Riddell J, IV, Amico K, Mayer KH.

This narrative review summarizes evidence on the use of tenofovir disoproxil fumarate (TDF)/emtricitabine for HIV preexposure prophylaxis (PrEP) and calls for increased prescribing of PrEP and research on measures to identify individuals at high risk for HIV to ensure their access to PrEP and maximize medication adherence.

No plan ever survives first contact with the enemy.— General Helmuth von Moltke, Prussian Army Chief of Staff Was von Moltke right, or was Winston Churchill, who said "He who fails to plan is planning to fail"? Recent events have increased concern about the consequences of nuclear terrorism.……

Becky McCall

The General Data Protection Regulation will start in May across the European Union, but doubts are being cast on how prepared researchers and clinicians are. Becky McCall reports.

Bauchner H, Fontanarosa PB, Golub RM.

The creation and communication of scientific and clinical content continue to undergo substantial change, and biomedical journals and other publications are evolving to develop new mechanisms and channels for efficient information dissemination. For example, open access journals and options for open access publication have become common. Many investigators are increasingly interested in speed to publication. Preprint servers that disseminate non–peer-reviewed content have proliferated. Team science, reflecting collaborative research involving multiple investigators and research groups, has become more prevalent with the growth of research networks and consortia and the continued emergence of big data and data sharing. Data sharing is evolving, with the International Committee of Medical Journal Editors (ICMJE) soon requiring greater transparency regarding sharing of data, with the expectation that every report of a randomized clinical trial will include a statement of whether data will be shared, and if so, how and with whom. More changes have come to the dissemination of scientific information in the last decade than in the previous 100 years.

The American Journal of Tropical Medicine and Hygiene

In this study, we describe an internally controlled, multiplex real-time reverse transcription PCR (rRT-PCR) for the detection of DENV and YFV. The DENV-YFV assay demonstrated specific detection and had a dynamic range of 2.0-8.0 log10 copies/μL of eluate for each DENV serotype and YFV. Clinical performance was similar to a published pan-DENV assay: 48/48 acute-phase samples from dengue cases were detected in both assays. For YFV detection, mock samples were prepared with nine geographically diverse YFV isolates over a range of concentrations. The DENV-YFV assay detected 62/65 replicates, whereas 54/65 were detected using a reference YFV rRT-PCR. Given the reemergence of DENV and YFV in areas around the world, the DENV-YFV assay should be a useful tool to narrow the differential diagnosis...

Mathieu, Calypso; Desrois, Martine; Kober, Frank; Lalevée, Nathalie; Lan, Carole; Fourny, Natacha; Iché-Torres, Magali; Tran, Thi Thom; Lê, Linh Thuy; Singer, Mervyn; Mège, Jean-Louis; Bernard, Monique; Leone, Marc

Objectives: To investigate any gender effect of the beta-1 adrenergic blocker, landiolol, on cardiac performance and energy metabolism in septic rats, and to explore the expression of genes and proteins involved in this process. Design: Randomized animal study. Setting: University research laboratory. Subjects: Male and female Wistar rats. Interventions: One hour after cecal ligation and puncture, male and female rats were randomly allocated to the following groups: sham male, cecal ligation and puncture male, cecal ligation and puncture + landiolol male, sham female, cecal ligation and puncture female, and cecal ligation and puncture + landiolol female. Cardiac MRI was carried out 18 hours after cecal ligation and puncture to assess in vivo cardiac function. Ex vivo cardiac function measurement and 31P magnetic resonance spectroscopy were subsequently performed using an isovolumic isolated heart preparation. Finally, we assessed cardiac gene and protein expression. Measurements and Main Results: In males, landiolol increased indexed stroke volume by reversing the indexed end-diastolic volume reduction without affecting left ventricle ejection fraction. In females, landiolol did not increase indexed stroke volume and indexed end-diastolic volume but decreased left ventricle ejection fraction. Landiolol had no effect on ex vivo cardiac function and on high-energy phosphate compounds. The effect of landiolol on the gene expression of natriuretic peptide receptor 3 and on protein expression of phosphorylated-AKT:AKT ratio and endothelial nitric oxide synthase was different in males and females. Conclusions: Landiolol improved the in vivo cardiac performance of septic male rats while deleterious effects were reported in females. Expression of natriuretic peptide receptor 3, phosphorylated-AKT:AKT, and endothelial nitric oxide synthase are signaling pathways to investigate to better understand the sex differences in sepsis. 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). Supported, in part, by Fondation pour la Recherche Médicale (DEA 20150633224), AOP Orphan, Lions Club Marseille Doyen and France Life Imaging (grant ANR-11-INBS-0006). Dr. Mathieu received funding from Fondation Recherche Médicale (DEA20150633224) and Lions club Marseille Doyen. Dr. Singer received funding from AOP Pharma. Dr. Mege disclosed government work. Dr. Leone’s institution received funding from AOP Orphan (provided treatment: landiolol). The remaining authors do not have any potential conflicts of interest. For information regarding this article, Email: marc.leone@ap-hm.fr Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Maurizio Muraca

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 7, Page 969-970, April 1, 2018.

S. Alex Mitsialis

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 7, Page 970-970, April 1, 2018.

Abstract Background Use of chloroquine, an otherwise safe and relatively affordable anti-malarial drug, was discontinued due to widespread prevalence of resistant parasites. Many entrant anti-malarial drugs for treatment of chloroquine resistant malaria raises the concerns of cost and safety among other challenges. Innovative ways of circumventing chloroquine resistance is of paramount importance. Such may include nanoparticulate delivery strategies and targeting. This study evaluated physicochemical properties and in vitro antiplasmodial activity of chloroquine encapsulated heparin functionalized solid lipid nanoparticles (CQ-Hep-SLNs) and non-heparin functionalized SLNs (CQ-SLN) against Plasmodium falciparum. Methods The modified double-emulsion solvent evaporation technique was used to prepare the nanoparticles. HPLC/UV was used to determine the in vitro drug release. The semi-automated micro-dilution technique was adapted in assessing the in vitro antiplasmodial activity to give drug concentration capable of inhibiting 50% of the P. falciparum (IC50), as a function of antiplasmodial efficacy. Results Prepared nanoparticles were below 500 nm in size with % drug loading (%DL) between 21 and 25% and encapsulation efficiency (%EE) of 78–90%. The drug-loaded SLN exhibited a biphasic drug release profile at pH 7.4, with an initial burst release during the first 24 h followed by sustained release in both formulations. Nanoformulated CQ-SLN (4.72 ± 0.14 ng/mL) and CQ-Hep-SLN (2.41 ± 0.27 ng/mL), showed enhanced in vitro antiplasmodial activities against chloroquine sensitive (D6) strain of P. falciparum, albeit with no activity against the chloroquine resistant W2 strain, compared to free CQ standard (5.81 ± 0.18 ng/mL). Conclusions These findings suggest that the nanoformulated drugs displayed enhanced anti-malarial activities against chloroquine sensitive (D6) strains of P. falciparum compared to the free CQ standard. There is some form of potential dual synergistic effect of CQ-loaded heparinized solid lipid nanoparticles (Hep-SLN), meaning that combining heparin and CQ in SLNs has beneficial effects, including potential for specific targeting of parasitized red blood cells as afforded by heparin. Thus, the study has produced SLNs nanoparticles that have superior in vitro activities than CQ on CQ-sensitive parasites.

To the Editor: In their study, Landry et al. (Nov. 16 issue) found that only 20% of young athletes who had sudden cardiac arrest during participation in competitive sports in Ontario, Canada, had a disorder that could have been detected by preparticipation screening electrocardiography (ECG). We……

de Vries R, Altenburg A, Nieuwkoop N, et al.

AbstractBackgroundHighly pathogenic avian influenza viruses continue to circulate in poultry and wild birds and occasionally infect humans, sometimes with fatal outcome. Development of vaccines is a priority to prepare for potential pandemics, however complicated by antigenic variation of the surface glycoprotein hemagglutinin. We report the immunological profile induced by human immunization with Modified Vaccinia virus Ankara expressing the hemagglutinin gene of H5N1 virus A/Vietnam/1194/04 (rMVA-H5).MethodsIn a double-blind phase 1/2a clinical trial, 79 individuals received one or two injections of rMVA-H5 or vector control. Twenty-seven study subjects received a booster immunization after one year. The breadth, magnitude, and properties of vaccine-induced antibody and T-cell responses were characterised.ResultsrMVA-H5 induced broadly-reactive antibody responses, demonstrated by protein microarray, hemagglutination inhibition, virus neutralization and antibody-dependent cellular cytotoxicity assays. Antibodies cross-reacted with antigenically distinct H5 viruses, including the recently emerged H5N6 and H5N8, and currently circulating H5N1 viruses. In addition, the induction of T-cells specific for H5 viruses of two different clades was demonstrated.ConclusionsrMVA-H5 induced immune responses that cross-reacted with H5 viruses of various clades. These findings validate rMVA-H5 as vaccine candidate against antigenically distinct H5 viruses. This trial is registered with the Dutch Trial Register, number NTR3401 (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3401).

