Resonantly damped surface and body MHD waves in a solar coronal slab with oblique propagation

The theory of magnetohydrodynamic (MHD) waves in solar coronal slabs in a zero-$\beta$ configuration and for parallel propagation of waves does not allow the existence of surface waves. When oblique propagation of perturbations is considered both surface and body waves are able to propagate. When the perpendicular wave number is larger than a certain value, the body kink mode becomes a surface wave. In addition, a sausage surface mode is found below the internal cut-off frequency. When non-uniformity in the equilibrium is included, surface and body modes are damped due to resonant absorption. In this paper, first, a normal-mode analysis is performed and the period, the damping rate, and the spatial structure of eigenfunctions are obtained. Then, the time-dependent problem is solved, and the conditions under which one or the other type of mode is excited are investigated.Comment: 19 pages, 9 figures, accepted for publication in Solar Physic

Computer modeling of diabetes and Its transparency: a report on the Eighth Mount Hood Challenge

Objectives The Eighth Mount Hood Challenge (held in St. Gallen, Switzerland, in September 2016) evaluated the transparency of model input documentation from two published health economics studies and developed guidelines for improving transparency in the reporting of input data underlying model-based economic analyses in diabetes. Methods Participating modeling groups were asked to reproduce the results of two published studies using the input data described in those articles. Gaps in input data were filled with assumptions reported by the modeling groups. Goodness of fit between the results reported in the target studies and the groups’ replicated outputs was evaluated using the slope of linear regression line and the coefficient of determination (R2). After a general discussion of the results, a diabetes-specific checklist for the transparency of model input was developed. Results Seven groups participated in the transparency challenge. The reporting of key model input parameters in the two studies, including the baseline characteristics of simulated patients, treatment effect and treatment intensification threshold assumptions, treatment effect evolution, prediction of complications and costs data, was inadequately transparent (and often missing altogether). Not surprisingly, goodness of fit was better for the study that reported its input data with more transparency. To improve the transparency in diabetes modeling, the Diabetes Modeling Input Checklist listing the minimal input data required for reproducibility in most diabetes modeling applications was developed. Conclusions Transparency of diabetes model inputs is important to the reproducibility and credibility of simulation results. In the Eighth Mount Hood Challenge, the Diabetes Modeling Input Checklist was developed with the goal of improving the transparency of input data reporting and reproducibility of diabetes simulation model results

Chemical synergy between ionophore PBT2 and zinc reverses antibiotic resistance

The World Health Organization reports that antibiotic-resistant pathogens represent an imminent global health disaster for the 21st century. Gram-positive superbugs threaten to breach last-line antibiotic treatment, and the pharmaceutical industry antibiotic development pipeline is waning. Here we report the synergy between ionophore-induced physiological stress in Gram-positive bacteria and antibiotic treatment. PBT2 is a safe-for-human-use zinc ionophore that has progressed to phase 2 clinical trials for Alzheimer's and Huntington's disease treatment. In combination with zinc, PBT2 exhibits antibacterial activity and disrupts cellular homeostasis in erythromycin-resistant group A Streptococcus (GAS), methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus (VRE). We were unable to select for mutants resistant to PBT2-zinc treatment. While ineffective alone against resistant bacteria, several clinically relevant antibiotics act synergistically with PBT2-zinc to enhance killing of these Gram-positive pathogens. These data represent a new paradigm whereby disruption of bacterial metal homeostasis reverses antibiotic-resistant phenotypes in a number of priority human bacterial pathogens.IMPORTANCE The rise of bacterial antibiotic resistance coupled with a reduction in new antibiotic development has placed significant burdens on global health care. Resistant bacterial pathogens such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus are leading causes of community- and hospital-acquired infection and present a significant clinical challenge. These pathogens have acquired resistance to broad classes of antimicrobials. Furthermore, Streptococcus pyogenes, a significant disease agent among Indigenous Australians, has now acquired resistance to several antibiotic classes. With a rise in antibiotic resistance and reduction in new antibiotic discovery, it is imperative to investigate alternative therapeutic regimens that complement the use of current antibiotic treatment strategies. As stated by the WHO Director-General, "On current trends, common diseases may become untreatable. Doctors facing patients will have to say, Sorry, there is nothing I can do for you."Lisa Bohlmann, David M. P. De Oliveira, Ibrahim M. El-Deeb, Erin B. Brazel, Nichaela Harbison-Pric

Rescuing tetracycline class antibiotics for the treatment of multidrug-resistant Acinetobacter baumannii pulmonary infection

