actual role of older oral antibiotics in the treatment of resistant urinary tract infections utis

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Clinical evaluation of guidelines and therapeutic approaches in multi drug-resistant urinary tract infections

Antibiotic resistance represents a real health emergency worldwide, mostly due to the lack of new antibiotics active against multidrug-resistant Enterobacteriaceae. Considering the global epidemiological situation in several infections, including urinary tract infections (UTIs), some antibiotics, such as fluoroquinolones and trimethoprim/sulphamethoxazole, can no longer be used for empiric treatment due to high resistance rates. However, some old antibiotics maintain high microbiological activity against UTI pathogens: according to many recent guidelines, fosfomycin trometamol, nitrofurantoin and pivmecillinam are recommended for the first-line treatment of uncomplicated UTIs. This article provides an overview of the therapeutic management of UTIs, especially uncomplicated and recurrent cystitis, as well as complicated UTIs such as catheter-related UTIs, and UTIs in males, post-menopausal women and diabetic patients, based on the main international guidelines

New antibiotic development: barriers and opportunities

Antibiotic resistance represents a serious threat to public health worldwide, leading to increased healthcare costs, prolonged hospital stays, treatment failures and deaths. To address the emergency of multidrug-resistance, the major international societies of infectious diseases and public health have developed strategies and guidelines to reduce unnecessary antimicrobial use as well as to incite the development of new antibiotics targeting multidrug-resistant pathogens. Even though pharmaceutical companies have been developing new antibiotics since 2010, the global situation is still worrisome. Indeed, the currently available data regarding new antibiotics are limited to microbiological activity and pharmacokinetic profile and their use for the treatment of life-threatening infections (i.e., sepsis) is often off-label. The aim of this article is to present the antibiotic molecules recently commercialized and with which clinicians will deal quite often in next years. We describe ceftolozane/tazobactam, ceftazidime/avibactam, eravacycline, plazomicin, dalbavancin, oritavancin and tedizolid in terms of mechanism of action, antimicrobial spectrum, trials behind the approval and possible indications for the future. In last few years, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved many new antibiotic molecules but, unfortunately, they lack in biological innovation and in wide clinical indications. These agents show appealing properties for off-label use, as we propose in the article, but caution is still needed considering that high-quality clinical data are limited

Fluorescence labeled PEI-based gene delivery systems for near infrared imaging in nude mice

