Infectious Complications of Ventricular Assist Device Use in Children in the US: Data from the Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs)

Background Infections are frequent in pediatric ventricular assist device (VAD) patients. In this study we aimed to describe infections in durable VAD patients reported to Pedimacs. Methods Durable VAD data from the Pedimacs registry (September 19, 2012 to December 31, 2015) were analyzed. Infections were described with standard descriptive statistics, Kaplan–Meier analysis and competing outcomes analysis. Results There were 248 implants in 222 patients, with a mean age and a median follow-up of 11 ± 6.4 years and 2.4 patient-months (<1 day to 2.6 years), respectively. Device types were pulsatile flow (PF) in 91 (41%) patients and continuous flow (CF) in 131 (59%) patients. PF patients were younger (4 ± 4 vs 14 ± 4 years; p < 0.0001) and were more likely to have congenital heart disease (25% vs 12%; p = 0.03), prior surgery (53% vs 26%; p < 0.0001) and prior extracorporeal membrane oxygenation (24% vs 7%; p = 0.0003). Infection accounted for 17% (96 of 564) of the reported adverse events (AEs). A non-device infection was most common (51%), followed by sepsis (24%), external pump component infection (20%) and internal pump component infection (5%). Most infections were bacterial (73%) and required intravenous therapy only (77%). The risk of infection in the constant phase was higher in patients with a history of prior infection and in patients with a history of a non-infectious major AEs. Survival was lower after infection only in CF patients (p = 0.008). Conclusions Infection was the most common AE after pediatric VAD implantation. Non-device infections were most common. The best predictor of a future infection was a past infection. CF patients have higher risk of death after an infection

Stereotactic ablative radiotherapy for comprehensive treatment of oligometastatic tumors (SABR-COMET): Study protocol for a randomized phase II trial

<p>Abstract</p> <p>Background</p> <p>Stereotactic ablative radiotherapy (SABR) has emerged as a new treatment option for patients with oligometastatic disease. SABR delivers precise, high-dose, hypofractionated radiotherapy, and achieves excellent rates of local control. Survival outcomes for patients with oligometastatic disease treated with SABR appear promising, but conclusions are limited by patient selection, and the lack of adequate controls in most studies. The goal of this multicenter randomized phase II trial is to assess the impact of a comprehensive oligometastatic SABR treatment program on overall survival and quality of life in patients with up to 5 metastatic cancer lesions, compared to patients who receive standard of care treatment alone.</p> <p>Methods</p> <p>After stratification by the number of metastases (1-3 vs. 4-5), patients will be randomized between Arm 1: current standard of care treatment, and Arm 2: standard of care treatment + SABR to all sites of known disease. Patients will be randomized in a 1:2 ratio to Arm 1:Arm 2, respectively. For patients receiving SABR, radiotherapy dose and fractionation depends on the site of metastasis and the proximity to critical normal structures. This study aims to accrue a total of 99 patients within four years. The primary endpoint is overall survival, and secondary endpoints include quality of life, toxicity, progression-free survival, lesion control rate, and number of cycles of further chemotherapy/systemic therapy.</p> <p>Discussion</p> <p>This study will provide an assessment of the impact of SABR on clinical outcomes and quality of life, to determine if long-term survival can be achieved for selected patients with oligometastatic disease, and will inform the design of a possible phase III study.</p> <p>Trial registration</p> <p>Clinicaltrials.gov identifier: NCT01446744</p

Low frequency observations of linearly polarized structures in the interstellar medium near the south Galactic pole

