Identifying #vancomycin as an effective #antibiotic for killing #Borrelia burgdorferi (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Identifying vancomycin as an effective antibiotic for killing Borrelia burgdorferi

Xiaoqian Wu, Bijaya Sharma, Samantha Niles, Kathleen O’Connor, Rebecca Schilling, Nicole Matluck, Anthony D’Onofrio, Linden T. Hu, Kim Lewis

DOI: 10.1128/AAC.01201-18

 

ABSTRACT

Borrelia burgdorferi is the causative agent of Lyme borreliosis. Antibiotic therapy of early acute infection is effective for most patients, but 10-20% go on to develop Post-Treatment Lyme Disease Syndrome. The nature of PTLDS remains unknown, but currently approved antibiotics for treatment of Lyme disease do not appear to impact these symptoms after they have developed. We reason that minimizing the time the pathogen interacts with the host will diminish the probability of developing PTLDS, irrespective of its nature. This calls for an efficient eradication of the pathogen during acute infection. In search of a superior killing antibiotic, we examined approved antibiotics for their ability to kill B. burgdorferi. Vancomycin proved more effective in killing the pathogen in vitro than ceftriaxone, the standard of care for disseminated B. burgdorferi infection. Both compounds were also the most effective in killing stationary phase cells. This is surprising, given that inhibitors of cell wall biosynthesis are known to only kill growing bacteria. We found that peptidoglycan synthesis continues in stationary cells of B. burgdorferi, explaining this paradox. A combination of vancomycin and gemifloxacin sterilized a stationary phase culture of B. burgdorferi. Examination of the action of antibiotics in immune-deficient SCID mice showed that doxycycline, a standard of care for uncomplicated acute infection, did not clear the pathogen. By contrast, both ceftriaxone and vancomycin cleared the infection. A trial examining early use of more potent antibiotics on development of PTLDS may be warranted.

 

FOOTNOTES

Corresponding author: Kim Lewis, k.lewis@neu.edu

Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords: Lyme borreliosis; Borrelia burgdorferi; Antibiotics; Vancomycin.

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#Viral genetic #diversity and protective #efficacy of a tetravalent #dengue #vaccine in two phase 3 trials (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

Viral genetic diversity and protective efficacy of a tetravalent dengue vaccine in two phase 3 trials

Michal Juraska, Craig A. Magaret, Jason Shao, Lindsay N. Carpp, Andrew J. Fiore-Gartland, David Benkeser, Yves Girerd-Chambaz, Edith Langevin, Carina Frago, Bruno Guy, Nicholas Jackson, Kien Duong Thi Hue, Cameron P. Simmons, Paul T. Edlefsen, and Peter B. Gilbert

PNAS August 20, 2018. 201714250; published ahead of print August 20, 2018. https://doi.org/10.1073/pnas.1714250115

Edited by Rafi Ahmed, Emory University, Atlanta, GA, and approved July 17, 2018 (received for review December 21, 2017)

 

Significance

Dengue virus (DENV) vaccine development is complicated by the existence of four genetically diverse DENV serotypes. A high degree of antigenic match between vaccine strains and circulating DENVs may be important to achieve high vaccine efficacy (VE). Using data from two phase 3 trials of the CYD-TDV vaccine, we assessed whether and how VE against virologically confirmed dengue varied with amino acid sequence characteristics and genotypes of the disease-causing DENVs. VE decreased with the degree of amino acid dissimilarity between the vaccine insert and disease-causing DENVs. After accounting for differential VE by serotype, this effect seemed to occur only for younger children, who also had lower baseline seropositivity and potentially a less broadly protective immune response.

