Clinicopathologic significance of the delta-like ligand 4, vascular endothelial growth factor, and hypoxia-inducible factor-2α in gallbladder cancer.

BACKGROUND: Gallbladder cancer (GBC) is usually detected in advanced stages with a low 5-year survival rate. Delta-like ligand 4 (DLL4), vascular endothelial growth factor (VEGF), and hypoxia-inducible factor-2alpha (HIF2α) have been studied for their role in tumorigenesis and potential for therapeutic target, and multiple clinical trials of the agents targeting them are ongoing. We investigated the expression of these markers in surgically resected GBC and tried to reveal their association with the clinicopathologic features, mutual correlation of their expression, and prognosis of the GBC patients by their expression. METHODS: We constructed the tissue microarray blocks of 99 surgically resected GBC specimens and performed immunohistochemistry of DLL4, VEGF, and HIF2α. We used the quantitative digital image analysis to evaluate DLL4 and VEGF expression, while the expression of HIF2α was scored manually. RESULTS: The expression of VEGF and HIF2α showed a significant trend with tumor differentiation (p= .028 and p= .006, respectively). We found that the high DLL4 and VEGF expression were significantly correlated with lymph node metastasis (p= .047, both). The expression of VEGF and HIF2α were significantly correlated (p < .001). The GBC patients with low HIF2α expression showed shorter recurrence-free survival than those with high HIF2α expression. CONCLUSIONS: This study suggested the possibility of the usage of DLL4 and VEGF to predict the lymph node metastasis and the possibility of VEGF and HIF2α to predict the expression level mutually. Further studies may be needed to validate our study results and eventually accelerate the introduction of the targeted therapy in GBC.

How many people participated in candlelight protests? Counting the size of a dynamic crowd.

The recent controversy about the size of crowds at candlelight protests in Korea raises an interesting question regarding the methods used to estimate crowd size. Protest organizers tend to count all participants in the event from its start to finish, while the police usually report the crowd size at its peak. While several counting methods are available to estimate the size of a crowd at a given time, counting the total number of the participants at a protest is not straightforward. In this paper, we propose a new estimator to count the total number of participants that we call the size of a dynamic crowd. We assume that the arrival and departure times of the crowd are randomly observed and that the number of the attendees in the crowd at a specific time is estimable. We estimate the number of total attendees during the entire gathering based on the capture-recapture model. We also propose a bootstrap procedure to construct a confidence interval for the crowd size. We demonstrate the performance of the proposed method with simulation studies and the data from Korea's March for Science, a global event across the world on Earth Day, April 22, 2017.

Second primary malignancy risk in thyroid cancer and matched patients with and without radioiodine therapy analysis from the observational health data sciences and informatics.

PURPOSE: Risk of second primary malignancy (SPM) after radioiodine (RAI) therapy has been continuously debated. The aim of this study is to identify the risk of SPM in thyroid cancer (TC) patients with RAI compared with TC patients without RAI from matched cohort. METHODS: Retrospective propensity-matched cohorts were constructed across 4 hospitals in South Korea via the Observational Health Data Science and Informatics (OHDSI), and electrical health records were converted to data of common data model. TC patients who received RAI therapy constituted the target group, whereas TC patients without RAI therapy constituted the comparative group with 1:1 propensity score matching. Hazard ratio (HR) by Cox proportional hazard model was used to estimate the risk of SPM, and meta-analysis was performed to pool the HRs. RESULTS: Among a total of 24,318 patients, 5,374 patients from each group were analyzed (mean age 48.9 and 49.2, women 79.4% and 79.5% for target and comparative group, respectively). All hazard ratios of SPM in TC patients with RAI therapy were ≤ 1 based on 95% confidence interval(CI) from full or subgroup analyses according to thyroid cancer stage, time-at-risk period, SPM subtype (hematologic or non-hematologic), and initial age (< 30 years or ≥ 30 years). The HR within the target group was not significantly higher (< 1) in patients who received over 3.7 GBq of I-131 compared with patients who received less than 3.7 GBq of I-131 based on 95% CI. CONCLUSION: There was no significant difference of the SPM risk between TC patients treated with I-131 and propensity-matched TC patients without I-131 therapy.

Estimation of the case fatality rate based on stratification for the COVID-19 outbreak.

