Risk Factors for Sternal Wound Infection After Open Heart Operations Vary According to Type of Operation

BACKGROUND This study evaluated whether risk factors for sternal wound infections vary with the type of surgical procedure in cardiac operations. METHODS This was a university hospital surveillance study of 3,249 consecutive patients (28% women) from 2006 to 2010 (median age, 69 years [interquartile range, 60 to 76]; median additive European System for Cardiac Operative Risk Evaluation score, 5 [interquartile range, 3 to 8]) after (1) isolated coronary artery bypass grafting (CABG), (2) isolated valve repair or replacement, or (3) combined valve procedures and CABG. All other operations were excluded. Univariate and multivariate binary logistic regression were conducted to identify independent predictors for development of sternal wound infections. RESULTS We detected 122 sternal wound infections (3.8%) in 3,249 patients: 74 of 1,857 patients (4.0%) after CABG, 19 of 799 (2.4%) after valve operations, and 29 of 593 (4.9%) after combined procedures. In CABG patients, bilateral internal thoracic artery harvest, procedural duration exceeding 300 minutes, diabetes, obesity, chronic obstructive pulmonary disease, and female sex (model 1) were independent predictors for sternal wound infection. A second model (model 2), using the European System for Cardiac Operative Risk Evaluation, revealed bilateral internal thoracic artery harvest, diabetes, obesity, and the second and third quartiles of the European System for Cardiac Operative Risk Evaluation were independent predictors. In valve patients, model 1 showed only revision for bleeding as an independent predictor for sternal infection, and model 2 yielded both revision for bleeding and diabetes. For combined valve and CABG operations, both regression models demonstrated revision for bleeding and duration of operation exceeding 300 minutes were independent predictors for sternal infection. CONCLUSIONS Risk factors for sternal wound infections after cardiac operations vary with the type of surgical procedure. In patients undergoing valve operations or combined operations, procedure-related risk factors (revision for bleeding, duration of operation) independently predict infection. In patients undergoing CABG, not only procedure-related risk factors but also bilateral internal thoracic artery harvest and patient characteristics (diabetes, chronic obstructive pulmonary disease, obesity, female sex) are predictive of sternal wound infection. Preventive interventions may be justified according to the type of operation.

Sampling in Open Source Software Development: The case for using the Debian GNUILinux Distribution

Research on open source software (OSS) projects often focuses on the SourceForge collaboration platform. We argue that a GNU/Linwr distribution, such as Debian, is better suited for the sampling ofprojects because it avoids biases and contains unique information only available in an integrated environment. Especially research on the reuse of components can build on dependency information inherent in the Debian GNU/Linux packaging system. This paper therefore contributes to the practice of sampling methods in OSS research and provides empirical data on reuse dependencies in Debian.

Viral Escape in the Central Nervous System with Multidrug-Resistant Human Immunodeficiency Virus-1

In this study, we report the case of a patient infected with human immunodeficiency virus (HIV)-1 who developed ataxia and neurocognitive impairment due to viral escape within the central nervous system (CNS) with a multidrug-resistant HIV-1 despite long-term viral suppression in plasma. Antiretroviral therapy optimization with drugs with high CNS penetration led to viral suppression in the CSF, regression of ataxia, and improvement of neurocognitive symptoms.

Effect of the REG1 anticoagulation system versus bivalirudin on outcomes after percutaneous coronary intervention (REGULATE-PCI): a randomised clinical trial.

