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Contemporary Management of Acute Aortic Occlusion Has Evolved but Outcomes Have Not Significantly Improved

Mon, 02/13/2017 - 2:59pm

BACKGROUND: Most existing series of acute aortic occlusion (AAO) predate the changes in surgical and endovascular therapy of the last 2 decades. We examined the contemporary management and outcomes of AAO.

METHODS: We reviewed consecutive patients with AAO at a tertiary referral center from 2004 to 2012. Outcomes were stratified and compared according to etiology and procedure performed.

RESULTS: AAO in 29 patients was due to in situ thrombosis in 21 (72%) and embolism in 8 (28%) patients. Vascular patients with embolism were on average older (77 +/- 7 vs. 66 +/- 12 years, P = 0.02) and had higher rates of atrial fibrillation (100% vs. 20%, P = 0.0002) and congestive heart failure (75% vs. 0%, P = 0.0001) in comparison with those with in situ thrombosis. Neurologic deficit was present in 16 (55%) patients. Six patients (21%) presented with bilateral paresis/paralysis secondary to spinal cord or lumbosacral plexus ischemia, and primary neurologic etiology was investigated before vascular consultation was obtained in 4 of these 6 patients. Of the 29 patients, 28 (97%) underwent revascularization including transfemoral embolectomy (n = 6), transperitoneal aortoiliac thrombectomy (n = 2), axillobifemoral bypass (n = 10), aortobifemoral bypass (n = 6), and endovascular therapy including thrombolysis, angioplasty +/- stenting (n = 4). In-hospital mortality was 31% and did not vary significantly according to etiology (embolism 38% vs. in situ thrombosis 29%, P = 0.67). In-hospital mortality varied widely according to procedure (transfemoral embolectomy 50%, aortoiliac thrombectomy 100%, axillobifemoral bypass 30%, aortobifemoral bypass 0%, and endovascular therapy 25%, P = 0.08). Major morbidity (59%), length of stay (8.6 +/- 8.0 days), and discharge to a rehabilitation facility (50%) did not vary by etiology or procedure. At a media follow-up of 361 +/- 460 days (range 3-2014), overall survival was 42%. There were no amputations among 20 survivors of initial hospitalization.

CONCLUSIONS: AAO is now more commonly caused by in situ thrombosis rather than embolism. A high index of suspicion for AAO is required for prompt diagnosis and treatment, particularly when patients present with profound lower extremity neurologic deficit. In comparison with previous reports, the contemporary management of AAO includes increased use of axillobifemoral bypass and now involves endovascular revascularization, although a variety of open surgical procedures are utilized. However, the in-hospital mortality and morbidity of AAO has not decreased significantly over the last 2 decades and mid-term survival remains limited. Further study is required to identify strategies that improve outcomes after AAO.

Outcomes of Noninvasive and Invasive Ventilation in Patients Hospitalized with Asthma Exacerbation

Mon, 02/13/2017 - 2:59pm

RATIONALE: Little is known about the effectiveness of noninvasive ventilation for patients hospitalized with asthma exacerbation.

OBJECTIVES: To assess clinical outcomes of noninvasive (NIV) and invasive mechanical ventilation (IMV) and examine predictors for NIV use in patients hospitalized with asthma.

METHODS: This was a retrospective cohort study at 97 U.S. hospitals using an electronic medical record database. We developed a hierarchical regression model to identify factors associated with the choice of initial ventilation and used the Laboratory Acute Physiological Score to adjust for differences in the severity of illness. We assessed the outcomes of patients treated with initial NIV or IMV in a propensity-matched cohort.

