Forgotten Antibiotics: An Inventory in Europe, the United States, Canada, and Australia

In view of the alarming spread of antimicrobial resistance in the absence of new antibiotics, this study aimed at assessing the availability of potentially useful older antibiotics. A survey was performed in 38 countries among experts including hospital pharmacists, microbiologists, and infectious disease specialists in Europe, the United States, Canada, and Australia. An international expert panel selected systemic antibacterial drugs for their potential to treat infections caused by resistant bacteria or their unique value for specific criteria. Twenty-two of the 33 selected antibiotics were available in fewer than 20 of 38 countries. Economic motives were the major cause for discontinuation of marketing of these antibiotics. Fourteen of 33 antibiotics are potentially active against either resistant Gram-positive or Gram-negative bacteria. Urgent measures are then needed to ensure better availability of these antibiotics on a global scal

Exposure-Response Relationships for Isavuconazole in Patients with Invasive Aspergillosis and Other Filamentous Fungi

Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent for the treatment of invasive fungal infections. The purpose of this analysis was to characterize the isavuconazole exposure-response relationship for measures of efficacy and safety in patients with invasive aspergillosis and infections by other filamentous fungi from the SECURE clinical trial. Two hundred thirty-one patients who received the clinical dosing regimen and had exposure parameters were included in the analysis. The primary drug exposure parameters included were predicted trough steady-state plasma concentrations, predicted trough concentrations after 7 and 14 days of drug administration, and area under the curve estimated at steady state (AUCss). The exposure parameters were analyzed against efficacy endpoints that included all-cause mortality through day 42 in the intent-to-treat (ITT) and modified ITT populations, data review committee (DRC)-adjudicated overall response at end of treatment (EOT)

Outplayed: Regaining Strategic Initiative in the Gray Zone, A Report Sponsored by the Army Capabilities Integration Center in Coordination with Joint Staff J-39/Strategic Multi-Layer Assessment Branch

U.S. competitors pursuing meaningful revision or rejection of the current U.S.-led status quo are employing a host of hybrid methods to advance and secure interests contrary to those of the United States. These challengers employ unique combinations of influence, intimidation, coercion, and aggression to incrementally crowd out effective resistance, establish local or regional advantage, and manipulate risk perceptions in their favor. So far, the United States has not come up with a coherent countervailing approach. It is in this “gray zone”—the awkward and uncomfortable space between traditional conceptions of war and peace—where the United States and its defense enterprise face systemic challenges to U.S. position and authority. Gray zone competition and conflict present fundamental challenges to U.S. and partner security and, consequently, should be important pacers for U.S. defense strategy.https://press.armywarcollege.edu/monographs/1924/thumbnail.jp

A Simple-to-Perform ifn-γ mRNA Gene Expression Assay on Whole Blood Accurately Appraises Varicella Zoster Virus-Specific Cell-Mediated Immunity After Allogeneic Hematopoietic Stem Cell Transplantation

Herpes zoster, which is due to the reactivation of Varicella zoster virus (VZV), is a leading cause of morbidity after allogeneic hematopoietic stem cell transplantation (allo-HSCT). While cell-mediated immunity (CMI) is critical to inhibiting VZV reactivation, CMI is not routinely assessed due to a lack of reliable tests. In this study, we aimed to evaluate VZV-specific CMI among allo-HSCT recipients (n = 60) and healthy individuals (HI, n = 17) through a panel of three immune functional assays after ex vivo stimulation by VZV antigen: quantification of (i) IFN-γ release in the supernatants, (ii) T-cell proliferation after a 7-day stimulation of peripheral blood mononuclear cells (PBMC), and (iii) measurement of the ifn-γ mRNA gene expression level after 24 h of stimulation of a whole-blood sample. VZV responsiveness was defined according to IFN-γ release from VZV-stimulated PBMC. Upon VZV stimulation, we found that allo-HSCT recipients at a median time of 6 [5-8] months post-transplant had lower IFN-γ release (median [IQR], 0.34 [0.12–8.56] vs. 409.5 [143.9–910.2] pg/ml, P <.0001) and fewer proliferating T cells (0.05 [0.01–0.57] % vs. 8.74 [3.12–15.05] %, P <.0001) than HI. A subset of allo-HSCT recipients (VZV-responders, n = 15/57, 26%) distinguished themselves from VZV-non-responders (n = 42/57, 74%; missing data, n = 3) by higher IFN-γ release (80.45 [54.3–312.8] vs. 0.22 [0.12–0.42] pg/ml, P <.0001) and T-cell proliferation (2.22 [1.18–7.56] % vs. 0.002 [0.001–0.11] %, P <.0001), suggesting recovery of VZV-specific CMI. Interestingly, VZV responders had a significant fold increase in ifn-γ gene expression, whereas ifn-γ mRNA was not detected in whole blood of VZV-non-responders (P <.0001). This study is the first to suggest that measurement of ifn-γ gene expression in 24-h-stimulated whole blood could be an accurate test of VZV-specific CMI. The routine use of this immune functional assay to guide antiviral prophylaxis at an individual level remains to be evaluated