 

Abstract

Two phase 3 placebo-controlled trials of the CYD-TDV vaccine, evaluated in children aged 2−14 y (CYD14) and 9−16 y (CYD15), demonstrated vaccine efficacy (VE) of 56.5% and 60.8%, respectively, against symptomatic virologically confirmed dengue (VCD). Sieve analyses were conducted to evaluate whether and how VE varied with amino acid sequence features of dengue viruses (DENVs). DENV premembrane/envelope amino acid sequences from VCD endpoint cases were aligned with the vaccine insert sequences, and extensions of the proportional hazards model were applied to assess variation in VE with amino acid mismatch proportion distances from vaccine strains, individual amino acid residues, and phylogenetic genotypes. In CYD14, VE against VCD of any serotype (DENV-Any) decreased significantly with increasing amino acid distance from the vaccine, whereas in CYD15, VE against DENV-Any was distance-invariant. Restricting to the common age range and amino acid distance range between the trials and accounting for differential VE by serotype, however, showed no evidence of VE variation with distance in either trial. In serotype-specific analyses, VE against DENV4 decreased significantly with increasing amino acid distance from the DENV4 vaccine insert and was significantly greater against residue-matched DENV4 at eight signature positions. These effects were restricted to 2- to 8-y-olds, potentially because greater seropositivity of older children at baseline might facilitate a broader protective immune response. The relevance of an antigenic match between vaccine strains and circulating DENVs was also supported by greater estimated VE against serotypes and genotypes for which the circulating DENVs had shorter amino acid sequence distances from the vaccine.

amino acid position signatures – CYD-TDV – dengue virus – sieve analysis – vaccine efficacy

 

Footnotes

1 P.T.E. and P.B.G. contributed equally to this work.

2 To whom correspondence should be addressed. Email: pgilbert@scharp.org.

Author contributions: M.J., C.A.M., B.G., N.J., P.T.E., and P.B.G. designed research; Y.G.-C., E.L., C.F., B.G., N.J., K.D.T.H., and C.P.S. performed research; K.D.T.H. led the operational aspects of the DENV prM/E sequencing; C.P.S. provided oversight of the dengue prM/E sequencing; Y.G.-C. and C.F. acquired data; M.J., C.A.M., J.S., A.J.F.-G., D.B., P.T.E., and P.B.G. analyzed data; C.A.M., Y.G.-C., and E.L. curated data; M.J., C.A.M., J.S., L.N.C., A.J.F.-G., D.B., Y.G.-C., B.G., N.J., P.T.E., and P.B.G. interpreted data; P.B.G. provided oversight of the statistical analyses; and M.J., L.N.C., and P.B.G. wrote the paper.

Conflict of interest statement: Y.G.-C., E.L., C.F., B.G., and N.J. are employees of Sanofi Pasteur. M.J., C.A.M., J.S., L.N.C., A.J.F.-G., P.T.E., and P.B.G. received a contract from Sanofi Pasteur to conduct the statistical analysis work. This work was supported by Sanofi Pasteur and the US National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under award number R37AI054165.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1714250115/-/DCSupplemental.

Published under the PNAS license.

Keywords: Dengue Fever; Vaccines.

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#Militarization fails to enhance #police #safety or reduce #crime but may harm police #reputation (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

Militarization fails to enhance police safety or reduce crime but may harm police reputation

Jonathan Mummolo

PNAS August 20, 2018. 201805161; published ahead of print August 20, 2018. https://doi.org/10.1073/pnas.1805161115

Edited by John Hagan, Northwestern University, Evanston, IL, and approved July 2, 2018 (received for review March 24, 2018)

 

Significance

National debates over heavy-handed police tactics, including so-called “militarized” policing, are often framed as a trade-off between civil liberties and public safety, but the costs and benefits of controversial police practices remain unclear due to data limitations. Using an array of administrative data sources and original experiments I show that militarized “special weapons and tactics” (SWAT) teams are more often deployed in communities of color, and—contrary to claims by police administrators—provide no detectable benefits in terms of officer safety or violent crime reduction, on average. However, survey experiments suggest that seeing militarized police in news reports erodes opinion toward law enforcement. Taken together, these findings suggest that curtailing militarized policing may be in the interest of both police and citizens.

