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.

Patralekha Chatterjee

When it comes to emergency response in low- and middle-income countries, psychosocial support is not usually a priority, but Kerala was prepared. Patralekha Chatterjee reports from Ernakulam.

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.

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.…

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?…

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.…

Abstract Background The new HIV treatment guidelines in China recommend antiretroviral therapy (ART) for all people living with HIV, but significant gaps in implementation still exist. Pre-exposure prophylaxis (PrEP) can effectively reduce the risk of HIV transmission among men who have sex with men (MSM). This study assessed the epidemiological impact and cost effectiveness of PrEP, enhanced biomedical interventions and their combination among MSM in China. Methods A deterministic mathematical model was developed and projected over 20 years to assess the impact of the PrEP, biomedical interventions and their combinations. Incidence and prevalence of HIV were measured, and cost-effectiveness was assessed using incremental cost (international dollars, Int.$) per quality-adjusted life year (QALY) gained. Results A total of 0.78 million new HIV infections were estimated to occur over the next 20 years if no additional interventions are implemented among MSM. The PrEP-only strategy covering 25–75% of HIV-negative high-risk MSM can prevent 0.09–0.20 million (12.1–25.7%) new infections, at a cost of 17,277–18,452 Int.$/QALY. The optimal cost-effectiveness path is from test-and-treat to the combination strategy of test-and-treat and PrEP. Some strategies could almost eliminate new HIV infections over the next 20 years. Conclusions PrEP, test-and-treat, and their combinations among MSM are effective and cost-effective relative to current policy. PrEP is an important and cost-effective addition to current policy in China.…

Beernink P, Ispasanie E, Lewis L, et al.

AbstractBackgroundMeningococcal outer membrane vesicle (OMV) vaccines are prepared with detergents to remove endotoxin, which also removes desirable antigens such as Factor H binding protein (FHbp). Native OMV (NOMV) vaccines with genetically attenuated endotoxin do not require detergent treatment and elicit broader serum bactericidal antibody (SBA) responses than OMV or recombinant FHbp (rFHbp) vaccines.MethodsWe measured human complement-mediated SBA responses of mice immunized with NOMV with over-expressed FHbp sub-family B (NOMV-FHbp), NOMV with FHbp genetically inactivated (NOMV-KO) and/or a control rFHbp vaccine against meningococcal and gonococcal strains.ResultsDespite having 36-fold less FHbp per dose, the NOMV-FHbp vaccine elicited a ≥3-fold higher serum IgG anti-FHbp geometric mean titer than control vaccines containing FHbp (p≤0.003). Against two meningococcal outbreak strains with mismatched PorA and heterologous FHbp sub-family B sequence variants, the NOMV-FHbp vaccine produced ≥30-fold higher SBA titers than control vaccines. Mice immunized with NOMV-FHbp and NOMV-KO vaccines also elicited SBA against a gonococcal strain (p

Chan, W.-Y., Entwisle, C., Ercoli, G., Ramos-Sevillano, E., McIlgorm, A., Cecchini, P., Bailey, C., Lam, O., Whiting, G., Green, N., Goldblatt, D., Wheeler, J. X., Brown, J. S.

Current vaccination against Streptococcus pneumoniae uses vaccines based on capsular polysaccharides from selected serotypes, and has led to non-vaccine serotype replacement disease. We have investigated an alternative serotype-independent approach, using multiple-antigen vaccines (MAV) prepared from S. pneumoniae TIGR4 lysates enriched for surface proteins by a chromatography step after culture under conditions that induce expression of heat shock proteins (Hsp, thought to be immune adjuvants). Proteomics and immunoblots demonstrated that compared to standard bacterial lysates, MAV was enriched with Hsps and contained several recognised protective protein antigens, including pneumococcal surface protein A (PspA) and pneumolysin (Ply). Vaccination of rodents with MAV induced robust antibody responses to multiple serotypes, including non-pneumococcal conjugate vaccine serotypes. Homologous and heterologous strains of S. pneumoniae were opsonised after incubation in sera from vaccinated rodents. In mouse models, active vaccination with MAV significantly protected against pneumonia, whilst passive transfer of rabbit serum from MAV vaccinated rabbits significantly protected against sepsis caused by both homologous and heterologous S. pneumoniae strains. Direct comparison of MAV preparations made with or without the heat-shock step showed no clear differences in protein antigen content and antigenicity, suggesting that the chromatography step rather than Hsp induction improved MAV antigenicity. Overall, these data suggest that the MAV approach may provide serotype-independent protection against S. pneumoniae.…

Spinelli, Matthew A.; Scott, Hyman M.; Vittinghoff, Eric; Liu, Albert Y.; Morehead-Gee, Alicia; Gonzalez, Rafael; Gandhi, Monica; Buchbinder, Susan P.

Abstract: Background: Timely pre-exposure prophylaxis (PrEP) initiation is critical in at-risk populations given that HIV acquisition risk persists during delays. Time to treatment initiation, a key metric in HIV care, has not been explored among PrEP users. Interventions that reduce time to PrEP initiation could prevent HIV infections. Setting: Individuals initiating PrEP in a large, primary care health network of 15 clinics, the San Francisco Primary Care Clinics (SFPCC) from July 2012-July 2017 (N=411). Methods: We examined factors associated with time from first PrEP discussion with a provider to PrEP initiation date using an adjusted Cox proportional-hazards model, with hazard ratios (HR) >1 indicating earlier initiation. We also examined the relationship between delayed PrEP initiation and PrEP persistence (staying on PrEP) in an adjusted Cox proportional-hazards model. Results: PrEP users initiated PrEP after a median of only 7 days. However, there were notable outliers, with 29% waiting >30 days and 12% waiting >90 days. In an adjusted proportional-hazards model, a panel management and patient navigation intervention was associated with earlier PrEP initiation (HR: 1.5; 95% CI: 1.1-2.0), while only other race/ethnicity compared to White race was associated with delayed PrEP initiation (HR:0.7; 0.5-1.0). Delayed PrEP initiation >30 days was associated with shorter PrEP persistence in an adjusted proportional-hazards model (HR: 1.3; 1.0-1.7). Conclusion: PrEP initiation within a week is feasible in a primary care safety-net health system. Setting a goal of rapid PrEP initiation, with the support of panel management and patient navigation, could address delays in at-risk groups. Correspondence: 25 Van Ness Avenue, Ste. 100, San Francisco, CA 94102, United States, Phone: 415-437-7483, Fax: 415-431-7029, Matthew.Spinelli@UCSF.edu Conflicts of Interest and Sources of Funding: The authors have no conflicts of interest to report. This work was supported by the National Institute of Mental Health at the National Institute of Health [R01MH109320]. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Abstract Background World Health Organization (WHO), the World Bank, UN System Influenza Coordination (UNSIC) and other international organizations released a series of documents to fight against the influenza pandemic. Those documents have great significance on guiding influenza pandemic preparedness and responses and providing a multilevel, multi-directional influenza pandemic prevention and control network for their member countries. This study focuses on the above-mentioned influenza pandemic preparedness guidelines with the aim of exploring the roles of the society, defining the relationship of different interventions and evaluating the planning on influenza pandemic preparedness. Methods Documents about pandemic influenza preparedness were retrieved from the official websites of the following three international organizations, World Health Organization (WHO), the World Bank, UN System Influenza Coordination (UNSIC) with the key words ‘pandemic’, ‘influenza’ and the Boolean combinations of these words as the retrieval strategy. Guidelines, research study and meeting reports were included in the study. The categories of the ministries/departments involved and their roles/responsibilities in pandemic influenza preparedness were summarized. Word frequency of selected vocabularies about pandemic influenza preventive measures were collected from the documents and the correlations between the word frequency of these measures were analyzed. Ochiai coefficient was employed to show the correlation between the word vocabularies. Results A total of 38 records on the topic of pandemic influenza preparedness were included. The responsibilities of the whole-of-society mentioned in the international organizations’ documents varied across the 2009 influenza pandemic period. Meanwhile, it had been emphasized that a comprehensive influenza prevention and control plan in every sector should be developed and evaluated. Because various measures were emphasized in the guidelines after 2009 pandemic influenza, the correlations between the word frequencies of the various influenza preventive measures became stronger after the pandemic influenza. Conclusions Responsibilities of ministries of education, ministries of energy, ministries of agriculture and animal health, ministries of communication and the business sector in the pandemic influenza preparedness were described more comprehensively in the international organizations’ documents in 2017. Better understanding the variations of the guidelines delivered by international organizations would be useful for the member countries to strengthen their influenza control network.…