BACKGROUND REG1 is a novel anticoagulation system consisting of pegnivacogin, an RNA aptamer inhibitor of coagulation factor IXa, and anivamersen, a complementary sequence reversal oligonucleotide. We tested the hypothesis that near complete inhibition of factor IXa with pegnivacogin during percutaneous coronary intervention, followed by partial reversal with anivamersen, would reduce ischaemic events compared with bivalirudin, without increasing bleeding. METHODS We did a randomised, open-label, active-controlled, multicentre, superiority trial to compare REG1 with bivalirudin at 225 hospitals in North America and Europe. We planned to randomly allocate 13,200 patients undergoing percutaneous coronary intervention in a 1:1 ratio to either REG1 (pegnivacogin 1 mg/kg bolus [>99% factor IXa inhibition] followed by 80% reversal with anivamersen after percutaneous coronary intervention) or bivalirudin. Exclusion criteria included ST segment elevation myocardial infarction within 48 h. The primary efficacy endpoint was the composite of all-cause death, myocardial infarction, stroke, and unplanned target lesion revascularisation by day 3 after randomisation. The principal safety endpoint was major bleeding. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, identifier NCT01848106. The trial was terminated early after enrolment of 3232 patients due to severe allergic reactions. FINDINGS 1616 patients were allocated REG1 and 1616 were assigned bivalirudin, of whom 1605 and 1601 patients, respectively, received the assigned treatment. Severe allergic reactions were reported in ten (1%) of 1605 patients receiving REG1 versus one (<1%) of 1601 patients treated with bivalirudin. The composite primary endpoint did not differ between groups, with 108 (7%) of 1616 patients assigned REG1 and 103 (6%) of 1616 allocated bivalirudin reporting a primary endpoint event (odds ratio [OR] 1·05, 95% CI 0·80-1·39; p=0·72). Major bleeding was similar between treatment groups (seven [<1%] of 1605 receiving REG1 vs two [<1%] of 1601 treated with bivalirudin; OR 3·49, 95% CI 0·73-16·82; p=0·10), but major or minor bleeding was increased with REG1 (104 [6%] vs 65 [4%]; 1·64, 1·19-2·25; p=0·002). INTERPRETATION The reversible factor IXa inhibitor REG1, as currently formulated, is associated with severe allergic reactions. Although statistical power was limited because of early termination, there was no evidence that REG1 reduced ischaemic events or bleeding compared with bivalirudin. FUNDING Regado Biosciences Inc.

Transmission of Mycobacterium chimaera from Heater-Cooler Units during Cardiac Surgery despite an Ultraclean Air Ventilation System.

Heater-cooler units (HCUs) were recently identified as a source of Mycobacterium chimaera causing surgical site infections. We investigated transmission of this bacterium from HCUs to the surgical field by using a thermic anemometer and particle counter, videotape of an operating room equipped with an ultraclean laminar airflow ventilation system, and bacterial culture sedimentation plates in a nonventilated room. Smoke from the HCU reached the surgical field in 23 s by merging with ultraclean air. The HCU produced on average 5.2, 139, and 14.8 particles/min in the surgical field at positions Off, On/oriented toward, and On/oriented away, respectively. Culture plates were positive for M. chimaera <5 m from the HCU in the test room. These experiments confirm airborne transmission of M. chimaera aerosols from a contaminated HCU to an open surgical field despite ultraclean air ventilation. Efforts to mitigate infectious risks during surgery should consider contamination from water sources and airflow-generating devices.

Impact of Taylor-Aris diffusivity on analyte and system zone dispersion in CZE assessed by computer simulation and experimental validation.

Application of pressure-driven laminar flow has an impact on zone and boundary dispersion in open tubular CE. The GENTRANS dynamic simulator for electrophoresis was extended with Taylor-Aris diffusivity which accounts for dispersion due to the parabolic flow profile associated with pressure-driven flow. Effective diffusivity of analyte and system zones as functions of the capillary diameter and the amount of flow in comparison to molecular diffusion alone were studied for configurations with concomitant action of imposed hydrodynamic flow and electroosmosis. For selected examples under realistic experimental conditions, simulation data are compared with those monitored experimentally using modular CE setups featuring both capacitively coupled contactless conductivity and UV absorbance detection along a 50 μm id fused-silica capillary of 90 cm total length. The data presented indicate that inclusion of flow profile based Taylor-Aris diffusivity provides realistic simulation data for analyte and system peaks, particularly those monitored in CE with conductivity detection.

Developing a point-of-care electronic medical record system for TB/HIV co-infected patients: experiences from Lighthouse Trust, Lilongwe, Malawi.