This work is motivated by the recent worldwide pandemic of the novel coronavirus disease (COVID-19). When an epidemiological disease is prevalent, estimating the case fatality rate, the proportion of deaths out of the total cases, accurately and quickly is important as the case fatality rate is one of the crucial indicators of the risk of a disease. In this work, we propose an alternative estimator of the case fatality rate that provides more accurate estimate during an outbreak by reducing the downward bias (underestimation) of the naive CFR, the proportion of deaths out of confirmed cases at each time point, which is the most commonly used estimator due to the simplicity. The proposed estimator is designed to achieve the availability of real-time update by using the commonly reported quantities, the numbers of confirmed, cured, deceased cases, in the computation. To enhance the accuracy, the proposed estimator adapts a stratification, which allows the estimator to use information from heterogeneous strata separately. By the COVID-19 cases of China, South Korea and the United States, we numerically show the proposed stratification-based estimator plays a role of providing an early warning about the severity of a epidemiological disease that estimates the final case fatality rate accurately and shows faster convergence to the final case fatality rate.

Serum fibrinogen as a diagnostic and prognostic biomarker for pancreatic ductal adenocarcinoma.

BACKGROUND/OBJECTIVES: Early diagnosis of pancreatic ductal adenocarcinoma (PDAC) is important as PDAC can lead to mortality; however, no specific biomarker has been identified for its early diagnosis. We previously identified fibrinogen α chain as a promising biomarker for differentiating between patients with and without PDAC using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Here, we aimed to validate the clinical usefulness of serum fibrinogen as a biomarker for PDAC. METHODS: From 2009 to 2011, blood samples of 67 PDAC patients and 43 healthy adults (controls) were prospectively collected. Serum fibrinogen levels and their clinical significances were evaluated. RESULTS: Mean fibrinogen levels were significantly higher in the PDAC group than in the control group (3.08 ± 0.565 vs. 2.54 ± 0.249 log10 ng/mL, P < 0.001). In the receiver operating characteristic analysis, overall sensitivity, and specificity of serum fibrinogen levels for differentiating PDAC patients from control patients were 67.4% and 83.6%, respectively, with a 427-ng/mL cutoff value. Serum fibrinogen levels were significantly higher in PDAC patients with distant metastasis than in those without distant metastasis (3.38 ± 0.581 vs. 2.93 ± 0.499 log10 ng/mL, P = 0.002). Median overall survival was significantly longer in PDAC patients with low fibrinogen levels (<1000 ng/mL) than in those with high fibrinogen levels (≥1000 ng/mL) [489 days (95% confidence interval, 248.1-729.9) vs. 172 days (58.4-285.6) (P = 0.008)]. Although serum fibrinogen levels were poorly correlated with carbohydrate antigen 19-9 levels, these two biomarkers together predicted survival better. CONCLUSIONS: Serum fibrinogen levels may be a useful biomarker for diagnosing and predicting PDAC prognosis.

Human field of regard, field of view, and attention bias.

BACKGROUND AND OBJECTIVE: Human field of regard (FOR) is an important concept that should be considered along with field of view (FOV) for people with/without handicaps, but previous studies have neglected this aspect of human perception. In the current study, we suggest and test a new virtual reality (VR) software with which to evaluate individual's detection abilities in the human FOR. METHODS: We conducted measurements of human FOV, FOR, and FOR with visual cue (FOR-cue), and we evaluated healthy adults' responses in a first experiment. Participants were asked to detect targets on a head-mounted display (HMD) as quickly as possible in three conditions: (a) FOV: the head rotation doesn't change the view of the screen in the HMD; (b) FOR: the head rotation changes the view of the screen in the HMD; and (c) FOR-cue: same with the FOR condition but an endogenous visual cue indicating the direction of stimulus. To address the need to increase the number of trials in the FOR condition, we also conducted a second experiment with new samples and four times of trial numbers. RESULTS: The participants' detection time results indicated that the FOV condition was faster than the FOR-cue and FOR conditions, and the FOR-cue was faster than the FOR condition. Interestingly, we found a unique characteristic in the FOR conditions that did not exist in the FOV condition: The target responses were faster for the left side than the right side. The results of the second experiment were consistent with the first, and head motion trajectory analysis showed that participants had more movement toward the left side than the right side in the early parts of each trial. CONCLUSIONS: In this study, we suggested a new virtual reality (VR) evaluation technique and measured the human searching pattern in the FOR condition. We found a unique left-side attention bias in the FOR condition, and discussed implication of these results and potential attention bias factors. We believe this work is an important foundation for interactive 3D UI design, and we hope it will help people who have FOR handicaps.