 

Abstract

The increasingly visible presence of heavily armed police units in American communities has stoked widespread concern over the militarization of local law enforcement. Advocates claim militarized policing protects officers and deters violent crime, while critics allege these tactics are targeted at racial minorities and erode trust in law enforcement. Using a rare geocoded census of SWAT team deployments from Maryland, I show that militarized police units are more often deployed in communities with large shares of African American residents, even after controlling for local crime rates. Further, using nationwide panel data on local police militarization, I demonstrate that militarized policing fails to enhance officer safety or reduce local crime. Finally, using survey experiments—one of which includes a large oversample of African American respondents—I show that seeing militarized police in news reports may diminish police reputation in the mass public. In the case of militarized policing, the results suggest that the often-cited trade-off between public safety and civil liberties is a false choice.

police militarization – public safety – crime – race and policing – bureaucratic reputation

Keywords: USA; Society; Poverty; Violence.

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#Economic #sanction: a weapon of mass destruction [#WMD] (Lancet, excerpt)

[Source: The Lancet, full page: (LINK). Excerpt, edited.]

Economic sanction: a weapon of mass destruction

Farrokh Habibzadeh

Published: August 20, 2018 – DOIhttps://doi.org/10.1016/S0140-6736(18)31944-5

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In ancient era, an army that could not conquer a city embraced by defensive walls would lay siege to the city to block the provision of necessary supplies to people residing therein. This strategy has not changed markedly since then.

Nowadays, only a few countries dare to use weapons of mass destruction; instead, economic sanctions are increasingly being used by some powerful nations, supposedly as a humane means to impose pressure on a country to change its behaviour and agree to comply with what it has been asked for.1

(…)

Published: August 20, 2018

IDENTIFICATION: DOI: 10.1016/S0140-6736(18)31944-5

Copyright © 2018 Elsevier Ltd. All rights reserved.

Keywords: Society; Iran; Iraq; Poverty; Wars.

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#Timescales of #influenza A/ #H3N2 #antibody #dynamics (PLoS Biology, abstract)

[Source: PLoS Biology, full page: (LINK). Abstract, edited.]

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

Timescales of influenza A/H3N2 antibody dynamics

Adam J. Kucharski , Justin Lessler, Derek A. T. Cummings, Steven Riley

Published: August 20, 2018 / DOI: https://doi.org/10.1371/journal.pbio.2004974 / This is an uncorrected proof.

 

Abstract

Human immunity influences the evolution and impact of influenza strains. Because individuals are infected with multiple influenza strains during their lifetime, and each virus can generate a cross-reactive antibody response, it is challenging to quantify the processes that shape observed immune responses or to reliably detect recent infection from serological samples. Using a Bayesian model of antibody dynamics at multiple timescales, we explain complex cross-reactive antibody landscapes by inferring participants’ histories of infection with serological data from cross-sectional and longitudinal studies of influenza A/H3N2 in southern China and Vietnam. We find that individual-level influenza antibody profiles can be explained by a short-lived, broadly cross-reactive response that decays within a year to leave a smaller long-term response acting against a narrower range of strains. We also demonstrate that accounting for dynamic immune responses alongside infection history can provide a more accurate alternative to traditional definitions of seroconversion for the estimation of infection attack rates. Our work provides a general model for quantifying aspects of influenza immunity acting at multiple timescales based on contemporary serological data and suggests a two-armed immune response to influenza infection consistent with competitive dynamics between B cell populations. This approach to analysing multiple timescales for antigenic responses could also be applied to other multistrain pathogens such as dengue and related flaviviruses.

 

Author summary

It is challenging to determine the true extent of influenza infection and immunity within a population, because a person’s immune response to a specific influenza strain depends both on past infections with that strain as well as immunity generated by related influenza strains. To untangle these processes, we developed a mathematical model that considered individual histories of influenza infection and immune dynamics acting at multiple timescales. We combined this model with surveys of antibody levels in different individuals, showing how antibody dynamics are influenced by a short-lived, broadly cross-reactive response against a wide range of strains that wanes over time to leave a long-term response against a narrower collection of strains. By accounting for such short- and long-term responses, we also found that it was possible to obtain better estimates of the frequency of influenza infection. These methods could help to guide the design of studies to estimate key aspects of influenza immune dynamics or to estimate historical infection rates and would also be applicable to other pathogens with multiple strains.

