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1.  Intraoperative Blood Loss in Female Patients with Adolescent Idiopathic Scoliosis during Different Phases of the Menstrual Cycle 
PLoS ONE  2014;9(11):e112499.
Background
The vast majority of AIS patients who require surgical intervention are women. Blood loss is a major concern during the operation.
Methods
The medical records of all female AIS patients who underwent posterior correction and fusion operations using the all-pedicle screw system from January 2012 to January 2014 were reviewed. Patients with irregular menstruation; underwent osteotomy; use coagulants were excluded from the study. The remaining patients were divided into 4 groups according to the operation date in the menstrual cycle (A: premenstrual group, 24–30 d; B: follicle group, 6–11 d; C: ovulatory group, 12–17 d; D: luteal group, 18–23 d). The information of patients from the 4 groups was reviewed. The data was analyzed using analysis of variance, the Student-Newman-Keels test and Kruskal-Wallis Test.
Results
A total of 161 patients were included in this study. There were 40 patients included in group A, 38 patients in group B, 41 patients in group C and 42 patients in group D. The 4 groups were matched in age (P = 0.238), body height (P = 0.291), body weight (P = 0.756), Risser sign (P = 0.576), mean curve Cobb angle (P = 0.520), and bending flexibility index (P = 0.547), the number of levels fused (P = 0.397). The activated partial thromboplastin time (P = 0.235) and prothrombin time (P = 0.074) tended to be higher in group A, but the difference was not statistically significant. The fibrinogen level was lower in group B than the other 3 groups (P = 0.039). Blood loss and normalized intraoperative blood loss (NBL) was significantly higher in group A than the other 3 groups (P<0.01).
Conclusions
The hemostatic function tended to be lower in the premenstrual phase. The fibrinogen level was lowest in the mid-follicle phase. Female AIS patients tended to endure more intraoperative blood loss when the operation was performed in the premenstrual phase during the menstrual cycle.
doi:10.1371/journal.pone.0112499
PMCID: PMC4244093  PMID: 25422893
2.  Ensemble-Based Network Aggregation Improves the Accuracy of Gene Network Reconstruction 
PLoS ONE  2014;9(11):e106319.
Reverse engineering approaches to constructing gene regulatory networks (GRNs) based on genome-wide mRNA expression data have led to significant biological findings, such as the discovery of novel drug targets. However, the reliability of the reconstructed GRNs needs to be improved. Here, we propose an ensemble-based network aggregation approach to improving the accuracy of network topologies constructed from mRNA expression data. To evaluate the performances of different approaches, we created dozens of simulated networks from combinations of gene-set sizes and sample sizes and also tested our methods on three Escherichia coli datasets. We demonstrate that the ensemble-based network aggregation approach can be used to effectively integrate GRNs constructed from different studies – producing more accurate networks. We also apply this approach to building a network from epithelial mesenchymal transition (EMT) signature microarray data and identify hub genes that might be potential drug targets. The R code used to perform all of the analyses is available in an R package entitled “ENA”, accessible on CRAN (http://cran.r-project.org/web/packages/ENA/).
doi:10.1371/journal.pone.0106319
PMCID: PMC4229114  PMID: 25390635
3.  SbacHTS: Spatial background noise correction for High-Throughput RNAi Screening 
Bioinformatics  2013;29(17):2218-2220.
Motivation: High-throughput cell-based phenotypic screening has become an increasingly important technology for discovering new drug targets and assigning gene functions. Such experiments use hundreds of 96-well or 384-well plates, to cover whole-genome RNAi collections and/or chemical compound files, and often collect measurements that are sensitive to spatial background noise whose patterns can vary across individual plates. Correcting these position effects can substantially improve measurement accuracy and screening success.
Result: We developed SbacHTS (Spatial background noise correction for High-Throughput RNAi Screening) software for visualization, estimation and correction of spatial background noise in high-throughput RNAi screens. SbacHTS is supported on the Galaxy open-source framework with a user-friendly open access web interface. We find that SbacHTS software can effectively detect and correct spatial background noise, increase signal to noise ratio and enhance statistical detection power in high-throughput RNAi screening experiments.
Availability: http://www.galaxy.qbrc.org/
Contact: Guanghua.Xiao@UTSouthwestern.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btt358
PMCID: PMC3740628  PMID: 23814141
4.  ATF3 functions as a novel tumor suppressor with prognostic significance in esophageal squamous cell carcinoma 
Oncotarget  2014;5(18):8569-8582.
