First-in-Human Assessment of cRGD-ZW800-1, a Zwitterionic, Integrin-Targeted, Near-Infrared Fluorescent Peptide in Colon Carcinoma.

PURPOSE: Incomplete oncologic resections and damage to vital structures during colorectal cancer surgery increases morbidity and mortality. Moreover, neoadjuvant chemoradiotherapy has become the standard treatment modality for locally advanced rectal cancer, where subsequent downstaging can make identification of the primary tumor more challenging during surgery. Near-infrared (NIR) fluorescence imaging can aid surgeons by providing real-time visualization of tumors and vital structures during surgery. EXPERIMENTAL DESIGN: We present the first-in-human clinical experience of a novel NIR fluorescent peptide, cRGD-ZW800-1, for the detection of colon cancer. cRGD-ZW800-1 was engineered to have an overall zwitterionic chemical structure and neutral charge to lower nonspecific uptake and thus background fluorescent signal. We performed a phase I study in 11 healthy volunteer as well as a phase II feasibility study in 12 patients undergoing an elective colon resection, assessing 0.005, 0.015, and 0.05 mg/kg cRGD-ZW800-1 for the intraoperative visualization of colon cancer. RESULTS: cRGD-ZW800-1 appears safe, and exhibited rapid elimination into urine after a single low intravenous dose. Minimal invasive intraoperative visualization of colon cancer through full-thickness bowel wall was possible after an intravenous bolus injection of 0.05 mg/kg at least 2 hours prior to surgery. Longer intervals between injection and imaging improved the tumor-to-background ratio. CONCLUSIONS: cRGD-ZW800-1 enabled fluorescence imaging of colon cancer in both open and minimal invasive surgeries. Further development of cRGD-ZW800-1 for widespread use in cancer surgery may be warranted given the ubiquitous overexpression of various integrins on different types of tumors and their vasculature.

Túneles de desinfección peatonal pulverizadores de ozono y otros desinfectantes para disminuir la propagación del SARS-CoV-2 / Pedestrian disinfection tunnels, ozone sprays and other disinfectants to reduce the spread of SARS-CoV-2