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.…

Abstract Background Anopheles sacharovi is a dominant malaria vector species in South Europe and the Middle East which has a highly plastic behaviour at both adult and larval stages. Such plasticity has prevented this species from eradication by several anti-vector campaigns. The development of new genome-based strategies for vector control will benefit from genome sequencing and physical chromosome mapping of this mosquito. Although a cytogenetic photomap for chromosomes from salivary glands of An. sacharovi has been developed, no cytogenetic map suitable for physical genome mapping is available. Methods Mosquitoes for this study were collected at adult stage in animal shelters in Armenia. Polytene chromosome preparations were prepared from ovarian nurse cells. Fluorescent in situ hybridization (FISH) was performed using PCR amplified probes. Results This study constructed a high-quality standard photomap for polytene chromosomes from ovarian nurse cells of An. sacharovi. Following the previous nomenclature, chromosomes were sub-divided into 39 numbered and 119 lettered sub-divisions. Chromosomal landmarks for the chromosome recognition were described. Using FISH, 4 PCR-amplified genic probes were mapped to the chromosomes. The positions of the probes demonstrated gene order reshuffling between An. sacharovi and Anopheles atroparvus which has not been seen cytologically. In addition, this study described specific chromosomal landmarks that can be used for the cytotaxonomic diagnostics of An. sacharovi based on the banding pattern of its polytene chromosomes. Conclusions This study constructed a high-quality standard photomap for ovarian nurse cell chromosomes of An. sacharovi and validated its utility for physical genome mapping. Based on the map, cytotaxonomic features for identification of An. sacharovi have been described. The cytogenetic map constructed in this study will assist in creating a chromosome-based genome assembly for this mosquito and in developing cytotaxonomic tools for identification of other species from the Maculipennis group.…

Mart L. Stein, Vincent Buskens, Peter G. M. van der Heijden, Jim E. van Steenbergen, Albert Wong, Martin C. J. Bootsma, Mirjam E. E. Kretzschmar

by Mart L. Stein, Vincent Buskens, Peter G. M. van der Heijden, Jim E. van Steenbergen, Albert Wong, Martin C. J. Bootsma, Mirjam E. E. Kretzschmar Respondent-driven detection is a chain recruitment method used to sample contact persons of infected persons in order to enhance case finding. It starts with initial individuals, so-called seeds, who are invited for participation. Afterwards, seeds receive a fixed number of coupons to invite individuals with whom they had contact during a specific time period. Recruitees are then asked to do the same, resulting in successive waves of contact persons who are connected in one recruitment tree. However, often the majority of participants fail to invite others, or invitees do not accept an invitation, and recruitment stops after several waves. A mathematical model can help to analyse how various factors influence peer recruitment and to understand under which circumstances sustainable recruitment is possible. We implemented a stochastic simulation model, where parameters were suggested by empirical data from an online survey, to determine the thresholds for obtaining large recruitment trees and the number of waves needed to reach a steady state in the sample composition for individual characteristics. We also examined the relationship between mean and variance of the number of invitations sent out by participants and the probability of obtaining a large recruitment tree. Our main finding is that a situation where participants send out any number of coupons between one and the maximum number is more effective in reaching large recruitment trees, compared to a situation where the majority of participants does not send out any invitations and a smaller group sends out the maximum number of invitations. The presented model is a helpful tool that can assist public health professionals in preparing research and contact tracing using online respondent-driven detection. In particular, it can provide information on the required minimum number of successfully sent invitations to reach large recruitment trees, a certain sample composition or certain number of waves.

Abstract Introduction Oral pre-exposure prophylaxis (PrEP) is an effective strategy to reduce the risk of HIV transmission in high risk individuals. However, the effectiveness of oral pre-exposure prophylaxis is highly dependent on user adherence, which some previous trials have struggled to optimise particularly in low and middle income settings. This systematic review aims to ascertain the reasons for non-adherence to pre-exposure prophylaxis to guide future implementation. Methods We performed structured literature searches of online databases and conference archives between August 8, 2016 and September 16, 2017. In total, 18 prospective randomized control trials and implementation studies investigating oral pre-exposure prophylaxis were reviewed. A structured form was used for data extraction and findings summarized regarding efficacy, effectiveness, adherence and possible reasons for non-adherence. Results Adherence varied between differing populations both geographically and socioeconomically. Common reasons for non-adherence reported over multiple studies were; social factors such as stigma, low risk perception, low decision making power, an unacceptable dosing regimen, side effects, and the logistics of daily life. Oral pre-exposure prophylaxis with included antiviral regimens was not associated with a high risk of antiviral resistance development in the reviewed studies. Conclusion Our findings indicate that oral pre-exposure prophylaxis should be delivered within a holistic intervention, acknowledging the other needs of the targeted demographic in order to maximise acceptability. Socioeconomic factors and poor governmental policy remain major barriers to widespread implementation of pre-exposure prophylaxis.…

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.…

Jinglan Jin MD, PhD , Hongqin Xu PhD , Ruihong Wu MM , Junqi Niu MD PhD , Shibo Li MD PhD

Abstract Purpose We aimed to study the aberrant DNA methylation profile associated with hepatitis B virus (HBV) infection and to identify key genes and pathways associated with the HBV infection stage. Methods A total of 54 antiviral treatment‐naive HBV‐infected patients and 6 healthy controls were included. Genome‐wide methylated DNA immunoprecipitation analysis was performed, as previously described, after which the chip data were preprocessed. Subsequently, Cytoscape software was used for the construction of a protein–protein interaction network, and Database for Annotation, Visualization, and Integrated Discovery software was used to conduct functional enrichment analysis. Results A total of 711,794 CpGs were obtained after data quality control, among which 152,780, 113,814, 90,747, and 175,868 CpGs showed differential methylation in acute hepatitis B (AHB) vs. Control, Total‐C vs. Control, CH1 vs. CA1, and AHB vs. Total‐C, respectively. Furthermore, RIPK3, PRDM10, JUN, and SNAI1 were at the center of the four associated networks, respectively. Differential methylated genes differentially methylated in these four comparisons were significantly enriched with olfactory transduction; positive regulation of transport; negative regulation of protein amino acid phosphorylation (e.g., JUN), phosphorylation, phosphorus metabolic process, and phosphate metabolic process; and programmed cell death, respectively. Conclusion RIPK3, PRDM10, JUN, and SNAI1 as well as olfactory transduction, positive regulation of transport, negative regulation of phosphorylation, and programmed cell death are important for the transformation associated with HBV infection stage. Moreover, JUN may be involved in HBV infection, mainly via the negative regulation of amino acid phosphorylation. This article is protected by copyright. All rights reserved.