ATF3 was a transcription factor involved in the progression of certain cancers. Here, we sought to explore the expression and biological function of ATF3 in esophageal squamous cell carcinomas (ESCC). The prognostic significance of ATF3 expression was evaluated in 150 ESCC samples and 21 normal squamous cell epithelium tissues. Results showed that ATF3 was down-regulated in ESCC lesions compared with paired non-cancerous tissues and low tumorous ATF3 expression significantly correlated with shorter overall survival (OS) and disease-free survival (DFS). Cox regression analysis confirmed that ATF3 expression was an independent prognostic factor. Experimentally, forced expression of ATF3 led to decreased growth and invasion properties of ESCC cells in vitro and in vivo, whereas knockdown of ATF3 did the opposite. Furthermore, ATF3 upregulated the expression of MDM2 by increasing the nuclear translocation of P53 and formed an ATF3/MDM2/MMP-2 complex that facilitated MMP-2 degradation, which subsequently led to inhibition of cell invasion. Finally, we showed that Cisplatin could restrain the invasion of ESCC cells by inducing the expression of ATF3 via P53 signaling. Combined, our findings highlight a suppressed role for ATF3 in ESCC and targeting ATF3 might be a potential therapeutic strategy.
PMCID: PMC4226705  PMID: 25149542
ATF3; independent prognostic factor; cell invasion and metastasis; MMP-2; esophageal squamous cell carcinoma
5.  Healthcare Resource Utilization for Recurrent Clostridium difficile Infection in a Large University Hospital in Houston, Texas 
PLoS ONE  2014;9(7):e102848.
Background
There are limited data examining healthcare resource utilization in patients with recurrent Clostridium difficile infection (CDI).
Methods
Patients with CDI at a tertiary-care hospital in Houston, TX, were prospectively enrolled into an observational cohort study. Recurrence was assessed via follow-up phone calls. Patients with one or more recurrence were included in this study. The location at which healthcare was obtained by patients with recurrent CDI was identified along with hospital length of stay. CDI-attributable readmissions, defined as a positive toxin test within 48 hours of admission and a primary CDI diagnosis, were also assessed.
Results
372 primary cases of CDI were identified of whom 64 (17.2%) experienced at least one CDI recurrence. Twelve of 64 patients experienced 18 further episodes of CDI recurrence. Of these 64 patients, 33 (50.8%) patients with recurrent CDI were readmitted of which 6 (18.2%) required ICU care, 29 (45.3%) had outpatient care only, and 2 (3.1%) had an ED visit. Nineteen (55.9%) readmissions were defined as CDI-attributable. For patients with CDI-attributable readmission, the average length of stay was 6±6 days.
Conclusion
Recurrent CDI leads to significant healthcare resource utilization. Methods of reducing the burden of recurrent CDI should be further studied.
doi:10.1371/journal.pone.0102848
PMCID: PMC4109955  PMID: 25057871
6.  Sparse Group Penalized Integrative Analysis of Multiple Cancer Prognosis Datasets 
Genetics research  2013;95(0):68-77.
SUMMARY
In cancer research, high-throughput profiling studies have been extensively conducted, searching for markers associated with prognosis. Because of the “large d, small n” characteristic, results generated from the analysis of a single dataset can be unsatisfactory. Recent studies have shown that integrative analysis, which simultaneously analyzes multiple datasets, can be more effective than single-dataset analysis and classic meta-analysis. In most of existing integrative analysis, the homogeneity model has been assumed, which postulates that different datasets share the same set of markers. Several approaches have been designed to reinforce this assumption. In practice, different datasets may differ in terms of patient selection criteria, profiling techniques, and many other aspects. Such differences may make the homogeneity model too restricted. In this study, we assume the heterogeneity model, under which different datasets are allowed to have different sets of markers. With multiple cancer prognosis datasets, we adopt the AFT (accelerated failure time) model to describe survival. This model may have the lowest computational cost among popular semiparametric survival models. For marker selection, we adopt a sparse group MCP (minimax concave penalty) approach. This approach has an intuitive formulation and can be computed using an effective group coordinate descent algorithm. Simulation study shows that it outperforms the existing approaches under both the homogeneity and heterogeneity models. Data analysis further demonstrates the merit of heterogeneity model and proposed approach.
doi:10.1017/S0016672313000086
PMCID: PMC4090387  PMID: 23938111
Integrative analysis; Cancer prognosis; Heterogeneity model; Penalization
7.  Using Functional Signature Ontology (FUSION) to Identify Mechanisms of Action for Natural Products 
Science signaling  2013;6(297):ra90.
