Deusch, Simon; Serrano-Villar, Sergio; Rojo, David; Martínez-Martínez, Mónica; Bargiela, Rafael; Vázquez-Castellanos, Jorge F.; Sainz, Talía; Barbas, Coral; Moya, Andrés; Moreno, Santiago; Gosalbes, María J.; Estrada, Vicente; Seifert, Jana; Ferrer, Manuel

Objective: In a recent blinded randomized study, we found that in HIV+ individuals a short supplementation with prebiotics (scGOS/lcFOS/glutamine) ameliorates dysbiosis of total gut bacteria, particularly among viremic untreated patients. Our study goal was to determine the fraction of the microbiota that becomes active during the intervention and that could provide additional functional information. Design: A total of six healthy individuals, and 16 HIV-infected patients comprising viremic untreated patients (n = 5) and antiretroviral therapy-treated (ART+) patients that are further divided into immunological responders (n = 7) and immunological nonresponders (n = 4) completed the 6-week course of prebiotic treatment, including six patients receiving a placebo. Methods: Alpha and beta diversity of potentially active and total gut microbiota was evaluated using shotgun proteomics and 16S rRNA gene sequencing. Results: HIV infection decreased dormancy and increased alpha diversity of active bacteria in comparison with the healthy controls, whose richness was not further influenced by the prebiotic intervention. The effect of the prebiotics was most evident at the beta-diversity of active bacteria, particularly within viremic untreated subjects. We found that the prebiotics did not only ameliorate dysbiosis of total bacteria in viremic untreated patients but also increased the abundance of active bacteria with strong immunomodulatory properties and amino acids metabolism, namely Bifidobacteriaceae, at similar levels to those in healthy individuals. This effect was attenuated in ART+ individuals. Conclusion: The effect of prebiotics was greater among ART-naive HIV-infected individuals than in ART+ patients and healthy controls. This highlights the importance of therapies aimed at manipulating the microbiome in this group of patients. Correspondence to Manuel Ferrer, Institute of Catalysis, Consejo Superior de Investigaciones Científicas (CSIC), Marie Curie 2, 28049 Madrid, Spain. Tel: +34 915854872; fax: +34 915854760; e-mail: mferrer@icpc.csic.es Received 23 November, 2017 Revised 13 March, 2018 Accepted 28 March, 2018 Copyright © 2018 Wolters Kluwer Health, Inc.

Sindy Magnan, Joseph E. Tota, Mariam El-Zein, Ann N. Burchell, John T. Schiller, Alex Ferenczy, Pierre-Paul Tellier, François Coutlée, Eduardo L. Franco, CATCH Study Group

We evaluated the efficacy of a carrageenan-based lubricant gel in reducing the risk of genital human papillomavirus (HPV) infections in women.

Abstract Background Alterations in inflammatory cytokines and genetic background of the host contribute to the outcome of malaria infection. Despite the promising protective role of IL-17 in infections, little attention is given to further understand its importance in the pathogenesis of severe malaria anaemia in chronic/endemic situations. The objective of this study, therefore, was to evaluate IL-17 levels in anaemic condition and its association with host genetic factors. Methods Two mice strains (Balb/c and CBA) were crossed to get the F1 progeny, and were (F1, Balb/c, CBA) taken through 6 cycles of Plasmodium berghei (ANKA strain) infection and chloroquine/pyrimethamine treatment to generate semi-immune status. Cytokine levels and kinetics of antibody production, CD4+CD25+T regulatory cells were evaluated by bead-based multiplex assay kit, ELISA and FACs, respectively. Results High survival with high Hb loss at significantly low parasitaemia was observed in Balb/c and F1. Furthermore, IgG levels were two times higher in Balb/c, F1 than CBA. While CD4+CD25+ Treg cells were lower in CBA; IL-4, IFN-γ, IL-12α and IL-17 were significantly higher (p …

Liliana López‐Carvajal , Iván Vélez , María Patricia Arbeláez , Piero Olliaro

Abstract Objective To document the sources of heterogeneity in outcomes and shortcomings in trial designs reported by previous systematic reviews. Methods Systematic review of clinical trials of CL treatments published since 1991, to assess and compare eligibility criteria and outcome measures in trials (any type of treatment) of CL (any form) reported before and after the publication of the CONSORT statement. Results We identified 106 eligible trials published between 1991 and 2015, 74% after the 2001 CONSORT statement; 58% (n = 63) were on Old‐World CL and 37% (n = 40) in New‐World CL; overall, 11 531 patients enrolled in 243 treatment groups on 30 different treatments. Both requirements and definitions for eligibility and outcome criteria varied. Compliance with CONSORT requirements increased for studies published after the 2010 update. As for entry criteria, 94% of studies had a requirement for sex (74% of those enrolling also women excluded those who were pregnant or lactating), 69% for age (variable age ranges), 99% parasitological confirmation, 43% prior duration of illness (14% excluded cases with previous episodes), 46% defined the number, 28% the size and 13% the type of lesions (27% with restrictions as to their anatomical location). Follow‐up ranged 1–24 months, with 14% and 91% of studies, respectively, having defined initial and final cure. Conclusions This review documents changes in reporting before and after the publication of the CONSORT statement. Lack of standardisation, compounded with the small number of trials relative to the magnitude of the disease in its multiple forms, and with the range of treatments tested explains why evidence to inform treatment guidelines is generally weak for CL. Adopting standardised methodologies will improve the quality and consistency of clinical trials, and ultimately yield better treatments for CL.

Hsing-Yu Chen, Ya-Sung Yang, Wei-Jane Hsu, Yu-Ching Chou, Li-Shan Huang, Yung-Chih Wang, Tzong-Shi Chiueh, Jun-Ren Sun

Acinetobacter nosocomialis is increasingly identified as a causative agent of nosocomial infections in recent year. Among the 111 bloodstream infection isolates, we observed 36.9% (41/ 111) of Acinetobacter nosocomialis isolates were imipenem non-susceptible. MLST type Sequence type 410 (ST410) harboring the plasmid pAB-NCGM253 which encodes the blaOXA-72 gene was the major group in the 41 imipenem non-susceptible Acinetobacter nosocomialis. To our knowledge, this is the first time that pAB-NCGM253 was found in Acinetobacter nosocomialis.

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

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

“Linking Individual Natural History to Population Outcomes in Tuberculosis” by Salvatore et al. [J Infect Dis 2017; 217(1): 112–21]. This is an Open Access article and should have contained the following copyright line: © The Authors [2018]. Published by Oxford University Press for the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract Background A yellow fever epidemic occurred in Angola in 2016 with 884 laboratory confirmed cases and 373 deaths. Eleven unvaccinated Chinese nationals working in Angola were also infected and imported the disease to China, thereby presenting the first importation of yellow fever into Asia. In Angola, there are about 259,000 Chinese foreign workers. The fact that 11 unvaccinated Chinese workers acquired yellow fever suggests that many more Chinese workers in Angola were not vaccinated. Methods We applied a previously developed model to back-calculate the number of unvaccinated Chinese workers in Angola in order to determine the extent of lack of vaccine coverage. Results Our models suggest that none of the 259,000 Chinese had been vaccinated, although yellow fever vaccination is mandated by the International Health Regulations. Conclusion Governments around the world including China need to ensure that their citizens obtain YF vaccination when traveling to countries where such vaccines are required in order to prevent the international spread of yellow fever.

