Comparing the effect of statins on hepatic fibrosis induced by carbon tetrachloride in Wistar rats

Background: The clinical studies have shown contrary results regarding hepatoprotective effect of statins. However, antifibrotic properties of statins in in vitro and in vivo experimental models have been demonstrated. The purpose of this study was to assess and compare the effect of statins on serum liver enzymes and their antifibrotic effects.Methods: Forty two rats were divided into 7 groups (I to VII) (n=6). Liver toxicity was induced by injecting carbon tetrachloride (1 ml/kg). Control groups received corn oil (0.1 ml/100 gm) and carboxy methyl cellulose (0.50%) respectively. Group III to VII received carbon tetrachloride (CCl4) for 6 weeks and then groups IV, V, VI and VII received simvastatin (10 mg/kg), atorvastatin (15 mg/kg), rosuvastatin (2 mg/kg) and silymarin (50 mg/kg) for another 8 weeks respectively. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels were estimated in all the groups at baseline, 6 weeks and 14 weeks. At 14 weeks, histopathology of liver was done in all groups.Results: At 14 weeks, all the test groups (IV, V and VI) showed a significant decrease in serum ALT, AST and ALP levels as compared to control (p<0.05) and group III (p<0.05). On intergroup comparison, liver enzymes in rats in group VI (rosuvastatin) and group V (atorvastatin) were decreased more in comparison to group IV (simvastatin) but the difference was not statistically significant except for AST levels where the difference was significant between the statins. There was decrease in hepatic fibrosis by statins with rosuvastatin being superior followed by atorvastatin and simvastatin.Conclusions: In the present study statins decreased the serum AST, ALT and ALP levels and histopathological changes were reversed by statins in CCl4 induced hepatotoxic models

Cost effectiveness of nusinersen for patients with infantile-onset spinal muscular atrophy in US

Background Patients with infantile-onset spinal muscular atrophy (SMA), a rare, genetic neuromuscular disease, do not achieve key motor function milestones (e.g., sitting) and have short life expectancy in the absence of treatment. Nusinersen is a disease-modifying therapy for patients with SMA. Objective The aim of this study was to estimate the cost-effectiveness of nusinersen compared to best supportive care (BSC) in patients diagnosed with infantile-onset SMA in the US. Methods A de novo economic model was developed with the following health states: “permanent ventilation”, “not sitting”, “sitting”, “walking”, and “death”. Short-term data were sourced from the pivotal clinical trials and studies of nusinersen (ENDEAR and SHINE). Motor function milestones achieved at the end of follow-up in the clinical trials were assumed to be sustained until death. Mortality risks were based on survival modelling of relevant published Kaplan–Meier data. Costs, life years (LYs), and quality-adjusted life years (QALYs) were discounted at 3% per annum, and the analyses were performed from a US health care sector perspective. Scenario analyses and sensitivity analyses were conducted to assess the robustness of the results to key parameters. Results In our base-case analysis, nusinersen treatment achieves greater QALYs and more LYs (3.24 and 7.64, respectively) compared with BSC (0.46 QALYs and 2.40 LYs, respectively), resulting in an incremental cost per QALY gained of approximately $1,112,000 and an incremental cost per LY gained of$590,000 for nusinersen compared to BSC. The incremental cost effectiveness ratios did not fall below $990,000 per QALY gained in scenario and sensitivity analyses. Results were most sensitive to the length of survival, background health care costs, and utility in the “not sitting” and “sitting” health states. Conclusions The estimated incremental cost-effectiveness of nusinersen from a US health care sector perspective exceeded traditional cost-effectiveness thresholds. Cost-effectiveness was dependent on assumptions made regarding survival, costs, utilities, and whether the motor function milestones were sustained over lifetime. Given the relatively short-term effectiveness data available for the treatment, a registry to collect long-term data of infantile-onset SMA patients is recommended

Different atmospheric moisture divergence responses to extreme and moderate El Niños