INTRODUCCIÓN: Queda mucho por aprender sobre el nuevo coronavirus (SARS-CoV-2) que causa la enfermedad por coronavirus 2019 (COVID-19). Según lo que se sabe actualmente sobre el virus y sobre coronavirus similares que causan SARS y MERS, la propagación de persona a persona ocurre con mayor frecuencia entre contactos cercanos (dentro de aproximadamente 2 metros) a través de gotitas respiratorias generadas por una persona infectada al toser o estornudar (CDC 2020). La transmisión también puede ocurrir de forma indirecta por contacto con superficies que se encuentran en el entorno inmediato de una persona infectada o con objetos que esta haya utilizado (OMS 2020b). La transmisión del coronavirus en general ocurre mucho más comúnmente a través de gotitas respiratorias que a través de fómites (CDC 2020). Por otro lado, se ha reportado que el SARS-CoV-2 puede permanecer viable durante horas o días en superficies hechas de una variedad de materiales. En ese sentido, la desinfección de superficies es considerada una buena práctica para la prevención de COVID-19 y otras enfermedades respiratorias virales en entornos comunitarios (CDC 2020). Sin embargo, en países como China, México y Argentina se han visto imágenes en donde los desinfectantes son rociados directamente a las personas cuando estas pasan a través de túneles instalados en lugares públicos de alto tránsito, como entradas a mercados, edificios administrativos u hospitales. Esta medida ha sido cuestionada ya que el desinfectante usado en estos túneles puede causar irritación en las personas, así como daño en la piel y los ojos (Neustaeter 2020). El túnel de desinfección peatonal consiste en un sistema de aspersores que rocían al peatón un desinfectante con el fin de desinfectar la ropa. Cada persona debe permanecer en el interior del túnel unos pocos segundos con las manos en alto para permitir que la mezcla sanitizante llegue a la mayoría de las partes del cuerpo (Infobae 2020). Dentro de los desinfectantes utilizados se encuentran el amonio cuaternario, el ozono, el ácido hipocloroso, el alcohol, soluciones de hipoclorito, catalizadores orgánicos, entre otros (Minsalud 2020). El uso de esta innovación tecnológica ha sido propuesto por algunas personas como una medida sanitaria adicional a las ya establecidas (distanciamiento físico, uso de mascarillas, lavado de mano) para reducir el contagio del SARS-CoV-2 en lugares públicos de alta concurrencia. Actualmente, esta propuesta se ha difundido de manera mediática captando el interés de diversas instituciones para su posible incorporación. Al respecto, la Dirección General de Salud Ambiental del Perú (DIGESA), con fecha 16 de abril de 2020, realizó un pronunciamiento desalentando el uso de túneles desinfectantes para evitar la transmisión de COVID-19. En esta nota se enfatiza que no existe evidencia científica de que los túneles desinfectantes sean efectivos para impedir la transmisión del virus, y que por el contrario, los desinfectantes dispersados sobre los peatones podrían ser dañinos para la salud e incluso aumentar el riesgo de dispersión del SARS-CoV-2. También se señala que toda desinfección para evitar la transmisión de COVID-19 se debe realizar sobre superficies inertes como mesas, pisos o estantes, y no sobre personas (DIGESA 2020). A pesar del pronunciamiento por parte de la DIGESA, el IETSI ha recibido solicitudes de evaluación, en donde se plantea el uso de túneles de desinfección generales y, específicamente, los de ozono. Así, surge la necesidad de conocer el funcionamiento de los túneles de desinfección peatonal pulverizadores de ozono y de otros desinfectantes, así como revisar la literatura pertinente a esta tecnología para evaluar su efectividad y seguridad para disminuir la propagación del SARS-CoV-2. MÉTODOS: Primero, se realizó una búsqueda manual de guías, reportes técnicos o recomendaciones para la desinfección en el contexto del COVID-19, en las páginas web de diversas sociedades y gobiernos alrededor del mundo, tales como World Health Organization (WHO), Centers for Disease Control and Prevention (CDC), European Centre for Disease Prevention and Control (ECDC), el Gobierno de Canadá, el Gobierno de Reino Unido, el Gobierno de Australia, el Gobierno de España, el Gobierno de Colombia, entre otros. Segundo, se realizó una búsqueda sistemática de guías o revisiones que brindaran recomendaciones con relación a la tecnología de interés utilizando la base de datos MEDLINE vía PubMed. La estrategia de búsqueda fue la siguiente: (sanitation[tiab] OR disinfect*[tiab]) AND (COVID-19 OR SARS-CoV-2 OR Coronavirus OR SARS) (144 ítems). Tercero, se realizó una búsqueda sistemática de estudios que evaluaran la efectividad y seguridad de los túneles de desinfección peatonal de ozono utilizando la base de datos MEDLINE vía PubMed, utilizando la siguiente estrategia de búsqueda: ozone AND (COVID-19 OR SARS-CoV-2 OR Coronavirus OR SARS) (10 ítems). Finalmente, se buscaron estudios adicionales que pudiesen haber escapado a las búsquedas con una estrategia de bola de nieve mediante la revisión de las listas de referencias de las publicaciones que sean de relevancia. RESULTADOS: Se identificó una guía técnica elaborada por el Ministerio de Salud y Protección de Colombia que evaluó el uso de sistemas de aspersión de productos desinfectantes sobre personas para la prevención de la trasmisión de COVID-19. También se identificó recomendaciones relacionadas al tema en las páginas web de la OMS y la EPA. CONCLUSIONES: No se recomienda el uso de túneles de desinfección peatonal pulverizadores de ozono u de otros desinfectantes ya que no se cuenta con evidencia científica sobre su efectividad para disminuir la propagación del COVID-19. Además, el uso de estos sistemas podría causar potenciales daños en la salud de las personas, como irritación de los ojos y de las vías respiratorias. De acuerdo a la información publicada por agencias regulatorias internacionales como la EPA, aún si el ozono se utilizara en concentraciones que no excedieran los estándares de salud pública, estos no eliminarían eficazmente los virus. Para el caso de túneles que utilizan otros agentes desinfectantes como soluciones de hipoclorito de sodio o alcohol, algunas instituciones ya han emitido pronunciamientos en contra del uso de estas tecnologías debido a la falta de evidencia que sustente su uso y al elevado riesgo de daño al peatón. Otros expertos señalan que el uso de túneles de desinfección podría tener un efecto opuesto al esperado, ya que la falsa sensación de seguridad por parte de los peatones podría hacer que estos disminuyan las medidas eficaces para disminuir el contagio del COVID19 como el distanciamiento social y el lavado de manos. Finalmente, a nivel mundial, el ozono y demás desinfectantes no están autorizados por ninguna autoridad de salud para su aplicación directa sobre humanos.

ZW800-1 for Assessment of Blood-Brain Barrier Disruption in a Photothrombotic Stroke Model.