Gene therapy is a research area where nucleic acids are transferred into cells to treat neoplastic, metabolic and hereditary diseases. Delivery of genetic material into living organisms can be achieved with viral or non-viral vectors. Viral gene carriers are very efficient but present some major disadvantages due to their pathogenicity and immunogenicity. Nonviral carriers are based on synthetic molecules binding and condensing nucleic acids into small, virus-like particles. The aim of this thesis was to study the biodistribution and tumor targeting properties of non-viral gene vectors based on polyethylenimine (PEI) after systemic injection into mice. The gene vectors were labeled with fluorescent dyes emitting in the near infrared (NIR), which allowed studying their bio-distribution in living animal over time. Owing to its amine groups PEI has a high positive charge density that enables electrostatic interactions with negatively charged nucleic acids and their efficient compaction into nucleic acid-PEI complexes, called polyplexes. The net positive surface charge of these polyplexes permits interactions with negatively charged cell surface molecules, thus leading to their internalization into the cell. To avoid unspecific interactions with blood components and nontarget tissues after intravenous application, polyplexes were shielded with the hydrophilic molecule polyethylene glycol (PEG). PEI-based gene carrier systems were tested on two subcutaneously implanted tumor types: Human Hepatocellular Carcinoma (HUH7) and Murine Neuroblastoma (N2a). HUH7 cells express epidermal growth factor (EGF) receptors, while N2a cells express transferrin (Tf) receptors on their surfaces. To enable targeting of the polyplexes to the tumor cells, polyplexes were generated containing the ligands EGF and Tf for targeting of HUH7 cells and N2a cells respectively. The targeted polyplexes were then intravenously injected into immunodeficient, athymic nu/nu mice in which HUH7 or N2a tumor cells had been previously set under their skin. To monitor the biodistribution of polyplexes throughout the mouse organism and to evaluate their gene delivery capability into the neoplastic cells, polyplexes were labeled with fluorescent dyes (Alexa 750, NIR 797) or near infrared emitting quantum dots (QD), whose fluorescent expression signal was detected and analyzed with a device for imaging in vivo. All fluorescent molecules and quantum dots were biocompatible and non-toxic. They emitted light in the near infrared area of the spectrum, thus avoiding overlapping phenomena with autofluorescent biomolecules or absorption of light by hemoglobin. With all dyes used for polyplex labeling a fluorescent signal could be observed in organs like liver and lung being clearly distinguishable from background fluorescence. Among the fluorescent molecules tested, quantum dots were identified being the most suitable method for in vivo studies, showing the highest signal/noise ratios. PEG-shielding led to best tumor targeting efficiency when administering EGF or Tf-targeted polypelxes in mice bearing HUH7 and N2a tumors respectively. A clear fluorescent signal specific for tumor tissue was detected; the imaging software used allowed quantitative analysis of this signal. For this reason this system is now available for further experimental applications.Gentherapie befasst sich mit der Insertion von Nukleinsäuren in Zellen, um neoplastische, metabolische sowie hereditäre Krankheiten zu behandeln. Der Transfer von genetischem Material in einen lebenden Organismus kann durch die Verwendung viraler oder nicht viraler Vektoren erfolgen. Viren sind zwar sehr effektiv, aber ihre Anwendung birgt auch Probleme, die meist durch ihre Pathogenität und Immunogenität bedingt sind. Nicht virale Vektoren sind synthetische Moleküle, die Nukleinsäuren in kleine, virusähnliche Partikeln einbinden und kondensieren. Das Ziel dieser Doktorarbeit war es die Bioverteilung und die gezielt gegen den Tumor gerichteten Eigenschaften von Genvektoren, die auf Polyethylenimin (PEI) basieren, nach intravenöser Injektion in Mäusen zu untersuchen. Die Genvektoren wurden mit fluoreszierenden Farbstoffen markiert, die Licht innerhalb des Nahinfrarot-Bereiches (NIR) emittieren und im Zeitverlauf die Beobachtung der Bioverteilung in lebenden Tieren erlauben. Dank seiner Aminogruppen hat PEI eine stark positive Ladung, die gute elektrostatische Bindungen zu negativ geladenen Nukleinsäuren erlaubt, mit denen es zum Aufbau eines Nukleinsäure-PEI-Komplexes führt, der Polyplex genannt wird. Die positiv geladene Oberfläche von PEI ermöglicht auch Interaktionen mit negativ geladenen Zellenoberflächen mit der Folge einer Internalisierung des Komplexes. Um unspezifische Interaktionen mit Blutbestandteilen oder anderen als dem Zielgewebe zu verhindern, wurden die Polyplexe mit dem hydrophilen Molekül Polyethylenglycol (PEG) umhüllt. Diese auf PEI-Basis synthetisierten Gencarrier-Systeme wurden dann an der humanen Leberzell Karzinom Linie HUH7 und der Maus Neuroblastom Linie N2a getestet. Die HUH7-Zellinie exprimiert Rezeptoren für den epidermalen Wachstumsfaktor (EGF) und die N2a-Zelllinie Rezeptoren für Transferrin (Tf) auf ihrer Oberfläche. Um ein gezieltes Tumor-Targeting von HUH7- oder N2a-Zellen zu ermöglichen, wurden Polyplexe erstellt, die EGF bzw. Transferrin an ihrer Oberfläche enthalten. Diese oberflächlich modifizierten Komplexe wurden dann intravenös in athymische nu/nu Mäuse verabreicht, die vorher HUH7- oder N2a-Zellen subkutan implantiert bekommen hatten. Um die Verteilung der Polyplexe als experimentelle genetische Medikamente innerhalb des murinen Organismus zu beobachten und die Akkumulation im Tumorgewebe auszumessen, waren sie mit fluoreszierenden Farbstoffen(Alexa 750, NIR 797) oder im Nahinfraroten emittierenden Quantum Dots (QD) markiert, deren Fluoreszenzsignalexpression mittels eines Messungsgerät für in vivo Analysen analysiert wurde. Alle fluoreszierenden Moleküle und Quantum Dots zeigten sich biokompatibel und nicht toxisch und emittierten Licht innerhalb des nahinfraroten Bereichs des Spektrums. Damit konnte die Lichtabsorption durch Hämoglobin ebenso vermieden werden, wie sämtliche Überschneidungsphänomene mit der Fluoreszenz anderer Biomoleküle. Bei allen für die Markierung von Polyplexen verwendeten Farbstoffen und den Quantum Dots wurde ein fluoreszierendes Signal in Organen wie Leber und Lunge beobachtet, das eindeutig von der Hintergrundfluoreszenz unterschieden werden konnte. Unter den getesteten fluoreszierenden Substanzen konnten Quantum Dots als beste Methode für die Fluoreszenzmarkierung festgelegt werden. Hier war das Signal am deutlichsten von störender Hintergrundstrahlung zu unterscheiden. Das PEG-Shielding erlaubte die höchste Effizienz im Tumor-Targeting vor allem bei Applikation von EGF- bzw. Tfmarkierten Polyplexen in Mäusen, die HUH7- bzw. den N2a-Tumor trugen. Ein ausgeprägtes und für Tumorgewebe spezifisches Signal konnte hier beobachtet werden. Die verwendete Imaging-Software für in vivo Applikationen ermöglichte eine quantitative Signalanalyse. Damit steht dieses System für weitere experimentelle Anwendungen zur Verfügung

