Emmanuel Zamparini, Piseth Seng, Matthieu Bardou, Nicolas Fakhry, Thomas Graillon, Stéphane Fuentes, Patrick Dessi, Andreas Stein

Figure 1.

“Aspirin” as a trade-mark will no longer exist if the recommendation of the Examiner of Interferences of the United States Patent Office is upheld, as it probably would be, should the matter be taken to the courts. The opinion of the Patent Office was the result of a petition by the United Drug Company in the case of that company against the Bayer Company, or, as it was called at the time the suit was brought, the Farbenfabriken of Elberfeld Company. The stand taken by the Patent Office is directly in line with that that has been held in this and other cases by The Journal, which has for years insisted that it was against public policy to permit patentees to extend the seventeen-year monopoly, which the patent laws grant, to a perpetual monopoly by the simple device of obtaining a trade-mark for the name of the thing patented. It is a fundamental principle in law that “no one can have a monopoly in the name of anything.” This of course has been recognized and admitted even by those manufacturers who have attempted to invoke the trade-mark laws to obtain an unwarranted advantage.

Sebastian R. Ott, N. Meier, Martin Kolditz, Torsten T. Bauer, Gernot Rohde, Elisabeth Presterl, Dirk Schürmann, Philipp M. Lepper, Felix C. Ringshausen, Holger Flick, Stephen L. Leib, Mathias W. Pletz, for the OPINION-study group

Pulmonary nocardiosis (PN) is an uncommon but potentially life-threatening infection. Most of our knowledge is derived from case reports or smaller case series. Recently, increasing PN incidence rates have been reported. We aim to describe the clinical course of and risk factors for PN in four Western European countries and to estimate population-based annual hospitalization rates.

Hilary S Whitworth, Amarjit Badhan, Aime A Boakye, Yemisi Takwoingi, Melanie Rees-Roberts, Christopher Partlett, Heather Lambie, John Innes, Graham Cooke, Marc Lipman, Christopher Conlon, Derek Macallan, Felix Chua, Frank A Post, Martin Wiselka, Gerrit Woltmann, Jonathan J Deeks, Onn Min Kon, Ajit Lalvani, Interferon-γ Release Assays for Diagnostic Evaluation of Active Tuberculosis study group

Commercially available IGRAs do not have sufficient accuracy for diagnostic evaluation of suspected tuberculosis. Second-generation tests, however, might have sufficiently high sensitivity, low negative likelihood ratio, and correspondingly high negative predictive value in low-incidence settings to facilitate prompt rule-out of tuberculosis.

Vivek Tiwari, Alpesh Goyal, Manoj Nagar, John A Santoshi

An 18-year-old man presented to our department with a 1-year history of pain in the region of his left hip and difficulty in squatting. He reported no history of any local trauma. There was no history suggestive of an autoimmune disorder. Clinical examination found a tender, hard mass in the left greater trochanteric region with painful, restricted rotation and abduction movements of the hip. Both his medical history and family history were unremarkable. Plain x-ray and CT scans of the pelvis (figure) showed bilateral—left greater than the right—and periarticular, lobulated, calcific, soft tissue masses.

The Lancet

If the events of the end of 2018 and early days of 2019 in Washington, DC, portend anything, it will be yet another contentious year ahead in the USA at the intersection of politics, governance, and health. The engine of much of the conflict is the acrimony resulting from years of partisan political entrenchment. Far-right conservatives within the Republican party, who have found an ally in President Donald Trump, have narrowed their political focus to essentially a single issue—national security.

Paul A Cohen, Anjua Jhingran, Ana Oaknin, Lynette Denny

Each year, more than half a million women are diagnosed with cervical cancer and the disease results in over 300 000 deaths worldwide. High-risk subtypes of the human papilloma virus (HPV) are the cause of the disease in most cases. The disease is largely preventable. Approximately 90% of cervical cancers occur in low-income and middle-income countries that lack organised screening and HPV vaccination programmes. In high-income countries, cervical cancer incidence and mortality have more than halved over the past 30 years since the introduction of formal screening programmes.

Paul Webster

After opening its legal national marijuana marketplace, the country now has to make provisions for different types of products, including edibles. Paul Webster reports.

Talha Burki

His role did not enable him to express his disagreement, says Walter Ricciardi. Talha Burki reports.

Miriam Shuchman

The ongoing outbreak in the DR Congo has recently surpassed 600 cases. To fight this outbreak, the Ebola response team faces many logistical challenges. Miriam Shuchman reports…

Xiao Hong Li, Anatoly Kondrashin, Brian Greenwood, Kim Lindblade, Gawrie Loku Galappaththy, Pedro Alonso

A malaria-free world remains the vision of the global community. Malaria elimination within the territory of a country is a pathway to achieving the ultimate goal of eradication. Certification of malaria elimination in a country is the official recognition of this important achievement. The concepts of eradication and elimination, and criteria for certification of malaria elimination, have guided national programs in their efforts to achieve and maintain elimination. They have evolved from the experiences and setbacks of the global eradication program, and on the contemporaneous understanding of the concepts of achieving and maintaining elimination.