Sabine Wronski, Julia Dannenmaier, Sabine Schild, Olaf Macke, Laura Müller, Yvonne Burmeister, Bernd Seilheimer, Meike Müller

by Sabine Wronski, Julia Dannenmaier, Sabine Schild, Olaf Macke, Laura Müller, Yvonne Burmeister, Bernd Seilheimer, Meike Müller Background Respiratory viruses such as respiratory syncytial virus (RSV) or rhinovirus are one of the major causes for respiratory tract infections causing common cold disease. Respiratory viral infections range from mild symptoms in adults to serious illness especially in the very young or elderly as well as patients suffering from lung diseases or being immunocompromised due to other reasons. Engystol (EGY-2) is a multicomponent, multitarget preparation consisting of Vincetoxicum hirundinaria and Sulfur in various dilutions. The study objective was to test the effect of EGY-2 on the innate immune response during the early onset of respiratory viral infection in vivo as exemplified in a mouse model of RSV-induced respiratory inflammation. Methods Naïve BALB/c mice were infected with 1x106 infectious units RSV A2 intranasally to cause a mild respiratory infection. EGY-2 was administered daily per oral gavage starting seven days prior to RSV infection at doses of 0.4 to 5.1 tablets/kg. Control groups received placebo treatment. Animals were sacrificed 1 to 3 days post infection (p.i.) to analyse the infection and induced immune response in the lung. Viral load in bronchoalveolar lavage fluid (BALF) and lung homogenate was determined by TCID50 assay as well as immunofluorescence staining of BALF cells using anti-RSV antibody and microscopic analysis. The RSV induced immune response was assessed by evaluation of BALF differential cell count, BALF cytokine secretion and analysis of the phagocytic capacity of alveolar macrophages. Results EGY-2 significantly reduced the RSV induced neutrophil and early lymphocyte influx on day 1 p.i. in BALF. EGY-2 treatment significantly diminished the RSV induced secretion of pro-inflammatory cytokines such as IFN-γ, IL-1β, IL-6, KC and TNF-α at day 1. EGY-2 treatment was not protective for RSV infection per se, as no alteration in the viral load in lung and BALF was detected. Enhanced numbers of phagocytic-active macrophages were observed in EGY-2 treated animals on day 1 and this macrophage population showed strongly enhanced phagocytic activity on day 1 and day 3. Conclusion The data suggest a beneficial immunomodulatory effect of EGY-2 during early onset of respiratory viral infection in vivo, mediated by stimulation of macrophage phagocytosis, resulting in a reduced innate inflammatory response in terms of neutrophil and early lymphocyte infiltration as well as reduced inflammatory cytokine secretion.

Bratcher, Anna; Wirtz, Susan Schlueter; Siegler, Aaron J.

No abstract available…

Falk J, Winkelmann M, Stöhr D, et al.

AbstractTo improve the potency of anti-human cytomegalovirus (HCMV) immunoglobulin preparations, we intended to find elite neutralizers among 9000 HCMV-seropositive blood donors. We identified 2.6 % top neutralizers using a high throughput screening and further analyzed the 80 most effective plasmas for strain-independent activity. Of those, 58 were broadly neutralizing towards various HCMV strains and hence regarded “elite” neutralizers. All elite neutralizers were then analyzed concerning their effect on individual virus particles during entry. Most of them preferentially inhibited viral penetration whereas two exceptional plasmas already prevented adsorption of virus to cells. Furthermore, the neutralizing capacity of three randomly chosen elite plasmas was up to 10-fold higher when compared with commercial immunoglobulins. In a retrospective analysis of six selected donors, anti-HCMV neutralization titers in repeated donations were constantly high over five years. In conclusion, plasma of elite donors can be considered to improve the antibody-based treatment of HCMV infections.

Thaden, Joshua T.; Gandhi, Monica; Okochi, Hideaki; Hurt, Christopher B.; McKellar, Mehri S.

Objective: We describe the third case report of seroconversion with multidrug resistant (MDR)-HIV despite pre-exposure prophylaxis (PrEP) with emtricitabine (FTC) and tenofovir (TFV) disoproxil (TDF). Design: Case report. Methods: PrEP adherence was assessed via self-report, pharmacy records, and measuring TFV/FTC levels with liquid-chromatography/tandem-mass-spectrometry in plasma and hair. Segmental hair analysis was performed to assess PrEP adherence over prior months. Genotypic resistance was assessed. Results: A 34 year-old white MSM started daily FTC/TDF in 2/2016 after being provided 11 refills. In 3/2017, he developed fevers, chills, myalgias and was assessed, but no HIV test was sent. In 4/2017, an antigen/antibody HIV test was reactive (day 0). On day 2. HIV-1 RNA was 27,316 copies/mL, genotyping revealed M184V, K65R, and K103N mutations, plasma TFV and FTC concentrations were consistent with recent dosing. To evaluate adherence over preceding months, a hair sample was collected at day 27 and segmental analysis of TFV/FTC levels performed in 1-centimeter segments from the scalp. Hair drug levels (0.0434-0.0520 ng TFV/mg hair) were commensurate with consistently high PrEP adherence over the prior 3 months. Conclusions: This study employs segmental analysis of PrEP drug levels in hair for the first time to assess adherence over preceding months in the setting of an HIV seroconversion on PrEP. High adherence over the period of likely acquisition makes MDR-HIV infection the most likely scenario in this case. Adequate adherence assessment when examining PrEP failures and ensuring best practices in PrEP prescribing and follow-up are important. Correspondence to Mehri S. McKellar, MD, MPH, Division of Infectious Diseases, Duke University, Duke Box 102359, Durham, NC 27710, USA. Tel: +1 919 613 6129; e-mail: mehri.mckellar@duke.edu Received 23 March, 2018 Revised 6 April, 2018 Accepted 10 April, 2018 Copyright © 2018 Wolters Kluwer Health, Inc.

Khurana, Nidhi; Yaylali, Emine; Farnham, Paul G.; Hicks, Katherine A.; Allaire, Benjamin T.; Jacobson, Evin; Sansom, Stephanie L.

Background: The effect of improving diagnosis, care, and treatment of persons living with HIV (PLWH) on PrEP effectiveness in the United States has not be well established. Methods: We used a dynamic, compartmental model that simulates the sexually active US population. We investigated the change in cumulative HIV incidence from 2016 to 2020 for three HIV care continuum levels, and the marginal benefit of PrEP compared with each. We also explored the marginal benefit of PrEP for individual risk groups, and as PrEP adherence, coverage and dropout rates varied. Results: Delivering PrEP in 2016 to persons at high risk of acquiring HIV resulted in an 18.1% reduction in new HIV infections from 2016 to 2020 under current care continuum levels. Achieving HIV national goals of 90% of PLWH with diagnosed infection, 85% of newly diagnosed PLWH linked to care at diagnosis, and 80% of diagnosed PLWH virally suppressed reduced cumulative incidence by 34.4%. Delivery of PrEP in addition to this scenario resulted in a marginal benefit of 11.1% additional infections prevented. When national goals were reached, PrEP prevented an additional 15.2% cases among men who have sex with men (MSM), 3.9% among heterosexuals, and 3.8% among persons who inject drugs. Conclusions: The marginal benefit of PrEP was larger when current HIV care continuum percentages were maintained, but continued to be substantial even when national care goals were met. The high-risk MSM population was the chief beneficiary of PrEP. Corresponding author: Nidhi Khurana, Office: 404-639-0922; email: kqt3@cdc.gov Conflicts of Interest and Source of Funding: Katherine A. Hicks is an employee of RTI Health Solutions and received research funding for this study from CDC under contract number 200-2012-53603. Benjamin T. Allaire is an employee for RTI International and received research funding for this study from CDC under contract number 200-2012-53603. The finding and conclusions in this paper are those of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention. A version of the supplemental material, the Technical Report, was previously published as supplementary material to the following paper: O’Leary A., DiNenno E., Honeycutt A., Allaire B., Neuwahl S., Hicks K., Sansom S. AIDS Behav (2017). doi:10.1007/s10461-016-1635-z” ** Current institution: Istanbul Technical University An earlier version of this research has been presented at INFORMS Annual Meeting (Houston, October 2017) Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Cesar Tovar, Amanda L. Patchett, Vitna Kim, Richard Wilson, Jocelyn Darby, A. Bruce Lyons, Gregory M. Woods

by Cesar Tovar, Amanda L. Patchett, Vitna Kim, Richard Wilson, Jocelyn Darby, A. Bruce Lyons, Gregory M. Woods The Tasmanian devil (Sarcophilus harrisii), the largest extant carnivorous marsupial and endemic to Tasmania, is at the verge of extinction due to the emergence of a transmissible cancer known as devil facial tumour disease (DFTD). DFTD has spread over the distribution range of the species and has been responsible for a severe decline in the global devil population. To protect the Tasmanian devil from extinction in the wild, our group has focused on the development of a prophylactic vaccine. Although this work has shown that vaccine preparations using whole DFTD tumour cells supplemented with adjuvants can induce anti-DFTD immune responses, alternative strategies that induce stronger and more specific immune responses are required. In humans, heat shock proteins (HSPs) derived from tumour cells have been used instead of whole-tumour cell preparations as a source of antigens for cancer immunotherapy. As HSPs have not been studied in the Tasmanian devil, this study presents the first characterisation of HSPs in this marsupial and evaluates the suitability of these proteins as antigenic components for the enhancement of a DFTD vaccine. We show that tissues and cancer cells from the Tasmanian devil express constitutive and inducible HSP. Additionally, this study suggests that HSP derived from DFTD cancer cells are immunogenic supporting the future development of a HSP-based vaccine against DFTD.

Willsey, G. G., Ventrone, S., Schutz, K. C., Wallace, A. M., Ribis, J. W., Suratt, B. T., Wargo, M. J.

The interactions between Klebsiella pneumoniae and the host environment at the site of infection largely unknown. Pulmonary surfactant serves as an initial point of contact for inhaled bacteria entering the lung and is thought to contain molecular cues that aid colonization and pathogenesis. To gain insight into this ecological transition, we characterized the transcriptional response of K. pneumoniae MGH 78578 to purified pulmonary surfactant. This work revealed changes within the K. pneumoniae transcriptome that likely contribute to host colonization, adaptation, and virulence in vivo. Notable transcripts expressed under these conditions include genes involved in capsule synthesis, LPS modification, antibiotic resistance, biofilm formation, and metabolism. In addition, we tested the contributions of other surfactant-induced transcripts to K. pneumoniae survival using engineered isogenic KPPR1 deletion strains in a murine model of acute pneumonia. In these infection studies we identified the MdtJI polyamine efflux pump and ProU glycine betaine ABC transporter as significant mediators of K. pneumoniae survival within the lung and confirmed previous evidence for the importance of de novo leucine synthesis to bacterial survival during infection. Finally, we determined that pulmonary surfactant promoted type 3 fimbriae-mediated biofilm formation in K. pneumoniae and identified two surfactant constituents, phosphatidylcholine and cholesterol, that drive this response. This study provides novel insight into the interactions occurring between K. pneumoniae and the host at an important infection site and demonstrates the utility of purified lung surfactant preparations for dissecting host-lung pathogen interactions in vitro.

