Fearon, Elizabeth; Phillips, Andrew; Mtetwa, Sibongile; Chabata, Sungai T; Mushati, Phillis; Cambiano, Valentina; Busza, Joanna; Napierala, Sue; Hensen, Bernadette; Baral, Stefan; Weir, Sharon S; Rice, Brian; Cowan, Frances M; Hargreaves, James R

Background: ‘HIV prevention cascades’ have been proposed to support programmes by identifying gaps in demand for, access to and capability to adhere to HIV prevention tools, but there are few empirical examples to guide development. We apply a prevention cascade framework to examine prevention coverage and factors associated with condoms and/or PrEP adherence among female sex workers (FSW). Setting: Seven sites across Zimbabwe. Methods: Seven respondent-driven sampling (RDS) surveys from the intervention sites of a pragmatic cluster-randomised trial in Zimbabwe in 2016 were analysed, and 611/1439 women testing HIV-negative included. We operationalised key components of an HIV prevention cascade including demand, supply and capability to adhere to two tools for HIV prevention: condoms and Pre-Exposure Prophylaxis (PrEP). We used adjusted logistic regression to identify determinants of adherence to condoms and PrEP in turn, examining the effect of adherence to one tool on adherence to the other. Results: There were 343/611, 54.7%, women reporting adherence to condoms and/or PrEP, leaving almost half uncovered. While women were aware that condoms prevented HIV and reported good access to them, only 45·5% reported full adherence to condom use. For PrEP, a new technology, there were gaps along all three domains of demand, supply and adherence. Alcohol use decreased adherence to PrEP and condoms. Younger and newer entrants to sex work were less likely to take PrEP every day. Conclusion: HIV prevention programming among FSW in Zimbabwe could consider increasing awareness of PrEP alongside supply, alcohol use interventions, and approaches to engaging younger women. 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 and requests for reprints: Dr Elizabeth FearonElizabeth.Fearon@lshtm.ac.uk +44 7927 2877 Department of Social and Environmental Health Research, Public Health and Policy, London School of Hygiene and Tropical Medicine 15-17 Tavistock Place, London WC1H 9SH Conflicts of Interest and Source of Funding: We have no conflicts of interest to report. These analyses were funded by the Bill and Melinda Gates Foundation via the Measurement and Surveillance of HIV Epidemics Consortium. The original trial from which data was collected was funded by DFID, Swedish SIDA and Irish Aid via Zimbabwe’s Integrated Support Programme, and UNFPA. Presented at IAS AIDS 2018 conference in Amsterdam, July 2018, not otherwise published. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Maher, Lisa; Grulich, Andrew; Bourne, Adam; Hammoud BPsych, Mohamed; Vaccher, Steffanie; Bavinton, Benjamin; Holt, Martin; Jin, Fengyi

Introduction: HIV pre-exposure prophylaxis (PrEP) has been increasingly adopted by gay and bisexual men (GBM). Little is known about whether individual GBM change their sexual behavior following PrEP initiation. Methods: Following Lives Undergoing Change (Flux) is a national, online, prospective observational study among Australian GBM. Using McNemar statistics, we compare rates of sexual behaviors prior to and coincident with PrEP initiation among 1518 non HIV-positive men recruited between August 2014 and July 2017 who had not commenced PrEP at baseline and who completed at least one six-monthly follow-up surveys by July 2018. Results: The proportion of men using PrEP rose to 24.2% over time. In total, 348 men initiated PrEP during follow-up. PrEP initiators were more likely to report particular sexual behaviors during the follow up period that they commenced PrEP compared with the period immediately prior: receptive condomless anal intercourse with casual partners increased from 31.0% to 48.9% (McNemar…

Racine T, Denizot M, Pannetier D, et al.

AbstractThere is no vaccine or approved therapy against lethal Ebola virus (EBOV). We investigated a proven technology platform to produce polyclonal IgG fragments, F(ab’)2, against EBOV. Horses immunized with virus-like-particles (VLPs) harboring surface glycoprotein trimers of EBOV-Zaire/Makona produced anti-Ebola IgG polyclonal antibodies with high neutralization activity. Highly-purified equine anti-Ebola F(ab’)2 showed strong cross-neutralization of two Zaire EBOV strains (Gabon 2001 and Makona) and in vivo three or five daily F(ab’)2 intraperitoneal injections provided 100% protection to BALB/c mice against lethal EBOV challenge. Rapid preparation of purified equine anti-Ebola F(ab’)2 offers a potentially efficient therapeutic approach against EBOV disease in humans.

Qian G, Hou L, Guo W.

A previously healthy 7-week-old infant had a 4-week history of a worsening, widespread, papulovesicular rash with nighttime irritability and restlessness; burrows were present, and Gram stain, potassium hydroxide preparation, and Tzanck smear were negative. A babysitter reported having nighttime pruritus. What would you do next?…

Julia Ledien, Kimsan Souv, Rithea Leang, Rekol Huy, Anthony Cousien, Muslim Peas, Yves Froehlich, Raphaël Duboz, Sivuth Ong, Veasna Duong, Philippe Buchy, Philippe Dussart, Arnaud Tarantola

by Julia Ledien, Kimsan Souv, Rithea Leang, Rekol Huy, Anthony Cousien, Muslim Peas, Yves Froehlich, Raphaël Duboz, Sivuth Ong, Veasna Duong, Philippe Buchy, Philippe Dussart, Arnaud Tarantola Dengue is a national priority disease in Cambodia. The Cambodian National Dengue Surveillance System is based on passive surveillance of dengue-like inpatients reported by public hospitals and on a sentinel, pediatric hospital-based active surveillance system. This system works well to assess trends but the sensitivity of the early warning and time-lag to usefully inform hospitals can be improved. During The ECOnomic development, ECOsystem MOdifications, and emerging infectious diseases Risk Evaluation (ECOMORE) project’s knowledge translation platforms, Cambodian hospital staff requested an early warning tool to prepare for major outbreaks. Our objective was therefore to find adapted tools to improve the early warning system and preparedness. Dengue data was provided by the National Dengue Control Program (NDCP) and are routinely obtained through passive surveillance. The data were analyzed at the provincial level for eight Cambodian provinces during 2008–2015. The R surveillance package was used for the analysis. We evaluated the effectiveness of Bayesian algorithms to detect outbreaks using count data series, comparing the current count to an expected distribution obtained from observations of past years. The analyses bore on 78,759 patients with dengue-like syndromes. The algorithm maximizing sensitivity and specificity for the detection of major dengue outbreaks was selected in each province. The overall sensitivity and specificity were 73% and 97%, respectively, for the detection of significant outbreaks during 2008–2015. Depending on the province, sensitivity and specificity ranged from 50% to 100% and 75% to 100%, respectively. The final algorithm meets clinicians’ and decisionmakers’ needs, is cost-free and is easy to implement at the provincial level.

Hojilla, J. Carlo; Satre, Derek D.; Glidden, David V.; McMahan, Vanessa M.; Gandhi, Monica; Defechereux, Patricia; Guanira, Juan V.; Mehrotra, Megha; Grant, Robert M.; Carrico, Adam W.

Background: Concomitant use of cocaine and HIV pre-exposure prophylaxis (PrEP) raises important clinical questions around adherence, retention in care, and renal toxicity. Methods: We assessed the associations of confirmed cocaine use with PrEP adherence (both ascertained via objective measures), care engagement, and renal function in the iPrEx open label extension. Cocaine use was measured in scalp hair samples and categorized as: light (500-3,000 pg/mg) and moderate to heavy (>3,000 pg/mg). PrEP adherence in the first three months was measured via plasma tenofovir concentrations. Disengagement from PrEP care was defined as a gap in follow-up greater than four months. Serum creatinine was assessed at baseline and quarterly visits. Results: Of the 400 participants included in this analysis, 90% were men who have sex with men, 10% transgender women, 74% Hispanic/Latino; 21% tested positive for cocaine use in the last three months. In adjusted analysis, light cocaine use (aOR 2.10 [95% CI 1.07-4.14]) and moderate to heavy use (aOR 2.32 [1.08-5.00]) were associated with greater odds of having plasma tenofovir concentrations below the level of quantitation. Participants with moderate to heavy use had a nearly three-fold higher rate of disengagement from PrEP care compared to non-users (aHR 2.90 [1.48-5.66]). We found no statistically or clinically significant differences in creatinine clearance and serum creatinine between participants who tested positive for cocaine and those who did not. Conclusions: Cocaine use decreases PrEP adherence and care engagement. Comprehensive approaches are needed to reduce cocaine use and enhance engagement along the PrEP care continuum. 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: J. Carlo Hojilla, RN, PhD University of California, San Francisco 401 Parnassus Ave San Francisco, CA 94143 Tel: 510-891-3631 Email: carlo.hojilla@ucsf.edu Conflicts of Interest and Sources of Funding: This study was supported by the National Institute on Drug Abuse (NIDA R36 DA041906 and T32 DA007250). iPrEx OLE was funded by the National Institute of Allergy and Infectious Diseases (NIAID U01 AI064002 and R01 AI118575). Hair collection was funded by NIAID R01 AI098472. Gilead Sciences donated tenofovir disoproxil fumarate and emtricitabine to the parent study but provided no other financial support and had no role in data interpretation or manuscript development. DVG has received fees from Gilead Sciences. RMG has received research funding from ViiV Healthcare. The remaining authors have no conflicts of interest to disclose. Parts of the data in this manuscript were presented at the HIV Research for Prevention Conference, Madrid, in October 2018. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Abstract Background In the spring of 1918, the “War to End All Wars”, which would ultimately claim more than 37 million lives, had entered into its final year and would change the global political and economic landscape forever. At the same time, a new global threat was emerging and would become one of the most devastating global health crises in recorded history. Main text The 1918 H1N1 pandemic virus spread across Europe, North America, and Asia over a 12-month period resulting in an estimated 500 million infections and 50–100 million deaths worldwide, of which ~ 50% of these occurred within the fall of 1918 (Emerg Infect Dis 12:15-22, 2006, Bull Hist Med 76:105-115, 2002). However, the molecular factors that contributed to the emergence of, and subsequent public health catastrophe associated with, the 1918 pandemic virus remained largely unknown until 2005, when the characterization of the reconstructed pandemic virus was announced heralding a new era of advanced molecular investigations (Science 310:77-80, 2005). In the century following the emergence of the 1918 pandemic virus we have landed on the Moon, developed the electronic computer (and a global internet), and have eradicated smallpox. In contrast, we have a largely remedial knowledge and understanding of one of the greatest scourges in recorded history. Conclusion Here, we reflect on the 1918 influenza pandemic, including its emergence and subsequent rapid global spread. In addition, we discuss the pathophysiology associated with the 1918 virus and its predilection for the young and healthy, the rise of influenza therapeutic research following the pandemic, and, finally, our level of preparedness for future pandemics.…