Abstract Background HIV pre-exposure prophylaxis (PrEP) is highly effective for prevention of HIV acquisition, but requires HIV testing at regular intervals. Female sex workers (FSWs) are a priority population for HIV prevention interventions in many settings, but face barriers to accessing healthcare. Here, we assessed the acceptability of HIV self-testing for regular HIV testing during PrEP implementation among FSWs participating in a randomized controlled trial of HIV self-testing delivery models. Methods We used data from two HIV self-testing randomized controlled trials with identical protocols in Zambia and in Uganda. From September–October 2016, participants were randomized in groups to: (1) direct delivery of an HIV self-test, (2) delivery of a coupon, exchangeable for an HIV self-test at nearby health clinics, or (3) standard HIV testing services. Participants completed assessments at baseline and 4 weeks. Participants reporting their last HIV test was negative were asked about their interest in various PrEP modalities and their HIV testing preferences. We used mixed effects logistic regression models to measure differences in outcomes across randomization arms at four weeks. Results At 4 weeks, 633 participants in Zambia and 749 participants in Uganda reported testing negative at their last HIV test. The majority of participants in both studies were “very interested” in daily oral PrEP (91% Zambia; 66% Uganda) and preferred HIV self-testing to standard testing services while on PrEP (87% Zambia; 82% Uganda). Participants in the HIV self-testing intervention arms more often reported preference for HIV self-testing compared to standard testing services to support PrEP in both Zambia (P = 0.002) and Uganda (P 

Abstract Background Plasmodium falciparum infected erythrocytes sequestering in placental tissue release Plasmodium lactate dehydrogenase (pLDH) and histidine-rich protein-II (HRP-II). These proteins can be detected in peripheral blood using monoclonal antibody-based rapid diagnostic tests (RDTs). Nevertheless, studies to evaluate the reliability of RDTs in detecting placental malaria compared with microscopy of placental tissue impression smear (PTIS) as the gold standard are scarce. Methods Between August 2013 and January 2015, Giemsa-stained blood smears for peripheral blood smear (Pbs), placental intervillous space (IVS) blood smear and placental tissue impression smear (PTIS)] were prepared from HIV-negative women during delivery at the Marie Reine Medical Health Centre in Yaoundé, Cameroon. RDTs with monoclonal antibodies specific to HRP-II (P.f) or pLDH (Pan) antigens were used to screen maternal peripheral blood samples. Results The prevalence of malaria was 16%, 7.5%, 11.5%, 8% and 13% for One Step malaria HRP-II and pLDH RDTs, peripheral blood smear, IVS blood and placental tissue impression smears, respectively. The proportion of women positive by One Step malaria pLDH RDT and Pbs increased with parasite density in PTIS, while One Step malaria HRP-II RDT detected high proportion of infected women even with low parasite density. Although the prevalence of malaria infection by both microscopy and RDTs decreased significantly with mother age (0.0008 ≤ p ≤ 0.025), parity seemed to have very little influence. The sensitivity of One Step malaria HRP-II and pLDH RDTs were 96.15% and 61.53%, respectively, compared to 80.76% for Pbs (p = 0.014 and 0.0029, respectively). The specificity of these RDTs was 96.49% and 100%, respectively, compared to 100% for Pbs (p ≥ 0.12). In addition, the positive predictive values were 80.64% and 100% for HRP-II and pLDH-based RDTs, respectively, compared to 100% for Pbs (p 

DeCourcey, Danielle D.; Silverman, Melanie; Oladunjoye, Adeolu; Wolfe, Joanne

Objectives: For children, adolescents, and young adults with complex chronic conditions advance care planning may be a vital component of optimal care. Advance care planning outcomes research has previously focused on seriously ill adults and adolescents with cancer where it is correlated with high-quality end-of-life care. The impact of advance care planning on end-of-life outcomes for children, adolescents, and young adults with complex chronic conditions is unknown, thus we sought to evaluate parental preferences for advance care planning and to determine whether advance care planning and assessment of specific family considerations during advance care planning were associated with differences in parent-reported end-of-life outcomes. Design: Cross-sectional survey. Setting: Large, tertiary care children’s hospital. Subjects: Bereaved parents of children, adolescents, and young adults with complex chronic conditions who died between 2006 and 2015. Interventions: None. Measurement and Main Results: One-hundred fourteen parents were enrolled (54% response rate) and all parents reported that advance care planning was important, with a majority (70%) endorsing that discussions should occur early in the illness course. Parents who reported advance care planning (65%) were more likely to be prepared for their child’s last days of life (adjusted odds ratio, 3.78; 95% CI, 1.33–10.77), to have the ability to plan their child’s location of death (adjusted odds ratio, 2.93; 95% CI, 1.06–8.07), and to rate their child’s quality of life during end-of-life as good to excellent (adjusted odds ratio, 3.59; 95% CI, 1.23–10.37). Notably, advance care planning which included specific assessment of family goals was associated with a decrease in reported child suffering at end-of-life (adjusted odds ratio, 0.23; 95% CI, 0.06–0.86) and parental decisional regret (adjusted odds ratio, 0.42; 95% CI, 0.02–0.87). Conclusions: Parents of children, adolescents, and young adults with complex chronic conditions highly value advance care planning, early in the illness course. Importantly, advance care planning is associated with improved parent-reported end-of-life outcomes for this population including superior quality of life. Further studies should evaluate strategies to ensure high-quality advance care planning including specific assessment of family goals. All authors approved the final article as submitted. Dr. DeCourcey conceptualized and designed the study, drafted the initial article, revised the article, and approved the final article as submitted. Dr. DeCourcey had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Ms. Silverman designed the data collection instruments, supervised the data collection, carried out the analyses, wrote the methods section, reviewed and revised the article, and approved the final article as submitted. Ms. Silverman also had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Mr. Oladunjoye coordinated and completed survey data collection and reviewed and revised the article. Dr. Wolfe participated in study design, data analyses, reviewed and revised the article, and approved the final article as submitted. 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). All phases of this study were supported, in part, by the Agency for Healthcare Research and Quality (AHRQ K12 HS 22986-02): Mentored Career Development Award in Child and Family Centered Outcomes Research. Dr. DeCourcey’s institution received funding from the Agency for Healthcare Research and Quality (AHRQ), and she received support from the AHRQ. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: danielle.decourcey@childrens.harvard.edu Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Kapogiannis, Bill G.; Nelson, Robert M.; Siberry, George K.; Lee, Sonia; Hazra, Rohan