BACKGROUND Implementation of user-friendly, real-time, electronic medical records for patient management may lead to improved adherence to clinical guidelines and improved quality of patient care. We detail the systematic, iterative process that implementation partners, Lighthouse clinic and Baobab Health Trust, employed to develop and implement a point-of-care electronic medical records system in an integrated, public clinic in Malawi that serves HIV-infected and tuberculosis (TB) patients. METHODS Baobab Health Trust, the system developers, conducted a series of technical and clinical meetings with Lighthouse and Ministry of Health to determine specifications. Multiple pre-testing sessions assessed patient flow, question clarity, information sequencing, and verified compliance to national guidelines. Final components of the TB/HIV electronic medical records system include: patient demographics; anthropometric measurements; laboratory samples and results; HIV testing; WHO clinical staging; TB diagnosis; family planning; clinical review; and drug dispensing. RESULTS Our experience suggests that an electronic medical records system can improve patient management, enhance integration of TB/HIV services, and improve provider decision-making. However, despite sufficient funding and motivation, several challenges delayed system launch including: expansion of system components to include of HIV testing and counseling services; changes in the national antiretroviral treatment guidelines that required system revision; and low confidence to use the system among new healthcare workers. To ensure a more robust and agile system that met all stakeholder and user needs, our electronic medical records launch was delayed more than a year. Open communication with stakeholders, careful consideration of ongoing provider input, and a well-functioning, backup, paper-based TB registry helped ensure successful implementation and sustainability of the system. Additional, on-site, technical support provided reassurance and swift problem-solving during the extended launch period. CONCLUSION Even when system users are closely involved in the design and development of an electronic medical record system, it is critical to allow sufficient time for software development, solicitation of detailed feedback from both users and stakeholders, and iterative system revisions to successfully transition from paper to point-of-care electronic medical records. For those in low-resource settings, electronic medical records for integrated care is a possible and positive innovation.

Cognitive-Behavioural Analysis System of Psychotherapy (CBASP), a drug, or their combination: differential therapeutics for persistent depressive disorder: a study protocol of an individual participant data network meta-analysis.

INTRODUCTION Despite important advances in psychological and pharmacological treatments of persistent depressive disorders in the past decades, their responses remain typically slow and poor, and differential responses among different modalities of treatments or their combinations are not well understood. Cognitive-Behavioural Analysis System of Psychotherapy (CBASP) is the only psychotherapy that has been specifically designed for chronic depression and has been examined in an increasing number of trials against medications, alone or in combination. When several treatment alternatives are available for a certain condition, network meta-analysis (NMA) provides a powerful tool to examine their relative efficacy by combining all direct and indirect comparisons. Individual participant data (IPD) meta-analysis enables exploration of impacts of individual characteristics that lead to a differentiated approach matching treatments to specific subgroups of patients. METHODS AND ANALYSIS We will search for all randomised controlled trials that compared CBASP, pharmacotherapy or their combination, in the treatment of patients with persistent depressive disorder, in Cochrane CENTRAL, PUBMED, SCOPUS and PsycINFO, supplemented by personal contacts. Individual participant data will be sought from the principal investigators of all the identified trials. Our primary outcomes are depression severity as measured on a continuous observer-rated scale for depression, and dropouts for any reason as a proxy measure of overall treatment acceptability. We will conduct a one-step IPD-NMA to compare CBASP, medications and their combinations, and also carry out a meta-regression to identify their prognostic factors and effect moderators. The model will be fitted in OpenBUGS, using vague priors for all location parameters. For the heterogeneity we will use a half-normal prior on the SD. ETHICS AND DISSEMINATION This study requires no ethical approval. We will publish the findings in a peer-reviewed journal. The study results will contribute to more finely differentiated therapeutics for patients suffering from this chronically disabling disorder. TRIAL REGISTRATION NUMBER CRD42016035886.