Abstract Background Microscopic research has shown that Plasmodium relictum is the most common agent of avian malaria. Recent molecular studies confirmed this conclusion and identified several mtDNA lineages, suggesting the existence of significant intra-species genetic variation or cryptic speciation. Most identified lineages have a broad range of hosts and geographical distribution. Here, a rare new lineage of P. relictum was reported and information about biological characters of different lineages of this pathogen was reviewed, suggesting issues for future research. Methods The new lineage pPHCOL01 was detected in Common chiffchaff Phylloscopus collybita, and the parasite was passaged in domestic canaries Serinus canaria. Organs of infected birds were examined using histology and chromogenic in situ hybridization methods. Culex quinquefasciatus mosquitoes, Zebra finch Taeniopygia guttata, Budgerigar Melopsittacus undulatus and European goldfinch Carduelis carduelis were exposed experimentally. Both Bayesian and Maximum Likelihood analyses identified the same phylogenetic relationships among different, closely-related lineages pSGS1, pGRW4, pGRW11, pLZFUS01, pPHCOL01 of P. relictum. Morphology of their blood stages was compared using fixed and stained blood smears, and biological properties of these parasites were reviewed. Results Common canary and European goldfinch were susceptible to the parasite pPHCOL01, and had markedly variable individual prepatent periods and light transient parasitaemia. Exo-erythrocytic and sporogonic stages were not seen. The Zebra finch and Budgerigar were resistant. Neither blood stages nor vector stages of all examined P. relictum lineages can be distinguished morphologically. Conclusion Within the huge spectrum of vertebrate hosts, mosquito vectors, and ecological conditions, different lineages of P. relictum exhibit indistinguishable, markedly variable morphological forms. Parasites of same lineages often develop differently in different bird species. Even more, the variation of biological properties (parasitaemia dynamics, blood pathology, prepatent period) in different isolates of the same lineage might be greater than the variation in different lineages during development in the same species of birds, indicating negligible taxonomic value of such features. Available lineage information is excellent for parasite diagnostics, but is limited in predictions about relationships in certain host-parasite associations. A combination of experiments, field observations, microscopic and molecular diagnostics is essential for understanding the role of different P. relictum lineages in bird health.

Abstract Background Angiocentric lymph proliferative disorder (ALPD) is a granulomatous lymphoproliferative condition associated with various primary and secondary immunodeficiency states. ALPD is so rare that its prevalence has not been established. Typically affecting middle-aged adults, this condition is often found in the context of Epstein Bar Virus infection and consists of angiocentric and angioinvasive pulmonary infiltrates. Herein, we present a biopsy-proven case of a patient manifesting with a viral meningoencephalomyelitis-like picture with brain, spinal cord, renal and splenic lesions. The diagnosis was confirmed to be ALPD in the context of newly diagnosed HIV infection. Case presentation A 35 year-old homosexual man presented with a 5-week history of headaches followed by a 3-week history of horizontal diplopia, limb weakness and right 6th cranial nerve palsy. Lumbar puncture revealed a lymphocytic pleocytosis, high protein and low glucose. Magnetic Resonance Imaging showed scattered lesions throughout the brain and spinal cord and Computed Tomography of the abdomen and pelvis revealed hypodensities involving the kidneys and spleen. HIV testing was positive, with a viral load of 11,096 copies/mL and CD4 count of 324 cells/μL. Serum Epstein Bar virus PCR was positive with 12,434 copies/ml. Right frontal brain biopsy revealed gray matter containing angiogentric cerebritis with organizing infarction but Epstein Bar Virus-in situ preparations were negative and no viral inclusions were identified. A diagnosis of ALPD (also known as lymphomatoid granulomatosis) was made. The patient was initiated on antiretroviral therapy and treated with intravenous rituximab every 3 weeks for 4 cycles and made progressive improvements. By the time of discharge his strength had improved and he was ambulating again although with a walker. Within 2 months, his HIV viral load was suppressed. Magnetic Resonance Imaging of the brain 6 months later revealed interval improvement. At his most recent follow-up, 34 months later, his neurological symptoms had almost completed resolved. Conclusion Albeit rare, ALPD should be considered in the differential diagnosis of central nervous system lesions in persons with HIV once common etiologies have been eliminated. Furthermore, ALPD involving the central nervous system may occur in in the absence of documented EBV infection in the central nervous system.

Abstract Background Co-infection with HIV negatively impacts the progression of chronic hepatitis B virus (HBV) infection, including causing rapid progression to liver fibrosis. Sub-Saharan Africa represents arguably the most important intersection of high endemicity of both chronic hepatitis B virus (HBV) infection and HIV infection. Methods We recruited 46 HBV/HIV-co-infected; 47 HBV-monoinfected; 39 HIV-monoinfected; and 37 HBV/HIV-uninfected patients from Tygerberg Hospital, Cape Town, South Africa. All HIV-infected patients were on antiretroviral therapy for ≥3 months. Liver stiffness measurements were assessed using the Fibroscan (Fibroscan 402, Echosens). Cell-based immunomarkers were measured by flow cytometry. Soluble serum/plasma immunomarkers were measured by Luminex technology and enzyme immunoassays. HIV (COBAS/Ampliprep TaqMan HIV-1) and HBV viral loads (in-house assay) were also performed. Results HBV/HIV co-infected patients showed significantly higher levels of immune activation %CD8+/HLA-DR+/CD38+ (median 30%, interquartile range: 17–53) and %CD8+/PD-1 (median 22%, interquartile range: 15–33), p ≤ 0.01 compared to all other study groups. Despite this, the HBV-mono-infected group had the highest proportion of patients with advanced liver fibrosis (≥13 kPa) as measured by Fibroscan (18%). HBV mono-infected patients showed highest expression of most cytokines including IL-17 and basic fibroblastic growth factor. There was significant positive correlation between detectable HIV and HBV viral replication and liver fibrosis but not immune activation or gut translocation. Discussion Highly-active antiretroviral therapy, including tenofovir, is effective against both HIV and HBV. Earlier therapy in the co-infected patients may therefore have controlled viral replication leading to better fibrosis scores when compared to HBV mono-infection in this study. On-going HBV and HIV viraemia, rather than microbial translocation or immune activation, appear to be the drivers of liver fibrosis. Moderate to advanced liver fibrosis in HBV-mono-infection may well indicate poor access to screening and treatment of HBV infection.

Andreas Rieckmann, Charlotte C. Tamason, Emily S. Gurley, Naja Hulvej Rod and Peter Kjær Mackie Jensen

Abstract. Cholera outbreaks in Africa have been attributed to both droughts and floods, but whether the risk of a cholera outbreak is elevated during droughts is unknown. We estimated the risk of cholera outbreaks during droughts and floods compared with drought- and flood-free periods in 40 sub-Saharan African countries during 1990–2010 based on data from Emergency Events Database: the Office of Foreign Disaster Assistance /Centre for Research on the Epidemiology of Disasters International Disaster Database (www.emdat.be). A cholera outbreak was registered in one of every three droughts and one of every 15 floods. We observed an increased incidence rate of cholera outbreaks during drought periods (incidence rate ratio [IRR] = 4.3, 95% confidence interval [CI] = 2.9–7.2) and during flood periods (IRR = 144, 95% CI = 101–208) when compared with drought/flood-free periods. Floods are more strongly associated with cholera outbreaks, yet the prevalence of cholera outbreaks is higher during droughts because of droughts’ long durations. The results suggest that droughts in addition to floods call for increased cholera preparedness.

Lee, Si-Huei; Hsu, Tzu-Chun; Lee, Meng-tse Gabriel; Chao, Christin Chihh-Ting; Lee, Wan-Chien; Lai, Chi-Cheng; Lee, Chien-Chang; for the National Taiwan University Health Economics and Outcome Research Group

