Positive Z-score Research Articles

Overcoming Dimensionality Constraints: A Gershgorin Circle Theorem-Based Feature Extraction for Weighted Laplacian Matrices in Computer Vision Applications.

In graph theory, the weighted Laplacian matrix is the most utilized technique to interpret the local and global properties of a complex graph structure within computer vision applications. However, with increasing graph nodes, the Laplacian matrix's dimensionality also increases accordingly. Therefore, there is always the "curse of dimensionality"; In response to this challenge, this paper introduces a new approach to reducing the dimensionality of the weighted Laplacian matrix by utilizing the Gershgorin circle theorem by transforming the weighted Laplacian matrix into a strictly diagonal domain and then estimating rough eigenvalue inclusion of a matrix. The estimated inclusions are represented as reduced features, termed GC features; The proposed Gershgorin circle feature extraction (GCFE) method was evaluated using three publicly accessible computer vision datasets, varying image patch sizes, and three different graph types. The GCFE method was compared with eight distinct studies. The GCFE demonstrated a notable positive Z-score compared to other feature extraction methods such as I-PCA, kernel PCA, and spectral embedding. Specifically, it achieved an average Z-score of 6.953 with the 2D grid graph type and 4.473 with the pairwise graph type, particularly on the E_Balanced dataset. Furthermore, it was observed that while the accuracy of most major feature extraction methods declined with smaller image patch sizes, the GCFE maintained consistent accuracy across all tested image patch sizes. When the GCFE method was applied to the E_MNSIT dataset using the K-NN graph type, the GCFE method confirmed its consistent accuracy performance, evidenced by a low standard deviation (SD) of 0.305. This performance was notably lower compared to other methods like Isomap, which had an SD of 1.665, and LLE, which had an SD of 1.325; The GCFE outperformed most feature extraction methods in terms of classification accuracy and computational efficiency. The GCFE method also requires fewer training parameters for deep-learning models than the traditional weighted Laplacian method, establishing its potential for more effective and efficient feature extraction in computer vision tasks.

The variation in preventable hospitalization in patients with type 2 diabetes in Kentucky before and after the Medicaid expansion.

Hospitalizations are more resource intensive and expensive than outpatient care. Therefore, type 2 diabetes-related preventable hospitalization are a major topic of research efficiency in the healthcare system. Analyze county level variation in type 2 diabetes-related preventable hospitalization rates in Kentucky before the Medicaid expansion (2010-2013) and after the Medicaid expansion (2014-2017). Geographic mapping and cluster analysis. Data for a state of the United States of America. We used the KID data to generate geographic mapping for type 2 diabetes-related preventable hospitalizations to visualize rates. We included all Kentucky discharges of age 18 years and older with the ICD9/10 principal diagnosis code for type 2 diabetes. Then, we conducted cluster analysis techniques to compare county-level variation in type 2 diabetes-related preventable hospitalization rates across Kentucky counties pre- and post-Medicaid expansion. County type 2 diabetes-related preventable hospitalization pre- and post-Medicaid expansion. From 2010-2017, type 2 diabetes-related preventable hospitalization discharge rates reduced significantly in the period of the post-Medicaid expansion (P=.001). The spatial statistics analysis revealed a significant spatial clustering of counties with similar rates of type 2 diabetes-related preventable hospitalization in the south, east, and southeastern Kentucky pre- and post-Medicaid expansion (positive z-score and positive Moran's Index value (P>.05). Also, there was a significant clustering of counties with low type 2 diabetes-related preventable hospitalization rates in the north, west, and central regions of the state pre-Medicaid expansion and post-Medicaid expansion (positive z-score and positive Moran's Index value (P>.05). Kentucky counties in the southeast have experienced a significant clustering of highly avoidable hospitalization rates during both periods. Focusing on the vulnerable counties and the economic inequality in Kentucky could lead to efforts to lowering future type 2 diabetes-related preventable hospitalization rates. We used de-identified data which does not provide insights into the frequency of hospitalizations per patient. An individual patient may be hospitalized several times and counted as several individuals.