Speech Communication

Contains reports on two research projects.National Institutes of Health (Grant 2 ROl1 NS04332)National Institutes of Health (Training Grant 5 T32 NS07040)C.J. LeBel FellowshipsNational Science Foundation (Grant BNS77-26871

World Caf\ue9 at Summer School of WHO Collaborating Centre for Epidemiology and Community Dentistry

Objectives of the study: This study is a qualitative evaluation of a teaching method. The 2015 Summer School organized by the WHO Collaborating Centre for Epidemiology and Community Dentistry of Milan took place in Sardinia. The educational objectives of the first day included: make an informal conversation with other members of the summer school; create an interesting exchange of ideas and experiences also between new, \u201chabitue\u301\u201d and beginners with senior professionals of this event; make a group for the works in the next days. Considering the different professional roles, age and context of origin, the purpose of the Pedagogists was to create a positive, relaxed but intimate atmosphere using the pleasure of \u201cinformal\u201d conversation, through a creative and practical method: The World Cafe\u300. Materials & methods: The Pedagogists\u2019 first task focused on: caring of the location and the physical setup of the table, creating relevant questions to the concerns of the group, establishing the rules, managing the process to encourage participants to have a non- formal learning experience consequently improving thinking, speaking and listening skills. Finally the participants answered self-administered questionnaire to write about their emotions and cognitive processes that went out during the World Cafe\u300. Results: The analysis of the questionnaires was carried out with Interpretative Phenomenological Analysis (IPA), The interpretative steps identified two emerging themes: \u201cdifferent vs peer\u201d and \u201cdiscovering vs practicing\u201d. Conclusions: The World Cafe\u301 experience improves learning by connection; thinking and learning become dynamic processes instead of learning outcomes

Aproximación Final y Aterrizaje Automático sin Potencia para un Avión Espacial

A partir del éxito del lanzador \textit{Falcon 9} de la firma \textit{Space X}, y del \textit{Orion} de \textit{Blue Origin}, los sistemas reutilizables de acceso al espacio están recibiendo fuerte atención debido a sus ventajas comerciales respecto de los lanzadores descartables tradicionales. La idea no es nueva, y a la fecha se han considerado dos aproximaciones principales: ``cohetes reutilizables\u27\u27 y ``fly-back booster\u27\u27 por un lado, y ``aviones espaciales\u27\u27 por el otro; cada uno con sus ventajas y desventajas. En relación a los aviones espaciales también se han propuesto diferentes estrategias para la fase de retorno, considerando vuelos propulsados y no propulsados. En este último caso la misión de retorno se separa en al menos tres fases principales: re-entrada (hipersónica), manejo de energía en el área terminal, y aproximación final y aterrizaje. En este trabajo se presenta una estrategia de guiado y control para ejecutar las fases de aproximación final y aterrizaje de forma autónoma para un planeador espacial. En primer término se presenta información de contexto y consideraciones de diseño, y luego se desarrolla la síntesis de los reguladores para las diferentes funciones de control. Finalmente se valida el desarrollo con una simulación de alta fidelidad, considerando el escenario nominal y dos condiciones no nominales: exceso de energía en el punto inicial y ensayo de caía

Cross-immunization against respiratory coronaviruses may protect children from SARS-CoV2: more than a simple hypothesis?

In January 2020, a new coronavirus was identified as responsible for a pandemic acute respiratory syndrome. The virus demonstrated a high infectious capability and not-neglectable mortality in humans. However, similarly to previous SARS and MERS, the new disease COVID-19 caused by SARS-CoV-2 seemed to relatively spare children and younger adults. Some hypotheses have been proposed to explain the phenomenon, including lower ACE2 expression in children, cross-immunization from measles/rubella/mumps and BCG-vaccination, as well as the integrity of respiratory mucosa. Herein, we hypothesize that an additional mechanism might contribute to children\u2019s relative protection from SARS-CoV-2, the cross-immunization conferred by previous exposures to other common respiratory coronaviruses. To support our hypothesis, we show a statistically significant similarity in genomic and protein sequences, including epitopes for B- and T-cell immunity, of SARS-CoV-2 and the other beta coronaviruses. Since these coronaviruses are highly diffused across pediatric populations, cross-reactive immunity might reasonably induce an at least partial protection from SARS-CoV-2 in children