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

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.

Shabihah Shahrudin, Cheng Chen, Shannon C. David, Eve V. Singleton, Justin Davies, Carl D. Kirkwood, Timothy R. Hirst, Michael Beard, Mohammed Alsharifi

by Shabihah Shahrudin, Cheng Chen, Shannon C. David, Eve V. Singleton, Justin Davies, Carl D. Kirkwood, Timothy R. Hirst, Michael Beard, Mohammed Alsharifi Rotavirus (RV) causes significant morbidity and mortality in developing countries, where children and infants are highly susceptible to severe disease symptoms. While live attenuated vaccines are available, reduced vaccine efficacy in developing countries illustrates the need for highly immunogenic alternative vaccines. Here, we studied the possible inactivation of RV using gamma(γ)-irradiation, and assessed the sterility and immunogenicity of γ-irradiated RV (γ-RV) as a novel vaccine candidate. Interestingly, the inactivation curve of RV did not show a log-linear regression following exposure to increased doses of γ-rays, and consequently the radiation dose required to achieve the internationally accepted Sterility Assurance Level could not be calculated. Nonetheless, we performed sterility testing based on serial passages of γ-RV, and our data clearly illustrate the lack of infectivity of γ-RV preparations irradiated with 50 kGy. In addition, we tested the immunogenicity of 50 kGy γ-RV in mice and our data illustrate the induction of strong RV-specific neutralising antibody responses following administration of γ-RV without using adjuvant. Therefore, whilst γ-RV may not constitute a replacement for current RV vaccines, this study represents a proof-of-concept that γ-irradiation can be applied to inactivate RV for vaccine purposes. Further investigation will be required to address whether γ-irradiation can be applied to improve safety and efficacy of existing live attenuated vaccines.

CynthiaHildenbrandMS , LauraWedekindBS , GeLiPhD , Jeanne E.vonRentzellBS , KrunalShahMS , PaulRooneyBS , Amanda T.HarringtonPhD , Richard Y.ZhaoPhD

Cytomegalovirus (CMV) infection is a leading cause of loss of hearing, vision, and mental retardation in congenitally infected children. It is also associated with complications of organ transplant and opportunistic HIV coinfection. The Roche COBAS® AmpliPrep/COBAS® TaqMan® CMV test is an FDA–approved test that measures CMV DNA viral load in plasma for the diagnosis and management of patients at risk of CMV‐associated diseases. Besides plasma, CMV is often found in bronchoalveolar lavage (BAL), cerebrospinal fluid (CSF), and urine. Thus, monitoring of CMV for critical care of patients in these nonplasma samples becomes necessary. The objective of this study was to conduct an analytic and clinical feasibility study of the Roche CMV test in BAL, CSF, and urine. The lower limit of detection, analytic measurement range, assay sensitivity, specificity, and precision were determined. Results of this study showed that the lower limit of detections were 50, 100, and 300 IU/mL for BAL, CSF, or urine, respectively. The analytic measurement ranges were from log10 2.48 to log10 5.48. The assay specificity was 94.4% for BAL and 100% for CSF and urine. The assay precision was all within the acceptable range. The performance of Roche test was further compared with 2 comparators including the RealTime CMV assay (Abbott Molecular) and a CMV Quantitative Polymerase Chain Reaction test (Vela Diagnostics). There was a general positive correlation between the Roche method and the Abbott or the Vela method. Overall, this study suggests that the Roche CMV test is suitable for the quantification of CMV viral load DNA in the described nonplasma samples.

Abstract Background Malaria case management in the context of the 2014–2016 West African Ebola virus disease (EVD) epidemic was complicated by a similar initial clinical presentation of the two diseases. In September 2014, the World Health Organization (WHO) released recommendations titled, “Guidance on temporary malaria control measures in Ebola-affected countries”, which aimed at reducing the risk of EVD transmission and improving malaria outcomes. This guidance recommended malaria diagnostic testing of fever cases only if adequate personal protective equipment (PPE) was available, defined as examination gloves, face shield, disposable gown, boots, and head cover; otherwise presumptive anti-malarial treatment was recommended. The extent to which health workers adhered to these guidelines in affected countries has not been assessed. Methods A cross-sectional survey was conducted in 118 health units in Guinea in November 2014 to produce a representative and probabilistic sample of health facilities and patients. Adherence to the EVD-specific malaria case management guidelines during the height of the EVD epidemic was assessed. Associations between case management practices and possible determinants were calculated using multivariate logistic regression, controlling for expected confounders and the complex sample design. Results Most (78%) facilities reported availability of examination gloves, but adequate PPE was available at only 27% of facilities. Only 28% of febrile patients received correct malaria case management per the WHO temporary malaria case management guidelines. The most common error was diagnostic testing in the absence of adequate PPE (45% of febrile patients), followed by no presumptive treatment in the absence of adequate PPE (14%). Having had a report of an EVD case at a health facility and health worker-reported participation in EVD-specific malaria trainings were associated with lower odds of diagnostic testing and higher odds of presumptive treatment. Conclusions Adherence to guidance on malaria case management in EVD-affected countries was low at the height of the EVD epidemic in Guinea, and there was substantial malaria diagnostic testing in the absence of adequate PPE, which could have contributed to increased EVD transmission in the healthcare setting. Conversely, low presumptive treatment when diagnostic tests were not performed may have led to additional morbidity and mortality among malaria positive patients. National malaria control programs may consider preparing contingency plans for future implementation of temporary changes to malaria case management guidelines to facilitate uptake by health workers. Additional training on standard and transmission-based precautions should help health workers understand how to protect themselves in the face of emerging and unknown pathogens.…

Willie D. Taylor Jr., Gregory L. Langham, James L. Weed, Thomas Rowe, Wei Song, Kristin A. Isenberg, Xiyan Xu, David E. Wentworth, George Lathrop, Nathaniel Powell

by Willie D. Taylor Jr., Gregory L. Langham, James L. Weed, Thomas Rowe, Wei Song, Kristin A. Isenberg, Xiyan Xu, David E. Wentworth, George Lathrop, Nathaniel Powell Seasonal influenza is a contagious respiratory illness that annually affects millions of people worldwide. To identify currently circulating influenza virus subtypes, the Centers for Disease Control and Prevention’s International Reagent Resource distributes the World Health Organization (WHO) influenza reagent kits, which are used globally by testing laboratories for influenza surveillance. The data generated by the kits aid in strain selection for the influenza vaccine each season. The use of animals to produce high quality and quantities of antibodies is critical to the production of these kits. In this study, we assessed the effects and efficacy of repeated sampling from automated plasmapheresis in goats. Analysis of blood samples demonstrated that repeated automated plasmapheresis procedures did not adversely affect the immediate or long-term health of goats. Further, our results indicate that repeated plasmapheresis in goats was capable of generating 2 liters of antibody-rich plasma per goat per week. This volume is sufficient to produce enough WHO influenza kits to conduct over 1 million tests. Thus, we have shown that the rapid production of plasma in goats can positively impact the public health preparedness and response to influenza.