Pasham, D. R., Remillard, R. A., Fragile, P. C., Franchini, A., Stone, N. C., Lodato, G., Homan, J., Chakrabarty, D., Baganoff, F. K., Steiner, J. F., Coughlin, E. R., Pasham, N. R.

The tidal forces close to massive black holes can rip apart stars that come too close to them. As the resulting stellar debris spirals toward the black hole, it heats up and emits x-rays. We report observations of a stable 131-s x-ray quasi-periodic oscillation from the tidal disruption event ASASSN-14li. Assuming the black hole mass indicated by host galaxy scaling relations, this implies that (i) the periodicity originates from close to the event horizon, and (ii) the black hole is rapidly spinning. Our findings demonstrate that tidal disruption events can generate quasi-periodic oscillations which encode information about the physical properties of their black holes.…

Ortega, Sterling B.; Pandiyan, Poornima; Windsor, Jana; Torres, Vanessa O.; Selvaraj, Uma M.; Lee, Amy; Morriss, Michael; Tian, Fenghua; Raman, Lakshmi; Stowe, Ann M.

Objectives: Extracorporeal membrane oxygenation provides short-term cardiopulmonary life support, but is associated with peripheral innate inflammation, disruptions in cerebral autoregulation, and acquired brain injury. We tested the hypothesis that extracorporeal membrane oxygenation also induces CNS-directed adaptive immune responses which may exacerbate extracorporeal membrane oxygenation-associated brain injury. Design: A single center prospective observational study. Setting: Pediatric and cardiac ICUs at a single tertiary care, academic center. Patients: Twenty pediatric extracorporeal membrane oxygenation patients (0–14 yr; 13 females, 7 males) and five nonextracorporeal membrane oxygenation Pediatric Logistic Organ Dysfunction score matched patients Interventions: None. Measurements and Main Results: Venous blood samples were collected from the extracorporeal membrane oxygenation circuit at day 1 (10–23 hr), day 3, and day 7 of extracorporeal membrane oxygenation. Flow cytometry quantified circulating innate and adaptive immune cells, and CNS-directed autoreactivity was detected using an in vitro recall response assay. Disruption of cerebral autoregulation was determined using continuous bedside near-infrared spectroscopy and acquired brain injury confirmed by MRI. Extracorporeal membrane oxygenation patients with acquired brain injury (n = 9) presented with a 10-fold increase in interleukin-8 over extracorporeal membrane oxygenation patients without brain injury (p < 0.01). Furthermore, brain injury within extracorporeal membrane oxygenation patients potentiated an inflammatory phenotype in adaptive immune cells and selective autoreactivity to brain peptides in circulating B cell and cytotoxic T cell populations. Correlation analysis revealed a significant relationship between adaptive immune responses of extracorporeal membrane oxygenation patients with acquired brain injury and loss of cerebral autoregulation. Conclusions: We show that pediatric extracorporeal membrane oxygenation patients with acquired brain injury exhibit an induction of pro-inflammatory cell signaling, a robust activation of adaptive immune cells, and CNS-targeting adaptive immune responses. As these patients experience developmental delays for years after extracorporeal membrane oxygenation, it is critical to identify and characterize adaptive immune cell mechanisms that target the developing CNS. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Drs. Ortega, Pandiyan, Raman, and Stowe contributed equally. Drs. Ortega and Pandiyan designed, performed, and analyzed the immunology-based assays and co-wrote the article. Dr. Pandiyan performed and analyzed the immunology-based assays as well as recruited patients and co-wrote the article. Ms. Windsor and Dr. Lee recruited patients and Ms. Windsor, Ms. Torres, Ms. Selvaraj, and Dr. Stowe processed samples. Dr. Tian quantified autoregulation disruption based on wavelength transform coherence. Dr. Morriss scored all neuroimaging. Drs. Raman and Stowe designed and supervised the study and co-wrote the article. All authors read, edited, and approved of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Drs. Tian and Raman were supported, in part by, American Heart Association (AHA) Beginning-Grant-in Aid (15BGIA25860045). Drs. Pandiyan and Raman were funded by Extracorporeal Life Support Organization research grant and UT Southwestern Center for Translational Medicine award. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1TR001105. Dr. Stowe was supported from the AHA (14SDG 18410020), National Institutes of Health/National Institute of Neurological Disorders and Stroke (NS088555), Dr. Ortega (14POST20480373) and Ms. Selvaraj (17PRE33660147) from the AHA. Drs. Ortega’s, Pandiyan’s, Windsor’s, and Stowe’s institutions received funding from Extracorporeal Life Support Organization and National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) under award number UL1TR001105. Drs. Ortega, Pandiyan, Windsor, Torres, Raman, and Stowe received support for article research from the NIH. Dr. Tian’s institution received funding from the American Heart Association, and he disclosed work for hire. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Ann M. Stowe, PhD, Department of Neurology, University of Kentucky College of Medicine, 741 S. Limestone St., BBSRB 363, Lexington, KY, 40536. E-mail: Ann.Stowe@uky.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Breanna Hodgins, Stephane Pillet, Nathalie Landry, Brian James Ward

