Hospital-based antimicrobial stewardship in Denmark, Greenland and the Faroe Islands - current landscape and barriers.

OBJECTIVES: To describe the current organization and implementation of formalized, multi-disciplinary hospital-based antimicrobial stewardship (AMS) structures in Denmark, the Faroe Islands and Greenland. METHODS: A structured electronic questionnaire was sent to all trainees and specialists in clinical microbiology (N=207) and infectious diseases (N=260), as well as clinical pharmacists (N=20) and paediatricians (N=10) with expertise in infectious diseases. The survey had 30 multiple-choice, rating-scale, and open-ended questions based on an international consensus checklist for hospital AMS, adapted to a Danish context. RESULTS: Overall, 145 individual responses representing 20 hospitals were received. Nine hospitals (45%) reported a formal AMS strategy, eight (40%) a formal organizational multi-disciplinary structure and a multi-disciplinary AMS team, and six (30%) a designated professional as a leader of the AMS team. A majority of hospitals reported access to updated guidelines (80%) and regularly monitored and reported the quantity of antibiotics prescribed (70% and 65%, respectively). Only one hospital (5%) reported a dedicated, sustainable and sufficient AMS budget, three hospitals (15%) audited courses of therapy for specific agents/clinical conditions and four hospitals (20%) had a document clearly defining roles, procedures of collaboration and responsibilities for AMS. A total of 42% of all individual respondents had received formal AMS training. Main barriers were a lack of financial resources (52%), a lack of mandate from the hospital management (30%) and AMS not being a priority (18%). CONCLUSIONS: Core elements important for multi-disciplinary hospital-based AMS can be strengthened in Danish hospitals. Funding, clear mandates, prioritization from the hospital management and the implementation of multi-disciplinary AMS structures may help close the identified gaps.

One-step replica-symmetry-breaking phase below the de Almeida-Thouless line in low-dimensional spin glasses.

The de Almeida-Thouless (AT) line is the phase boundary in the temperature-magnetic field plane of an Ising spin glass at which a continuous (i.e., second-order) transition from a paramagnet to a replica-symmetry-breaking (RSB) phase occurs, according to mean-field theory. Here, using field-theoretic perturbative renormalization group methods on the Bray-Roberts reduced Landau-Ginzburg-type theory for a short-range Ising spin glass in space of dimension d, we show that at nonzero magnetic field the nature of the corresponding transition is modified as follows: (a) For d-6 small and positive, with increasing field on the AT line, first, the ordered phase just below the transition becomes the so-called one-step RSB, instead of the full RSB that occurs in mean-field theory; the transition on the AT line remains continuous with a diverging correlation length. Then at a higher field, a tricritical point separates the latter transition from a quasi-first-order one, that is one at which the correlation length does not diverge, and there is a jump in part of the order parameter, but no latent heat. The location of the tricritical point tends to zero as d→6^{+}. (b) For d≤6, we argue that the quasi-first-order transition could persist down to arbitrarily small nonzero fields, with a transition to full RSB still expected at lower temperature. Whenever the quasi-first-order transition occurs, it is at a higher temperature than the AT transition would be for the same field, preempting it as the temperature is lowered. These results may explain the reported absence of a diverging correlation length in the presence of a magnetic field in low-dimensional spin glasses in some simulations and in high-temperature series expansions. We also draw attention to the similarity of the "dynamically frozen" state, which occurs at temperatures just above the quasi-first-order transition, and the "metastate-average state" of the one-step RSB phase, and discuss the issue of the number of pure states in either.

Ultrafast transition between exciton phases in van der Waals heterostructures.