MEASUREMENTS AND MAIN RESULTS: Among 13,930 subjects, 73% were women and 54% were white. The median age was 53 years. Overall, 1,254 patients (9%) required ventilatory support (NIV or IMV). NIV was the initial ventilation method for 556 patients (4.0%) and IMV for 668 (5.0%). Twenty-six patients (4.7% of patients treated with NIV) had to be intubated (NIV failure). The in-hospital mortality was 0.2, 2.3, 14.5, and 15.4%, and the median length of stay was 2.9, 4.1, 6.7, and 10.9 days among those not ventilated, ventilated with NIV, ventilated with IMV, and with NIV failure, respectively. Older patients were more likely to receive NIV (odds ratio, 1.06 per 5 yr; 95% confidence interval [CI], 1.01-1.11), whereas those with higher acuity (Laboratory Acute Physiological Score per 5 units: odds ratio, 0.85; 95% CI, 0.82-0.88) and those with concomitant pneumonia were less likely to receive NIV. In a propensity-matched sample, NIV was associated with a lower inpatient risk of dying (risk ratio, 0.12; 95% CI, 0.03-0.51) and shorter lengths of stay (4.3 d less; 95% CI, 2.9-5.8) than IMV.

CONCLUSIONS: Among patients hospitalized with asthma exacerbation and requiring ventilatory support (NIV or IMV), more than 40% received NIV. Although patients successfully treated with NIV appear to have better outcomes than those treated with IMV, the low rate of NIV failure suggests that NIV was being used selectively in a lower risk group. The increased risk of mortality for patients who fail NIV highlights the need for careful monitoring to avoid possible delay in intubation.

Patient-reported outcome measures in arthroplasty registries

Mon, 02/13/2017 - 2:59pm

The International Society of Arthroplasty Registries (ISAR) Steering Committee established the Patient-Reported Outcome Measures (PROMs) Working Group to convene, evaluate, and advise on best practices in the selection, administration, and interpretation of PROMs and to support the adoption and use of PROMs for hip and knee arthroplasty in registries worldwide. The 2 main types of PROMs include generic (general health) PROMs, which provide a measure of general health for any health state, and specific PROMs, which focus on specific symptoms, diseases, organs, body regions, or body functions. The establishment of a PROM instrument requires the fulfillment of methodological standards and rigorous testing to ensure that it is valid, reliable, responsive, and acceptable to the intended population. A survey of the 41 ISAR member registries showed that 8 registries administered a PROMs program that covered all elective hip or knee arthroplasty patients and 6 registries collected PROMs for sample populations; 1 other registry had planned but had not started collection of PROMs. The most common generic instruments used were the EuroQol 5 dimension health outcome survey (EQ-5D) and the Short Form 12 health survey (SF-12) or the similar Veterans RAND 12-item health survey (VR-12). The most common specific PROMs were the Hip disability and Osteoarthritis Outcome Score (HOOS), the Knee injury and Osteoarthritis Outcome Score (KOOS), the Oxford Hip Score (OHS), the Oxford Knee Score (OKS), the Western Ontario and McMaster Universities Arthritis Index (WOMAC), and the University of California at Los Angeles Activity Score (UCLA).

Patient-reported outcome measures in arthroplasty registries Report of the Patient-Reported Outcome Measures Working Group of the International Society of Arthroplasty Registries Part II. Recommendations for selection, administration, and analysis

Mon, 02/13/2017 - 2:59pm

The International Society of Arthroplasty Registries (ISAR) Patient-Reported Outcome Measures (PROMs) Working Group have evaluated and recommended best practices in the selection, administration, and interpretation of PROMs for hip and knee arthroplasty registries. The 2 generic PROMs in common use are the Short Form health surveys (SF-36 or SF-12) and EuroQol 5-dimension (EQ-5D). The Working Group recommends that registries should choose specific PROMs that have been appropriately developed with good measurement properties for arthroplasty patients. The Working Group recommend the use of a 1-item pain question ("During the past 4 weeks, how would you describe the pain you usually have in your [right/left] [hip/knee]?"; response: none, very mild, mild, moderate, or severe) and a single-item satisfaction outcome ("How satisfied are you with your [right/left] [hip/knee] replacement?"; response: very unsatisfied, dissatisfied, neutral, satisfied, or very satisfied). Survey logistics include patient instructions, paper- and electronic-based data collection, reminders for follow-up, centralized as opposed to hospital-based follow-up, sample size, patient- or joint-specific evaluation, collection intervals, frequency of response, missing values, and factors in establishing a PROMs registry program. The Working Group recommends including age, sex, diagnosis at joint, general health status preoperatively, and joint pain and function score in case-mix adjustment models. Interpretation and statistical analysis should consider the absolute level of pain, function, and general health status as well as improvement, missing data, approaches to analysis and case-mix adjustment, minimal clinically important difference, and minimal detectable change. The Working Group recommends data collection immediately before and 1 year after surgery, a threshold of 60% for acceptable frequency of response, documentation of non-responders, and documentation of incomplete or missing data.