Efficacy of colistin alone and in various combinations for the treatment of experimental osteomyelitis due to carbapenemase-producing Klebsiella pneumoniae

Objectives: In a new experimental model of carbapenemase-producing Klebsiella pneumoniae osteomyelitis we evaluated the efficacy of colistin alone and in various combinations and examined the emergence of colistin-resistant strains and cross- resistance to host defence peptides (HDPs).Methods: KPC-99YC is a clinical strain with intermediate susceptibility to meropenem (MIC = 4 mg/L) and full susceptibility to gentamicin, colistin and tigecycline (MICs = 1 mg/L) and fosfomycin (MIC = 32 mg/L). Time–kill curves were performed at 4× MIC. Osteomyelitis was induced in rabbits by tibial injection of 2 × 108 cfu. Treatment started 14 days later for 7 days in seven groups: (i) control; (ii) colistin; (iii) colistin + gentamicin; (iv) colistin + tigecycline; (v) colistin + meropenem; (vi) colistin + meropenem + gentamicin; and (vii) colistin +  fosfomycin.Results: In vitro, colistin was rapidly bactericidal, but regrowth occurred after 9 h. Combinations of colistin with meropenem or fosfomycin were synergistic, whereas combination with tigecycline was antagonistic. In vivo, colistin alone was not effective. Combinations of colistin with meropenem or fosfomycin were bactericidal (P  < 0.001) and the addition of gentamicin enhanced the efficacy of colistin + meropenem (P = 0.025). Tigecycline reduced the efficacy of colistin (P = 0.007). Colistin-resistant strains emerged in all groups except colistin + fosfomycin and two strains showed cross-resistance to HDP LL-37.Conclusions: In this model, combinations of colistin plus meropenem, with or without gentamicin, or colistin plus fosfomycin were the only effective therapies. The combination of colistin and tigecycline should be administered with caution, as it may be antagonistic in vitro and in vivo

US Cosmic Visions: New Ideas in Dark Matter 2017: Community Report

This white paper summarizes the workshop "U.S. Cosmic Visions: New Ideas in Dark Matter" held at University of Maryland on March 23-25, 2017.Comment: 102 pages + reference

Correlations of behavioral deficits with brain pathology assessed through longitudinal MRI and histopathology in the R6/1 mouse model of huntington's disease

Huntington's disease (HD) is caused by the expansion of a CAG repeat in the huntingtin (HTT) gene. The R6 mouse models of HD express a mutant version of exon 1 HTT and typically develop motor and cognitive impairments, a widespread huntingtin (HTT) aggregate pathology and brain atrophy. Unlike the more commonly used R6/2 mouse line, R6/1 mice have fewer CAG repeats and, subsequently, a less rapid pathological decline. Compared to the R6/2 line, fewer descriptions of the progressive pathologies exhibited by R6/1 mice exist. The association between the molecular and cellular neuropathology with brain atrophy, and with the development of behavioral phenotypes remains poorly understood in many models of HD. In attempt to link these factors in the R6/1 mouse line, we have performed detailed assessments of behavior and of regional brain abnormalities determined through longitudinal, in vivo magnetic resonance imaging (MRI), as well as an end-stage, ex vivo MRI study and histological assessment. We found progressive decline in both motor and non-motor related behavioral tasks in R6/1 mice, first evident at 11 weeks of age. Regional brain volumes were generally unaffected at 9 weeks, but by 17 weeks there was significant grey matter atrophy. This age-related brain volume loss was validated using a more precise, semi-automated Tensor Based morphometry assessment. As well as these clear progressive phenotypes, mutant HTT (mHTT) protein, the hallmark of HD molecular pathology, was widely distributed throughout the R6/1 brain and was accompanied by neuronal loss. Despite these seemingly concomitant, robust pathological phenotypes, there appeared to be little correlation between the three main outcome measures: behavioral performance, MRI-detected brain atrophy and histopathology. In conclusion, R6/1 mice exhibit many features of HD, but the underlying mechanisms driving these clear behavioral disturbances and the brain volume loss, still remain unclear. © 2013 Rattray et al

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Etude des altérations fonctionnelles du système immunitaire des sujets immunodéprimés