Objective: We aimed to compare the sepsis incidence, mortality rates, and primary sites of infection among adult, elderly, and octogenarian patients with sepsis. Design: Population-based cohort study. Setting: The entire health insurance claims data of Taiwan, which enrolled 99.8% of the 23 million Taiwanese population. Patients: Sepsis patients were identified by International Classification of Diseases, 9th Edition, Clinical Modification codes for both infection and organ dysfunction from January 1, 2002, to December 31, 2012. Patients were categorized into three age groups: 1) adults (18–64 yr); 2) elderly (65–84 yr); and 3) oldest old (≥ 85 yr). The 30-day all-cause mortality was verified by a linked national death certificate database. Interventions: None. Measurements and Main Results: From 2002 to 2012, we identified 1,259,578 patients with sepsis, of which 417,328 (33.1%) were adults, 652,618 (51.8%) were elderly, and 189,632 (15.1%) were oldest old. We determined that the incidence of sepsis in the oldest old was 9,414 cases per 100,000 population on 2012, which was 31-fold greater than the adult incidence (303 cases per 100,000 population) and three-fold greater than the elderly incidence (2,908 cases per 100,000 population). Despite the increasing trend in incidence, the mortality decreased by 34% for adults, 24% for elderly, and 22% for oldest old. However, systemic fungal infection was disproportionately increased in oldest old patients (1.76% annual increase) and the elderly patients (1.00% annual increase). Conclusion: The incidence of sepsis is disproportionately increased in elderly and oldest old patients. Despite the increasing trend in incidence, the mortality rate in geriatric patients with sepsis has decreased. However, the increased incidence of fungal infections in the geriatric population warrants further attention. Additional members of the National Taiwan University Health Economics and Outcome Research Group are: Meng-Che Wu, Shyr-Chyr Chen, Wan-Ting Hsu, Szu-Ta Chen, and Ke-ying Su. No funding bodies had any role in the study design, data collection and analysis, decision to publish, or preparation of the article. The interpretation and conclusions contained herein do not represent those of Bureau of National Health Insurance, Department of Health, or National Health Research Institutes. Dr. S.-H. Lee drafted the analytical plan, guided the statistical analysis, interpreted the data, and wrote the draft. Ms. Hsu and Ms. W.-C. Lee conducted all the statistical analysis. Dr. M.-t.G. Lee interpreted the results, and wrote the final draft and point-to-point response. Dr. Chao helped with language editing and provided critical comments. Dr. Lai analyzed the data, provided critical feedback, and authorized the final article. Dr. C.-C. Lee designed the study, obtained funding, drafted the analytical plan, guided the statistical analysis, interpreted the data, and wrote the draft. 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). Supported, in part, by the Taiwan National Science Foundation Grant NSC 102-2314-B-002 -131 -MY3, National Taiwan University Hospital Grant NTUH.106-P04, and Taiwan National Ministry of Science and Technology Grants MOST 104-2314-B-002 -039 -MY3 and MOST 106-2811-B-002-048. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: cclee100@gmail.com Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Hoornenborg, Elske; Coyer, Liza; van Laarhoven, Anna; Achterbergh, Roel; de Vries, Henry; Prins, Maria; Loeff, Maarten Schim van der; on behalf of the Amsterdam PrEP Project team in the HIV Transmission Elimination Amsterdam Initiative

Objective: HIV pre-exposure prophylaxis (PrEP) use may lead to higher STI incidence via behavioral risk compensation. We examined changes in sexual behaviour between baseline and six months after PrEP initiation among men who have sex with men (MSM) and transgender women (TGW). Design: Prospective, open-label demonstration study at a large sexually transmitted infections (STI) clinic in Amsterdam, the Netherlands. Methods: Participants answered questions about sexual behaviour in the preceding three months, including number of anal sex partners and frequency of anal sex with and without condom by partner type and were tested for STI. Sexual behaviour at baseline was compared with six months after PrEP initiation using Wilcoxon signed rank tests. Logistic regression was used to identify factors associated with an increase in receptive condomless anal sex acts (rCASa) with casual partners. Results: Data were available for 328 (99.4%) MSM and 2 (0.6%) TGW. The number of receptive and insertive condomless anal sex acts (CASa) increased (baseline: median 11, IQR 4-23; 6 months: median 14 IQR 6-26, p …

Heffron, Renee; Mugo, Nelly; Hong, Ting; Celum, Connie; Marzinke, Mark A.; Ngure, Kenneth; Asiimwe, Stephen; Katabira, Elly; Bukusi, Elizabeth; Odoyo, Josephine; Tindimwebwa, Edna; Bulya, Nulu; Baeten, Jared M.; for the Partners Demonstration Project and the Partners PrEP Study Teams

Background: Global guidelines recommend pre-exposure prophylaxis (PrEP) use by women at risk for HIV, including during pregnancy, a period with heightened HIV risk. However, data to support safety of PrEP use during pregnancy are limited, particularly from women using PrEP throughout pregnancy. Methods: In an open-label delivery study of PrEP integrated with ART for high risk HIV serodiscordant couples in Kenya and Uganda (the Partners Demonstration Project), women who became pregnant while using PrEP were offered the option to continue PrEP throughout pregnancy. We compared pregnancy outcomes and one-year infant growth from pregnancies with exposure to PrEP throughout pregnancy to those without any exposure, with data from the placebo arm of a prior efficacy trial of PrEP conducted in the same setting. Results: Outcomes from 30 women who elected to continue PrEP throughout pregnancy were compared to those from 96 pregnancies among PrEP-unexposed women. There were small non-significant decreases in the frequency of pregnancy loss (16.7% PrEP-exposed versus 23.5% PrEP-unexposed, adjusted odds ratio [aOR] = 0.59, p = 0.4) and preterm delivery (0 versus 7.7%, [aOR] = 0.54, exact p = 0.6). No congenital anomalies occurred among PrEP-exposed infants. PrEP-exposed infants had slightly lower adjusted mean z-scores for length (−1.73 versus −0.79, p = 0.05) and head circumference (0.24 versus 1.07, p = 0.04) one month after birth but were comparable to PrEP-unexposed infants in these measurements one year after birth. Conclusions: This first evaluation among women using PrEP throughout pregnancy indicates no greater frequency of adverse pregnancy outcomes or restricted infant growth; these findings support recommendations permitting PrEP use during pregnancy. Correspondence to Renee Heffron, International Clinical Research Center, University of Washington, 325 Ninth Avenue Box 359927, Seattle, WA, USA. Tel: +12065203817; fax: +12065203831; e-mail: rheffron@uw.edu Received 6 December, 2017 Revised 17 March, 2018 Accepted 26 March, 2018 Copyright © 2018 Wolters Kluwer Health, Inc.

Volmar Morais Fontoura, Iolanda Graepp-Fontoura, Floriacy Stabnow Santos, Marcelino Santos Neto, Hanari Santos de Almeida Tavares, Maria Onice Lopes Bezerra, Marcela de Oliveira Feitosa, Adriano Figuerêdo Neves, Jesuane Cavalcante Melo de Morais, Luiz Fernando Costa Nascimento

by Volmar Morais Fontoura, Iolanda Graepp-Fontoura, Floriacy Stabnow Santos, Marcelino Santos Neto, Hanari Santos de Almeida Tavares, Maria Onice Lopes Bezerra, Marcela de Oliveira Feitosa, Adriano Figuerêdo Neves, Jesuane Cavalcante Melo de Morais, Luiz Fernando Costa Nascimento Background Diarrhea is a waterborne disease that affects children, especially those under 5 years of age. The objective of this study was to identify the spatial patterns of distribution of diarrheal disease in under 5-year-old children in the State of Tocantins, Brazil, from 2008 to 2013. Methods Geoprocessing tools were used to carry out an epidemiological study, to prepare thematic maps in the TerraView 4.2.2 software based on secondary data. General indicators of the disease, presence of spatial dependence through the Global Moran’s Index (I) and the Spatial Association Index (LISA) were described. Results There were 3,015 cases of under 5-year-old children hospitalized for diarrhea, with an average annual rate (AAR) of 4.10/1,000 inhabitants (inhab.). Among the main characteristics were: increasing rates in under 1-year-old children (6.16 to 9.66/1,000 inhabitants); children aged 1 to 4 full years (63%); males (55%); 8 deaths of under one-year-old children (75%); county of Araguaína (67%); incidence in the county of Nazaré (63.97/1,000 inhab.); prevalence and incidence in the Araguaína microregion (45%, AAR 9.38/1,000 inhab.). The presence of a cluster with spatial autocorrelation was found in the Araguaína microregion, which was statistically significant (I = 0.11, p-value < 0.03), with priority of intervention (Moran Map). Conclusions There was an increase in the number of hospitalizations for diarrhea in under 5–year-old children in the state of Tocantins. The spatial analysis identified clusters of priority areas for measures of maintenance and control of diarrheal diseases.

Doblecki-Lewis, Susanne; Liu, Albert Y.; Feaster, Daniel J.; Cohen, Stephanie E.; Elion, Richard; Bacon, Oliver; Coleman, Megan; Cardenas, Gabriel; Kolber, Michael A.

Background: Safe and effective use of pre-exposure prophylaxis (PrEP) depends on retention in care after initial engagement. Setting: The United States PrEP Demonstration Project offered daily oral tenofovir/emtricitabine to participants in San Francisco, Miami, and Washington, D.C. for 48 weeks from 2012-2014. Methods: Demo Project participants’ patterns of retention were assigned to one of three categories: early loss to follow-up (ELTF) within the first 12 weeks of the study, retention throughout the study, or intermittent retention in which missed or delayed visits resulted in gaps in medication availability. For each group, baseline characteristics were tabulated. A two-step multivariable analysis was performed. Results: Overall, 366/554 (66.1%) of enrolled participants were retained for all study visits, 127/554 (22.9%) had intermittent retention, and 61/554 (11.0%) early loss to follow-up (ELTF). In multivariable analysis Miami compared to San Francisco site was associated with ELTF rather than full retention (aOR 2.84; CI:1.24-6.47) and also with intermittent rather than full retention (aOR 2.70; CI:1.43-5.11). Younger age was associated with ELTF (aOR 1.80 for each 10-year decrement in age; CI:1.26-2.57) and intermittent retention (aOR 1.47; CI:1.17-1.84) compared with full retention. Factors associated with ELTF (but not intermittent retention) compared with full retention, were black race compared with white (aOR 3.32; CI:1.09-10.16), reported sex work (aOR 4.67; CI 1.49-14.58), lack of regular employment (aOR 2.53; CI: 1.27-5.05), and lack of prior PrEP awareness (aOR 2.01; CI:1.01 -3.96). Conclusion: Tailored interventions addressing causes and risk factors for loss from PrEP care may improve retention and consistency of PrEP use. Corresponding Author (and requests for reprints): Susanne Doblecki-Lewis, MD, MSPH Division of Infectious Diseases University of Miami Miller School of Medicine 1120 NW 14th Street #850 Miami, Florida, USA 33155 305-243-4598 (telephone) 305-243-4037 (fax) sdoblecki@med.miami.edu The authors report no conflicts of interest related to this work. Funding Sources: National Institute for Allergy and Infectious Diseases: Miami Center for AIDS Research (P30AI073961; PI: S. Pahwa; supplement award to S. Doblecki-Lewis); PrEP Demonstration Project (UO1 AI069451; PI: A. Liu). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Guiteau MOISE, Colette; RIVERA, Vanessa R; HENNESSEY, Kelly A; BELLOT, Clovy; NICHOLAS, Chris; FANG, Anna P; VERDIER, Rose Irène; SEVERE, Patrice; SAINVIL, Alix; CHARLES, Benedict; DORVAL, Derothy; ST. AMOUR, Juseline; PAPE, Jean W; KOENIG, Serena P