What Outcomes are Important for Gout Patients? In-Depth Qualitative Research into the Gout Patient Experience to Determine Optimal Endpoints for Evaluating Therapeutic Interventions

Mon, 02/13/2017 - 2:59pm

BACKGROUND AND OBJECTIVES: Characterized by sudden onset of severe joint pain, swelling, redness, and tenderness to touch, gout 'flare ups' have a substantial impact on quality of life (QoL). This research employed a patient-centered approach to explore the symptoms and impacts of gout, and assess the content validity of existing patient-reported outcomes (PROs).

METHODS: Qualitative interviews were conducted with 30 US gout patients (non-tophaceous: n = 20, tophaceous: n = 10) and five expert rheumatologists. Each interview included both concept elicitation (CE) questioning to learn about the patient experience and cognitive debriefing to assess the content validity of three PRO instruments (HAQ-DI, GAQ, and TIQ-20). Nine of the patients provided further real-time qualitative data through a smart phone application. All qualitative data were subject to thematic analysis using Atlas.ti. Two patient advisors and three expert clinicians were engaged as advisors at key stages throughout the research.

RESULTS: Interview and real-time data identified the same core symptoms and proximal impact concepts. Severe pain (typically in joints of extremities) was described as the cardinal symptom, often accompanied by swelling, redness, heat, sensitivity to touch, and stiffness. Domains of QoL impacted included physical functioning, sleep, daily activities, and work. The PRO instruments were generally well-understood by patients, but each included items with questionable relevance to at least some of the sample, dependent on the specific joints affected.

CONCLUSIONS: Gout patients experience severe pain in affected joints, resulting in substantial limitations in physical functioning. Both the HAQ-DI and the TIQ-20 are useful for specific research purposes in the gout population, although modifications are recommended.

The Physician-as-Stakeholder: An Exploratory Qualitative Analysis of Physicians' Motivations for Using Shared Decision Making in the Emergency Department

Mon, 02/13/2017 - 2:59pm

BACKGROUND: Shared decision making (SDM) is increasingly recognized as an important facet of patient-centered care. Despite growing interest in SDM in the emergency department (ED), little is known about emergency physicians' (EPs') motivations for using SDM. Understanding current patterns of SDM use and EP's rationale for using SDM is essential for the development of interventions to increase use.

OBJECTIVES: Recognizing the EP as an important stakeholder in SDM research, we sought to identify and explore factors that may motivate EPs' engagement in SDM.

METHODS: In this qualitative study, informed by the Theory of Planned Behavior and Social Cognitive Theory, we conducted semistructured interviews with a purposeful sample of EPs. Interviews were recorded and transcribed verbatim. Using a directed qualitative content analysis approach, three members of the research team performed open coding of the transcripts in an iterative process, building a provisional code book as coding progressed. Respondent validation was employed to ensure methodologic rigor.

RESULTS: Fifteen EPs, ages 31-65, from both academic and community practice settings, were interviewed. Several had not heard of the specific phrase "shared decision making," but all understood the concept and felt that they used SDM techniques to some degree. Most noted they had often had an agenda when they used SDM, which often motivated them to have the conversation. Agendas described included counteracting an algorithmic or defensive approach to diagnosis and treatment, avoiding harmful tests, or sharing uncertainty. All participants believed that patients benefited from SDM in terms of satisfaction, engagement, or education. Nearly all participants identified research outcomes that they felt would encourage their use of SDM (e.g., improvements in patient engagement, mitigation of risk) and many prioritized patient-centered outcomes over systems outcomes such as improved resource utilization. Little consensus was seen, however, regarding the importance of individual outcomes: of eight potential research outcomes participants endorsed, no single outcome was endorsed by even half of the physicians interviewed.