A challenge for biomedical research is the development of pharmaceuticals that appropriately target disease mechanisms. Natural products can be a rich source of bioactive chemicals for medicinal applications but can act through unknown mechanisms and can be difficult to produce or obtain. To address these challenges, we developed a new marine-derived, renewable natural products resource and a method for linking bioactive derivatives of this library to the proteins and biological processes that they target in cells. We used cell-based screening and computational analysis to match gene expression signatures produced by natural products to those produced by siRNA and synthetic microRNA libraries. With this strategy, we matched proteins and microRNAs with diverse biological processes and also identified putative protein targets and mechanisms of action for several previously undescribed marine-derived natural products. We confirmed mechanistic relationships for selected short-interfering RNAs, microRNAs, and compounds with functional roles in autophagy, chemotaxis mediated by discoidin domain receptor 2, or activation of the kinase AKT. Thus, this approach may be an effective method for screening new drugs while simultaneously identifying their targets.
doi:10.1126/scisignal.2004657
PMCID: PMC4075427  PMID: 24129700
8.  Computational detection and suppression of sequence-specific off-target phenotypes from whole genome RNAi screens 
Nucleic Acids Research  2014;42(13):8214-8222.
A challenge for large-scale siRNA loss-of-function studies is the biological pleiotropy resulting from multiple modes of action of siRNA reagents. A major confounding feature of these reagents is the microRNA-like translational quelling resulting from short regions of oligonucleotide complementarity to many different messenger RNAs. We developed a computational approach, deconvolution analysis of RNAi screening data, for automated quantitation of off-target effects in RNAi screening data sets. Substantial reduction of off-target rates was experimentally validated in five distinct biological screens across different genome-wide siRNA libraries. A public-access graphical-user-interface has been constructed to facilitate application of this algorithm.
doi:10.1093/nar/gku306
PMCID: PMC4117740  PMID: 24972830
9.  Modified posterior soft tissue repair for the prevention of early postoperative dislocation in total hip arthroplasty 
International Orthopaedics  2013;37(6):1039-1044.
Purpose
Dislocation following total hip arthroplasty (THA) with the posterior approach has been quite a common and bothering complication. Previous researches suggest that careful repair of the posterior structures significantly reduces this risk. The purposes of the present study were to describe a modified posterior soft tissue repair procedure in THA using a suture anchor (TwinFix Ti 5.0, Smith & Nephew, Andover, MA) and evaluate the early postoperative dislocation rate.
Methods
From July 2004 to June 2008, 220 consecutive primary total hip arthroplasties were performed using the modified surgical approach. The average age in the group was 46.4 years (range from 21 to 90) at the time of the procedure. The rate of postoperative hip dislocation, as well as any signs of complications related to the technique, has been observed and analyzed in this study.
Results
There was no postoperative dislocation following primary THA in 220 cases, and no signs of complications related to the technique, such as greater trochanteric fractures and sciatic nerve palsy, have been noted in any of the cases at their most recent follow-up.
Conclusions
These initial results demonstrate that the modified repair in THA using the suture anchor can serve as an effective and reliable mean for prevention of early postoperative dislocation
doi:10.1007/s00264-013-1874-9
PMCID: PMC3664159  PMID: 23549842
10.  Human lung epithelial cells progressed to malignancy through specific oncogenic manipulations 
Molecular cancer research : MCR  2013;11(6):638-650.
We used CDK4/hTERT-immortalized normal human bronchial epithelial cells (HBECs) from several individuals to study lung cancer pathogenesis by introducing combinations of common lung cancer oncogenic changes (p53, KRAS, MYC) and followed the stepwise transformation of HBECs to full malignancy. This model demonstrated that: 1) the combination of five genetic alterations (CDK4, hTERT, sh-p53, KRASV12, and c-MYC) is sufficient for full tumorigenic conversion of HBECs; 2) genetically-identical clones of transformed HBECs exhibit pronounced differences in tumor growth, histology, and differentiation; 3) HBECs from different individuals vary in their sensitivity to transformation by these oncogenic manipulations; 4) high levels of KRASV12 are required for full malignant transformation of HBECs, however prior loss of p53 function is required to prevent oncogene-induced senescence; 5) over-expression of c-MYC greatly enhances malignancy but only in the context of sh-p53+KRASV12; 6) growth of parental HBECs in serum-containing medium induces differentiation while growth of oncogenically manipulated HBECs in serum increases in vivo tumorigenicity, decreases tumor latency, produces more undifferentiated tumors, and induces epithelial-to-mesenchymal transition (EMT); 7) oncogenic transformation of HBECs leads to increased sensitivity to standard chemotherapy doublets; 8) an mRNA signature derived by comparing tumorigenic vs. non-tumorigenic clones was predictive of outcome in lung cancer patients. Collectively, our findings demonstrate this HBEC model system can be used to study the effect of oncogenic mutations, their expression levels, and serum-derived environmental effects in malignant transformation, while also providing clinically translatable applications such as development of prognostic signatures and drug response phenotypes.
doi:10.1158/1541-7786.MCR-12-0634-T
PMCID: PMC3687022  PMID: 23449933
p53; KRAS; c-MYC; immortalized human bronchial epithelial cell; in vitro transformation model of lung cancer; epithelial mesenchymal transition
11.  Synthesis, Characterization, In Vitro Cytotoxicity, and Apoptosis-Inducing Properties of Ruthenium(II) Complexes 
PLoS ONE  2014;9(5):e96082.
