Zeros

Background: Outcome measures that are count variables with excessive zeros are common in health behaviors research. There is a lack of empirical data about the relative performance of prevailing statistical models when outcomes are zero-inflated, particularly compared with recently developed approaches. Methods: The current simulation study examined five commonly used analytical approaches for count outcomes, including two linear models (with outcomes on raw and log-transformed scales, respectively) and three count distribution-based models (i.e., Poisson, negative binomial, and zero-inflated Poisson (ZIP) models). We also considered the marginalized zero-inflated Poisson (MZIP) model, a novel alternative that estimates the effects on overall mean while adjusting for zero-inflation. Extensive simulations were conducted to evaluate their the statistical power and Type I error rate across various data conditions. Results: Under zero-inflation, the Poisson model failed to control the Type I error rate, resulting in higher than expected false positive results. When the intervention effects on the zero (vs. non-zero) and count parts were in the same direction, the MZIP model had the highest statistical power, followed by the linear model with outcomes on raw scale, negative binomial model, and ZIP model. The performance of a linear model with a log-transformed outcome variable was unsatisfactory. When only one of the effects on the zero (vs. non-zero) part and the count part existed, the ZIP model had the highest statistical power. Conclusions: The MZIP model demonstrated better statistical properties in detecting true intervention effects and controlling false positive results for zero-inflated count outcomes. This MZIP model may serve as an appealing analytical approach to evaluating overall intervention effects in studies with count outcomes marked by excessive zeros

Agmatine modulates the phenotype of macrophage acute phase after spinal cord injury in rats

Agmatine is a decarboxylated arginine by arginine decarboxylase. Agmatine is known to be a neuroprotective agent. It has been reported that agmatine works as a NMDA receptor blocker or a competitive nitric oxide synthase inhibitor in CNS injuries. In spinal cord injury, agmatine showed reduction of neuropathic pain, improvement of locomotor function, and neuroprotection. Macrophage is a key cellular component in neuroinflammation, a major cause of impairment after spinal cord injury. Macrophage has subtypes, M1 and M2 macrophages. M1 macrophage induces a pro-inflammatory response, but M2 inspires an anti-inflammatory response. In this study, it was clarified whether the neuroprotective effect of agmatine is related with the modulation of macrophage subdivision after spinal cord injury. Spinal cord injury was induced in rats with contusion using MASCIS. Animals received agmatine (100 mg/ kg, IP) daily for 6 days beginning the day after spinal cord injury. The proportion of M1 and M2 macrophages are confirmed with immunohistochemistry and FACS. CD206+ & ED1+ cells were counted as M2 macrophages. The systemic treatment of agmatine increased M2 macrophages caudal side to epicenter 1 week after spinal cord injury in immunohistochemistry. M2 macrophage related markers, Arginase-1 and CD206 mRNA, were increased in the agmatine treatment group and M2 macrophage expressing and stimulated cytokine, IL-10 mRNA, also was significantly overexpressed by agmatine injection. Among BMPs, BMP2/4/7, agmatine significantly increased only the expression of BMP2 known to reduce M1 macrophage under inflammatory status. These results suggest that agmatine reduces impairment after spinal cord injury through modulating the macrophage phenotype. © Experimental Neurobiology 201

The prevalence and risk factors for pterygium in South Korea: the Korea National Health and Nutrition Examination Survey

OBJECTIVES: To determine the prevalence and risk factors for pterygium in the adult Korean population of South Korea. METHODS: Data were analyzed from 9,193 participants who were 40 years of age or older from the Korea National Health and Nutrition Examination Survey (KNHANES), conducted from 2009 to 2010. Standardized slit-lamp examinations were performed by study ophthalmologists to examine the anterior segment for evidence of pterygium. Pterygium was graded clinically as T1 (atrophic), T2 (intermediate), or T3 (opaque). Every participant underwent ocular and systemic examinations, as well as interviewer-administered questionnaires. Any evidence of pterygium and observed association between the risk factors were recorded. RESULTS: The mean age of the subjects was 55.7 (± 0.2) years. Of the 9,193 eligible subjects, 935 had pterygium in at least one eye. In a multivariate logistic regression analysis adjusted for age and sex, pterygium was significantly associated with rural vs. urban residence (odds ratio [OR], 1.7; 95% confidence interval [CI], 1.4 to 2.0), lower level of education (OR, 4.5; 95% CI, 3.1 to 6.6), low income (OR, 1.3; 95% CI, 1.0 to 1.8), smoking (OR, 0.7; 95% CI, 0.5 to 1.0), and more hours of sun exposure (OR, 1.5; 95% CI, 1.2 to 1.8). After adjusting for all variables, the prevalence of pterygium was significantly associated with age, sex, residence, education level, and smoking. CONCLUSIONS: This is a nationwide epidemiologic study in South Korea to assess the prevalence of and risk factors for pterygium. The overall prevalence of pterygium was 8.8% among Koreans aged 40 years or older. Older age, male gender, rural residence, lower level of education, and non-smoking were associated with the development of pterygium