Abstract Background Candida bloodstream infections carry a significant mortality risk, justifying the importance of adequate antifungal therapy. This study describes trends in antifungal consumption using the Defined Daily Dose (DDD) and Days of Therapy (DOT) metrics, identifies the microbiological profile, the time to initiation of empirical therapy, the adjustment after positive blood culture results for Candida, and the impact on in-hospital mortality rate in patients with candidemia. Methods An analysis of antifungal consumption from 2008 to 2016, and of candidemia cases from 2012 to 2016 was carried out in a private tertiary hospital. Results A total of 11,273 admissions were identified with a prescription for at least one type of antifungal therapy. Fluconazole was the most prescribed antifungal drug in terms of general consumption. Through the DDD and DOT metrics, we observed that over time, there was an increase in the consumption of liposomal amphotericin B, micafungin and voriconazole. Candida albicans was the most isolated species in blood cultures. Regarding candidemia, we analyzed samples from 115 patients. Empirical therapy was started within 24 h of blood culture in 44.3% of the cases, and in 81.7% of the cases, the antifungal was deemed to be adequate based in antifungal susceptibility testing, both of which were not associated with the in-hospital mortality rate. Conclusions Our study reinforces the importance of monitoring the consumption of antifungal agents, which helps in proposing actions that lead to their rational use and, consequently, reduces the appearance of resistant strains.

Intussusception is a rare event that occurs when one segment of the bowel telescopes into another, which results in obstruction. A previously licensed rotavirus vaccine (RotaShield, Wyeth-Lederle Laboratories) was found to be associated with intussusception after its introduction in the routine……

Inês Bártolo, Ana Rita Diniz, Pedro Borrego, João Pedro Ferreira, Maria Rosário Bronze, Helena Barroso, Rui Pinto, Carlos Cardoso, João F. Pinto, Rafael Ceña Diaz, Pilar Garcia Broncano, Maria Angel Muñoz-Fernández, Nuno Taveira

by Inês Bártolo, Ana Rita Diniz, Pedro Borrego, João Pedro Ferreira, Maria Rosário Bronze, Helena Barroso, Rui Pinto, Carlos Cardoso, João F. Pinto, Rafael Ceña Diaz, Pilar Garcia Broncano, Maria Angel Muñoz-Fernández, Nuno Taveira Microbicides are an important strategy for preventing the sexual transmission of HIV but, so far, the most advanced tenofovir-based microbicides have had modest efficacy. This has been related to adherence problems and high prevalence of tenofovir-resistant HIV-1 strains. P3 is a new peptide with potent activity against HIV that may be a good microbicide candidate. In this work P3 was formulated in a gel of hydroxyethyl cellulose and its activity, stability and safety profile in Balb/c mice were evaluated. HIV infection was fully blocked by a 1.5% gel containing P3 at the IC90 (366.4 nM) concentration. The antiviral activity did not change at 4°C during 4 months and at 25, 37 and 65°C for 1 week. P3 was stable and fully functional at acidic pH up to 24h, under different concentrations of hydrogen peroxide and in the presence of genital fluids up to 48h. P3 had no antibacterial activity and did not affect sperm motility and vitality. Finally, P3 didn’t cause significant alterations in the vaginal epithelium of Balb/c mice at 0.06 (456.8 μM) and 0.2 mg/day (1522.7 μM) doses. These findings indicate that P3 is an excellent candidate for further development as a microbicide gel for the prevention of HIV transmission in women.

Deep, Akash; Sagar, Hiremath; Goonasekera, Chulananda; Karthikeyan, Palaniswamy; Brierley, Joe; Douiri, Abdel

Objectives: There are no studies in pediatrics evaluating the progression of acute kidney injury in septic shock. We investigated the evolution of sepsis-associated acute kidney injury and its association with systemic hemodynamics in children with fluid-refractory septic shock. Design: Prospective cohort study. Setting: PICU of a tertiary care hospital. Patients: All patients with fluid-refractory septic shock (n = 61) between September 2010 and February 2014. Interventions: Hemodynamic variables using noninvasive ultrasound cardiac output monitor were measured at admission and 6 hourly thereafter till 48 hours. We used the Kidney Disease: Improving Global Outcomes criteria to define and stage acute kidney injury. Associations between various hemodynamic variables and development of acute kidney injury were evaluated. Severe acute kidney injury was defined as stage 2 or 3 acute kidney injury and was compared with no acute kidney injury or stage 1 acute kidney injury. Measurements and Main Results: Severe acute kidney injury developed in 29.5% (n = 18) of the 61 children with fluid-refractory septic shock, whereas 43 patients (70.49%) had either no or stage 1 acute kidney injury. Most patients who developed acute kidney injury did so within the first 48 hours of PICU admission. Severe acute kidney injury conferred a three-fold increased risk of death by day 28 (hazard ratio, 3.23; 95% CI, 1.52–6.67; p = 0.002), longer ICU stay, and increased duration of mechanical ventilation. Central venous pressure at presentation was higher in severe acute kidney injury by 5 cm H2O. Highest lactate in the first 24 hours of PICU admission, low diastolic blood pressure, low systemic vascular resistance index at admission were associated with severe acute kidney injury. This model reliably predicted stage 2/3 acute kidney injury by day 3 with area under the curve equals to 94%; 95% CI, 88.3–99.99. None of the other hemodynamic variables showed any association with severe acute kidney injury. Conclusions: Manifestations of sepsis-associated acute kidney injury often occur early after PICU admission and is associated with increased morbidity and mortality. There is a need to develop a predictive model in septic shock which could facilitate early detection of acute kidney injury. This work was performed at King’s College Hospital, Denmark Hill, London SE5 9RS, United Kingdom. Ethical Statement: This was an observational study of routinely monitored hemodynamic and biochemical variables in the clinical management of children in septic shock in PICU and their outcomes. All children received standard therapies. Therefore, according to local guidelines, Ethics Committee review was not required. However, this study was registered as a service evaluation project at King’s College Hospital (Clinical Audit Support System project no. 2902). Dr. Deep is the supervisor who conceptualized the project and supervised data collection, interpretation and has reviewed and edited the article. He is the corresponding author. Drs. Sagar and Karthikeyan collected the data and contributed to the initial article. Drs. Goonasekera and Brierley helped edit the article. Dr. Douiri is senior lecturer of Biostatistics and Epidemiology in the department of primary care and public health sciences at King’s College London who advised the statistical design and analysis of the data. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Dr. Douiri acknowledges financial support from the National Institute for Health Research (NIHR) Biomedical Research and from the NIHR Collaboration for Leadership in Applied Health Research and Care South London at King’s College Hospital NHS Foundation Trust. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Akash Deep, MD, FRCPCH, PICU, King’s College Hospital, Denmark Hill, London SE5 9RS, United Kingdom. E-mail: akash.deep@nhs.net Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Julien Marlet, Catherine Gaudy-Graffin, Daniel Marc, Ronan Boennec, Alain Goudeau

by Julien Marlet, Catherine Gaudy-Graffin, Daniel Marc, Ronan Boennec, Alain Goudeau Current influenza vaccination strategy is based on limited analyses of circulating strains and has some drawbacks, as illustrated during the 2014–2015 season with the circulation of A(H3N2) viruses belonging to divergent genetic subgroups. We reasoned that these strains, poorly neutralized in vitro, may have been associated with vaccination failure and more severe diseases. We conducted a study on a continuous series of 249 confirmed influenza infections. Incidence was three fold greater than in the previous three years. Most isolates were A(H3N2) viruses (78%) and clustered in subgroups 3C.2a (57%) and 3C.3b (43%). We identified 23 non-synonymous mutations that had already been identified during previous seasons at low frequencies, except mutation Q197H, present in 26% of 3C.3b isolates. We identified lung disorder, tobacco smoking and A(H1N1)pdm09 infection as risk factor of severe influenza disease. In contrast, young age (< 5 years), A(H3N2) infection and initial admission to an emergency department were associated with a better outcome of influenza infection.