Background: Since it is known that serum albumin-bound dyes can cross the blood-brain barrier (BBB) after ischemia, Evans Blue dye is commonly used to assess BBB disruption because of its rapid binding to serum albumin. In addition, indocyanine green (ICG), a clinically available dye, binds to serum proteins that could also be used for assessment of BBB impairment. Unlike these near-infrared (NIR) dyes, zwitterionic NIR fluorophore (ZW800-1) shows no serum binding, ultralow non-specific tissue uptake, and rapid elimination from the body via renal filtration. In this study, we report the use of ZW800-1 as a NIR fluorescence imaging agent for detecting BBB disruption in rat stroke models. Methods: Three types of NIR fluorophores, Evans Blue, ICG, and ZW800-1, were administered intraperitoneally into rat photothrombotic stroke models by using 4% concentration of each NIR dye. The NIR fluorescence signals in the infarcted brain tissue and biodistribution were observed in real-time using the Mini-FLARE® imaging system up to 24 h post-injection. Results: ZW800-1 provided successful visualization of the ischemic injury site in the brain tissue, while the remaining injected dye was clearly excreted from the body within a certain period of time. Although Evans Blue and ICG provided mapping of the infarcted brain lesions, they exhibited high non-specific uptake in most of the tissues and organs and persisted in the body over 24 h post-injection. Conclusion: Our results suggest the promising application of ZW800-1 as a new strategy in BBB experiments and future therapeutic development.

In vitro assessment of an antibacterial quaternary ammonium-based polymer loaded with chlorhexidine for the coating of polypropylene prosthetic meshes.

PURPOSE: This study assesses the use of an absorbable polymer loaded with chlorhexidine (CHX) as an antibacterial coating for polypropylene (PP) meshes employed in hernia repair. METHODS: The polymer N,N-dimethyl-N-benzyl-N-(2-methacryloyloxyethyl) ammonium bromide was loaded with CHX (1 % w/w). Fragments (1 cm2) of Optilene® Mesh Elastic were coated either with the unloaded (POL) or CHX-loaded polymer (POL-CHX). Uncoated fragments (PP) served as controls. The release kinetics of the POL-CHX coating was monitored by HPLC. Sterile fragments were placed on agar plates previously contaminated with 106 CFU of Staphylococcus aureus (Sa) ATCC25923, Staphylococcus epidermidis (Se) ATCC12228, or Escherichia coli (Ec) ATCC25922 and incubated at 37 °C for 1/2/7 days. At each time point, inhibition halos were measured and bacterial adhesion to the meshes quantified by sonication and scanning electron microscopy. Coating cytotoxic effects were examined on cultured fibroblasts. RESULTS: The polymer coating gradually released CHX over 3 days. Inhibition halos were produced only around the POL-CHX-coated meshes and these were significantly smaller for Ec than Sa or Se (p < 0.01). While POL-CHX prevented bacterial adhesion to the mesh, the reduced bacterial yields over time were observed for the POL-coated versus control PP meshes (p < 0.001). By day 7, only Ec remained attached to the surface of control meshes. The POL coating was not cytotoxic, yet POL-CHX reduced the viability of cultured fibroblasts. CONCLUSIONS: When loaded with the antiseptic CHX, this quaternary ammonium-based polymer coating released its contents in a controlled manner indicating its potential prophylactic use to reduce the risk of infection following PP mesh implantation.

A pilot study to assess the effectiveness and cost of routine universal use of peracetic acid sporicidal wipes in a real clinical environment.

BACKGROUND: Peracetic acid sporicidal wipes have been shown to be an effective disinfectant, but in controlled test environments. Their high cost may restrict use. AIMS: This pilot study investigated the efficacy and compared the costs of routine universal use of peracetic acid sporicidal wipes versus sporicidal quaternary ammonium compound and alcohol wipes in the disinfection of a hospital environment. METHODS: The routine universal use of peracetic acid wipes (Clinell Sporicidal; GAMA Healthcare Ltd, London, UK) was allocated to a study ward, whereas the control ward continued with the use of quaternary ammonium compound wipes (Tuffie 5; Vernacare, Bolton, UK) and alcohol wipes (PDI Sani-Cloth 70; PDI, Flint, UK). Twenty high-touch areas in the 2 wards were sampled for the presence of indicator organisms. The weekly detection rates of indicator organisms and weekly healthcare associated infection (HCAI) rates in the 2 wards were compared and examined for decreasing trends over the trial period. RESULTS: The detection rates of indicator organisms and HCAI rates were not significantly different in the 2 wards, and did not decrease significantly over the trial period. However, the peracetic acid wipes seem to be more effective against gram-negative organisms but at a significantly higher cost. CONCLUSIONS: Further prospective studies are needed to assess the cost-effectiveness of peracetic acid wipes.

Effectiveness of Professionally-Applied Silver Diamine Fluoride in Arresting Dental Caries.

The purpose of Linking Research to Clinical Practice is to present evidence based information to clinical dental hygienists so that they can make informed decisions regarding patient treatment and recommendations. Each issue will feature a different topic area of importance to clinical dental hygienists with A BOTTOM LINE to translate the research findings into clinical application.