Lalley-Chareczko, Linden; Clark, Devon; Conyngham, S. Caitlin; Zuppa, Athena; Moorthy, Ganesh; Mounzer, Karam; Koenig, Helen

Background: Pre-exposure prophylaxis(PrEP) for HIV prevention with daily TDF/FTC is effective when taken consistently. Currently, there is no objective way to monitor PrEP adherence. Urine has been shown to be highly correlated with plasma tenofovir levels, with urine tenofovir levels >1000ng/mL demonstrating recent(1-2 days) adherence to PrEP. Setting: The present study was conducted at an urban community health center in Philadelphia, Pennsylvania. Methods: PrEP was administered to 50 young men who have sex with men and transgender women of color using weekly, biweekly, and/or monthly dispensation schedules. Primary objectives were retention at 48 weeks(in care at week 48 and completing ≥50% of medication pick-ups) and adherence assessed by urine tenofovir levels. Risk behaviors and sexually transmitted infections(STIs) diagnoses were also collected. Results: 70% of participants were retained in care at 48 weeks. The proportion of subjects with urine tenofovir consistent with recent adherence was 80%, 74.4%, 82.4%, 82.4% and 69.7% at weeks 4, 12, 24, 36, and 48 respectively. 61 STIs were diagnosed over 231 screenings throughout 48 weeks, with no significant change between the first and second 24-week periods (p=0.43; 0 seroconversions). At week 48, more than half of subjects reported an increase or no change in condom use, an increase in their ability to discuss HIV with partners, and no change in number of sexual partners from baseline. Conclusions: These data demonstrate PrEP can be successfully delivered to a high-risk population with high program retention and medication adherence measured by urine tenofovir levels. Corresponding author: Linden Lalley-Chareczko, 1233 Loucst St, 5th Floor, Philadelphia, PA 19107, Tel: 215-525-8695; Fax: 215-985-4954, email: lchareczko@fight.org The authors report no conflicts of interest related to this work. These data were presented at the Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017 in Seattle, Washington, abstract #975. This research was funded by Gilead Sciences, Inc. Funds were used for medical equipment and supplies, patient stipends, and clinical analyses. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Sirikamon Koosakulnirand, Phornpun Phokrai, Kemajittra Jenjaroen, Rosemary A. Roberts, Pongsak Utaisincharoen, Susanna J. Dunachie, Paul J. Brett, Mary N. Burtnick, Narisara Chantratita

by Sirikamon Koosakulnirand, Phornpun Phokrai, Kemajittra Jenjaroen, Rosemary A. Roberts, Pongsak Utaisincharoen, Susanna J. Dunachie, Paul J. Brett, Mary N. Burtnick, Narisara Chantratita Burkholderia pseudomallei is a flagellated Gram-negative bacterium which is the causative agent of melioidosis. The disease poses a major public health problem in tropical regions and diabetes is a major risk factor. The high mortality rate of melioidosis is associated with severe sepsis which involves the overwhelming production of pro-inflammatory cytokines. Bacterial flagellar protein (flagellin) activates Toll-like receptor 5 (TLR5)-mediated innate immune signaling pathways and induces adaptive immune response. However, previous studies of TLR5 signaling in melioidosis have been performed using recombinant flagellin from Salmonella Typhimurium instead of B. pseudomallei. This study aimed to investigate human innate immune response and antibody response against a recombinant B. pseudomallei flagellin (rFliC). We prepared B. pseudomallei rFliC and used it to stimulate HEK-BlueTM-hTLR5 and THP1-DualTM cells to assess TLR5 activation. Subsequently, whole blood stimulation assays with rFliC were performed ex vivo. TLR5-flagellin interactions trigger activation of transcription factor NF-κB in HEK-BlueTM-hTLR5 cells. Pro-inflammatory cytokine (IL-1β, IL-6, and TNF-α) productions from whole blood in response to rFliC differed between fourteen healthy individuals. The levels of these cytokines changed in a dose and time-dependent manner. ELISA was used to determine rFliC-specific antibodies in serum samples from different groups of melioidosis patients and healthy subjects. IgG antibody to rFliC in melioidosis patients with diabetes were higher compared with non-diabetic patients. Our results show that B. pseudomallei flagellin is a potent immune stimulator and that the immune responses to rFliC are different among individuals. This may provide valuable insights toward the potential use of rFliC in vaccine development.

Corien Swaan, Anouk van den Broek, Mirjam Kretzschmar, Jan Hendrik Richardus

by Corien Swaan, Anouk van den Broek, Mirjam Kretzschmar, Jan Hendrik Richardus Introduction Timely notification of infectious diseases is crucial for prompt response by public health services. Adequate notification systems facilitate timely notification. A systematic literature review was performed to assess outcomes of studies on notification timeliness and to determine which aspects of notification systems are associated with timely notification. Methodology Articles reviewing timeliness of notifications published between 2000 and 2017 were searched in Pubmed and Scopus. Using a standardized notification chain, timeliness of reporting system for each article was defined as either sufficient (≥ 80% notifications in time), partly sufficient (≥ 50–80%), or insufficient (< 50%) according to the article’s predefined timeframe, a standardized timeframe for all articles, and a disease specific timeframe. Electronic notification systems were compared with conventional methods (postal mail, fax, telephone, email) and mobile phone reporting. Results 48 articles were identified. In almost one third of the studies with a predefined timeframe (39), timeliness of notification systems was either sufficient or insufficient (11/39, 28% and 12/39, 31% resp.). Applying the standardized timeframe (45 studies) revealed similar outcomes (13/45, 29%, sufficient notification timeframe, vs 15/45, 33%, insufficient). The disease specific timeframe was not met by any study. Systems involving reporting by laboratories most often complied sufficiently with predefined or standardized timeframes. Outcomes were not related to electronic, conventional notification systems or mobile phone reporting. Electronic systems were faster in comparative studies (10/13); this hardly resulted in sufficient timeliness, neither according to predefined nor to standardized timeframes. Conclusion A minority of notification systems meets either predefined, standardized or disease specific timeframes. Systems including laboratory reporting are associated with timely notification. Electronic systems reduce reporting delay, but implementation needs considerable effort to comply with notification timeframes. During outbreak threats, patient, doctors and laboratory testing delays need to be reduced to achieve timely detection and notification. Public health authorities should incorporate procedures for this in their preparedness plans.…

Campos, Nicole G.; Lince-Deroche, Naomi; Chibwesha, Carla J.; Firnhaber, Cynthia; Smith, Jennifer S.; Michelow, Pam; Meyer-Rath, Gesine; Jamieson, Lise; Jordaan, Suzette; Sharma, Monisha; Regan, Catherine; Sy, Stephen; Liu, Gui; Tsu, Vivien; Jeronimo, Jose; Kim, Jane J.