Yang, M.-M., Kim, D. J., Alexe, M.

It is highly desirable to discover photovoltaic mechanisms that enable a higher efficiency of solar cells. Here, we report that the bulk photovoltaic effect, which is free from the thermodynamic Shockley-Queisser limit but usually manifested only in noncentrosymmetric (piezoelectric or ferroelectric) materials, can be realized in any semiconductor, including silicon, by mediation of flexoelectric effect. We introduce strain gradients using either an atomic force microscope or a micron-scale indentation system, creating giant photovoltaic currents from centrosymmetric single crystals of SrTiO3, TiO2, and Si. This strain-gradient-induced bulk photovoltaic effect, which we call the flexo-photovoltaic effect, functions in the absence of a p-n junction. This finding may extend present solar cell technologies by boosting the solar energy conversion efficiency from a wide pool of established semiconductors.

Abstract Background To evaluate the predictive value of analytical markers of full blood count that can be assessed in the emergency department for HIV infected patients, with community-acquired pneumonia (CAP). Methods Prospective 3-year study including all HIV-infected patients that went to our emergency department with respiratory clinical infection, more than 24-h earlier they were diagnosed with CAP and required admission. We assessed the different values of the first blood count performed on the patient as follows; total white blood cells (WBC), neutrophils, lymphocytes (LYM), basophils, eosinophils (EOS), red blood cells (RBC), hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin concentration, mean corpuscular hemoglobin, red blood cell distribution width (RDW), platelets (PLT), mean platelet volume, and platelet distribution width (PDW). The primary outcome measure was 30-day mortality and the secondary, admission to an intensive care unit (ICU). The predictive power of the variables was determined by statistical calculation. Results One hundred sixty HIV-infected patients with pneumonia were identified. The mean age was 42 (11) years, 99 (62%) were male, 79 (49%) had ART. The main route of HIV transmission was through parenteral administration of drugs. Streptococcus pneumonia was the most frequently identified etiologic agent of CAP The univariate analysis showed that the values of PLT (p 

Amlabu E, Mensah-Brown H, Nyarko P, et al.

AbstractPlasmodium falciparum erythrocyte invasion is a multi-step process that involves a spectrum of interactions that are not well characterized. We have characterized a 113 kDa immunogenic protein PF3D7_1431400 (PF14_0293) that possesses coiled-coil structures. The protein is localized on the surfaces of both merozoites and gametocytes, hence the name PlasmodiumfalciparumSurface Related Antigen (PfSRA). The processed 32 kDa fragment of PfSRA binds normal human erythrocytes with different sensitivities to enzyme treatments. Temporal imaging from initial attachment to internalization of viable merozoites revealed that a fragment of PfSRA along with PfMSP119 are internalized post-invasion. Moreover, parasite growth inhibition assays showed that PfSRA P1 antibodies potently inhibited erythrocyte invasion of both sialic acid-dependent and -independent parasite strains. Also, immuno-epidemiological studies show that malaria-infected populations have naturally-acquired antibodies against PfSRA. Overall, the results demonstrate that PfSRA has the structural and functional characteristics of a very promising target for vaccine development.

With an estimated global prevalence of 288,000 cases, β-thalassemia is one of the most common genetic diseases in the world, and every year another 60,000 infants are born with the disease. Of these patients, 60 to 80% have a severe form of the disease and require regular red-cell transfusions and……

The β-hemoglobinopathies, which include β-thalassemia and sickle cell disease, are among the most prevalent monogenic disorders worldwide. β-thalassemia is caused by more than 200 mutations in the HBB globin gene, which encodes the beta subunit of the most common form of adult hemoglobin, HbA.……

Martin E, Kuypers J, Chu H, et al.

AbstractBackgroundDespite the frequency of human rhinovirus (HRV), data describing the molecular epidemiology of HRV in the community are limited. Child care centers are optimal settings to characterize heterotypic HRV co-circulation.MethodsHRV specimens were prospectively obtained from a cohort of child care attendees at enrollment and weekly during respiratory illness. Sequences of the 5’ non-coding region were used to determine HRV species (A, B, or C) and genotypes.ResultsAmong 225 children followed, sequence data were available for 92 HRV infections. HRV-A (n=80; 59%) was most common followed by HRV-C (n=52, 39%) and HRV-B (n=3, 2%). Forty-one genotypes were identified and co-circulation was common. Frequent spread between classrooms occurred with two specific HRV-A genotypes. Repeated detections within single illnesses were a combination of persistent (n=7) and distinct (n=7) genotypes. Prevalence of HRV among asymptomatic children was 41%. HRV-C was clinically similar to HRV-A and HRV-B.ConclusionsHRV epidemiology in child care consists of heterotypic co-circulation of genotypes with periodic spread of genotypes within and among classrooms. Based on our finding of multiple HRV genotypes evident during the course of single respiratory illnesses, the use of sequence-based HRV type determination is critical in longitudinal studies of HRV epidemiology and transmission.

Anne-Louise Ponsonby, Angela Pezic, Fergus J. Cameron, Christine Rodda, Andrew S. Kemp, John B. Carlin, Heikki Hyoty, Amirbabak Sioofy-Khojine, Terence Dwyer, Justine A. Ellis, Maria E. Craig

by Anne-Louise Ponsonby, Angela Pezic, Fergus J. Cameron, Christine Rodda, Andrew S. Kemp, John B. Carlin, Heikki Hyoty, Amirbabak Sioofy-Khojine, Terence Dwyer, Justine A. Ellis, Maria E. Craig We aimed to examine the association between parental occupational social contact and hygiene factors on type 1 diabetes (T1D) risk and possible mediation of these effects through child enteroviral infection. We interviewed 333 incident T1D cases and 660 controls from 2008–2011 in Melbourne, Australia. Enteroviral indices (ribonucleic acid by reverse transcription polymerase chain reaction and Coxsackie B virus antibody levels) in peripheral blood were measured in nested case control samples. Parent occupational social contact was assessed by the number of well or sick children, adults or animals contacted daily through work. Higher parental occupational social contact was strongly associated with reduced T1D risk with evidence of dose response (contact with the well or sick score, Adjusted odds ratio (AOR) per category: 0.73 (95% Confidence Interval (CI): 0.66, 0.81); p