by Breanna Hodgins, Stephane Pillet, Nathalie Landry, Brian James Ward Background The elderly are at high risk from influenza, in part because immunity wanes with age and through the accumulation of comorbidities. A novel plant-derived virus-like-particle (VLP) vaccine bearing influenza hemagglutinin can induce a balanced humoral and cellular response in old mice (16–18 months) while split virion vaccines elicit mostly antibodies. Because mice also collect comorbidities and lose immune competence as they age, we wished to determine how the plant-derived VLP vaccine would perform in animals approaching the end of their life-span. Materials and methods Old (24–26 months) female BALB/c mice received two intramuscular doses of H1-VLP vaccine, an inactivated H1N1 vaccine (IIV) (both based on A/H1N1/California/07/09) (3μg each) or PBS. Serum was collected on day 42 and humoral responses were measured by enzyme-linked immunosorbent assay (ELISA), microneutralization (MN) and hemagglutination inhibition (HI) assays. Influenza-specific splenocyte CD4+ & CD8+ T cell responses were measured by flow cytometry. Full body computed tomography (CT) and structured necropsies were performed on day 42. Comorbidities including reduced lung volume (kyphosis), masses, abscesses, etc. were assessed using a standard scoring system (1–21) and mice with scores ≥5 were considered to have important comorbidities. Results Overall, 53.3% of the animals had significant comorbidities. Three weeks post-boost, HI and MN titres were mostly undetectable but ELISA titres were significantly higher in the H1-VLP animals compared to the IIV group (GMT (95% CI): 961 (427, 2163) vs 425 (200, 903): p = 0.03). Both CD4+(TNFα, IFNγ) and CD8+ (IFNγ) T cell responses were also greater in the H1-VLP group than the IIV. Conclusions Even in very old mice with comorbidities, the plant-made H1-VLP vaccine elicited a stronger and more balanced immune response than IIV. Animals with fewer comorbidities tended to have the better composite (humoral and cellular) responses. These novel vaccines have the potential to address some of the limitations of current vaccines in the elderly.…

Erwan Atcheson, Karolis Bauza, Arturo Reyes-Sandoval

by Erwan Atcheson, Karolis Bauza, Arturo Reyes-Sandoval Malaria remains one the world’s most deadly infectious diseases, with almost half a million deaths and over 150 million clinical cases each year. An effective vaccine would contribute enormously to malaria control and will almost certainly be required for eventual eradication of the disease. However, the leading malaria vaccine candidate, RTS,S, shows only 30–50% efficacy under field conditions, making it less cost-effective than long-lasting insecticide treated bed nets. Other subunit malaria vaccine candidates, including TRAP-based vaccines, show no better protective efficacy. This has led to increased interest in combining subunit malaria vaccines as a means of enhancing protective efficacy. Mathematical models of the effect of combining such vaccines on protective efficacy can help inform optimal vaccine strategies and decision-making at all stages of the clinical process. So far, however, no such model has been developed for pre-clinical murine studies, the stage at which all candidate antigens and combinations begin evaluation. To address this gap, this paper develops a mathematical model of vaccine combination adapted to murine malaria studies. The model is based on simple probabilistic assumptions which put the model on a firmer theoretical footing than previous clinical models, which rather than deriving a relationship between immune responses and protective efficacy posit the relationship to be either exponential or Hill curves. Data from pre-clinical murine malaria studies are used to derive values for unknowns in the model which in turn allows simulations of vaccine combination efficacy and suggests optimal strategies to pursue. Finally, the ability of the model to shed light on fundamental biological variables of murine malaria such as the blood stage growth rate and sporozoite infectivity is explored.

Jiayou Liu, Jodi R. Parrish, Julie Hines, Linda Mansfield, Russell L. Finley Jr.

by Jiayou Liu, Jodi R. Parrish, Julie Hines, Linda Mansfield, Russell L. Finley Jr. Campylobacter jejuni (C. jejuni) is a foodborne intestinal pathogen and major cause of gastroenteritis worldwide. C. jejuni proteins that are immunogenic have been sought for their potential use in the development of biomarkers, diagnostic assays, or subunit vaccines for humans or livestock. To identify new immunogenic C. jejuni proteins, we used a native protein microarray approach. A protein chip, with over 1400 individually purified GST-tagged C. jejuni proteins, representing over 86% of the proteome, was constructed to screen for antibody titers present in test sera raised against whole C. jejuni cells. Dual detection of GST signals was incorporated as a way of normalizing the variation of protein concentrations contributing to the antibody staining intensities. We detected strong signals to 102 C. jejuni antigens. In addition to antigens recognized by antiserum raised against C. jejuni, parallel experiments were conducted to identify antigens cross-reactive to antiserum raised against various serotypes of E. coli or Salmonella or to healthy human sera. This led to the identification of 34 antigens specifically recognized by the C. jejuni antiserum, only four of which were previously known. The chip approach also allowed identification of conformational antigens. We demonstrate in the case of Cj1621 that antigen signals are lost to denaturing conditions commonly used in other approaches to identify immunogens. Antigens identified in this study include those possessing sequence features indicative of cell surface localization, as well as those that do not. Together, our results indicate that the unbiased chip-based screen can help reveal the full repertoire of host antibodies against microbial proteomes.

