Vascular comorbidities worsen prognosis of patients with heart failure hospitalised with COVID-19.

BACKGROUND: Prior diagnosis of heart failure (HF) is associated with increased length of hospital stay (LOS) and mortality from COVID-19. Associations between substance use, venous thromboembolism (VTE) or peripheral arterial disease (PAD) and its effects on LOS or mortality in patients with HF hospitalised with COVID-19 remain unknown. OBJECTIVE: This study identified risk factors associated with poor in-hospital outcomes among patients with HF hospitalised with COVID-19. METHODS: Case-control study was conducted of patients with prior diagnosis of HF hospitalised with COVID-19 at an academic tertiary care centre from 1 January 2020 to 28 February 2021. Patients with HF hospitalised with COVID-19 with risk factors were compared with those without risk factors for clinical characteristics, LOS and mortality. Multivariate regression was conducted to identify multiple predictors of increased LOS and in-hospital mortality in patients with HF hospitalised with COVID-19. RESULTS: Total of 211 patients with HF were hospitalised with COVID-19. Women had longer LOS than men (9 days vs 7 days; p<0.001). Compared with patients without PAD or ischaemic stroke, patients with PAD or ischaemic stroke had longer LOS (7 days vs 9 days; p=0.012 and 7 days vs 11 days, p<0.001, respectively). Older patients (aged 65 and above) had increased in-hospital mortality compared with younger patients (adjusted OR: 1.04; 95% CI 1.00 to 1.07; p=0.036). Prior diagnosis of VTE increased mortality more than threefold in patients with HF hospitalised with COVID-19 (adjusted OR: 3.33; 95% CI 1.29 to 8.43; p=0.011). CONCLUSION: Vascular diseases increase LOS and mortality in patients with HF hospitalised with COVID-19.

Z Probe, An Efficient Tool for Characterizing Long Non-Coding RNA in FFPE Tissues.

Formalin-fixed paraffin embedded (FFPE) tissues are a valuable resource for biomarker discovery in order to understand the etiology of different cancers and many other diseases. Proteins are the biomarkers of interest with respect to FFPE tissues as RNA degradation is the major challenge in these tissue samples. Recently, non-protein coding transcripts, long non-coding RNAs (lncRNAs), have gained significant attention due to their important biological actions and potential involvement in cancer. RNA sequencing (RNA-seq) or quantitative reverse transcription-polymerase chain reaction (qRT-PCR) are the only validated methods to evaluate and study lncRNA expression and neither of them provides visual representation as immunohistochemistry (IHC) provides for proteins. We have standardized and are reporting a sensitive Z probe based in situ hybridization method to visually identify and quantify lncRNA in FFPE tissues. This assay is highly sensitive and identifies transcripts visible within different cell types and tumors. We have detected a scarcely expressed tumor suppressor lncRNA NRON (non-coding repressor of nuclear factor of activated T-cells (NFAT)), a moderately expressed oncogenic lncRNA UCA1 (urothelial cancer associated 1), and a highly studied and expressed lncRNA MALAT1 (metastasis associated lung adenocarcinoma transcript 1) in different cancers. High MALAT1 staining was found in colorectal, breast and pancreatic cancer. Additionally, we have observed an increase in MALAT1 expression in different stages of colorectal cancer.

"Enhanced Recovery" Protocol Compliance Influences Length of Stay: Resolving Barriers to Implementation.

Initial implementation and maintenance of an enhanced recovery protocol (ERP) is complex and has not been adequately described. The aim of this study was to investigate the efficacy of an ERP at a tertiary care academic institution. A secondary aim was to identify barriers to implementation and continued protocol compliance (PC) to further decrease length of stay (LOS). Patients undergoing colon resection from February 2, 2011 to December 19, 2014 were compared with patients that followed implementation of an ERP from August 10, 2015 to July 14, 2016. The primary endpoint was LOS. Secondary endpoints were PC, analgesia requirements, time to return of bowel function, and ileus. One hundred and seventy-seven historical controls were compared with 68 ERP patients. LOS was shorter in study patients (4.9 vs 7.1 days for open surgery; 3.3 vs 6.1 for laparoscopic surgery). Intraoperative IVF balance, morphine equivalents, and length of time to return of bowel function were significantly less in the ERP group (1445.89 ± 845.25 mL vs 3006.08 ± 1197.97 mL), (64.48 ± 114.49 vs 232.90 ± 541.47), (2.41 ± 1.32 days vs 3.82 ± 2.00 days). Rate of ileus was less in study patients (4.8 vs 14.7%). The readmission rate and 30-day National Surgical Quality Improvement Program complication rates were not significantly different. PC was negatively associated with LOS (r = -0.35, P = 0.0026). Similar to prior studies, this study demonstrates the efficacy of an ERP. Increased PC is associated with decreased LOS, thus providing further evidence that ERPs should be the standard of care. Scheduled interdisciplinary meetings to discuss patient outcomes and methods to increase PC can help further improve efficacy of ERPs.