Heterostructures of atomically thin van der Waals bonded monolayers have opened a unique platform to engineer Coulomb correlations, shaping excitonic1-3, Mott insulating4 or superconducting phases5,6. In transition metal dichalcogenide heterostructures7, electrons and holes residing in different monolayers can bind into spatially indirect excitons1,3,8-11 with a strong potential for optoelectronics11,12, valleytronics1,3,13, Bose condensation14, superfluidity14,15 and moiré-induced nanodot lattices16. Yet these ideas require a microscopic understanding of the formation, dissociation and thermalization dynamics of correlations including ultrafast phase transitions. Here we introduce a direct ultrafast access to Coulomb correlations between monolayers, where phase-locked mid-infrared pulses allow us to measure the binding energy of interlayer excitons in WSe2/WS2 hetero-bilayers by revealing a novel 1s-2p resonance, explained by a fully quantum mechanical model. Furthermore, we trace, with subcycle time resolution, the transformation of an exciton gas photogenerated in the WSe2 layer directly into interlayer excitons. Depending on the stacking angle, intra- and interlayer species coexist on picosecond scales and the 1s-2p resonance becomes renormalized. Our work provides a direct measurement of the binding energy of interlayer excitons and opens the possibility to trace and control correlations in novel artificial materials.

The impact of early surgical intervention in free intestinal perforation: a time-to-intervention pilot study.

PURPOSES: An abdominal inflammatory focus is the second most often source of sepsis with a high risk of death in surgical intensive care units. By establishing evidence-based bundled strategies the surviving sepsis campaign provided an optimized rapid and continuous treatment of these emergency patients. Hereby the hospital mortality decreased from 35 to 30 %. Sepsis treatment is based on three major therapeutic elements: surgical treatment (source control), antiinfective treatment, and supportive care. The international guidelines of the surviving sepsis campaign were updated recently and recommend rapid diagnosis of the infection and source control within the first 12 h after the diagnosis (grade 1c). Interestingly this recommendation is mainly based on studies on soft tissue infections. METHODS: In this retrospective analysis 76 septic patients with an intraabdominal inflammatory focus were included. All patients underwent surgery at different time-points after diagnosis. RESULTS: With 80 % patients of the early intervention group had an improved overall survival (vs. 73 % in the late intervention group). CONCLUSIONS: Literature on the time dependency of early source control is rare and in part contradicting. Results of this pilot study reveal that immediate surgical intervention might be of advantage for septic emergency patients. Further multi-center approaches will be necessary to evaluate, whether the TTI has any impact on the outcome of septic patients with intestinal perforation.

[The role of biomarkers in the diagnostics of acute mesenteric ischemia]. / Die Rolle von Biomarkern in der Diagnostik der akuten Mesenterialischämie.

Acute mesenteric ischemia is a severe and challenging disease. Unspecific symptoms in the initial phase make a fast diagnosis difficult although it is of major importance to protect patients from irreversible ischemia, extended bowel resection, sepsis and death in the late phase. In contrast to troponin as an early biomarker for cardiac ischemia, a reliable biomarker for acute intestinal ischemia has not yet been identified in the current literature and clinical practice. This would allow the early identification of these critically ill patients in the initial reversible phase of acute intestinal ischemia.This review highlights the pathophysiology, epidemiology and clinical findings of acute mesenteric ischemia and gives an overview of biomarkers which have been investigated in mesenteric ischemia with a special focus on lactate, which is the only parameter routinely used in the diagnostic setting of acute mesenteric ischemia.

[The effect of peridural analgesia on long-term survival after surgery in patients with colorectal cancer : A systematic meta-analysis]. / Effekt einer perioperativen Periduralanalgesie auf das Langzeitüberleben von Patienten nach Resektion eines kolorektalen Karzinoms : Eine systematische Metaanalyse.

BACKGROUND: The results of recent clinical studies suggest a potential benefit of peridural analgesia (PDA) during general anesthesia on long-term survival in patients after surgery for colorectal cancer. In order to test the hypothesis a meta-analysis was performed. OBJECTIVES: To determine the prognostic impact of perioperative PDA on long-term survival in patients with colorectal cancer who underwent surgical resection. MATERIAL AND METHODS: By searching the relevant literature (up to May 2014) a total of 5 studies were identified from a total of 608 publications and a meta-analysis was carried out. Adjusted hazard ratios (HR) with 95 % confidence intervals (CI) were used to assess the strength of associations. The random effects model was used to analyze the data and a modified forest plot was applied. Additionally, a potential publication bias was visually examined in a funnel plot. RESULTS: A positive association between PDA and improved long-term survival was observed in patients who underwent surgery for colorectal cancer without metastases (HR = 0.81, 95 % CI 0.68-0.96, p = 0.055). CONCLUSION: Despite a publication bias the use of PDA in patients who underwent surgery for colorectal cancer without metastases seemed to be advantageous. Randomized controlled trials are warranted to confirm the positive effects of additional PDA. The exact mechanisms of tumor suppressive effects of PDA have not yet been elucidated.