New proposal of silver diamine fluoride use in arresting approximal caries: study protocol for a randomized controlled trial.

BACKGROUND: Approximal surfaces are a challenge to caries lesions control. Silver diamine fluoride (SDF) is a simple,low-cost and promisor intervention for arresting caries lesions, but it has never been tested on approximal surfaces. Our aim is to evaluate the efficacy and cost-efficacy of SDF in arresting initial lesions compared to resin infiltration and exclusively flossing (control group). Our second aim is to assess discomfort and satisfaction regarding interventions. METHODS/DESIGN: This is a randomized clinical trial, double-blinded, placebo-controlled study. Children/adolescents presenting at least one approximal initial caries lesion in primary molars/permanent premolars and molars will be included. Surfaces with advanced dentine lesions identified by radiography and participants who refuse to participate or present negative behaviors will be excluded. A minimum sample size of 504 surfaces will be required for each subgroup. Individuals will be randomly allocated in three groups of interventions: SDF, resin infiltration, and control group. Depending on the allocation, the patients will receive the active treatment and respective placebo therapies. All patients will be oriented to daily flossing the included surfaces. Our primary outcome will be caries progression by clinical and radiographic examinations. Appointments will be timed and costs of materials will be considered to calculate cost-efficacy. Patient discomfort will be assessed after interventions. Parent and patient satisfaction with the treatment will be collected after treatment and in the last follow-up visit. Individuals will be assessed at 1 and 3 months after treatment to evaluate dental biofilm and at 6, 12, and 24 months to assess caries progression by visual examination and/or radiography. Multilevel analyses will be used to verify if the type of treatment influenced on the tested outcomes. Costs will be compared and analyses of cost-efficacy will be performed. Poisson analysis will test the association between intervention and reported discomfort and satisfaction. DISCUSSION: Our hypothesis is that SDF is the most cost-efficacious option from all tested interventions. If our hypothesis is confirmed, the use of SDF in private and public contexts could represent an easier and effective option in the treatment of enamel approximal caries in children/adolescents. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01477385), Initial release: 11/16/2011: last update: 06/02/2014.

Assessment of bactericidal effects of quaternary ammonium-based antibacterial monomers in combination with colloidal platinum nanoparticles.

Pretreatment of dentin using colloidal platinum nanoparticles (CPtN) can enhance the bond strength of dentin adhesives. However, the combination of CPtN, which is negatively charged, with cationic monomer-containing adhesive may reduce the antibacterial activity of the original material. Thus, the purpose of this study was to assess the effect of CPtN on the bactericidal activity of two cationic antibacterial monomers, 12-methacryloyloxydodecylpyridinium bromide (MDPB) and methacryloxylethyl cetyl dimethyl ammonium chloride (DMAE-CB). The rapid killing effects of the two monomers against planktonic or attached Streptococcus mutans in the presence or absence of CPtN were examined by viable cell counts. The measurement of minimum inhibitory and bactericidal concentrations demonstrated that CPtN up to 2.5 mM has no antibacterial activity. In the absence of CPtN, rapid killing of both planktonic and attached Streptococcus mutans were achieved by the two cationic monomers. Combination with 0.1 mM CPtN did not reduce the bactericidal effects of the two monomers, indicating that CPtN may be used as a pretreatment with antibacterial adhesives.

Bayesian analysis of clustered interval-censored data.

The recording of multiple interval-censored failure times is common in dental research. Modeling multilevel data has been a difficult task. This paper aims to use the Bayesian approach to analyze a set of multilevel clustered interval-censored data from a clinical study to investigate the effectiveness of silver diamine fluoride and sodium fluoride varnish in arresting active dentin caries in Chinese pre-school children. The time to arrest dentin caries on a surface was measured. A three-level random-effects Weibull regression model was used. Analysis was performed with WinBUGS. Results revealed a strong positive correlation (0.596) among the caries lesions' arrest times on different surfaces from the same child. The software WinBUGS made the above complicated estimation simple. In conclusion, the annual application of silver diamine fluoride on caries lesions, and caries removal before the application, were found to shorten the arrest time.

[A comparative assessment of 2 analgesic, antispastic and anti-inflammatory drug combinations]. / Studio comparativo tra due associazioni ad effetto analgesico, antispastico, antipiretico.

A comparison was made between the analgesic, antispastic and sedative action of two associations whose only difference lay in the fact that in the second amobarbital had been replaced by diphenhydramine to withdraw possible side-effects of the barbiturate. The results obtained in patients with various diseases and a constant picture of pain and/or spasm and signs of unsettledness made it clear that both associations have much the same therapeutic action.