Grumaz, Silke; Grumaz, Christian; Vainshtein, Yevhen; Stevens, Philip; Glanz, Karolina; Decker, Sebastian O.; Hofer, Stefan; Weigand, Markus A.; Brenner, Thorsten; Sohn, Kai

Objectives: Culture-based diagnostics represent the standard of care in septic patients, but are highly insensitive and in many cases unspecific. We recently demonstrated the general feasibility of next-generation sequencing-based diagnostics using free circulating nucleic acids (cell-free DNA) in plasma samples of septic patients. Within the presented investigation, higher performance of next-generation sequencing-based diagnostics was validated by comparison to matched blood cultures. Design: A secondary analysis of a prospective, observational, single-center study. Setting: Surgical ICU of a university hospital and research laboratory. Patients: Fifty patients with septic shock, 20 uninfected patients with elective surgery as control cohort. Interventions: None. Measurements and Main Results: From 256 plasma samples of 48 septic patients at up to seven consecutive time points within the 28-day observation period, cell-free DNA was isolated and analyzed by next-generation sequencing and relevance scoring. In parallel, results from culture-based diagnostics (e.g., blood culture) were obtained. Plausibility of blood culture and next-generation sequencing results as well as adequacy of antibiotic therapy was evaluated by an independent expert panel. In contrast to blood culture with a positivity rate of 33% at sepsis onset, the positivity rate for next-generation sequencing-based pathogen identification was 72%. Over the whole study period, blood culture positivity was 11%, and next-generation sequencing positivity was 71%. Ninety-six percent of positive next-generation sequencing results for acute sepsis time points were plausible and would have led to a change to a more adequate therapy in 53% of cases as assessed by the expert evaluation. Conclusions: Our results show that next-generation sequencing-based analyses of bloodstream infections provide a valuable diagnostic platform for the identification of clinically relevant pathogens with higher sensitivity and specificity than blood culture, indicating that patients might benefit from a more appropriate therapy based on next-generation sequencing-based diagnosis. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Drs. Brenner and Sohn share senior authorship. Drs. S. Grumaz, Decker, Hofer, Brenner, and Sohn conceived of, designed, and supervised the study. Drs. Decker, Hofer, and Brenner collected clinical samples and clinical data. Drs. S. Grumaz, C. Grumaz, and Glanz performed all sample processing and next-generation sequencing experiments. Drs. Vainshtein and Stevens performed bioinformatic data processing and statistical analyses. Drs. S. Grumaz, C. Grumaz, Stevens, and Sohn analyzed the data. Drs. Hofer, Weigand, Brenner, and Sohn provided materials. Drs. S. Grumaz and C. Grumaz prepared the tables and figures. Drs. S. Grumaz and Sohn wrote the article with contributions from all other authors. All authors read, critically revised, and approved the final article. A data visualization tool associated with this article can be viewed here: https://lippincott.shinyapps.io/Sohn/. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by the Fraunhofer IGB (Stuttgart, Germany), Fraunhofer Future Foundation, Department of Anesthesiology (University of Heidelberg, Germany), Heidelberg Foundation of Surgery (University of Heidelberg, Germany). Our study sponsors were not involved in study design, collection, analysis, or interpretation of data. Drs. Decker and Brenner received project funding from Heidelberg Foundation of Surgery. Drs. S. Grumaz, Stevens, and Sohn disclosed that they are co-founders of the company Noscendo active in molecular diagnostics for infectious diseases. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: kai.sohn@igb.fraunhofer.de Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Cohen M, Donnell D.

HIVPrEPTDF/FTCacquisitionpreventiontransmission…

Ortiz J, Neuzil K.

AbstractInfluenza vaccines have a long history of safety and demonstrated efficacy; however, they are seldom used in low- and middle-income countries (LMICs). While reasons for underutilization are multifactorial and differ from country to country, the need for up to twice-annual reformulation and yearly vaccination are obstacles to influenza prevention in LMICs. Major efforts are underway to produce next-generation influenza vaccines that provide durable protection against drifted strains, and such vaccines could address these unmet needs. However, additional information is required to influence immunization policies in most LMICs. Better estimates of vaccine impact on important public health outcomes, more affordable vaccines, improved programmatic suitability, and strengthened immunization delivery infrastructures are needed and must be considered early during the development of new vaccines if widespread adoption in LMICs is to be achieved.

Crank M, Mascola J, Graham B.

InfluenzaVaccinePandemic…

E. Farag et al.

Sibiude, Jeanne; Warszawski, Josiane; Tubiana, Roland; Chenadec, Jérôme LE; Meier, Françoise; Faye, Albert; Blanche, Stéphane; Mandelbrot, Laurent; the ANRS-French Perinatal Cohort Study Group

Background High rates of liver enzyme elevation (LEE) in women receiving antiretroviral treatment (ART) during pregnancy have been reported but causes remain unclear. We estimated the prevalence and risk factors of LEE in a national prospective multicenter cohort. Methods We studied 5748 pregnant women living with HIV enrolled in the French Perinatal Cohort 2005-2014, treated with ART, with no active hepatitis B or C co-infection. Adjusted hazard ratio (aHR) were estimated using Cox models with ART as time-dependent variable, separately for women on ART at conception and those initiating ART during pregnancy. Results LEE (grade>1) was observed in 16.7%, grade 3-4 in 2%. Among women with LEE, 6.7% had preeclampsia, 9.8% intrahepatic cholestasis of pregnancy, and 1.4% other identified medical causes. Most LEE (82.2%) were unexplained. In women with unexplained LEE, LEE was the reason for hospitalization in 51 (6%) women, cesarean section in 13 (2%), induction of labour in 3 (0.4%), and change in ART regimen in 49 (6%) women. Unexplained LEE was associated with higher risk of preterm births, p

Calabrese S, Krakower D, Willie T, et al.

AbstractClinical guidelines for HIV pre-exposure prophylaxis (PrEP) developed by the US Centers for Disease Control and Prevention have been instrumental to the implementation of PrEP in medical practices throughout the country. However, the eligibility criteria contained within may inadvertently limit PrEP access for some patients. We describe key considerations and caveats surrounding these criteria: (1) promotion of a selective vs. universal approach to sexual health education involving PrEP; (2) misalignment between criteria stated in the table and text boxes; (3) problematic categorization and confounding of sexual orientation, gender identity, and risk behavior; (4) underemphasis of network/community-level drivers of HIV transmission; (5) oversimplification of serodiscordant risk; and (6) lack of clarity surrounding the relevance of condoms to PrEP eligibility. We offer concrete recommendations to address the identified issues and strengthen future iterations of the guidelines, applying these recommendations in an alternative table of “criteria.”…

Abstract Background The development of malaria transmission-blocking strategies including the generation of malaria refractory mosquitoes to replace the wild populations through means of gene drives hold great promise. The standard membrane feeding assay (SMFA) that involves mosquito feeding on parasitized blood through an artificial membrane system is a vital tool for evaluating the efficacy of transmission-blocking interventions. However, despite the availability of several published protocols, the SMFA remains highly variable and broadly insensitive. Methods The SMFA protocol was optimized through coordinated culturing of Anopheles coluzzii mosquitoes and Plasmodium falciparum parasite coupled with placing mosquitoes under a strict dark regime before, during, and after the gametocyte feed. Results A detailed description of essential steps is provided toward synchronized generation of highly fit An. coluzzii mosquitoes and P. falciparum gametocytes in preparation for an SMFA. A dark-infection regime that emulates the natural vector-parasite interaction system is described, which results in a significant increase in the infection intensity and prevalence. Using this optimal SMFA pipeline, a series of putative transmission-blocking antimicrobial peptides (AMPs) were screened, confirming that melittin and magainin can interfere with P. falciparum development in the vector. Conclusion A robust SMFA protocol that enhances the evaluation of interventions targeting human malaria transmission in laboratory setting is reported. Melittin and magainin are identified as highly potent antiparasitic AMPs that can be used for the generation of refractory Anopheles gambiae mosquitoes.…

Probert, M., Zhou, X., Goodall, M., Johnston, S. A., Bielska, E., Ballou, E. R., May, R. C.