In 2022, the ability of the immune system to respond to an antigenic, infectious, or vaccine stimulus became a central question within the scientific community. Immunosuppression is a state in which the immune system is weakened due to an alteration, either primary or secondary, of all or parts of its components. Regardless of its origin, this more or less lasting immune system alteration induces an increased sensitivity and a significant morbidity and mortality linked to infections. Measuring the functionality of the immune response is therefore essential to guide and optimize the management of immunocompromised patients. Nevertheless, quantitative and phenotypic tools traditionally used in routine laboratories have shown some limitations and only partially reflect the complexity of the immune system. Ex vivo stimulation tests, called Immune Functional Assays (IFA) enable to evaluate the functionality of the immune system, and can be used to assess the interactions between its various components as well as potential dysfunctions. In this work, we first confirmed the reproducibility and robustness of a standardized whole blood IFA, by analyzing the post-stimulation transcriptomic response of healthy volunteers, using a 44-gene immune response-related signature panel. Then, using this tool in a cohort of immunocompromised patients having received an allogeneic hematopoietic stem cell transplantation (allo-HSCT), we highlighted an incomplete functional immune reconstitution at 6 months post-transplantation. In addition, 17 genes with an expression defect and associated with the reactivation of Herpesvirus have been identified. This functional immune alteration was not captured using traditional quantitative and phenotypic tests. Given the negative impact of Herpesvirus viral reactivation in immunocompromised patients, we then evaluated within the same cohort, the interest of IFA for prophylaxis optimization against Varicella Zoster virus (VZV) which is a leading cause of morbidity after allo-HSCT. We developed a whole blood IFA, based on the IFN-γ gene expression analysis, post VZV stimulation. This analysis reflects the capacity of the cell-mediated immune response, which is a key controller of viral infection and is more specific than serological markers, the interpretation of which is sometimes debated. As specific T-cell immunity is essential in the control of viral infections, we also designed a semi-automated whole blood IFA post SARS-CoV-2 peptide stimulation, to assess the specific T-cell immunity through the measurement of IFN-γ secretion. This test is standardized and suitable for use in clinical routine. Our work suggests that the establishment of robust tests reflecting the functional status of the immune system or allowing the measurement of cellular memory offers many perspectives regarding the management of infectious risk in immunocompromised patientsEn 2022, le questionnement sur les capacités du système immunitaire à répondre à une infection ou un vaccin, est au centre de l’attention de la communauté scientifique. L’immunodépression est un état d’affaiblissement des capacités du système immunitaire causé par une altération primitive ou secondaire, de tout ou partie de ses composants. Indépendamment de son origine, cette altération plus ou moins durable du système immunitaire induit une sensibilité accrue aux infections et une importante morbi-mortalité associée. La mesure de la réponse immunitaire fonctionnelle est essentielle afin de guider et optimiser la prise en charge des patients immunodéprimés. Néanmoins, les outils quantitatifs et phénotypiques traditionnels en laboratoire de routine ont montré certaines limites et ne reflètent que partiellement la complexité du système immunitaire. Les tests immunitaires après stimulation cellulaire ex vivo (IFA par leur acronyme anglophone de « Immune Functional Assays ») permettent, d’évaluer les interactions des différents composants du système immunitaire et d'appréhender de potentiels dysfonctionnements. Dans ce travail, nous avons tout d’abord confirmé la reproductibilité et la robustesse d’un IFA standardisé sur sang-total chez des volontaires sains, en analysant la réponse transcriptomique post-stimulation à l’aide d’une signature de 44 gènes reliés à la réponse immunitaire. Ensuite, en utilisant cet outil dans une cohorte de patients immunodéprimés receveurs d’une allogreffe de cellules souches hématopoïétiques (CSH), nous avons mis en évidence une reconstitution immunitaire fonctionnelle incomplète à 6 mois post transplantation. De plus, 17 gènes présentant un défaut d’expression et associés à une réactivation d’un herpèsvirus ont été identifiés. Cette altération immunitaire fonctionnelle n’était pas mise en évidence par des tests quantitatifs et phénotypiques classiques. Au regard de l’impact négatif des réactivations virales à herpèsvirus chez les patients immunodéprimés, nous avons ensuite évalué au sein de la même cohorte, l’intérêt des IFA pour l’optimisation des prophylaxies vis-à-vis du virus Varicelle Zona (VZV) qui représente une cause majeure de morbidité après une allogreffe de CSH. Nous avons développé un IFA sur sang-total basé sur l’analyse après stimulation de l’expression du gène de l’IFN-γ après stimulation par le VZV. Cette analyse reflète la capacité de la réponse immunitaire à médiation cellulaire, élément clé du contrôle de l'infection virale et qui est plus spécifique que les marqueurs sérologiques, dont l'interprétation est parfois débattue. Enfin, comme l'immunité spécifique des lymphocytes T est essentielle dans le contrôle des infections virales, nous avons également développé un IFA semi-automatisé sur sang-total post-stimulation avec des peptides du SARS-CoV-2, pour évaluer la réponse immunitaire cellulaire T spécifique grâce à la mesure de la sécrétion d'IFN-γ. Ce test est standardisé et adapté à une utilisation en routine clinique. Nos travaux suggèrent que la mise en place de tests robustes reflétant le statut immunitaire fonctionnel ou permettant la mesure de la mémoire cellulaire offre de nombreuses perspectives dans la gestion du risque infectieux des patients immunodéprimé