Tobin, Stacey C.

No abstract available…

Amy J. Vogler, Jason W. Sahl, Nilma C. Leal, Marise Sobreira, Charles H. D. Williamson, Molly C. Bollig, Dawn N. Birdsell, Andrew Rivera, Brian Thompson, Roxanne Nottingham, Antonio M. Rezende, Paul Keim, Alzira M. P. Almeida, David M. Wagner

by Amy J. Vogler, Jason W. Sahl, Nilma C. Leal, Marise Sobreira, Charles H. D. Williamson, Molly C. Bollig, Dawn N. Birdsell, Andrew Rivera, Brian Thompson, Roxanne Nottingham, Antonio M. Rezende, Paul Keim, Alzira M. P. Almeida, David M. Wagner Yersinia pestis was introduced to Brazil during the third plague pandemic and currently exists in several recognized foci. There is currently limited available phylogeographic data regarding Y. pestis in Brazil. We generated whole genome sequences for 411 Y. pestis strains from six Brazilian foci to investigate the phylogeography of Y. pestis in Brazil; these strains were isolated from 1966 to 1997. All 411 strains were assigned to a single monophyletic clade within the 1.ORI population, indicating a single Y. pestis introduction was responsible for the successful establishment of endemic foci in Brazil. There was a moderate level of genomic diversity but little population structure among the 411 Brazilian Y. pestis strains, consistent with a radial expansion wherein Y. pestis spread rapidly from the coast to the interior of Brazil and became ecologically established. Overall, there were no strong spatial or temporal patterns among the Brazilian strains. However, strains from the same focus tended to be more closely related and strains isolated from foci closer to the coast tended to fall in more basal positions in the whole genome phylogeny than strains from more interior foci. Overall, the patterns observed in Brazil are similar to other locations affected during the 3rd plague pandemic such as in North America and Madagascar.

Kangkang Yu, Li Song, Jiming Zhang, Ning Li

Prendki Virginie, Huttner Benedikt, Marti Christophe, Mamin Aline, Fubini Pietro Elias, Meynet Marie-Pierre, Scheffler Max, Montet Xavier, Janssens Jean-Paul, Reny Jean-Luc, Kaiser Laurent, Garin Nicolas, Stirnemann Jérôme

NCT02467192…

To the Editor: Zaenglein (Oct. 4 issue) notes that "in the United States, minocycline is the most commonly used antibiotic for acne, followed closely by doxycycline." However, there is no evidence that minocycline is superior to other antibiotics, including doxycycline, in the treatment of acne.……

Until the early 20th century, the human life expectancy was less than 50 years, and infections were often fatal. Only in the past century have humans, on average, lived long enough for cardiovascular disease to develop regularly and have antimicrobial therapies made survival from infection the……

To the Editor: A rapid increase in the prevalence of vaping among adolescents has aroused public health concern. Adolescents who "vape" use a device such as an electronic cigarette to inhale a heated aerosol, which typically contains nicotine. In 2017, vaping was the most common use of any……

Blume GB.

To the Editor Dr Adashi and colleagues stated that DPC enhances primary care–patient relationships and improves care coordination efforts while causing steep cost-sharing burdens, circumvention of quality metrics and incentive structures, increased primary care physician need, and exacerbation of disparities in primary care coverage. I have observed other benefits and question these drawbacks.

Adashi EY, Clodfelter RP, George P.

In Reply We share the view of Dr Breen and Dr Blume that access to longitudinal primary care constitutes the foundation of an effective health care system and that DPC may contribute to that foundation. However, despite its potential, evidence is lacking.

Alberto Benazzo, Stefan Schwarz, Moritz Muckenhuber, Thomas Schweiger, Gabriela Muraközy, Bernhard Moser, José Matilla Sigüenza, György Lang, Shahrokh Taghavi, Walter Klepetko, Konrad Hoetzenecker, Peter Jaksch, Cristopher Lambers

by Alberto Benazzo, Stefan Schwarz, Moritz Muckenhuber, Thomas Schweiger, Gabriela Muraközy, Bernhard Moser, José Matilla Sigüenza, György Lang, Shahrokh Taghavi, Walter Klepetko, Konrad Hoetzenecker, Peter Jaksch, Cristopher Lambers Question addressed by the study The value of induction therapy in lung transplantation is controversial. According to the ISHLT, only about 50% of patients transplanted within the last 10 years received induction therapy. We reviewed our institutional experience to investigate the impact of induction therapy on short- and long-term outcomes. Materials/Patients and methods Between 2007 and 2015, 446 patients with a complete follow-up were included in this retrospective analysis. Analysis comprised long-term kidney function, infectious complications, incidence of rejection and overall survival. Results A total of 231 patients received alemtuzumab, 50 patients antithymocyte globulin (ATG) and 165 patients did not receive induction therapy (NI). The alemtuzumab group revealed the lowest rate of chronic kidney insufficiency (NI: 52.2%; ATG: 60%; alemtuzumab: 36.6%; p = 0.001). Both, the NI group (p

Craig P. Hersh

American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 2, Page 246-248, January 15, 2019. …

Blumenthal KG, Shenoy ES.

