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Characterization of HIV-1 pol sequences in newly HIV-1 diagnosed patients: identification of drug resistance markers and their involvement in the transmission events
Get PDFAd oggi sono disponibili 25 farmaci per il trattamento dell’infezione da HIV. L’uso combinato di tali farmaci, la cosiddetta Highly Active Antiretroviral Therapy (HAART), ha consentito di migliorare le prospettive e la qualità di vita dei pazienti, rendendo possibile la soppressione della replicazione virale nella maggior parte dei soggetti infetti.
Tuttavia, se la terapia non riesce a sopprimere adeguatamente il virus, si osserva l’insorgenza di ceppi virali farmaco-resistenti in grado di compromettere inesorabilmente l’efficacia dei farmaci stessi. Attualmente, la presenza di virus farmaco-resistenti è messa in evidenza attraverso il test di resistenza genotipica che prevede il sequenziamento dei geni bersaglio dei farmaci antiretrovirali. Recentemente, sono state inoltre messe a punto delle metodiche in grado di rilevare ceppi resistenti anche in forma minoritaria, presenti cioè con una prevalenza inferiore al 20% nell’intera popolazione virale, il cui utilizzo nella pratica clinica è però ancora compromesso dai costi elevati. La più nota tra tutte è sicuramente il pyrosequencing.
Un problema strettamente connesso all’insorgenza di ceppi resistenti è rappresentato dalla loro trasmissione (sia come specie predominante che in forma minoritaria) a soggetti HIV-infetti che non hanno mai assunto alcun farmaco antiretrovirale (definiti drug-naïve). Attualmente, nei paesi occidentali, la prevalenza di virus resistente nei pazienti drug-naïve è stimata intorno al 10%, e diversi studi hanno evidenziato come tali ceppi (anche quando presenti in specie minoritarie) possano compromettere il successo della prima linea terapeutica.
In base a quanto riportato, l’obiettivo di questa tesi è stato quindi quello di caratterizzare la distribuzione e la diffusione della resistenza trasmessa in Italia, con particolare attenzione alle dinamiche di trasmissione della stessa e al ruolo che i soggetti drug-naïve rivestono in questo fenomeno.
Un ulteriore obiettivo è stato quello di definire nuovi marcatori genetici di HIV rilevabili attraverso metodiche standard di sequenziamento in grado di predire la presenza di varianti minoritarie resistenti nella popolazione virale. L’individuazione di mutazioni “sentinella” in grado di predire la presenza di quasispecie minoritarie resistenti riveste un ruolo centrale nel miglioramento dell’interpretazione genotipica e nella selezione di pazienti potenzialmente portatori di farmaco-resistenza.
Analizzando 255 pazienti di nuova diagnosi e naïve alla terapia antiretrovirale, abbiamo riscontrato che il 5,9% di questi mostrava resistenza trasmessa; in particolare il 3,9% era resistente alla classe farmacologica degli analoghi nucleosidici della trascrittasi inversa (NRTI), il 3,5% alla classe dei non-NRTI e lo 0,4% alla classe degli inibitori della proteasi (PI). Il 3,5% dei pazienti era inoltre portatore di un virus resistente a più classi farmacologiche. Comparando pazienti con infezione recente a pazienti con infezione cronica, abbiamo riscontrato che la prevalenza di virus farmaco-resistente era leggermente più bassa nella prima categoria rispetto alla seconda (3,4% versus 6,6%, anche se accompagnata da un P=0,09 non significativo), riflettendo probabilmente l’uso negli ultimi anni di farmaci sempre più potenti ed ad alta barriera genetica. Infine, la via di trasmissione che più delle altre sembrava incidere nella trasmissione della farmaco-resistenza era l’omosessualità (OR 7,7; 95% CI: 1,7–35,0, P=0,008).
Nella seconda parte di questa tesi, mediante metodiche filogenetiche avanzate, abbiamo caratterizzato i clusters epidemiologici di infezione in una coorte di 884 pazienti HIV-positivi, di cui 306 naïve alla terapia e 578 trattati. Da questa analisi è emerso come benché la fonte principale di trasmissione di virus farmaco-resistente fosse rappresentata dai pazienti in fallimento terapeutico, ben il 38,5% dei virus resistenti figurava in clusters composti esclusivamente da individui drug-naïve con infezione sia recente che cronica, sostenendo il ruolo di tali pazienti quale ulteriore fonte di farmaco-resistenza.
Nella terza parte di questa tesi abbiamo identificato alcune mutazioni nella trascrittasi inversa di HIV, la cui presenza nel test di resistenza genotipico correlava in modo significativo con specie minoritarie farmaco resistenti. In particolare, l’analisi di di 40 pazienti drug-naïve ha mostrato come il 70% di pazienti con la mutazioni L210M presentasse specie minoritarie farmaco-resistenti (P=0.03), supportando il ruolo di tale mutazione come “sentinella” di farmaco-resistenza nascosta.