Disseminated infections with the fungal species Cryptococcus neoformans or, less frequently, C. gattii, are an important cause of mortality in immunocompromised individuals. Central to the virulence of both species is an elaborate polysaccharide capsule that consists predominantly of glucuronoxylomannan (GXM). Due to its abundance, GXM is an ideal target for host antibodies, and several monoclonal antibodies (mAbs) have previously been derived using purified GXM or whole capsular preparations as antigen. In addition to their application in the diagnosis of cryptococcosis, anti-GXM mAbs are invaluable tools for studying capsule structure. In this study, we report the production and characterisation of a novel anti-GXM mAb, Crp127, that unexpectedly reveals a role for GXM remodelling during the process of fungal Titanisation. We show that Crp127 recognises a GXM epitope in an O-acetylation dependent, but xylosylation-independent, manner. The epitope is differentially expressed by the four main serotypes of Cryptococcus neoformans and gattii, is heterogeneously expressed within clonal populations of C. gattii serotype B strains and is typically confined to the central region of the enlarged capsule. Uniquely, however, this epitope redistributes to the capsular surface in Titan cells, a recently characterised morphotype where haploid 5 μm cells convert to highly polyploid cells >10 μm with distinct but poorly understood capsular characteristics. Titans are produced in the host lung and critical for successful infection. Crp127 therefore advances our understanding of cryptococcal morphological change and may hold significant potential as a tool to differentially identify cryptococcal strains and subtypes.…

Yang, M., Du, K., Hou, Y., Xie, S., Dong, Y., Li, D., Du, Y.

C. albicans is a human opportunistic pathogen that causes superficial and life-threatening infections. An important reason for the failure of current antifungal drugs is related to biofilm formation, mostly associated with implanted medical devices. The present study investigated the synergistic antifungal efficacy of low-frequency and low-intensity ultrasound combined with amphotericin B-loaded PLGA nanoparticles (AmB-NPs) on C. albicans biofilms. AmB-NPs were prepared by a double emulsion method and demonstrated lower toxicity than free AmB. We then established biofilms and treated them with ultrasound and AmB-NPs separately or jointly in vitro and in vivo. The results demonstrated that the activity, biomass, and proteinase and phospholipase activities of biofilms were decreased significantly after the combination treatment of AmB-NPs with 42 KHz ultrasound irradiation at an intensity of 0.30 W/cm2 for 15 min compared with the controls, with AmB alone, or with ultrasound treatment alone (P < 0.01). The morphology of the biofilms was altered remarkably after joint treatment based on confocal laser scanning microscopy (CLSM), especially in regard to reduced thickness and loosened structure. Furthermore, the same synergistic effects were found in a subcutaneous catheter biofilm rat model. The number of colony forming units from the catheter exhibited a significant reduction after AmB-NPs and ultrasound joint treatment for 7 continuous days, and CLSM and scanning electron microscopy (SEM) images revealed that the biofilm on the catheter surface was substantially eliminated. This method may provide a new noninvasive, safe, and effective therapy for C. albicans biofilm infection.…

Gandhi, Monica; Bacchetti, Peter; SpinelliI, Matthew A.; Okochi, Hideaki; Baeten, Jared M.; Siriprakaisil, Oraphan; Klinbuayaem, Virat; Rodrigues, Warren C.; Wang, Guohang; Vincent, Michael; Cressey, Tim R.; Drain, Paul K.

Background: Current pharmacologic adherence monitoring for antiretrovirals involves expensive, labor-intensive liquid-chromatography/tandem-mass-spectrometry (LC-MS/MS)-based methods. Antibody-based assays can monitor and support adherence in real-time. We developed a tenofovir (TFV)-based immunoassay and further validated it in a directly-observed-therapy (DOT) study. Design: Pharmacologic DOT study of TFV disoproxil fumarate (TDF)/emtricitabine (FTC) administered to HIV-noninfected volunteers Methods: The TARGET study provided directly-observed TDF 300mg/FTC 200mg 7 (high adherence), 4 (moderate) and 2 doses/week (low) to 30 volunteers (10/group) in Thailand, collecting a total of 637 urine samples over 6-weeks of administration and during wash-out. ELISA measured urine TFV levels by the immunoassay and LC-MS/MS-based concentrations served as the gold-standard. A mixed-effects regression model evaluated cut-offs for a point-of-care (POC) assay. Performance characteristics of the immunoassay were compared to LC-MS/MS at a chosen cut-off. Results: Median TFV levels were 12,000ng/mL by the immunoassay 1-day after dosing; 5000ng/mL 2-days after dosing; 1500ng/mL 3-days after dosing and below the lower-limit-of-quantification (LLOQ) thereafter (≥4 days). An immunoassay cut-off of 1500ng/mL accurately classified 98% of patients who took a dose 24 hours ago as adherent. The specificity and sensitivity of the immunoassay compared to LC-MS/MS at the 1500ng/mL cut-off were 99% and 94%; the correlation between TFV levels by the two assays was high (0.92, p

Abstract Background Rapid and accurate pathogen identification in blood cultures is very important for septic patients and has major consequences on morbidity and mortality rates. In recent years, matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS)-based technology has become useful for highly specific and sensitive identification of bacteria and yeasts from clinical samples including sterile body fluids. Additional in-house methods enabled direct identification from blood cultures following various preparation protocols. Methods Blood culture (5 ml) was harvested from each positive bottle following growth identification by BACTEC™ FX system and transferred into a VACUETTE® Z Serum Sep Clot Activator tube containing an inert gel, which following centrifugation separates microorganisms from the blood cells. We used MALDI-TOF MS analysis for identification of microorganisms collected from the gel surface. Results Positive blood culture bottles (186) were collected. In comparison with the routine method, 99% (184/186) and 90% (168/186) of the isolates were correctly identified by the SepsiTyper kit and the in-house method, respectively. We found high concordance (Pearson coefficient = 0.7, p 

Trisha A. Rettig, Bailey A. Bye, Nina C. Nishiyama, Savannah Hlavacek, Claire Ward, Michael J. Pecaut, Stephen K. Chapes

by Trisha A. Rettig, Bailey A. Bye, Nina C. Nishiyama, Savannah Hlavacek, Claire Ward, Michael J. Pecaut, Stephen K. Chapes Spaceflight affects the immune system, but the effects on the antibody repertoire, responsible for humoral immunity, has not been well explored. In particular, the complex gene assembly and expression process; including mutations, might make this process vulnerable. Complementarity determining region 3 (CDR3), composed of parts of the V-(D-)J-gene segments, is very important for antigen binding and can be used as an important measure of variability. Skeletal unloading, and the physiological effects of it, parallel many impacts of space flight. Therefore, we explored the impact of skeletal unloading using the antiorthostatic suspension (AOS) model. Animals were experimentally challenged with tetanus toxoid (TT) and/or the adjuvant CpG. Blood was analyzed for anti-TT antibody and corticosterone concentrations. Whole spleen tissue was prepared for repertoire characterization. AOS animals showed higher levels of corticosterone levels, but AOS alone did not affect anti-TT serum antibody levels. Administration of CpG significantly increased the circulating anti-TT antibody concentrations. AOS did alter constant gene usage resulting in higher levels of IgM and lower levels of IgG. CpG also altered constant gene region usage increasing usage of IgA. Significant changes could be detected in multiple V-, D-, and J-gene segments in both the heavy and light chains in response to AOS, TT, and CpG treatments. Analysis of class-switched only transcripts revealed a different pattern of V-gene segment usage than detected in the whole repertoire and also showed significant alterations in gene segment usage after challenge. Alterations in V/J pairing were also detected in response to challenge. CDR3 amino acid sequence overlaps were similar among treatment groups, though the addition of CpG lowered overlap in the heavy chain. We isolated 3,045 whole repertoire and 98 potentially TT-specific CDR3 sequences for the heavy chain and 569 for the light chain. Our results demonstrate that AOS alters the repertoire response to challenge with TT and/or CpG.

Douglas Drak, Hamish Barratt, David J. Templeton, Catherine C. O’Connor, David M. Gracey

by Douglas Drak, Hamish Barratt, David J. Templeton, Catherine C. O’Connor, David M. Gracey Background Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) significantly reduces the risk of HIV acquisition. TDF is a known nephrotoxin however, renal dysfunction from TDF is mostly reversible following discontinuation. Aims To describe the renal function, risk factors for renal disease and associated clinical testing practices in a cohort of PrEP patients. Methods A retrospective review was conducted of all PrEP patients commenced on TDF/FTC at an inner metropolitan sexual health clinic in Sydney, Australia between April 2016 and July 2017, with follow-up data obtained at 3-monthly intervals until 18 months. Results 525 patients met inclusion criteria. Patients were almost exclusively male and median age was 34 years (IQR: 28 to 42). At baseline, 1.5% had an estimated glomerular filtration rate (eGFR)…

Tobin, Stacey C

No abstract available…

Spinelli, Matthew A.; Glidden, David V.; Rodrigues, Warren C.; Wang, Guohong; Vincent, Michael; Okochi, Hideaki; Kuncze, Karen; Mehrotra, Megha; Defechereux, Patricia; Buchbinder, Susan P.; Grant, Robert M.; Gandhi, Monica

Objective: We examined the relationship between urine tenofovir (TFV) levels measured with a novel immunoassay, which permits point-of-care (POC) testing, with HIV seroconversion and objective adherence metrics in a large PrEP demonstration project. Design: Secondary analysis of stored specimens from an open-label PrEP cohort study Methods: We examined the association between undetectable urine TFV levels and HIV seroconversion in iPrEx-OLE using generalized estimating equations. We examined rank correlations between levels of TFV and emtricitabine (FTC) in urine, dried blood spots (DBS), and hair and determined the sensitivity and specificity of undetectable urine TFV for predicting dosing cut-offs in DBS. Results: The median urinary TFV level was 15,000 ng/ml in those who remained HIV-negative (n = 105; IQR:1,000–45,000); 5,500 in those who eventually seroconverted (n = 11; IQR:1,000–12,500); and all were undetectable at seroconversion (n = 9; p …

Katz, David A.; Dombrowski, Julia C.; Barry, Michael; Spellman, Dawn; Bell, Teal R.; Golden, Matthew R.