This JAMA Patient Page describes evaluation for and diagnosis of penicillin allergy.

Nicolas Papon, Brad M. Binder

Ethylene is a gas and a plant hormone with wide ranging effects and a well defined signaling pathway. The recent identification of ethylene receptors in various microorganisms provides new insights into the early propagation of the ethylene signaling pathway in the course of evolution.

Camille Ehre

American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 2, Page 171-180, January 15, 2019. …

Gabriele Grunig

American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 2, Page 138-140, January 15, 2019. …

Abstract Purpose We studied the incidence, morbidity and mortality of all patients presenting in our teaching hospital with proven influenza virus and/or respiratory syncytial virus (RSV) infection during the influenza epidemic season 2018 which was characterized by a predominant incidence of influenza virus B type B of the Yamagata line. Methods In the fall of 2017, specific precaution measures in addition to standard measures were implemented, including standardized testing for influenza virus A,B and RSV by multiplex PCR of pharyngeal swabsData from all consecutive patients were analyzed retrospectively. Results Overall 651 patients were examined for the presence of influenza virus and RSV; 214 patients had influenza virus A (n = 36), B (n = 152), and/or RSV (n = 30), including four patients with dual infection. 86% of cases had influenza virus (80% B), and 14% RSV infection. N = 23 cases were treated as outpatients. The rate of acute viral respiratory infections (influenza virus and RSV) was 191 of 2776 (6.9%) admissions to medical wards. Of n = 191 hospitalized cases, n = 44 cases (20.6%) had nosocomial infection. Viral infections were associated with a high morbidity (pneumonia 28.5%, mortality 4.7%). Independent predictors of prolonged hospitalization were the presence of pneumonia, NIV and renal complications, and independent predictors of pneumonia were age ≥ 65 years, bedridden status and CRP ≥ 2.9 mg/dL. Conclusions The rate of nosocomial cases was high despite established precaution measures. RSV was associated with morbidity and mortality comparable to influenza. Pneumonia remains the main complication of acute viral respiratory infections, and antimicrobial treatment should include both antiviral as well as antibacterial agents.…

Sivaram Gunisetty, Kaustuv Nayak, Ramesh Chandra Rai, Yadya Chawla, Seetharami Reddy Elluri, Charu Aggarwal, Deepti Maheshwari, Harekrushna Panda, Nasim Akhtar Ansari, Prabhat Singh, Manpreet Kaur, Kritika Dixit, Pragati Sharma, Priya Bhatnagar, Lalita Priyamvada, Siddhartha Kumar Bhaumik, Syed Fazil Ahamed, Rosario Vivek, Pratima Ray, Anita Shet, Poonam Coshic, Rakesh Lodha, Sushil Kumar Kabra, Dil Afroze, Adfar Yousuf, Rafi Ahmed, Kaja Murali-Krishna, Anmol Chandele

Abstract Background The erythrocytic stage of Plasmodium falciparum parasites in humans is clinically important, as the parasites at this growth stage causes malarial symptoms. Most of the currently available anti-malarial drugs target this stage, but the emergence and spread of parasites resistant to anti-malarial drugs are a major challenge to global eradication efforts; therefore, the development of novel medicines is urgently required. In this study, the in vitro anti-malarial activity of five current anti-malarial drugs (artemisinin, atovaquone, chloroquine, mefloquine, and pyrimethamine) and 400 compounds from the Pathogen Box provided by the Medicines for Malaria Venture on P. falciparum parasites was characterized using the XN-30 analyzer. Furthermore, the outcomes obtained using the analyser were classified according to the parasitaemias of total and each developmental stages. Results The growth inhibition rate and the half-maximal (50%) inhibitory concentration (IC50) of the five current anti-malarial drugs were calculated from the parasitaemia detected using the XN-30 analyzer. Respective strains and drugs presented strongly fitted sigmoidal curves, and the median SD at all tested concentrations was 1.6, suggesting that the variation in values measured with the analyser was acceptably low for the comparison of drug efficacy. Furthermore, the anti-malarial activity of the 400 compounds from the Pathogen Box was tested, and 141 drugs were found to be effective. In addition, the efficacy was classified into 4 types (Type I, parasites were arrested or killed without DNA replication; Type II, parasites were arrested or killed similar to Type I, and the parasitaemia was apparently decreased; Type III, parasites progressed to trophozoite without sufficient DNA replication; and Type IV, parasites were arrested at late trophozoite or schizont after DNA replication). Conclusion The current study demonstrates that the XN-30 analyzer objectively, reproducibly, and easily evaluated and characterized the anti-malarial efficacy of various compounds. The results indicate the potential of the XN-30 analyzer as a powerful tool for drug discovery and development in addition to its use as an important diagnostic tool.…

McLean, K., Holmes, E. A., Penewit, K., Lee, D. K., Hardy, S. R., Ren, M., Krist, M. P., Huang, K., Waalkes, A., Salipante, S. J.