[Diagnosis and therapy of an acute abdomen]. / Diagnostik und Therapie des akuten Abdomens.

Patients with signs of an acute abdomen continue to be a challenge for both the emergency physician and the intensivist. Clinical symptoms usually result from secondary peritonitis possibly progressing to intraabdominal sepsis. Critically ill patients need rapid diagnostic work-up and an interdisciplinary therapeutic approach. Among patients with secondary peritonitis, those with postoperative peritonitis (e.g., after anastomotic leakage) show a particularly high mortality because of unspecific symptoms. Beyond routine diagnostic procedures, patients with an acute abdomen often require a CT scan which helps to detect the septic focus, thereby often allowing an interventional source control. Therapy consists of three main elements: source control, broad-spectrum antimicrobial therapy, and supportive intensive care medicine.

Public health decisions: actions and consequences.

The goal of public health is to promote the best possible health for the whole population. Public health issues are numerous and can be unbelievably complex in form, scope, and possible consequence. Most public health decisions involve assessing several different options, weighing the respective benefits and risks of those options, and making difficult decisions that hopefully provide the greatest benefit to the affected populations. Many risk management decisions involve a variety of societal factors which modify risk assessment choices. The purpose of this paper is to point out difficulties in making decisions that impact public health. The intent of such decisions is to improve public health, but as illustrated in the paper, there can be unintended adverse consequences. Such unplanned issues require continued attention and efforts for responsible officials in the protection of environmental public health. This article presents examples of such events, when in the past, it was necessary to assess and regulate a number of potentially hazardous chemicals commonly used as insecticides, gasoline additives, and wood preservatives.

Enalapril and ASS inhibit tumor growth in a transgenic mouse model of islet cell tumors.

Accumulating evidence suggests a role for angiotensin-converting enzymes involving the angiotensin II-receptor 1 (AT1-R) and the cyclooxygenase pathway in carcinogenesis. The effects of ASS and enalapril were assessed in vitro and in a transgenic mouse model of pancreatic neuroendocrine neoplasms (pNENs). The effects of enalapril and ASS on proliferation and expression of the AGTR1A and its target gene vascular endothelial growth factor (Vegfa) were assessed in the neuroendocrine cell line BON1. Rip1-Tag2 mice were treated daily with either 0.6 mg/kg bodyweight of enalapril i.p., 20 mg/kg bodyweight of ASS i.p., or a vehicle in a prevention (weeks 5-12) and a survival group (week 5 till death). Tumor surface, weight of pancreatic glands, immunostaining for AT1-R and nuclear factor kappa beta (NFKB), and mice survival were analyzed. In addition, sections from human specimens of 20 insulinomas, ten gastrinomas, and 12 non-functional pNENs were evaluated for AT1-R and NFKB (NFKB1) expression and grouped according to the current WHO classification. Proliferation was significantly inhibited by enalapril and ASS in BON1 cells, with the combination being the most effective. Treatment with enalapril and ASS led to significant downregulation of known target genes Vegf and Rela at RNA level. Tumor growth was significantly inhibited by enalapril and ASS in the prevention group displayed by a reduction of tumor size (84%/67%) and number (30%/45%). Furthermore, daily treatment with enalapril and ASS prolonged the overall median survival compared with vehicle-treated Rip1-Tag2 (107 days) mice by 9 and 17 days (P=0.016 and P=0.013). The AT1-R and the inflammatory transcription factor NFKB were abolished completely upon enalapril and ASS treatment. AT1-R and NFKB expressions were observed in 80% of human pNENs. Enalapril and ASS may provide an approach for chemoprevention and treatment of pNENs.

Smartphones and burn size estimation: "Rapid Burn Assessor".