Background: Men who have sex with men (MSM) with bacterial STDs are at elevated risk for HIV. We evaluated the integration of pre-exposure prophylaxis (PrEP) referrals into STD partner services (PS) for MSM. Setting: King County, Washington Methods: Disease Intervention Specialists (DIS) in King County attempt to provide PS to all MSM with early syphilis and, as resources allow, MSM with gonorrhea or chlamydia. Our health department defines MSM with any of the following as at high HIV risk: early syphilis, rectal gonorrhea, methamphetamine/poppers use, sex work, or an HIV-unsuppressed partner. DIS offer high-risk MSM referral to our STD Clinic for PrEP and other MSM referral to community providers. In 2017, we interviewed a random sample of MSM offered referrals in 2016 to assess PrEP initiation following PS. Results: From 8/2014-8/2017, 7546 cases of bacterial STDs were reported among HIV-negative MSM. DIS provided PS to 3739 MSM, of whom 2055 (55%) were at high risk. DIS assessed PrEP use in 1840 (90%) of these men, 895 (49%) of whom reported already using PrEP. DIS offered referrals to 693 (73%) of 945 MSM not on PrEP; 372 (54%) accepted. Among 132 interviewed for the random sample, men who accepted referrals at initial interview were more likely to report using PrEP at follow-up (32/68=47%) than those who did not (12/64=19%) [p=0.0006]. 10.4% of all interviewed MSM initiated PrEP following PS-based referral. Conclusions: Integrating PrEP referrals into STD PS is an effective population-based strategy to link MSM at high HIV risk to PrEP. Corresponding author: David A. Katz, PhD, MPH University of Washington 325 Ninth Avenue, Box 359931 Seattle, WA 98104 Telephone: 206-744-5877 Email: dkatz7@uw.edu Conflicts of Interest and Sources of Funding: MRG has received research support from Cempra Pharmaceuticals and Melinta Therapeutics. JCD has conducted research supported by grants to the University of Washington from Hologic, Quidel, and ELITech and received travel support to a conference supported by Gilead. The remaining authors have no potential conflicts of interest to declare. Requests for reprints should be addressed to corresponding author. This program and its evaluation were supported by the U.S. Centers for Disease Control and Prevention [H25 PS004364]; the Washington State Department of Health; and Public Health – Seattle & King County. The evaluation was also supported by the National Center For Advancing Translational Sciences of the National Institutes of Health [UL1 TR002319] and by the National Institute of Allergy and Infectious Diseases; National Cancer Institute; National Institute of Mental Health; National Institute of Child Health and Human Development; National Heart, Lung, and Blood Institute; National Institute on Aging; National Institute of General Medical Sciences; and National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health [P30 AI027757]. Note: This work was presented in part at the 2017 Conference on Retroviruses and Opportunistic Infections in Seattle, WA, and the 2018 Conference on Retroviruses and Opportunistic Infections in Boston, MA. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Patel, Anar S.; Goparaju, Lakshmi; Sales, Jessica M.; Mehta, C. Christina; Blackstock, Oni J.; Seidman, Dominika; Ofotokun, Igho; Kempf, Mirjam-Colette; Fischl, Margaret A.; Golub, Elizabeth T.; Adimora, Adaora A.; French, Audrey L.; DeHovitz, Jack; Wingood, Gina; Kassaye, Seble; Sheth, Anandi N.

Background: Among women in the US, non-Latina Black women in the South have disproportionately high rates of new HIV infections, but low use of pre-exposure prophylaxis (PrEP). Effective strategies to identify factors associated with PrEP eligibility could facilitate improved screening, offering, and uptake of PrEP among US women at risk for HIV. Setting and Methods: We applied 2014 CDC criteria for PrEP use to at-risk HIV-negative women enrolled in the Southern US sites (Atlanta, Chapel Hill, Birmingham/Jackson, Miami) of the Women’s Interagency HIV Study from 2014-2015 to estimate PrEP eligibility and assess PrEP knowledge and acceptability. Factors associated with PrEP eligibility were assessed using multivariable models. Results: Among 225 women, 72 (32%) were PrEP eligible; the most common PrEP indicator was condomless sex. The majority of PrEP-eligible women (88%) reported willingness to consider PrEP. Only 24 (11%) PrEP-eligible women had previously heard of PrEP and only 1 reported prior use. Education level less than high school (aOR 2.56; 95% CI 1.22, 5.37), history of sexual violence (aOR 4.52; 95% CI 1.52, 17.76), and medium to high self-perception of HIV risk (aOR 6.76; 95% CI 3.26, 14.05) were significantly associated with PrEP eligibility in adjusted models. Conclusion: Extremely low PrEP awareness and use despite a high proportion of eligibility and acceptability signify a critical need to enhance PrEP education and delivery for women in this region. Supplementing CDC eligibility criteria with questions about history of sexual violence and HIV risk self-assessment may enhance PrEP screening and uptake among US women. Requests for Reprints and Corresponding Author: Anandi N. Sheth, MD, MSc Emory University Department of Medicine, Division of Infectious Diseases 49 Jesse Hill Jr Drive Atlanta, GA 30303 Phone Number: (404) 616-6240 Fax Number: (404) 880-9305 Email Address: ansheth@emory.edu Prior Presentations: Presented in part at: Conference on Retroviruses and Opportunistic Infections (CROI 2018), Boston, MA, March 4 – 7, 2018, Abstract 1048 Funding: This work was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health award number TL1 TR002382 (PI: Dr. Henry M. Blumberg), the National Institute of Allergy and Infectious Diseases award number 5U01AI103408 (PI Dr. Igho Ofotokun) and the National Institute of Allergy and Immunology award number 1K23AI114407 (PI: Anandi N. Sheth). The authors have no financial disclosures to report. The authors report no conflicts of interest related to this work. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Costello SP, Hughes PA, Waters O, et al.

This randomized clinical trial compares the ability of anaerobically prepared pooled donor vs autologous fecal microbiota transplantation to induce remission in patients with ulcerative colitis (UC).

Ubaldo Mushabe Bahemuka, Andrew Abaasa, Eugene Ruzagira, Christina Lindan, Matt A. Price, Anatoli Kamali, Pat Fast

by Ubaldo Mushabe Bahemuka, Andrew Abaasa, Eugene Ruzagira, Christina Lindan, Matt A. Price, Anatoli Kamali, Pat Fast Introduction People living in fishing communities around Lake Victoria may be suitable for enrolment in HIV prevention trials because of high HIV incidence. We assessed the ability to recruit and retain individuals from fishing communities into an HIV vaccine preparedness cohort study in Masaka, Uganda. Methods HIV high risk, sero-negative adults (18–49 years) were identified from four fishing villages bordering Lake Victoria through door-to-door HIV counselling and testing (HCT). Interested persons were referred for screening, enrolment, and quarterly follow-up visits at a study clinic located approximately 30–40 kilometres away. Repeat HCT, HIV risk assessment, and evaluation and treatment for sexually transmitted infections were provided. Rates of and factors associated with study dropout were assessed using Poisson regression models. Results A total of 940 participants were screened between January 2012 and February 2015, of whom 654 were considered for the analysis. Over a two-year follow-up period, 197 (30.1%) participants dropped out of the study over 778.9 person-years, a dropout rate of 25.3 / 100 person-years of observation. Dropout was associated with being female (aRR = 1.56, 95% confidence interval [CI] 1.12–2.18), being 18–24 years (aRR = 1.64; 95% CI 1.03–2.60) or being 25–34 years (aRR = 1.63; 95% CI 1.04–2.55) compared to being 35+ years; having no education (aRR = 2.02; 95% CI: 1.23–3.31); living in the community for less than one year (aRR = 2.22; 95% CI: 1.46–3.38), or 1–5 years (aRR = 1.68; 95% CI: 1.16–2.45), compared to more than five years. Conclusions Our results suggest that individuals from fishing communities can be recruited and retained in longitudinal studies; however, intensified participant tracing may be necessary for women, younger volunteers, those who are less educated and new residents.…

Abriham Zegeye, Getnet Dessie, Fasil Wagnew, Alemu Gebrie, Sheikh Mohammed Shariful Islam, Bekele Tesfaye, Dessalegn Kiross

by Abriham Zegeye, Getnet Dessie, Fasil Wagnew, Alemu Gebrie, Sheikh Mohammed Shariful Islam, Bekele Tesfaye, Dessalegn Kiross Background Tuberculosis is a global public health problem. One of the overarching dilemmas and challenges facing most tuberculosis program is non-adherence to treatment. However, in Ethiopia there are few studies with variable and inconsistent findings regarding non-adherence to treatment for tuberculosis. Methods This systematic review and meta-analysis was conducted to determine the prevalence of non-adherence to tuberculosis treatment and its determinants in Ethiopia. Biomedical databases including PubMed, Google Scholar, Science Direct, HINARI, EMBASE and Cochrane Library were systematically and comprehensively searched. To estimate the pooled prevalence, studies reporting the prevalence of adherence or non-adherence to tuberculosis treatment and its determinants were included. Data were extracted using a standardized data extraction tool prepared in Microsoft Excel and transferred to STATA/se version-14 statistical software for further analyses. To assess heterogeneity, the Cochrane Q test statistics and I2 test were performed. Since the included studies exhibited high heterogeneity, a random effects model meta- analysis was used to estimate the pooled prevalence of non-adherence to tuberculosis treatment. Finally, the association between determinant factors and non-adherence to tuberculosis treatment was assessed. Results The result of 13 studies revealed that the pooled prevalence of non-adherence to tuberculosis treatment in Ethiopia was found to be 21.29% (95% CI: 15.75, 26.68). In the subgroup analysis, the highest prevalence was observed in Southern Nations and Nationalities of Ethiopia, 23.61% (95% CI: 21.05, 26.17) whereas the lowest prevalence was observed in Amhara region, 10.0% (95% CI: 6.48, 13.17.0;). Forgetfulness (OR = 3.22, 95% CI = 2.28, 4.53), fear side effect of the drugs (OR = 1.93, 95% CI = 1.37, 2.74), waiting time ≥ 1 hour during service (OR = 4.88, 95% CI = 3.44, 6.91) and feeling distance to health institution is long (OR = 5.35, 95% CI = 4.00, 7.16) were found to be determinants of non-adherence to tuberculosis treatment. Conclusion In this meta-analysis, the pooled prevalence of non-adherence to tuberculosis treatment in Ethiopia was high. Forgetfulness, fear of side effect of the drugs, long waiting time (≥1 hour) during service and feeling distance to health institution is long were the main risk factors for non-adherence to tuberculosis treatment in Ethiopia. Early monitoring of the side effects and other reasons which account for missing medication may increase medication adherence in patients with tuberculosis in Ethiopia.…

