Operative Environment

Postoperative SSIs are believed to occur via bacterial inoculation at the time of surgery or as a result of bacterial contamination of the wound via open pathways to the deep tissue layers.1–3 The probability of SSI is reflected by interaction of parameters that can be categorized into three major groups.2 The first group consists of factors related to the ability of bacteria to cause infection and include initial inoculation load and genetically determined virulence factors that are required for adherence, reproduction, toxin production, and bypassing host defense mechanisms. The second group involves those factors related to the defense capacity of the host including local and systemic defense mechanisms. The last group contains environmental determinants of exposure such as size, time, and location of the surgical wound that can provide an opportunity for the bacteria to enter the surgical wound, overcome the local defense system, sustain their presence, and replicate and initiate local as well as systemic inflammatory reactions of the host. The use of iodine impregnated skin incise drapes shows decreased skin bacterial counts but no correlation has been established with SSI. However, no recommendations regarding the use of skin barriers can be made (see this Workgroup, Question 27)

Internet-based medical education: a realist review of what works, for whom and in what circumstances

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Weak Responses to Auditory Feedback Perturbation during Articulation in Persons Who Stutter: Evidence for Abnormal Auditory-Motor Transformation

Previous empirical observations have led researchers to propose that auditory feedback (the auditory perception of self-produced sounds when speaking) functions abnormally in the speech motor systems of persons who stutter (PWS). Researchers have theorized that an important neural basis of stuttering is the aberrant integration of auditory information into incipient speech motor commands. Because of the circumstantial support for these hypotheses and the differences and contradictions between them, there is a need for carefully designed experiments that directly examine auditory-motor integration during speech production in PWS. In the current study, we used real-time manipulation of auditory feedback to directly investigate whether the speech motor system of PWS utilizes auditory feedback abnormally during articulation and to characterize potential deficits of this auditory-motor integration. Twenty-one PWS and 18 fluent control participants were recruited. Using a short-latency formant-perturbation system, we examined participants’ compensatory responses to unanticipated perturbation of auditory feedback of the first formant frequency during the production of the monophthong [ε]. The PWS showed compensatory responses that were qualitatively similar to the controls’ and had close-to-normal latencies (~150 ms), but the magnitudes of their responses were substantially and significantly smaller than those of the control participants (by 47% on average, p<0.05). Measurements of auditory acuity indicate that the weaker-than-normal compensatory responses in PWS were not attributable to a deficit in low-level auditory processing. These findings are consistent with the hypothesis that stuttering is associated with functional defects in the inverse models responsible for the transformation from the domain of auditory targets and auditory error information into the domain of speech motor commands

In Vivo CD8+ T-Cell Suppression of SIV Viremia Is Not Mediated by CTL Clearance of Productively Infected Cells

The CD8+ T-cell is a key mediator of antiviral immunity, potentially contributing to control of pathogenic lentiviral infection through both innate and adaptive mechanisms. We studied viral dynamics during antiretroviral treatment of simian immunodeficiency virus (SIV) infected rhesus macaques following CD8+ T-cell depletion to test the importance of adaptive cytotoxic effects in clearance of cells productively infected with SIV. As previously described, plasma viral load (VL) increased following CD8+ T-cell depletion and was proportional to the magnitude of CD8+ T-cell depletion in the GALT, confirming a direct relationship between CD8+ T-cell loss and viral replication. Surprisingly, first phase plasma virus decay following administration of antiretroviral drugs was not slower in CD8+ T-cell depleted animals compared with controls indicating that the short lifespan of the average productively infected cell is not a reflection of cytotoxic T-lymphocyte (CTL) killing. Our findings support a dominant role for non-cytotoxic effects of CD8+ T-cells on control of pathogenic lentiviral infection and suggest that cytotoxic effects, if present, are limited to early, pre-productive stages of the viral life cycle. These observations have important implications for future strategies to augment immune control of HIV

HSV Infection Induces Production of ROS, which Potentiate Signaling from Pattern Recognition Receptors: Role for S-glutathionylation of TRAF3 and 6