Functional and transcriptional sequelae of cardiomyocyte telomere shortening and their pathologic relevance in dilated cardiomyopathy and ischemic heart failure

Abstract Background Heart failure (HF) is associated with cardiomyocyte (CM) telomere shortening. Sequelae have been described with the telomere-p53-mitochondrion model. P53 deficiency only partially ameliorates mitochondrial defects in telomerase deficient mice hinting at additional pathways. Purpose We assessed the cardiac phenotype and transcriptome of early/advanced telomere shortening and evaluated the pathological relevance by correlation to published HF datasets. Methods Male (6-8w) telomerase RNA-component deficient mice, early (generation 2, mTRG2) and advanced (mTRG5) were phenotyped vs age-matched C57BL/6 mice (B6). Adult CMs from mTRG2/G5 vs B6 mice were characterized (live imaging, quantitative fluorescence in situ hybridization (Q-FISH) and transcriptome analysis (microarray Mouse MTA 1.0)). Gene expression analysis was performed (Ingenuity Pathway Analysis, Qiagen) and correlated to comparable datasets from > 120 000 curated datasets. Results CMs exhibited significant telomere shortening in mTR(-/-) mice increasing with every generation (mTRG2/G5 p<0.0001 vs B6). In parallel, echocardiography revealed increasing defects of left ventricular (LV) systolic function (LVEF, mTRG5 <0.01 vs B6), LV global longitudinal strain mTRG2/G5 p<0.001 vs B6) and LV contractile reserve (mTRG2/G5 p<0.05 vs B6). Live imaging showed increasing impairment of mitochondrial polarization with all energy substrates (mTRG2/G5 p<0.0001 vs B6). Transcriptome analysis revealed 357/2906 differentially expressed genes (DEGs) in mTRG2/G5-CMs vs B6-CMs (fold change <-1.5 or >1.5 and p-value <0.05). Upstream Regulator (UR) analysis revealed significant overrepresentation of numerous regulators including angiotensinogen (z-score 7.5, p-value 1.1E-32), transforming growth factor (TGF)-b1 (z-score 7.5, p-value 2.2E-60), interleukin (IL)-1 (z-score 5.6, p-value 1.1E-26), IL-6 (expression fold change 11.3, z-score 6.9 p-value 2.65E-32), IL-17A (z-score 4.8, p-value 4.4E-27) and NFkB (z-score 6.0 p-value 4.9E-19). Activation of TP53 (z-score 5.8, p-value 5.3E-31) and inhibition of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) (z-score -4.4, p-value 6.3E-19) confirmed the relevance of the p53-mitochondrion-axis. Analysis matching revealed a significant overlap of gene expression patterns in the same direction (positive z-score) between mTR-/--mice and all comparable datasets of dilated (DCM) and ischemic cardiomyopathy (ICM) (human/mouse), the overlap increasing with increasing telomere shortening (e.g. DCM vs mTRG2: z-score 17.7, UR p-value 1.5E-16; DCM vs mTRG5: z-score 56.8, UR-value 1.5E-62). Matching to datasets after cardiac regeneration (e.g. after left ventricular assist device implantation) revealed a reversal of gene expression patterns (negative z-score). Conclusions Our results reveal the large extent of transcriptional alterations upon cardiac telomere shortening and support their central role in the pathogenesis of HF.

Surfaceome profiling to reveal unique therapeutic vulnerabilities in transcriptional subtypes of small cell lung cancer (SCLC).

8515 Background: Effective treatment options for SCLC remain limited and new treatment approaches are needed to improve outcome. We sought to validate the initial observation in cell lines and limited tissue samples of SCLC of a differential expression of cancer/testis (CT) antigens and TACSD2 gene that encodes surface protein, Trop2 across various subtypes of SCLC. We also tested whether overall surfaceome profile as previously described in other tumor types will show hierarchical priority of expression between transcriptionally defined SCLC subtypes. Methods: We conducted a comprehensive surfaceome profiling of SCLC samples using data generated by RNA sequencing (whole transcriptome) at Caris Life Sciences (Phoenix, AZ). SCLC tumors were stratified into 5 subgroups (SCLC-A/N/Y/P and -mixed) based on the relative expression of the four transcription factors. Expression values were converted to z-scores (the expression value for each gene is normalized to the average expression of that specific gene such that the z-score reflects the number of standard deviations above or below the average). The highest positive z-score among the 4 transcription factors determined subgroup. If all transcription factor z-scores for a given sample were negative, the sample was assigned to ‘Mixed’ subgroup. Significance was tested by Chi-square, Fisher’s exact test, or Mann-Whitney U test. Results: We employed data generated from 674 SCLC samples; median age of 66 years and male (48.7%). The SCLC subtype distribution was 241 (35.8%), 120 (17.8%), 40 (5.9%), 143 (21.2%), 130 (19.3%) for types A, N, P, Y and mixed respectively. Supervised analysis for TACSTD2 expression showed highest levels in YAP1 subtype and was overall significantly increased in SCLC-Y (̃3-fold) and SCLC-P (̃2-fold) subtypes compared to A, N and mixed subtypes. Similarly, SCLC-Y subtype showed the highest median expression as well as the strongest correlation with most TACSTD2-interacting and regulatory genes. A top 10 list of candidate surface protein gene out of 3699 surfaceome genes was defined for each subtype based on the strength of correlation. The top candidate surface protein gene and CT antigen gene respectively by subtype were: SCN3A (r = 0.7033, p = 1.08E-101) and NOL4, (r = 0.574, p = 2.46E-60) for SCLC-A; SSTR2, (r = 0.742, p = 8.18E-119) and TMEFF1, (r = 0.3601, p = 4.53E-22) for SCLC-N; TMPRSS13 (r = 0.5699, p = 2.64E-59) and LY6K (r = 0.4778, p = 9.80E-40) for SCLC-P; and CYBRD1 (r = 0.8559, p = 1.18E-194) and CTAGE5 (r = 0.5521, p = 4.95E-55) for SCLC-Y. Conclusions: SCLC-Y subtype showed the highest expression of TACSTD2 and its interacting and regulatory genes. This subtype could serve as an enrichment factor for antibody-drug-construct targeting TROP2. Several candidate CT antigens and surfaceome genes showing strong correlation with lineage-defining transcription factors offer additional therapeutic targets in SCLC.