Acinetobacter baumannii causes high mortality in ventilator-associated pneumonia patients, and antibiotic treatment is compromised by multidrug-resistant strains resistant to β-lactams, carbapenems, cephalosporins, polymyxins, and tetracyclines. Among COVID-19 patients receiving ventilator support, a multidrug-resistant A. baumannii secondary infection is associated with a 2-fold increase in mortality. Here, we investigated the use of the 8-hydroxyquinoline ionophore PBT2 to break the resistance of A. baumannii to tetracycline class antibiotics. In vitro, the combination of PBT2 and zinc with either tetracycline, doxycycline, or tigecycline was shown to be bactericidal against multidrug-resistant A. baumannii, and any resistance that did arise imposed a fitness cost. PBT2 and zinc disrupted metal ion homeostasis in A. baumannii, increasing cellular zinc and copper while decreasing magnesium accumulation. Using a murine model of pulmonary infection, treatment with PBT2 in combination with tetracycline or tigecycline proved efficacious against multidrug-resistant A. baumannii. These findings suggest that PBT2 may find utility as a resistance breaker to rescue the efficacy of tetracycline-class antibiotics commonly employed to treat multidrug-resistant A. baumannii infections. Importance: Within intensive care unit settings, multidrug-resistant (MDR) Acinetobacter baumannii is a major cause of ventilator-associated pneumonia, and hospital-associated outbreaks are becoming increasingly widespread. Antibiotic treatment of A. baumannii infection is often compromised by MDR strains resistant to last-resort β-lactam (e.g., carbapenems), polymyxin, and tetracycline class antibiotics. During the on-going COVID-19 pandemic, secondary bacterial infection by A. baumannii has been associated with a 2-fold increase in COVID-19-related mortality. With a rise in antibiotic resistance and a reduction in new antibiotic discovery, it is imperative to investigate alternative therapeutic regimens that complement the use of current antibiotic treatment strategies. Rescuing the efficacy of existing therapies for the treatment of MDR A. baumannii infection represents a financially viable pathway, reducing time, cost, and risk associated with drug innovation.David M.P. De Oliveira, Brian M. Forde, Minh-Duy Phan, Bernhard Steiner, Bing Zhang, Johannes Zuegg, Ibrahim M. El-deeb, Gen Li, Nadia Keller, Stephan Brouwer, Nichaela Harbison-Price, Amanda J. Cork, Michelle J. Bauer, Saleh F. Alquethamy, Scott A. Beatson, Jason A. Roberts, David L. Paterson, Alastair G. McEwan, Mark A.T. Blaskovich, Mark A. Schembri, Christopher A. McDevitt, Mark von Itzstein, Mark J. Walke

Evaluating the ability of economic models of diabetes to simulate new cardiovascular outcomes trials : a report on the Ninth Mount Hood Diabetes Challenge

Objectives The cardiovascular outcomes challenge examined the predictive accuracy of 10 diabetes models in estimating hard outcomes in 2 recent cardiovascular outcomes trials (CVOTs) and whether recalibration can be used to improve replication. Methods Participating groups were asked to reproduce the results of the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) and the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program. Calibration was performed and additional analyses assessed model ability to replicate absolute event rates, hazard ratios (HRs), and the generalizability of calibration across CVOTs within a drug class. Results Ten groups submitted results. Models underestimated treatment effects (ie, HRs) using uncalibrated models for both trials. Calibration to the placebo arm of EMPA-REG OUTCOME greatly improved the prediction of event rates in the placebo, but less so in the active comparator arm. Calibrating to both arms of EMPA-REG OUTCOME individually enabled replication of the observed outcomes. Using EMPA-REG OUTCOME–calibrated models to predict CANVAS Program outcomes was an improvement over uncalibrated models but failed to capture treatment effects adequately. Applying canagliflozin HRs directly provided the best fit. Conclusions The Ninth Mount Hood Diabetes Challenge demonstrated that commonly used risk equations were generally unable to capture recent CVOT treatment effects but that calibration of the risk equations can improve predictive accuracy. Although calibration serves as a practical approach to improve predictive accuracy for CVOT outcomes, it does not extrapolate generally to other settings, time horizons, and comparators. New methods and/or new risk equations for capturing these CV benefits are needed