The innate immune response constitutes the first line of defense against infections. Pattern recognition receptors recognize pathogen structures and trigger intracellular signaling pathways leading to cytokine and chemokine expression. Reactive oxygen species (ROS) are emerging as an important regulator of some of these pathways. ROS directly interact with signaling components or induce other post-translational modifications such as S-glutathionylation, thereby altering target function. Applying live microscopy, we have demonstrated that herpes simplex virus (HSV) infection induces early production of ROS that are required for the activation of NF-κB and IRF-3 pathways and the production of type I IFNs and ISGs. All the known receptors involved in the recognition of HSV were shown to be dependent on the cellular redox levels for successful signaling. In addition, we provide biochemical evidence suggesting S-glutathionylation of TRAF family proteins to be important. In particular, by performing mutational studies we show that S-glutathionylation of a conserved cysteine residue of TRAF3 and TRAF6 is important for ROS-dependent activation of innate immune pathways. In conclusion, these findings demonstrate that ROS are essential for effective activation of signaling pathways leading to a successful innate immune response against HSV infection

Mindful "Vitality in Practice": an intervention to improve the work engagement and energy balance among workers; the development and design of the randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Modern working life has become more mental and less physical in nature, contributing to impaired mental health and a disturbed energy balance. This may result in mental health problems and overweight. Both are significant threats to the health of workers and thus also a financial burden for society, including employers. Targeting work engagement and energy balance could prevent impaired mental health and overweight, respectively.</p> <p>Methods/Design</p> <p>The study population consists of highly educated workers in two Dutch research institutes. The intervention was systematically developed, based on the Intervention Mapping (IM) protocol, involving workers and management in the process. The workers' needs were assessed by combining the results of interviews, focus group discussions and a questionnaire with available literature. Suitable methods and strategies were selected resulting in an intervention including: eight weeks of customized mindfulness training, followed by eight sessions of e-coaching and supporting elements, such as providing fruit and snack vegetables at the workplace, lunch walking routes, and a buddy system. The effects of the intervention will be evaluated in a RCT, with measurements at baseline, six months (T1) and 12 months (T2). In addition, cost-effectiveness and process of the intervention will also be evaluated.</p> <p>Discussion</p> <p>At baseline the level of work engagement of the sample was "average". Of the study population, 60.1% did not engage in vigorous physical activity at all. An average working day consists of eight sedentary hours. For the Phase II RCT, there were no significant differences between the intervention and the control group at baseline, except for vigorous physical activity. The baseline characteristics of the study population were congruent with the results of the needs assessment. The IM protocol used for the systematic development of the intervention produced an appropriate intervention to test in the planned RCT.</p> <p>Trial registration number</p> <p>Netherlands Trial Register (NTR): <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2199">NTR2199</a></p

Myocarditis in CD8-Depleted SIV-Infected Rhesus Macaques after Short-Term Dual Therapy with Nucleoside and Nucleotide Reverse Transcriptase Inhibitors

Background: Although highly active antiretroviral therapy (HAART) has dramatically reduced the morbidity and mortality associated with HIV infection, a number of antiretroviral toxicities have been described, including myocardial toxicity resulting from the use of nucleotide and nucleoside reverse transcriptase inhibitors (NRTIs). Current treatment guidelines recommend the use of HAART regimens containing two NRTIs for initial therapy of HIV-1 positive individuals; however, potential cardiotoxicity resulting from treatment with multiple NRTIs has not been addressed. Methodology/Principal Findings: We examined myocardial tissue from twelve CD8 lymphocyte-depleted adult rhesus macaques, including eight animals infected with simian immunodeficiency virus, four of which received combined antiretroviral therapy (CART) consisting of two NRTIs [(9-R-2-Phosphonomethoxypropyl Adenine) (PMPA) and (+/−)-beta-2′,3′-dideoxy-5-fluoro-3′-thiacytidine (RCV)] for 28 days. Multifocal infiltrates of mononuclear inflammatory cells were present in the myocardium of all macaques that received CART, but not untreated SIV-positive animals or SIV-negative controls. Macrophages were the predominant inflammatory cells within lesions, as shown by immunoreactivity for the macrophage markers Iba1 and CD68. Heart specimens from monkeys that received CART had significantly lower virus burdens than untreated animals (p<0.05), but significantly greater quantities of TNF-α mRNA than either SIV-positive untreated animals or uninfected controls (p<0.05). Interferon-γ (IFN-γ), IL-1β and CXCL11 mRNA were upregulated in heart tissue from SIV-positive monkeys, independent of antiretroviral treatment, but CXCL9 mRNA was only upregulated in heart tissue from macaques that received CART. Conclusions/Significance: These results suggest that short-term treatment with multiple NRTIs may be associated with myocarditis, and demonstrate that the CD8-depleted SIV-positive rhesus monkey is a useful model for studying the cardiotoxic effects of combined antiretroviral therapy in the setting of immunodeficiency virus infection