Manuel Gerónimo Feria, Natalia Andrea Taborda, Juan C. Hernandez, Maria Teresa Rugeles

by Manuel Gerónimo Feria, Natalia Andrea Taborda, Juan C. Hernandez, Maria Teresa Rugeles Background Human immunodeficiency virus (HIV) promotes an inflammatory process, leading to the progressive loss of the functional capacity of the immune system. The HIV infection induces alterations in several tissues, but mainly in the gut-associated lymphoid tissue (GALT). However, the degree of GALT deterioration varies among infected individuals. In fact, it has been shown that HIV-controllers, who spontaneously control viral replication, exhibit a lower inflammatory response, and a relative normal frequency and function of most of the immune cells. Inflammasomes are molecular complexes involved in the inflammatory response, being NLRP1, NLRP3, NLRC4, AIM2 and Pyrin inflammasomes, the best characterized so far. These complexes regulate the maturation of cytokines of the IL-1 family, including IL-1β and IL-18. These cytokines have been associated with immune activation and expansion of HIV target cells, promoting viral replication. Interesting, some reports indicate that HIV induces the activation of the NLRP3 inflammasome, but the role of this, and other inflammasomes during HIV infection, especially in GALT, remains unclear. Objective To compare the relative expression of inflammasome components and the proinflammatory response related to their activity, between HIV-progressors and HIV-controllers. Methods GALT biopsies and peripheral blood mononuclear cells (PBMCs) from 15 HIV-controllers and 15 HIV-progressors were obtained. The relative expression of the following inflammasome components were evaluated by RT-PCR: NLRP3, NLRC4, NLRP1, AIM2, ASC, Caspase-1, IL-1β and IL-18. In addition, plasma concentration of IL-18 was evaluated as an indicator of baseline proinflammatory status. Finally, in supernatants of PBMCs in vitro stimulated with inflammasome agonists, the concentrations of IL-1β and IL-18 were quantified by ELISA. Results HIV-progressors exhibited higher expression of IL-1β, IL-18 and caspase-1 genes in GALT and PBMCs compared with HIV-controllers. In addition, HIV-progressors had also increased expression of ASC in PBMCs. When plasma levels were evaluated, IL-18 was increased in HIV-progressors. Interesting, these patients also showed an increased production of IL-1β in supernatants of PBMCs stimulated in vitro with the agonists of AIM2, NLRP1 and NLRC4 inflammasomes. Finally, the expression of caspase-1, NLRP1, IL-1β and IL-18 in GALT or peripheral blood was correlated with CD4+ T-cell count and viral load. Conclusion Our results suggest that during HIV-infection, the required signals to induce the expression of different components of the inflammasomes are produced, both in GALT and in periphery. The activation of these molecular complexes could increase the number of target cells, favoring HIV replication and cell death, promoting the disease progression.

Ducloy, Camille; Su, Bin; Mayr, Luzia; Klingler, Jéromine; Decoville, Thomas; Schmidt, Sylvie; Laumond, Géraldine; Salomé, Nathalie; Bahram, Seiamak; Moog, Christiane

Objective: In the semen, both free virus and infected cells are able to establish HIV infection during sexual intercourse. An efficient vaccine should, therefore, inhibit both infectious states. The aim of this study was to analyze the capacity of broadly neutralizing antibodies (bNAbs) to inhibit HIV transmission by the infected cells. Design/methods: We developed an in-vitro model aiming to mimic mucosal HIV transmission via infected cells. PHA-activated CD4+ T cells stained with PKH26 from donor A were infected and co-cultured with CD4+ T cells and dendritic cells from donor B in the presence of bNAbs. Results: We showed that dendritic cells were the preferential HIV target cells at early time points in this co-culture model. In the context of this co-culture model where infection and transmission occurred simultaneously, bNAbs efficiently inhibited HIV replication as well as HIV transmission from infected cells to allogenic dendritic cells and CD4+ T cells. Conclusion: Overall, our results indicate that dendritic cells, in addition to CD4+ T cells, are key cells that are efficiently infected by HIV and bNAbs are potent inhibitors of infection of both target cells. Future HIV prophylactic vaccine design should develop immune strategies able to prevent the infection of dendritic cells, in addition to the inhibition of CD4+ T-cell infection. Correspondence to Christiane Moog, PhD, INSERM U1109, Université de Strasbourg, 3 rue Koeberlé, Strasbourg 67000, France. Tel: +33 368 853 742; fax: +33 368 854 016; e-mail: c.moog@unistra.fr Received 22 December, 2017 Revised 27 February, 2018 Accepted 17 March, 2018 Copyright © 2018 Wolters Kluwer Health, Inc.

Nadezhda A. Wall, C. Coral Dominguez-Medina, Sian E. Faustini, Charlotte N. Cook, Andrew McClean, Mark D. Jesky, Marisol Perez-Toledo, Matthew D. Morgan, Alexandra G. Richter, Charles J. Ferro, Paul Cockwell, Paul A. Moss, Ian R. Henderson, Lorraine Harper, Adam F. Cunningham

by Nadezhda A. Wall, C. Coral Dominguez-Medina, Sian E. Faustini, Charlotte N. Cook, Andrew McClean, Mark D. Jesky, Marisol Perez-Toledo, Matthew D. Morgan, Alexandra G. Richter, Charles J. Ferro, Paul Cockwell, Paul A. Moss, Ian R. Henderson, Lorraine Harper, Adam F. Cunningham Patients with chronic kidney disease (CKD) have an increased risk of infection and poorer responses to vaccination. This suggests that CKD patients have an impaired responsiveness to all antigens, even those first encountered before CKD onset. To examine this we evaluated antibody responses against two childhood vaccine antigens, tetanus (TT) and diphtheria toxoids (DT) and two common pathogens, cytomegalovirus (CMV) and Salmonella enterica serovar Enteritidis (SEn) in two independent cohorts consisting of age-matched individuals with and without CKD. Sera were evaluated for antigen-specific IgG titres and the functionality of antibody to SEn was assessed in a serum bactericidal assay. Surprisingly, patients with CKD and control subjects had comparable levels of IgG against TT and DT, suggesting preserved humoral memory responses to antigens encountered early in life. Lipopolysaccharide-specific IgG titres and serum bactericidal activity in patients with CKD were also not inferior to controls. CMV-specific IgG titres in seropositive CKD patients were similar or even increased compared to controls. Therefore, whilst responses to new vaccines in CKD are typically lower than expected, antibody responses to antigens commonly encountered prior to CKD onset are not. The immunodeficiency of CKD is likely characterised by failure to respond to new antigenic challenges and efforts to improve patient outcomes should be focussed here.

Jing-yang Li, Shang-qin Chen, Yan-yan Yan, Ying-ying Hu, Jia Wei, Qiu-ping Wu, Zhen-lang Lin, Jing Lin

The purpose of the study is to analyze the distribution and antimicrobial resistance of common bacterial pathogens causing neonatal septicemia based on a systematic review of the published studies in China.

Naresh Dangi, Un Taek Lim

by Naresh Dangi, Un Taek Lim A strain (ARP14) of the entomopathogenic fungus Beauveria bassiana (Balsamo) Vuillemin was isolated from field-collected Riptortus pedestris (Fabricius) (Hemiptera: Alydidae). The lethal median concentration of the ARP14 strain was compared with that of a commercialized strain (GHA) of the same fungus against R. pedestris and its two egg parasitoids, Ooencyrtus nezarae Ishii (Hymenoptera: Encyrtidae) and Gryon japonicum (Ashmead) (Hymenoptera: Platygastridae). Mortality and mycosis rates were evaluated after exposure to five concentrations of the fungus, i.e., 1×109, 1×108, 1×107, 1×106, and 1×105 conidia/mL, using a glass scintillation vial as an exposure arena in 25.0 ± 0.5°C and 93.7 ± 2.9% RH. The lethal median concentrations (LC50) for 2nd and 4th instar nymphs, and adults of R. pedestris were not significantly different between the two strains of B. bassiana. However, the mycosis rate of ARP14 was 1.3 and 1.8 times higher than that of the GHA strain in 4th instar nymphs and adult females of R. pedestris, respectively, at the 1×108 conidia/mL concentration. More interestingly, the mycosis rates at 1×108 conidia/mL concentration in the parasitoids G. japonicum and O. nezarae were much lower in the ARP14 strain (15.0 and 0%) than in the GHA strain (73.3 and 66.0%), respectively, suggesting that the B. bassiana strain ARP14 is less virulent to these parasitoids than the commercially available strain. Our results suggest that B. bassiana ARP14 may be a potential new biopesticide against R. pedestris with fewer negative effects on beneficial parasitoids than currently available options.