Two new Ru(II) complexes, [Ru(bpy)2(FAMP)](ClO4)2 1 and 2, are synthesized and characterized by elemental analysis, electrospray mass spectrometry, and 1H nuclear magnetic resonance. The in vitro cytotoxicities and apoptosis-inducing properties of these complexes are extensively studied. Complexes 1 and 2 exhibit potent antiproliferative activities against a panel of human cancer cell lines. The cell cycle analysis shows that complexes 1 and 2 exhibit effective cell growth inhibition by triggering G0/G1 phase arrest and inducing apoptosis by mitochondrial dysfunction. The in vitro DNA binding properties of the two complexes are investigated by different spectrophotometric methods and viscosity measurements.
doi:10.1371/journal.pone.0096082
PMCID: PMC4013043  PMID: 24804832
12.  Comparison of conventional medicine, TCM treatment, and combination of both conventional medicine and TCM treatment for patients with chronic obstructive pulmonary disease: study protocol of a randomized comparative effectiveness research trial 
Trials  2014;15:153.
Background
Chronic obstructive pulmonary disease (COPD) affects millions worldwide. Although many therapies exist and are being developed to relieve symptoms and reduce mortality, few data are available to understand which of the therapeutic alternatives is the most cost-effective for COPD patients in everyday clinical practice, especially for traditional Chinese medicine (TCM). Comparative effectiveness research can help patients, clinicians, and decision-makers make best informed treatment decisions where such evidence was previously lacking. This study aims to compare the effectiveness and economic evaluation of three treatments: (1) conventional Western medicine; (2) TCM treatments, which have been evaluated and have certain effect; and (3) a combination of both conventional Western medicine and TCM treatments, and then determine which treatment is the most suitable for COPD patients.
Methods/design
A multicenter, pragmatic, randomized, controlled trial is adopted. A total of 360 patients will be recruited and randomly assigned to one of the three treatments group, with 120 in each group. Patients in the conventional Western medicine group will be given Salbutamol, Formoterol, Salmeterol/fluticasone, respectively, according to the guidelines. For the TCM group, patients will be given Bufei granule, Bu-Fei Jian-Pi granule, Bu-Fei Yi-Shen granule, and Yi-Qi Zi-Shen granule based on their corresponding TCM syndrome patterns, respectively. For the combination of conventional medicine and TCM treatments group, patients will be given a combination of conventional Western medicine and TCM granules. Treatments in each group are recognized as a whole comprehensive intervention. After the 26-week treatment, another 26 weeks will be followed up. The outcome measures including the frequency and duration of acute exacerbations, lung function, dyspnea, exercise capacity, quality of life, and economic evaluation will be assessed.
Discussion
It is hypothesized that each of the three treatments will have beneficial effects in reducing the frequency and duration of acute exacerbations, improving exercise capacity and psychosocial function of COPD patients. In addition, the combination of conventional medicine and TCM treatments may be most suitable for COPD patients with better effectiveness and economic evaluation.
Trial registration
ClinicalTrials.gov NCT01836016.
doi:10.1186/1745-6215-15-153
PMCID: PMC4017822  PMID: 24885672
Chronic obstructive pulmonary disease; Comparative effectiveness research; Traditional Chinese medicine
13.  A Model-Based Approach to Identify Binding Sites in CLIP-Seq Data 
PLoS ONE  2014;9(4):e93248.
Cross-linking immunoprecipitation coupled with high-throughput sequencing (CLIP-Seq) has made it possible to identify the targeting sites of RNA-binding proteins in various cell culture systems and tissue types on a genome-wide scale. Here we present a novel model-based approach (MiClip) to identify high-confidence protein-RNA binding sites from CLIP-seq datasets. This approach assigns a probability score for each potential binding site to help prioritize subsequent validation experiments. The MiClip algorithm has been tested in both HITS-CLIP and PAR-CLIP datasets. In the HITS-CLIP dataset, the signal/noise ratios of miRNA seed motif enrichment produced by the MiClip approach are between 17% and 301% higher than those by the ad hoc method for the top 10 most enriched miRNAs. In the PAR-CLIP dataset, the MiClip approach can identify ∼50% more validated binding targets than the original ad hoc method and two recently published methods. To facilitate the application of the algorithm, we have released an R package, MiClip (http://cran.r-project.org/web/packages/MiClip/index.html), and a public web-based graphical user interface software (http://galaxy.qbrc.org/tool_runner?tool_id=mi_clip) for customized analysis.
doi:10.1371/journal.pone.0093248
PMCID: PMC3979666  PMID: 24714572
14.  Cross-sectional study of the relationship of peripheral blood cell profiles with severity of infection by adenovirus type 55 
BMC Infectious Diseases  2014;14:147.