External Validation of Velazquez-Gomez Severity Score Index and ATLAS Scores and the Identification of Risk Factors Associated with Mortality in Clostridium difficile Infections.

Treatment guidelines for Clostridium difficile infection (CDI) are limited by a lack of widely accepted clinical prediction tools (CPTs). Two published CPTs, the Velazquez-Gomez Severity Score Index (VGSSI) and ATLAS scores, were evaluated, and variables showing the greatest correlation with mortality in patients with CDI were identified to further develop an objective, mortality-based CPT. A retrospective review of the charts of 271 hospitalized patients with CDI was performed. VGSSI and ATLAS scores were assigned. Means and correlations of these scores with mortality were evaluated. Multivariate logistic regression analysis was performed on 32 known potential mortality predictor variables. Mortality was overall strongly associated with VGSSI and ATLAS scores with poor correlation within the intermediate ranges. Mean scores for nonsurvivors indicated poor calibration. The variables most associated with mortality were Age, vasopressors, steroids, creatinine level, and albumin. Although both CPTs revealed the ability to discriminate patients at greater risk for mortality, precision and overall calibration were lacking. Five variables were identified which had the greatest correlation with mortality. Utilization of these variables to enhance or modify the existing CPTs is suggested as the next step in the development of a useful and accurate mortality-based CPT for the treatment of CDI.

A single-center retrospective review of postoperative infectious complications in the surgical management of mandibular fractures: Postoperative antibiotics add no benefit.

BACKGROUND: Mandibular fractures are common facial injuries and treatment may be complicated by post-operative infection. Risk of infection from contamination with oral flora is well established but no consensus exists regarding antibiotic prophylaxis. The purpose of this study is to assess risk factors and perioperative antibiotics on surgical site infection (SSI) rates following mandibular fracture surgery. METHODS: Retrospective medical record review was completed for trauma patients of any age surgically treated for mandibular fractures at a Level I Trauma Center from September 2006 to June 2012. Outcomes analysis was performed to determine SSI rates related to perioperative antibiotic use and other risk factors that may contribute to SSI. RESULTS: 359 patients met inclusion criteria for analysis. 76% were male. Mean age was 30.5 years. Thirty-eight patients developed SSI (10.6%). SSI rate was lower in closed versus open surgery (3.2% vs. 16.3%, p=0.0001), and in closed versus open fractures (1% vs. 14%, p=0.0005). SSI rate increased in patients with tobacco, alcohol, and drug use (14.6%, 13.2%, 53.6%, p<0.0001), traumatic dental injuries (19.6%, p=0.0110), and patients in motor vehicle crashes (12.2%, p=0.0062). SSI rates stratified by Injury Severity Score (ISS) less than or equal to 16 (23/255 [9%]) versus ISS greater than 16 (15/104 [14%]) trended toward more severely injured patients developing SSI, p=0.1347. SSI rate was similar in patients who did and did not receive post-operative antibiotics (14.7% vs. 9.6%, p=0.2556). Type of antibiotic, duration of post-operative antibiotic administration, and duration between injury and surgery did not effect SSI rate. CONCLUSIONS: Findings suggest that following surgical treatment of mandible fractures, open surgery, open fractures, and risk factors including substance abuse, traumatic dental injury, and mechanism of injury significantly increase SSI rates, while post-operative antibiotics do not appear to provide additional benefit compared to pre-operative antibiotics alone. LEVEL OF EVIDENCE: Therapeutic study, level IV.

The Effect of Progressive-Tension Closure on Donor Site Seroma Formation in Delayed Latissimus Dorsi Flaps for Breast Reconstruction.