Background: Women with HIV face an increased risk of human papillomavirus (HPV) acquisition and persistence, cervical intraepithelial neoplasia, and invasive cervical cancer. Our objective was to determine the cost-effectiveness of different cervical cancer screening strategies among women with HIV in South Africa. Methods: We modified a mathematical model of HPV infection and cervical disease to reflect co-infection with HIV. The model was calibrated to epidemiologic data from HIV-infected women in South Africa. Clinical and economic data were drawn from in-country data sources. The model was used to project reductions in the lifetime risk of cervical cancer and incremental cost-effectiveness ratios (ICERs) of Pap and HPV DNA screening and management algorithms beginning at HIV diagnosis, at one-, two-, or three-year intervals. Strategies with an ICER below South Africa’s 2016 per capita GDP (US$5,270) were considered ‘cost-effective.’ Results: HPV testing followed by treatment (test-and-treat) at two-year intervals was the most effective strategy that was also cost-effective, reducing lifetime cancer risk by 56·6% with an ICER of US$3,010 per year of life saved (YLS). Other cost-effective strategies included Pap (referral threshold: HSIL+) at one-, two-, and three-year intervals, and HPV test-and-treat at three-year intervals. Pap (ASCUS+), HPV testing with 16/18 genotyping, and HPV testing with Pap or visual triage of HPV-positive women were less effective and more costly than alternatives. Conclusion: Considering per capita GDP as the benchmark for cost-effectiveness, HPV test-and-treat is optimal in South Africa. At lower cost-effectiveness benchmarks, Pap (HSIL+) would be optimal. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Corresponding author: Nicole G. Campos, Center for Health Decision Science, 718 Huntington Avenue, Boston, MA 02115; Phone: 617-432-2019; Fax: 617-432-0190; E-mail: ncampos@hsph.harvard.edu Conflicts of Interest and Source of Funding: This study was funded by the US National Cancer Institute (U01CA199334) and The Bill & Melinda Gates Foundation (OPP1086544). The funders had no role in study design; data collection, analysis, or interpretation; decision to publish; or preparation of the manuscript. The costing work that preceded this study was made possible by the generous support of the American people through the United States Agency for International Development (USAID), award number AID-674-A-12-00029. The contents are the responsibility of the Health Economics and Epidemiology Research Office, a Division of the Wits Health Consortium (Pty) Ltd and do not necessarily reflect the views of USAID or the United States Government. NGC reports grants from the Bill & Melinda Gates Foundation during the conduct of the study. NLD has nothing to disclose. CJC has nothing to disclose. CF has nothing to disclose. JSS has nothing to disclose. PM has nothing to disclose. GMR has nothing to disclose. LJ has nothing to disclose. SJ has nothing to disclose. MS has nothing to disclose. CR reports grants from the Bill & Melinda Gates Foundation during the conduct of the study. SS reports grants from the Bill & Melinda Gates Foundation during the conduct of the study. GL has nothing to disclose. VT reports grants from the Bill & Melinda Gates Foundation during the conduct of the study. JJ was a consultant for Qiagen Inc. and Global Good Fund I, LLC; he was the co-owner and Deputy Manager of Onco Prev International, a Peruvian company, from 2012 through March 2017. Onco Prev International offers cervical cancer screening services and in 2016 also began positioning for distribution of medical devices including colposcopes and the Liger thermocoagulator. Onco Prev International did not commercialize any medical instrument during the time JJ was part of the company. JJK reports grants from the Bill & Melinda Gates Foundation during the conduct of the study. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Pasipanodya E, Jain S, Sun X, et al.

AbstractBackgroundAdherence is necessary for efficacy of pre-exposure prophylaxis (PrEP) and text-messaging methodologies are promising, both for adherence assessment and support. Although PrEP adherence is variable, little research has examined patterns of variability or factors associated with longitudinal use.MethodsIn the context of a randomized controlled trial of text-messaging versus standard of care for PrEP adherence, 181 men who have sex with men received once-daily tenofovir disoproxil fumarate/emtricitabine and daily adherence texts for 48 weeks. Growth Mixture Modeling (GMM) was used to identify subgroups of individuals with similar trajectories of text-reported adherence. Between-group differences in pharmacologic measures of adherence (tenofovir diphosphate and emtricitabine triphosphate), as well as predictors and study-end attitudes associated with group membership, were examined.ResultsGMM identified four trajectories of text-reported adherence. Classes with higher text-reported adherence had higher drug concentrations. Younger age and minority race were associated with lower adherence and individuals in classes with lower adherence had greater baseline levels of depression, substance use concerns, and sexual risk. Differences in study satisfaction were also associated with adherence.ConclusionThis study supports the use of text-reported PrEP adherence; identifying factors associated with less-than-optimal adherence may aid clinicians in anticipating at-risk patients requiring augmented intervention.RegistrationNCT01761643. https://clinicaltrials.gov/ct2/show/NCT01761643…

Xia Wang, Adam Bourne, Pulin Liu, Jiangli Sun, Thomas Cai, Gitau Mburu, Matteo Cassolato, Bangyuan Wang, Wang Zhou

by Xia Wang, Adam Bourne, Pulin Liu, Jiangli Sun, Thomas Cai, Gitau Mburu, Matteo Cassolato, Bangyuan Wang, Wang Zhou Background Oral pre-exposure prophylaxis (PrEP) is recommended as an additional prevention choice for men who have sex with men (MSM) at substantial risk of HIV. The aim of this study was to evaluate the extent, and reasons, for MSM’s willingness to use oral PrEP in Wuhan and Shanghai, China. Methods Between May and December 2015, a cross-sectional survey was conducted among 487 MSM recruited through snowball sampling in physical locations frequented by MSM and through social media applications. Exploratory factor analysis was used to group reasons for being willing or not willing to use PrEP. Chi-square tests were used to explore bivariate associations between groupings of reasons for being willing or unwilling to use PrEP, and key sociodemographic and sexual-behavioral characteristics of MSM. Results Overall, 71.3% of respondents were willing to use PrEP. The most commonly reported reasons for being willing to use PrEP were preventing HIV infection (91.6%), taking responsibility for own sexual health (72.6%) and protecting family members from harm (59.4%). The main reasons for being unwilling to use PrEP were being worried about side effects (72.9%), the necessity of taking PrEP for long periods of time (54.3%) and cost (40.4%). Individual characteristics that influenced the type of reasons given for being willing or unwilling to use PrEP included being married to a woman, having a regular sex partner, rates of condom use with regular and casual sex partners, and the number of casual sex partners. Conclusion The introduction of PrEP in China could benefit from promotion campaigns that emphasize its role in preventing HIV infection, in taking responsibility for own sexual health, and in protecting family members from potential harm. To reduce uptake barriers, it will be essential to provide accurate information to potential PrEP users about the mild and short-term nature of side effects, and the possibility of taking PrEP only during particular periods of life when the risk of HIV exposure might be highest.…

Abramowitz S, Hipgrave D, Witchard A, et al.