Adaptation of Staphylococcus aureus to host microenvironments during chronic infection involves spontaneous mutations, yet changes underlying adaptive phenotypes remain incompletely explored. Here we employed artificial selection and whole genome sequencing to better characterize spontaneous chromosomal mutations that alter two pathogenicity phenotypes relevant to chronic infection in S. aureus: intracellular invasiveness and intracellular cytotoxicity. We identified 23 genes whose alteration coincided with enhanced virulence, 11 that were previously known and 12 of which (52%) had no previously described role in S. aureus pathogenicity. Using precision genome editing, transposon mutants, and gene complementation, we empirically assessed the contributions of individual genes to the two virulence phenotypes. We functionally validated 14 of 21 genes tested as measurably influencing invasion and/or cytotoxicity, including 8 newly implicated by this study. We identified inactivating mutations (murA, ndhC, and a hypothetical membrane protein) and gain-of-function mutations (aroE Thr182Ile, yhcF Thr74Ile, and Asp486Glu in a hypothetical peptidase) in previously unrecognized S. aureus virulence genes that enhance pathogenesis when introduced into a clean genetic background, as well as a novel activating mutation in known virulence regulator saeS (Ala106Thr). Investigation of potentially epistatic interactions identified a tufA mutation (Ala271Val) that enhances virulence only in the context of purine operon repressor (purR) inactivation. This project reveals a functionally diverse range of genes affected by gain- or loss-of-function mutations that contribute to S. aureus adaptive virulence phenotypes. More generally, the work establishes artificial selection as a means to determine the genetic mechanisms underlying complex bacterial phenotypes relevant to adaptation during infection.…

Marshall, A. C., Kidd, S. E., Lamont-Friedrich, S. J., Arentz, G., Hoffmann, P., Coad, B. R., Bruning, J. B.

Aspergillus fumigatus infections are associated with high mortality rates and high treatment costs. Limited available antifungals and increasing antifungal resistance highlight an urgent need for new antifungals. Thioredoxin reductase (TrxR) is essential for maintaining redox homeostasis and presents as a promising target for novel antifungals. We show that ebselen (2-phenyl-1,2-benzoselenazol-3(2H)-one) is an inhibitor of A. fumigatus TrxR (Ki = 0.22 μM) and inhibits growth of Aspergillus spp. with in vitro MIC values of 16-64 μg/mL. Mass spectrometry analysis demonstrates that ebselen interacts covalently with a catalytic cysteine of TrxR, Cys148. We also present the X-ray crystal structure of A. fumigatus TrxR, and use in silico modeling of the enzyme-inhibitor complex to outline key molecular interactions. This provides a scaffold for future design of potent and selective antifungal drugs that target TrxR, improving upon the potency of ebselen towards inhbition of A. fumigatus growth.…

Brown JL, Coles A, Horakova D, et al.

In this cohort study, initial treatment of patients with relapsing-remitting multiple sclerosis (MS) with disease-modifying therapies (fingolimod, natalizumab, or alemtuzumab) was associated with a lower risk of conversion to secondary progressive MS compared with interferon beta or glatiramer acetate therapy.

Sayyad Khanizadeh, Banafsheh Hasanvand, Hadi Razavi Nikoo, Khatereh Anbari, Hemanta Adhikary, Somayeh Shirkhani, Hamed Esmaeili Lashgarian

Abstract Hepatitis B virus (HBV) infection is one of the clinical dilemmas in chronic liver diseases. MicroRNAs (miRNAs) are small non‐codding RNA molecules that play an important role in the pathogenesis of liver diseases and single nucleotide polymorphisms (SNPs) in miRNA genes affect the clinical course of HBV infection. Previous studies have shown that miRNA‐146a rs2910164 polymorphism can be associated with the pathogenesis of liver diseases such as hepatocellular carcinoma (HCC). The present study investigated the association between miRNA‐146a ‐2 rs2910164 polymorphism and susceptibility to HBV infection in an Iranian population. The study comprised 266 patients with chronic HBV infection, 172 patients with spontaneous viral clearance (SVC) after acute HBV infection, and 266 healthy control (HCL) adjusted for gender and age. The genotyping of the miRNA‐146a rs2910164 polymorphism was performed by PCR‐RFLP method. Our data revealed that GG genotype and G allele of miRNA‐146a rs2910164 SNP is dominated (P

Halberstadt C.