Background: Recommendations for universal antiretroviral therapy (ART) have greatly increased the number of HIV-infected patients who qualify for treatment, particularly with early clinical disease. Less intensive models of care are needed for clinically stable patients. Setting: A Rapid Pathway (RP) model of expedited outpatient care for clinically stable patients was implemented at the Haitian Group for the Study of Kaposi’s Sarcoma and Opportunistic Infections (GHESKIO) Center, Port-au-Prince, Haiti. Expedited visits included nurse-led assessments and point-of-service ART dispensing. Methods: We conducted a retrospective analysis including patients who initiated RP care between June 1, 2014 and September 30, 2015, comparing outcomes of patients with timely visit attendance (never >3 days late) with patients with ≥1 non-timely visit within 6 months prior to RP enrollment. We calculated retention in care and adherence at 12 months, and assessed predictors of both outcomes. Results: Of the 2361 patients who initiated RP care during the study period, 1429 (61%) had timely visit attendance and 932 (39%) had ≥1 non-timely visit prior to RP enrollment. Among RP-enrolled patients, 94% were retained at 12 months and 75% had ≥90% adherence, with higher proportions in those with timely pre-RP visits (95% vs. 92%; 87% vs. 55%). In multivariable analysis, pre-RP visit timeliness was associated with both retention (adjusted OR [aOR]: 1.67;95% confidence interval [CI]: 1.08-2.59) and adherence (aOR: 4.53; 95% CI: 3.58-5.72). Conclusion: Rapid Pathway care was associated with high levels of retention and adherence for clinically stable patients. Timeliness of pre-RP visits was predictive of outcomes after RP initiation. Correspondence and reprint requests to: Serena Koenig, MD, MPH, Division of Global Health Equity, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA, USA 02115, 617-413-4090 (phone); 617-432-6958 (fax); skoenig@bwh.harvard.edu (e-mail), Colette Guiteau, MD, GHESKIO, 33 Harry Truman Boulevard, Port-au-Prince, Haiti, 011-509-3449-3596 (phone); colette0786@hotmail.com (email) Conflicts of Interest and Sources of Funding: All authors declare that they have no conflicts of interest. These data were presented in part at the Conference for Retroviruses and Opportunistic Infections (CROI), Boston, MA, February, 2016. This project was supported by the National Institute of Allergy and Infectious Diseases (NIAID) grant numbers R01AI104344 and 1 R01 AI131998, Fogarty International Center grant number D43TW010062-01, and by the Caribbean, Central and South America network for HIV epidemiology (CCASAnet), a member cohort of the International Epidemiologic Databases to Evaluate AIDS (leDEA) (U01AI069923), which is funded by the following institutes: Eunice Kennedy Shriver National Institute of Child Health and Human Development, Office of the Director, National Institutes of Health, NIAD, National Cancer Institute, and the National Institute of Mental Health. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. * These two authors contributed equally Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Bubak A, Como C, Blackmon A, et al.

AbstractBackgroundVaricella zoster virus (VZV) can present as a myelopathy with spinal astrocyte infection. Recent studies support a role for the neurokinin-1 receptor (NK-1R) in virus infections, as well as for cytoskeletal alterations that may promote viral spread. Thus, we examined the role of NK-1R in VZV-infected primary human spinal astrocytes (HA-sps) to shed light on the pathogenesis of VZV myelopathy.MethodsMock- and VZV-infected HA-sps were examined for substance P (subP) production, NK-1R localization, morphological changes and viral spread in the presence or absence of NK-1R antagonists, aprepitant and rolapitant.ResultsVZV infection of HA-sps induced nuclear localization of full-length and truncated NK-1R in the absence of the endogenous ligand, subP, and was associated with extensive lamellipodia formation and viral spread that was inhibited by NK-1R antagonists.ConclusionsWe have identified a novel, subP-independent, proviral function of nuclear NK-1R associated with lamellipodia formation and viral spread that is distinct from subP-induced NK-1R cell membrane/cytoplasmic localization without lamellipodia formation. These results suggest that binding of a putative viral ligand to NK-1R produces a dramatically different NK-1R downstream effect than binding of subP. Finally, NK-1R antagonists aprepitant and rolapitant provide promising alternatives to nucleoside analogs in treating VZV infections, including myelopathy.

Jorgensen, K. M., Astvad, K. M. T., Hare, R. K., Arendrup, M. C.

Olorofim is a novel antifungal agent with in vitro activity against Aspergillus and some other moulds. Here we addressed technical aspects for EUCAST olorofim testing and generated contemporary MIC data.EUCAST E.Def 9.3.1 testing was performed comparing two plate preparation methods (serial-dilution in medium (serial-plates) versus pre-dilution in DMSO (ISO-plates)), two lots of olorofim, visual (visual-MIC) versus spectrophotometer (spec-MIC) reading and four polystyrene plates using 34-53 Aspergillus isolates from five genera. Subsequently, olorofim MICs were compared to itraconazole, voriconazole, posaconazole and amphotericin B MICs for 298 clinical mould isolates (2016-2017). Wild-type upper limits (WT-UL) were determined following EUCAST principles for ECOFF setting.Olorofim median MICs comparing serial-plates and ISO-plates were identical (25/36, 69%) or one dilution apart (11/36, 31%). Inter-person agreement for visual-MICs was 92-94%/100% for ≤1/≤2 dilutions, respectively. Visual-MICs across tested microtitre plates and olorofim lots revealed only discrete differences (≤1 dilution lower for treated plates). No single spec-MIC criteria was applicable to all species.Olorofim MICs were low against 275 Aspergillus spp. isolates (modal-MIC=0.06 mg/L, MIC range

Johnson, Wayne D.; O’Leary, Ann; Flores, Stephen A.

Objective: Few studies have examined condom effectiveness for HIV prevention among men who have sex with men (MSM). We estimated condom effectiveness per partner in four cohorts of MSM during 1993–2003 (JumpStart, Vaccine Preparedness Study, VAX004 and Project Explore). Methods: We used logistic regression to estimate the increase in odds of new HIV infection per HIV-positive partner for condom-protected receptive anal intercourse (PRAI; partners with whom condoms were always used) and condomless (unprotected) receptive anal intercourse (URAI; partners with whom condoms were sometimes or never used). To estimate condom effectiveness for preventing HIV transmission we applied the concept of excess odds, the odds ratio minus 1. The condom failure rate was estimated as the excess odds per PRAI partner divided by the excess odds per URAI partner. Condom effectiveness was then 1 minus the failure rate. Results: The excess odds of HIV infection per HIV-positive partner were 83% for URAI and 7% for PRAI. The resulting failure rate (9%) indicated per-partner condom effectiveness of 91% (95% confidence interval 69–101). Conclusion: The increase in odds of new HIV infection per HIV-positive partner for RAI was reduced by 91% for each partner with whom condoms were always used. Correspondence to Wayne D. Johnson, PhD, MSPH, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, 1600 Clifton Rd MS-37, Atlanta, GA 30333. Tel: +404 639 1932; fac: 404 639 1950; e-mail: wdj0@cdc.gov Received 9 December, 2017 Revised 2 April, 2018 Accepted 10 April, 2018 Copyright © 2018 Wolters Kluwer Health, Inc.

Roberts, Michael B.; Glaspey, Lindsey J.; Mazzarelli, Anthony; Jones, Christopher W.; Kilgannon, Hope J.; Trzeciak, Stephen; Roberts, Brian W.

Objectives: Posttraumatic stress disorder among survivors of critical illness is of public health importance, as it is common and reduces patient quality of life. The objective of this systematic review was to collate the world’s literature on interventions aimed at preventing posttraumatic stress disorder among survivors of critical illness. Data Sources: We performed a search of CENTRAL, MEDLINE, EMBASE, CINAHL, and clinical trials registry platforms, with no restriction to language using a comprehensive strategy. Study Selection: Study inclusion criteria were as follows: 1) adult human subjects, 2) patients treated in an ICU setting, 3) intervention arm aimed at reducing posttraumatic stress disorder symptoms, 4) use of a control arm, and 5) an outcome measure assessing development of acute stress or posttraumatic stress disorder symptoms. Data Extraction: We performed a qualitative analysis to collate and summarize effects of identified interventions according to the recommended methodology from the Cochrane Handbook. Data Synthesis: Seventeen studies met all inclusion and no exclusion criteria. There was heterogeneity in interventions and outcome measures used. All studies had some concern for risk of bias as per the Cochrane tool for assessing risk of bias. In eight of 12 studies (67%) testing early interventions (i.e., initiated in the ICU course) and one of five studies (20%) testing delayed interventions following ICU discharge, posttraumatic stress disorder symptoms were decreased among the intervention group compared with controls. Conclusions: Despite a paucity of high-quality clinical investigations, the preponderance of evidence to date suggests that 1) posttraumatic stress disorder among survivors of critical illness may be preventable and 2) early interventions may be the most effective. All authors have made substantial contributions to this article; contributed to the development of the selection criteria, the risk of bias assessment strategy, and data extraction criteria; read and contributed substantially to revision of the final article; and approved the article in its final form. Drs. M. B. Roberts and B. W. Roberts developed the search strategy and drafted the article. B. W. Roberts supervised all aspects of the study design and takes responsibility for the article as a whole. 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). Dr. Jones’ institution received funding from Roche Diagnostics, AstraZeneca, Janssen, and Hologic (investigator for an ongoing study). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: roberts-brian-w@cooperhealth.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Chen, Song; Wang, Xiaoyu; Zhu, Haipeng; Tang, Qin; DU, Wei; CAO, Huanhuan; LAI, Chunhui; GUO, Weizhong; FU, Linchun; LU, Wei