AbstractThis systematic literature review compared the epidemiological (EPI) research and the qualitative social and behavioral science (SBS) research published during the West Africa Ebola virus disease (EVD) epidemic. Beginning with an initial capture of over 2,000 articles, we extracted 236 EPI and 171 SBS studies to examine how disciplinary priorities affected research conducted during the EVD response, with implications for epidemic response effectiveness. Building on this research, we set forth a roadmap for the closer integration of EPI and SBS research in all aspects of epidemic preparedness and response that incorporates the lessons of the West Africa EVD outbreak. Key priorities include: (1) developing the capacity to systematically quantify qualitative sociocultural variables, (2) establishing interdisciplinary collaborations to improve “risk segmentation” practices, (3) creating and pre-positioning qualitative indicators and composite sociocultural indexes for rapid deployment in outbreaks; (4) integrating novel systems with community resources; (5) developing new techniques for modeling social mobilization and community engagement; (6) prioritizing good data and complex analyses early in emergencies, and (7) learning from past experiences. Our findings support a program of action that situates data collection and analysis in real-time, recursive, integrated efforts to move community attitudes, behaviors, and responses into epidemiological research.

Fuentes S, Ravichandran S, Khurana S.

AbstractSeveral Ebola vaccines and therapeutics are under clinical development. However, limited knowledge exists on the quality of antibody response generated by different Ebola vaccines. In this study, antibody repertoire induced by vaccination of transchromosomal bovine (TcB) with Ebola virus (EBOV) glycoprotein ([GP]; recombinant GP [rGP]) encoded by either deoxyribonucleic acid (DNA) or nanoparticle-based vaccine platform was analyzed using EBOV genome fragment phage display library and surface plasmon resonance (SPR)-based real-time kinetics assay to measure antibody affinity maturation to both native and partially denatured Ebola GP as well as GP containing the receptor binding domain but lacking the mucin-like domain. Immunoglobulin (IgG) obtained from rGP nanoparticle-vaccinated TcB demonstrated ~4-fold higher binding affinity compared with DNA-vaccinated TcB-induced IgG against the native rGP’s. The rGP nanoparticle vaccine generated a more robust and diverse antibody immune response to the native EBOV-GP compared with the DNA vaccine, which may explain the protective efficacy observed for these antibody preparations.

Hickmann, Cheryl E.; Castanares-Zapatero, Diego; Deldicque, Louise; Van den Bergh, Peter; Caty, Gilles; Robert, Annie; Roeseler, Jean; Francaux, Marc; Laterre, Pierre-François

Objectives: As the catabolic state induced by septic shock together with the physical inactivity of patients lead to the rapid loss of muscle mass and impaired function, the purpose of this study was to test whether an early physical therapy during the onset of septic shock regulates catabolic signals and preserves skeletal muscle mass. Design: Randomized controlled trial. Setting: Tertiary mixed ICU. Patients: Adult patients admitted for septic shock within the first 72 hours. Interventions: Patients were assigned randomly into two groups. The control group benefited from manual mobilization once a day. The intervention group had twice daily sessions of both manual mobilization and 30-minute passive/active cycling therapy. Measurements and Main Results: Skeletal muscle biopsies and electrophysiology testing were performed at day 1 and day 7. Muscle biopsies were analyzed for histology and molecular components of signaling pathways regulating protein synthesis and degradation as well as inflammation markers. Hemodynamic values and patient perception were collected during each session. Twenty-one patients were included. Three died before the second muscle biopsy. Ten patients in the control and eight in the intervention group were analyzed. Markers of the catabolic ubiquitin-proteasome pathway, muscle atrophy F-box and muscle ring finger-1 messenger RNA, were reduced at day 7 only in the intervention group, but without difference between groups (muscle atrophy F-box: –7.3% ± 138.4% in control vs –56.4% ± 37.4% in intervention group; p = 0.23 and muscle ring finger-1: –30.8% ± 66.9% in control vs –62.7% ± 45.5% in intervention group; p = 0.15). Muscle fiber cross-sectional area (µm2) was preserved by exercise (–25.8% ± 21.6% in control vs 12.4% ± 22.5% in intervention group; p = 0.005). Molecular regulations suggest that the excessive activation of autophagy due to septic shock was lower in the intervention group, without being suppressed. Markers of anabolism and inflammation were not modified by the intervention, which was well tolerated by the patients. Conclusions: Early physical therapy during the first week of septic shock is safe and preserves muscle fiber cross-sectional area. 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. This work was performed at ICU, Saint Luc university hospital, Université catholique de Louvain (UCL), Brussels, Belgium. Clinical trial registered with www.clinicaltrials.gov (NCT01787045). 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 funds from the “Department of Critical Care Medicine of Saint Luc University Hospital.” During study inclusions, the ICU received a lending from RECK-Technik GmbH & Co. (KG, 88422 Betzenweiler, Germany) of the motorized cycling device MOTOmed Viva2 with MOTOmed sam2 training analysis program. Drs. Hickman and Laterre disclosed that, during study inclusions, the ICU received a lending from RECK-Technik GmbH & Co. (KG, 88422 Betzenweiler, Germany) of the motorized cycling device MOTOmed Viva2 with MOTOmed sam2 training analysis program (the company RECK-Technik GmbH & Co had no role in the study design, conduction of the study, analyses, and article preparation). The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Pierre-François Laterre, MD, ICU, Department of Critical Care Medicine, Saint Luc University Hospital, Université catholique de Louvain (UCL), Avenue Hippocrate 10, 1200 Brussels, Belgium. E-mail: pierre-francois.laterre@uclouvain.be Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Roux, P; Fressard, L; Suzan-Monti, M; Chas, J; Sagaon-Teyssier, L; Capitant, C; Meyer, L; Tremblay, C; Rojas-Castro, D; Pialoux, G; Molina, JM; Spire, B