BACKGROUND: Autologous tissue flaps play an integral part in breast reconstruction. The latissimus dorsi myocutaneous flap is an effective and aesthetic method of immediate breast reconstruction, although a high rate of donor site seroma formation has plagued this procedure. Many techniques to reduce donor site seromas have been undertaken. This study evaluates the effect of progressive-tension closure (PTC) on postoperative seroma. METHODS: This is a retrospective cohort study of 100 breasts reconstructed using a traditional closure versus PTC of the donor site. Outcomes collected include patient age, date of surgery, side of surgery, body mass index (BMI), smoking status, diabetes diagnosis, number of days the initial operative drain was present, seroma occurrence, seroma aspirations, seroma catheters placed, and operative interventions. RESULTS: The PTC technique significantly decreased seroma formation, with 40% of the traditional closure sites developing seromas and only 14% in the PTC group (P = 0.0078). The mean number of days the postoperative drain remained was significantly reduced with the PTC technique, just 16.6 days compared to 27.8 days (P < 0.0001). Of the seromas which did develop, the PTC group had significantly fewer aspirations (38.9% vs 14%, P = 0.014), drains placed (15.8% vs 4.6%, P < 0.0001), and operative interventions (7% vs 0%, P < 0.0001). There was no significant difference in mean patient age (54.1, 52.4) or body mass index (28.1, 27.3) between the groups. CONCLUSIONS: The PTC technique of closing latissimus dorsi donor sites significantly decreases seroma formation, number of days a drain is present, and postoperative interventions. This decreases the time and resources devoted to addressing seromas.

Evaluating application of the National Healthcare Safety Network central line-associated bloodstream infection surveillance definition: a survey of pediatric intensive care and hematology/oncology units.

OBJECTIVE: To evaluate the application of the National Healthcare Safety Network (NHSN) central line-associated bloodstream infection (CLABSI) definition in pediatric intensive care units (PICUs) and pediatric hematology/oncology units (PHOUs) participating in a multicenter quality improvement collaborative to reduce CLABSIs; to identify sources of variability in the application of the definition. DESIGN: Online survey using 18 standardized case scenarios. Each described a positive blood culture in a patient and required a yes- or-no answer to the question "Is this a CLABSI?" NHSN staff responses were the reference standard. SETTING: Sixty-five US PICUs and PHOUs. PARTICIPANTS: Staff who routinely adjudicate CLABSIs using NHSN definitions. RESULTS: Sixty responses were received from 58 (89%) of 65 institutions; 78% of respondents were infection preventionists, infection control officers, or infectious disease physicians. Responses matched those of NHSN staff for 78% of questions. The mean (SE) percentage of concurring answers did not differ for scenarios evaluating application of 1 of the 3 criteria ("known pathogen," 78% [1.7%]; "skin contaminant, >1 year of age," 76% [SE, 2.5%]; "skin contaminant, ≤1 year of age," 81% [3.8%]; [Formula: see text]). The mean percentage of concurring answers was lower for scenarios requiring respondents to determine whether a CLABSI was present or incubating on admission (64% [4.6%]; [Formula: see text]) or to distinguish between primary and secondary bacteremia (65% [2.5%]; [Formula: see text]). CONCLUSIONS: The accuracy of application of the CLABSI definition was suboptimal. Efforts to reduce variability in identifying CLABSIs that are present or incubating on admission and in distinguishing primary from secondary bloodstream infection are needed.

Surveillance of hospital-acquired central line-associated bloodstream infections in pediatric hematology-oncology patients: lessons learned, challenges ahead.

Across 36 US pediatric oncology centers, 576 central line-associated bloodstream infections (CLABSIs) were reported over a 21-month period. Most infections occurred in those with leukemia and/or profound neutropenia. The contribution of viridans streptococci infections was striking. Study findings depict the contemporary epidemiology of CLABSIs in hospitalized pediatric cancer patients.

Empirical bayesian selection of hypothesis testing procedures for analysis of sequence count expression data.

Differential expression analysis of sequence-count expression data involves performing a large number of hypothesis tests that compare the expression count data of each gene or transcript across two or more biological conditions. The assumptions of any specific hypothesis-testing method will probably not be valid for each of a very large number of genes. Thus, computational evaluation of assumptions should be incorporated into the analysis to select an appropriate hypothesis-testing method for each gene. Here, we generalize earlier work to introduce two novel procedures that use estimates of the empirical Bayesian probability (EBP) of overdispersion to select or combine results of a standard Poisson likelihood ratio test and a quasi-likelihood test for each gene. These EBP-based procedures simultaneously evaluate the Poisson-distribution assumption and account for multiple testing. With adequate power to detect overdispersion, the new procedures select the standard likelihood test for each gene with Poisson-distributed counts and the quasi-likelihood test for each gene with overdispersed counts. The new procedures outperformed previously published methods in many simulation studies. We also present a real-data analysis example and discuss how the framework used to develop the new procedures may be generalized to further enhance performance. An R code library that implements the methods is freely available at www.stjuderesearch.org/depts/biostats/software.