Falk J, Winkelmann M, Stöhr D, et al.

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

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

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

Abstract Purpose Mycobacterium abscessus, and rapidly growing mycobacteria in general, are rare but increasing causes of central nervous system (CNS) infections. The aim of this study is to highlight the importance of considering these microorganism in the differential diagnosis of CNS infections, obtaining a prompt diagnosis, and improving clinical outcomes. Methods Case report and literature review. Results We report a case of meningeal infection in a patient who underwent decompressive craniectomy after a craniofacial trauma. The diagnosis was made analyzing a sample obtained during a second operation of cranioplasty. A regimen of amikacin, clarithromycin, and imipenem/cilastatin was started. In the following days, the patient experienced a variety of side effects. So, first clarithromycin was replaced with linezolid, then amikacin was stopped and cefoxitin added to the therapy and at the end all the antibiotics were withdrawn. The patient was discharged in good conditions and a clinical interdisciplinary follow-up was started. After 12 months, the patient is still doing well. After a literature analysis, 15 cases of M. abscessus CNS infections were identified. Various modes of acquisition, underlying disease and therapeutic schemes were evident. Conclusions Considering the results of the literature analysis and the increasing incidence of M. abscessus, all specialists involved in the management of CNS infection should be aware of the importance of atypical microorganisms in differential diagnosis.

Leyes, Pere; Cofan, Montserrat; González-Cordón, Ana; de Lazzari, Elisa; Trabal, Joan; Domingo, Pere; Negredo, Eugenia; Vidal, Francesc; Forga, Maria T.; Gatell, Jose M.; Ros, Emili; Martínez, Esteban

Objective: The aim of this study was to compare the differential effects of first-line efavirenz (EFV)-based vs. boosted lopinavir-based antiretroviral regimens on cholesterol metabolism. Design: Multicentre, open-label, randomized clinical trial. Methods: Forty-nine naïve HIV-infected patients were randomized (1 : 1) to receive either ritonavir-boosted lopinavir (LPV/r) or EFV both in combination with tenofovir and emtricitabine (ClinicalTrials.gov: NCT00759070). Lipid profile and serum phytosterols and cholesterol precursors were determined at baseline and after 16 weeks. Results: After 16 weeks of intervention, total HDL and non-HDL cholesterol as well as triglyceride levels significantly increased in the LPV/r-group (+1.0 ± 0.8; +0.8 ± 0.7 and +0.8 ± 1.5 mmol/l, respectively), but not in the EFV-group (+0.4 ± 0.7; +0.4 ± 0.6 and 0.2 ± 0.5 mmol/l, respectively). Markers of cholesterol absorption (campesterol-to-cholesterol and sitosterol-to-cholesterol ratios) significantly increased in the LPV/r-group, but not in the EFV-group, whereas there were no changes in either group of the lathosterol-to-cholesterol ratio, a marker of cholesterol synthesis. Conclusion: Treatment with an LPV/r-based therapy increased total cholesterol relative to EFV-based therapy. Our data suggest that absorption rather than synthesis is the mechanism involved in LPV/r-associated increased total cholesterol. Correspondence to Dr. Pere Leyes, Endocrinology and Nutrition Service, Hospital Clínic de Barcelona, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain. Tel: +34 932 279 846; e-mail: pleyes@clinic.cat Received 21 December, 2017 Revised 11 March, 2018 Accepted 13 March, 2018 Copyright © 2018 Wolters Kluwer Health, Inc.

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

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

Mariëtte B. van Ravenhorst, Gerco den Hartog, Fiona R. M. van der Klis, Debbie M. van Rooijen, Elisabeth A. M. Sanders, Guy A. M. Berbers

by Mariëtte B. van Ravenhorst, Gerco den Hartog, Fiona R. M. van der Klis, Debbie M. van Rooijen, Elisabeth A. M. Sanders, Guy A. M. Berbers Background Meningococcal infection starts with colonisation of the upper respiratory tract. Mucosal immunity is important for protection against acquisition and subsequent meningococcal carriage. In this study, we assessed salivary antibody levels against meningococcal serogroup A (MenA), W (MenW) and Y (MenY) after vaccination with a quadrivalent MenACWY conjugated vaccine. We also compared salivary meningococcal serogroup C (MenC) antibody levels after monovalent MenC and quadrivalent MenACWY conjugated vaccination. Methods Healthy participants, who had received MenC conjugate vaccine between 14 months and 3 years of age, received a (booster) MenC or MenACWY vaccination at age 10–15 years. MenA-, MenC-, MenW- and MenY-polysaccharide (PS) specific IgG and IgA levels in saliva and serum and PS specific secretory component levels in saliva were measured using the fluorescent-bead-based multiplex immunoassay. Results MenACYW vaccination increased salivary PS-specific IgA (2-fold) and IgG levels(>10-fold) for MenA, MenY, and MenW. After one year, salivary IgA levels had returned to baseline levels. Both vaccines induced an increase in salivary MenC-PS specific IgA (>3-fold) and IgG (>100-fold), with higher levels after MenC as compared to MenACWY vaccination. The antibody decay rate of MenC in saliva between one month and one year was similar for both vaccines. The overall correlation between serum and saliva IgA levels was low (R = 0.39, R = 0.58, R = 0.31, and R = 0.36 for MenA, MenC, MenW and MenY, respectively). Serogroup-PS specific IgG levels between serum and saliva correlated better (R ranged from 0.51 to 0.88). Conclusions Both primary (MenA, MenY, and MenW) and booster (MenC) parenteral meningococcal conjugate vaccination induced high salivary antibody levels. The strong correlation for MenC, MenW and MenY between saliva and serum IgG levels indicates that saliva might be used as a reliable tool to measure vaccine responses after both primary and booster meningococcal vaccination.

Muhubiri Kabuyaya, Moses John Chimbari, Samson Mukaratirwa

Charles J. Russell, Meng Hu, Faten A. Okda

For decades, hemagglutinin (HA) protein structure and its refolding mechanism have served as a paradigm for understanding protein-mediated membrane fusion. HA trimers are in a high-energy state and are functionally activated by low pH. Over the past decade, HA stability (or the pH at which irreversible conformational changes are triggered) has emerged as an important determinant in influenza virus host range, infectivity, transmissibility, and human pandemic potential. Here, we review HA protein structure, assays to measure its stability, measured HA stability values, residues and mutations that regulate its stability, the effect of HA stability on interspecies adaptation and transmissibility, and mechanistic insights into this process.

Kristina Keitel, Valérie D’Acremont

The lack of effective, integrated diagnostic tools pose a major challenge to the primary care management of febrile childhood illnesses. These limitations are especially evident in low-resource settings and are often inappropriately compensated by antimicrobial over-prescription. Interactive electronic decision trees (IEDTs) have the potential to close these gaps: guiding antibiotic use and better identifying serious disease.