Background: Chemsex - the use of psychoactive substances during sexual encounters - among men who have sex with men (MSM) is a growing concern. On-demand HIV pre-exposure prophylaxis (PrEP) may be a suitable tool to prevent HIV transmission among “chemsexers”. We used the Open Label extension study of the ANRS-IPERGAY trial to describe chemsexers and their PrEP use. Methods: Among the 361 MSM enrolled in ANRS-IPERGAY’s open-label extension study, we selected the 331 with available data on drug use. A two-monthly web questionnaire on socio-behavioural data was used to compare sexual behaviours between questionnaires where chemsex was reported and those where it was not. Using a GEE logistic regression, we studied whether practicing chemsex was associated with correct PrEP use. Results: Among the 331 participants, 30% reported chemsex practice at least once during follow-up and were considered chemsexers. Chemsex was reported in 16% of all questionnaires. Chemsexers were not significantly different from non-chemsexers regarding sociodemographic characteristics, although they reported greater use of anxiolytics and more sensation seeking. Reporting chemsex was associated with more high-risk sexual practices and a higher perception of risk. After adjustment for other potential correlates, chemsex remained associated with correct PrEP use (OR[95%CI=2.24 [1.37;3.66]). Conclusion: Our findings show that chemsexers were more likely to report high-risk sexual practices but also had a higher perception of risk. They were also more likely to use PrEP correctly when practicing chemsex. Consequently, PrEP may be a suitable tool to reduce HIV risk transmission among chemsexers. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. Corresponding author: Roux Perrine, INSERM U1252 – SESSTIM, 27 bd Jean Moulin, 13005 Marseille, France. +33 4 13 73 22 78: + 33 4 96 10 28 99@: perrine.roux@inserm.fr Competing interests: JC has received consulting fees from Gilead, Abbvie and BMS. CT reports receiving support from Gilead Sciences and Pfizer. GP has received consulting fees from BMS, Boehringer Ingelheim, Tibotec, Nephrotek, Gilead Sciences, Roche, MSD, Abbott, and ViiV Healthcare, and research grants from BMS and Gilead Sciences. J-MM reports receiving support as an adviser for Gilead Sciences, Merck, Janssen, Bristol–Myers Squib (BMS), and ViiV Healthcare, and research grants from Gilead Sciences and Merck. BS reports receiving support as an adviser for Gilead Sciences, Merck, Janssen, and BMS, and research grants from Gilead Sciences and Merck. All other authors declare no competing interests. Authors’ contributions: J-MM, BS, S-MM, CJ, CC, LM, CT, DR-C and GP participated in the conception and the design of the study. PR and LF designed the analysis. LS-T, LF and PR analysed the data. PR coordinated the analysis and oversaw data management. PR drafted the first version of the manuscript. All authors critically reviewed and approved the manuscript. Disclosure of funding: This study was supported by ANRS, the Canadian HIV Trials Network, the Fonds de Dotation Pierre Bergé pour la Prévention, and the Bill and Melinda Gates Foundation. Gilead Sciences donated the TDF-FTC and placebo used in the study, and partly?? fundeding for the pharmacokinetics analysis. Conference oral presentation: 9th International AIDS Conference in Paris, 23-26 July 2017. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Daniela Gonzalez, Jorge Ragusa, Peter C. Angeletti, Gustavo Larsen

by Daniela Gonzalez, Jorge Ragusa, Peter C. Angeletti, Gustavo Larsen In this study, heparin-loaded poly-ɛ-caprolactone (PCL) fibrous mats were prepared and characterized based on their physical, cytotoxic, thermal, and biological properties. The main objective of the work described here was to test the hypothesis that incorporation of heparin into a PCL carrier could serve as bio-compatible material capable of inhibiting Human Papillomavirus (HPV) infection. The idea of firmly anchoring heparin to capture soluble virus, vs. a slow heparin release to inhibit a virus in solution was tested. Thus, one material was produced via conventional heparin matrix encapsulation and electrohydrodynamic fiber processing in one step. A second type of material was obtained via heparin crosslinking. This was achieved by running a carbodiimide/N-hydroxysuccinimide (EDC/NHS) coupling reaction on preformed PCL fibers. In vitro HPV16 L1 protein binding capacity studies were performed. Infectivity assays were done using HPV16 pseudoviruses (PsVs) carrying a GFP plasmid to directly test the ability of the fibrous mats to prevent internalization of HPV PsVs. The crosslinked heparin material presented a dissociation constant (Kd) value comparable to those found in the literature for different heparin-protein L1 peptide interactions. Both materials significantly reduced internalization of HPV PsVs, with a reduction of 94% of PsVs internalization when matrix encapsulated heparin-loaded material was present. Differences in performance between the two proposed structures are discussed.

Reyniers, Thijs; Nöstlinger, Christiana; Laga, Marie; De Baetselier, Irith; Crucitti, Tania; Wouters, Kristien; Smekens, Bart; Buyze, Jozefien; Vuylsteke, Bea

Background: Daily and event-driven Pre-Exposure Prophylaxis (PrEP) are efficacious in reducing HIV transmission among men who have sex with men (MSM). We analysed baseline data from a PrEP demonstration project ‘Be-PrEP-ared’ in Antwerp, Belgium to understand preferences for daily or event-driven PrEP among MSM at high risk for HIV, and factors influencing their initial choice. Methods: Cross-sectional data from an open-label prospective cohort study, using mixed methods. Participants who pre-registered online were screened for eligibility and tested for sexually transmitted infections (STIs). Eligible participants chose between daily and event-driven PrEP and reported on behavioural data through an electronic questionnaire. In-depth interviews were conducted with a selected sub-sample. Bivariate associations were examined between preferred PrEP regimens and sociodemographic factors, sexual behaviour, and STIs at screening. Results: In total, 200 participants were enrolled between October 2015 and December 2016. Self-reported levels of sexual risk-taking before enrolment were high. STI screening revealed that 39.5% had at least one bacterial STI. At baseline, 76.5% of participants preferred daily and 23.5% event-driven PrEP. Feeling able to anticipate HIV risk was the most frequent reason for preferring event-driven PrEP. Regimen choice was associated with sexual risk-taking behaviour in the last three months. Almost all participants (95.7%) considered it likely that they would change their dosing regimen the following year. Conclusion: Event-driven PrEP was preferred by 23.5% of the participants, which better suits their preventive needs. Event-driven PrEP should be included in PrEP provision as a valuable alternative to daily PrEP for MSM at high risk for HIV. Corresponding Author: Dr. Thijs Reyniers, Department of Public Health, Institute of Tropical Medicine, Nationalestraat 155, 2000 Antwerp, Belgium, Email: treyniers@itg.be, telephone: +32 247 65 39 Conflict of Interest and Source of Funding: A grant was obtained from the Flemish Agency for Innovation and Entrepreneurship. Gilead Sciences donated the drugs (Truvada) for the study. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Jonathan S. Schultz, Adam J. Atherly and Andrés F. Henao-Martínez