Despite significant additions to the HIV prevention toolbox, infection rates across the US continue to rise among vulnerable adolescents and young adults. Access to these interventions by youth at risk for HIV is limited by the lack of data about their safety and use, compounding the myriad contextual barriers to effectively preventing HIV in this group. The NIH-funded Adolescent Trials Network implemented an innovative approach to the inclusion of adolescents at-risk for HIV infection who consented for their own participation in the first adolescent study of HIV pre-exposure prophylaxis (PrEP). This model of mature minor consent was supported by state-based adolescent treatment statutes which extend an adolescent’s ability to consent to participation in research with a sufficient prospect of clinical benefit from the intervention to justify the potential risks, and a balance of benefits and risks that is at least as favorable as available evidence-based alternatives. Important data on the safety and patterns of PrEP use by at-risk adolescents prompted the FDA to revise the label. The expanded indication of PrEP for HIV prevention in adolescents is hoped to inform clinical guidelines and provide a powerful tool to reduce new infections in the US among vulnerable at-risk adolescents. Lessons learned from this years-long iterative endeavor have implications for improving access to the rapidly evolving landscape of HIV prevention modalities, including recently implemented studies of long-acting PrEP formulations designed to reduce the burden of daily adherence required by oral PrEP, a major clinical pitfall for adolescent clinicians and their patients. Corresponding Author: Bill G. Kapogiannis, M.D. Maternal and Pediatric Infectious Diseases Branch, Eunice Kennedy Shriver National Institutes of Child Health and Human Development, National Institutes of Health, 6710B Rockledge Dr., Room 2150, MSC 7002, Bethesda, MD 20892, Voicemail: (301) 402-0698, email: kapogiannisb@mail.nih.gov Conflicts: All authors have no conflicts to declare * Present affiliation for Dr. Nelson: Child Health Innovation Leadership Department (CHILD), Johnson & Johnson, Raritan, NJ Disclaimer: The comments and views of the authors do not necessarily represent the views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health or the US Food and Drug Administration. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Mwinnyaa, George; Gray, Ronald H.; Grabowski, Mary K.; Ssekasanvu, Joseph; Ndyanabo, Anthony; Ssekubugu, Robert; Kagaayi, Joseph; Kigozi, Godfrey; Nakigozi, Gertrude; Serwadda, David M.; Laeyendecker, Oliver

Background: Age-disparate relationships are associated with increased HIV prevalence. We determined whether the frequency of age-disparate relationships in never married women changed over time and whether they are associated with HIV prevalence in Rakai, Uganda. Methods: 10,061 never married women, aged 15-49 in the Rakai Community Cohort Study provided information on the age of their male sexual partners from 1997 to 2013. Logistic regression was used to assess trends in age-disparate relationships (≥5 years) between never married women and their male partners. Log-binomial regression was used to estimate adjusted prevalence ratios (adjPR) of HIV prevalence associated with age-disparate relationships. Results: 2,992 women (30%) had a male partner ≥5 years older which remained stable over time. The prevalence of HIV among women in age-disparate relationships was 14%, 10% for women in relationships with men 0-4 years older (adjPR 1.36, 95% CI 1.22, 1.53) not controlling women’s age, however after age adjustment the impact of age-disparate relationships on HIV prevalence was attenuated. Age-disparate relationships were associated with increased HIV prevalence among women aged 15-17 (adjPR 1.83, 95% CI 1.10, 3.19), but not in other age groups. Conclusions: The frequency of age-disparate relationships among never married women were unchanged over a 15-year period in Rakai, Uganda. Age-disparate relationships were associated with increased HIV prevalence among adolescents 15-17, but not older women. Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government. Corresponding Author: Oliver Laeyendecker 855 North Wolfe St. Rangos Building Room 538A Baltimore MD, 21205 email: olaeyen1@jhmi.edu The authors report no conflicts of interest related to this work. The study was presented at the Conference on Retroviruses and Opportunistic Infections (CROI), Boston, March 3-7, 2018. Supported by the National Institute of Mental Health (R01MH107275), the National Institute of Allergy and Infectious Diseases (R01AI110324, U01AI100031, U01AI075115, R01AI110324, R01AI102939, K01AI125086-01), the National Institute of Child Health and Development (RO1HD070769, R01HD050180), and Division of Intramural Research of the National Institute for Allergy and Infectious Diseases, the World Bank, the Doris Duke Charitable Foundation, the Bill & Melinda Gates Foundation (#08113, 22006.02), and the Johns Hopkins University Center for AIDS Research (P30AI094189). The findings and conclusions in this report are those of the authors and do not represent the official position of the funding agencies. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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.

Hua-Wei Chen, Heather Lukas, Kira Becker, Giulia Weissenberger, Eric S. Halsey, Carolina Guevara, Enrique Canal, Eric Hall, Ryan C. Maves, Drake H. Tilley, Lynn Kuo, Tadeusz J. Kochel and Wei-Mei Ching

Abstract. Leptospirosis is a neglected zoonotic disease with worldwide endemicity and continues to be a significant public health burden on resource-limited populations. Previously, we produced three highly purified recombinant antigens (rLipL32, rLipL41, and rLigA-Rep) and evaluated their performance of detecting Leptospira-specific antibodies in enzyme-linked immunosorbent assay (ELISA) as compared with the microscopic agglutination test (MAT). The overall sensitivity of this assay approached 90%. Recently, another recombinant antigen (rLigB-Rep) was prepared. We tested each individual antigen and a 1:1:1:1 mixture of these four antigens for the detection of Leptospira-specific antibodies in ELISA. The performance of these recombinant antigens was evaluated with a much larger febrile patient panel (337 MAT-confirmed positive sera and 92 MAT-negative sera from febrile patients). Combining the detection results of immunoglobulin M and immunoglobulin G from these four individual antigens, the overall sensitivity was close to 90% but the specificity was only 66%, based on the MAT reference method. The overall sensitivity and specificity of the four-antigen mixture were 82% and 86%, respectively. The mixture of four antigens also exhibited a broader reactivity with MAT-positive samples of 18 serovars from six major pathogenic Leptospira species. Given the limitations of MAT, the data were further analyzed by Bayesian latent class model, showing that ELISA using a 1:1:1:1 mixture still maintained high sensitivity (79%) and specificity (88%) as compared with the sensitivity (90%) and specificity (83%) of MAT. Therefore, ELISA using a mixture of these four antigens could be a very useful test for seroprevalence studies.…

Abstract Background Malaria is one of the major public health problems worldwide. In Ethiopia, there is a significant decline in disease burden; however, the overall trend of malaria prevalence is not studied or well-documented in different localities. Hence, the initiation of this study was to analyse the 5-year trends of malaria prevalence in Ataye, North Shoa, Ethiopia. Methods A retrospective laboratory record review was conducted in Ataye Hospital, North-Shoa, Ethiopia. Malaria data reported from 2013 to 2017 were carefully reviewed from January to March 2018. Results A total of 31,810 blood films were prepared and examined from malaria-suspected patients at Ataye District Hospital from 2013 to 2017. Of the examined blood films, 2670 (8.4%) were microscopically confirmed malaria cases. The trend of malaria prevalence in the present study seems non- fluctuating. Plasmodium falciparum and Plasmodium vivax accounted for 2087 (78.2%) and 557 (20.9%) cases, respectively. From total positive cases, 1.0% of cases were mixed P. falciparum/P. vivax infections, and that no Plasmodium malariae and Plasmodium ovale infections were found by malaria microscopists. Malaria cases were higher in males 1584 (5.0%) than females 1086 (3.4%). With regard to age groups, higher numbers of malaria cases were observed in age group 15–45 years old. Malaria cases were high in spring (September to December), which is a peak malaria transmission period in Ethiopia. Conclusion Malaria is still among the major public health problems in the country. P. falciparum is the dominant species in the study area followed by P. vivax. Enhancing malaria detection and speciation skill of laboratory personnel and scaling up malaria control and prevention activities are very crucial to significantly reduce the burden of malaria in the study area.…

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.

Tamma, P. D., Fan, Y., Bergman, Y., Pertea, G., Kazmi, A., Lewis, S., Carroll, K. C., Schatz, M. C., Timp, W., Simner, P. J.