Abstract Background Chronic active Epstein-Barr virus (EBV) disease (CAEBV) is defined as a severe, progressive lymphoproliferative disorder associated with active EBV infection persisting longer than 6 months and developing in patients without recognised immunodeficiency. Rarely, interstitial pneumonitis (IP) occurs as a serious complication in CAEBV patients. The standard therapeutic regimen for IP in CAEBV has not yet been defined. Although interferon alpha (IFN-alpha) is known to suppress viral DNA replication by affecting its basal promoter activation process, it is rarely used in CAEBV patients. Case presentation A 22-year-old Caucasian woman, diagnosed with CAEBV 1.5 years earlier, was admitted to the Immunology Clinic due to a 4-week history of productive cough, fever and general weakness. Cultures of blood, urine and sputum were negative, but EBV DNA copies were found in the sputum, whole blood, isolated peripheral blood lymphocytes as well as in the blood plasma. Cytokine assessment in peripheral blood revealed the lack of IFN-alpha synthesis. Disseminated maculate infiltrative areas in both lungs were observed on a computed tomography (CT) chest scan. The patient was not qualified for the allogeneic hematopoietic stem cell transplantation (allo-HSCT) due to the risk of immunosuppression-related complications of infectious IP. Inhaled (1.5 million units 3 times a day) and subcutaneous (6 million units 3 times a week) IFN-alpha was implemented. To the best of our knowledge, this was the first documented use of inhaled IFN-alpha in a patient with CAEBV and concomitant IP. Patient’s status has improved, and she was eventually qualified to allo-HSCT with reduced conditioning. Currently, the patient feels well, no EBV was detected and further regression of pulmonary changes was documented. Conclusions CAEBV should be considered in patients who present with interstitial lung infiltration and involvement of other organs. Although more promising results have been obtained with allo-HSCT, inhaled IFN-alpha may also be a therapeutic option in patients with CAEBV and a concomitant IP.

Vijayashree Yellappa , Tullia Battaglioli , Sanath Kumar Gurum , Devadasan Narayanan , Patrick Van der Stuyft

Abstract Objectives To assess a multicomponent intervention to improve private practitioners (PPs) involvement in referral of presumptive pulmonary TB (PTB) cases to the Revised National TB Control Programme (RNTCP) for sputum examination. Methods Randomised controlled trial. We randomly allocated all 189 eligible PPs in Tumkur city, South India, to intervention or control arm. The intervention, implemented between December 2014 and January 2016, included two sets of activities, one targeted at health system strengthening (building RNTCP staff capacity to collaborate with PPs, provision of feedback on referrals through SMS) and one targeted at intervention PPs (training in RNTCP, provision of referral pads and education materials and monthly visits to PPs by RNTCP staff). Crude and adjusted referral and PTB case‐finding rate ratios were calculated with negative binomial regression. Results PPs referred 836 individuals (548 from intervention and 169 from control arm PPs) of whom 176 were diagnosed with bacteriologically confirmed PTB. The proportion (95% confidence interval) of referring PPs [0.59 (0.49, 0.68) vs. 0.42 (0.32, 0.52) in the intervention and control arm, respectively], mean referral rate per PP‐year [(5.7 (3.8, 8.7) vs. 1.8 (1.2, 2.8)] and smear‐positive PTB case‐finding rate per PP‐year [(1.5 (0.9, 2.2) vs. 0.6 (0.3, 0.9)] were significantly higher in the intervention than the control arm. Stratifying by qualification, a statistically significant difference in the above indicators remained only among GPs and internists. Overall, surgeons, paediatricians and gynaecologists referred few patients. PP referrals contributed to 20% of the sputum smear positive PTB cases detected by RNTCP in Tumkur city (14% were from intervention arm PPs). Conclusions We demonstrated the effectiveness of a health system‐oriented intervention to improve PP’s referrals of presumptive PTB cases to RNTCP.

Linghang Wang, Yonghong Zhang, Keyi Xu, Tao Dong, Sarah Rowland-Jones, Louis-Marie Yindom

by Linghang Wang, Yonghong Zhang, Keyi Xu, Tao Dong, Sarah Rowland-Jones, Louis-Marie Yindom Background The HIV pandemic remains the most serious challenge to public health worldwide. The hallmark characteristics of the disease is the eventual failure of the immune system to control opportunistic infections and death. However not everyone who has HIV develops the disease at the same rate and so we are studying how the immune system works to control the virus in those who have been infected for decades and remain relatively healthy without the need of anti-retroviral therapy (ART). Methods Genomic DNA samples from 513 Chinese Han individuals from Henan province were typed for 15 KIR and 3 HLA class I genes. Genotype frequencies were compared between a village cohort of 261 former plasma donors (SM cohort) infected with HIV-1 through an illegal plasma donor scheme who survived more than 10 years of infection without ART and 252 ethnically-matched healthy controls from a nearby village. KIR and HLA were molecularly typed using a combination of polymerase chain reaction (PCR) with sequence-specific primers (PCR-SSP) and sequence based techniques. Results All 15 KIR genes were observed in the study population at various frequencies. KIR2DL3 was significantly less common in the HIV-1 infected group (95.8% vs 99.2%, p = 0.021). The combination of KIR3DS1 with homozygosity for HLA-Bw4 alleles (the putative ligand for KIR3DS1) was significantly less frequent in the HIV-1 infected group than in the control group (6.0% vs 12.0% respectively, p = 0.023). Conclusion Specific KIR-HLA compound genotypes associate with differential outcomes to infection and disease progression following exposure to a narrow-source HIV-1.

Abstract Background Several studies have applied ecological factors such as meteorological variables to develop models and accurately predict the temporal pattern of dengue incidence or occurrence. With the vast amount of studies that investigated this premise, the modeling approaches differ from each study and only use a single statistical technique. It raises the question of whether which technique would be robust and reliable. Hence, our study aims to compare the predictive accuracy of the temporal pattern of Dengue incidence in Metropolitan Manila as influenced by meteorological factors from four modeling techniques, (a) General Additive Modeling, (b) Seasonal Autoregressive Integrated Moving Average with exogenous variables (c) Random Forest and (d) Gradient Boosting. Methods Dengue incidence and meteorological data (flood, precipitation, temperature, southern oscillation index, relative humidity, wind speed and direction) of Metropolitan Manila from January 1, 2009 – December 31, 2013 were obtained from respective government agencies. Two types of datasets were used in the analysis; observed meteorological factors (MF) and its corresponding delayed or lagged effect (LG). After which, these datasets were subjected to the four modeling techniques. The predictive accuracy and variable importance of each modeling technique were calculated and evaluated. Results Among the statistical modeling techniques, Random Forest showed the best predictive accuracy. Moreover, the delayed or lag effects of the meteorological variables was shown to be the best dataset to use for such purpose. Thus, the model of Random Forest with delayed meteorological effects (RF-LG) was deemed the best among all assessed models. Relative humidity was shown to be the top-most important meteorological factor in the best model. Conclusion The study exhibited that there are indeed different predictive outcomes generated from each statistical modeling technique and it further revealed that the Random forest model with delayed meteorological effects to be the best in predicting the temporal pattern of Dengue incidence in Metropolitan Manila. It is also noteworthy that the study also identified relative humidity as an important meteorological factor along with rainfall and temperature that can influence this temporal pattern.