Estimation of the total body surface area burned (%TBSA) following a burn injury is used in determining whether to transfer the patient to a burn center and the required fluid resuscitation volumes. Unfortunately, the commonly applied methods of estimation have revealed inaccuracies, which are mostly related to human error. To calculate the %TBSA (quotient), it is necessary to divide the burned surface area (Burned BSA) (numerator in cm2) by the total body surface area (Total BSA) (denominator in cm2). By using everyday objects (eg. credit cards, smartphones) with well-defined surface areas as reference for estimations of Burned BSA on the one hand and established formulas for Total BSA calculation on the other (eg. Mosteller), we propose an approximation method to assess %TBSA more accurately than the established methods. To facilitate distribution, and respective user feedback, we have developed a smartphone app integrating all of the above parameters, available on popular mobile device platforms. This method represents a simple and ready-to-use clinical decision support system which addresses common errors associated with estimations of Burned BSA (=numerator). Following validation and respective user feedback, it could be deployed for testing in future clinical trials. This study has a level of evidence of IV and is a brief report based on clinical observation, which points to further study.

L'estimation de la totale de la surface corporelle brûlée (% de la SCT) à la suite d'une brûlure est importante en déterminant le transfert du patient vers un centre de brûlés et les volumes nécessaires des fluides de réanimation. Malheureusement, les méthodes d'estimation couramment appliquées ont révélé des inexactitudes, qui sont principalement liés à l'erreur humaine. Pour calculer le % de la SCT il faut diviser la surface brûlée (numérateur en cm2) de la surface corporelle totale (dénominateur en cm2). En utilisant des objets du quotidien (par exemple cartes de crédit et smartphones) avec des surfaces bien définies comme référence pour les estimations de la SC brûlée d'une part, et des formules établies pour le calcul de la SC totale sur l'autre (par exemple Mosteller), nous proposons une méthode d'approximation d'évaluer le % de la SCT brûlée plus de précision que les méthodes établies. Pour faciliter la distribution, et les commentaires des utilisateurs, nous avons développé une application intégrant tous les paramètres ci-dessus, disponibles sur les plates-formes d'appareils mobiles populaires. Cette méthode représente un système simple et prêt à l'emploi aide à la décision clinique qui traite les erreurs courantes associées aux estimations de BSA brûlé (= numérateur). Après la validation et la rétroaction des utilisateurs, il pourrait être déployé pour les tests dans les futurs essais cliniques. Cette étude a un niveau de preuve IV et elle présente un bref rapport basé sur l'observation clinique, qui pointe vers une étude plus approfondie.

Chemical risk assessment and uncertainty associated with extrapolation across exposure duration.

The Agency for Toxic Substances and Disease Registry (ATSDR) prepares toxicological profiles on priority substances in which available epidemiologic and toxicologic data are reviewed, summarized, and interpreted. When adequate data are available, ATSDR derives health guidance values called minimal risk levels (MRLs) for acute, intermediate, and chronic durations of exposure for oral and inhalation routes of exposure. The MRLs are generally derived by use of the no-observed-adverse-effect level (NOAEL) or the lowest-observed-adverse-effect level/uncertainty factor (LOAEL/UF) approach. The UF usually employed are for LOAEL-to-NOAEL extrapolation, animal to -human extrapolation, and inter-human variability. These health guidance values are intended to serve as screening tools for health assessors and other responders to identify contaminants of concern and potential health effects in the community at hazardous waste sites and during unplanned releases. When guidance values are not available for a specific exposure scenario because of a lack of chronic data, extrapolation across exposure durations may be made. For example, chronic guidance values may be derived from subchronic data by applying an additional uncertainty factor of 10 for extrapolation to chronic exposure duration. In this paper, we analyzed the ratio of chemical-specific LOAELs from acute to intermediate and from intermediate to chronic durations for oral and inhalation exposure routes. In addition, we investigated the impact of chemical structure and chemical structure activity relationship on validation of predictions across exposure durations.

Public health assessment of hexachlorobenzene.