Objective: Standard antimicrobial susceptibility testing (AST) approaches lead to delays in the selection of optimal antimicrobial therapy. We sought to determine the accuracy of antimicrobial resistance (AMR) determinants identified by Nanopore whole genome sequencing in predicting AST results.Methods: Using a cohort of 40 clinical isolates (21 carbapenemase-producing carbapenem-resistant Klebsiella pneumoniae, 10 non-carbapenemase-producing carbapenem resistant K. pneumoniae, and 9 carbapenem-susceptible K. pneumoniae), three separate sequencing and analysis pipelines were performed: (1) a real-time Nanopore analysis approach identifying acquired AMR genes, (2) an assembly-based Nanopore approach identifying acquired AMR genes and chromosomal mutations, and (3) an approach using short read correction of Nanopore assemblies. The short read correction of Nanopore assemblies served as the reference standard to determine the accuracy of Nanopore sequencing results.Results: With the real-time analysis approach, full annotation of acquired AMR genes occurred within 8 hours of subcultured isolates. Assemblies sufficient for full resistance gene and single nucleotide polymorphism annotation were available within 14 hours from subcultured isolates. The overall agreement of genotypic results and anticipated AST results for the 40 K. pneumoniae isolates was 77% (range 30-100%) and 92% (range 80-100%) for the real-time approach and the assembly approach, respectively. Evaluating the patients contributing the 40 isolates, the real-time approach and assembly approach could shorten the median time to effective antibiotic therapy by 20 hours and 26 hours, respectively, compared to standard AST.Conclusions: Nanopore sequencing offers a rapid approach to both accurately identify resistance mechanisms as well as predict AST results for K. pneumoniae isolates. Bioinformatics improvements enabling real-time alignment coupled with rapid extraction and library preparation will further enhance the accuracy and workflow of the Nanopore real-time approach.…

Abstract Background A mosquito-based arbovirus surveillance system was set up at Barkedji, Senegal after the first outbreak of Rift valley fever in West Africa in 1988. This system was recently updated using more sampling methods and collecting in greater number of ponds and villages sites. Methods For the current study, mosquitoes were sampled biweekly between July and December 2012 and 2013 using CDC+CO2 light traps set at ground and canopy level, mosquito nets baited with goat, sheep, human or chicken, light traps baited with goat, sheep and chicken; bird-baited traps using pigeons or chickens placed either at the ground or canopy level. Collected mosquitoes were identified, pooled and screened for arboviruses. Results A total of 42,969 mosquitoes in 4,429 pools were processed for virus isolation. Ten virus species were identified among 103 virus isolates. West Nile virus (WNV; 31 isolates), Barkedji virus (BARV; 18), Sindbis virus (SINV; 13), Usutu virus (USUV; 12), Acado virus (ACAV; 8), Ndumu virus (NDUV; 9), Sanar virus (SANV; 7), Bagaza virus (BAGV; 3), Rift valley fever virus (RVFV; 1), and Yaounde virus (YAOV; 1) were isolated from 9 ponds (91 strains) and 7 villages (12 strains). Only 3 virus species (WNV, NDU and SINV) were isolated from villages. The largest numbers of isolates were collected in October (29.1% of total isolates) and November (50.5%). Viruses were isolated from 14 mosquito species including Cx. neavei (69.9% of the strains), Cx. antennatus (9.7%), and Ma. uniformis (4.8%). NDUV, ACAV, and SINV are herein reported for the first time in the Barkedji area. Isolation of ACAV and SANV from a pool of male Ma. uniformis and USUV and BARV from a pool of male Cx. neavei, are reported for the first time to our knowledge. Conclusion Our data indicate that the Barkedji area is characterized by a high diversity of viruses of medical, veterinary and unknown importance. Arboviruses were first detected in July at the beginning of the rainy season and peaked in abundance in October and November. The Barkedji area, an enzootic focus of several potentially emerging arboviruses, should be surveilled annually to be prepared to deal with future disease emergence events.…

Abstract Background Recent reports highlight malaria as a frequent diagnosis in migrants who originate from Eritrea. A descriptive analysis of GeoSentinel cases of malaria in Eritrean migrants was done together with a literature review to elucidate key attributes of malaria in this group with a focus on possible areas of acquisition of malaria and treatment challenges. Results A total of 146 cases were identified from the GeoSentinel database from 1999 through September 2017, with a marked increase in 2014 and 2015. All patients originated from Eritrea and the main reporting GeoSentinel sites were in Norway, Switzerland, Sweden, Israel and Germany. The majority of patients (young adult males) were diagnosed with malaria following arrival in the host country. All patients had a possible exposure in Eritrea, but may have been exposed in documented transit countries including Ethiopia, Sudan and possibly Libya in detention centres. Most infections were due to Plasmodium vivax (84.2%), followed by Plasmodium falciparum (8.2%). Two patients were pregnant, and both had P. vivax malaria. Some 31% of the migrants reported having had malaria while in transit. The median time to onset of malaria symptoms post arrival in the host country was 39 days. Some 66% of patients were hospitalized and nine patients had severe malaria (according to WHO criteria), including five due to P. vivax. Conclusions The 146 cases of mainly late onset, sometimes severe, P. vivax malaria in Eritrean migrants described in this multi-site, global analysis reflect the findings of single-centre analyses identified in the literature search. Host countries receiving asylum-seekers from Eritrea need to be prepared for large surges in vivax and, to a lesser extent, falciparum malaria, and need to be aware and prepared for glucose-6-phosphate dehydrogenase deficiency testing and primaquine treatment, which is difficult to procure and mainly unlicensed in Europe. There is an urgent need to explore the molecular epidemiology of P. vivax in Eritrean asylum-seekers, to investigate the area of acquisition of P. vivax along common transit routes and to determine whether there has been re-introduction of malaria in areas, such as Libya, where malaria is considered eliminated, but where capable vectors and Plasmodium co-circulate.…

Roberts, Brian W.; Kilgannon, J. Hope; Hunter, Benton R.; Puskarich, Michael A.; Shea, Lisa; Donnino, Michael; Jones, Christopher; Fuller, Brian M.; Kline, Jeffrey A.; Jones, Alan E.; Shapiro, Nathan I.; Abella, Benjamin S.; Trzeciak, Stephen