Background
The immunologic profiles of patients with human adenovirus serotype 55 (HAdV-55) infections were characterized in subjects diagnosed with silent infections (n = 30), minor infections (n = 27), severe infections (n = 34), and healthy controls (n = 30) during a recent outbreak among Chinese military trainees.
Methods
Blood was sampled at the disease peak and four weeks later, and samples were analyzed to measure changes in leukocyte and platelet profiles in patients with different severities of disease. Differential lymphocyte subsets and cytokine profiles were measured by flow cytometry and Luminex xMAP®, and serum antibodies were analyzed by ELISA and immunofluorescence staining.
Results
Patients with severe HAdV infections had higher proportions of neutrophils and reduced levels of lymphocytes (p < 0.005 for both). Patients with minor and severe infections had significantly lower platelet counts (p < 0.005 for both) than those with silent infections. The silent and minor infection groups had higher levels of dendritic cells than the severe infection group. Relative to patients with silent infections, patients with severe infections had significantly higher levels of IL-17+CD4+ cells, decreased levels of IL-17+CD8+ cells, and higher levels of IFN-γ, IL-4, IL-10, and IFN-α2 (p < 0.001 for all comparisons).
Conclusions
Patients with different severities of disease due to HAdV-55 infection had significantly different immune responses. These data provide an initial step toward the identification of patients at risk for more severe disease and the development of treatments against HAdV-55 infection.
doi:10.1186/1471-2334-14-147
PMCID: PMC4000060  PMID: 24646014
Infectious diseases; Adenovirus; Immunopathology; Outbreak
15.  A 12-Gene Set Predicts Survival Benefits from Adjuvant Chemotherapy in Non-Small-Cell Lung Cancer Patients 
Purpose
Prospectively identifying who will benefit from adjuvant chemotherapy (ACT) would improve clinical decisions for non-small-cell lung cancer (NSCLC) patients. In this study, we aim to develop and validate a functional gene set that predicts the clinical benefits of ACT in NSCLC.
Experimental Design
An 18-hub-gene prognosis signature was developed through a systems biology approach, and its prognostic value was evaluated in six independent cohorts. The 18-hub-gene set was then integrated with genome-wide functional (RNAi) data and genetic aberration data to derive a 12-gene predictive signature for ACT benefits in NSCLC.
Results
Using a cohort of 442 Stage I–III NSCLC patients who underwent surgical resection, we identified an 18-hub-gene set which robustly predicted the prognosis of patients with adenocarcinoma in all validation datasets across four microarray platforms. The hub genes, identified through a purely data-driven approach, have significant biological implications in tumor pathogenesis, including NKX2-1, Aurora Kinase A, PRC1, CDKN3, MBIP, RRM2. The 12-gene predictive signature was successfully validated in two independent datasets (N=90 and N=176). The predicted benefit group showed significant improvement in survival after ACT (UT Lung SPORE data: hazard ratio=0.34, p=0.017; JBR.10 clinical trial data: hazard ratio=0.36, p=0.038), while the predicted non-benefit group showed no survival benefit for two datasets (hazard ratio=0.80, p=0.70; hazard ratio= 0.91, p=0.82).
Conclusions
This is the first study to integrate genetic aberration, genome-wide RNAi data, and mRNA expression data to identify a functional gene set that predicts which resectable patients with non-small-cell lung cancer will have a survival benefit with ACT.
doi:10.1158/1078-0432.CCR-12-2321
PMCID: PMC3619002  PMID: 23357979
non-small-cell lung cancer; predictive gene signature; adjuvant chemotherapy; integrative analysis; hub genes
16.  27-Hydroxycholesterol Promotes Cell-autonomous ER-positive Breast Cancer Growth 
Cell reports  2013;5(3):637-645.