Analisis Titik Rawan Kecelakaan di Jalan Kertanegara Kabupaten Malang

Kertanegara is one of the roads in Malang Regency. The location of Kartanegara Road is considered to be one of the locations prone to accidents due to the lack of traffic infrastructures such as signs and road markings. The road is also an alternative highway that connects Malang Regency to Batu City. The data obtained shows that traffic accidents amounted to 43 of all types of traffic violations from 2016-2018. In 2016, 2017, and 2018, the number of accident victims was 18 accidents, 9 accidents, and 16 accidents. The purpose of this study is to determine the characteristics of Kertanegara road, accident-prone points, and solutions used to reduce the number of accidents. The analytical method used is the analysis of road characteristics, Z-Score, and Cusum analysis. The results obtained that service level of Kertanegara road is 0.61 where the flow is stable, the traffic density is moderate. Based on the analysis of the determination of accident-prone points, the result of Kartanegara road segment, Malang Regency, has a Z-Score for segment I of 0.25 and segment II of 0.17 which is included in the accident-prone criteria because it has a positive Z-Score. Kartanegara Road has also been identified as a black spot because it has a positive cusum value, including the Cusum segment I values of 7.00 and segment II of 13.3. The solution is to provide a traffic sign in the form of a traffic light at the intersection of Police Karangploso road and the intersection of Sentana road, providing management officer traffic flow in Simpang Nuril road and providing warning signs that are prone to accidents and vehicle speed limit at the Crossroads Kauman I and intersection Nuril road.

Enhancing Classification Performance of fNIRS-BCI by Identifying Cortically Active Channels Using the z-Score Method.

A state-of-the-art brain–computer interface (BCI) system includes brain signal acquisition, noise removal, channel selection, feature extraction, classification, and an application interface. In functional near-infrared spectroscopy-based BCI (fNIRS-BCI) channel selection may enhance classification performance by identifying suitable brain regions that contain brain activity. In this study, the z-score method for channel selection is proposed to improve fNIRS-BCI performance. The proposed method uses cross-correlation to match the similarity between desired and recorded brain activity signals, followed by forming a vector of each channel’s correlation coefficients’ maximum values. After that, the z-score is calculated for each value of that vector. A channel is selected based on a positive z-score value. The proposed method is applied to an open-access dataset containing mental arithmetic (MA) and motor imagery (MI) tasks for twenty-nine subjects. The proposed method is compared with the conventional t-value method and with no channel selected, i.e., using all channels. The z-score method yielded significantly improved (p < 0.0167) classification accuracies of 87.2 ± 7.0%, 88.4 ± 6.2%, and 88.1 ± 6.9% for left motor imagery (LMI) vs. rest, right motor imagery (RMI) vs. rest, and mental arithmetic (MA) vs. rest, respectively. The proposed method is also validated on an open-access database of 17 subjects, containing right-hand finger tapping (RFT), left-hand finger tapping (LFT), and dominant side foot tapping (FT) tasks.The study shows an enhanced performance of the z-score method over the t-value method as an advancement in efforts to improve state-of-the-art fNIRS-BCI systems’ performance.