Objectives: Laboratory studies suggest elevated blood pressure after resuscitation from cardiac arrest may be protective; however, clinical data are limited. We sought to test the hypothesis that elevated postresuscitation mean arterial blood pressure is associated with neurologic outcome. Design: Preplanned analysis of a prospective cohort study. Setting: Six academic hospitals in the United States. Patients: Adult, nontraumatic cardiac arrest patients treated with targeted temperature management after return of spontaneous circulation. Interventions: Mean arterial blood pressure was measured noninvasively after return of spontaneous circulation and every hour during the initial 6 hours after return of spontaneous circulation. Measures and Main Results: We calculated the mean arterial blood pressure and a priori dichotomized subjects into two groups: mean arterial blood pressure 70–90 and greater than 90 mm Hg. The primary outcome was good neurologic function, defined as a modified Rankin Scale less than or equal to 3. The modified Rankin Scale was prospectively determined at hospital discharge. Of the 269 patients included, 159 (59%) had a mean arterial blood pressure greater than 90 mm Hg. Good neurologic function at hospital discharge occurred in 30% of patients in the entire cohort and was significantly higher in patients with a mean arterial blood pressure greater than 90 mm Hg (42%) as compared with mean arterial blood pressure 70–90 mm Hg (15%) (absolute risk difference, 27%; 95% CI, 17–37%). In a multivariable Poisson regression model adjusting for potential confounders, mean arterial blood pressure greater than 90 mm Hg was associated with good neurologic function (adjusted relative risk, 2.46; 95% CI; 2.09–2.88). Over ascending ranges of mean arterial blood pressure, there was a dose-response increase in probability of good neurologic outcome, with mean arterial blood pressure greater than 110 mm Hg having the strongest association (adjusted relative risk, 2.97; 95% CI, 1.86–4.76). Conclusions: Elevated blood pressure during the initial 6 hours after resuscitation from cardiac arrest was independently associated with good neurologic function at hospital discharge. Further investigation is warranted to determine if targeting an elevated mean arterial blood pressure would improve neurologic outcome after cardiac arrest. All authors have made substantial contributions to this article: Dr. Trzeciak supervised all aspects of the study and takes responsibility for the article as a whole. Drs. Roberts, Kilgannon, and Trzeciak conceived this study. Dr. Roberts, Dr. Kilgannon, and Ms. Shea managed the data. Drs. Roberts and Trzeciak analyzed the data and interpreted results. Drs. Roberts and Trzeciak drafted the article, and all authors contributed substantially to its revision. All authors took part in acquiring the data and approved the article in its final form. 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 National Heart, Lung, and Blood Institute (United States), R01HL112815 and K23HL126979. Dr. Roberts’ institution received funding from National Heart, Lung, and Blood Institute (NHLBI). Dr. Kilgannon’s institution received funding from NHLBI R01HL112815 and K23HL126979. Drs. Hunter’s, Donnino’s, Shapiro’s institution received funding from the National Institutes of Health (NIH). Dr. Puskarich’s institution received funding from NHLBI, K23GM113041, National Institute for General Medical Sciences for salary support, and he received funding from NIH Loan Repayment Program. Dr. Shea’s institution received funding from NIH R01, NIH K23. Dr. Jones’ institution received funding from Roche, AstraZeneca, and Hologic, and he disclosed he is an investigator on studies for which his department has received research grants from Roche, AstraZeneca, Janssen, and Hologic. Dr. Abella’s institution received funding from NHLBI, Medtronic Foundation, Patient-Centered Outcomes Research Institute, American Heart Association, and Physio-Control, and he received funding from Physio-Control, CardioReady, and CR Bard. Drs. Roberts, Kilgannon, Hunter, Puskarich, Shea, Donnino, Shapiro, and Trzeciak received support for article research from the NIH. 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.

Abstract Background To investigate the associations between the perceived barriers and benefits of using HIV pre-exposure prophylaxis medication, including worries about the side effects, disliking taking drugs, perceived burden of taking medication, positive expectations as to the efficacy of the drugs, favourable doctor-patient relationships, and medication adherence among men who have sex with men (MSM) to provide a target for improving medication adherence and reducing HIV infection among MSM. Methods MSM were recruited in western China from April 2013 to October 2014, administered oral tenofovir (TDF) daily and followed up every 12 weeks for 2 years. At each follow-up, the medication rate was calculated based on the self-reported number of missed doses over 2 weeks, and then, the medication adherence was evaluated. The barriers and benefits perceived during medication were obtained by a self-administered questionnaire, and their effects on medication adherence were analysed by linear mixed models. Results A total of 411 participants were enrolled in this study, and 1561 follow-up observation points were obtained. The average medication rate was 0.62 ± 0.37, and the medication rate increased with longer follow-up (P 

Abstract Background Microscopic examination of Giemsa-stained blood films remains a major form of diagnosis in malaria case management, and is a reference standard for research. However, as with other visualization-based diagnoses, accuracy depends on individual technician performance, making standardization difficult and reliability poor. Automated image recognition based on machine-learning, utilizing convolutional neural networks, offers potential to overcome these drawbacks. A prototype digital microscope device employing an algorithm based on machine-learning, the Autoscope, was assessed for its potential in malaria microscopy. Autoscope was tested in the Iquitos region of Peru in 2016 at two peripheral health facilities, with routine microscopy and PCR as reference standards. The main outcome measures include sensitivity and specificity of diagnosis of malaria from Giemsa-stained blood films, using PCR as reference. Methods A cross-sectional, observational trial was conducted at two peripheral primary health facilities in Peru. 700 participants were enrolled with the criteria: (1) age between 5 and 75 years, (2) history of fever in the last 3 days or elevated temperature on admission, (3) informed consent. The main outcome measures included sensitivity and specificity of diagnosis of malaria from Giemsa-stained blood films, using PCR as reference. Results At the San Juan clinic, sensitivity of Autoscope for diagnosing malaria was 72% (95% CI 64–80%), and specificity was 85% (95% CI 79–90%). Microscopy performance was similar to Autoscope, with sensitivity 68% (95% CI 59–76%) and specificity 100% (95% CI 98–100%). At San Juan, 85% of prepared slides had a minimum of 600 WBCs imaged, thus meeting Autoscope’s design assumptions. At the second clinic, Santa Clara, the sensitivity of Autoscope was 52% (95% CI 44–60%) and specificity was 70% (95% CI 64–76%). Microscopy performance at Santa Clara was 42% (95% CI 34–51) and specificity was 97% (95% CI 94–99). Only 39% of slides from Santa Clara met Autoscope’s design assumptions regarding WBCs imaged. Conclusions Autoscope’s diagnostic performance was on par with routine microscopy when slides had adequate blood volume to meet its design assumptions, as represented by results from the San Juan clinic. Autoscope’s diagnostic performance was poorer than routine microscopy on slides from the Santa Clara clinic, which generated slides with lower blood volumes. Results of the study reflect both the potential for artificial intelligence to perform tasks currently conducted by highly-trained experts, and the challenges of replicating the adaptiveness of human thought processes.…

Carlos Iniesta, Débora Álvarez-del Arco, Luis Miguel García-Sousa, Belén Alejos, Asunción Díaz, Nieves Sanz, Jorge Garrido, Michael Meulbroek, Ferran Pujol, Santiago Moreno, María José Fuster-Ruiz de Apocada, Pep Coll, Antonio Antela, Jorge del Romero, Oskar Ayerdi, Melchor Riera, Juanse Hernández, Julia del Amo

by Carlos Iniesta, Débora Álvarez-del Arco, Luis Miguel García-Sousa, Belén Alejos, Asunción Díaz, Nieves Sanz, Jorge Garrido, Michael Meulbroek, Ferran Pujol, Santiago Moreno, María José Fuster-Ruiz de Apocada, Pep Coll, Antonio Antela, Jorge del Romero, Oskar Ayerdi, Melchor Riera, Juanse Hernández, Julia del Amo Objective To assess the awareness, knowledge, use, and willingness to use and need of PrEP among men who have sex with men (MSM) and transgender women (TW) who attended World Gay Pride (WGP) 2017 in Madrid. Design and methods Online survey. Participants were recruited through gay-oriented dating apps and HIV Non-Governmental Organizations´ social media. Inclusion criteria included being MSM or TW, age 18 years old or above, and having attended WGP in Madrid. Information regarding the participant’s awareness and knowledge, use or willingness to use, and need for PrEP was collected, as well as sociodemographic characteristics. Participants were considered to be in need of PrEP if they met one of the following indication criteria: having practiced unprotected anal intercourse with more than 2 partners, having practiced chemsex, or having engaged in commercial sex—all in the preceding 6 months. Descriptive and multivariable analyses with logistic regression were conducted. Results 472 participants met the inclusion criteria and completed the questionnaire. The mean age was 38, 97.7% were MSM, 77% had a university education, and 85% were living in Spain, mostly in big cities. Overall, 64% of participants were aware of PrEP, but only 33% knew correctly what PrEP was. 67% of HIV-negative participants were willing to take PrEP, although only 5% were taking it during WGP, mostly due to lack of access. 43% of HIV-negative respondents met at least one PrEP indication criteria. For HIV-negative men living in Spain, university education and living in big cities was associated with PrEP awareness. Lower education level and meeting PrEP criteria was associated with willingness to use PrEP. Conclusions Our study shows that among MSM attending WGP 2017 in Madrid, there was limited PrEP awareness, low accuracy of PrEP knowledge, and a high need and willingness to use PrEP. Health authorities should strengthen existing preventive strategies and implement PrEP.…