Mariane Martins Araújo Stefani, Patricia Sammarco Rosa, Mauricio Barcelos Costa, Antônio Pedro Mendes Schetinni, Igor Manhães, Maria Araci Andrade Pontes, Patricia Costa, Luciana Raquel Vincenzi Fachin, Ida Maria Foschiani Dias Batista, Marcos Virmond, Emília Pereira, Maria Lucia Fernandes Penna, Gerson Oliveira Penna

by Mariane Martins Araújo Stefani, Patricia Sammarco Rosa, Mauricio Barcelos Costa, Antônio Pedro Mendes Schetinni, Igor Manhães, Maria Araci Andrade Pontes, Patricia Costa, Luciana Raquel Vincenzi Fachin, Ida Maria Foschiani Dias Batista, Marcos Virmond, Emília Pereira, Maria Lucia Fernandes Penna, Gerson Oliveira Penna There is evidence that in southern US, leprosy is a zoonosis infecting wild Dasypus novemcinctus armadillos but the extent of this finding is unknown. This ecological study investigated leprosy in rural communities and in wild armadillos from the Brazilian Amazon. The study area was the Mamiá Lake of Coari municipality, Amazonas State, Northern region, a hyper endemic leprosy area where residents live on subsistence farming, fishing and armadillo hunting and its meat intake are frequent. The leprosy survey was conducted in sixteen communities by a visiting team of specialists. Local partakers provided wild armadillos to investigate M. leprae infection. Volunteers had complete dermato-neurological examination by a dermatologist with expertise in leprosy diagnosis, suspect skin lesions were biopsied for histopathology (Hematoxylin-eosin/HE, Fite-Faraco/FF staining); slit skin smears were collected. Armadillos’ tissue fragments (skins, spleens, livers, lymph nodes, adrenal glands, others) were prepared for histopathology (HE/FF) and for M. leprae repetitive element-RLEP-qPCR. Among 176 volunteers, six new indeterminate leprosy cases were identified (incidence = 3.4%). Suspect skin sections and slit skin smears were negative for bacilli. Twelve wild D. novemcinctus were investigated (48 specimens/96 slides) and histopathological features of M. leprae infection were not found, except for one skin presenting unspecific inflammatory infiltrate suggestive of indeterminate leprosy. Possible traumatic neuroma, granuloma with epithelioid and Langhans cells, foreign-body granuloma were also identified. Granulomatous/non-granulomatous dermatitides were periodic-acid-Schiff/PAS negative for fungus. M. leprae-RLEP-qPCR was negative in all armadillos’ tissues; no bacillus was found in histopathology. Our survey in rural communities confirmed the high endemicity for leprosy while one armadillo was compatible with paucibacillary M. leprae infection. At least in the highly endemic rural area of Coari, in the Brazilian Amazon region where infectious sources from untreated multibacillary leprosy are abundant, M. leprae infected armadillos may not represent a major source of infection nor a significant public health concern.

Minnis, Alexandra M.; Browne, Erica N.; Boeri, Marco; Agot, Kawango; van der Straten, Ariane; Ahmed, Khatija; Weinrib, Rachel; Mansfield, Carol

Background: Integrating end-user perspectives into the design of new biomedical HIV prevention products is recognized as vital to informing the product development pipeline. Setting: Kisumu, Kenya; Soshanguve, South Africa Methods: We conducted a discrete choice experiment survey with 536 women aged 18-30 to assess preferences for hypothetical HIV prevention products characterized by the attributes of efficacy, pregnancy prevention, delivery form, dosing frequency and side effects. Participants included product-experienced women from TRIO, a cross-over clinical study evaluating three placebo delivery forms (oral tablets, vaginal rings and injections), and a product-naïve sample recruited from the same communities. Analyses used random parameters logit and latent class models. Results: HIV prevention efficacy was a strong determinant of stated choice overall; however, in South Africa, delivery form was just as important, with an injection every 2-3 months most preferred and a daily oral tablet least preferred. In Kenya, product-experienced women preferred monthly injections and least preferred a monthly ring. Respondents indicated a preference for multi-purpose prevention technologies (MPTs) that combine HIV and pregnancy protection. Latent class analyses confirmed these findings and delineated heterogeneity in preferences across subgroups defined by age, past experience with the delivery forms, and education. Conclusions: Despite an overall preference for products with high efficacy, we identified attributes salient to future uptake and use of HIV prevention products. Preferences for injectable products underscored interest in this pre-exposure prophylaxis (PrEP) delivery form. Likewise, the MPT feature was valued in both Kenya and South Africa and most influenced interest in vaginal rings. 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: Alexandra Minnis, PhD, MPH Senior Research Epidemiologist RTI International 351 California Street, Suite 500 San Francisco, CA, 94121 Telephone: 415-848-1323 Fax: 415-848-1330 Email: aminnis@rti.org Conflicts of Interest and Source of Funding: No conflicts of interest are declared. The TRIO Study was funded by the Bill & Melinda Gates Foundation (OPP1114942). Presentation of this work: several of the results reported here were presented at the Microbicides Trials Network Annual Meeting, Washington, DC, March 2018. Slides from the plenary presentation are not publicly available. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Monica Ganan, Silje B. Lorentzen, Jane W. Agger, Catherine A. Heyward, Oddmund Bakke, Svein H. Knutsen, Berit B. Aam, Vincent G. H. Eijsink, Peter Gaustad, Morten Sørlie

by Monica Ganan, Silje B. Lorentzen, Jane W. Agger, Catherine A. Heyward, Oddmund Bakke, Svein H. Knutsen, Berit B. Aam, Vincent G. H. Eijsink, Peter Gaustad, Morten Sørlie Due to their antifungal activity, chitosan and its derivatives have potential to be used for treating yeast infections in humans. However, to be considered for use in human medicine, it is necessary to control and know the chemical composition of the compound, which is not always the case for polymeric chitosans. Here, we analyze the antifungal activity of a soluble and well-defined chito-oligosaccharide (CHOS) with an average polymerization degree (DPn) of 32 and fraction of acetylation (FA) of 0.15 (C32) on 52 medically relevant yeast strains. Minimal inhibitory concentrations (MIC) varied widely among yeast species, strains and isolates (from > 5000 to < 9.77 μg mL-1) and inhibition patterns showed a time- and dose-dependencies. The antifungal activity was predominantly fungicidal and was inversely proportional to the pH, being maximal at pH 4.5, the lowest tested pH. Furthermore, antifungal effects of CHOS fractions with varying average molecular weight indicated that those fractions with an intermediate degree of polymerization, i.e. DP 31 and 54, had the strongest inhibitory effects. Confocal imaging showed that C32 adsorbs to the cell surface, with subsequent cell disruption and accumulation of C32 in the cytoplasm. Thus, C32 has potential to be used as a therapy for fungal infections.

Hightow-Weidman L, Magnus M, Beauchamp G, et al.

AbstractBackgroundHPTN 073 assessed the feasibility, acceptability, and safety of pre-exposure prophylaxis (PrEP) for Black men who have sex with men (BMSM). The purpose of this analysis was to characterize the relationship between PrEP uptake and use, and incident STIs among participants enrolled in HPTN 073.Methods226 HIV-uninfected BMSM were enrolled in three US cities; all participants received client-centered care coordination (C4) and were offered daily oral PrEP. Participants were followed for 12 months with STI testing (rectal and urine NAAT for gonorrhea and chlamydia, RPR for syphilis) conducted at baseline, week 26 and week 52. Logistic regression was used to examine associations between STI incidence and PrEP uptake. Generalized estimating equations (GEE) evaluated associations between age, PrEP acceptance, sexual behaviors, and incident STI cases.ResultsBaseline STI prevalence was 14.2%. Men

T. Rampling et al.

Reintam Blaser, Annika; Regli,, Adrian; De Keulenaer,, Bart; Kimball,, Edward J.; Starkopf, Liis; Davis,, Wendy A.; Greiffenstein,, Patrick; Starkopf,, Joel; the Incidence, Risk Factors, and Outcomes of Intra-Abdominal (IROI) Study Investigators