This is an author-created, un-copyedited version of an article published in The Astrophysical Journal. IOP Publishing Ltd is not responsible for any errors or omissions in this version of the manuscript or any version derived from it. The Version of Record is available online at https://doi.org/10.3847/0004-637X/830/1/38We present deep polarimetric observations at 154 MHz with the Murchison Widefield Array (MWA), covering 625 deg^2 centered on RA=0 h, Dec=-27 deg. The sensitivity available in our deep observations allows an in-band, frequency-dependent analysis of polarized structure for the first time at long wavelengths. Our analysis suggests that the polarized structures are dominated by intrinsic emission but may also have a foreground Faraday screen component. At these wavelengths, the compactness of the MWA baseline distribution provides excellent snapshot sensitivity to large-scale structure. The observations are sensitive to diffuse polarized emission at ~54' resolution with a sensitivity of 5.9 mJy beam^-1 and compact polarized sources at ~2.4' resolution with a sensitivity of 2.3 mJy beam^-1 for a subset (400 deg^2) of this field. The sensitivity allows the effect of ionospheric Faraday rotation to be spatially and temporally measured directly from the diffuse polarized background. Our observations reveal large-scale structures (~1 deg - 8 deg in extent) in linear polarization clearly detectable in ~2 minute snapshots, which would remain undetectable by interferometers with minimum baseline lengths >110 m at 154 MHz. The brightness temperature of these structures is on average 4 K in polarized intensity, peaking at 11 K. Rotation measure synthesis reveals that the structures have Faraday depths ranging from -2 rad m^-2 to 10 rad m^-2 with a large fraction peaking at ~+1 rad m^-2. We estimate a distance of 51+/-20 pc to the polarized emission based on measurements of the in-field pulsar J2330-2005. We detect four extragalactic linearly polarized point sources within the field in our compact source survey. Based on the known polarized source population at 1.4 GHz and non-detections at 154 MHz, we estimate an upper limit on the depolarization ratio of 0.08 from 1.4 GHz to 154 MHz.Peer reviewedFinal Accepted Versio

Does the pain-protective GTP cyclohydrolase haplotype significantly alter the pattern or severity of pain in humans with chronic pancreatitis?

<p>Abstract</p> <p>Background</p> <p>Pain is often a dominant clinical feature of chronic pancreatitis but the frequency and severity is highly variable between subjects. We hypothesized that genetic polymorphisms contribute to variations in clinical pain patterns. Since genetic variations in the GTP cyclohydrolase (GCH1) gene have been reported to protect some patients from pain, we investigated the effect of the "pain protective haplotype" in well characterized patients with chronic pancreatitis (CP) or recurrent acute pancreatitis (RAP) from the North American Pancreatitis Study 2 (NAPS2).</p> <p>Results</p> <p>Subjects in the NAPS2 study were asked to rank their pain in one of 5 categories reflecting different levels of pain frequency and severity. All subjects were genotyped at rs8007267 and rs3783641 to determine the frequency of the GCH1 pain-protective haplotype. In Caucasian subjects the frequency of the pain-protective GCH1 haplotype was no different in the control group (n = 236), CP patients (n = 265), RAP patients (N = 131), or in CP patients subclassified by pain category compared to previously reported haplotype frequencies in the general Caucasian population.</p> <p>Conclusion</p> <p>The GCH1 pain-protective haplotype does not have a significant effect on pain patterns or severity in RAP or CP. These results are important for helping to define the regulators of visceral pain, and to distinguish different mechanisms of pain.</p

Do motor control genes contribute to interindividual variability in decreased movement in patients with pain?

<p>Abstract</p> <p>Background</p> <p>Because excessive reduction in activities after back injury may impair recovery, it is important to understand and address the factors contributing to the variability in motor responses to pain. The current dominant theory is the "fear-avoidance model", in which the some patients' heightened fears of further injury cause them to avoid movement. We propose that in addition to psychological factors, neurochemical variants in the circuits controlling movement and their modification by pain may contribute to this variability. A systematic search of the motor research literature and genetic databases yielded a prioritized list of polymorphic motor control candidate genes. We demonstrate an analytic method that we applied to 14 of these genes in 290 patients with acute sciatica, whose reduction in movement was estimated by items from the Roland-Morris Disability Questionnaire.</p> <p>Results</p> <p>We genotyped a total of 121 single nucleotide polymorphisms (SNPs) in 14 of these genes, which code for the dopamine D2 receptor, GTP cyclohydrolase I, glycine receptor α1 subunit, GABA-A receptor α2 subunit, GABA-A receptor β1 subunit, α-adrenergic 1C, 2A, and 2C receptors, serotonin 1A and 2A receptors, cannabinoid CB-1 receptor, M1 muscarinic receptor, and the tyrosine hydroxylase, and tachykinin precursor-1 molecules. No SNP showed a significant association with the movement score after a Bonferroni correction for the 14 genes tested. Haplotype analysis of one of the blocks in the GABA-A receptor β1 subunit showed that a haplotype of 11% frequency was associated with less limitation of movement at a nominal significance level value (p = 0.0025) almost strong enough to correct for testing 22 haplotype blocks.</p> <p>Conclusion</p> <p>If confirmed, the current results may suggest that a common haplotype in the GABA-A β1 subunit acts like an "endogenous muscle relaxant" in an individual with subacute sciatica. Similar methods might be applied a larger set of genes in animal models and human laboratory and clinical studies to understand the causes and prevention of pain-related reduction in movement.</p