On seasonal and inter-annual time scales, vertically integrated moisture divergence provides a useful measure of the tropical atmospheric hydrological cycle. It reflects the combined dynamical and thermodynamical effects, and is not subject to the limitations that afflict observations of evaporation minus precipitation. An empirical orthogonal function (EOF) analysis of the tropical Pacific moisture divergence fields calculated from the ERA-Interim reanalysis reveals the dominant effects of the El Niño-Southern Oscillation (ENSO) on inter-annual time scales. Two EOFs are necessary to capture the ENSO signature, and regression relationships between their Principal Components and indices of equatorial Pacific sea surface temperature (SST) demonstrate that the transition from strong La Niña through to extreme El Niño events is not a linear one. The largest deviation from linearity is for the strongest El Niños, and we interpret that this arises at least partly because the EOF analysis cannot easily separate different patterns of responses that are not orthogonal to each other. To overcome the orthogonality constraints, a self-organizing map (SOM) analysis of the same moisture divergence fields was performed. The SOM analysis captures the range of responses to ENSO, including the distinction between the moderate and strong El Niños identified by the EOF analysis. The work demonstrates the potential for the application of SOM to large scale climatic analysis, by virtue of its easier interpretation, relaxation of orthogonality constraints and its versatility for serving as an alternative classification method. Both the EOF and SOM analyses suggest a classification of “moderate” and “extreme” El Niños by their differences in the magnitudes of the hydrological cycle responses, spatial patterns and evolutionary paths. Classification from the moisture divergence point of view shows consistency with results based on other physical variables such as SST

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Infant and Child Mortality in India in the Last Two Decades: A Geospatial Analysis

Studies examining the intricate interplay between poverty, female literacy, child malnutrition, and child mortality are rare in demographic literature. Given the recent focus on Millennium Development Goals 4 (child survival) and 5 (maternal health), we explored whether the geographic regions that were underprivileged in terms of wealth, female literacy, child nutrition, or safe delivery were also grappling with the elevated risk of child mortality; whether there were any spatial outliers; whether these relationships have undergone any significant change over historical time periods.The present paper attempted to investigate these critical questions using data from household surveys like NFHS 1992-1993, NFHS 1998-1999 and DLHS 2002-2004. For the first time, we employed geo-spatial techniques like Moran's-I, univariate LISA, bivariate LISA, spatial error regression, and spatiotemporal regression to address the research problem. For carrying out the geospatial analysis, we classified India into 76 natural regions based on the agro-climatic scheme proposed by Bhat and Zavier (1999) following the Census of India Study and all estimates were generated for each of the geographic regions.This study brings out the stark intra-state and inter-regional disparities in infant and under-five mortality in India over the past two decades. It further reveals, for the first time, that geographic regions that were underprivileged in child nutrition or wealth or female literacy were also likely to be disadvantaged in terms of infant and child survival irrespective of the state to which they belong. While the role of economic status in explaining child malnutrition and child survival has weakened, the effect of mother's education has actually become stronger over time

Prevalence of pulmonary tuberculosis among the tribal populations in India

IMPORTANCE: There is no concrete evidence on the burden of TB among the tribal populations across India except for few studies mainly conducted in Central India with a pooled estimation of 703/100,000 with a high degree of heterogeneity. OBJECTIVE: To estimate the prevalence of TB among the tribal populations in India. DESIGN, PARTICIPANTS, SETTING: A survey using a multistage cluster sampling design was conducted between April 2015 and March 2020 covering 88 villages (clusters) from districts with over 70% tribal majority populations in 17 States across 6 zones of India. The sample populations included individuals ≥15 years old. MAIN OUTCOME AND MEASURES: Eligible participants who were screened through an interview for symptoms suggestive of pulmonary TB (PTB); Two sputum specimens were examined by smear and culture. Prevalence was estimated after multiple imputations for non-coverage and a correction factor of 1.31 was then applied to account for non-inclusion of X-ray screening. RESULTS: A total of 74532 (81.0%) of the 92038 eligible individuals were screened; 2675 (3.6%) were found to have TB symptoms or h/o ATT. The overall prevalence of PTB was 432 per 100,000 populations. The PTB prevalence per 100,000 populations was highest 625 [95% CI: 496–754] in the central zone and least 153 [95% CI: 24–281] in the west zone. Among the 17 states that were covered in this study, Odisha recorded the highest prevalence of 803 [95% CI: 504–1101] and Jammu and Kashmir the lowest 127 [95% CI: 0–310] per 100,000 populations. Findings from multiple logistic regression analysis reflected that those aged 35 years and above, with BMI <18.5 Kgs /m(2), h/o ATT, smoking, and/or consuming alcohol had a higher risk of bacteriologically positive PTB. Weight loss was relatively more important symptom associated with tuberculosis among this tribal populations followed by night sweats, blood in sputum, and fever. CONCLUSION AND RELEVANCE: The overall prevalence of PTB among tribal groups is higher than the general populations with a wide variation of prevalence of PTB among the tribal groups at zone and state levels. These findings call for strengthening of the TB control efforts in tribal areas to reduce TB prevalence through tribal community/site-specific intervention programs