Background: sCD163, a biomarker of monocyte-macrophage activation, has been identified as a predictor of all-cause mortality in treated HIV-infected individuals. Nevertheless, little is known about whether different antiretroviral drugs differentially regulate sCD163 levels and monocyte activation. Methods: A total of 123 patients receiving zidovudine (ZDV)-based (n = 55) or tenofovir disoproxil fumarate (TDF)-based (n = 68) antiretroviral regimens were enrolled, and their viral loads, CD4 counts, as well as plasma sCD163 and sCD14 levels were quantified. Twenty-eight (14 in each group) patients donated additional blood samples for flow cytometry and gene expression analyses using purified monocytes. THP-1 cultures were also used to investigate the effect of ZDV on ADAM17, which is responsible for CD163 shedding. Results: As compared to the TDF-treated group, the ZDV-treated group had lower plasma sCD163 levels and higher CD163 expression on CD14++CD16- monocytes. Five metabolic-inflammatory genes exhibited significantly different expression levels between purified monocytes of the ZDV and TDF groups (IL-6, 2.90-fold lower in ZDV group, P < 0.001; iNOS, 1.81-fold higher; CX3CR1, 1.72-fold lower; MIP-1β, 1.10-fold lower; and PPARγ-1, 1.36-fold higher, P < 0.05). Moreover, we show that ZDV treatment increases the surface expression of CD163 in cultured THP-1 cells, accompanied by the inhibition of glycosylation and surface expression of ADAM17. Conclusions: Compared to TDF treatment, ZDV treatment causes lower plasma sCD163 levels, probably by inhibiting the glycosylation of ADAM17 and CD163 shedding. Our results show that ZDV functions as an ADAM17 inhibitor in vivo and extend our understanding of its immune-modulatory effects and adverse effects. Authors responsible for correspondence: LU W (louis.luwei@ird.fr); FU LC (linchunfu@gzucm.edu.cn). Potential conflicts of interest: No reported conflicts were existed. Financial support: This work was supported by the China National Major Projects of Science and Technology (2014ZX10005002), the Project for Innovation Team of Guangzhou University of Chinese Medicine (2016KYTD04), and the Dongguan Key Project for Social Science and Technology Development (2014108101025). Disclaimer: The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. * CHEN S., WANG X.Y., and ZHU H.P. contributed equally to this work. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Koethe, John R.; Jenkins, Cathy A.; Furch, Briana D.; Lake, Jordan E.; Barnett, Louise; Hager, Cindy C.; Smith, Rita; Hulgan, Todd; Shepherd, Bryan E.; Kalams, Spyros A.

Background: Obesity alters adipose tissue immunology, and these changes may be reflected in circulating soluble inflammatory biomarker and T cell subset profiles measured in HIV research studies. Methods: We recruited 70 adults with HIV (50% obese) on efavirenz, tenofovir, and emtricitabine, virologic suppression for >2 years, and no rheumatologic or other known inflammatory conditions. We measured fasting plasma levels of several markers of innate immunity and major CD4+ and CD8+ T cell subsets. We assessed relationships between measurements of total adiposity (body mass index [BMI], DEXA fat mass index [FMI], and plasma leptin) and the immunologic parameters using covariate-adjusted Spearman’s rank correlations. Results: The cohort was 43% female, 54% non-white, and median age was 45 years. Higher BMI, FMI and plasma leptin were consistently associated with higher C-reactive protein, serum amyloid A, and interleukin (IL)-6 (p

Roger Kneebone

For many clinicians, the word improvisation has a pejorative whiff—it smacks of being lazy, unprepared, or unprofessional. But improvisation is essential to clinical practice and we should prize, embrace, and practise it.

Emily K. Sims, Grace Park, Kieren J. Mather, Raghavendra G. Mirmira, Ziyue Liu, Samir K. Gupta

by Emily K. Sims, Grace Park, Kieren J. Mather, Raghavendra G. Mirmira, Ziyue Liu, Samir K. Gupta HIV infection has been associated with increased diabetes risk, but prior work has mostly focused on insulin resistance, as opposed to beta cell effects, or included patients on antiretroviral therapies (ART) directly linked to metabolic toxicity. In this analysis, we measured markers of glucose homeostasis and beta cell function, stress, and death in fasting sera from a cross section of HIV+ individuals off ART (n = 43), HIV+ individuals on ART (n = 23), and HIV- controls (n = 39). Markers included glucose, HOMA%S, HOMA%B, proinsulin:C-peptide ratio (PI:C ratio), and circulating preproinsulin (INS) DNA. We performed multiple linear regressions with adjustments for age, sex, race, BMI, and smoking status. Compared to HIV- controls, HIV+ participants off ART exhibited similar beta cell function and insulin sensitivity, without increases in markers of beta cell stress or death. Specifically, in HIV+ participants with CD4 counts…

Mischlinger J, Pitzinger P, Veletzky L, et al.

AbstractBackgroundDiagnosis of malaria is usually based on samples of peripheral blood. However, it is unclear whether capillary (CAP) or venous (VEN) blood samples provide better diagnostic performance. Quantitative differences of parasitemia between CAP and VEN blood and diagnostic performance characteristics were investigated.MethodsPatients were recruited between September 2015 and February 2016 in Gabon. Light microscopy and qPCR quantified parasitemia of paired CAP and VEN samples, whose preparation followed the exact same methodology. CAP and VEN performance characteristics using microscopy were evaluated against a qPCR gold-standard.ResultsMicroscopy revealed a median (IQR) parasites/L of 495 (853,243) in CAP and 429 (524,074) in VEN samples manifesting in a +16.6% (p=0.04) higher CAPparasitemia compared with VENparasitemia. Concordantly, qPCR demonstrated that -0.278 (p=0.006) cycles were required for signal detection in CAP samples. CAPsensitivity of microscopy relative to the gold-standard was 81.5% (77.485.6%) versus VENsensitivity of 73.4% (68.878.1%), while CAPspecificity and VENspecificity were 91%. CAPsensitivity and VENsensitivity dropped to 63.3% and 45.9%, respectively for a sub-population of low-level parasitemias while specificities were 92%.ConclusionsCAP sampling leads to higher parasitemias compared to VEN sampling and improves diagnostic sensitivity. These findings may have important implications for routine diagnostics, research and elimination campaigns of malaria.

Jain, Vageesh; Duse, Adriano; Bausch, Daniel G.

Purpose of review Less than two decades into the 21st century, the world has already witnessed numerous large epidemics or pandemics. These events have highlighted inadequacies in both national and international capacity for outbreak prevention, detection, and response. Here, we review some of the major challenges from a policy perspective. Recent findings The most important challenges facing policymakers include financing outbreak preparedness and response in a complex political environment with limited resources, coordinating response efforts among a growing and diverse range of national and international actors, accurately assessing national outbreak preparedness, addressing the shortfall in the global biomedical workforce, building surge capacity of both human and material resources, balancing investments in public health and curative services, building capacity for outbreak-related research and development, and reinforcing measures for infection prevention and control. Summary In recent years, numerous epidemics and pandemics have caused not only considerable loss of life but also billions of dollars of economic loss. Although the events have served as a wake-up call and led to the implementation of relevant policies and counter-measures, such as the Global Health Security Agenda, many questions remain and much work to be done. Wise policies and approaches for outbreak control exist, but will require the political will to implement them. Correspondence to Daniel G. Bausch, MD, MPH & TM, Director, UK Public Health Rapid Support Team (UK-PHRST), Public Health England/London School of Hygiene and Tropical Medicine, Faculty of Infectious and Tropical Diseases, Department of Disease Control, Keppel Street, London UK WC1E 7HT, United Kingdom. Tel: +44 78 10057096; e-mail: Daniel.Bausch@lshtm.ac.uk Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Sietske Kooijman, Jolanda Brummelman, Cécile A. C. M. van Els, Fabio Marino, Albert J. R. Heck, Elly van Riet, Bernard Metz, Gideon F. A. Kersten, Jeroen L. A. Pennings, Hugo D. Meiring

by Sietske Kooijman, Jolanda Brummelman, Cécile A. C. M. van Els, Fabio Marino, Albert J. R. Heck, Elly van Riet, Bernard Metz, Gideon F. A. Kersten, Jeroen L. A. Pennings, Hugo D. Meiring Aluminum-based adjuvants have widely been used in human vaccines since 1926. In the absence of antigens, aluminum-based adjuvants can initiate the inflammatory preparedness of innate cells, yet the impact of antigens on this response has not been investigated so far. In this study, we address the modulating effect of vaccine antigens on the monocyte-derived innate response by comparing processes initiated by Al(OH)3 and by Infanrix, an Al(OH)3-adjuvanted trivalent combination vaccine (DTaP), containing diphtheria toxoid (D), tetanus toxoid (T) and acellular pertussis (aP) vaccine antigens. A systems-wide analysis of stimulated monocytes was performed in which full proteome analysis was combined with targeted transcriptome analysis and cytokine analysis. This comprehensive study revealed four major differences in the monocyte response, between plain Al(OH)3 and DTaP stimulation conditions: (I) DTaP increased the anti-inflammatory cytokine IL-10, whereas Al(OH)3 did not; (II) Al(OH)3 increased the gene expression of IFNγ, IL-2 and IL-17a in contrast to the limited induction or even downregulation by DTaP; (III) increased expression of type I interferons-induced proteins was not observed upon DTaP stimulation, but was observed upon Al(OH)3 stimulation; (IV) opposing regulation of protein localization pathways was observed for Al(OH)3 and DTaP stimulation, related to the induction of exocytosis by Al(OH)3 alone. This study highlights that vaccine antigens can antagonize Al(OH)3-induced programming of the innate immune responses at the monocyte level.