Abstract MP05: Impact of Gentrification on Cardiovascular Risk Factors and Outcomes in England: 2004-2018

Introduction: Dynamic changes to neighborhoods due to forces such as gentrification impact the health of residents. Much of this research has been conducted within the United States, where racial disparities and access to healthcare impact risk for health outcomes. Internationally, other factors may play a more prominent role in the association between gentrification and cardiovascular risk factors and outcomes. Hypothesis: Residents living in gentrified vs. non-gentrified neighborhoods will have lower odds of diabetes (DM), hypertension (HTN), depression and cardiovascular disease (CVD). Methods: We defined gentrification using changes in domains of the Index of Multiple Deprivation (IMD) at the level of the Lower Layer Super Output Areas (LSOA) in England from 2004-2010. We used all IMD domains (income, employment, education, crime, barriers to housing, and living environment), except the health domain, from 2004 and 2010 to define LSOA deprivation. The IMD for each LSOA was standardized to the mean IMD of England using z-scores. LSOAs were eligible to be gentrified if they had a positive z-score in 2004 and were considered to gentrify if they had a negative change in the transformed IMD from 2004 to 2010. We linked these data to individual participants in the Understanding Society Study (USS). The USS is a nationally representative cohort study of 60,000 United Kingdom residents started in 2009 with follow-up ongoing. We limited the analysis to residents in England who lived in top and bottom 25% deprived LSOAs (n=8782). We used multivariable logistic regression to calculate the odds ratio for self-reported DM, HTN, depression, and CVD in residents in neighborhoods that did and did not gentrify, adjusting for race, sex, length of residence (LOR), baseline IMD score, and baseline prevalence of health conditions. Results were stratified by age (&lt;65 &amp; &gt;=65 years) and median LOR (&lt;13 &amp; &gt;=13 years). Results: At baseline, 8782 participants had a median age of 43 years, 4% were black and 55% were female. There was no significant difference in the prevalence of DM, HTN, depression, or CVD at baseline. At follow-up, overall, there were no significant difference in the odds of DM, HTN, or CVD between residents living in gentrified vs. non-gentrified neighborhoods. Residents in neighborhoods that gentrified had a 39% lower odds of depression as compared to participants living in neighborhoods that did not gentrify (p=0.01). Results were not significantly modified by age or length of residence. Conclusions: Residents living in gentrified neighborhoods did not have differential risk for most CVD risk factors and outcomes as compared to residents living in neighborhoods that did not gentrify. However, the impact of gentrification on health is not uniform across all conditions. The positive health impact seen may suggest gentrification increases access to resources not present prior to gentrification.

P135 MAJOR GENE REGULATORS AFFECTED IN COLON AND BLOOD OF DEXTRAN SODIUM SULFATE ACUTE COLITIS MURINE MODEL

Abstract Background Dextran sulfate sodium (DSS) ulcerative colitis (UC) murine models have long been used for in vivo studies. DSS is a negatively charged polysaccharide with colitogenic properties. Although the mechanisms by which DSS induces intestinal inflammation are not fully understood, there are several good reasons why the DSS chemical colitis model for investigating the immunopathogenesis mechanism of UC is widely used. These include strong phenotypic clinical manifestations which emulate numerous clinical and histopathological features of human UC, ease of use, low mortality rate and high reproducibility. Here, by using high-throughput RNA sequencing analysis we set to investigate the major predicted gene regulators (GRs) affected by differentially expressed genes in the DSS treated UC model in order to obtain regulatory insights into the pathogenic mechanisms of UC development. Methods A DSS-induced mouse model of UC was established. Total RNA from colon tissue and blood of 3 healthy and 3 DSS-treated mice was extracted and sequenced by Illumina HiSeq 4000. Gene expression levels were obtained by mapping and quantification to the annotated mouse genome. Subsequently, differential gene expression analysis between DSS-treated and control mice both in colon and blood was performed. Ingenuity pathway analysis software (IPA®, Qiagen) was used to predict/identify major GRs affected by significantly differentially expressed genes (SDEGs, FC &amp;gt; |2|, p ≤0.05) in both colon and blood. Results Our analysis revealed how many and which major GRs are affected in DSS-treated mice and also the direction of change as compared to healthy (untreated) mice. In colon, 595 activated and 198 inhibited major GRs (p-value of overlap ≤0.05) in relation to ∼ 3180 SDEGs were identified, while in blood, we identified 205 activated and 62 inhibited GRs (in relation to ∼650 SDEGs). Colon and blood share 181 activated and 41 inhibited GRs. Identified GRs include transcription regulators, cytokines, transmembrane receptors and enzymes that mainly contribute to the development of inflammatory/immune responses. In colon and blood, the top 10 activated and inhibited regulators with the highest positive and negative activation z-score with target molecules as well as expression in the datasets are indicated in Figure 1a and 1b, respectively. Conclusion In this study, we analyzed linkage of GRs to SDEGs through coordinated expression and identified potential major regulators that have significant effect on UC pathogenic-related gene expression. These GRs seem to be the key regulators of transcriptomic changes induced by inflammation. These findings expand our molecular understanding of putative new targets that may be important in the pathophysiology of UC and provide biological insights into the observed expression changes between the UC and healthy controls.

