Intrinsic antimicrobial resistance determinants in the superbug Pseudomonas aeruginosa

Antimicrobial-resistant bacteria pose a serious threat in the clinic. This is particularly true for opportunistic pathogens that possess high intrinsic resistance. Though many studies have focused on understanding the acquisition of bacterial resistance upon exposure to antimicrobials, the mechanisms controlling intrinsic resistance are not well understood. In this study, we subjected the model opportunistic superbug Pseudomonas aeruginosa to 14 antimicrobials under highly controlled conditions and assessed its response using expression-and fitness-based genomic approaches. Our results reveal that gene expression changes and mutant fitness in response to sub-MIC antimicrobials do not correlate on a genomewide scale, indicating that gene expression is not a good predictor of fitness determinants. In general, fewer fitness determinants were identified for antiseptics and disinfectants than for antibiotics. Analysis of gene expression and fitness data together allowed the prediction of antagonistic interactions between antimicrobials and insight into the molecular mechanisms controlling these interactions. IMPORTANCE Infections involving multidrug-resistant pathogens are difficult to treat because the therapeutic options are limited. These infections impose a significant financial burden on infected patients and on health care systems. Despite years of antimicrobial resistance research, we lack a comprehensive understanding of the intrinsic mechanisms controlling antimicrobial resistance. This work uses two fine-scale genomic approaches to identify genetic loci important for antimicrobial resistance of the opportunistic pathogen Pseudomonas aeruginosa. Our results reveal that antibiotics have more resistance determinants than antiseptics/disinfectants and that gene expression upon exposure to antimicrobials is not a good predictor of these resistance determinants. In addition, we show that when used together, genomewide gene expression and fitness profiling can provide mechanistic insights into multidrug resistance mechanisms.open

Improved costs and outcomes with conscious sedation vs general anesthesia in TAVR patients: Time to wake up?

BackgroundTranscatheter aortic valve replacement (TAVR) has become a commonplace procedure for the treatment of aortic stenosis in higher risk surgical patients. With the high cost and steadily increasing number of patients receiving TAVR, emphasis has been placed on optimizing outcomes as well as resource utilization. Recently, studies have demonstrated the feasibility of conscious sedation in lieu of general anesthesia for TAVR. This study aimed to investigate the clinical as well as cost outcomes associated with conscious sedation in comparison to general anesthesia in TAVR.MethodsRecords for all adult patients undergoing TAVR at our institution between August 2012 and June 2016 were included using our institutional Society of Thoracic Surgeons (STS) and American College of Cardiology (ACC) registries. Cost data was gathered using the BIOME database. Patients were stratified into two groups according to whether they received general anesthesia (GA) or conscious sedation (CS) during the procedure. No-replacement propensity score matching was done using the validated STS predicted risk of mortality (PROM) as a propensity score. Primary outcome measure with survival to discharge and several secondary outcome measures were also included in analysis. According to our institution's data reporting guidelines, all cost data is presented as a percentage of the general anesthesia control group cost.ResultsOf the 231 patients initially identified, 225 (157 GA, 68 CS) were included for analysis. After no-replacement propensity score matching, 196 patients (147 GA, 49 CS) remained. Overall mortality was 1.5% in the matched population with a trend towards lower mortality in the CS group. Conscious sedation was associated with significantly fewer ICU hours (30 vs 96 hours, p = <0.001) and total hospital days (4.9 vs 10.4, p<0.001). Additionally, there was a 28% decrease in direct cost (p<0.001) as well as significant decreases in all individual all cost categories associated with the use of conscious sedation. There was no difference in composite major adverse events between groups. These trends remained on all subsequent subgroup analyses.ConclusionConscious sedation is emerging as a safe and viable option for anesthesia in patients undergoing transcatheter aortic valve replacement. The use of conscious sedation was not only associated with similar rates of adverse events, but also shortened ICU and overall hospital stays. Finally, there were significant decreases in all cost categories when compared to a propensity matched cohort receiving general anesthesia

In vivo evaluation of edge-loading in metal-on-metal hip resurfacing patients with pseudotumours

Objectives: Pseudotumours (abnormal peri-prosthetic soft-tissue reactions) following metal-on-metal hip resurfacing arthroplasty (MoMHRA) have been associated with elevated metal ion levels, suggesting that excessive wear may occur due to edge-loading of these MoM implants. This study aimed to quantify in vivo edge-loading in MoMHRA patients with and without pseudotumours during functional activities. Methods: The duration and magnitude of edge-loading in vivo was quantified during functional activities by combining the dynamic hip joint segment contact force calculated from the three-dimensional (3D) motion analysis system with the 3D reconstruction of orientation of the acetabular component and each patient’s specific hip joint centre, based on CT scans. Results: Edge-loading in the hips with pseudotumours occurred with a four-fold increase in duration and magnitude of force compared with the hips without pseudotumours (p = 0.02). Conclusions: The study provides the first in vivo evidence to support that edge-loading is an important mechanism that leads to localised excessive wear (edge-wear), with subsequent elevation of metal ion levels in MoMHRA patients with pseudotumours