I have closed the book of my mind.Sometimes it is the only way to readsounds, air, light, the memories of rainand wind, the touch of rocks climbingand pools of water forming and drying.

To the Editor: Colangeli et al. (Aug. 30 issue) report that higher minimum inhibitory concentration (MIC) values of rifampin and isoniazid were associated with a greater risk of treatment failure and relapse of tuberculosis than lower MIC values. We agree that critical concentrations may not be……

Henly, E. L., Dowling, J. A. R., Maingay, J. B., Lacey, M. M., Smith, T. J., Forbes, S.

Background: Uropathogenic Escherichia coli (UPEC) are a frequent cause of catheter associated urinary tract infection (CAUTI). Biocides have been incorporated into catheter-coatings to inhibit bacterial colonisation whilst ideally exhibiting low cytotoxicity and mitigating the selection of resistant bacterial populations. We compared the effects of long-term biocide exposure on susceptibility, biofilm-formation and relative-pathogenicity in eight UPEC isolates.Methods: Minimum inhibitory concentrations (MIC), minimum bactericidal concentrations (MBC), minimum biofilm eradication concentrations (MBEC) and antibiotic susceptibilities were determined before and after long-term exposure to triclosan, polyhexamethylene biguanide (PHMB), benzalkonium chloride (BAC) and silver nitrate. Biofilm-formation was quantified using a crystal violet assay and relative-pathogenicity was assessed via a Galleria mellonella waxworm model. Cytotoxicity and resulting biocompatability index values were determined against an L929 murine fibroblast cell line.Results: Biocide exposure resulted in multiple decreases in biocide susceptibility in planktonic and biofilm associated UPEC. Triclosan exposure induced the largest frequency and magnitude of susceptibility decreases at MIC, MBC and MBEC, which correlated to an increase in biofilm biomass in all isolates. Induction of antibiotic-cross-resistance occurred in 6/84 possible combinations of bacteria, biocide and antibiotic. Relative-pathogenicity significantly decreased after triclosan exposure (5/8 isolates), increased after silver nitrate exposure (2/8 isolates) and varied between isolates for PHMB and BAC. Biocompatibility index ranked antiseptic potential as PHMB>triclosan>BAC>silver nitrate.Conclusion: Biocide exposure in UPEC may lead to reductions in biocide and antibiotic susceptibility, changes in biofilm-formation and alterations relative-pathogenicity. These data indicate the multiple consequences of biocide adaptation that should be considered when selecting an anti-infective catheter-coating agent.…

Anuradha Rose, Amrita Sekhar

Abstract Background Biofilm production by Haemophilus influenzae and Streptococcus pneumoniae has been implicated in the pathogenesis of otitis media, mainly in chronic and recurrent cases. We studied the “in vitro” biofilm production by these 2 species isolated alone or together from the nasopharynx of children with acute otitis media. Methods The studied strains were from 3 pneumococcal conjugate vaccine (PCV) periods: pre-PCV7, post-PCV7/pre-PCV13 and post-PCV13. A modified microtiter plate assay with crystal violet stain was used to study the biofilm production of 182 H. influenzae and 191 S. pneumoniae strains. Results Overall, 117/181 (64.6%) H. influenzae and 128/191 (66.8%) S. pneumoniae strains produced biofilm. The proportion of biofilm-producing H. influenzae strains was greater with than without the isolation of S. pneumoniae in the same sample (75.5% vs 52.3%, p = 0.001). Conversely, the proportion of biofilm-producing S. pneumoniae strains was not affected by the presence or not of H. influenzae (66.3% vs 67.4%). S. pneumoniae serotypes 6B, 15B/C, 19A, 35F and 35B were the better biofilm producers (80%). Serotypes 11A, 14, 15A, 19F and 19A were more associated with H. influenzae biofilm-producing strains. Overall, 89/94 (94.6%) of cases with combined isolation showed biofilm production by S. pneumoniae or H. influenzae. Conclusion This study emphasizes the high proportion of biofilm production by H. influenzae and S. pneumoniae strains isolated from the nasopharynx of children with acute otitis media, which reinforces the results of studies suggesting the importance of biofilm in the pathogenesis of acute otitis media.…

Paiva, José-Artur; Pereira, José M.

