Ampliación de la distribución norte de Neoraimondia arequipensis subsp. gigantea (Werd. & Backeberg) Ostolaza

Neoraimondia arequipensis subsp. gigantea is registered in the dry forests of Tumbes, expanding its geographical distribution in northern Peru, based on the phenotypic identification of 70 individuals and genotypic by sequencing the matK gene (Maturase K gene). The habitat of this species is characterized by the presence of stony and rocky soil, located adjacent to areas of ravines and altitudes between 20 to 60 meters above sea level. In addition, we include the record of biological interactions of this cactus with endemic fauna and flora of the department of Tumbes.Se registra Neoraimondia arequipensis subesp. gigantea en los bosques secos de Tumbes, ampliándose su distribución geográfica en el norte del Perú. Se realizó la identificación fenotípica de 70 individuos y genotípica basada en la secuenciación del gen matK (Maturase K gene). El hábitat de esta especie se caracteriza por la presencia de suelo de tipo pedregoso y rocoso, ubicados aledaños a zonas de quebradas y altitudes entre 20 a 60 m. Además, se registran observaciones de interacciones biológicas de este cactus con fauna y flora endémica del departamento de Tumbes

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8+ cells

Human immunodeficiency virus (HIV) persists indefinitely in individuals with HIV who receive antiretroviral therapy (ART) owing to a reservoir of latently infected cells that contain replication-competent virus1–4. Here, to better understand the mechanisms responsible for latency persistence and reversal, we used the interleukin-15 superagonist N-803 in conjunction with the depletion of CD8+ lymphocytes in ART-treated macaques infected with simian immunodeficiency virus (SIV). Although N-803 alone did not reactivate virus production, its administration after the depletion of CD8+ lymphocytes in conjunction with ART treatment induced robust and persistent reactivation of the virus in vivo. We found viraemia of more than 60 copies per ml in all macaques (n = 14; 100%) and in 41 out of a total of 56 samples (73.2%) that were collected each week after N-803 administration. Notably, concordant results were obtained in ART-treated HIV-infected humanized mice. In addition, we observed that co-culture with CD8+ T cells blocked the in vitro latency-reversing effect of N-803 on primary human CD4+ T cells that were latently infected with HIV. These results advance our understanding of the mechanisms responsible for latency reversal and lentivirus reactivation during ART-suppressed infection

Precision mouse models with expanded tropism for human pathogens

A major limitation of current humanized mouse models is that they primarily enable the analysis of human-specific pathogens that infect hematopoietic cells. However, most human pathogens target other cell types, including epithelial, endothelial and mesenchymal cells. Here, we show that implantation of human lung tissue, which contains up to 40 cell types, including nonhematopoietic cells, into immunodeficient mice (lung-only mice) resulted in the development of a highly vascularized lung implant. We demonstrate that emerging and clinically relevant human pathogens such as Middle East respiratory syndrome coronavirus, Zika virus, respiratory syncytial virus and cytomegalovirus replicate in vivo in these lung implants. When incorporated into bone marrow/liver/thymus humanized mice, lung implants are repopulated with autologous human hematopoietic cells. We show robust antigen-specific humoral and T-cell responses following cytomegalovirus infection that control virus replication. Lung-only mice and bone marrow/liver/thymus-lung humanized mice substantially increase the number of human pathogens that can be studied in vivo, facilitating the in vivo testing of therapeutics