Bacteremia After Prophylaxis II

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141639/1/jper0371.pd

Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017 : a systematic analysis for the Global Burden of Disease Study 2017

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk outcome pairs, and new data on risk exposure levels and risk outcome associations. Methods: We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017. Findings: In 2017,34.1 million (95% uncertainty interval [UI] 33.3-35.0) deaths and 121 billion (144-1.28) DALYs were attributable to GBD risk factors. Globally, 61.0% (59.6-62.4) of deaths and 48.3% (46.3-50.2) of DALYs were attributed to the GBD 2017 risk factors. When ranked by risk-attributable DALYs, high systolic blood pressure (SBP) was the leading risk factor, accounting for 10.4 million (9.39-11.5) deaths and 218 million (198-237) DALYs, followed by smoking (7.10 million [6.83-7.37] deaths and 182 million [173-193] DALYs), high fasting plasma glucose (6.53 million [5.23-8.23] deaths and 171 million [144-201] DALYs), high body-mass index (BMI; 4.72 million [2.99-6.70] deaths and 148 million [98.6-202] DALYs), and short gestation for birthweight (1.43 million [1.36-1.51] deaths and 139 million [131-147] DALYs). In total, risk-attributable DALYs declined by 4.9% (3.3-6.5) between 2007 and 2017. In the absence of demographic changes (ie, population growth and ageing), changes in risk exposure and risk-deleted DALYs would have led to a 23.5% decline in DALYs during that period. Conversely, in the absence of changes in risk exposure and risk-deleted DALYs, demographic changes would have led to an 18.6% increase in DALYs during that period. The ratios of observed risk exposure levels to exposure levels expected based on SDI (O/E ratios) increased globally for unsafe drinking water and household air pollution between 1990 and 2017. This result suggests that development is occurring more rapidly than are changes in the underlying risk structure in a population. Conversely, nearly universal declines in O/E ratios for smoking and alcohol use indicate that, for a given SDI, exposure to these risks is declining. In 2017, the leading Level 4 risk factor for age-standardised DALY rates was high SBP in four super-regions: central Europe, eastern Europe, and central Asia; north Africa and Middle East; south Asia; and southeast Asia, east Asia, and Oceania. The leading risk factor in the high-income super-region was smoking, in Latin America and Caribbean was high BMI, and in sub-Saharan Africa was unsafe sex. O/E ratios for unsafe sex in sub-Saharan Africa were notably high, and those for alcohol use in north Africa and the Middle East were notably low. Interpretation: By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning

Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013

BACKGROUND: The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between 1990 and 2013, and an opportunity to assess whether accelerated progress has occured since the Millennium Declaration. METHODS: To estimate incidence and mortality for HIV, we used the UNAIDS Spectrum model appropriately modified based on a systematic review of available studies of mortality with and without antiretroviral therapy (ART). For concentrated epidemics, we calibrated Spectrum models to fit vital registration data corrected for misclassification of HIV deaths. In generalised epidemics, we minimised a loss function to select epidemic curves most consistent with prevalence data and demographic data for all-cause mortality. We analysed counterfactual scenarios for HIV to assess years of life saved through prevention of mother-to-child transmission (PMTCT) and ART. For tuberculosis, we analysed vital registration and verbal autopsy data to estimate mortality using cause of death ensemble modelling. We analysed data for corrected case-notifications, expert opinions on the case-detection rate, prevalence surveys, and estimated cause-specific mortality using Bayesian meta-regression to generate consistent trends in all parameters. We analysed malaria mortality and incidence using an updated cause of death database, a systematic analysis of verbal autopsy validation studies for malaria, and recent studies (2010-13) of incidence, drug resistance, and coverage of insecticide-treated bednets. FINDINGS: Globally in 2013, there were 1·8 million new HIV infections (95% uncertainty interval 1·7 million to 2·1 million), 29·2 million prevalent HIV cases (28·1 to 31·7), and 1·3 million HIV deaths (1·3 to 1·5). At the peak of the epidemic in 2005, HIV caused 1·7 million deaths (1·6 million to 1·9 million). Concentrated epidemics in Latin America and eastern Europe are substantially smaller than previously estimated. Through interventions including PMTCT and ART, 19·1 million life-years (16·6 million to 21·5 million) have been saved, 70·3% (65·4 to 76·1) in developing countries. From 2000 to 2011, the ratio of development assistance for health for HIV to years of life saved through intervention was US$4498 in developing countries. Including in HIV-positive individuals, all-form tuberculosis incidence was 7·5 million (7·4 million to 7·7 million), prevalence was 11·9 million (11·6 million to 12·2 million), and number of deaths was 1·4 million (1·3 million to 1·5 million) in 2013. In the same year and in only individuals who were HIV-negative, all-form tuberculosis incidence was 7·1 million (6·9 million to 7·3 million), prevalence was 11·2 million (10·8 million to 11·6 million), and number of deaths was 1·3 million (1·2 million to 1·4 million). Annualised rates of change (ARC) for incidence, prevalence, and death became negative after 2000. Tuberculosis in HIV-negative individuals disproportionately occurs in men and boys (versus women and girls); 64·0% of cases (63·6 to 64·3) and 64·7% of deaths (60·8 to 70·3). Globally, malaria cases and deaths grew rapidly from 1990 reaching a peak of 232 million cases (143 million to 387 million) in 2003 and 1·2 million deaths (1·1 million to 1·4 million) in 2004. Since 2004, child deaths from malaria in sub-Saharan Africa have decreased by 31·5% (15·7 to 44·1). Outside of Africa, malaria mortality has been steadily decreasing since 1990. INTERPRETATION: Our estimates of the number of people living with HIV are 18·7% smaller than UNAIDS's estimates in 2012. The number of people living with malaria is larger than estimated by WHO. The number of people living with HIV, tuberculosis, or malaria have all decreased since 2000. At the global level, upward trends for malaria and HIV deaths have been reversed and declines in tuberculosis deaths have accelerated. 101 countries (74 of which are developing) still have increasing HIV incidence. Substantial progress since the Millennium Declaration is an encouraging sign of the effect of global action. FUNDING: Bill & Melinda Gates Foundation

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

A clinical genetic method to identify mechanisms by which pain causes depression and anxiety

BACKGROUND: Pain patients are often depressed and anxious, and benefit less from psychotropic drugs than pain-free patients. We hypothesize that this partial resistance is due to the unique neurochemical contribution to mood by afferent pain projections through the spino-parabrachial-hypothalamic-amygdalar systems and their projections to other mood-mediating systems. New psychotropic drugs for pain patients might target molecules in such brain systems. We propose a method to prioritize molecular targets by studying polymorphic genes in cohorts of patients undergoing surgical procedures associated with a variable pain relief response. We seek molecules that show a significant statistical interaction between (1) the amount of surgical pain relief, and (2) the alleles of the gene, on depression and anxiety during the first postoperative year. RESULTS: We collected DNA from 280 patients with sciatica due to a lumbar disc herniation, 162 treated surgically and 118 non-surgically, who had been followed for 10 years in the Maine Lumbar Spine Study, a large, prospective, observational study. In patients whose pain was reduced >25% by surgery, symptoms of depression and anxiety, assessed with the SF-36 Mental Health Scale, improved briskly at the first postoperative measurement. In patients with little or no surgical pain reduction, mood scores stayed about the same on average. There was large inter-individual variability at each level of residual pain. Polymorphisms in three pre-specified pain-mood candidate genes, catechol-O-methyl transferase (COMT), serotonin transporter, and brain-derived neurotrophic factor (BDNF) were not associated with late postoperative mood or with a pain-gene interaction on mood. Although the sample size did not provide enough power to persuasively search through a larger number of genes, an exploratory survey of 25 other genes provides illustrations of pain-gene interactions on postoperative mood – the mu opioid receptor for short-term effects of acute sciatica on mood, and the galanin-2 receptor for effects of unrelieved post-discectomy pain on mood one year after surgery. CONCLUSION: Genomic analysis of longitudinal studies of pain, depression, and anxiety in patients undergoing pain-relieving surgery may help to identify molecules through which pain alters mood. Detection of alleles with modest-sized effects will require larger cohorts