Study of drug utilization, morbidity pattern and cost of hypolipidemic agents in a tertiary care hospital

Background: Data on the extent of use and costs of lipid-lowering agents are not widely available. Our aim was to study the drug utilization and morbidity pattern, cost of different hypolipidemic drugs along with the risk assessment for coronary heart disease.Methods: After approval of protocol by the Institutional Review Board, an observational, prospective study was carried out in 300 patients using NCEP and ATP III Guidelines-2002 for evaluation of presence or absence of risk factors for coronary heart diseases. Data were analysed using SPSS software version 16.0and WHO Core Drug Prescribing Indicators.Results: Patient’s morbidity pattern revealed that 62%, 49.3%, 28% suffered from ischemic heart disease, hypertension and type 2 diabetes mellitus respectively. On risk assessment, 48%, 13.3% patients had borderline and high level of total cholesterol respectively; 42%, 22.7% had borderline and high triglyceride levels respectively; 71.1% men and 62% women had low HDL cholesterol levels while 17.3%, 6% and 2.7% patients had borderline high, high and very high level of LDL cholesterol levels respectively. Frequency of prescriptions was atorvastatin (82%), rosuvastatin (9.3%) and simvastatin (4.7%) among the most frequently prescribed statins drug group. The mean number of drugs per prescription was 7.34. Drugs prescribed by generic name and from essential drugs list was 24.96% and 71.81% respectively. Mean cost of hypolipidemic agents/prescription/day was 10.74 (±1.96) Indian Rupees with rosuvastatin being the costliest.Conclusion: Rational use of hypolipidemic agents with an increasing trend of statins prescriptions will significantly reduce the morbidity and mortality from coronary heart diseases.

Modeling Meets Metabolomics-The WormJam Consensus Model as Basis for Metabolic Studies in the Model Organism Caenorhabditis elegans.

Metabolism is one of the attributes of life and supplies energy and building blocks to organisms. Therefore, understanding metabolism is crucial for the understanding of complex biological phenomena. Despite having been in the focus of research for centuries, our picture of metabolism is still incomplete. Metabolomics, the systematic analysis of all small molecules in a biological system, aims to close this gap. In order to facilitate such investigations a blueprint of the metabolic network is required. Recently, several metabolic network reconstructions for the model organism Caenorhabditis elegans have been published, each having unique features. We have established the WormJam Community to merge and reconcile these (and other unpublished models) into a single consensus metabolic reconstruction. In a series of workshops and annotation seminars this model was refined with manual correction of incorrect assignments, metabolite structure and identifier curation as well as addition of new pathways. The WormJam consensus metabolic reconstruction represents a rich data source not only for in silico network-based approaches like flux balance analysis, but also for metabolomics, as it includes a database of metabolites present in C. elegans, which can be used for annotation. Here we present the process of model merging, correction and curation and give a detailed overview of the model. In the future it is intended to expand the model toward different tissues and put special emphasizes on lipid metabolism and secondary metabolism including ascaroside metabolism in accordance to their central role in C. elegans physiology

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

What are housekeeping genes?

The concept of "housekeeping gene" has been used for four decades but remains loosely defined. Housekeeping genes are commonly described as "essential for cellular existence regardless of their specific function in the tissue or organism", and "stably expressed irrespective of tissue type, developmental stage, cell cycle state, or external signal". However, experimental support for the tenet that gene essentiality is linked to stable expression across cell types, conditions, and organisms has been limited. Here we use genome-scale functional genomic screens together with bulk and single-cell sequencing technologies to test this link and optimize a quantitative and experimentally validated definition of housekeeping gene. Using the optimized definition, we identify, characterize, and provide as resources, housekeeping gene lists extracted from several human datasets, and 10 other animal species that include primates, chicken, and C. elegans. We find that stably expressed genes are not necessarily essential, and that the individual genes that are essential and stably expressed can considerably differ across organisms; yet the pathways enriched among these genes are conserved. Further, the level of conservation of housekeeping genes across the analyzed organisms captures their taxonomic groups, showing evolutionary relevance for our definition. Therefore, we present a quantitative and experimentally supported definition of housekeeping genes that can contribute to better understanding of their unique biological and evolutionary characteristics

StanDep: Capturing transcriptomic variability improves context-specific metabolic models.

Diverse algorithms can integrate transcriptomics with genome-scale metabolic models (GEMs) to build context-specific metabolic models. These algorithms require identification of a list of high confidence (core) reactions from transcriptomics, but parameters related to identification of core reactions, such as thresholding of expression profiles, can significantly change model content. Importantly, current thresholding approaches are burdened with setting singular arbitrary thresholds for all genes; thus, resulting in removal of enzymes needed in small amounts and even many housekeeping genes. Here, we describe StanDep, a novel heuristic method for using transcriptomics to identify core reactions prior to building context-specific metabolic models. StanDep clusters gene expression data based on their expression pattern across different contexts and determines thresholds for each cluster using data-dependent statistics, specifically standard deviation and mean. To demonstrate the use of StanDep, we built hundreds of models for the NCI-60 cancer cell lines. These models successfully increased the inclusion of housekeeping reactions, which are often lost in models built using standard thresholding approaches. Further, StanDep also provided a transcriptomic explanation for inclusion of lowly expressed reactions that were otherwise only supported by model extraction methods. Our study also provides novel insights into how cells may deal with context-specific and ubiquitous functions. StanDep, as a MATLAB toolbox, is available at https://github.com/LewisLabUCSD/StanDep

Inferring a spatial code of cell-cell interactions across a whole animal body.

Cell-cell interactions shape cellular function and ultimately organismal phenotype. Interacting cells can sense their mutual distance using combinations of ligand-receptor pairs, suggesting the existence of a spatial code, i.e., signals encoding spatial properties of cellular organization. However, this code driving and sustaining the spatial organization of cells remains to be elucidated. Here we present a computational framework to infer the spatial code underlying cell-cell interactions from the transcriptomes of the cell types across the whole body of a multicellular organism. As core of this framework, we introduce our tool cell2cell, which uses the coexpression of ligand-receptor pairs to compute the potential for intercellular interactions, and we test it across the Caenorhabditis elegans' body. Leveraging a 3D atlas of C. elegans' cells, we also implement a genetic algorithm to identify the ligand-receptor pairs most informative of the spatial organization of cells across the whole body. Validating the spatial code extracted with this strategy, the resulting intercellular distances are negatively correlated with the inferred cell-cell interactions. Furthermore, for selected cell-cell and ligand-receptor pairs, we experimentally confirm the communicatory behavior inferred with cell2cell and the genetic algorithm. Thus, our framework helps identify a code that predicts the spatial organization of cells across a whole-animal body