Jalil, Emilia M.; Grinsztejn, Beatriz; Velasque, Luciane; Makkeda, Alessandra Ramos; Paula M. Luz, ; Moreira, Ronaldo I.; Kamel, Luciana; Fernandes, Nilo M.; Ferreira, Ana Cristina G.; Hoagland, Brenda; Wagner, Sandra; Liu, Albert; McFarland, Willi; Buchbinder, Susan; Veloso, Valdilea G.; Wilson, Erin; for Transcender Study Team

Background: HIV epidemics disproportionately affect transwomen worldwide. Trans-specific guidance, outreach, and interventions to increase pre-exposure prophylaxis (PrEP) use among transwomen are scarce. Setting: Rio de Janeiro, Brazil. Methods: We measured awareness and willingness to use PrEP and examined factors associated with those outcomes among transwomen in Rio de Janeiro, and estimated how many transwomen would be eligible for PrEP. Data originate from Transcender study, a respondent-driven sampling survey conducted from August 2015 to January 2016. We performed regression models for PrEP awareness and willingness. Results: 131 (38.0%) out of 345 participants had heard of PrEP. Among transwomen who self-reported as HIV-negative, 162 (76.4%) out of 212 (with available data) reported willingness to use it and 163 (66.8%) out of 244 met behavioral eligibility criteria for PrEP. Transwomen with health access in the prior six months, who reported HIV-infected sexual partner, and with 8+ years of schooling had increased odds of PrEP awareness. Lower PrEP awareness was associated with condomless anal intercourse and a newly diagnosed HIV-infection. Younger age and perceiving themselves at risk of HIV-infection increased the odds of PrEP willingness. Lower odds of PrEP willingness was associated with concerns about long-term effects of PrEP and with difficulties in getting access to health care due to transphobia. Conclusion: Combination of low awareness, high willingness and substantial PrEP eligibility corroborates transwomen as a key-population for HIV prevention. PrEP is a promising and empowering strategy for HIV prevention among transwomen, but trans-specific recommendations are needed to effectively implement PrEP in this population. Corresponding author: Emilia M. Jalil, MD, PhD, Evandro Chagas National Institute of Infectious Diseases, Oswaldo Cruz Foundation, Avenida Brasil 4365 Manguinhos - Rio de Janeiro, Brazil 21040-360, Phone: +55 21 22707064, Email: emiliajalil@gmail.com Conflicts of Interest and Source of Funding: We declare that we have no conflicts of interest. This work was supported in part by Brazilian Research Council (470056/2014-2) and NIAID-NIH (UM1AI069496). Meetings: Results from this manuscript were presented in part at the HIV Research for Prevention 2016 in Chicago, USA on October 17th 2016. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Abstract Purpose In this study, we assessed the incidence, contributing factors and outcome of prolonged neutropenia above 7 days and of bacteraemia in patients with lymphoma and multiple myeloma who underwent autologous haematopoietic stem cell transplantation (AHSCT) without antibacterial prophylaxis. Methods This is a retrospective chart review of 190 adult patients who underwent AHSCT between 2005 and 2015 at a Lebanese hospital. Results Neutropenia of 7 days duration and longer was documented in 66% of the patient population. Through univariate analysis, patients with lymphoma were significantly more likely to have prolonged neutropenia (≥ 7 days) compared to those with myeloma. Mucositis above grade 3, diarrhoea and fever were more likely to occur in patients with prolonged neutropenia. Bacteraemia was documented in 12.6% of the patients. Total mortality rate was 3.7%, and that attributed to bacteraemia was 12.5% in the bacteraemia subgroup. Among bacterial isolates recovered from clinical specimens (89 isolates), 70% were Gram-negative, of which 57% were fluoroquinolone susceptible. Ninety-five percent of the Gram-negative bacteria causing bacteraemia were susceptible to fluoroquinolones. Conclusion Bacterial pathogens causing bacteraemia were still highly susceptible to fluoroquinolones, despite the high prevalence of fluoroquinolone-resistant strains in the general bacterial ecology. Accordingly, the pertinence of fluoroquinolone prophylaxis in the AHSCT setting warrants further investigation. Moreover, continuous surveillance of local antibiograms in this patient population has become a must in an era of preponderant antibiotic resistance.…

Abstract Background Reducing the number of people with undiagnosed HIV infection is a major goal of HIV control and prevention efforts in Europe and elsewhere. We analysed data from a large multi-city European bio-behavioural survey conducted among Men who have Sex with Men (MSM) for previously undiagnosed HIV infections, and aimed to characterise undiagnosed MSM who test less frequently than recommended. Methods Data on sexual behaviours and social characteristics of MSM with undiagnosed HIV infection from Sialon II, a bio-behavioural cross-sectional survey conducted in 13 European cities in 2013/2014, were compared with HIV-negative MSM. Based on reported HIV-testing patterns, we distinguished two subgroups: MSM with a negative HIV test result within 12 months prior to the study, i.e. undiagnosed incident infection, and HIV positive MSM with unknown onset of infection. Bivariate and multivariate associations of explanatory variables were analysed. Distinct multivariate multi-level random-intercept models were estimated for the entire group and both subgroups. Results Among 497 participants with HIV-reactive specimens, 234 (47.1%) were classified as previously diagnosed, 106 (21.3%) as incident, and 58 (11.7%) as unknown onset based on self-reported status and testing history. MSM with incident HIV infection were twice as likely (odds ratio (OR) = 2.22, 95% confidence interval (95%CI): 1.17–4.21) to have used recreational substances during their last anal sex encounter and four times more likely (OR = 3.94, 95%CI: 2.14–7.27) not to discuss their HIV status with the last anal sex partner(s). MSM with unknown onset of HIV infection were 3.6 times more likely (OR = 3.61, 95%CI: 1.74–7.50) to report testing for a sexually transmitted infection (STI) during the last 12 months. Conclusions Approximately one third of the study participants who are living with HIV were unaware of their infection. Almost two-third (65%) of those with undiagnosed HIV appeared to have acquired the infection recently, emphasizing a need for more frequent testing. Men with the identified behavioural characteristics could be considered as primary target group for HIV Pre-Exposure Prophylaxis (PrEP) to avoid HIV infection. The increased odds of those with unknown onset of HIV infection to have had an STI test in the past year strongly suggests a lost opportunity to offer HIV testing.…

If current trends persist, one in six U.S. men who have sex with men will be infected with human immunodeficiency virus (HIV) in their lifetime, according to the Centers for Disease Control and Prevention (CDC). This prediction highlights the long road ahead if we are to end the spread of HIV in……

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…

Kim J, Stewart R, Yoon J.

In Reply In response to Drs Thombs and Ziegelstein, the EsDEPACS trial was preplanned as a component of the larger Korean Depression in Acute Coronary Syndrome (K-DEPACS) study investigating interrelationships between depression and cardiac outcomes following ACS using randomized and prospective observational designs. Cardiovascular outcomes have been described and reported in the previously published design article including both the EsDEPACS and K-DEPACS studies and in prior research using this data set. We agree that MACE has been inconsistently defined in this field, but our MACE definition (a composite of all-cause mortality, myocardial infarction, and percutaneous coronary intervention) has been used in well-cited cardiovascular research studies and so is not unique to our work. Concerning treatment effects, we believe that an incorrect comparison is being made. Thombs and Ziegelstein present results for the primary analysis based on the total sample of 300 patients. However, to compare with the number achieving remission of depression, the post hoc analysis of 217 patients achieving remission must be used. The difference in MACE numbers was 15 between the placebo group (n = 61) and escitalopram group (n = 46), in line with the differences in depression remission. The difference in MACE occurrence appearing beyond 1 year after randomization is a reasonable concern. However, a meta-analysis of 16 studies of depression following ACS found that differences in MACE occurrence became prominent after 1 year and over longer follow-up intervals; this is in keeping with our findings, although we agree that further replication should be sought.