The Dynamic Interplay between HIV-1 and T cells

Although it is well-documented that T cells are crucial in the pathogenesis of human immunodeficiency virus type 1 (HIV-1) yet the dynamic interplay between HIV-1 and T cells has not been fully elucidated. The effects that HIV-1 has on T cell diversity and the effects that T cell diversity has on HIV viral escape have not been well characterized; an understanding of these effects could have crucial implications for design of CTL vaccines. In particular, such information could provide insights needed to develop methods for reconstitution of sufficient diversity in the immune systems of HIV+ persons to allow CTL vaccines to be effective. Furthermore, such information could be helpful in the development of CTL vaccines against semi-conserved epitopes, so as to prevent viral escape. These are the aims this dissertation will attempt to address.One major problem with the current approach to HIV-1 vaccine development is that the strategies currently being employed ultimately fail; this is mostly, but not entirely, due to HIV-1's high rate of mutation. This ultimately results in the escape of the virus from vaccine-induced immunity, thereby rendering such vaccines useless. Both CD4+ and CD8+ T cells play a major role in immune responses to HIV-1. However, during the course of infection, CD4+ T cells are depleted, not only in number, but also in diversity. Limited CD4+ T cell diversity cripples the immune system, as such CD4+ T cells are not able to provide the help necessary for effective innate and adaptive immune system responses to HIV, including help to CTL, which is of particular importance for this dissertation. CTL responses constitute one of the crucial arms of the immune system that is highly responsible for responding to HIV-1 infection. However, immune defenses mediated by CTL ultimately fail in HIV infection, which is, again, also largely (but not entirely) due to high rates of HIV-1 mutation that cause constant viral escape, which, in turn, drives chronic immune activation and ultimately CTL exhaustion.We have addressed each of these problems in this dissertation. In Chapter Two, we present results of studies in which we examined thymic output and CD4+ T cell diversity from HIV+ persons who were perinatally infected, were in treatment and had lived with the infection for over two decades. In Chapter Three, we present results of studies in which we screened for CTL responses against the gag 162-173 KAFSPEVIPMF epitope from multiple persons and identified and cloned the TCR responsible for these responses, using a novel technique TCR identification and cloning technique that we also present in this chapter. Finally, we functionally tested the cloned KF11-specific TCR to confirm that this panel was able to recognize and lyse the most common circulating variants of the KF11 epitope.The results presented in Chapter Two of this dissertation show that HIV+ participants had reduced CD4+ T cell levels, with predominant depletion of the memory subset, but preservation of naive cells. In most of these HIV+ participants, levels of CD4+ T cells that were recent thymic emigrants' CD4+ T cell levels were normal, and enhanced thymopoiesis was present, as indicated by higher proportions of CD4+ T cells containing TCR recombination excision circles. Memory CD4+ T cell depletion was highly associated with CD8+ T-cell activation in HIV-1-infected persons, and plasma interlekin-7 levels were correlated with levels of naive CD4+ T cells, suggesting activation-driven loss and compensatory enhancement of thymopoiesis. Deep sequencing of CD4+ T cell receptor sequences in HIV+ subjects who had high levels of compensatory enhancement of thymopoiesis revealed supranormal TCR diversity, providing additional evidence of enhanced thymic output.In Chapter Three we introduce and describe an inexpensive new technique to quickly and efficiently identify, clone and functionally test epitope-specific TCR. Using this new technique and samples from multiple HIV+ HLA-B*5701 persons, we identified, cloned and functionally tested four KF11-specific TCR. The four identified KF11-specific TCR were able to recognize and lyse target cells that were peptide-loaded with the six most common circulating variants of KF11. These six variants make up 97% of all circulating variants, according to the Los Alamos HIV database. The functional avidity and killing efficiency of the KF11-specific TCR were also investigated. Consonant with prior supporting data on KF11-specific TCR, the functional avidity observed for these four KF11-specific TCR had a range of 89 ng/ml to 832 ng/ml. One of the KF11-specific TCR was tested for its ability to lyse HIV-infected cells. This TCR was able to lyse cells infected with three of the four variants that were previously recognized and lysed in the peptide-loaded target cells. If these TCR are validated in vivo, and they are to prevent viral escape, the process could be repeated with other HLA restricted epitopes in order to develop a new treatment against HIV-1

In vivo suppression of HIV by antigen specific T cells derived from engineered hematopoietic stem cells.

The HIV-specific cytotoxic T lymphocyte (CTL) response is a critical component in controlling viral replication in vivo, but ultimately fails in its ability to eradicate the virus. Our intent in these studies is to develop ways to enhance and restore the HIV-specific CTL response to allow long-term viral suppression or viral clearance. In our approach, we sought to genetically manipulate human hematopoietic stem cells (HSCs) such that they differentiate into mature CTL that will kill HIV infected cells. To perform this, we molecularly cloned an HIV-specific T cell receptor (TCR) from CD8+ T cells that specifically targets an epitope of the HIV-1 Gag protein. This TCR was then used to genetically transduce HSCs. These HSCs were then introduced into a humanized mouse containing human fetal liver, fetal thymus, and hematopoietic progenitor cells, and were allowed to differentiate into mature human CD8+ CTL. We found human, HIV-specific CTL in multiple tissues in the mouse. Thus, genetic modification of human HSCs with a cloned TCR allows proper differentiation of the cells to occur in vivo, and these cells migrate to multiple anatomic sites, mimicking what is seen in humans. To determine if the presence of the transgenic, HIV-specific TCR has an effect on suppressing HIV replication, we infected with HIV-1 mice expressing the transgenic HIV-specific TCR and, separately, mice expressing a non-specific control TCR. We observed significant suppression of HIV replication in multiple organs in the mice expressing the HIV-specific TCR as compared to control, indicating that the presence of genetically modified HIV-specific CTL can form a functional antiviral response in vivo. These results strongly suggest that stem cell based gene therapy may be a feasible approach in the treatment of chronic viral infections and provide a foundation towards the development of this type of strategy