1965P - Comparison of molecular profiles between primary tumour and matched metastasis in non-small cell lung cancer

1965P - Comparison of molecular profiles between primary tumour and matched metastasis in non-small cell lung cancer

Abstract 017: Impact of Gentrification on Cardiovascular Disease Surveillance Using Data from the Electronic Health Record

Introduction: Current static approaches of CVD surveillance may not capture the true health of neighborhoods as the influx of younger, healthier, and wealthier individuals (i.e., gentrification) can impact long term residents (LTR) who can be older and of lower socioeconomic status (SES), potentially biasing prevalence estimates. Hypothesis: LTR in gentrifying vs. LTR in non-gentrifying neighborhoods will have a lower prevalence of CVD related conditions. Methods: We quantified the census tract prevalence of diabetes (DM), hypertension (HTN), obesity, and CVD (myocardial infarction or stroke hospitalization) using electronic health record (EHR) data from the Duke Health System and Lincoln Community Health Center from 2008-2010 and 2014-2016. The EHR population was 116,760 patients living in Durham County in 2008 followed until 12/31/16. LTR were patients with the same 2010 and 2015 address; patients moving in/out (i.e., movers) did not have a recorded address in 2010 or 2015. A census tract was defined as gentrifying if 3 of 4 SES indicators (positive z-score for median household income, median rental price, % with bachelor’s degree, or a negative z-score for % living below the poverty line) improved. In difference-in-difference (DiD) analysis, we compared changes in prevalence of CVD health indicators between LTR in gentrifying and non-gentrifying neighborhoods. Results: At baseline, patients had a median age of 43 years, 42% were black and 61% were female. The overall prevalence of DM, HTN, obesity, and CVD was 12%, 32%, 19%, and 5% in 2010 &amp; 14%, 31%, 32%, and 7% in 2016. The prevalence increased in gentrifying and non-gentrifying neighborhoods over time and was higher in LTR than comparable movers. Estimates from DiD models were not statistically significant (Figure 1). Conclusions: LTR vs. movers and not gentrification impacted the surveillance of CVD health indicators. Novel public health informatics methods are needed to address dynamic changes in neighborhoods that may bias the enumeration of CVD health indicators.

Geospatial mapping can be used to identify geographic areas and social factors associated with intentional injury as targets for prevention efforts distinct to a given community.

Geographic information systems (GIS) have proven effective in studying intentional injury in various communities; however, GIS is not implemented widely for use by Level I trauma centers in understanding patient populations. Our study of intentional injury combines the capabilities of GIS with a Level I trauma center registry to determine the spatial distribution of victims and correlated socioeconomic factors. One thousand ninety-nine of 3,109 total incidents of intentional trauma in the trauma registry from 2005 to 2015 had sufficient street address information to be mapped in GIS. Comparison of these data, coupled with demographic data at the block group level, determined if any clustering or spatial patterns existed. Geographic information systems delivered these comparisons using several spatial statistics including kernel density, ordinary least squares test, and Moran's index. Kernel density analysis identified four major areas with significant clustering of incidents. The Moran's I value was 0.0318. Clustering exhibited a positive z-score and significant p value (p < 0.01). Examination of socioeconomic factors by spatial correlation with the distribution of intentional injury incidents identified three significant factors: unemployment, single-parent households, and lack of a high school degree. Tested factors did not exhibit substantial redundancy (variance inflation factor < 7.5). Nonsignificant tested factors included race, proximity to liquor stores and bars, median household income, per capita income, rate with public assistance, and population density. Spatial representation of trauma registry data using GIS effectively identifies high-risk areas for intentional injury. Analysis of local socioeconomic data identifies factors unique to those high-risk areas in the observed community. Implications of this study may include the routine use of GIS by Level I trauma centers in assessing intentional injury in a given community, the use of that data to guide the development of trauma prevention, and the assessment of other mechanisms of trauma using GIS. Epidemiological, level IV.

TUSC2(FUS1)-erlotinib Induced Vulnerabilities in Epidermal Growth Factor Receptor(EGFR) Wildtype Non-small Cell Lung Cancer(NSCLC) Targeted by the Repurposed Drug Auranofin.