Familial Clustering of Gastric Cancer: A Retrospective Study Based on the Number of First-Degree Relatives.

This comprehensive cross-sectional study aimed to identify factors contributing to familial aggregation of gastric cancer (GC). A total of 1058 GC patients and 1268 controls were analyzed separately according to the presence or absence of a first-degree relative of GC (GC-relative). Logistic regression analysis adjusted for age, gender, residence during childhood, smoking, alcohol intake, monthly income, spicy food ingestion, Helicobacter pylori status and host cytokine polymorphisms was performed. Cytotoxin-associated gene A (cagA) positivity was a distinctive risk factor for GC in the family history (FH)-positive group (odds ratio [OR], 2.39; 95% confidence interval [CI], 1.42-4.00), while current/ex-smoker, moderate to strong spicy food ingestion, and non-B blood types were more closely associated with GC in the FH-negative group. Among the FH-positive group, alcohol consumption showed a synergistic carcinogenic effect in the at least 2 GC-relatives group compared to the 1 GC-relative group (1.71 vs. 9.58, P for interaction = 0.026), and this was dose-dependent. In the subjects with ≥2 GC-relatives, TGFB1-509T/T was a risk factor for GC (OR 23.74; 95% CI 1.37-410.91), as were rural residency in childhood, alcohol consumption, spicy food ingestion, and cagA positivity. These results suggest that subjects with FH may be a heterogeneous group in terms of gastric cancer susceptibility. Especially, subjects with ≥2 GC-relatives should undergo risk stratification including TGFB1-509T/T and alcohol consumption.

Association between RELN Gene Polymorphisms and Attention Deficit Hyperactivity Disorder in Korean Children.

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is common disorder of the school-age population. ADHD is familial and genetic studies estimate heritability at 80-90%. The aim of the present study was to investigate the association between the genetic type and alleles for RELNgene (rs736707, rs2229864, rs362746, rs362726, rs362691, rs1062831, rs607755, and rs2072403) in Korean children with ADHD. METHODS: The sample consisted of 180 ADHD children and 159 control children. We diagnosed ADHD according to DSM-IV. ADHD symptoms were evaluated with Conners' Parent Rating Scales and Dupaul Parent ADHD Rating Scales. Blood samples were taken from the 339 subjects, DNA was extracted from blood lymphocytes, and PCR was performed for RELN Polymorphism. Alleles and genotype frequencies were compared using the chi-square test. We compared the allele and genotype frequencies of RELN gene polymorphism in the ADHD and control groups. RESULTS: This study showed that there was a significant correlation among the frequencies of the rs736707 (OR=1.40, 95% CI=1.03-1.90, p=0.031) of alleles of RELN, but the final conclusions are not definite. CONCLUSION: Follow up studies with larger patient or pure subgroups are expected. These results suggested that RELN might be related to ADHD symptoms.

Incorporating spatial dependence into Bayesian multiple testing of statistical parametric maps in functional neuroimaging.

The analysis of functional neuroimaging data often involves the simultaneous testing for activation at thousands of voxels, leading to a massive multiple testing problem. This is true whether the data analyzed are time courses observed at each voxel or a collection of summary statistics such as statistical parametric maps (SPMs). It is known that classical multiplicity corrections become strongly conservative in the presence of a massive number of tests. Some more popular approaches for thresholding imaging data, such as the Benjamini-Hochberg step-up procedure for false discovery rate control, tend to lose precision or power when the assumption of independence of the data does not hold. Bayesian approaches to large scale simultaneous inference also often rely on the assumption of independence. We introduce a spatial dependence structure into a Bayesian testing model for the analysis of SPMs. By using SPMs rather than the voxel time courses, much of the computational burden of Bayesian analysis is mitigated. Increased power is demonstrated by using the dependence model to draw inference on a real dataset collected in a fMRI study of cognitive control. The model also is shown to lead to improved identification of neural activation patterns known to be associated with eye movement tasks.

Detection of pancreatic cancer biomarkers using mass spectrometry.