Objectives: To identify the prevalence, risk factors, and outcomes of intra-abdominal hypertension in a mixed multicenter ICU population. Design: Prospective observational study. Setting: Fifteen ICUs worldwide. Patients: Consecutive adult ICU patients with a bladder catheter. Interventions: None. Measurements and Main Results: Four hundred ninety-one patients were included. Intra-abdominal pressure was measured a minimum of every 8 hours. Subjects with a mean intra-abdominal pressure equal to or greater than 12 mm Hg were defined as having intra-abdominal hypertension. Intra-abdominal hypertension was present in 34.0% of the patients on the day of ICU admission (159/467) and in 48.9% of the patients (240/491) during the observation period. The severity of intra-abdominal hypertension was as follows: grade I, 47.5%; grade II, 36.6%; grade III, 11.7%; and grade IV, 4.2%. The severity of intra-abdominal hypertension during the first 2 weeks of the ICU stay was identified as an independent predictor of 28- and 90-day mortality, whereas the presence of intra-abdominal hypertension on the day of ICU admission did not predict mortality. Body mass index, Acute Physiology and Chronic Health Evaluation II score greater than or equal to 18, presence of abdominal distension, absence of bowel sounds, and positive end-expiratory pressure greater than or equal to 7 cm H2O were independently associated with the development of intra-abdominal hypertension at any time during the observation period. In subjects without intra-abdominal hypertension on day 1, body mass index combined with daily positive fluid balance and positive end-expiratory pressure greater than or equal to 7 cm H2O (as documented on the day before intra-abdominal hypertension occurred) were associated with the development of intra-abdominal hypertension during the first week in the ICU. Conclusions: In our mixed ICU patient cohort, intra-abdominal hypertension occurred in almost half of all subjects and was twice as prevalent in mechanically ventilated patients as in spontaneously breathing patients. Presence and severity of intra-abdominal hypertension during the observation period significantly and independently increased 28- and 90-day mortality. Five admission day variables were independently associated with the presence or development of intra-abdominal hypertension. Positive fluid balance was associated with the development of intra-abdominal hypertension after day 1. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. The Incidence, Risk Factors, and Outcomes of Intra-Abdominal (IROI) Study Investigators are listed in the Acknowledgments. 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). ConvaTec Limited (Deerside, United Kingdom) provided either the Abdo-Pressure (Foley manometer method) or AbViser systems (modified Kron’s method) for intra-abdominal pressure measurements free of charge for all participating sites if products were licensed in the respective countries. Dr. Reintam Blaser received funding (honoraria for advisory board meetings or speaker fees) from Nestlé, Fresenius, and Nutricia, and shedisclosed she is a member of Executive Committee of the Abdominal Compartment Society. Drs. Regli, De Keulenaer, and Kimball disclosed that ConvaTec Limited (Deerside, United Kingdom) provided either Abdo-Pressure (modified Kron’s method) or AbViser systems (Foley Manometer method) for intra-abdominal pressure measurements free of charge for all the participating sites if products were licensed in the countries. ConvaTec Limited had no influence on study design, analysis of data, or manuscript preparation. Dr. Joel Starkopf has received speaker fees from B. Braun and Fresenius. Dr. Greiffenstein received funding from Zimmer Biomet, DuPuy Synthes, and KLS Martin, and he disclosed that Atox Bio Ltd. (http://www.atoxbio.com) is sponsoring a Phase III Drug trial for which he is Principal Investigator at his site/hospital, but he does not receive any funds directly. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: annika.reintam.blaser@ut.ee Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Abstract Background There has been significant progress in eliminating malaria in Iran. The aim of this study is to investigate the structure of inter-organizational collaboration networks in the field of unauthorized immigrants and refugees access to services in order to eliminate malaria. Methods This study employed social network analysis, in which nodes represented stakeholders associated with providing access of immigrants and refugees to services in the field of malaria elimination, and ties indicated the level of collaboration. This study adopted socio-centric analysis and the whole network was studied. In this regard, 12 districts of the malaria-endemic area in Iran were selected. Participants included 360 individuals (30 representatives of the organization/group in each district). The data were gathered by interview, using the levels of collaboration scale. UCINET 6 was used for data analysis. The indices of density, centralization, reciprocity, and clustering were investigated for each twelve network and at each level of collaboration. Results The average density of the networks was 0.22 (SD: 0.04). In districts with a high incidence of imported malaria, the values of network density and centralization were high and the networks comprised of a larger connected component (less isolated clusters). There were significant correlations between density of network (r = 0.66, P = 0.02), degree centralization (r = 0.65, P = 0.02), betweenness centralization (r = 0.76, P = 0.004), and imported malaria cases. In general, the degree centrality and betweenness centrality of the organizations of health, district governor, and foreign immigrants’ affairs were higher. In all networks, 60% of the relationships were bilateral. At a higher level of collaboration, the centralization declined and reciprocity increased. The average of betweenness centralization index was 22.76 (SD = 3.88). Conclusions Higher values of network indices in border districts and districts with more cases of imported malaria, in terms of density and centralization measures, can propose the hypothesis that higher preparedness against the issue and centralization of power can enable a better top-down outbreak management, which needs further investigations. Higher centrality of governmental organizations indicates the need for involving private, non-governmental organizations and representatives of immigrant and refugee groups. Recognition of the existing network structure can help the authorities increase access to malaria prevention, diagnosis, and treatment services among immigrants and refugees.…

Rupa R. Patel, John S. Crane, Julia López, Philip A. Chan, Albert Y. Liu, Rubabin Tooba, Aimee S. James

by Rupa R. Patel, John S. Crane, Julia López, Philip A. Chan, Albert Y. Liu, Rubabin Tooba, Aimee S. James Pre-exposure prophylaxis (PrEP) is effective in preventing HIV infections among men who have sex with men (MSM). PrEP uptake and adherence remain low and product preferences are unknown, especially among young African American MSM who are most at-risk. We conducted 26 qualitative interviews from 2014–2016 among young adult HIV-negative African American MSM regarding PrEP product preferences in Missouri. While the pill and injectable were most liked of all modalities, about a quarter preferred rectal products or patches. Most participants preferred a long-acting injectable (LAI) to daily oral pills due to better medication adherence and a dislike for taking pills. Many participants preferred daily oral pills to on-demand oral PrEP due to the inability to predict sex and the perception that insufficient time or medication would not achieve HIV protection with on-demand. A fear of needles and the perception that there would not be therapeutic levels for a long duration were concerns with injectable PrEP. Study findings highlight the need for a range of prevention options for African American MSM and can inform PrEP product development as well as dissemination and implementation efforts.

Kathy Baisley, Natsayi Chimbindi, Nondumiso Mthiyane, Sian Floyd, Nuala McGrath, Deenan Pillay, Janet Seeley, Thembelihle Zuma, Jaco Dreyer, Dickman Gareta, Theresa Smit, Tinofa Mutevedzi, Justin Fenty, Kobus Herbst, Isolde Birdthistle, Maryam Shahmanesh

by Kathy Baisley, Natsayi Chimbindi, Nondumiso Mthiyane, Sian Floyd, Nuala McGrath, Deenan Pillay, Janet Seeley, Thembelihle Zuma, Jaco Dreyer, Dickman Gareta, Theresa Smit, Tinofa Mutevedzi, Justin Fenty, Kobus Herbst, Isolde Birdthistle, Maryam Shahmanesh Background Young men are less likely than young women to engage with HIV prevention and care, and their HIV-related mortality is higher. We describe HIV incidence and uptake of HIV services in men 20–29 years(y) in rural KwaZulu-Natal, South Africa, before the roll-out of DREAMS. Methods We used data from a population-based demographic and HIV surveillance cohort. HIV incidence was estimated from anonymised testing in an annual serosurvey. Service uptake was assessed in 2011 and 2015, through two self-reported outcomes: 1) HIV testing in the past 12 months(m); 2) voluntary medical male circumcision(VMMC). Logistic regression was used to estimate odds ratios(OR) and 95% confidence intervals(CI) for factors associated with each outcome. Results HIV incidence in 2011–2015 was 2.6/100 person-years (95%CI = 2.0–3.4) and 4.2 (95%CI = 3.1–5.6) among men 20-24y and 25-29y, respectively, with no significant change from 2006–2010. N = 1311 and N = 1221 young men participated in the 2011 and 2015 surveys, respectively. In both years, 1 partner in the past 12m, or condom use at last sex, but lower in those reporting a casual partner (adjusted (a)OR = 0.53, 95%CI = 0.37–0.75). VMMC uptake was associated with survey year and higher education. Men aged 25-29y and those who were employed (aOR = 0.66; 95%CI = 0.49–0.89) were less likely to report VMMC. Conclusions HIV incidence in men 20-29y was very high, and pre-exposure prophylaxis (PrEP) should be considered in this population. Uptake of services was low. VMMC coverage increased dramatically from 2011 to 2015, especially among younger men, suggesting a demand for this service. Interventions designed with and for young men are urgently needed.…

Griffin, Benjamin R.; Jovanovich, Anna; You, Zhiying; Palevsky, Paul; Faubel, Sarah; Jalal, Diana

Objectives: Thrombocytopenia is common in critically ill patients with severe acute kidney injury and may be worsened by the use of renal replacement therapy. In this study, we evaluate the effects of renal replacement therapy on subsequent platelet values, the prognostic significance of a decrease in platelets, and potential risk factors for platelet decreases. Design: Post hoc analysis of the Acute Renal Failure Trial Network Study. Setting: The Acute Renal Failure Trial Network study was a multicenter, prospective, randomized, parallel-group trial of two strategies for renal replacement therapy in critically ill patients with acute kidney injury conducted between November 2003 and July 2007 at 27 Veterans Affairs and university-affiliated medical centers. Subjects: The Acute Renal Failure Trial Network study evaluated 1,124 patients with severe acute kidney injury requiring renal replacement therapy. Interventions: Predictor variables were thrombocytopenia at initiation of renal replacement therapy and platelet decrease following renal replacement therapy initiation. Measurements and Main Results: Outcomes were mortality at 28 days, 60 days, and 1 year, renal recovery, renal replacement therapy free days, ICU-free days, and hospital-free days. Baseline thrombocytopenia in patients requiring renal replacement therapy was associated with increased mortality and was also associated with lower rates of renal recovery. A decrease in platelet values following renal replacement therapy initiation was associated with increased mortality. Continuous renal replacement therapy was not an independent predictor of worsening thrombocytopenia compared with those treated with intermittent hemodialysis. Conclusions: Baseline thrombocytopenia and platelet decrease following renal replacement therapy initiation were associated with increased mortality, and baseline thrombocytopenia was associated with decreased rates of renal recovery. Continuous renal replacement therapy did not decrease platelets compared with hemodialysis. The analyses presented in this article were not prepared in conjunction with the Acute Renal Failure Trial Network (ATN) Study investigators and do not represent the opinions or views of the ATN study, the Veterans Affairs, or the National Institute of Diabetes and Digestive and Kidney Diseases. Drs. Griffin, Jovanovich, Palevsky, Faubel, Jalal contributed to research idea and study design and data analysis/interpretation. Dr. Griffin contributed to data acquisition. Dr. You contributed to statistical analysis. Drs. Jovanovich, Palevsky, Faubel, Jalal contributed to supervision or mentorship. Each author contributed important intellectual content during article drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. 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). The Department of Veterans Affairs (VA)/National Institutes of Health Acute Renal Failure Trial Network study was supported, in part, by the Cooperative Studies Program (CSP) of the VA Office of Research and Development as CSP number 530 and by the National Institute of Diabetes and Digestive and Kidney Diseases under interagency agreement Y1-DK-3508-01. Dr. Griffin’s institution received funding from National Kidney Foundation, and he received funding from the Nephrology Young Investigators Meeting (travel). Dr. Griffin is supported by a National Research Service Award Institutional Predoctoral Training Grant (T32), grant number T32 DK 007135. Dr. Jovanovich’s institution received funding from Veterans Affairs, and she disclosed government work. Dr. Jovanovich is supported by Veterans Affairs CDA 5IK2CX001030-04. Drs. Palevsky and Jalal received support for article research from the National Institutes of Health. Dr. Palevsky also received support for article research from the United States Department of Veterans Affairs. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: benjamin.griffin@ucdenver.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Mehta, Anuj B.; Walkey, Allan J.; Curran-Everett, Douglas; Matlock, Daniel; Douglas, Ivor S.

