Christian Discernment of Divine Revelation: Benedict XVI and the International Theological Commission on the Dark Passages of the Old Testament

En su reciente documento Dios Trinidad, unidad de los hombres, la Comisión Teológica Internacional ofrece principios para reconciliar los muchos textos del Antiguo Testamento en los que Dios actúa ostensiblemente contra su propia naturaleza, al ordenar acciones como la masacre de hombres, mujeres y niños. Este trabajo enmarca la discusión de los llamados «pasajes oscuros» a la luz de tres claves hermenéuticas: la pedagogía divina, el discernimiento de las afirmaciones del autor, y el sentido espiritual. En particular, estos principios se aplicarán al Salmo 137, uno de los textos más bellos y, sin embargo, inquietantes, del Antiguo Testamento.In its recent document God the Trinity and the Unity of Humanity, the International Theological Commission offers principles to reconcile the many Old Testament texts in which God ostensibly acts against his own nature by commanding deeds such as the slaughter of men, women, and children. This piece frames discussion of so-called «dark passages» in light of three hermeneutical keys: the divine pedagogy, the discernment of authorial assertions, and the spiritual sense. In particular, these principles will be applied to Psalm 137, one of the most beautiful and yet disturbing texts of the Old Testament

Effects of Disturbance and Conspecific Negative Density Dependence on Forest Composition and Diversity: A Simulation-Based Approach

Forests provide a wide range of services to humans and create critical habitat for countless species. Tree species composition and diversity, key attributes of forest health and identity, are influenced by both disturbance and conspecific negative density dependence (CNDD). These factors have been thoroughly researched in isolation, but much less is known about how they interact. We present results of a simulation model constructed to investigate the interactions of variable CNDD strengths and disturbance types. We found that while CNDD consistently increased diversity, the magnitude of this effect was heavily influenced by the disturbance regime. The difference between weak and strong CNDD was most pronounced with understory disturbance, and the greatest diversity overall was achieved when strong CNDD was paired with understory disturbance. Empirical studies of CNDD have yielded widely divergent results. Our study suggests a comprehensive understanding of forest ecosystems may require simultaneous consideration of both disturbance and CNDD

Adrenal insufficiency

This issue of eMedRef provides information to clinicians on the pathophysiology, diagnosis, and therapeutics of adrenal insufficiency

Model Results and Software Comparisons in Myrtle Beach, SC Using Virtual Beach and R Regression Toolboxes

Utilizing R software and a variety of data sources, daily forecasts of bacteria levels were developed and automated for beach waters in Myrtle Beach, SC. Modeled results are then shown for beach locations via a website and mobile device app. While R provides a robust set of tools for use in forecast modeling, the software has an extensive learning curve and requires skilled statistical interpretation of results. The Environmental Protection Agency (EPA) created the “Virtual Beach” software package to address these concerns. To evaluate the utility of the more user-friendly Virtual Beach modeling toolbox, predictive models were developed and model results were analyzed using the two software suites. Recommendations were made based on ease of use and several performance measures. Model results indicate the two software toolboxes yield comparable outputs. However, Virtual Beach tends to create more robust model forecasts, while R provides more options for model setup and outputs

Draft genome sequence of isolate Staphylococcus aureus LHSKBClinical, isolated from an infected hip

We report here the genome sequence of a clinical isolate of <i>Staphylococcus aureus</i> from an orthopedic infection. Phenotypically diverse <i>Staphylococcus aureus</i> strains are associated with orthopedic infections and subsequent implant failure, and some are highly resistant to antibiotics. This genome sequence will support further analyses of strains causing orthopedic infections

In vitro bacterial vaginosis biofilm community manipulation using endolysin therapy

Bacterial vaginosis (BV) affects approximately 26% of women of childbearing age globally, presenting with 3–5 times increased risk of miscarriage and two-fold risk of pre-term birth. Antibiotics (metronidazole and clindamycin) are typically employed to treat BV; however the success rate is low due to the formation of recalcitrant polymicrobial biofilms. As a novel therapeutic, promising results have been obtained in vitro using Gardnerella endolysins, although to date their efficacy has only been demonstrated against simple biofilm models. In this study, a four-species biofilm was developed consisting of Gardnerella vaginalis, Fannyhessea vaginae, Prevotella bivia and Mobiluncus curtisii. Biofilms were grown in NYC III broth and treated using antibiotics and an anti-Gardnerella endolysin (CCB7.1) for 24 h. Biofilm composition, viability and structure were assessed using colony counts, live/dead qPCR and scanning electron microscopy. All species colonised biofilms to varying degrees, with G. vaginalis being the most abundant. Biofilm composition remained largely unchanged when challenged with escalated concentrations of conventional antibiotics. A Gardnerella-targeted endolysin candidate (CCB7.1) showed efficacy against several Gardnerella species planktonically, and significantly reduced viable G. vaginalis within polymicrobial biofilms at 1 to 4X pMIC (p < 0.05 vs. vehicle control). Collectively, this study highlights the resilience of biofilm-embedded pathogens against the currently used antibiotics and provides a polymicrobial model that allows for more effective pre-clinical screening of BV therapies. The Gardnerella-specific endolysin CCB7.1 demonstrated significant activity against G. vaginalis within polymicrobial biofilms, altering the overall community dynamic and composition