Summary
To date estrogen is the only known endogenous estrogen receptor (ER) ligand that promotes ER+ breast tumor growth. We report that the cholesterol metabolite 27-hydroxycholesterol (27HC) stimulates MCF-7 cell xenograft growth in mice. More importantly, in ER+ breast cancer patients, 27HC content in normal breast tissue is increased compared to that in cancer-free controls, and tumor 27HC content is further elevated. Increased tumor 27HC is correlated with diminished expression of CYP7B1, the 27HC metabolizing enzyme, and reduced expression of CYP7B1 in tumors is associated with poorer patient survival. Moreover, 27HC is produced by MCF-7 cells and it stimulates cell-autonomous, ER-dependent and GDNF-RET-dependent cell proliferation. Thus, 27HC is a locally-modulated, non-aromatized ER ligand that promotes ER+ breast tumor growth.
doi:10.1016/j.celrep.2013.10.006
PMCID: PMC3950897  PMID: 24210818
17.  Antibiotic expected effectiveness and cost under real life microbiology: evaluation of ertapenem and ceftriaxone in the treatment of community-acquired pneumonia for elderly patients in Spain 
Background
Clinical efficacy of antibiotics may be affected by changes in the susceptibility of microorganisms to antimicrobial agents. The purpose of this study is to assess how these changes could affect the initial efficacy of ertapenem and ceftriaxone in the treatment of community-acquired pneumonia (CAP) in elderly patients and the potential consequences this may have in health care costs.
Methods
Initial efficacy in elderly was obtained from a combined analysis of two multicenter, randomized studies. An alternative scenario was carried out using initial efficacy data according to the pneumonia severity index (PSI). Country-specific pathogens distribution was obtained from a national epidemiological study, and microbiological susceptibilities to first- and second-line therapies were obtained from Spanish or European surveillance studies. A decision analytic model was used to compare ertapenem versus ceftriaxone for CAP inpatient treatment. Inputs of the model were the expected effectiveness previously estimated and resource use considering a Spanish national health system perspective. Outcomes include difference in proportion of successfully treated patients and difference in total costs between ertapenem and ceftriaxone. The model performed one-way and probabilistic sensitivity analyses.
Results
First-line treatment of CAP with ertapenem led to a higher proportion of successfully treated patients compared with ceftriaxone in Spain. One-way sensitivity analysis showed that length of stay was the key parameter of the model. Probabilistic sensitivity analysis showed that ertapenem can be a cost-saving strategy compared with ceftriaxone, with a 59% probability of being dominant (lower costs with additional health benefits) for both, elderly patients (>65 years) and patients with PSI >3.
Conclusion
The incorporation of the current antimicrobial susceptibility into the initial clinical efficacy has a significant impact in outcomes and costs in CAP treatment. The treatment with ertapenem compared with ceftriaxone resulted in better clinical outcomes and lower treatment costs for two segments of the Spanish population: elderly patients and patients with severe pneumonia (PSI >3).
doi:10.2147/CEOR.S55265
PMCID: PMC3928454  PMID: 24611019
antibacterial agent; bacterial infection; cost-effectiveness analyses; drug costs; Spain; aged
18.  Statistical Methods for Integrating Multiple Types of High-Throughput Data 
Large-scale sequencing, copy number, mRNA, and protein data have given great promise to the biomedical research, while posing great challenges to data management and data analysis. Integrating different types of high-throughput data from diverse sources can increase the statistical power of data analysis and provide deeper biological understanding. This chapter uses two biomedical research examples to illustrate why there is an urgent need to develop reliable and robust methods for integrating the heterogeneous data. We then introduce and review some recently developed statistical methods for integrative analysis for both statistical inference and classification purposes. Finally, we present some useful public access databases and program code to facilitate the integrative analysis in practice.
doi:10.1007/978-1-60761-580-4_19
PMCID: PMC3912747  PMID: 20652519
Integrative analysis; high-throughput data analysis; microarray
19.  Targeted zwitterionic near-infrared fluorophores for improved optical imaging 
Nature biotechnology  2013;31(2):10.1038/nbt.2468.
The signal-to-background ratio (SBR) is the key determinant of sensitivity, detectability, and linearity in optical imaging. As signal strength is often constrained by fundamental limits, background reduction becomes an important approach for improving SBR. We recently reported that a zwitterionic near-infrared (NIR) fluorophore, ZW800-1, exhibits low background. Here we show that this fluorophore provides much-improved SBR when targeted to cancer cells or proteins by conjugation with a cyclic RGD peptide, fibrinogen, or antibodies. ZW800-1 outperforms the commercially available NIR fluorophores IRDye800-CW and Cy5.5 in vitro for immunocytometry, histopathology and immunoblotting, and in vivo for image-guided surgery. In tumor model systems, tumor-to-background ratios of 17.2 are achieved after only 4 h post-injection, compared with 5.1 for IRDye800-CW and 2.7 for Cy5.5. Our results suggest that introducing zwitterionic properties into targeted fluorophores may be a general strategy for improving the SBR in diagnostic and therapeutic applications.
doi:10.1038/nbt.2468
PMCID: PMC3568187  PMID: 23292608
20.  PIPE-CLIP: a comprehensive online tool for CLIP-seq data analysis 
Genome Biology  2014;15(1):R18.