BACKGROUND: Pancreatic cancer is the fourth leading cause of cancer-related deaths. Therefore, in order to improve survival rates, the development of biomarkers for early diagnosis is crucial. Recently, diabetes has been associated with an increased risk of pancreatic cancer. The aims of this study were to search for novel serum biomarkers that could be used for early diagnosis of pancreatic cancer and to identify whether diabetes was a risk factor for this disease. METHODS: Blood samples were collected from 25 patients with diabetes (control) and 93 patients with pancreatic cancer (including 53 patients with diabetes), and analyzed using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF/MS). We performed preprocessing, and various classification methods with imputation were used to replace the missing values. To validate the selection of biomarkers identified in pancreatic cancer patients, we measured biomarker intensity in pancreatic cancer patients with diabetes following surgical resection and compared our results with those from control (diabetes-only) patients. RESULTS: By using various classification methods, we identified the commonly splitting protein peaks as m/z 1,465, 1,206, and 1,020. In the follow-up study, in which we assessed biomarkers in pancreatic cancer patients with diabetes after surgical resection, we found that the intensities of m/z at 1,465, 1,206, and 1,020 became comparable with those of diabetes-only patients.

Development and validation of the Good Outcome Following Attempted Resuscitation (GO-FAR) score to predict neurologically intact survival after in-hospital cardiopulmonary resuscitation.

IMPORTANCE: Informing patients and providers of the likelihood of survival after in-hospital cardiac arrest (IHCA), neurologically intact or with minimal deficits, may be useful when discussing do-not-attempt-resuscitation orders. OBJECTIVE: To develop a simple prearrest point score that can identify patients unlikely to survive IHCA, neurologically intact or with minimal deficits. DESIGN, SETTING, AND PARTICIPANTS: The study included 51,240 inpatients experiencing an index episode of IHCA between January 1, 2007, and December 31, 2009, in 366 hospitals participating in the Get With the Guidelines-Resuscitation registry. Dividing data into training (44.4%), test (22.2%), and validation (33.4%) data sets, we used multivariate methods to select the best independent predictors of good neurologic outcome, created a series of candidate decision models, and used the test data set to select the model that best classified patients as having a very low (<1%), low (1%-3%), average (>3%-15%), or higher than average (>15%) likelihood of survival after in-hospital cardiopulmonary resuscitation for IHCA with good neurologic status. The final model was evaluated using the validation data set. MAIN OUTCOMES AND MEASURES: Survival to discharge after in-hospital cardiopulmonary resuscitation for IHCA with good neurologic status (neurologically intact or with minimal deficits) based on a Cerebral Performance Category score of 1. RESULTS: The best performing model was a simple point score based on 13 prearrest variables. The C statistic was 0.78 when applied to the validation set. It identified the likelihood of a good outcome as very low in 9.4% of patients (good outcome in 0.9%), low in 18.9% (good outcome in 1.7%), average in 54.0% (good outcome in 9.4%), and above average in 17.7% (good outcome in 27.5%). Overall, the score can identify more than one-quarter of patients as having a low or very low likelihood of survival to discharge, neurologically intact or with minimal deficits after IHCA (good outcome in 1.4%). CONCLUSIONS AND RELEVANCE: The Good Outcome Following Attempted Resuscitation (GO-FAR) scoring system identifies patients who are unlikely to benefit from a resuscitation attempt should they experience IHCA. This information can be used as part of a shared decision regarding do-not-attempt-resuscitation orders.

Spatially discordant voltage alternans cause wavebreaks in ventricular fibrillation.

BACKGROUND: Ventricular fibrillation (VF) is characterized by complex ECG patterns emanating from multiple, short-lived, reentrant electrical waves. The incessant breakup and creation of new daughter waves (wavebreaks) perpetuate VF. Dispersion of refractoriness (static or dynamic) has been implicated as a mechanism underlying wavebreaks. OBJECTIVE: The purpose of this study was to investigate the mechanisms underlying wavefront instability in VF by localizing wave fractionation sites (the appearance of multiple waves) and their relationship to local spatial dispersion of voltage (V(m)) oscillations. METHODS: Wave fractionations were identified by tracking V(m) oscillations optically at unprecedented spatial (100 x 100 pixels) and temporal (2,000 frames per second) resolution using a CMOS camera viewing the surface (1 x 1 cm(2)) of perfused guinea pig hearts (n = 6). VF was induced by burst stimulation, and wavefront dynamics were highlighted using region-based image analysis to automatically detect wavebreaks. Direct detection of wavebreak locations by image analysis was more reliable than the phase reconstruction method because baseline noise obstructed the correct identification of phase singularities by detecting false-positives. RESULTS: Wave fractionations (34 +/- 4 splits/s.cm(2)) fell into three categories: decremental conduction (49% +/- 7%), wave collisions (32% +/- 8%), and wavebreaks (17 +/- 2%). Wavebreaks occurred at a frequency of 5.8 +/- 1 splits/s.cm(2) and did not preferentially occur at anatomic obstacles (i.e., coronary vessels) but coincided with discordant alternans where V(m) amplitudes and durations shifted from high to low to from low to high on opposite sides of wavebreak sites. CONCLUSION: Spatial discordant alternans cause wavebreaks most likely because they are sites of abrupt dispersion of refractoriness.