Novel role of miR-29a in pancreatic cancer autophagy and its therapeutic potential

Pancreatic Ductal Adenocarcinoma (PDAC) is a highly lethal malignancy that responds poorly to current therapeutic modalities. In an effort to develop novel therapeutic strategies, we found downregulation of miR-29 in pancreatic cancer cells, and overexpression of miR-29a sensitized chemotherapeutic resistant pancreatic cancer cells to gemcitabine, reduced cancer cell viability, and increased cytotoxicity. Furthermore, miR-29a blocked autophagy flux, as evidenced by an accumulation of autophagosomes and autophagy markers, LC3B and p62, and a decrease in autophagosome-lysosome fusion. In addition, miR-29a decreased the expression of autophagy proteins, TFEB and ATG9A, which are critical for lysosomal function and autophagosome trafficking respectively. Knockdown of TFEB or ATG9A inhibited autophagy similar to miR-29a overexpression. Finally, miR-29a reduced cancer cell migration, invasion, and anchorage independent growth. Collectively, our findings indicate that miR-29a functions as a potent autophagy inhibitor, sensitizes cancer cells to gemcitabine, and decreases their invasive potential. Our data provides evidence for the use of miR-29a as a novel therapeutic agent to target PDAC

Sex Differences in Factors Associated with General Life Satisfaction among Occupationally Injured Workers in Korea:A Panel Analysis of the 2013-2017 Panel Study of Worker's Compensation Insurance

The majority of previous occupational studies focused on factors affecting life satisfaction among occupationally injured workers have been based on a cross-sectional design, not a sex-aggregated model. This study aimed to identify sex differences in factors related to life satisfaction among workers who experienced work-related injuries using nationally representative panel data from South Korea. Data from the first to fifth (2013-2017) waves of the Panel Study of Worker's Compensation Insurance were analyzed. Of 1514 respondents, those who participated in all five survey waves were included in the final study population. To assess the factors associated with general life satisfaction of the occupationally injured workers, a panel data analysis was conducted using generalized estimating equations. The impacts of education level, return to work, self-rated health, task performance, self-esteem, and self-efficacy were significant in both sexes. On the other hand, the influence of age, marital status, personal labor income, and National Basic Livelihood Act recipient status significantly varied by sex. There were sex differences in factors related to general life satisfaction among occupationally injured workers, highlighting the need for sex-specific intervention programs. Employers, healthcare providers, and other stakeholders need to pay attention to vulnerable groups and investigate the most appropriate financial support

Circular Stochastic Fluctuations in SIS Epidemics with Heterogeneous Contacts Among Sub-populations

The conceptual difference between equilibrium and non-equilibrium steady state (NESS) is well established in physics and chemistry. This distinction, however, is not widely appreciated in dynamical descriptions of biological populations in terms of differential equations in which fixed point, steady state, and equilibrium are all synonymous. We study NESS in a stochastic SIS (susceptible-infectious-susceptible) system with heterogeneous individuals in their contact behavior represented in terms of subgroups. In the infinite population limit, the stochastic dynamics yields a system of deterministic evolution equations for population densities; and for very large but finite system a diffusion process is obtained. We report the emergence of a circular dynamics in the diffusion process, with an intrinsic frequency, near the endemic steady state. The endemic steady state is represented by a stable node in the deterministic dynamics; As a NESS phenomenon, the circular motion is caused by the intrinsic heterogeneity within the subgroups, leading to a broken symmetry and time irreversibility.Comment: 29 pages, 5 figure

Ambient interaction and situational influence: case studies in public sites.

An audience's direct physical intervention is widely believed to be instrumental in the field of interactive art. However, this long established expectation faces new challenges through the increasing accessibility of a growing diversity of interactive technologies and ubiquitous smart media. Such innovations are often fully integrated components of interactive public artworks, many of which do not directly involve audiences or individuals as key agents in the functional or aesthetic realisation of the work. Based on three case studies of interactive artworks in public places, this article identifies an important characteristic of interactivity in interactive art, through the largely unexplored concept of 'Ambient Interaction' in which artworks are embodied and enacted through environmental conditions and situational influences rather than exclusively through people's intentional and direct physical engagement

Dealing with missing standard deviation and mean values in meta-analysis of continuous outcomes: a systematic review