COMPREHENSIVE CALCULATION-BASED IMRT QA USING R&V DATA, TREATMENT RECORDS, AND A SECOND TREATMENT PLANNING SYSTEM

Purpose: Traditional patient-specific IMRT QA measurements are labor intensive and consume machine time. Calculation-based IMRT QA methods typically are not comprehensive. We have developed a comprehensive calculation-based IMRT QA method to detect uncertainties introduced by the initial dose calculation, the data transfer through the Record-and-Verify (R&V) system, and various aspects of the physical delivery. Methods: We recomputed the treatment plans in the patient geometry for 48 cases using data from the R&V, and from the delivery unit to calculate the “as-transferred” and “as-delivered” doses respectively. These data were sent to the original TPS to verify transfer and delivery or to a second TPS to verify the original calculation. For each dataset we examined the dose computed from the R&V record (RV) and from the delivery records (Tx), and the dose computed with a second verification TPS (vTPS). Each verification dose was compared to the clinical dose distribution using 3D gamma analysis and by comparison of mean dose and ROI-specific dose levels to target volumes. Plans were also compared to IMRT QA absolute and relative dose measurements. Results: The average 3D gamma passing percentages using 3%-3mm, 2%-2mm, and 1%-1mm criteria for the RV plan were 100.0 (σ=0.0), 100.0 (σ=0.0), and 100.0 (σ=0.1); for the Tx plan they were 100.0 (σ=0.0), 100.0 (σ=0.0), and 99.0 (σ=1.4); and for the vTPS plan they were 99.3 (σ=0.6), 97.2 (σ=1.5), and 79.0 (σ=8.6). When comparing target volume doses in the RV, Tx, and vTPS plans to the clinical plans, the average ratios of ROI mean doses were 0.999 (σ=0.001), 1.001 (σ=0.002), and 0.990 (σ=0.009) and ROI-specific dose levels were 0.999 (σ=0.001), 1.001 (σ=0.002), and 0.980 (σ=0.043), respectively. Comparing the clinical, RV, TR, and vTPS calculated doses to the IMRT QA measurements for all 48 patients, the average ratios for absolute doses were 0.999 (σ=0.013), 0.998 (σ=0.013), 0.999 σ=0.015), and 0.990 (σ=0.012), respectively, and the average 2D gamma(5%-3mm) passing percentages for relative doses for 9 patients was were 99.36 (σ=0.68), 99.50 (σ=0.49), 99.13 (σ=0.84), and 98.76 (σ=1.66), respectively. Conclusions: Together with mechanical and dosimetric QA, our calculation-based IMRT QA method promises to minimize the need for patient-specific QA measurements by identifying outliers in need of further review.

Improved Techniques for Acquisition and Analysis of Dynamic Contrast-Enhanced Magnetic Resonance Imaging for Detecting Vascular Permeability in the Central Nervous System

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a noninvasive technique for quantitative assessment of the integrity of blood-brain barrier and blood-spinal cord barrier (BSCB) in the presence of central nervous system pathologies. However, the results of DCE-MRI show substantial variability. The high variability can be caused by a number of factors including inaccurate T1 estimation, insufficient temporal resolution and poor contrast-to-noise ratio. My thesis work is to develop improved methods to reduce the variability of DCE-MRI results. To obtain fast and accurate T1 map, the Look-Locker acquisition technique was implemented with a novel and truly centric k-space segmentation scheme. In addition, an original multi-step curve fitting procedure was developed to increase the accuracy of T1 estimation. A view sharing acquisition method was implemented to increase temporal resolution, and a novel normalization method was introduced to reduce image artifacts. Finally, a new clustering algorithm was developed to reduce apparent noise in the DCE-MRI data. The performance of these proposed methods was verified by simulations and phantom studies. As part of this work, the proposed techniques were applied to an in vivo DCE-MRI study of experimental spinal cord injury (SCI). These methods have shown robust results and allow quantitative assessment of regions with very low vascular permeability. In conclusion, applications of the improved DCE-MRI acquisition and analysis methods developed in this thesis work can improve the accuracy of the DCE-MRI results.

Development of HIF-1α/HIF-1β heterodimerization inhibitors using a novel bioluminescence reporter assay system for in vitro high throughput screening and in vivo imaging

Tumor growth often outpaces its vascularization, leading to development of a hypoxic tumor microenvironment. In response, an intracellular hypoxia survival pathway is initiated by heterodimerization of hypoxia-inducible factor (HIF)-1α and HIF-1β, which subsequently upregulates the expression of several hypoxia-inducible genes, promotes cell survival and stimulates angiogenesis in the oxygen-deprived environment. Hypoxic tumor regions are often associated with resistance to various classes of radio- or chemotherapeutic agents. Therefore, development of HIF-1α/β heterodimerization inhibitors may provide a novel approach to anti-cancer therapy. To this end, a novel approach for imaging HIF-1α/β heterodimerization in vitro and in vivo was developed in this study. Using this screening platform, we identified a promising lead candidate and further chemically derivatized the lead candidate to assess the structure-activity relationship (SAR). The most effective first generation drug inhibitors were selected and their pharmacodynamics and anti-tumor efficacy in vivo were verified by bioluminescence imaging (BLI) of HIF-1α/β heterodimerization in the xenograft tumor model. Furthermore, the first generation drug inhibitors, M-TMCP and D-TMCP, demonstrated efficacy as monotherapies, resulting in tumor growth inhibition via disruption of HIF-1 signaling-mediated tumor stromal neoangiogenesis.