Damaged Intestinal Epithelial Integrity Linked to Microbial Translocation in Pathogenic Simian Immunodeficiency Virus Infections

The chronic phase of HIV infection is marked by pathological activation of the immune system, the extent of which better predicts disease progression than either plasma viral load or CD4+ T cell count. Recently, translocation of microbial products from the gastrointestinal tract has been proposed as an underlying cause of this immune activation, based on indirect evidence including the detection of microbial products and specific immune responses in the plasma of chronically HIV-infected humans or SIV-infected Asian macaques. We analyzed tissues from SIV-infected rhesus macaques (RMs) to provide direct in situ evidence for translocation of microbial constituents from the lumen of the intestine into the lamina propria and to draining and peripheral lymph nodes and liver, accompanied by local immune responses in affected tissues. In chronically SIV-infected RMs this translocation is associated with breakdown of the integrity of the epithelial barrier of the gastrointestinal (GI) tract and apparent inability of lamina propria macrophages to effectively phagocytose translocated microbial constituents. By contrast, in the chronic phase of SIV infection in sooty mangabeys, we found no evidence of epithelial barrier breakdown, no increased microbial translocation and no pathological immune activation. Because immune activation is characteristic of the chronic phase of progressive HIV/SIV infections, these findings suggest that increased microbial translocation from the GI tract, in excess of capacity to clear the translocated microbial constituents, helps drive pathological immune activation. Novel therapeutic approaches to inhibit microbial translocation and/or attenuate chronic immune activation in HIV-infected individuals may complement treatments aimed at direct suppression of viral replication

The relationship between doses of mindfulness-based programs and depression, anxiety, stress, and mindfulness: a dose-response meta-regression of randomized controlled trials

Abstract Objectives: Research with mindfulness-based programs (MBPs) has found participating in an MBP to predict beneficial outcomes, however, there is currently mixed research regarding the most helpful dose. This review aimed to determine whether different doses related to MBPs significantly predict outcomes. Methods: Systematic literature searches of electronic databases and trial registration sites for all randomized controlled trials of MBPs identified 203 studies (N=15,971). Depression was the primary outcome at post-program and follow-up, with secondary outcomes being mindfulness, anxiety and stress. Doses examined related to session numbers, duration and length, facilitator contact and practice. Dose-response relationships were analyzed using meta-regression in R with separate analyses for inactive and active controls. Results: Initial meta-analyses found significant between-group differences favoring MBPs for all outcomes. Meta-regression results suggested significant dose-response relationships for the mindfulness outcome for doses relating to face-to-face contact (d=0.211; C.I.[0.064,0.358]), program intensity (d=0.895; C.I.[0.315,1.474]) and actual program use (d=0.013; C.I.[0.001,0.024]). The majority of results for psychological outcomes, including depression, were not significant. Conclusions: This meta-regression examines dose-response relationships for different types and doses relating to MBPs. Considered together, MBPs appeared helpful compared to controls, supporting previous research. Based on meta-regression results, there was no evidence that larger doses are more helpful than smaller doses for predicting psychological outcomes; a finding consistent with some previous research particularly with non-clinical populations. Additionally, greater contact, intensity and actual use of MBPs predicting increased mindfulness corresponds with previous research and theory. Potential limitations and recommendations for future research are explored

Uncharted waters: rare and unclassified cardiomyopathies characterized on cardiac magnetic resonance imaging

Cardiac magnetic resonance imaging (CMR) has undergone considerable technology advances in recent years, so that it is now entering into mainstream cardiac imaging practice. In particular, CMR is proving to be a valuable imaging tool in the detection, morphological assessment and functional assessment of cardiomyopathies. Although our understanding of this broad group of heart disorders continues to expand, it is an evolving group of entities, with the rarer cardiomyopathies remaining poorly understood or even unclassified. In this review, we describe the clinical and pathophysiological aspects of several of the rare/unclassified cardiomyopathies and their appearance on CMR