Expression of the TUSC2/FUS1 tumor suppressor gene in TUSC2 deficient EGFR wildtype lung cancer cells increased sensitivity to erlotinib. Microarray mRNA expression analysis of TUSC2 inducible lung cancer cells treated with erlotinib uncovered defects in the response to oxidative stress suggesting that increasing reactive oxygen species (ROS) would enhance therapeutic efficacy. Addition of the thioredoxin reductase 1 inhibitor (TXNRD1) auranofin (AF) to NSCLC cells treated with combination of TUSC2 forced expression with erlotinib increased tumor cell apoptosis and inhibited colony formation. TXNRD1 overexpression rescued tumors from AF-TUSC2-erlotinib induced apoptosis. Neutralizing ROS with nordihydroguaiaretic acid (NDGA) abrogated cell death induced by AF-TUSC2-erlotinib, indicating a regulatory role for ROS in the efficacy of the three drug combination. Isobologram-based statistical analysis of this combination demonstrated superior synergism, compared with each individual treatment at lower concentrations. In NSCLC tumor xenografts, tumor growth was markedly inhibited and animal survival was prolonged over controls by AF-TUSC2-erlotinib. Microarray mRNA expression analysis uncovered oxidative stress and DNA damage gene signatures significantly upregulated by AF-TUSC2-erlotinib compared to TUSC2-erlotinib. Pathway analysis showed the highest positive z-score for the NRF2-mediated oxidative stress response. Taken together these findings show that the combination of TUSC2-erlotinib induces additional novel vulnerabilities that can be targeted with AF.

The Relationship Between Medial Temporal Lobe Atrophy and Cognitive Impairment in Patients With Dementia With Lewy Bodies.

The relationship between medial temporal lobe atrophy (MTA) and cognitive impairment in patients with dementia with Lewy bodies (DLB) remains unclear. We examined this relationship using voxel-based specific regional analysis system for Alzheimer disease (VSRAD) advance software, which allowed us to quantify the degree of MTA on images obtained from magnetic resonance imaging (MRI) scans. Thirty-seven patients diagnosed with DLB were recruited and scanned with a 1.5 Tesla MRI scanner. All MRI data were analyzed using VSRAD advance. The target volume of interest (VOI) included the entire region of the entorhinal cortex, hippocampus, and amygdala. The degree of MTA was obtained from the averaged positive z-score (Z score) on the target VOI, with higher scores indicating more severe MTA. Mini-Mental State Examination (MMSE) and the Revised Hasegawa Dementia Scale (HDS-R), which strengthened the measures of memory and language more than MMSE, were used to assess the presence of cognitive impairment. A negative correlation was found between the Z score and MMSE total scores or the HDS-R total scores. A stepwise multiple regression analysis performed to adjust the covariate effects of sex, age, the onset age of the disease, duration of DLB, years of education, and donepezil treatment showed that the HDS-R total scores were independently associated with the Z score, whereas MMSE total scores were not. These results suggest that MTA is related to cognitive impairment in patients with DLB, particularly the regions of orientation, immediate and delayed recall, and word fluency.

MRI assessment of the effects of acetazolamide and external lumbar drainage in idiopathic normal pressure hydrocephalus.

BackgroundThe objective was to identify changes in quantitative MRI measures in patients with idiopathic normal pressure hydrocephalus (iNPH) occurring in common after oral acetazolamide (ACZ) and external lumbar drainage (ELD) interventions.MethodsA total of 25 iNPH patients from two clinical sites underwent serial MRIs and clinical assessments. Eight received ACZ (125-375 mg/day) over 3 months and 12 underwent ELD for up to 72 hours. Five clinically-stable iNPH patients who were scanned serially without interventions served as controls for the MRI component of the study. Subjects were divided into responders and non-responders to the intervention based on gait and cognition assessments made by clinicians blinded to MRI results. The MRI modalities analyzed included T1-weighted images, diffusion tensor Imaging (DTI) and arterial spin labelling (ASL) perfusion studies. Automated threshold techniques were used to define regions of T1 hypo-intensities.ResultsDecreased volume of T1-hypointensities and decreased mean diffusivity (MD) within remaining hypointensities was observed after ACZ and ELD but not in controls. Patients responding positively to these interventions had more extensive decreases in T1-hypointensites than non-responders: ACZ-responders (4,651 ± 2,909 mm3), ELD responders (2,338 ± 1,140 mm3), ELD non-responders (44 ± 1,188 mm3). Changes in DTI MD within T1-hypointensities were greater in ACZ-responders (7.9% ± 2%) and ELD-responders (8.2% ± 3.1%) compared to ELD non-responders (2.1% ± 3%). All the acetazolamide-responders showed increases in whole-brain-average cerebral blood flow (wbCBF) estimated by ASL (18.8% ± 8.7%). The only observed decrease in wbCBF (9.6%) occurred in an acetazolamide-non-responder. A possible association between cerebral atrophy and response was observed, with subjects having the least cortical atrophy (as indicated by a positive z-score on cortical thickness measurements) showing greater clinical improvement after ACZ and ELD.ConclusionsT1-hypointensity volume and DTI MD measures decreased in the brains of iNPH patients following oral ACZ and ELD. The magnitude of the decrease was greater in treatment responders than non-responders. Despite having different mechanisms of action, both ELD and ACZ may decrease interstitial brain water and increase cerebral blood flow in patients with iNPH. Quantitative MRI measurements appear useful for objectively monitoring response to acetazolamide, ELD and potentially other therapeutic interventions in patients with iNPH.