Abstract. Uninsured and unprepared travelers to countries with endemic tropical diseases pose great health-care burdens and financial risks on returning to the United States. We discuss the delayed presentation of an uninsured U.S. traveler returning from West Africa with severe malaria who required intensive care measures to save his life. Despite being critically ill on his return, he sat rigoring on his couch taking antipyretics for 3 days, while he applied for insurance on the Affordable Care Act website and waited for approval because he was fearful of the costs of seeking care. He also had limited access to affordable pretravel consultation and prophylactic medications and did not take them because he had no insurance. Average fees for a malaria hospitalization cost $25,789; however, this patient accumulated fees nearing $300,000—and his care was reimbursed by emergency Medicaid with $39,000, because his newly accepted insurance did not cover his hospitalization. This patients’ experience in the U.S. health-care system with a deadly tropical disease exemplifies the need for affordable universal coverage of pretravel consultation and malaria prophylaxis. In this uncertain political time and the recent removal of the health insurance mandate, along with the White House and Congress wanting to reform health care, this case supports the American Society of Tropical Medicine and Hygiene (ASTMH) statements showing the need for funding of tropical medicine education, research, and public health services for travelers, not cuts to important agencies and insurances that keep our country safe from imported deadly tropical diseases.…

Thomas Weitzel, Ju Jiang, Gerardo Acosta-Jamett, Constanza Martínez-Valdebenito, Javier López, Allen L. Richards, Katia Abarca

by Thomas Weitzel, Ju Jiang, Gerardo Acosta-Jamett, Constanza Martínez-Valdebenito, Javier López, Allen L. Richards, Katia Abarca Background Scrub typhus is a potentially life-threatening vector-borne infection caused by Orientia species. It occurs mainly in the Asian-Pacific region, where it causes significant morbidity and mortality. Recently, an endemic focus of scrub typhus has been described in South America, on Chiloé Island in southern Chile. Dogs have been used as sentinel hosts to determine the presence and spatial distribution of various vector-borne infections. Their suitability to gain insight into human exposure to Orientia tsutsugamushi has been suggested in studies from Asia. Methodology In January 2016, we conducted a cross-sectional study, which included the two main cities on Chiloé Island. Canine blood samples were obtained in households, chosen by double stratified random sampling in urban and by convenience in rural locations. Specimens were tested by ELISA for IgG antibodies against whole-cell antigen preparations from three strains of O. tsutsugamushi. Data were further analyzed for factors associated with seropositivity including spatial clustering. Results Serum samples from 202 dogs (104 urban, 98 rural) were tested for IgG against O. tsutsugamushi, of which 43 (21.3%) were positive. Seroprevalence rates were higher in rural than in urban settings (p…

Bassett, Ingrid V.; Xu, Ai; Govere, Sabina; Thulare, Hilary; Frank, Simone C.; Psaros, Christina; Parker, Robert A.

No abstract available…

Jason R. Gantenberg, Maximilian King, Madeline C. Montgomery, Omar Galárraga, Mattia Prosperi, Philip A. Chan, Brandon D. L. Marshall

by Jason R. Gantenberg, Maximilian King, Madeline C. Montgomery, Omar Galárraga, Mattia Prosperi, Philip A. Chan, Brandon D. L. Marshall Objectives Identifying prescribing strategies that improve the efficiency of PrEP should increase its impact at the population level. This study identifies PrEP allocation criteria that most effectively reduce 10-year HIV incidence by 25%, in accordance with the US National HIV/AIDS Strategy’s goal for the proportionate reduction in new diagnoses. Methods We used a discrete-time stochastic agent-based model to simulate several PrEP engagement strategies. The model represented MSM aged 15–74 in Rhode Island and was calibrated to statewide prevalence from 2009–2014. We simulated HIV transmission in the absence of PrEP and compared the following PrEP engagement scenarios: 1) allocation to the current patient population; 2) random allocation; 3) allocation to MSM with greater than 5 sexual partners in one year; 4) allocation to MSM with greater than 10 sexual partners in one year.For each scenario and coverage level we estimated the number and proportion of infections averted and the person-years on PrEP per averted infection. Results In 2014, HIV prevalence before PrEP implementation was between 4% and 5%. In the No PrEP scenario 826 new infections (95% simulation limits [SL]: 711, 955) occurred over 10 years, with an incidence rate of 3.51 per 1000 person-years (95% SL: 3.00, 4.08). Prevalence rose to 7.4% (95% SL: 6.7, 8.1). None of the PrEP scenarios reduced new HIV infections by 25% while covering less than 15% of the HIV-uninfected population. At 15% coverage, allocating PrEP to the current patient population, MSM with greater than 5 sexual partners in a year, and MSM with greater than 10 partners reduced new infections by at least 25%, requiring 161 (95% SL: 115, 289), 150 (95% SL: 107, 252), and 128 (95% SL: 100, 184) person-years on PrEP per averted infection, respectively. Conclusions Engaging MSM with high numbers of sexual partners would improve the population-level impact and efficiency of PrEP in settings where PrEP coverage remains low. However, the sustained population-level PrEP coverage needed to reduce new infections by 25% is substantially higher than current levels of PrEP uptake.…

Noret, Marion; Balavoine, Stéphanie; Noret, Marion; Pintado, Claire; Siguier, Martin; Brun, Alexandre; Bauer, Rebecca; Loze, Bénédicte; Leplatois, Anne; Aslan, Alexandre; Moudachirou, Khafil; Delaugerre, Constance; Rozenbaum, Willy; Molina, Jean-Michel

Background: On Demand oral TDF/FTC has been approved for pre-exposure prophylaxis (PrEP) in men who have sex with men (MSM) in France following the results of clinical studies but data are limited on real-world experience. Design: A single center, open-label, prospective cohort study that recruited people at high risk of HIV infection in Paris. Methods: Subjects were enrolled in a single hospital-based outpatient clinic and were proposed to start PrEP with daily or on demand TDF/FTC. At baseline and every 3 months thereafter subjects were tested for HIV and creatinine plasma levels and data on sexual behavior, other sexually transmitted infections (STIs), and tolerability were collected. Results: From November 10, 2015 to April 30, 2017, 1069 subjects were screened and 1049 (98.1%) started PrEP. Median age was 36 years, 99.4% were MSM with a median number of partners of 10, and 793 (75.6%) opted for on demand PrEP. Over 486 person-years (PY) of follow-up, 4 HIV-infection were diagnosed in poorly or non-adherent subjects (incidence: 0.82/100 PY). Rate of condomless sex at last intercourse increased from 53.3% at baseline to 79% at month 12 (p …

Monogue, M. L., Giovagnoli, S., Bissantz, C., Zampaloni, C., Nicolau, D. P.