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Citation: Kucharski AJ, Lessler J, Cummings DAT, Riley S (2018) Timescales of influenza A/H3N2 antibody dynamics. PLoS Biol 16(8): e2004974. https://doi.org/10.1371/journal.pbio.2004974

Academic Editor: Sarah Rowland-Jones, Weatherall Institute of Molecular Medicine, University of Oxford, United States of America

Received: November 30, 2017; Accepted: August 7, 2018; Published: August 20, 2018

Copyright: © 2018 Kucharski et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: Code and data available at https://github.com/adamkucharski/flu-model.

Funding: Wellcome Trust and Royal Society (grant number 206250/Z/17/Z). Received by AJK. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Medical Research Council (grant number MR/K021524/1). Received by AJK. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Wellcome Trust (grant number 093488/Z/10/Z, 200861/Z/16/Z, 200187/Z/15/Z). Received by SR. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Medical Research Council (grant number MR/J008761/1). Received by SR. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Institute for General Medical Sciences (grant number MIDAS U01 GM110721- 01). Received by SR. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Institute for Health Research (grant number Health Protection Research Unit funding). Received by SR. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: CrI, credibility interval; HA, haemagglutinin; HI, haemagglutination inhibition; MCMC, Markov chain Monte Carlo; RMSE, root-mean-square error; SDDR, Savage-Dickey density ratio

Keywords: Seasonal Influenza; H3N2.

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Recent #advances in #understanding and #treating #ARDS (F100Res., abstract)

[Source: F1000 Research, full page: (LINK). Abstract, edited.]

Recent advances in understanding and treating acute respiratory distress syndrome [version 1; referees: 2 approved]

Rahul S. Nanchal1, Jonathon D. Truwit2

Author details: 1 Pulmonary and Critical Care Medicine, Medical College of Wisconsin, Milwaukee, WI, USA; 2 Pulmonary and Critical Care Medicine, Froedtert & Medical College of Wisconsin, Milwaukee, WI, USA

 

Abstract

Acute respiratory distress syndrome (ARDS) is a clinically and biologically heterogeneous disorder associated with many disease processes that injure the lung, culminating in increased non-hydrostatic extravascular lung water, reduced compliance, and severe hypoxemia. Despite enhanced understanding of molecular mechanisms, advances in ventilatory strategies, and general care of the critically ill patient, mortality remains unacceptably high. The Berlin definition of ARDS has now replaced the American-European Consensus Conference definition. The recently concluded Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG-SAFE) provided worldwide epidemiological data of ARDS including prevalence, geographic variability, mortality, and patterns of mechanical ventilation use. Failure of clinical therapeutic trials prompted the investigation and subsequent discovery of two distinct phenotypes of ARDS (hyper-inflammatory and hypo-inflammatory) that have different biomarker profiles and clinical courses and respond differently to the random application of positive end expiratory pressure (PEEP) and fluid management strategies. Low tidal volume ventilation remains the predominant mainstay of the ventilatory strategy in ARDS. High-frequency oscillatory ventilation, application of recruitment maneuvers, higher PEEP, extracorporeal membrane oxygenation, and alternate modes of mechanical ventilation have failed to show benefit. Similarly, most pharmacological therapies including keratinocyte growth factor, beta-2 agonists, and aspirin did not improve outcomes. Prone positioning and early neuromuscular blockade have demonstrated mortality benefit, and clinical guidelines now recommend their use. Current ongoing trials include the use of mesenchymal stem cells, vitamin C, re-evaluation of neuromuscular blockade, and extracorporeal carbon dioxide removal. In this article, we describe advances in the diagnosis, epidemiology, and treatment of ARDS over the past decade.