The effectiveness of web-based programs on the reduction of childhood obesity in school-aged children: A systematic review.

Review Objective The objective of this review is to synthesise the best available evidence on the effectiveness of web-based programs on the reduction of childhood obesity in school age children. Types of Participants This review will consider studies that include school age children regardless of gender, ethnicity, or national origin from 4-18 years of age. Types of Interventions This review will consider the use of web-based programs including, but not limited to the Internet, social networking media, Internet mobile applications, and email aimed at the reduction of obesity among school age children. Types of Outcomes The outcomes to be considered in this review include measures of overweight and obesity among school aged children as measured by valid and reliable measurements including but not limited BMI, body weight, and/or waist circumference.

The Biflavonoid Isoginkgetin Is a General Inhibitor of Pre-mRNA Splicing

Membrane-permeable compounds that reversibly inhibit a particular step in gene expression are highly useful tools for cell biological and biochemical/structural studies. In comparison with other gene expression steps where multiple small molecule effectors are available, very few compounds have been described that act as general inhibitors of pre-mRNA splicing. Here we report construction and validation of a set of mammalian cell lines suitable for the identification of small molecule inhibitors of pre-mRNA splicing. Using these cell lines, we identified the natural product isoginkgetin as a general inhibitor of both the major and minor spliceosomes. Isoginkgetin inhibits splicing both in vivo and in vitro at similar micromolar concentrations. It appears to do so by preventing stable recruitment of the U4/U5/U6 tri-small nuclear ribonucleoprotein, resulting in accumulation of the prespliceosomal A complex. Like two other recently reported general pre-mRNA splicing inhibitors, isoginkgetin has been previously described as an anti-tumor agent. Our results suggest that splicing inhibition is the mechanistic basis of the anti-tumor activity of isoginkgetin. Thus, pre-mRNA splicing inhibitors may represent a novel avenue for development of new anti-cancer agents.

An easy Z-score imaging system for discrimination between very early Alzheimer??s disease and controls using brain perfusion SPECT in a multicentre study

In Alzheimer's disease (AD), regional cerebral blood flow (rCBF) in the posterior cingulate gyrus and precuneus has been reported to decrease even at a very early stage. We performed a multicentre SPECT study to evaluate the discrimination ability of an easy Z-score imaging system (eZIS) by detecting an rCBF decrease in this area with a common normal database between very early AD patients at the stage of mild cognitive impairment and age-matched healthy volunteers. Brain perfusion SPECT images of 40 Alzheimer's disease patients and 40 healthy volunteers were acquired from four gamma camera systems in different institutions. Systematic differences of SPECT images between different gamma cameras were corrected using conversion maps calculated from the SPECT images of the same brain phantom. Ten observers with various degrees of expertise graded eZIS results for receiver operating characteristic (ROC) curves. ROC curves for a positive Z-score in the volume of interest (VOI) of the posterior cingulate gyrus and precuneus were also analysed. An area under the ROC curve value (AZ) for ten observers showed the highest value of 0.866 on average with the smallest standard deviation of 0.027 in the condition of the lower threshold of a Z-score map of 2 without superimposition of VOI. Automated analysis of a Z-score in the VOI showed an AZ value of 0.895. Since the degree of expertise of the observers with respect to reading eZIS did not influence the performance and an eZIS can use a common normal database by converting site-specific SPECT data to the core data, the eZIS was considered to be very useful for diagnosing early AD in routine studies in many institutions.