Diosgenin Induces Apoptosis in HepG2 Cells through Generation of Reactive Oxygen Species and Mitochondrial Pathway

Diosgenin, a naturally occurring steroid saponin found abundantly in legumes and yams, is a precursor of various synthetic steroidal drugs. Diosgenin is studied for the mechanism of its action in apoptotic pathway in human hepatocellular carcinoma cells. Based on DAPI staining, diosgenin-treated cells manifested nuclear shrinkage, condensation, and fragmentation. Treatment of HepG2 cells with 40 μM diosgenin resulted in activation of the caspase-3, -8, -9 and cleavage of poly-ADP-ribose polymerase (PARP) and the release of cytochrome c. In the upstream, diosgenin increased the expression of Bax, decreased the expression of Bid and Bcl-2, and augmented the Bax/Bcl-2 ratio. Diosgenin-induced, dose-dependent induction of apoptosis was accompanied by sustained phosphorylation of JNK, p38 MAPK and apoptosis signal-regulating kinase (ASK)-1, as well as generation of the ROS. NAC administration, a scavenger of ROS, reversed diosgene-induced cell death. These results suggest that diosgenin-induced apoptosis in HepG2 cells through Bcl-2 protein family-mediated mitochndria/caspase-3-dependent pathway. Also, diosgenin strongly generated ROS and this oxidative stress might induce apoptosis through activation of ASK1, which are critical upstream signals for JNK/p38 MAPK activation in HepG2 cancer cells

Post-Intubation Tracheoesophageal Fistula with Posterior Glottic Web

Tracheoesophageal fistula (TEF) after prolonged intubation could present as chronic aspiration and could be mistaken as unilateral or bilateral vocal fold palsy, especially when there was combined posterior glottic synechia. We present a case of post-intubation TEF which was successfully treated with tracheal resection and anastomosis with primary esophageal closure. The accompanying posterior glottic web was treated by endoscopic technique of web lysis, with topical application of mitomycin C solution

The 5'-end transitional CpGs between the CpG islands and retroelements are hypomethylated in association with loss of heterozygosity in gastric cancers

BACKGROUND: A loss of heterozygosity (LOH) represents a unilateral chromosomal loss that reduces the dose of highly repetitive Alu, L1, and LTR retroelements. The aim of this study was to determine if the LOH events can affect the spread of retroelement methylation in the 5'-end transitional area between the CpG islands and their nearest retroelements. METHODS: The 5'-transitional area of all human genes (22,297) was measured according to the nearest retroelements to the transcription start sites. For 50 gastric cancer specimens, the level of LOH events on eight cancer-associated chromosomes was estimated using the microsatellite markers, and the 5'-transitional CpGs of 20 selected genes were examined by methylation analysis using the bisulfite-modified DNA. RESULTS: The extent of the transitional area was significantly shorter with the nearest Alu elements than with the nearest L1 and LTR elements, as well as in the extragenic regions containing a higher density of retroelements than in the intragenic regions. The CpG islands neighbouring a high density of Alu elements were consistently hypomethylated in both normal and tumor tissues. The 5'-transitional methylated CpG sites bordered by a low density of Alu elements or the L1 and LTR elements were hypomethylated more frequently in the high-level LOH cases than in the low-level LOH cases. CONCLUSION: The 5'-transitional methylated CpG sites not completely protected by the Alu elements were hypomethylated in association with LOH events in gastric cancers. This suggests that an irreversible unbalanced decrease in the genomic dose reduces the spread of L1 methylation in the 5'-end regions of genes

The Redistribution of Power: Neurocardiac Signaling, Alcohol and Gender

Human adaptability involves interconnected biological and psychological control processes that determine how successful we are in meeting internal and environmental challenges. Heart rate variability (HRV), the variability in consecutive R-wave to R-wave intervals (RRI) of the electrocardiogram, captures synergy between the brain and cardiovascular control systems that modulate adaptive responding. Here we introduce a qualitatively new dimension of adaptive change in HRV quantified as a redistribution of spectral power by applying the Wasserstein distance with exponent 1 metric (W1) to RRI spectral data. We further derived a new index, D, to specify the direction of spectral redistribution and clarify physiological interpretation. We examined gender differences in real time RRI spectral power response to alcohol, placebo and visual cue challenges. Adaptive changes were observed as changes in power of the various spectral frequency bands (i.e., standard frequency domain HRV indices) and, during both placebo and alcohol intoxication challenges, as changes in the structure (shape) of the RRI spectrum, with a redistribution towards lower frequency oscillations. The overall conclusions from the present study are that the RRI spectrum is capable of a fluid and highly flexible response, even when oscillations (and thus activity at the sinoatrial node) are pharmacologically suppressed, and that low frequency oscillations serve a crucial but less studied role in physical and mental health