Purpose of review The incidence of lung fungal infections, namely invasive pulmonary aspergillosis (IPA) and mucormycosis, is increasing in neutropenic and nonneutropenic patients. As they are a major cause of death, early diagnosis and antifungal therapy are crucial for outcome. The role of biomarkers in the management of this infections is the scope of this review. Recent findings Galactomannan in bronchoalveolar lavage shows the best discriminatory power for IPA diagnosis. At baseline, serum galactomannan may be useful to predict outcome and its kinetics may be informative to assess response to antifungal therapy. Recent standardization of PCR technology brought some improvements in IPA and mucormycosis diagnosis. Several new biomarkers are currently under investigation, but none showed a better performance than current available biomarkers. To improve diagnostic accuracy, a combination of biomarkers, including galactomannan, has been proposed. Summary Biomarkers may play an important role in the early diagnosis of fungal lung infections and in prognostic assessment and response monitoring, but more research is needed to determine the best strategy for their clinical use. Correspondence to José-Artur Paiva, MD, PhD, Intensive Care Medicine Department, Centro Hospitalar São João, Porto, Portugal. Tel: +351 913 899 800; e-mail: jarturpaiva@gmail.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Abstract Background Bovine tuberculosis is among the primary zoonotic disease caused by Mycobacterium bovis which has significant impact on the health of livestock and human. It has been significantly a cause for great economic loss in animal production. Methodology A cross-sectional study was conducted from December 2014 to June 2016 on 315 cattle in selected areas of eastern Ethiopia, aiming to estimate the occurrence of bovine tuberculosis using comparative intradermal tuberculin skin test and assess cattle owners’ awareness on its public health implication. Random sampling method was applied in order to select animals from farm/household and associated risk factors were recorded before purified protein derivative (PPD) injection. Forty three farm/household owners of tuberculin tested animals were interviewed using pre-tested structured questionnaires. Results The overall prevalence of bovine tuberculosis was 20.3% (n = 64) in dairy cattle at recommended cut off > 4 mm. From a total of 43 farms/households tested, 22 were positive; each farm exhibited at least one tuberculin positive reactor animal with a total herd level prevalence of 51.2%. The prevalence of bovine tuberculosis in individual animal level was significantly different (χ2 = 45.2; P-value = 0.000) in different sites with a higher prevalence (50%) in Dire Dawa. Farming system, herd size and other risk factors were significantly (p 

Webel, Allison R.; Jenkins, Trevor; Vest, Marianne; Oliveria, Vitor H.F.; Longenecker, Chris T.; Liu, Jintao; Currie, Jackson; Sattar, Abdus; Josephson, Richard

Objective: Our objective was to examine the effect of a lifestyle diet and exercise intervention on CRF and to examine predictors of change in CRF. Design: People living with HIV (PLHIV) are at increased risk for cardiovascular disease (CVD). Cardiorespiratory fitness (CRF) is a better predictor of CVD-related mortality than established risk factors yet very little is known about CRF in PLHIV. Methods: One-hundred and seven virally suppressed PLHIV were randomized to a group-based intervention to improve lifestyle behaviors or a control condition. All PLHIV maximal cardiorespiratory stress test to determine VO2 peak, VO2 at anaerobic threshold, and VE/VCO2, at baseline and six months later. Participants wore an accelerometer to measure physical activity, completed waist-hip circumference measures, and had a fasting lipid profile, interleukin-6, and hsCRP analyzed. Generalized estimating equations were used to examine the effect of the intervention on CRF and predictors of change in CRF. Results: Participants were approximately 53 years old, 65% male (n = 70), and 86% African American (n = 93). There was no effect of the intervention on markers of CRF over time (p > 0.05). After controlling for age, gender, waist-hip-ratio, the inflammatory biomarker IL-6 was inversely associated with a decline in both VO2 peak (p = 0.03) and VO2 at anaerobic threshold (p = 0.03). Additionally, participants who walked an additional 10,000 steps per day had a 2.69 ml/kg/min higher VO2 peak (p = 0.02). Conclusions: Despite HIV viral suppression, PLHIV had remarkably poor CRF and inflammation was associated with a clinically adverse CRF profile. However, increased physical activity was associated with improved CRF. Correspondence to Allison R. Webel, RN, PhD, Assistant Professor, Case Western Reserve University, 10900 Euclid Avenue, Cleveland Ohio 44122. Tel: +01 216 368 3939; e-mail: arw72@case.edu Received 4 September, 2018 Revised 20 December, 2018 Accepted 21 December, 2018 Copyright © 2019 Wolters Kluwer Health, Inc.

Presentation of Case. Dr. Timothy J. Petersen: A 34-year-old man was evaluated at this hospital because of headaches, cognitive changes, mood symptoms, flashbacks, chest pain, arm tingling, and gastrointestinal symptoms. The patient had served as a special operations combat medic in the U.S. Army……

Arena, F., Marchetti, L., De Angelis, L. H., Maglioni, E., Contorni, M., Cassetta, M. I., Novelli, A., Rossolini, G. M.

Ceftolozane-tazobactam (C/T) pharmacokinetics during extracorporeal membrane oxygenation (ECMO) has not been previously studied. In this work we report on the C/T plasmatic levels in a lung transplant (LTX) recipient during ECMO, treated with C/T (i.v., 2 g ceftolozane and 1 g tazobactam, every 8 hours]) for a Pseudomonas aeruginosa pulmonary infection.…

DeMets DL, Cook T.

This Viewpoint reviews the rationale for intention-to-treat (ITT) analyses of randomized trials, explains how commonly used alternatives reintroduce confounding that randomization is intended to eliminate, and emphasizes that even an ITT analysis is no substitute for informed scientific and clinical judgement when interpreting trial results.