Keywords: ARDS, acute respiratory distress syndrome

Corresponding author: Jonathon D. Truwit

Competing interests: No competing interests were disclosed.Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright:  © 2018 Nanchal RS and Truwit JD. This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Nanchal RS and Truwit JD. Recent advances in understanding and treating acute respiratory distress syndrome [version 1; referees: 2 approved]. F1000Research 2018, 7(F1000 Faculty Rev):1322 (doi: 10.12688/f1000research.15493.1)

First published: 20 Aug 2018, 7(F1000 Faculty Rev):1322 (doi: 10.12688/f1000research.15493.1)

Latest published: 20 Aug 2018, 7(F1000 Faculty Rev):1322 (doi: 10.12688/f1000research.15493.1)

Keywords: ARDS.

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Correlation between #apoptosis and in situ immune response in #fatal cases of #microcephaly caused by #Zika virus (Am J Pathol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Am J Pathol. 2018 Aug 16. pii: S0002-9440(18)30153-6. doi: 10.1016/j.ajpath.2018.07.009. [Epub ahead of print]

Correlation between apoptosis and in situ immune response in fatal cases of microcephaly caused by Zika virus.

de Sousa JR1, Azevedo RSS1, Martins Filho AJ2, Araujo MTF2, Moutinho ERC2, Baldez Vasconcelos BC3, Cruz ACR4, Oliveira CS1, Martins LC1, Baldez Vasconcelos BH5, Casseb LMN1, Chiang JO1, Quaresma JAS6, Vasconcelos PFC7.

Author information: 1 Department of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Ministry of Health, Ananindeua, Brazil. 2 Department of Pathology, Evandro Chagas Institute, Ministry of Health, Ananindeua, Brazil. 3 Center of Biological and Health Sciences, State University of Pará, Belém, Brazil. 4 Department of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Ministry of Health, Ananindeua, Brazil; Center of Biological and Health Sciences, State University of Pará, Belém, Brazil. 5 Tropical Medicine Center, Federal University of Pará, Belém, Brazil. 6 Department of Pathology, Evandro Chagas Institute, Ministry of Health, Ananindeua, Brazil; Center of Biological and Health Sciences, State University of Pará, Belém, Brazil; Tropical Medicine Center, Federal University of Pará, Belém, Brazil. Electronic address: pedrovasconcelos@iec.pa.gov.br. 7 Department of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Ministry of Health, Ananindeua, Brazil; Center of Biological and Health Sciences, State University of Pará, Belém, Brazil. Electronic address: pedrovasconcelos@iec.pa.gov.br.

 

Abstract

Zika virus (ZIKV) is a single-stranded positive-sense RNA flavivirus that possesses a genome approximately 10.7 Kb in length. Although pro- and anti-inflammatory cytokines, and apoptotic markers belonging to the extrinsic and intrinsic pathways are suggested to be involved in fatal cases of ZIKV-induced microcephaly, their exact roles and associations are unclear. To address this, brain tissue samples were collected from 10 individuals, five of whom were diagnosed as ZIKV-positive with microcephaly and a further five were flavivirus-negative controls that died because of other causes. Examination of material from the fatal cases of microcephaly revealed lesions in the cerebral cortex, edema, vascular proliferation, neuronal necrosis, gliosis, neuronophagy, calcifications, apoptosis, and neuron loss. The expression of various apoptosis markers in the neural parenchyma, including FASL, FAS, BAX, BCL2, and Caspase 3 differed between ZIKV-positive cases and controls. Further investigation of Th1 and Th2 cytokines confirmed a greater anti-inflammatory response in fatal ZIKV-associated microcephaly cases. Finally, an analysis of the linear correlation between tumor necrosis facor-α, interleukin (IL)-1β, IL-4, IL-10, transforming growth factor-β, and IL-33 expression, and various apoptotic markers, suggested that the immune response may be associated with the apoptotic phenomenon observed in ZIKV-induced microcephaly.

PMID: 30121258 DOI: 10.1016/j.ajpath.2018.07.009

Keywords: Zika Virus; Microcephaly; Viral Pathogenesis.

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