CLIP-seq is widely used to study genome-wide interactions between RNA-binding proteins and RNAs. However, there are few tools available to analyze CLIP-seq data, thus creating a bottleneck to the implementation of this methodology. Here, we present PIPE-CLIP, a Galaxy framework-based comprehensive online pipeline for reliable analysis of data generated by three types of CLIP-seq protocol: HITS-CLIP, PAR-CLIP and iCLIP. PIPE-CLIP provides both data processing and statistical analysis to determine candidate cross-linking regions, which are comparable to those regions identified from the original studies or using existing computational tools. PIPE-CLIP is available at http://pipeclip.qbrc.org/.
doi:10.1186/gb-2014-15-1-r18
PMCID: PMC4054095  PMID: 24451213
21.  dCLIP: a computational approach for comparative CLIP-seq analyses 
Genome Biology  2014;15(1):R11.
Although comparison of RNA-protein interaction profiles across different conditions has become increasingly important to understanding the function of RNA-binding proteins (RBPs), few computational approaches have been developed for quantitative comparison of CLIP-seq datasets. Here, we present an easy-to-use command line tool, dCLIP, for quantitative CLIP-seq comparative analysis. The two-stage method implemented in dCLIP, including a modified MA normalization method and a hidden Markov model, is shown to be able to effectively identify differential binding regions of RBPs in four CLIP-seq datasets, generated by HITS-CLIP, iCLIP and PAR-CLIP protocols. dCLIP is freely available at http://qbrc.swmed.edu/software/.
doi:10.1186/gb-2014-15-1-r11
PMCID: PMC4054096  PMID: 24398258
22.  Massive heterotopic ossification associated with late deficits in posterior wall of acetabulum after failed acetabular fracture operation 
Background
Heterotopic ossification is a common postoperative complication of acetabular fracture. However, functionally significant heterotopic ossification with associated late bone defects in the posterior wall of the acetabulum is rare and challenging to treat. When heterotopic ossification is a late complication of failed acetabular fracture operation, it is disabling and may only be treated by THA. THA is highly susceptible to premature failure in young and active patients and may require numerous revisions.
Case presentation
This article describes a 40-year-old man with massive heterotopic ossification associated with late bone defects in the posterior wall of the acetabulum after a failed acetabular fracture operation. The primary fracture type was a 62-A2.3 fracture according to the AO/OTA Classification.Surgical excision and anatomical reconstruction of the acetabular wall using heterotopic ossific bone were performed 10 months after the fracture repair. Postoperatively, indomethacin was administered for prophylaxis against recurrence of heterotopic ossification, and hip range of motion was progressively increased. At 5 years and 6 months follow-up, the patient’s pain was relieved and hip function had recovered. Though radiography and CT showed minimal subchondral cysts and mild joint-space narrowing, there was no evidence of graft resorption, progressive posttraumatic osteoarthritis or necrosis of the femoral head.
Conclusion
To the authors’ knowledge, this is the first case of such a challenging condition. Although it is an extremely rare case, it provides an attractive option for avoiding THA, as the long-term follow-up shows a satisfactory outcome.
doi:10.1186/1471-2474-14-368
PMCID: PMC3877962  PMID: 24369897
Heterotopic ossification; Late bone defects; Posterior wall; Acetabulum; Acetabular fracture
23.  Application of Ni-Ti Alloy connector for the treatment of comminuted coronal plane supracondylar-condylar femoral fractures: a retrospective review of 21 patients 
Background
Our preliminary retrospective study assessed outcomes after the use of Ni-Ti arched shape-memory connector (ASC) combined with partially threaded cancellous screws (PTCS) to repair coronal plane supracondylar-condylar femoral fractures.
Methods
Twenty-one patients (16 men and 5 women) with a mean age of 34.1 years (range, 28 to 44 years) with coronal plane supracondylar and condylar fractures of the distal femur were included in this study. Each patient underwent open reduction and internal fixation using the ASC and PTCS. Active functional exercises with restricted weight bearing were initiated the first postoperative day. A gradual increase in weight bearing status and range of motion was permitted and subjects progressed to full weight bearing by 8 weeks. Surgical time, blood loss, postoperative knee range of motion, American Knee Society Scores (KSS), and postoperative complications were assessed.
Results
The mean surgical time was 75 mins (range, 45 to 100 mins) and average blood loss was 105 ml (range, 35 to 130 ml). Mean follow-up was 65 months (range, 22 to 90 months). No subjects demonstrated evidence of osteonecrosis or arthritis at the final follow-up. The mean KSS was excellent (≥85) in 8 subjects, good (70-84) in 11 subjects, and fair (60-69) in 2 subjects. The mean active range of motion of knee flexion at final follow-up was 100 degrees (range, 85 to 110 degrees).