Objectives: Prior studies investigating hospital mechanical ventilation volume-outcome associations have had conflicting findings. Volume-outcome relationships within contemporary mechanical ventilation practices are unclear. We sought to determine associations between hospital mechanical ventilation volume and patient outcomes. Design: Retrospective cohort study. Setting: The California Patient Discharge Database 2016. Patients: Adult nonsurgical patients receiving mechanical ventilation. Interventions: The primary outcome was hospital death with secondary outcomes of tracheostomy and 30-day readmission. We used multivariable generalized estimating equations to determine the association between patient outcomes and hospital mechanical ventilation volume quartile. Measurements and Main Results: We identified 51,689 patients across 274 hospitals who required mechanical ventilation in California in 2016. 38.2% of patients died in the hospital with 4.4% receiving a tracheostomy. Among survivors, 29.5% required readmission within 30 days of discharge. Patients admitted to high versus low volume hospitals had higher odds of death (quartile 4 vs quartile 1 adjusted odds ratio, 1.40; 95% CI, 1.17–1.68) and tracheostomy (quartile 4 vs quartile 1 adjusted odds ratio, 1.58; 95% CI, 1.21–2.06). However, odds of 30-day readmission among survivors was lower at high versus low volume hospitals (quartile 4 vs quartile 1 adjusted odds ratio, 0.77; 95% CI, 0.67–0.89). Higher hospital mechanical ventilation volume was weakly correlated with higher hospital risk-adjusted mortality rates (ρ = 0.16; p = 0.008). These moderately strong observations were supported by multiple sensitivity analyses. Conclusions: Contrary to previous studies, we observed worse patient outcomes at higher mechanical ventilation volume hospitals. In the setting of increasing use of mechanical ventilation and changes in mechanical ventilation practices, multiple mechanisms of worse outcomes including resource strain are possible. Future studies investigating differences in processes of care between high and low volume hospitals are necessary. This work was performed at the National Jewish Health, Denver, CO. Dr. Mehta helped to study design, statistical analysis, data interpretation, and article preparation. Dr. Walkey helped to data interpretation and article preparation. Dr. Curran-Everett helped to statistical analysis and article preparation. Dr. Matlock helped to data interpretation and article preparation. Dr. Douglas helped to study design, data interpretation, and article preparation. Dr. Mehta takes full responsibility for the content of the article, data analysis, and data interpretation. 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. Mehta is supported, in part, by National Institutes of Health (NIH) K12HL137862. Dr. Walkey is supported by NIH K01HL116768 and R01HL136660. Dr. Curran-Everett is supported by NIH RHL089897B-08. Dr. Matlock is supported by NIH R01HL136403-01. Dr. Douglas is supported by NIH 1R01NR016459-01. Drs. Mehta and Matlock received support for article research from the National Institutes of Health. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: mehtaa@njhealth.org Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Welin, E. R., Ngamnithiporn, A., Klatte, M., Lapointe, G., Pototschnig, G. M., McDermott, M. S. J., Conklin, D., Gilmore, C. D., Tadross, P. M., Haley, C. K., Negoro, K., Glibstrup, E., Grünanger, C. U., Allan, K. M., Virgil, S. C., Slamon, D. J., Stoltz, B. M.

The bis-tetrahydroisoquinoline (bis-THIQ) natural products have been studied intensively over the past four decades for their exceptionally potent anticancer activity, in addition to strong gram-positive and -negative antibiotic character. Synthetic strategies toward these complex polycyclic compounds have relied heavily on electrophilic aromatic chemistry, such as the Pictet-Spengler reaction, that mimics their biosynthetic pathways. Herein we report an approach to two bis-THIQ natural products, jorunnamycin A and jorumycin, that instead harnesses the power of modern transition-metal catalysis for the three major bond-forming events and proceeds with high efficiency (15 and 16 steps, respectively). By breaking from biomimicry, this strategy allows for the preparation of a more diverse set of non-natural analogs.…

Harper, Kristin Nicole

No abstract available…

Heffron, Renee; Stalter, Randy; Pyra, Maria; Nanda, Kavita; Erikson, David W.; Hladik, Florian; Blue, Steven W.; Davis, Nicole L.; Mugo, Nelly; Kourtis, Athena P.; Lingappa, Jairam R.; Baeten, Jared M.; for the Partners PrEP Study and Partners in Prevention HSV/HIV Transmission Study Teams

Background: Some observational studies have found increased HIV risk associated with self-reported use of injectable depot medroxyprogesterone acetate (DMPA). Testing blood samples for MPA, the progestin in DMPA, permits validation of self-reported data and exploration of whether potential HIV risk is correlated with MPA levels, which are highest soon after injection. Methods: We conducted a case-control study testing archived serum from women who participated in three longitudinal studies of HIV prevention in East and southern Africa. Case samples, from women who acquired HIV, were from visits that occurred at or immediately prior to the first evidence of HIV infection. Secondary analyses restricted to case samples collected within 15 and 30 days of the estimated date of HIV infection. Matched control samples were from women who remained HIV-uninfected. We used multivariable conditional logistic regression to compare exogenous hormone levels, quantified through mass spectrometry, among cases and controls. Results: When restricted to cases with samples collected within ≤15 days of estimated date of HIV infection, MPA detection was more frequent among women who acquired HIV (adjusted odds ratio [AOR] = 2.75, 95% confidence interval [CI] 1.22–6.19). In this subset, the increase in HIV risk was only among samples with MPA detected at a low level of 0.02–0.50ng/ml: 36.7% of cases and 9.4% of controls, AOR = 6.03, 95% CI 2.50–14.54. Conclusions: Detection of MPA at low levels close to the estimated time of HIV acquisition was significantly more frequent among women who acquired HIV. Studies are needed that explore biological mechanisms elicited by any MPA level and HIV risk. Correspondence to Renee Heffron, 325 Ninth Avenue Box 359927, Seattle, WA 98104. Tel: +206 520 3800; fax: +206 530 3831; e-mail: rheffron@uw.edu Received 27 October, 2018 Revised 6 December, 2018 Accepted 10 December, 2018 Copyright © 2018 Wolters Kluwer Health, Inc.

Soentjens P, De Koninck K, Tsoumanis A, et al.

AbstractBACKGROUNDEffective and safe single-visit rabies vaccination for pre- and post-exposure prophylaxis (PrEP and PEP) could substantially simplify rabies prevention and therefore increase compliance.METHODSIn a comparative trial, 303 healthy adults received a primary vaccination consisting of two intradermal (ID) doses of 0.1mL of the purified chicken embryo cell vaccine (PCEV) during a single visit. One year later, subjects were randomly assigned to receive either four or two ID PEP booster doses of 0.1mL of PCEV during a single visit.The primary endpoint for immunogenicity was the percentage of subjects with an adequate antibody level (>0.5 IU/mL) seven days after the booster doses. The safety endpoint was the proportion of participants developing adverse events (AE) following primary and/or booster vaccination.RESULTSll subjects, except one (99.3%) in each study group, had a rabies antibody titer >0.5 IU/mL on day 7 following the booster schedules.Subjects exposed to the four-dose PEP schedule had a geometric mean titer of 20 IU/mL versus 14 IU/mL for the two-dose PEP schedule (p=0.0228).Local reactions at the injection site following PrEP and PEP were mild and transient and only seen in 14.9% and 49.6 to 53% of the participants respectively. No serious AE were reported.CONCLUSIONIn healthy adults, a two-dose (2x 0.1mL) single-visit intradermal post-exposure prophylaxis schedule was as immunologically adequate and safe as a four-dose (4x 0.1mL) single-visit PEP schedule, seven to twenty-eight months following a two-dose (2x 0.1mL) single-visit intradermal pre-exposure prophylaxis.

GBD 2017 Influenza Collaborators

This comprehensive assessment of the burden of influenza LRTIs shows the substantial annual effect of influenza on global health. Although preparedness planning will be important for potential pandemics, health loss due to seasonal influenza LRTIs should not be overlooked, and vaccine use should be considered. Efforts to improve influenza prevention measures are needed.