CONCLUSION: Emergency physicians identified many factors that motivated them to use SDM. This study informs current research on SDM in the ED, particularly regarding the motivations of the physician-as-stakeholder.

Lithium in Paediatric Patients with Bipolar Disorder: Implications for Selection of Dosage Regimens via Population Pharmacokinetics/Pharmacodynamics

Mon, 02/13/2017 - 2:59pm

BACKGROUND: Lithium is a well-established treatment for bipolar I disorder in adults. However, there is a paucity of information on its pharmacokinetics/pharmacodynamics in children and adolescents. We aimed to develop the first lithium dosage regimens based on population pharmacokinetics/pharmacodynamics for paediatric patients.

METHODS: Lithium concentrations, Young Mania Rating Scale (YMRS) and Clinical Global Impressions-Improvement (CGI-I) scores over 24 weeks were available from 61 paediatric patients with bipolar I disorder. The population pharmacokinetics/pharmacodynamics were co-modelled. Concentrations and clinical effects following several dosage regimens were predicted by Monte Carlo simulations.

RESULTS: The pharmacokinetics were well characterised by a two compartment model with linear elimination. Including the effect of total body weight (TBW) or lean body weight (LBW) on clearance and volume of distribution decreased the unexplained inter-individual variability by up to 12 %. The population mean (inter-individual variability) clearance was 1.64 L/h/53 kg LBW0.75 (19 %) and central volume of distribution 23.6 L/53 kg LBW (6.8 %). The average lithium concentration over a dosing interval required for a 50 % reduction in YMRS was 0.711 mEq/L (59 %). A maintenance dose of 25 mg/kg TBW/day lithium carbonate in two daily doses was predicted to achieve a > /=50 % reduction in YMRS in 74 % of patients, while ~8 % of patients would be expected to have trough concentrations above the nominal safety threshold of 1.4 mEq/L. Therefore, therapeutic drug monitoring will still be required even with these dosing strategies.

CONCLUSIONS: When accounting for body size, the pharmacokinetic parameters in paediatric patients were within the range of estimates from adults. Pharmacokinetic/pharmacodynamic modelling supported development of practical scientifically-based dosage regimens for paediatric patients.

Comparison of Self-reported and Measured Pre-pregnancy Weight: Implications for Gestational Weight Gain Counseling

Mon, 02/13/2017 - 11:52am

Objectives: To examine clinical and demographic characteristics associated with availability of self-reported and measured pre-pregnancy weight, differences in these parameters, and characteristics associated with self-report accuracy.

Methods: Retrospective cohort of 7483 women who delivered at a large academic medical center between 2011 and 2014. Measured pre-pregnancy weights recorded within a year of conception and self-reported pre-pregnancy weights reported anytime during pregnancy were abstracted from electronic medical records. Difference in weights was calculated as self-reported minus measured pre-pregnancy weight. Logistic and linear regression models estimated associations between demographic and clinical characteristics, and presence of self-reported and measured weights, and weight differences.

Results: 42.2% of women had both self-reported and measured pre-pregnancy weight, 49.7% had only self-reported, and 2.8% had only measured. Compared to white women, black women and women of other races/ethnicities were less likely to have self-reported weight, and black, Asian, and Hispanic women, and women of other races/ethnicities were less likely to have measured weights. For 85%, pre-pregnancy BMI categorized by self-reported and measured weights were concordant. Primiparas and multiparas were more likely to underreport their weight compared to nulliparas (b = -1.32 lbs, 95% CI -2.24 to -0.41 lbs and b = -2.74 lbs, 95% CI -3.82 to -1.67 lbs, respectively).

Discussion: Utilization of self-reported or measured pre-pregnancy weight for pre-pregnancy BMI classification results in identical categorization for the majority of women. Providers may wish to account for underreporting for patients with a BMI close to category cutoff by recommending a range of gestational weight gain that falls within recommendations for both categories where feasible.