Plasma gut hormone levels in 37 patients with pheochromocytomas

Pheochromocytomas are usually recognized by the effects of overproduction of catecholamines, but there are clinical features that cannot be ascribed to catecholamine excess that may be due to vasoactive peptides. We, therefore, measured blood levels of vasoactive intestinal peptides (VIP), substance P, somatostatin (SS), and motilin in 50 instances in 37 patients with pheochromocytomas-21 malignant, 10 benign intra-adrenal, and 6 ectopic (5 paracardial and 1 perirenal). Hormone levels were considered raised if the level was more than 3 S.D. above the mean value found in 52 healthy subjects. Of the 37 patients, 20 (54%) had an abnormality in 1 or more gut hormone levels. The most common abnormality was a raised SS in 9/37 (24%). In addition to these, however, 3 (8%) others had raised VIP, 5 (13.5%) raised motilin, and 3 (8%) raised substance P. Patients with benign adrenal adenomas had raised levels of SS and substance P. Ectopic pheochromocytomas produced only SS in addition to catecholamines, but malignant pheochromocytomas could secrete all 4 peptides, and more than 1 in the same patient. We conclude that pheochromocytomas may secrete multiple vasoactive peptides, and they are more likely to do so if malignant. Somatostatin is the most commonly secreted peptide and is found with benign adrenal and ectopic (paracardiac) tumors. If the level of more than 1 peptide is elevated, the likelihood of malignancy is significantly increased . Les phéochromocytomes sont généralement déceléspar les effets dûs à la surproduction de catécholamines, mais certains troubles ne peuvent être attribués à ce phénomène et relèvent peut être de l'action de peptides vasoactifs. Les auteurs se sont donc attachés à doser dans le sang le VIP, la substance P, la somatostatine (SS), et la motiline. Ces dosages furent pratiqués 50 fois chez 37 malades porteurs de phéochromocytomes: 21 malins, 10 bénins et 6 ectopiques (5 paracardiaque et 1 péri-rénal). Les taux des hormones furent considérés comme élevés lorsque leur niveau fut supérieur à plus de 3 fois le taux de 52 sujets sains. Sur les 37 malades 20 (54%) présentaient un excès d'une ou de plusieurs hormones digestives. L'anomalie constatée la plus fréquente fut l'élévation de la SS (9 fois sur 37 soit 24%). Ajoutée à ce fait fut l'élévation de la VIP chez 3 sujets (8%), de la motiline chez 5 (13.5%) et de la substance P chez 3 (8%). Les phéochromocytomes bénins surrénaliens présentaient à la fois une élévation du taux de la SS et de la substance P. Les phéochromocytomes ectopiques en revanche présentaient seulement une élévation de la SS. Les phéochromocytomes malins pouvaient sécréter les 4 peptides ou plus d'un chez le même malade. En conclusion les phéochromocytomes peuvent secréter de multiples peptides vasoactifs et plus particulièrement lorsqu'ils sont malins. La SS est la substance qui est la plus souvent secrétée et elle est trouvée dans les tumeurs bénignes surrénaliennes ou ectopiques. Si plus d'une de ces substances est produite en excès les risques de malignité de la tumeur sont significativement plus importants. Los feocromocitomas generalmente son diagnosticados por los efectos del exceso de producción de catecolaminas pero hay características clínicas que no pueden ser atribuidas al exceso de catecolaminas y que pueden ser más bien manifestación de péptidos vasoactivos. Hemos establecido los niveles sanguíneos del péptido intestinal vasoactivo (VIP), de la sustancia P, de la somatostatina (SS), y de la motilina en 50 determinaciones en 37 pacientes con feocromocitomas; 21 malignos, 10 benignos intra-adrenales, y 6 ectópicos (5 paracardiales y 1 perirrenal). Se consideró que los niveles hormonales estaban elevados cuando el nivel era de más de 3 de desviación estandar sobre el valor promedio en 52 individuos normales. De 37 pacientes, 20 (54%) presentaron un valor anormal en 1 o más determinaciones del nivel de hormonas intestinales. La anormalidad más común fue la elevación de la SS en 9/37 (24%). Además de esto, sinembargo, otros 3 (8%) presentaban elevación de VIP, 5 (13.5%) elevación de sustancia P. Los adenomas suprarrenales benignos exhibieron niveles elevados de SS y de sustancia P. Los feocromocitomas ectópicos demostraron producción sólo de SS además de catecolaminas, pero los feocromocitomas malignos demostraron ser capaces de secretar todos los 4 péptidos, y más de 1 en el mismo paciente. Hemos llegado a la conclusión de que los feocromocitomas pueden secretar múltiples peptidos vasoactivos y que ésto tiende a ocurrir cuando son malignos. La SS es el péptido más frecuentemente secretado y se lo encuentra en los tumores suprarrenales benigno y ectópico (paracardiacos). Si se encuentran niveles elevados de más de 1 péptido, la posibilidad de malignidad aparece significativamente aumentada.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41274/1/268_2005_Article_BF01655534.pd