A mouse model of the most aggressive subgroup of human medulloblastoma.

Medulloblastomas that display a large cell/anaplastic morphology and overexpress the cellular c-MYC gene are highly aggressive and carry a very poor prognosis. This so-called MYC-subgroup differs in its histopathology, gene expression profile, and clinical behavior from other forms of medulloblastoma. We generated a mouse model of MYC-subgroup medulloblastoma by transducing Trp53-null cerebellar progenitor cells with Myc. The cardinal features of these mouse medulloblastomas closely mimic those of human MYC-subgroup tumors and significantly differ from mouse models of the Sonic-Hedgehog- and WNT-disease subgroups. This mouse model should significantly accelerate understanding and treatment of the most aggressive form of medulloblastoma and infers distinct roles for MYC and MYCN in tumorigenesis.

A procedure to statistically evaluate agreement of differential expression for cross-species genomics.

MOTIVATION: Animal models play a pivotal role in translation biomedical research. The scientific value of an animal model depends on how accurately it mimics the human disease. In principle, microarrays collect the necessary data to evaluate the transcriptomic fidelity of an animal model in terms of the similarity of expression with the human disease. However, statistical methods for this purpose are lacking. RESULTS: We develop the agreement of differential expression (AGDEX) procedure to measure and determine the statistical significance of the similarity of the results of two experiments that measure differential expression across two groups. AGDEX defines a metric of agreement and determines statistical significance by permutation of each experiment's group labels. Additionally, AGDEX performs a comprehensive permutation-based analysis of differential expression for each experiment, including gene-set analyses and meta-analytic integration of results across studies. As an example, we show how AGDEX was recently used to evaluate the similarity of the transcriptome of a novel model of the brain tumor ependymoma in mice to that of a subtype of the human disease. This result, combined with other observations, helped us to infer the cell of origin of this devastating human cancer. AVAILABILITY: An R package is currently available from www.stjuderesearch.org/site/depts/biostats/agdex and will shortly be available from www.bioconductor.org.

A Phenotype-Driven Dimension Reduction (PhDDR) approach to integrated genomic association analyses.

An immediate challenge in integrated genomic analysis involving several types of genomic factors all measured genome-wide is the ultra-high dimensionality. Screening all possible relationships among the genomic factors is an NP-hard problem; therefore in practice proper dimension reduction is necessary. In this paper we develop the Phenotype-Driven Dimension Reduction (PhDDR) approach to the analysis of gene co-expressions, and discuss its extensions to integration of other genetic factors. This approach is then illustrated by an application to gene co-expression analysis of treatment response of childhood leukemia.

Graph ranking for exploratory gene data analysis.

BACKGROUND: Microarray technology has made it possible to simultaneously monitor the expression levels of thousands of genes in a single experiment. However, the large number of genes greatly increases the challenges of analyzing, comprehending and interpreting the resulting mass of data. Selecting a subset of important genes is inevitable to address the challenge. Gene selection has been investigated extensively over the last decade. Most selection procedures, however, are not sufficient for accurate inference of underlying biology, because biological significance does not necessarily have to be statistically significant. Additional biological knowledge needs to be integrated into the gene selection procedure. RESULTS: We propose a general framework for gene ranking. We construct a bipartite graph from the Gene Ontology (GO) and gene expression data. The graph describes the relationship between genes and their associated molecular functions. Under a species condition, edge weights of the graph are assigned to be gene expression level. Such a graph provides a mathematical means to represent both species-independent and species-dependent biological information. We also develop a new ranking algorithm to analyze the weighted graph via a kernelized spatial depth (KSD) approach. Consequently, the importance of gene and molecular function can be simultaneously ranked by a real-valued measure, KSD, which incorporates the global and local structure of the graph. Over-expressed and under-regulated genes also can be separately ranked. CONCLUSION: The gene-function bigraph integrates molecular function annotations into gene expression data. The relevance of genes is described in the graph (through a common function). The proposed method provides an exploratory framework for gene data analysis.