In conclusione, questa tesi ha consentito di caratterizzare la resistenza trasmessa e le dinamiche di trasmissione di ceppi HIV-farmacoresistenti in Italia. Queste informazioni sono di fondamentale importanza per impostare programmi di sorveglianza e prevenzione dell’infezione da HIV. Tale tesi ha portato inoltre all’identificazione di mutazioni “sentinella” in grado di predire la presenza di specie minoritarie resistenti non rilevabili dai test genotipici utilizzati comunemente nella pratica clinica. Ciò è di fondamentale importanza per ottimizzare la gestione clinica del pazienti infetto da HIV.To date 25 drugs are available for the HIV-1 treatment. The combined use of these drugs, known as Highly Active Antiretroviral Therapy (HAART) has successfully suppressed the HIV-1 replication and has dramatically improved the prognosis of HIV-1 infected patients.
However, if viral rebound occurs during therapy, viruses with mutations conferring drug resistance can be selected. To date, drug resistant viruses can be detected by the genotypic resistance test, based on the sequencing of the genes target of the antiretroviral therapy. Recently, new assays (as ultra deep pyrosequencing) have allowed to assess antiretroviral drug resistance even when present as minority species (with a prevalence <20% of the entire viral population). However, their use is still limited in clinical practice due to their high cost.
The frequently selection of drug resistant strains in treatment failing patients can in turn increase the risk of their transmission (both in predominant and both in minority species) to HIV-1 infected individuals, naïve to the antiretroviral drugs (drug-naïve). To date, in countries with a wide access to HAART, the prevalence of drug resistant strains in drug-naïve patients is around 10%, and many studies have demonstrated that these drug resistance strains (also in minority species) are associated with an increased probability of virological failure to the first-line antiretroviral therapy.
In this light, the aim of this thesis was to characterize the distribution and the spread of HIV-1 drug resistance in Italy, with particular attention to the population dynamics of transmitted resistance and the role of untreated patients in the spread of drug-resistance. The last objective of this thesis was to define new genetic markers of HIV that can predict the presence of transmitted drug resistant minority species. The identification of these “sentinel” mutations could improve the genotypic interpretation and could help the selection of patients potentially reservoir of drug-resistance.
Among 255 newly diagnosed and untreated individuals, the 5.9% of patients showed signs of transmitted resistance; in particular, 3.9% of patients was infected with nucleoside reverse-transcriptase inhibitors (NRTI)-resistant viruses, 3.5% with non-NRTI-resistant viruses and 0.4% with protease inhibitors-resistant viruses. In addition, the 3.5% of patients carried HIV-1 resistant strains with more than one major drug resistance mutation. Comparing chronic infections with recent infections, we also found a decreased rate of resistance in recent infections (P=0.09), reflecting the increasing use of potent drugs and highly active antiretroviral regimens in recent years. Homosexual individuals were also more likely to harbour a virus with at least one primary resistance mutation (OR 7.7; 95% CI: 1.7–35.0, P=0.008).
In the second part of this thesis, we have investigated the epidemiological networks characterizing the HIV-1 infection by using a phylogenetic approach in a cohort of 884 patients. Of them, 306 were drug-naïve and 578 were HAART-treated individuals. Even if patients failing HAART remained the principal source of transmitted drug resistance, the 38.5% of drug resistant viruses was involved in clusters composed only by drug-naïve individuals, supporting the role of these patients as drug-resistance transmitters.
In the third part of this thesis, we have characterized specific mutations in the reverse-transcriptase of HIV, those presence significantly correlated with minority drug resistance variants. In particular, among the 40 drug naïve patients analyzed, we found that the 70.0% of patients with L210M carried drug resistance minority species (P=0.03), supporting the role of this mutation as “sentinel” of hidden drug resistance mutations.
In conclusion, this thesis was able to characterize the HIV-1 transmitted drug resistance and the transmission dynamics of HIV-1 drug resistant strains in Italy. These data were essential to improve the surveillance and the preventive programmes on HIV infections. This thesis has also characterized “sentinel” mutations able to predict minority drug resistance variants, undetectable by standard genotypic tests. Taking into account these genetic markers right from diagnosis can help clinicians to improve the management of HIV-1 infected patients
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
Author Under Sail The Imagination of Jack London, 1893-1902
No full textIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Intro -- Title Page -- Copyright Page -- Dedication -- Contents -- Acknowledgments -- Introduction -- 1. Spirit Truth -- 2. From Absorption to Theatricality and Back Again -- 3. "I Will Build a New Present" -- 4. Sons as Authors -- 5. Fathers as Publishers -- 6. The Daughter as Author -- 7. Lovers as Authors -- 8. At Sea with the Family -- 9. Yellow News, Yellow Stories -- 10. The Return Home -- Notes -- Bibliography -- Index -- About Jay WilliamsIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries
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