Recently, hexachlorobenzene (HCB) was proposed for inclusion in the system of toxicity equivalency factors (TEFs) currently used for dioxin-like compounds. In this paper, we explore the practical implications of the proposition to the Agency for Toxic Substances and Disease Registry (ATSDR) programs by comparing respective health guidance values for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and HCB (expressed as total toxicity equivalents [TEQs]), reviewing possible interactions between HCB and dioxin-like chemicals, and by providing information on actual co-existence of HCB and dioxin-like chemicals at hazardous waste sites. We found a good correlation between the TEF-adjusted oral exposure guidance values for HCB and guidance values for TCDD. The combination of HCB and other dioxin-like compounds was not found in soil, air, or water media at hazardous waste sites. Based on this fact, it is not necessary to include HCB in the total TEQ count at hazardous waste sites at this time.

Site-specific consultation for a chemical mixture.

The Agency for Toxic Substances and Disease Registry (ATSDR) uses the weight of evidence methodology to evaluate interactions of chemical mixtures. In the process, toxicity, toxicokinetics, and toxicodynamics of chemical components of the mixture are carefully examined. Based on the evaluation, predictions are made that can be used in real-life situations at hazardous waste sites. In this paper, health outcomes were evaluated for a mixture of eight compounds that were found at a specific site. These eight chemicals were identified and possibly associated with human exposure. The health assessors could consider similar thought processes when evaluating chemical mixtures at hazardous waste sites.

Expression of the death gene Bik/Nbk promotes sensitivity to drug-induced apoptosis in corticosteroid-resistant T-cell lymphoma and prevents tumor growth in severe combined immunodeficient mice.

Members of the Bcl-2 gene family have been implicated in the regulation of cell death induced by cytostatic drugs. In some malignancies such as B-cell lymphoma, there is evidence that high expression of Bcl-2 is an independent negative prognostic marker and the overexpression of Bcl-2 has been shown to confer resistance to cytotoxic drugs by preventing drug-induced apoptosis. This function of Bcl-2 can be antagonized by apoptosis-promoting members of the Bcl-2 family. We previously showed that overexpression of Bax restores the chemosensitivity of Bax-deficient breast cancer cell lines. Therefore, we investigated whether the death-promoting Bcl-2 homologue Bik/Nbk can enhance cytostatic drug-induced apoptosis. As a model, we used the T-cell leukemia H9 (CD3(+) and CD4(+)CD8(-)), which is resistant to corticosteroid-induced cell death and does not express endogenous Bik/Nbk. Sensitivity for drug-induced apoptosis was increased 10- to 39-fold in cells transfected with the full-length coding sequence of Bik/Nbk. In addition, apoptosis induced via CD95/Fas or heat shock was increased to a similar extent. These data show that Bik/Nbk, which, unlike Bax, carries only a BH3 but no BH1 or BH2 domain may be a target to enhance chemosensitivity. The complete suppression of tumor growth in a severe combined immunodeficient mouse xenotransplant model suggests that, in analogy to Bax, Bik/Nbk may function as a tumor suppressor gene.

Reducing uncertainty in the derivation and application of health guidance values in public health practice. Dioxin as a case study.

We were requested by the U.S. Environmental Protection Agency (EPA) to clarify the relationships among the minimal risk level (MRL), action level, and environmental media evaluation guide (EMEG) for dioxin established by the Agency for Toxic Substances and Disease Registry (ATSDR). In response we developed a document entitled "Dioxin and Dioxin-Like Compounds in Soil, Part I: ATSDR Interim Policy Guideline"; and a supporting document entitled "Dioxin and Dioxin-Like Compounds in Soil, Part II: Technical Support Document". In these documents, we evaluated the key assumptions underlying the development and use of the ATSDR action level, MRL, and EMEG for dioxin. We described the chronology of events outlining these different health guidance values for dioxin and identified the areas of uncertainty surrounding these values. Four scientific assumptions were found to have had a great impact on this process; these were: (1) the specific uncertainty factors used, (2) the toxicity equivalent (TEQ) approach, (3) the fractional exposure from different pathways, and (4) the use of body burdens in the absence of exposure data. This information was subsequently used to develop a framework for reducing the uncertainties in public health risk assessment associated with exposure to other chemical contaminants in the environment. Within this framework are a number of future directions for reducing uncertainty, including physiologically based pharmacokinetic modeling (PBPK), benchmark dose modeling (BMD), functional toxicology, and the assessment of chemical mixture interactions.