Understanding the Patient Experience with Carcinoid Syndrome: Exit Interviews from a Randomized, Placebo-Controlled Study of Telotristat Ethyl

Purpose: Telotristat ethyl, an oral tryptophan hydroxylase inhibitor, is intended to treat carcinoid syndrome by reducing serotonin production. Telotristat ethyl was evaluated in TELESTAR, a Phase III study for patients who had carcinoid syndrome with at least 4 bowel movements (BMs) per day and who were receiving somatostatin analogue therapy. This interview substudy was conducted to provide insight into the patient experience in TELESTAR and to help understand whether reductions in BM frequency (the primary end point) and other symptoms were clinically meaningful. Methods: Participating sites were asked to invite (before randomization) all eligible patients to telephone interviews scheduled at the end of the double-blind treatment period. Patients and interviewers were blinded to treatment. Findings: All 35 interviewed participants reported diarrhea and/or excessive BMs at baseline. Patients reported that these symptoms negatively affected emotional, social, physical, and occupational well-being. Prespecified criteria for treatment response (achieving ≥ 30% reduction in BM frequency for at least 50% of the days) were met by 8 of 26 patients taking telotristat ethyl and 1 of 9 patients taking placebo. All 8 patients taking telotristat ethyl described clinically meaningful reductions in BM frequency and were very satisfied with the ability of the study drug to control their carcinoid syndrome symptoms. Overall, reports of being very satisfied were observed in 12 patients taking telotristat ethyl and 0 taking placebo. Implications: Patient interviews revealed that TELESTAR patients, at baseline, were significantly affected by their high BM frequency. Patient reports of their clinical trial experience supported the significance of the primary end point and clinical responder analysis in TELESTAR, helping identify and understand clinically meaningful change produced by telotristat ethyl

Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways

UNLABELLED Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. SIGNIFICANCE The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293

A novel metabolomic approach used for the comparison of Staphylococcus aureus planktonic cells and biofilm samples

Introduction: Bacterial cell characteristics change significantly during differentiation between planktonic and biofilm states. While established methods exist to detect and identify transcriptional and proteomic changes, metabolic fluctuations that distinguish these developmental stages have been less amenable to investigation. Objectives: The objectives of the study were to develop a robust reproducible sample preparation methodology for high throughput biofilm analysis and to determine differences between Staphylococcus aureus in planktonic and biofilm states. Methods: The method uses bead beating in a chloroform/methanol/water extraction solvent to both disrupt cells and quench metabolism. Verification of the method was performed using liquid-chromatography-mass spectrometry. Raw mass-spectrometry data was analysed using an in-house bioinformatics pipe-line incorporating XCMS, MzMatch and in-house R-scripts, with identifications matched to internal standards and metabolite data-base entries. Results: We have demonstrated a novel mechanical bead beating method that has been optimised for the extraction of the metabolome from cells of a clinical Staphylococcus aureus strain existing in a planktonic or biofilm state. This high-throughput method is fast and reproducible, allowing for direct comparison between different bacterial growth states. Significant changes in arginine biosynthesis were identified between the two cell populations. Conclusions: The method described herein represents a valuable tool in studying microbial biochemistry at a molecular level. While the methodology is generally applicable to the lysis and extraction of metabolites from Gram positive bacteria, it is particularly applicable to biofilms. Bacteria that exist as a biofilm are shown to be highly distinct metabolically from their ‘free living’ counterparts, thus highlighting the need to study microbes in different growth states. Metabolomics can successfully distinguish between a planktonic and biofilm growth state. Importantly, this study design, incorporating metabolomics, could be optimised for studying the effects of antimicrobials and drug modes of action, potentially providing explanations and mechanisms of antibiotic resistance and to help devise new antimicrobials