Unexpected role of interferon-gamma in regulating neuronal connectivity and social behaviour

Sun, 02/12/2017 - 5:07pm

Immune dysfunction is commonly associated with several neurological and mental disorders. Although the mechanisms by which peripheral immunity may influence neuronal function are largely unknown, recent findings implicate meningeal immunity influencing behaviour, such as spatial learning and memory. Here we show that meningeal immunity is also critical for social behaviour; mice deficient in adaptive immunity exhibit social deficits and hyper-connectivity of fronto-cortical brain regions. Associations between rodent transcriptomes from brain and cellular transcriptomes in response to T-cell-derived cytokines suggest a strong interaction between social behaviour and interferon-gamma (IFN-gamma)-driven responses. Concordantly, we demonstrate that inhibitory neurons respond to IFN-gamma and increase GABAergic (gamma-aminobutyric-acid) currents in projection neurons, suggesting that IFN-gamma is a molecular link between meningeal immunity and neural circuits recruited for social behaviour. Meta-analysis of the transcriptomes of a range of organisms reveals that rodents, fish, and flies elevate IFN-gamma/JAK-STAT-dependent gene signatures in a social context, suggesting that the IFN-gamma signalling pathway could mediate a co-evolutionary link between social/aggregation behaviour and an efficient anti-pathogen response. This study implicates adaptive immune dysfunction, in particular IFN-gamma, in disorders characterized by social dysfunction and suggests a co-evolutionary link between social behaviour and an anti-pathogen immune response driven by IFN-gamma signalling.

Data Formats in Bioinformatics

Sun, 02/12/2017 - 5:07pm

Here we introduce several interchangeable data formats that are commonly used in bioinformatics.

Identifying Regions Enriched in a ChIP-seq Data Set (Peak Finding)

Sun, 02/12/2017 - 5:07pm

This protocol demonstrates how to use MACS software to call peaks in a ChIP-seq data set. MACS is one of the most widely used peak-calling programs. The protocol describes how to run MACS in a UNIX environment and on Galaxy and how to extract the sequences of +/-50 bp around the summits of the 500 MACS peaks with the most significant P values.

Analysis of Microarray and RNA-seq Expression Profiling Data

Sun, 02/12/2017 - 5:07pm

Gene expression profiling refers to the simultaneous measurement of the expression levels of a large number of genes (often all genes in a genome), typically in multiple experiments spanning a variety of cell types, treatments, or environmental conditions. Expression profiling is accomplished by assaying mRNA levels with microarrays or next-generation sequencing technologies (RNA-seq). This introduction describes normalization and analysis of data generated from microarray or RNA-seq experiments.

Motif Finding

Sun, 02/12/2017 - 5:07pm

Here we provide an introduction to sequence motifs, including prediction of transcription factor-binding sites and general approaches to finding motifs enriched in a set of regulatory sequences.

Peak-Finding Algorithms

Sun, 02/12/2017 - 5:07pm

Microarray and next-generation sequencing technologies have greatly expedited the discovery of genomic DNA that can be enriched using various biochemical methods. Chromatin immunoprecipitation (ChIP) is a general method for enriching chromatin fragments that are specifically recognized by an antibody. The resulting DNA fragments can be assayed by microarray (ChIP-chip) or sequencing (ChIP-seq). This introduction focuses on ChIP-seq data analysis. The first step of analyzing ChIP-seq data is identifying regions in the genome that are enriched in a ChIP sample; these regions are called peaks.

Discovering cis-Regulatory Motifs

Sun, 02/12/2017 - 5:07pm

This protocol describes a suite of tools for motif finding, using cis-regulatory motifs as an example. The first part of this protocol demonstrates the use of MEME (ab initio motif discovery), JASPAR (a motif database), Clover (searching for enriched known motifs), and MAST (scanning a sequence for motif sites) on a set of computationally predicted CREB-binding sequences downloaded from the UCSC Table Browser. The second part of the protocol shows how to use MEME-ChIP, an integrated suite of tools for analyzing ChIP-seq data, to discover motifs in STAT1 ChIP-seq peaks and compare them with known motifs in the JASPAR database.