Shin Ae Kim, Samuel Smith, Carlos Beauchamp, Yang Song, Martin Chiang, Anthony Giuseppetti, Stanislav Frukhtbeyn, Ian Shaffer, Joshua Wilhide, Denis Routkevitch, John M. Ondov, Jeffrey J. Kim

by Shin Ae Kim, Samuel Smith, Carlos Beauchamp, Yang Song, Martin Chiang, Anthony Giuseppetti, Stanislav Frukhtbeyn, Ian Shaffer, Joshua Wilhide, Denis Routkevitch, John M. Ondov, Jeffrey J. Kim Background Most electronic-cigarette liquids contain propylene glycol, glycerin, nicotine and a wide variety of flavors of which many are sweet. Sweet flavors are classified as saccharides, esters, acids or aldehydes. This study investigates changes in cariogenic potential when tooth surfaces are exposed to e-cigarette aerosols generated from well-characterized reference e-liquids with sweet flavors. Methods Reference e-liquids were prepared by combining 20/80 propylene glycol/glycerin (by volume fraction), 10 mg/mL nicotine, and flavors. Aerosols were generated by a Universal Electronic-Cigarette Testing Device (49.2 W, 0.2 Ω). Streptococcus mutans (UA159) were exposed to aerosols on tooth enamel and the biological and physiochemical parameters were measured. Results E-cigarette aerosols produced four-fold increase in microbial adhesion to enamel. Exposure to flavored aerosols led to two-fold increase in biofilm formation and up to a 27% decrease in enamel hardness compared to unflavored controls. Esters (ethyl butyrate, hexyl acetate, and triacetin) in e-liquids were associated with consistent bacteria-initiated enamel demineralization, whereas sugar alcohol (ethyl maltol) inhibited S. mutans growth and adhesion. The viscosity of the e-liquid allowed S. mutans to adhere to pits and fissures. Aerosols contained five metals (mean ± standard deviation): calcium (0.409 ± 0.002) mg/L, copper (0.011 ± 0.001) mg/L, iron (0.0051 ± 0.0003) mg/L, magnesium (0.017 ± 0.002) mg/L, and silicon (0.166 ± 0.005) mg/L. Conclusions This study systematically evaluated e-cigarette aerosols and found that the aerosols have similar physio-chemical properties as high-sucrose, gelatinous candies and acidic drinks. Our data suggest that the combination of the viscosity of e-liquids and some classes of chemicals in sweet flavors may increase the risk of cariogenic potential. Clinical investigation is warranted to confirm the data shown here.…

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…

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 

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.

Abstract Background Male circumcision provides men with approximately 60% protection from acquiring HIV infection via heterosexual sex, and has become a key component of HIV prevention efforts in sub-Saharan Africa. Possible mechanisms for this protection include removal of the inflammatory anaerobic sub-preputial environment and the high concentration of Langerhans cells on the inside of the foreskin, both believed to promote local vulnerability to HIV infection. In people who do acquire HIV, viral load is partially determined by infecting partner viral load, potentially mediated by size of infecting inoculum. By removing a portal for virion entry, prior male circumcision could decrease infecting inoculum and thus viral load in men who become HIV-infected, conferring the known associated benefits of slower progression to disease and decreased infectiousness. Methods We performed an as-treated analysis of plasma samples collected under a randomized controlled trial of male circumcision for HIV prevention, comparing men based on their circumcision status at the time of HIV acquisition, to determine whether circumcision is associated with lower viral load. Eligible men were seroconverters who had at least one plasma sample available drawn at least 6 months after infection, reported no potential exposures other than vaginal sex and, for those who were circumcised, were infected more than 6 weeks after circumcision, to eliminate the open wound as a confounder. Initial viral load testing indicated that quality of pre-2007 samples might have been compromised during storage and they were excluded, as were those with undetectable or unquantifiable results. Log viral loads were compared between groups using univariable and multivariable linear regression, adjusting for sample age and sexually transmitted infection diagnosis with 3.5 months of seroconversion, with a random effect for intra-individual clustering for samples from the same man. A per-protocol analysis was also performed. Results There were no viral load differences between men who were circumcised and uncircumcised at the time of HIV infection (means 4.00 and 4.03 log10 copies/mL respectively, p = .88) in any analysis. Conclusion Circumcision status at the time of HIV infection does not affect viral load in men. Trial registration The original RCT which provided the samples was ClinicalTrials.gov trial NCT00059371.…

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.

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.

Jin, S., Huang, M., Kwon, Y., Zhang, L., Li, B.-W., Oh, S., Dong, J., Luo, D., Biswal, M., Cunning, B. V., Bakharev, P. V., Moon, I., Yoo, W. J., Camacho-Mojica, D. C., Kim, Y.-J., Lee, S. H., Wang, B., Seong, W. K., Saxena, M., Ding, F., Shin, H.-J., Ruoff, R. S.

Single-crystal metals have unique properties due to the absence of grain boundaries and strong anisotropy. Commercial single-crystal metals are usually synthesized by bulk crystal growth or by deposition of thin films onto substrates, and they are expensive and small. We prepare extremely large single-crystal metal foils by ‘contact-free annealing’ from commercial polycrystalline foils. The colossal grain growth (up to 32 cm2) is achieved by minimizing contact stresses, resulting in a preferred in-plane and out-of-plane crystal orientation, and is driven by surface energy minimization during the rotation of the crystal lattice followed by ‘consumption’ of neighboring grains. Industrial scale production of single-crystal metal foils is possible from this discovery.…

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.…

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

No abstract available…

Marijke C. C. Langenberg, Linda J. Wammes, Matthew B. B. McCall, Else M. Bijker, Geert-Jan van Gemert, Wouter Graumans, Marga G. van de Vegte-Bolmer, Karina Teelen, Cornelis C. Hermsen, Rob Koelewijn, Jaap J. van Hellemond, Perry J. J. van Genderen and Robert W. Sauerwein

Abstract. Controlled human malaria infections (CHMIs) with Plasmodium falciparum (Pf) parasites are well established. Exposure to five Pf (NF54)-infected Anopheles mosquitoes results in 100% infection rates in malaria-naïve volunteers. Recently Pf clones NF135.C10 and NF166.C8 were generated for application in CHMIs. Here, we tested the clinical infection rates of these clones, using graded numbers of Pf-infected mosquitoes. In a double-blind randomized trial, we exposed 24 malaria-naïve volunteers to bites from one, two, or five mosquitoes infected with NF135.C10 or NF166.C8. The primary endpoint was parasitemia by quantitative polymerase chain reaction. For both strains, bites by five infected mosquitoes resulted in parasitemia in 4/4 volunteers; 3/4 volunteers developed parasitemia after exposure to one or two infected mosquitoes infected with either clone. The prepatent period was 7.25 ± 4.0 days (median ± range). There were no serious adverse events and comparable clinical symptoms between all groups. These data confirm the eligibility of NF135.C10 and NF166.C8 for use in CHMI studies.…