Abstract Background Norovirus is a leading cause of viral gastroenteritis worldwide with a peak of disease seen in children. The epidemiological analysis regarding the virus strains in Africa is limited. The first report of norovirus in Botswana was in 2010 and currently, the prevalence and circulating genotypes of norovirus are unknown, as the country has no systems to report the norovirus cases. This study investigated the prevalence, patterns and molecular characteristics of norovirus infections among children ≤5 years of age admitted with acute gastroenteritis at four hospitals in Botswana. Methods A total of 484 faecal samples were collected from children who were admitted with acute gastroenteritis during the rotavirus vaccine impact survey between July 2013 and December 2015. Norovirus was detected using real-time RT-PCR. Positive samples were genotyped using conventional RT-PCR followed by partial sequencing of the capsid and RdRp genes. Norovirus strains were determined by nucleotide sequence analysis using the online Norovirus Genotyping Tool Version 1.0, and confirmed using maximum likelihood tree construction as implemented in MEGA 6.0. Results The prevalence of norovirus was 9.3% (95% CI 6.7–11.9). The genotype diversity was dominated by the GII.4 strain at 69.7%. This was followed by GII.2, GII.12 each at 9.1%, GI.9 at 6.6% and GII.6, GII.10 each at 3.0%. The most common combined RdRp/Capsid genotype was the GII.Pe/GII.4 Sydney 2012. Norovirus was detected during most part of the year; however, there was a preponderance of cases in the wet season (December to March). Conclusion The study showed a possible decline of norovirus infections in the last 10 years since the first report. An upward trend seen between 2013 and 2015 may be attributable to the success of rotavirus vaccine introductions in 2012. Knowledge of circulating genotypes, seasonal trends and overall prevalence is critical for prevention programming and possible future vaccine design implications.

Abstract Prupose To examine current risk behavior, awareness, experience, and attitudes towards pre-exposure-prophylaxis (PrEP), and to estimate a potential impact on the prevention of HIV transmission among HIV-negative MSM in Germany. PrEP was not officially licensed at the time of survey. Methods Web-based questionnaire from 03–06/2016. Potential participants were informed through social media, flyers, and advertisements. Risk contacts were defined as unprotected sexual intercourse under the influence of recreational drugs in the past 6 months. Results In total, 1208 subjects participated, 342 subjects were excluded for being HIV-infected or non-MSM, leaving 866 subjects to be evaluated in this analysis. Mean age was 37.0 ± 10.4 years. 593 participants (68.5%) were tested for HIV within the past 12 months. A total of 206 STDs in the past 6 months were reported by 144 (16.6%). Aware of PrEP was 748 (86.4%) respondents, while 65.1% reported willingness to use it. Risk behavior was significantly associated with higher PrEP acceptance (OR 2.90, 95% CI 2.14–3.90), as was a history of STDs (OR 1.85, 95% CI 1.17–2.91). The use of condoms would forgo 52.3% of subjects if taking PrEP. Sixty-five respondents (7.5%) reported PrEP use. Only 19 (29.2%) had accessed PrEP under medical supervision. PrEP use was reported by 14.8% with > 5 risk contacts in the past 6 months, compared to 6.3% with one risk contact (p 

Calabrese, Sarah K.; Dovidio, John F.; Tekeste, Mehrit; Taggart, Tamara; Galvao, Rachel W.; Safon, Cara B.; Willie, Tiara C.; Caldwell, Abigail; Kaplan, Clair; Kershaw, Trace S.

Background: PrEP uptake has lagged among US women. PrEP stigma is a recognized barrier to uptake among MSM but remains largely unexplored among women. This study examined the pervasiveness of PrEP stigma among US women and its implications for uptake. Setting/Methods: In a 2017 online survey of Planned Parenthood patients drawn from the three cities with the highest numbers of new HIV infections in Connecticut, 597 heterosexually-active, HIV-negative, PrEP-inexperienced women reported background characteristics, two dimensions of anticipated PrEP stigma (PrEP-user stereotypes and PrEP disapproval by others), and three indicators of potential PrEP uptake (interest in learning more about PrEP, intention to use PrEP, and comfort discussing PrEP with a provider). Results: Participants commonly perceived PrEP-user stereotypes, with many believing that others would regard them as promiscuous (37%), HIV-positive (32%), bad (14%), or gay (11%) if they used PrEP. Thirty percent would feel ashamed to disclose PrEP use. Many participants expected disapproval by family (36%), sex partners (34%), and friends (25%). In adjusted analyses, perception of PrEP-user stereotypes was uniquely associated with lower comfort discussing PrEP with a provider. Expected PrEP disapproval by others was uniquely associated with less PrEP interest, less intention to use PrEP, and less comfort discussing PrEP with a provider. Exploratory moderation analyses suggested intention to use PrEP was greatest when participants anticipated low levels of both PrEP-user stereotypes and PrEP disapproval by others. Conclusion: Findings highlight the need for positive messaging targeting potential PrEP users and their social networks to increase PrEP acceptance and uptake. Requests for reprints and other correspondence concerning this article should be addressed to Sarah K. Calabrese, 2125 G Street NW, Washington, DC 20052, USA; Email: skcalabrese@gwu.edu; Phone: 202-994-8337; Fax: N/A Disclosure: The authors report no conflicts of interest related to this work. Prior Presentation of Data: Some of the results presented in this manuscript were presented at the 12th International Conference on HIV Treatment and Prevention Adherence (Miami, FL; 6/04/17) and the CFAR Social and Behavioral Sciences Network 2017 Annual Meeting (San Francisco, CA; 10/24/17). Sources of Support: Funding for this research was provided by the Yale University Center for Interdisciplinary Research on AIDS and the National Institute of Mental Health (NIMH) via Award Number P30-MH062294. SKC was supported by the NIMH via Award Number K01-MH103080. TT was supported by the NIMH and the National Institute on Drug Abuse (NIDA) via Award Numbers T32-MH020031 and R25-DA035692, respectively. TCW was supported by the NIMH via Award Numbers F31-MH113508 and R25-MH083620. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIMH, NIDA, National Institutes of Health (NIH), or Planned Parenthood Federation of America, Inc. The authors report no conflicts of interest related to this work. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Pascal K, Dudgeon D, Trefry J, et al.

AbstractBackgroundFor most classes of drugs rapid development of therapeutics to treat emerging infections is challenged by the timelines needed to identify compounds with the desired efficacy, safety and PK profiles. Fully human monoclonal antibodies (mAbs) provide an attractive method to overcome many of these hurdles to rapidly produce therapeutics for emerging diseases.MethodsHere we deployed a platform to generate, test and develop fully human antibodies to Zaire ebolavirus. We obtained specific anti-EBOV antibodies by immunizing VelocImmune® mice that use human Ig variable regions in their humoral responses.ResultsOf the antibody clones isolated, three were selected as best at neutralizing EBOV and triggering FcRIIIa. Binding studies and negative-stain electron microscopy revealed that the three selected antibodies bind to non-overlapping epitopes, including a potentially new protective epitope not targeted by other antibody-based treatments. When combined, a single dose of a cocktail of the three antibodies protected non-human primates from EBOV disease even after disease symptoms were apparent.ConclusionsThis antibody cocktail provides complementary mechanisms of actions, incorporates novel specificities and demonstrates high-level post-exposure protection from lethal EBOV disease in NHP. It is now undergoing testing in normal healthy volunteers in preparation for potential use in future Ebola epidemics.

Abstract Background The quantitative suspension array technology (qSAT) is a useful platform for malaria immune marker discovery. However, a major challenge for large sero-epidemiological and malaria vaccine studies is the comparability across laboratories, which requires the access to standardized control reagents for assay optimization, to monitor performance and improve reproducibility. Here, the Plasmodium falciparum antibody reactivities of the newly available WHO reference reagent for anti-malaria human plasma (10/198) and of additional customized positive controls were examined with seven in-house qSAT multiplex assays measuring IgG, IgG1–4 subclasses, IgM and IgE against a panel of 40 antigens. The different positive controls were tested at different incubation times and temperatures (4 °C overnight, 37 °C 2 h, room temperature 1 h) to select the optimal conditions. Results Overall, the WHO reference reagent had low IgG2, IgG4, IgM and IgE, and also low anti-CSP antibody levels, thus this reagent was enriched with plasmas from RTS,S-vaccinated volunteers to be used as standard for CSP-based vaccine studies. For the IgM assay, another customized plasma pool prepared with samples from malaria primo-infected adults with adequate IgM levels proved to be more adequate as a positive control. The range and magnitude of IgG and IgG1–4 responses were highest when the WHO reference reagent was incubated with antigen-coupled beads at 4 °C overnight. IgG levels measured in the negative control did not vary between incubations at 37 °C 2 h and 4 °C overnight, indicating no difference in unspecific binding. Conclusions With this study, the immunogenicity profile of the WHO reference reagent, including seven immunoglobulin isotypes and subclasses, and more P. falciparum antigens, also those included in the leading RTS,S malaria vaccine, was better characterized. Overall, incubation of samples at 4 °C overnight rendered the best performance for antibody measurements against the antigens tested. Although the WHO reference reagent performed well to measure IgG to the majority of the common P. falciparum blood stage antigens tested, customized pools may need to be used as positive controls depending on the antigens (e.g. pre-erythrocytic proteins of low natural immunogenicity) and isotypes/subclasses (e.g. IgM) under study.