Analyzing Microarray Data

Sun, 02/12/2017 - 5:07pm

Because there is no widely used software for analyzing RNA-seq data that has a graphical user interface, this protocol provides an example of analyzing microarray data using Babelomics. This analysis entails performing quantile normalization and then detecting differentially expressed genes associated with the transgenesis of a human oncogene c-Myc in mice. Finally, hierarchical clustering is performed on the differentially expressed genes using the Cluster program, and the results are visualized using TreeView.

Mapping Short Sequence Reads to a Reference Genome

Sun, 02/12/2017 - 5:07pm

This protocol describes mapping short sequence reads to a reference genome using several programs. The example in this protocol starts with a ChIP-seq data set in FASTQ format, aligns the reads to the human genome using Bowtie, and uses some useful utilities of SAMtools and BEDTools. SAMtools and BEDTools are two collections of executables for manipulating the results of short-read aligners. By combining these tools, one can summarize and visualize alignments produced by Bowtie and perform basic analysis, such as determining the number of reads that are mapped to a certain gene. These tools can also be easily incorporated into computational pipelines of more complex analyses.

Designing Polymerase Chain Reaction Primers Using Primer3Plus

Sun, 02/12/2017 - 5:07pm

Designing oligonucleotide primers is a crucial step for successful molecular biology experiments that require the use of the polymerase chain reaction (PCR). PCR involves cycles of three steps: denaturation, annealing, and extension. During denaturation, double-stranded DNA (dsDNA) molecules (templates) are separated into single strands. During annealing, a pair of primers is annealed to the complementary regions of the single-stranded molecules. In the extension step, DNA polymerase extends the primers to produce DNA molecules that correspond to the region bracketed by the primers (the amplicons). All of these steps are temperature sensitive, and the common choice of temperatures is 94 degrees C, 60 degrees C, and 70 degrees C, respectively. Poorly designed primers may lead to no amplification product or additional undesired amplified fragments. The goals of primer design include good primer specificity, high annealing efficiency, appropriate melting temperature, proper GC content, and the prevention of primer hairpins or primer dimers.

Performance of ZDOCK and IRAD in CAPRI rounds 28-34

Sun, 02/12/2017 - 5:07pm

We report the performance of our protein-protein docking pipeline, including the ZDOCK rigid-body docking algorithm, on 19 targets in CAPRI rounds 28-34. Following the docking step, we reranked the ZDOCK predictions using the IRAD scoring function, pruned redundant predictions, performed energy landscape analysis, and utilized our interface prediction approach RCF. In addition, we applied constraints to the search space based on biological information that we culled from the literature, which increased the chance of making a correct prediction. For all but two targets we were able to find and apply biological information and we found the information to be highly accurate, indicating that effective incorporation of biological information is an important component for protein-protein docking. Proteins 2016.

DNApi: A De Novo Adapter Prediction Algorithm for Small RNA Sequencing Data

Sun, 02/12/2017 - 5:06pm

With the rapid accumulation of publicly available small RNA sequencing datasets, third-party meta-analysis across many datasets is becoming increasingly powerful. Although removing the 3 adapter is an essential step for small RNA sequencing analysis, the adapter sequence information is not always available in the metadata. The information can be also erroneous even when it is available. In this study, we developed DNApi, a lightweight Python software package that predicts the 3 adapter sequence de novo and provides the user with cleansed small RNA sequences ready for down stream analysis. Tested on 539 publicly available small RNA libraries accompanied with 3 adapter sequences in their metadata, DNApi shows near-perfect accuracy (98.5%) with fast runtime (~2.85 seconds per library) and efficient memory usage (~43 MB on average). In addition to 3 adapter prediction, it is also important to classify whether the input small RNA libraries were already processed, i.e. the 3 adapters were removed. DNApi perfectly judged that given another batch of datasets, 192 publicly available processed libraries were "ready-to-map" small RNA sequence. DNApi is compatible with Python 2 and 3, and is available at The 731 small RNA libraries used for DNApi evaluation were from human tissues and were carefully and manually collected. This study also provides readers with the curated datasets that can be integrated into their studies.