Guidelines for the treatment of chronic obstructive pulmonary disease (COPD) have consistently recommended long-acting inhaled bronchodilators — either long-acting muscarinic antagonists (LAMAs) or long-acting inhaled beta-agonists (LABAs) — as initial maintenance therapy. If disease control is not……

Abstract Purpose The incidence of Staphylococcus aureus skin and soft tissue infection (SSTI) is high in sub-Saharan Africa. This is fueled by a high prevalence of Panton-Valentine leukocidin (PVL), which can be associated with necrotizing disease. The aim was to describe the clinical presentation and the treatment of SSTI in the African setting and to identify challenges in the management. Methods Patients (n = 319) were recruited in DR Congo (n = 56, 17.6%), Gabon (n = 89, 27.9%), Mozambique (n = 79, 24.8%) and Tanzania (n = 95, 29.8%) during the prospective observational StaphNet cohort study (2010–2015). A physician recorded the clinical management in standardized questionnaires and stratified the entity of SSTI into superficial (sSSTI) or deep-seated (dSSTI). Selected virulence factors (PVL, β hemolysin) and multilocus sequence types (MLST) were extracted from whole genome sequencing data. Results There were 220/319 (69%) sSSTI and 99/319 (31%) dSSTI. Compared to sSSTI, patients with dSSTI were more often hospitalized (13.2 vs. 23.5%, p = 0.03), HIV-positive (7.6 vs. 15.9%, p = 0.11), and required more often incision and drainage (I&D, 45.5 vs. 76.5%, p = 0.04). The proportion of an adequate antimicrobial therapy increased marginally from day 1 (empirical therapy) to day 3 (definite therapy), for sSSTI (70.7 to 72.4%) and dSSTI (55.4 to 58.9%). PVL was a risk factor for I&D (OR = 1.7, p = 0.02) and associated with MLST clonal complex CC121 (OR = 2.7, p 

Marian Loveday, Kristina Wallengren, Tarylee Reddy, Donela Besada, James C. M. Brust, Anna Voce, Harsha Desai, Jacqueline Ngozo, Zanele Radebe, Iqbal Master, Nesri Padayatchi, Emmanuelle Daviaud

by Marian Loveday, Kristina Wallengren, Tarylee Reddy, Donela Besada, James C. M. Brust, Anna Voce, Harsha Desai, Jacqueline Ngozo, Zanele Radebe, Iqbal Master, Nesri Padayatchi, Emmanuelle Daviaud Background South Africa has a high burden of MDR-TB, and to provide accessible treatment the government has introduced different models of care. We report the most cost-effective model after comparing cost per patient successfully treated across 5 models of care: centralized hospital, district hospitals (2), and community-based care through clinics or mobile injection teams. Methods In an observational study five cohorts were followed prospectively. The cost analysis adopted a provider perspective and economic cost per patient successfully treated was calculated based on country protocols and length of treatment per patient per model of care. Logistic regression was used to calculate propensity score weights, to compare pairs of treatment groups, whilst adjusting for baseline imbalances between groups. Propensity score weighted costs and treatment success rates were used in the ICER analysis. Sensitivity analysis focused on varying treatment success and length of hospitalization within each model. Results In 1,038 MDR-TB patients 75% were HIV-infected and 56% were successfully treated. The cost per successfully treated patient was 3 to 4.5 times lower in the community-based models with no hospitalization. Overall, the Mobile model was the most cost-effective. Conclusion Reducing the length of hospitalization and following community-based models of care improves the affordability of MDR-TB treatment without compromising its effectiveness.

Almeida-Brasil, Celline C.; Moodie, Erica E.M.; Mclinden, Taylor; Hamelin, Anne-Marie; Walmsley, Sharon L.; Rourke, Sean B.; Wong, Alexander; Klein, Marina B.; Cox, Joseph

Objective: To identify potential pathways by which a variety of factors act to lead to unsuppressed viral load. Design: A prospective cohort of HIV–HCV co-infected adults receiving care from 18 HIV clinics across Canada was followed every 6 months between November 2012 and October 2015. Participants with at least two visits while receiving combined antiretroviral treatment (cART) were included. Methods: A path analysis was conducted on the basis of ordered sequences of multivariate logistic regressions using generalized estimating equations. The first regression model used incomplete viral suppression (viral load >50 copies/ml) as the outcome of interest and all other variables (i.e. nonadherence, food insecurity, treatment attributes, and other sociodemographic, behavioural, and clinical factors) as potential predictors. Any variable determined to be a statistically significant predictor of incomplete viral suppression was then used as the next outcome of interest in the subsequent regression, until all predictors of each selected outcome were purely explanatory variables. Results: A total of 566 participants had at least two visits. Drivers of incomplete viral suppression included injection drug use, age 45 years or less, living alone, poor health status, longer duration of HIV infection and baseline CD4+ 200 cells/μl or less. Nonadherence, food insecurity, and the use of multitablet regimens mediated the effects of these factors on incomplete viral suppression. Conclusion: Our results suggest that nonadherence, multitablet regimens, and food insecurity are key points in the pathway to incomplete HIV suppression. These are potentially amenable intervention targets that would not be revealed using traditional regression analyses. Correspondence to Joseph Cox, Department of Medicine, Division of Infectious Diseases/Chronic Viral Illness Service, McGill University Health Centre, Montreal, QC, Canada. E-mail: joseph.cox@mcgill.ca Received 8 November, 2017 Revised 6 March, 2018 Accepted 16 March, 2018 Copyright © 2018 Wolters Kluwer Health, Inc.

Abstract Multiplicity of infection (MOI), also termed complexity of infection (COI), is defined as the number of genetically distinct parasite strains co-infecting a single host, which is an important indicator of malaria epidemiology. PCR-based genotyping often underestimates MOI. Next generation sequencing technologies provide much more accurate and genome-wide characterization of polyclonal infections. However, complete haplotype characterization of multiclonal infections remains a challenge due to PCR artifacts and sequencing errors, and requires efficient computational tools. In this review, the advantages and limitations of current molecular approaches to determine multiplicity of malaria parasite infection are discussed.

Bull, Marta E.; Mitchell, Caroline; Soria, Jaime; Styrchak, Sheila; Williams-Wietzikoski, Corey; Legard, Jillian; Mckernan-Mullin, Jennifer; Kraft, Kelli; Onchiri, Frankline; Stern, Joshua; Holte, Sarah; Ryan, Kevin J.; Acosta, Edward P.; La Rosa, Alberto; Coombs, Robert W.; Ticona, Eduardo; Frenkel, Lisa M.