Fei Zhang, Qin Zhao, Keji Quan, Zhuang Zhu, Yusheng Yang, Xintian Wen, Yung-Fu Chang, Xiaobo Huang, Rui Wu, Yiping Wen, Qigui Yan, Yong Huang, Xiaoping Ma, Xinfeng Han, Sanjie Cao

by Fei Zhang, Qin Zhao, Keji Quan, Zhuang Zhu, Yusheng Yang, Xintian Wen, Yung-Fu Chang, Xiaobo Huang, Rui Wu, Yiping Wen, Qigui Yan, Yong Huang, Xiaoping Ma, Xinfeng Han, Sanjie Cao GALT is an important antigen of Actinobacillus pleuropneumoniae (APP), which was shown to provide partial protection against APP infection in a previous study in our lab. The main purpose of the present study is to investigate GALT induced cross-protection between different APP serotypes and elucidate key mechanisms of the immune response to GALT antigenic stimulation. Bioinformatic analysis demonstrated that galT is a highly conserved gene in APP, widely distributed across multiple pathogenic strains. Homologies between any two strains ranges from 78.9% to 100% regarding the galT locus. Indirect enzyme-linked immunosorbent assay (ELISA) confirmed that GALT specific antibodies could not be induced by inactivated APP L20 or MS71 whole cell bacterin preparations. A recombinant fusion GALT protein derived from APP L20, however has proven to be an effective cross-protective antigen against APP sevorar 1 MS71 (50%, 4/8) and APP sevorar 5b L20 (75%, 6/8). Histopathological examinations have confirmed that recombinant GALT vaccinated animals showed less severe pathological signs in lung tissues than negative controls after APP challenge. Immunohistochemical (IHC) analysis indicated that the infiltration of neutrophils in the negative group is significantly increased compared with that in the normal control (p

Evelyne Kestelyn, Stephen Agaba, Jennifer Ilo Van Nuil, Mireille Uwineza, Marie Michelle Umulisa, Lambert Mwambarangwe, Jean Claude Ndagijimana, Irith De Baetselier, Jozefien Buyze, Thérèse Delvaux, Tania Crucitti, Vicky Jespers, Janneke H. H. M. van de Wijgert, for the Ring Plus Study Group

by Evelyne Kestelyn, Stephen Agaba, Jennifer Ilo Van Nuil, Mireille Uwineza, Marie Michelle Umulisa, Lambert Mwambarangwe, Jean Claude Ndagijimana, Irith De Baetselier, Jozefien Buyze, Thérèse Delvaux, Tania Crucitti, Vicky Jespers, Janneke H. H. M. van de Wijgert, for the Ring Plus Study Group Background Contraceptive vaginal rings could play a role in expanding the contraceptive method mix and in preparing communities for the introduction of HIV prevention and multipurpose rings. Methods We conducted an open label single-centre randomised clinical trial of intermittent versus continuous use of NuvaRing® in Kigali, Rwanda, in 2013–2014. We randomised 120 HIV-negative women 1:1 to intermittent use (three rings with a ring-free week in between rings) or continuous use (four rings without ring-free weeks). Women underwent an interview, counselling, and a speculum examination, and were tested for pregnancy, bacterial vaginosis (BV) by Nugent scoring, yeasts and trichomonads on wet mount, and sexually transmitted infections. Findings Only one woman withdrew early. Deliberate ring removals were rare, but spontaneous ring expulsions occurred during 14% of ring use periods. There were no incident pregnancies, serious adverse events, serious social harms, or early discontinuations for safety reasons. Systemic side effects were uncommon, and local side effects were not significantly differently distributed between groups except for lower abdominal pain (P = 0.013). The incidence of vaginal yeasts during ring use was high: 22% of intermittent users and 27% of continuous users had incident vaginal yeasts at one or multiple ring removal visits (P = 0.666), and symptomatic vaginal yeast cases were more common in the continuous than intermittent users (P = 0.031). In contrast, mean Nugent scores improved over time in both groups. Conclusions Intermittent and continuous NuvaRing® use were safe in Rwandan women and improved Nugent scores over time. However, attention should be paid to ring expulsions and to a potential increased risk of vaginal candidiasis.

Vanderven H, Wragg K, Ana-Sosa-Batiz F, et al.

AbstractBackgroundNew treatments for severe influenza are needed. Passive transfer of influenza-specific hyperimmune pooled immunoglobulin (Flu-IVIG) boosts neutralising antibody responses to past strains in influenza-infected subjects. The effect of Flu-IVIG on antibodies with Fc-mediated functions, which may target diverse influenza strains, is unclear.MethodsWe studied the capacity of Flu-IVIG, relative to standard IVIG, to bind to Fc receptors and mediate antibody-dependent cellular cytotoxicity in vitro. The effect of Flu-IVIG infusion, compared to placebo infusion, was examined in serial plasma samples from 24 subjects with confirmed influenza infection in the INSIGHT FLU005 pilot study.ResultsFlu-IVIG contains higher concentrations of Fc-functional antibodies than IVIG against a diverse range of influenza hemagglutinins. Following infusion of Flu-IVIG into influenza-infected subjects, a transient increase in Fc-functional antibodies was present for 1-3 days against infecting and non-infecting strains of influenza.ConclusionsFlu-IVIG contains antibodies with Fc-mediated functions against influenza virus and passive transfer of Flu-IVIG increases anti-influenza Fc-functional antibodies in the plasma of influenza-infected subjects. Enhancement of Fc-functional antibodies to a diverse range of influenza strains suggests that Flu-IVIG infusion could prove useful in the context of novel influenza virus infections, when there may be minimal or no neutralising antibodies in the Flu-IVIG preparation.

Kato, K. C., de Morais-Teixeira, E., Islam, A., Leite, M. F., Demicheli, C., de Castro, W. V., Correa-Junior, J. D., Rabello, A., Frezard, F.

Progress towards the improvement of meglumine antimoniate (MA) commercially known as Glucantime®, a highly effective but also toxic antileishmanial drug, has been hindered by the lack of knowledge and control on its chemical composition. Here, MA was manipulated chemically with the aim of achieving an orally effective drug. MA compounds were synthesized from either antimony pentachloride (MA-SbCl5) or potassium hexahydroxyantimonate (MA-KSb(OH)6) and prepared under low polymerization state. Those were compared to Glucantime® regarding chemical composition, permeation properties across cellulose membrane and Caco-2 cell monolayer and uptake by peritoneal macrophages. MA-SbCl5 and MA-KSb(OH)6 were characterized as less polymerized and more permeable 2:2 Sb-meglumine complexes, when compared to Glucantime® that consisted in a mixture of 2:3 and 3:3 Sb-meglumine complexes. The antileishmanial activity and hepatic uptake of all compounds were evaluated after oral administration in BALB/c mice infected with Leishmania infantum chagasi, as model of visceral leishmaniasis (VL). The synthetic MA compounds given at 300 mg Sb/kg/12h for 30 days reduced significantly spleen and liver parasite burdens, in contrast to Glucantime® at the same dose. The greater activity of synthetic compounds could be attributed to their higher intestinal absorption and accumulation efficiency in the liver. MA-SbCl5 given orally was as efficacious as Glucantime® by parenteral route (80 mg Sb/kg/24h IP). This data taken altogether suggests that treatment with less polymerized form of MA by oral route may be effective for the treatment of VL.

Halsie Donaldson, Daniel Lucey

Nipah virus, within the paramyxoviridae family (Wang et al., 2001), was first identified in humans with encephalitis in the 1998-1999 outbreak in Malaysia and Singapore involving at least 276 cases and 106 deaths (Chua et al., 2000). The epidemiologic link was from fruit bats infecting pigs that then served as an amplifier host and infected humans through close contact. Person-to-person transmission was rarely documented, and no further human cases have been reported from either country. Detailed analyses of the environmental changes that triggered this outbreak connecting wildlife (bats), livestock (pigs) and humans was reported (Pulliam et al., 2012, Daszak et al., 2013).

Cristina Tintori, Giulia Iovenitti, Elisa Rita Ceresola, Roberto Ferrarese, Claudio Zamperini, Annalaura Brai, Giulio Poli, Elena Dreassi, Valeria Cagno, David Lembo, Filippo Canducci, Maurizio Botta

by Cristina Tintori, Giulia Iovenitti, Elisa Rita Ceresola, Roberto Ferrarese, Claudio Zamperini, Annalaura Brai, Giulio Poli, Elena Dreassi, Valeria Cagno, David Lembo, Filippo Canducci, Maurizio Botta Although highly active antiretroviral therapies (HAART) remarkably increased life expectancy of HIV positive people, the rate of novel HIV-1 infections worldwide still represent a major concern. In this context, pre-exposure prophylaxis (PrEP) approaches such as vaginal microbicide gels topically releasing antiretroviral drugs, showed to have a striking impact in limiting HIV-1 spread. Nevertheless, the co-presence of other genital infections, particularly those due to HSV-1 or 2, constitute a serious drawback that strongly limits the efficacy of PrEP approaches. For this reason, combinations of different compounds with mixed antiviral and antiretroviral activity are thoroughly investigated Here we report the synthesis and the biological evaluation of a novel series of rhodanine derivatives, which showed to inhibit both HIV-1 and HSV-1/2 replication at nanomolar concentration, and were found to be active also on acyclovir resistant HSV-2 strains. The compounds showed a considerable reduction of activity in presence of serum due to a high binding to serum albumin, as determined through in vitro ADME evaluations. However, the most promising compound of the series maintained a considerable activity in gel formulation, with an EC50 comparable to that obtained for the reference drug tenofovir. Moreover, the series of compounds showed pharmacokinetic properties suitable for topical formulation, thus suggesting that the novel rhodanine derivatives could represent effective agents to be used as dual anti HIV/HSV microbicides in PrEP approaches.