How accurately can we control the FDR in analyzing microarray data?

SUMMARY: We want to evaluate the performance of two FDR-based multiple testing procedures by Benjamini and Hochberg (1995, J. R. Stat. Soc. Ser. B, 57, 289-300) and Storey (2002, J. R. Stat. Soc. Ser. B, 64, 479-498) in analyzing real microarray data. These procedures commonly require independence or weak dependence of the test statistics. However, expression levels of different genes from each array are usually correlated due to coexpressing genes and various sources of errors from experiment-specific and subject-specific conditions that are not adjusted for in data analysis. Because of high dimensionality of microarray data, it is usually impossible to check whether the weak dependence condition is met for a given dataset or not. We propose to generate a large number of test statistics from a simulation model which has asymptotically (in terms of the number of arrays) the same correlation structure as the test statistics that will be calculated from the given data and to investigate how accurately the FDR-based testing procedures control the FDR on the simulated data. Our approach is to directly check the performance of these procedures for a given dataset, rather than to check the weak dependency requirement. We illustrate the proposed method with real microarray datasets, one where the clinical endpoint is disease group and another where it is survival.

Development of PCR-ELISA for the detection of hepatitis B virus x gene expression and clinical application.

The presence of hepatitis B virus x (HBx) antigen/antibody is known to correlate with the well-established serological markers of ongoing viral replication in the chronic phase of HBV infection, and strongly suggests that the level and duration of HBx expression may influence the outcome of the chronic infection. In this research, we developed a polymerase chain reaction enzyme-linked immunosorbent assay (PCR-ELISA) method for the detection of HBx gene expression. We also investigated its relationship to the progress of the disease in HBV-related patients. Peripheral blood mononuclear cells (PBMCs) were purely isolated, and reverse transcription-PCR (RT-PCR) was performed for improved sensitivity. The PCR products were determined by ELISA, and we investigated the relationship of the proposed method to the clinical status of the patients. The PCR-ELISA used in this work was found to be at least 100 times more sensitive than the conventional PCR method, and even 8,000-fold diluted PCR products could be detected. The HBx concentrations significantly differed among control subjects (0.36+/-0.09, [P<0.01] and patients with chronic hepatitis (1.13+/-0.34 [P<0.01 compared to control]), liver cirrhosis (LC; 1.37+/-0.28 [P<0.01 compared to control]), and hepatocellular carcinoma (HCC; 1.48+/-0.95 [P<0.01 compared to control]). These findings suggest that monitoring of HBx could be useful for early diagnosis and prognosis in patients with chronic HBV infection, LC, and HCC.

Effects of ylang-ylang essential oil on the relaxation of rat bladder muscle in vitro and white rabbit bladder in vivo.

Current and primary treatment modality in overactive bladder includes the administration of anticholinergics. The demand for new agents has been rising since anticholinergics have proven to come with many side effects. This study was designed to investigate the effects of ylang-ylang essential oil (YYEO) on the relaxation of urinary bladder muscle in vitro and in vivo. Effects of YYEO were assessed on resting tension, and electrical field stimulation- and various drug-induced contraction in vitro by checking the isometric tension changes of muscle strips and same procedures were repeated in the presence of methylene blue, Nw-Nitro-L-arginine methyl ester hydrochloride (L-NAME), or N-ethylmaleimide, and in vivo. YYEO decreased significantly the contractility of strips. There was no statistically significant difference between the treated group only with YYEO and the pretreated group with YYEO and methylene blue or L-NAME. When N-ethylmaleimide was employed, there was a statistically significant decrease in the rate of contraction. In vivo studies showed the same results compared with in vitro study. The results of this study indicate that YYEO has a relaxing effect on the bladder, and such mechanism is thought to be brought about by a pathway mediated by c-AMP.