Urinary tract infections (UTIs) are a tremendous burden to the healthcare system due to the vast number of infections resulting in antibiotic therapy and/or hospitalization. Additionally, these infections are frequently caused by multi-drug resistant (MDR) organisms, limiting the availability of effective antimicrobials. Nacubactam is a novel non-β-lactam-β-lactamase inhibitor with in vitro activity against class A and class C β-lactamases. Nacubactam is being developed in combination with meropenem, providing broad-spectrum activity in addition to improved stability against common β-lactamases. Herein, we utilized a neutropenic murine complicated UTI (cUTI) model to determine the potential clinical utility of meropenem-nacubactam compared with meropenem and nacubactam alone against 10 K. pneumoniae, E. coli, and E. cloacae isolates with diverse genotypic and phenotypic profiles, including NDM, KPC, OXA, CTX-M, SHV, and TEM producing enzymes. Selected isolates had meropenem-nacubactam MICs between 1-8 μg/mL. Meropenem-nacubactam demonstrated the greatest in vivo efficacy against 9 of 10 isolates, achieving ≥ 3 log reduction from 48h control in all isolates tested, including isolates prepared as high inoculums. Nacubactam alone confirmed anti-bacterial properties, achieving > 1 log reduction against the majority of isolates. The combination of meropenem-nacubactam further enhanced the activity of either agent alone, notably against meropenem-resistant isolates. Against ceftazidime-avibactam resistant isolates, meropenem-nacubactam demonstrated antibacterial kill upwards of 6 log10 CFU from 48h control. Our data support the potential clinical utility of meropenem-nacubactam for cUTI in man against MDR Enterobacteriaceae, although further clinical data supporting meropenem-nacubactam efficacy are needed.…

Smith, R. A., Wu, V. H., Zavala, C. G., Raugi, D. N., Ba, S., Seydi, M., Gottlieb, G. S., for the University of Washington-Dakar HIV-2 Study Group

We examined the antiviral activity of the integrase inhibitor (INI) cabotegravir against HIV-2 isolates from INI-naïve individuals. HIV-2 was sensitive to cabotegravir in both single-cycle and spreading infection assays, with EC50 values in the low to sub-nanomolar range; comparable results were obtained for HIV-1 in both assay formats. Our findings suggest that cabotegravir should be evaluated in clinical trials as a potential option for ART and PrEP in HIV-2–prevalent settings.…

Davey R, Jr, Dodd L, Proschan M, et al.

AbstractBackgroundThe 2013–2016 outbreak of Ebola virus disease (EVD) in West Africa led to unprecedented morbidity and mortality. Although different classes of putative antiviral agents with supportive preclinical data were available for testing, and although several attempts to perform meaningful evaluation of these agents were undertaken during the epidemic, different research methods, a lack of appropriate controls in most studies, and formidable logistical challenges to completion of studies under field conditions hampered the success of these efforts. Ultimately only 1 randomized, placebo-controlled clinical trial (PREVAIL II) was performed in this setting, and, owing to a decrease in the number of new cases available for study, it, too, ended prior to reaching definitive results. Retrospective review of the lessons learned from this outbreak argues strongly for the need for much better preparedness in terms of selecting the trial design and drug(s) for use during the next outbreak.MethodsUsing recent data provided by representatives from the pharmaceutical industry, clinical and laboratory subject matter experts from the National Institute of Allergy and Infectious Diseases, other US government agencies, and academic partners were consulted regarding the current state of knowledge about several lead compounds with putative activity against EVD. Consensus was sought on recommendations concerning the most promising treatment strategies against EVD that should be studied in the context of a randomized clinical trial during the next outbreak.ResultsFour compounds from 2 different classes (monoclonal antibody [mAb] cocktails and direct-acting antiviral agents [DAAs]) were highlighted as lead candidates, limitations in the current knowledge base about these drug classes were reviewed, and recommendations about the optimal clinical research design for studying combinations of these different agents were made.ConclusionsAlthough achieving the desired sample size could be challenging, a randomized, controlled clinical trial based on a combination strategy of a mAb with a DAA was recommended as the most appropriate clinical trial design to be undertaken during the next outbreak of EVD.

Goedel, William C.; King, Maximilian R.F.; Lurie, Mark N.; Nunn, Amy S.; Chan, Philip A.; Marshall, Brandon D.L.

Background: Pre-exposure prophylaxis (PrEP) uptake has been slow among African American men who have sex with men (AAMSM) in the United States. We used an agent-based model (ABM) to simulate race-specific PrEP coverage to estimate their impact on racial disparities in HIV incidence among MSM in Atlanta, Georgia. Methods: An ABM was constructed to simulate HIV transmission in a dynamic network of 10,000 MSM over ten years, beginning in 2015. We modeled a base scenario with estimated PrEP coverage of 2.5% among AAMSM and 5.0% among white MSM (WMSM). We then compared HIV incidence over ten years and calculated a disparity ratio of AAMSM to WMSM incidence rates across varying PrEP scale-up scenarios, with equal and unequal coverage among AAMSM and WMSM. Results: Assuming current coverage remains constant, the model predicts HIV incidence rates of 2.95 and 1.76 per 100 person-years among AAMSM and WMSM respectively, with a disparity ratio of 1.68. If PrEP coverage were to increase six-fold without addressing inequities in PrEP uptake, the model predicts incidences of 2.65 and 1.34, corresponding to a mean decrease of 10.4% and 24.0% in HIV incidence, respectively. This stronger benefit for WMSM increased the disparity ratio to 1.98. Equal PrEP coverage among AAMSM and WMSM resulted in lower incidence rates overall with lower disparity ratios. Conclusion: Lower uptake among AAMSM relative to WMSM may limit the population-level impact of PrEP use among AAMSM, which may ultimately culminate in wider racial disparities in HIV incidence among MSM. Address Correspondence to: Brandon D.L. Marshall, PhD, Brown University School of Public Health, Department of Epidemiology, 121 South Main Street, Box GS-121-2, Providence, Rhode Island 02912. Phone: (401) 863-6427. Fax: (401) 863-3713. E-mail Address: brandon_marshall@brown.edu. Sources of Funding and Conflicts of Interest: This work was supported by the National Institute on Drug Abuse (DP2 DA040236) and the National Institute on Mental Health (R21 MH109360). Mark N. Lurie, PhD is also supported by grants from the National Institute on Mental Health (R01 MH106600) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R24 HD077976). Amy S. Nunn, ScD and Philip A. Chan, MD, MS are supported in part by grants from the National Institute on Mental Health (R01 MH114657 and R34 MH109371). The funders had no role in the study analysis, decision to published, or preparation of this manuscript. The authors report no conflicts of interest. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Sumet Ongwandee, Cheewanan Lertpiriyasuwat, Thana Khawcharoenporn, Ploenchan Chetchotisak, Ekkachai Thiansukhon, Niramon Leerattanapetch, Banlang Leungwaranan, Chomnad Manopaiboon, Thanongsri Phoorisri, Prin Visavakum, Bongkoch Jetsawang, Monsicha Poolsawat, Somboon Nookhai, Monthinee Vasanti-Uppapokakorn, Samart Karuchit, Chonticha Kittinunvorakoon, Philip Mock, Dimitri Prybylski, Ake-Chittra Sukkul, Thierry Roels, Michael Martin