Abstract Background Hepatitis E virus (HEV) is a leading cause of hepatitis worldwide. However, its infection biology and pathogenesis remain largely elusive. Furthermore, no proven medication is available for treating hepatitis E. Robust experimental models are urgently required to advance the research of HEV infection. Because of the lacking of a sophisticated small animal model, this study aimed to establish a mouse model of HEV infection. Methods We constructed a full-length swine HEV cDNA clone of genotype 4 (named as pGEM-HEV) by reverse genetics approach. And we inoculated with HEV RNA in BALB/c mice to establish small animal model for HEV infection and pathogenesis studies. Results The capped RNA transcripts of pGEM-HEV prepared in vitro were replication-competent in HepG2 cells. Importantly, BALB/c mice intravenously inoculated with RNA transcripts of pGEM-HEV developed an active infection as shown by shedding viruses in feces, detectable negative strand of HEV in the liver, spleen and kidney, and causing liver inflammation. Conclusion In this study, we successfully established of BALB/c mice-based small animal model for HEV provides an opportunity to further understand HEV pathogenesis and to develop effective antiviral medications.…

Abstract Background The number of cases of Lymphogranuloma venereum (LGV) is increasing in Europe. The described epidemic is mostly confined to HIV positive men who have sex with men (MSM). However, dissemination of LGV from HIV positive to HIV negative MSM could take place due to the implementation of pre-exposure prophylaxis (PrEP) and subsequent possible decrease in condom use. We describe here the LGV epidemiology in Belgium before the PrEP-era, starting from 2011 up to the end of the first half of 2017. Methods A descriptive analysis of the socio-demographic and clinical characteristics of all LGV cases was performed. Fisher’s exact test was used to compare symptomatic to asymptomatic patients. Logistic regression models were used to check for trends over time for: number of LGV cases, HIV status and symptoms. Results The number of LGV cases rose by a factor four, from 21 in 2011 to 88 in 2016, and regression models showed a positive trend estimate of 14% increase per half year (p 

Willie, Tiara C.; Stockman, Jamila K.; Keene, Danya E.; Calabrese, Sarah K.; Alexander, Kamila A.; Kershaw, Trace S.

Background: In the U.S., women represent less than 5% of all pre-exposure prophylaxis (PrEP) users. Social networks may promote and/or inhibit women’s PrEP awareness, which could influence PrEP intentions. Further, women experiencing intimate partner violence (IPV) may have smaller, less supportive networks, which could deter or have no impact on PrEP care engagement. This study examined associations between network characteristics and women’s PrEP awareness, interest, uptake, and perceived candidacy; and analyzed IPV as an effect modifier. Setting/Methods: From 2017 to 2018, data were collected from a prospective cohort study of 218 PrEP-eligible women with (n=94) and without (n=124) IPV experiences in Connecticut. Women completed surveys on demographics, IPV, social networks, and PrEP care continuum outcomes. Results: Adjusted analyses showed that PrEP awareness related to having more PrEP-aware alters. PrEP intentions related to having more alters with favorable opinions of women’s potential PrEP use and a smaller network size. Viewing oneself as an appropriate PrEP candidate related to having more PrEP-aware alters and more alters with favorable opinions of women’s potential PrEP use. IPV modified associations between network characteristics and PrEP care. Having members who were aware of and/or used PrEP was positively associated with PrEP care engagement for women without IPV experiences, but had either no effect or the opposite effect for women experiencing IPV. Conclusion: Improving PrEP attitudes might improve its utilization among women. Social network interventions might be one way to increase PrEP uptake among many U.S. women, but may not be as effective for women experiencing IPV. Corresponding author: Tiara C. Willie, MA; Center for Interdisciplinary Research on AIDS, Yale University, New Haven, CT, USA; Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA. Email: tiara.willie@yale.edu, Phone: 336-327-0064 Conflicts of Interest and Sources of support: Authors declare no conflicts of interest. 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 P30-MH062294. TCW was supported by the NIMH via F31-MH113508 and R25-MH083620. Support for SKC was provided by the National Institutes of Mental Health via Award Number K01-MH103080. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (NIH). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Bordallo-Cardona, M. A., Sanchez-Carrillo, C., Bouza, E., Munoz, P., Escribano, P., Guinea, J.

Infections caused by the co-existence of C. glabrata echinocandin-resistant- and echinocandin-susceptible cells may be possible and the detection of FKS mutants when the proportions of FKS mutants are underrepresented poses a problem. We assessed the role of EUCAST and methods directly performed on positive blood cultures – Etest (ETDIR) and anidulafungin-containing agar plates – for detecting resistance in C. glabrata isolates containing different amounts of echinocandin-susceptible/resistant Candida glabrata isolates.We studied ten pairs of C. glabrata involving parental echinocandin-susceptible and isogenic echinocandin-resistant FKS mutant isolates. Three inocula per pair (1-5 x 103, 1-5 x 102, and 10-50 CFU/mL) were prepared spanning suspensions with different amounts of susceptible/resistant isolates (9/1, 5/5, and 1/9). Suspensions were spiked in BACTEC bottles and incubated until positive and compared the three methods.The EUCAST showed echinocandin resistance when the bottles were spiked with resistant isolates at 5/5 and 1/9 proportions; the suspensions with a 9/1 proportion of resistant isolates resulted susceptible in three pairs. We observed with the ETDIR, resistance to both echinocandins in all pairs (resistance to micafungin and anidulafungin, MICs ≥ 0.064 mg/L and ≥ 0.125 mg/L, respectively) and a double ring of growth inhibition in two pairs. The anidulafungin-containing plates showed fungal growth in the 90 spiked blood cultures at 48 hours. Testing of echinocandin susceptibility with the ETDIR directly on blood positive bottles is a reliable and rapid method to detect echinocandin resistance in C. glabrata. On the other hand, resistance can be missed with the EUCAST method when resistant-isolates are underrepresented.…

McGowan, Ian; Wilkin, Timothy; Landovitz, Raphael J.; Wu, Chunyuan; Chen, Ying; Marzinke, Mark A.; Hendrix, Craig W.; Richardson, Paul; Eshleman, Susan H.; Andrade, Adriana; Chege, Wairimu; Anderson, Peter L.; McCauley, Marybeth; Farley, Jason; Mayer, Kenneth H.; Anton, Peter; Brand, Rhonda M.; Cranston, Ross D.; Gulick, Roy

Objective: HIV Prevention Trials Network 069/AIDS Clinical Trials Group A5305 was a study of 48-week oral pre-exposure prophylaxis (PrEP) regimens in MSM and transgender women. A rectal substudy was included to evaluate drug concentrations in rectal compartment vs. blood, gut-associated lymphoid tissue (GALT) responses to four antiretroviral PrEP regimens [maraviroc (MVC), MVC + emtricitabine (FTC), MVC + tenofovir (TFV) disoproxil fumarate, and TFV disoproxil fumarate + FTC], and to determine whether ARV exposure was associated with ex-vivo suppression of HIV infection in colorectal explants. Methods: C-C chemokine receptor type 5 (CCR5) genotype was characterized using PCR. At baseline and at Weeks 24, 48, and 49, GALT phenotype was characterized by flow cytometry, rectal biopsies were challenged with HIV-1BaL, and tissue and plasma pharmacokinetics were measured via mass spectrometry. Results: Exposure to MVC was not associated with increased expression of CD4+/CCR5+ HIV target T cells. Significant ex-vivo viral suppression compared with baseline was seen at Weeks 24 and 48, ranging from 1.4 to 1.8 log10 for all study regimens except the MVC-alone arm which did not show statistically significant viral suppression at Week 48. Tissue concentrations of TFV, TFV-diphosphate, and FTC were correlated with viral suppression. Conclusion: MVC-containing HIV PrEP regimens did not increase GALT CD4+ T-cell activation or the CD4+/CCR5+ phenotype. No virologic suppression was seen with MVC-alone at Week 48 compared with combination regimens, suggesting MVC monotherapy might be less effective than combination antiretroviral PrEP regimens. Correspondence to Ian McGowan, MD, PhD, FRCP, Chief Scientific Officer, Orion Biotechnology 343 Preston St, Ottawa, Ontario, K1S 1N4, Canada. Tel: +1 412 352 5270; e-mail: ian.m@orionbiotechnology.com Received 15 December, 2017 Accepted 8 July, 2018 Copyright © 2018 Wolters Kluwer Health, Inc.

Wray, Tyler B.; Chan, Philip A.; Kahler, Christopher W.; Simpanen, Erik M.; Liu, Tao; Mayer, Kenneth H.

Background: Pre-exposure prophylaxis (PrEP) is highly efficacious, but some groups of men who have sex with men (MSM) may have difficulty adhering to daily dosing. Prevention-effective adherence suggests that PrEP’s efficacy depends on adherence at the time of HIV exposure, yet few studies have examined how exposures (i.e., high-risk sex) overlap with periods of consecutive missed PrEP doses. Substance use may also play a role in these vulnerable periods. Methods: We used digital pill bottles to monitor the daily adherence of 40 PrEP-experienced patients recruited from an outpatient clinic in the Northeastern US over a six-month period. Participants also completed detailed online diaries every two weeks during this time that surveyed their sexual behavior and substance use each day. Results: Daily adherence was high overall (M = 83.9%, SD = 18.0%), but 53% (N = 21) had a lapse of > 3 consecutive daily PrEP doses over six months. Participants’ rate of engaging in high-risk condomless anal sex (CAS) did not differ across lapse days versus continuously-adherent days. Alcohol use was not associated with engaging in CAS during a PrEP lapse. However, participants reported engaging in CAS significantly more often during a PrEP adherence lapse on days when they also used stimulant drugs. Conclusions: MSM may have periodic difficulty adhering to PrEP at the specific times when they are at-risk. Stimulant drug use could play an important role in increasing HIV risk specifically during adherence lapses. Correspondence regarding this article may be sent to: Tyler B. Wray, Ph.D. Center for Alcohol and Addictions Studies Brown University School of Public Health 121 South Main Street Providence, RI 02912 Phone: 401-863-6659 Fax: 401-863-6697 Email: tyler_wray@brown.edu Conflicts of Interest: The authors have no conflicts of interest to report. Conflicts of interest: Dr. Mayer has received unrestricted research grants from Gilead Sciences and ViiV. Compliance with Ethical Standards Informed consent: Informed consent was obtained from all individual participants included in the study. Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.