Objective: During effective antiretroviral therapy (ART), low-level plasma viremias (LLV) (HIV RNA >30–1000 copies/ml) can be detected intermittently. We hypothesized that systemic inflammation is associated with LLV either as the cause or result of the production of virions from clonally expanded cells. Methods: Prospective cohort study of HIV-infected ART-naïve Peruvians enrolled prior to ART and followed for 2 years. Plasma HIV RNA and peripheral blood mononuclear cell (PBMC) HIV DNA concentrations were quantified pre-ART from individuals whose plasma HIV RNA was ART-suppressed. Inflammatory biomarker concentrations were measured pre and during ART. Single-genome amplification (SGA) derived HIV env and pol genotypes from pre-ART and LLV specimens. Antiretroviral levels during ART assessed adherence. Statistical associations and phylogenetic relationships were examined. Results: Among 82 participants with median plasma HIV RNA less than 30 copies/ml, LLV were detected in 33/82 (40%), with a LLV median HIV RNA of 73 copies/ml. Participants with vs. without LLV had significantly higher pre-ART plasma HIV RNA (P …

Yun-Hsiang Cheng, Cherng-Lih Perng, Ming-Jr Jian, Yu-Hsuan Cheng, Shih-Yi Lee, Jun-Ren Sun, Hung-Sheng Shang

Rapid identification of Elizabethkingia species is essential because these species show variations in antibiotic susceptibility and clinical outcomes. Many recent inaccuracies in Elizabethkingia identification by matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS) have been noted. Accordingly, in this study, we evaluated the use of MALDI-TOF MS with an amended database to identify isolates of Elizabethkingia anophelis, E. miricola, and E. meningoseptica. We then investigated the antimicrobial susceptibility of Elizabethkingia.

Gershom Chongwe, Charles Michelo, Edford Sinkala, Violet Kayamba, Jean-Baptiste Nzayisenga, Francis Drobniewski, Paul Kelly

Schumer, M., Xu, C., Powell, D. L., Durvasula, A., Skov, L., Holland, C., Blazier, J. C., Sankararaman, S., Andolfatto, P., Rosenthal, G. G., Przeworski, M.

To investigate the consequences of hybridization between species, we studied three replicate hybrid populations that formed naturally between two swordtail fish species, estimating their fine-scale genetic map and inferring ancestry along the genomes of 690 individuals. In all three populations, ancestry from the "minor" parental species is more common in regions of high recombination and where there is linkage to fewer putative targets of selection. The same patterns are apparent in a reanalysis of human and archaic admixture. These results support models in which ancestry from the minor parental species is more likely to persist when rapidly uncoupled from alleles that are deleterious in hybrids. Our analyses further indicate that selection on swordtail hybrids stems predominantly from deleterious combinations of epistatically interacting alleles.

Preiser, Jean-Charles; Lheureux, Olivier; Thooft, Aurelie; Brimioulle, Serge; Goldstein, Jacques; Vincent, Jean-Louis

Objectives: Tight glycemic control using intermittent blood glucose measurements is associated with a risk of hypoglycemia. Glucose concentrations can now be measured near continuously (every 5–15 min). We assessed the quality and safety of glycemic control guided by a near-continuous glucose monitoring system in ICU patients. Design: Prospective, cluster-randomized, crossover study. Setting: Thirty-five–bed medico-surgical department of intensive care with four separate ICUs. Patients: Adult patients admitted to the department and expected to stay for at least 3 days were considered for inclusion if they had persistent hyperglycemia (blood glucose > 150 mg/dL) up to 6 hours after admission and/or were receiving insulin therapy. Interventions: A peripheral venous catheter was inserted in all patients and connected to a continuous glucose monitoring sensor (GlucoClear; Edwards Lifesciences, Irvine, CA). The four ICUs were randomized in pairs in a crossover design to glycemic control using unblinded or blinded continuous glucose monitoring monitors. The insulin infusion rate was adjusted to keep blood glucose between 90 and 150 mg/dL using the blood glucose values displayed on the continuous glucose monitor (continuous glucose monitoring group—unblinded units) or according to intermittent blood glucose readings (intermittent glucose monitoring group—blinded units). Measurements and Main Results: The quality and safety of glycemic control were assessed using the proportion of time in range, the frequency of blood glucose less than 70 mg/dL, and the time spent with blood glucose less than 70 mg/dL (TB70), using blood glucose values measured by the continuous glucose monitoring device. Seventy-seven patients were enrolled: 39 in the continuous glucose monitoring group and 38 in the intermittent glucose monitoring group. A total of 43,107 blood glucose values were recorded. The time in range was similar in the two groups. The incidence of hypoglycemia (8/39 [20.5%] vs 15/38 [39.5%]) and the TB70 (0.4% ± 0.9% vs 1.6% ± 3.4%; p < 0.05) was lower in the continuous glucose monitoring than in the intermittent glucose monitoring group. Conclusions: Use of a continuous glucose monitoring–based strategy decreased the incidence and severity of hypoglycemia, thus improving the safety of glycemic control. ClinicalTrials.gov registration number: NCT 03047824. Dr. Preiser conceived the study, recruited patients, collected and analyzed the data, drafted the article, and approved the final text. Drs. Lheureux, Thooft, and Brimioulle recruited patients, collected the data, revised the article for critical content, and approved the final text. Drs. Goldstein and Vincent conceived the study, revised the article for critical content, and approved the final text. Dr. Preiser’s institution received funding from Edwards Lifesciences, and he received honoraria for consultancy from Edwards, Maquet, and Optiscan. Dr. Goldstein received funding from Edwards, and he is a former Edwards Lifesciences employee and reports equity ownership in Edwards Lifesciences. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: jean-charles.preiser@erasme.ulb.ac.be Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Abstract Background Congenital malaria is the direct infection of an infant with malaria parasites from their mother prior to or during birth. Neonatal malaria is due to an infective mosquito bite after birth. Neonatal and congenital malaria (NCM) are potentially life-threatening conditions that are believed to occur at relatively low rates in malaria endemic regions. However, recent reports suggest that the number of NCM cases is increasing, and its epidemiology remains poorly described. NCM can mimic other neonatal conditions and because it is thought to be rare, blood film examinations for malaria are not always routinely performed. Consequently, many cases of NCM are likely to be undiagnosed. A retrospective chart review for all neonates admitted with suspected sepsis between January and July 2017 was conducted and noted four cases of NCM since routine malaria testing was introduced as part of standard of care for suspected sepsis at Mbale Regional Referral Hospital Neonatology Unit. This description highlights the need to conduct routine malaria diagnostic testing for febrile neonates in malaria endemic areas, and supports the urgent need to undertake pharmacological studies on therapeutic agents in this population. Case presentation Four cases (two congenital malaria cases and two neonatal malaria cases) are described after presenting for care at the Mbale Regional Referral Hospital Neonatal Unit (Mbale RRH-NNU). The maternal age was similar across the cases, but both neonatal malaria cases were born to primigravidae. At presentation three cases had fever and history of fever, but one was hypothermic (34.8 °C) and no history of fever. One case of congenital malaria had low birth weight, while the other was born to an HIV positive mother. Both cases of congenital malaria presented with poor feeding, in addition one of them had clinical jaundice. The neonatal malaria cases presented in the third week compared to the congenital malaria cases that presented within 48 h after birth. All of the cases of NCM were treated with intravenous artesunate. The admitting clinicians also instituted a course of antibiotics empirically to cover against possible bacterial co-infections. All four cases recovered and were discharged alive. Conclusion At the Mbale RRH-NNU, the finding of cases of NCM was not expected, therefore, neonates presenting with features of suspected sepsis in malaria endemic settings should be routinely screened for NCM. There is currently a lack of appropriate guidelines for treatment of NCM in the era of artemisinin-based combination therapy (ACT), therefore, efforts to establish the safety profile and efficacy of ACT anti-malarials in neonates to guide development of evidence-based treatment guidelines for NCM are needed.

Voelker R.

Combination antiretroviral (AR) therapy has allowed most—but not all—people with HIV to manage their infection as a chronic disease. But for those with multidrug-resistant (MDR) HIV-1 that hasn’t responded to multiple treatment regimens, the FDA has approved a new treatment.