Use of Spatial Autocorrelation to Investigate Clustering of Health Deprivation

SM2-PD-02 Introduction: The susceptibility of people to develop ill health can be influenced by characteristics of their neighborhood. Moreover, populations in socioeconomic deprived areas are considered more susceptible to poor health compared with those in affluent areas. Here, we aimed to use methods of spatial statistics and apply them in the context of environmental epidemiology. Specifically, we aimed to test for spatial autocorrelation to investigate clustering of indicators of health, in the Northeast of England. Methods: We abstracted data on the English Health Deprivation and Disability Index (HDDI), which comprises of 4 measures of ill health. These were downloaded for the smallest possible spatial unit comprising of a mean population of 1500, called Lower Super Output Areas (LSOA). We used Geographical Information Systems to map HDDI for the Northeast of England, as well as for each county and unitary authority (UA) in the region. We used the global Moran's I statistic to investigate spatial autocorrelation. Global autocorrelation statistics provide a single measure for clustering (positive spatial autocorrelation) or dispersion (negative spatial autocorrelation) of an attribute, in a spatial unit. A Moran's Index value near +1.0 indicates clustering, whereas an index value near −1.0 indicates dispersion. Results: We detected positive spatial autocorrelation in all spatial units assessed. A high positive z-score for all tests indicated that the observed clustering was statistically significant (P < 0.01). The strongest positive spatial autocorrelation was detected in counties Durham (Moran's I = 0.68, z = 10.4) and Northumberland (Moran's I = 0.68, z = 8.5). Clustering of health deprived areas was apparent in the eastern part of both counties. Weak positive spatial autocorrelation was found in Darlington UA (Moran's I = 0.18, z = 3.8) and Hartlepool UA (Moran's I = 0.24, z = 3.2). Moderate positive spatial autocorrelation was detected for the Northeast of England (Moran's I = 0.34, z = 22.4) and the other spatial units. Discussion and Conclusions: The global Moran's test was successful in identifying spatial autocorrelation of health indicators, separating spatial units with high, moderate, and weak clustering. In those areas where county and UA level clustering was moderate or weak, the local Moran's I test may be able to detect more localized clustering in smaller spatial units. We conclude that susceptibility to develop ill health is strongly clustered at county level in some counties but not in others.

Tissue-dependent and tissue-independent gene expression changes in metastatic colon cancer

20014 Background: Changes in gene expression that occur during cellular transformation and establishment of metastases provide valuable information that may help determine prognosis and direct treatment. We have obtained gene expression profiles from primary colon tumors and metastases to the liver (V), lung (L), and peritoneum (P). Methods: Ten cases, with matched controls, were profiled for the expression of &gt;18,000 human transcripts using Affymetrix U133A chips. Data were filtered using GeneSifter analysis software to identify genes with 2-fold or greater differences in expression relative to the control group. Gene expression levels for primary colon samples were compared to normal colon while metastatic tissues were compared to primary colon samples. Differentially regulated genes were then associated with KEGG pathways for additional analysis. Results: Relative to normal colon samples, primary colon samples displayed high positive z-score values for genes involved in nitrogen and sulfur metabolism (7.30 and 8.10, respectively). Expression level changes for individual genes in each cluster were statistically significant (e.g. p = 0.014 for carbonic anhydrase I in the nitrogen metabolism cluster). Metastatic tissue from liver, lung and peritoneum all displayed substantially decreased expression for genes involved in butanoate and propanoate metabolism, valine, leucine and isoleucine degradation, and moderately decreased expression for genes involved in JAK-STAT signaling. For example, L-3-hydroxyacyl-Coenzyme A dehydrogenase (short chain), a gene involved in both butanoate metabolism and valine, leucine and isoleucine degradation, was down-regulated in tissue from all three metastatic sites relative to primary colon tumor tissue [p = 0.024 (V), p = 0.022 (L), p = 0.005 (P)]. In addition, genes involved in phosphatidylinositol signaling were down-regulated in liver metastases but not in lung or peritoneal metastatic tissue. Conclusions: These results demonstrate that changes in expression levels for genes involved in basic metabolism and cell signaling occur during the course of metastasis. The changes that occur during development of the metastatic phenotype can be independent of, or specific to, the site of metastasis. No significant financial relationships to disclose.

Computed Tomographic Characterization of Malignant Peritoneal Mesothelioma

Peritoneal mesothelioma is a rare disease with a universally fatal outcome when managed in a traditional palliative manner. New approaches to treatment using cytoreductive surgery and intraperitoneal chemotherapy suggest that long-term survival is possible in selected patients. Early recognition of this disease process with an orderly surgical approach will begin to optimize treatment. Thirty-three patients with malignant peritoneal mesothelioma had CT scans available for review. A Z-score was used to evaluate the incidence of cancer at a particular anatomic site as compared to a general incidence of disease at all sites. CT was analyzed by abdominopelvic anatomic sites (16), abdominopelvic regions (9), and for presence versus absence of disease in the chest. Interpretative CT findings (class 0-III) were determined for these 33 patients. Eight of 33 patients had pleural abnormalities. In an analysis of 16 abdominopelvic anatomic sites, the vesical or rectal uterine pouch was involved in 97% and the greater omentum in 91%. These anatomic sites were the only ones with a positive Z-score of >1. In the analysis of 9 abdominopelvic regions, the central and pelvic regions had Z-scores >2 for large volume disease >5 cm. For CT interpretative findings class I, class II and class III was determined in approximately one-third in each category. Sixty-six percent of the patients had ascites by CT. Malignant peritoneal mesothelioma by CT evaluation predominates in tumor mass within the central and pelvic portions of the abdomen. Minimal, moderate, and extensive small bowel enlargements were seen in roughly one-third of the patients. With the use of the Z-score and interpretative small bowel findings a radiologic characterization of this disease for primary radiologic diagnosis is possible.