Conclusions
ASC combined with PTCS can serve as an effective means for managing comminuted femoral fractures that extend from the condyle to the supracondylar region. However, further prospective comparative studies and biomechanical analyses are needed to evaluate long-term outcomes using these materials.
doi:10.1186/1471-2474-14-355
PMCID: PMC3878495  PMID: 24341860
Shape memory alloy; Treatment; Comminuted; Coronal plane; Femoral fracture
24.  Socioeconomic disparities in lung cancer treatment and outcome persist within a single academic medical center 
Clinical lung cancer  2012;13(6):448-457.
Background
Socioeconomic disparities in treatment and outcomes of non-small cell lung cancer (NSCLC) are well established. To explore whether these differences are secondary to individual or institutional characteristics, we examined treatment selection and outcome in a diverse population treated at a single medical center.
Patient and Methods
We performed a retrospective analysis of consecutive patients diagnosed with NSCLC stages I-III from 2000-2005 at the University of Texas Southwestern Medical Center. Treatment selection was dichotomized as “standard” (surgery for stage I-II; surgery and/or radiation therapy for stage III) or “other.” Associations between patient characteristics (including socioeconomic status) and treatment selection were examined using logistic regression; associations between characteristics and overall survival were examined using Cox regression models and Kaplan-Meier survival analysis.
Results
A total of 450 patients were included. Twenty-eight percent of patients had private insurance, 43% had Medicare, and 29% had an indigent care plan. The likelihood of receiving “standard” therapy was significantly associated with insurance type [indigent plan versus private insurance OR 0.13 (95% CI 0.04-0.43) for stage I-II; OR 0.38 (95% CI 0.14-1.00) for stage III]. For patients with stage I-II NSCLC, survival was associated with age, gender, insurance type (indigent plan versus private insurance HR 1.98; 95% CI 1.16-3.37), stage, and treatment selection. In stage III NSCLC, survival was associated with treatment selection.
Conclusion
Within a single academic medical center, socioeconomically disadvantaged patients with stage I-III NSCLC are less likely to receive “standard” therapy. Socioeconomically disadvantaged patients with stage I-II NSCLC have inferior survival independent of therapy.
doi:10.1016/j.cllc.2012.03.002
PMCID: PMC3436959  PMID: 22512997
Surgery; radiation therapy; chemotherapy; underserved; minorities; socioeconomic disparities
25.  Selective laser sintering fabrication of nano-hydroxyapatite/poly-ε-caprolactone scaffolds for bone tissue engineering applications 
The regeneration of functional tissue in osseous defects is a formidable challenge in orthopedic surgery. In the present study, a novel biomimetic composite scaffold, here called nano-hydroxyapatite (HA)/poly-ε-caprolactone (PCL) was fabricated using a selective laser sintering technique. The macrostructure, morphology, and mechanical strength of the scaffolds were characterized. Scanning electronic microscopy (SEM) showed that the nano-HA/PCL scaffolds exhibited predesigned, well-ordered macropores and interconnected micropores. The scaffolds have a range of porosity from 78.54% to 70.31%, and a corresponding compressive strength of 1.38 MPa to 3.17 MPa. Human bone marrow stromal cells were seeded onto the nano-HA/PCL or PCL scaffolds and cultured for 28 days in vitro. As indicated by the level of cell attachment and proliferation, the nano-HA/PCL showed excellent biocompatibility, comparable to that of PCL scaffolds. The hydrophilicity, mineralization, alkaline phosphatase activity, and Alizarin Red S staining indicated that the nano-HA/PCL scaffolds are more bioactive than the PCL scaffolds in vitro. Measurements of recombinant human bone morphogenetic protein-2 (rhBMP-2) release kinetics showed that after nano-HA was added, the material increased the rate of rhBMP-2 release. To investigate the in vivo biocompatibility and osteogenesis of the composite scaffolds, both nano-HA/PCL scaffolds and PCL scaffolds were implanted in rabbit femur defects for 3, 6, and 9 weeks. The wounds were studied radiographically and histologically. The in vivo results showed that both nano-HA/PCL composite scaffolds and PCL scaffolds exhibited good biocompatibility. However, the nano-HA/PCL scaffolds enhanced the efficiency of new bone formation more than PCL scaffolds and fulfilled all the basic requirements of bone tissue engineering scaffolds. Thus, they show large potential for use in orthopedic and reconstructive surgery.
doi:10.2147/IJN.S50685
PMCID: PMC3818022  PMID: 24204147
osseous defects; orthopedic surgery; biomimetic composite scaffold; reconstructive surgery

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