by Sumet Ongwandee, Cheewanan Lertpiriyasuwat, Thana Khawcharoenporn, Ploenchan Chetchotisak, Ekkachai Thiansukhon, Niramon Leerattanapetch, Banlang Leungwaranan, Chomnad Manopaiboon, Thanongsri Phoorisri, Prin Visavakum, Bongkoch Jetsawang, Monsicha Poolsawat, Somboon Nookhai, Monthinee Vasanti-Uppapokakorn, Samart Karuchit, Chonticha Kittinunvorakoon, Philip Mock, Dimitri Prybylski, Ake-Chittra Sukkul, Thierry Roels, Michael Martin Introduction Antiretroviral therapy reduces the risk of serious illness among people living with HIV and can prevent HIV transmission. We implemented a Test, Treat, and Prevent HIV Program among men who have sex with men (MSM) and transgender women at five hospitals in four provinces of Thailand to increase HIV testing, help those who test positive start antiretroviral therapy, and increase access to pre-exposure prophylaxis (PrEP). Methods We implemented rapid HIV testing and trained staff on immediate antiretroviral initiation at the five hospitals and offered PrEP at two hospitals. We recruited MSM and transgender women who walked-in to clinics and used a peer-driven intervention to expand recruitment. We used logistic regression to determine factors associated with prevalent HIV infection and the decision to start antiretroviral therapy and PrEP. Results During 2015 and 2016, 1880 people enrolled. Participants recruited by peers were younger (p

Gretchen Weiss, Dawn K. Smith, Sarah Newman, Jeffrey Wiener, Alyssa Kitlas, Karen W. Hoover

by Gretchen Weiss, Dawn K. Smith, Sarah Newman, Jeffrey Wiener, Alyssa Kitlas, Karen W. Hoover Objective The United States Public Health Service released clinical practice guidelines for daily oral preexposure prophylaxis (PrEP) in May 2014. Local health departments (LHDs) are expected to play a critical role in PrEP implementation. We surveyed LHDs to assess awareness of and interest in supporting PrEP implementation, what roles they were taking, or believed they should take, in supporting PrEP, and what resources would be required to do so. Methods LHDs were surveyed in 2015 to assess their engagement in PrEP implementation (n = 500). The study employed a cross-sectional survey design with a randomly selected stratified sample. Results Among responding LHDs (n = 284), 109 (29%, weighted proportion) reported engagement in PrEP implementation. LHDs serving large jurisdictions (population 500,000+) and located in the West were more likely to be engaged in PrEP implementation. Making referrals for PrEP (74%) and conducting education and outreach to community members (51%) were the activities most frequently reported by LHDs engaged in PrEP implementation; 45% anticipated expanding their level of engagement. Among LHDs not engaged in PrEP implementation, 13% expected to become engaged over the next four years, 46% were undecided, and 41% reported it was unlikely. Information about PrEP for health care providers and information about PrEP for health department staff were the most frequently reported resource needs for LHDs engaged and not engaged in PrEP implementation, respectively. Conclusions PrEP implementation by LHDs was limited in 2015, three years after Food and Drug Administration approval and one year after the U.S. Public Health Service issued clinical practice guidelines. PrEP is a recently available intervention that is requiring LHDs to adjust existing HIV prevention efforts and service delivery models. Additional resources and implementation research is needed to effectively support PrEP scale-up by LHDs. Efforts must also be undertaken to increase PrEP awareness, knowledge, and implementation capacity among LHDs.…

Every spring, public health officials prepare for an upsurge in vectorborne diseases. As mosquito-borne illnesses have notoriously surged in the Americas, the U.S. incidence of tickborne infections has risen insidiously, triggering heightened attention from clinicians and researchers. According to……

Abstract Purpose To describe the presentation and management of bacterial brain abscess and subdural empyema in adults treated at two tertiary centers. In addition, to identify factors that may predict a poor clinical outcome. Methods A retrospective analysis of data obtained from clinical records was performed, followed by multivariate regression analysis of patient and treatment-related factors. Results 113 patients were included with a median age of 53 years and a male preponderance. At presentation symptoms were variable, 28% had a focal neurological deficit, and 39% had a reduced Glasgow coma scale (GCS). Brain abscesses most frequently affected the frontal, temporal, and parietal lobes while 36% had a subdural empyema. An underlying cause was identified in 76%; a contiguous ear or sinus infection (43%), recent surgery or trauma (18%) and haematogenous spread (15%). A microbiological diagnosis was confirmed in 86%, with streptococci, staphylococci, and anaerobes most frequently isolated. Treatment involved complex, prolonged antibiotic therapy (> 6 weeks in 84%) combined with neurosurgical drainage (91%) and source control surgery (34%). Mortality was 5% with 31% suffering long-term disability and 64% achieving a good clinical outcome. A reduced GCS, focal neurological deficit, and seizures at presentation were independently associated with an unfavorable clinical outcome (death or disability). Conclusions Complex surgical and antimicrobial treatment achieves a good outcome in the majority of patients with bacterial brain abscess and subdural empyema. Factors present at diagnosis can help to predict those likely to suffer adverse outcomes. Research to determine optimal surgical and antibiotic management would be valuable.…

Abstract Background Stenotrophomonas maltophilia (S. maltophilia) is an emerging global multiple-drug-resistant organism. It becomes increasingly challenging to treat S. maltophilia infection effectively. Novel therapeutic and preventive approaches targeting S. maltophilia infection are still lacking. This study aims to isolate outer membrane proteins (Omps) from S. maltophilia and use immunoproteomic technology to identify potential vaccine candidates of Omps against S. maltophilia infections. Methods Omps from S. maltophilia culture were separated by two-dimensional electrophoresis and identified by matrix-assisted laser desorption/ionization time of flight mass spectrometry and nano liquid chromatography coupled fourier transform ion cyclotron resonance tandem mass spectrometry. Recombinant Omps were prepared and used to immunize mice, and the potency of mouse anti-Omp serum was tested in opsonophagocytic killing assay (OPKA). The effects of immunization with recombinant Omp on blood and tissue bacterial loads in a mouse model of S. maltophilia-induced infection were analyzed. Results Outer membrane protein A (OmpA) and Smlt4123 were identified by mass spectrometry. Mouse anti-Smlt4123 serum significantly reduced the bacterial counts in healthy individuals’ blood in OPKA (P