Background: Rigorous, informative meta-analyses rely on availability of appropriate summary statistics or individual participant data. For continuous outcomes, especially those with naturally skewed distributions, summary information on the mean or variability often goes unreported. While full reporting of original trial data is the ideal, we sought to identify methods for handling unreported mean or variability summary statistics in meta-analysis. Methods: We undertook two systematic literature reviews to identify methodological approaches used to deal with missing mean or variability summary statistics. Five electronic databases were searched, in addition to the Cochrane Colloquium abstract books and the Cochrane Statistics Methods Group mailing list archive. We also conducted cited reference searching and emailed topic experts to identify recent methodological developments. Details recorded included the description of the method, the information required to implement the method, any underlying assumptions and whether the method could be readily applied in standard statistical software. We provided a summary description of the methods identified, illustrating selected methods in example meta-analysis scenarios. Results: For missing standard deviations (SDs), following screening of 503 articles, fifteen methods were identified in addition to those reported in a previous review. These included Bayesian hierarchical modelling at the meta-analysis level; summary statistic level imputation based on observed SD values from other trials in the meta-analysis; a practical approximation based on the range; and algebraic estimation of the SD based on other summary statistics. Following screening of 1124 articles for methods estimating the mean, one approximate Bayesian computation approach and three papers based on alternative summary statistics were identified. Illustrative meta-analyses showed that when replacing a missing SD the approximation using the range minimised loss of precision and generally performed better than omitting trials. When estimating missing means, a formula using the median, lower quartile and upper quartile performed best in preserving the precision of the meta-analysis findings, although in some scenarios, omitting trials gave superior results. Conclusions: Methods based on summary statistics (minimum, maximum, lower quartile, upper quartile, median) reported in the literature facilitate more comprehensive inclusion of randomised controlled trials with missing mean or variability summary statistics within meta-analyses

Kinetics of fragmentation-annihilation processes

We investigate the kinetics of systems in which particles of one species undergo binary fragmentation and pair annihilation. In the latter, nonlinear process, fragments react at collision to produce an inert species, causing loss of mass. We analyse these systems in the reaction-limited regime by solving a continuous model within the mean-field approximation. The rate of fragmentation, for a particle of mass $x$ to break into fragments of masses $y$ and $x-y$, has the form $x^{\lambda-1}$ ($\lambda>0$), and the annihilation rate is constant and independent of the masses of the reactants. We find that the asymptotic regime is characterized by the annihilation of small-mass clusters. The results are compared with those for a model with linear mass-loss (i.e.\ with a sink). We also study more complex models, in which the processes of fragmentation and annihilation are controlled by mutually-reacting catalysts. Both pair- and linear-annihilation are considered. Depending on the specific model and initial densities of the catalysts, the time-decay of the cluster-density can now be very unconventional and even non-universal. The interplay between the intervening processes and the existence of a scaling regime are determined by the asymptotic behaviour of the average-mass and of the mass-density, which may either decay indefinitely or tend to a constant value. We discuss further developments of this class of models and their potential applications.Comment: 16 pages(LaTeX), submitted to Phys. Rev.

Interventions for treating depression after stroke

Background: Depression is an important consequence of stroke that impacts on recovery yet is often not detected or inadequately treated. This is an update of a Cochrane review first published in 2004. Objectives: To determine whether pharmaceutical, psychological, or electroconvulsive treatment (ECT) of depression in patients with stroke can improve outcome. Search strategy: We searched the trials registers of the Cochrane Stroke Group (last searched October 2007) and the Cochrane Depression Anxiety and Neurosis Group (last searched February 2008). In addition, we searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 1, 2008), MEDLINE (1966 to May 2006), EMBASE (1980 to May 2006), CINAHL (1982 to May 2006), PsycINFO (1967 to May 2006) and other databases. We also searched reference lists, clinical trials registers, conference proceedings and dissertation abstracts, and contacted authors, researchers and pharmaceutical companies. Selection criteria: Randomised controlled trials comparing pharmaceutical agents with placebo, or various forms of psychotherapy or ECT with standard care (or attention control), in patients with stroke, with the intention of treating depression. Data collection and analysis: Two review authors selected trials for inclusion and assessed methodological quality; three review authors extracted, cross-checked and entered data. Primary analyses were the prevalence of diagnosable depressive disorder at the end of treatment. Secondary outcomes included depression scores on standard scales, physical function, death, recurrent stroke and adverse effects. Main results: Sixteen trials (17 interventions), with 1655 participants, were included in the review. Data were available for 13 pharmaceutical agents, and four trials of psychotherapy. There were no trials of ECT. The analyses were complicated by the lack of standardised diagnostic and outcome criteria, and differing analytic methods. There was some evidence of benefit of pharmacotherapy in terms of a complete remission of depression and a reduction (improvement) in scores on depression rating scales, but there was also evidence of an associated increase in adverse events. There was no evidence of benefit of psychotherapy. Authors' conclusions: A small but significant effect of pharmacotherapy (not psychotherapy) on treating depression and reducing depressive symptoms was found, as was a significant increase in adverse events. More research is required before recommendations can be made about the routine use of such treatments